CADTH Reimbursement Review

Normal Immunoglobulin (Human) 10% and Recombinant Human Hyaluronidase (HyQvia)

Sponsor: Takeda Canada Inc.

Therapeutic area: Humoral immunodeficiency

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Introduction

Immunodeficiencies are characterized by the inability to produce an adequate immune response because the components of the immune system are either absent or functionally inadequate. Primary immunodeficiency disorders (PIDs) or inborn errors of immunity encompass a heterogeneous group of disorders that are genetically determined, resulting from inherited defects in the development and/or function of the immune system.¹ An estimated 1 in 1,200 people living in Canada live with a PID, with more than 70% of patients remaining undiagnosed.² The drug under review is indicated for the treatment of humoral immunodeficiencies, which result from B-cell defects that lead to antibody deficiencies and account for 50% to 60% of PIDs.³ Living with a PID predisposes affected people to an increase in the frequency and severity of infections, autoimmunity, and aberrant inflammation and malignancy.¹ The presentation of PIDs can occur at any age, and patients with B-cell (antibody deficiency) disorders typically present after 6 months of age with recurrent and often severe sinopulmonary infections such as otitis media, sinusitis, pneumonia, and gastrointestinal infections. Diarrhea, fatigue, autoimmune manifestations (such as autoimmune cytopenia), and hearing loss are also common.^1,4 Consultation with a clinical immunologist or other specialist experienced in managing PIDs is recommended for diagnosis,⁵ which is based on a combination of clinical presentation and laboratory tests. Typically, these tests include an evaluation of serum antibody levels and a measurement of serum-specific antibody titres in response to vaccine antigens.^1,6

Secondary immunodeficiency disorders (SIDs) are acquired and much more common than PIDs. They may result from systemic disorders, immunosuppressive treatments, or prolonged serious illness.^3,7 Additionally, patients who are critically ill, older, or hospitalized are susceptible to an acquired immunodeficiency or SID.^3,7 Secondary humoral immunodeficiency is a type of SID that occurs across a wide spectrum of diseases with a range in the level of susceptibility to infection and can sometimes be reversed.⁷ The diagnosis of secondary humoral immunodeficiency relies on screening and monitoring patients who are at risk of developing a secondary antibody deficiency.⁷ The laboratory tests used to confirm a diagnosis are consistent with those used for a PID. An estimation of the prevalence and incidence of SIDs or secondary humoral immunodeficiency in Canada was not identified; however, a study by Patel et al. (2019)⁷ reported that secondary humoral deficiencies are estimated to be 30-fold more common than primary humoral immunodeficiencies.

Human immunoglobulin preparations for IV or subcutaneous administration, or immunoglobulin replacement therapy (IgRT), are the cornerstone of treatment in patients with immunodeficiencies affecting the humoral immune system. The clinical experts consulted by CADTH indicated it is important to note that patients with predominantly antibody deficiencies and those with other forms of PIDs, such as combined immunodeficiencies or inborn errors of immunity, also might require long-term or even lifelong IgRT. Both IV immunoglobulin (IVIg) and subcutaneous immunoglobulin (SCIg) therapies have limitations, 1 of which is that both IVIg and SCIg are associated with adverse events (AEs). AEs associated with SCIg tend to be local reactions, whereas systemic AEs are more commonly reported with IVIg.⁸ Other reasons for using SCIg include improved consistency of immunoglobulin G (IgG) serum levels (less of a difference between peak and trough levels), that administration may be performed at home, and that there is no requirement for venous access. Disadvantages of SCIg compared with IVIg include a higher frequency of infusions and a requirement for multiple injection sites, as well as reduced compliance by some patients.¹ Treatment with IVIg allows for the administration of larger volumes of IgG compared with SCIg, more frequent and direct contact with health care professionals, and less frequent administration.⁸ In addition to IgRT, early and aggressive treatment of infections with antimicrobial drugs is essential in patients with several forms of inborn errors of immunity, including primary humoral immunodeficiency.^1,9 Non-drug approaches for the treatment of humoral immunodeficiencies include avoidance of some live vaccines for selected diseases and close monitoring and co-treatment for comorbidities, including autoimmune diseases (cytopenias, enteropathies, celiac disease, thyroid disease, granulomas), respiratory status and function, and malignancies.⁹

The product under review at CADTH is normal immunoglobulin (human) 10% and recombinant human hyaluronidase (IgHy10) (HyQvia) used in combination, which is a replacement therapy for immunodeficiencies. The sponsor has requested reimbursement of IgHy10 as per the indication, which is as replacement therapy for primary and secondary humoral immunodeficiency in adult patients.¹⁰

Both components of IgHy10 are unique drug products provided as individual solutions. They are administered by subcutaneous infusion and must be infused sequentially, beginning with hyaluronidase. The full therapeutic dose can be administered in 1 to 2 sites up to every 4 weeks. The frequency and number of infusion sites used to administer IgHy10 may be adjusted for volume, total infusion time, and tolerability to ensure the patient receives the same weekly dose equivalent of the required therapeutic dose.

The recommended dose of IgHy10 varies by previous treatment experience, as follows:

• For patients naive to IgG treatment, administer IgHy10 gradually from a weekly equivalent dose to a 3- or 4-week interval at 300 mg/kg to 800 mg/kg. Adjust the dosage and treatment interval as necessary based on serum IgG trough levels and infection rates.

• For patients switching directly from IV administration of immunoglobulin, or who have had a previous IV dose of immunoglobulin that can be referenced, IgHy10 should be administered at the same dose and at the same frequency as their previous IVIg treatment. When switching from IV treatment, begin IgHy10 1 to 2 weeks after the last IV dose. If patients were previously on a 3-week dosing regimen, increasing the interval to 4 weeks can be accomplished by administering the same weekly equivalents.

• For patients currently being administered immunoglobulin subcutaneously, the initial dose of IgHy10 is the same as for subcutaneous treatment but may be adjusted to a 3- or 4-week interval based on the weekly equivalents. The first infusion of IgHy10 should be given 1 week after the last treatment with the previous immunoglobulin.

The objective of this review is to perform a systematic review of the beneficial and harmful effects of IgHy10 for the treatment of primary and secondary humoral immunodeficiency in adult and pediatric patients 2 years of age and older. Of note, the systematic review protocol was established before the granting of a Notice of Compliance from Health Canada.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups that responded to CADTH’s call for patient input and from the clinical experts consulted by CADTH for the purpose of this review.

Patient Input

One patient group submitted input for the review of IgHy10, the Canadian Immunodeficiencies Patient Organization (CIPO). Information for the patient group submission was collected through an online survey of patients and caregivers (N = 246) and semi-structured telephone interviews with patients (N = 8) living with a PID. A total of 233 (95%) of the survey respondents were patients living with a PID, and 13 (5%) were caregivers responding on behalf of patients. The telephone interviews were with patients currently receiving IgRT for PID. None of the patients captured in the patient group submission had experience with IgHy10.

The patient group submission described living with a PID as being prone to a wide range of infections that are often severe, chronic, and debilitating. According to CIPO, the frequency of infections is dramatically reduced with IgRT. As many patients with a PID require lifelong therapy, the method of administration and setting where the treatment is administered are important factors that can significantly affect health-related quality of life (HRQoL). Patient preference is strongly considered when selecting SCIg or IVIg therapy, along with the efficacy of the specific therapy.

According to CIPO, patients want a treatment that minimizes disruptions to their career or personal life. It was noted that administering therapy at a lower frequency and reducing the need to travel to an infusion clinic would help minimize disruption to everyday life as well as reduce the risk of hospital-acquired infections. Telephone interview respondents indicated curiosity about trying IgHy10, but also described a desire for the same result from treatment, voiced concerns about having a negative experience due to switching therapies and wondered whether IgHy10 would be an appropriate treatment option for an individual patient seeking treatment.

Clinician Input

Input From the Clinical Experts Consulted by CADTH

The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of PID and SID in pediatric and adult patients.

The clinical experts stated that treatments for primary humoral immunodeficiency that reverse the course of disease are limited. The experts also noted that treatments for secondary humoral immunodeficiency are limited, but that some etiologies can be reversed. Current options for IgRT are effective, but the clinical experts noted there is a need for treatment options that improve adherence and convenience. The clinical experts indicated that current treatments are time-consuming and can negatively affect daily function due to the duration and/or frequency of administration, as well as the need to administer IVIg in a hospital setting. The clinical experts also expressed a need for treatments that are better tolerated, noting IVIg is associated with side effects, including headaches, myalgia, arthralgia, and nausea, and requires pre-medication with antipyretics and anti-nausea drugs. Some patients were also reported as having experienced transient acute kidney injury, aseptic meningitis, thrombotic- and hyperviscosity-related side effects, and fever. Lastly, the experts reported that not all patients respond to currently available IVIg and conventional SCIg (cSCIg) treatments, and that it is difficult to achieve target levels of immunoglobulin in selected patients with IVIg due to its pharmacokinetics (greater variation in peaks and troughs between infusions), which can translate to suboptimal clinical control of disease.

According to the clinical experts consulted by CADTH for this review, IgHy10 would present an additional treatment option to patients, either as first line for patients who were expected to benefit from SCIg or as second line for those who do not tolerate IVIg or SCIg. Both experts felt IgHy10 had the potential to cause a shift in the current treatment paradigm, particularly in terms of SCIg therapies, as it would expand options for IgRT for patients with primary and secondary humoral immunodeficiency.

The clinical experts indicated the patients who would be expected to benefit from SCIg or IVIg would also be expected to benefit from treatment with IgHy10. The clinical experts also indicated that patients who would be expected to benefit most from switching from IVIg to treatment with IgHy10 include patients with certain comorbidities as well as those with limited access to health care facilities, who have had severe adverse effects to IVIg, who have difficult venous access, or who prefer not to miss school or work to receive treatment. The clinical experts also noted that the patients who are likely to benefit from switching from cSCIg to IgHy10 include those who require large doses or volumes due to higher body weight (BW) or who require immunomodulation, those who have a needle phobia and want to avoid using multiple injection sites, those who want to infuse SCIg less frequently, and those who are unable to adhere to weekly SCIg infusions.

Patients identified by the clinical experts as being least suitable for treatment included those who have little to no subcutaneous tissue (very low body fat) or who have severe skin conditions preventing the subcutaneous administration. The clinical experts also felt that patients with complex conditions who require frequent clinical and immunoglobulin monitoring and regular in-person reassessment (potentially coordinated with other IV treatments) would be less suitable for treatment with IgHy10. Lastly, the clinical experts noted that patients with a history of poor adherence to treatment, inappropriate compliance, or inappropriate support from a caregiver (particularly for pediatric patients) may also be less suitable for treatment with IgHy10.

The clinical experts indicated that patients with primary or secondary humoral immunodeficiency who are starting treatment with IgHy10 and who also have chronic or active infections would be expected to respond to treatment with an improvement in clinical state and normalized blood IgG levels (i.e., IgG target levels achieved). The clinical experts described long-term expectations for response to treatment as a reduction in the frequency and severity of infections, which should result in fewer visits to outpatient clinics, a reduced rate of emergency visits and/or hospitalizations due to infections, a reduced need for antimicrobial treatments or prophylactic use, fewer missed days from school or work, and improved overall health and HRQoL. The experts would also expect the overall burden experienced by caregivers and by the health care system to be reduced.

The experts described a clinically meaningful response to treatment as one that would include maintenance of target steady-state serum IgG trough levels (at least 7 g/L), reduced infection rate (no serious infections or significantly less severe infections per year), no emergency room visits or hospital admissions due to infections, significant reduction in days missed from work or school, improved survival and HRQoL, and remission of autoimmune and inflammatory diseases associated with inborn error of immunity, if present. Further, the experts noted that all of these outcomes are clinically meaningful when achieved without serious adverse events (SAEs).

The clinical experts suggested that patients treated with IgHy10 should be assessed for response to treatment every 3 to 6 months, depending on the disease severity, which is consistent with current clinical practice for patients with a PID or SID.

Feedback from the clinical experts indicated that discontinuation of treatment with IgRT would be considered if there is a lack of improvement in immunoglobulin replacement levels, or if response to treatment (as described previously) is not achieved despite increasing doses of IgRT. The experts also noted that issues with adherence (identified by an inability to maintain therapeutic serum IgG levels) may result in discontinuation from IgHy10, as these patients may be better served by IVIg. Discontinuation from IgHy10 may also be considered based on patient preference, or for patients who do not exhibit an improvement in HRQoL, as described by the clinical experts.

According to the clinical experts, IgHy10 can be administered at home after appropriate training by a patient support program, which is similar to current practice for other SCIg preparations. The experts also noted that select cases may warrant infusion of IgHy10 in a health care facility (infusion clinic, outpatient clinic, in-hospital medical day treatment unit), such as when the caregiver/patient is unable to administer the infusion. The experts indicated that a specialist with appropriate knowledge and training in PIDs and SIDs should be involved in the diagnosis and initiation of therapy. This may include immunologists, rheumatologists, and hematologists with training in IgRT.

Clinician Group Input

Seven clinicians authored 2 clinician group input submissions on behalf of 2 clinician groups: the Clinical Immunology Network-Canada (CINC) and the CIPO Medical and Scientific Advisory Committee. The clinician group input was aligned with the input provided by the clinical experts consulted by CADTH, with the exception of place in therapy and assessment of treatment response, which differed slightly. The clinician groups felt that IgHy10 would likely be used as a second-line treatment (following IVIg or cSCIg) for primary or secondary humoral immunodeficiency in general but could become a first-line treatment option in certain subpopulations of patients with the greatest unmet need. The clinician group input recommended that treatment response be assessed at least every 6 to 12 months, which is longer than the frequency of 3 to 6 months suggested by the clinical experts consulted by CADTH. The clinician groups also noted there are considerable benefits associated with the ability to treat patients at home, particularly in terms of rising capacity issues for both inpatient and outpatient beds and the increasing costs of medicines.

Drug Program Input

The drug program implementation questions were aimed at gaining insight from the clinical experts consulted by CADTH about how IgHy10 compares with other available treatments. The clinical experts consulted by CADTH did not have direct experience using IgHy10 in their clinical practices, but they generally described their expectations for IgHy10 as performing similarly to cSCIg with less frequent administration, which is aligned with the draft product monograph. The drug plans were also interested in how the implementation of IgHy10 would differ from cSCIg. The clinical experts consulted by CADTH expected that patients who were able to administer cSCIg at home would also be able to self-administer IgHy10 if patient education and training specific to IgHy10 were added to the specialized training program that is currently used for cSCIg. The clinical experts estimated this would involve an extra 15 to 30 minutes of training on top of the currently available program. Additionally, the drug plans were interested in whether patients could switch to other brands of immunoglobulin during the course of treatment with IgHy10. The clinical experts consulted by CADTH did not expect there would be any issues with switching from IgHy10 to other options for IgRT and, further, they did not express any safety concerns with the use of IgHy10 that would require additional monitoring of safety issues.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

Two sponsor-submitted, phase III, open-label, non-randomized, single-group, prospective studies were included in this review. The pivotal study, Study 160603 (N = 89), evaluated the efficacy and tolerability of IgHy10 in patients aged 2 years and older with a PID that required antibody replacement therapy. Patients were also required to have a serum IgG trough level greater than 4.5 g/L and to have received regular IgRT for at least 3 months before enrolment. Study 160902 (N = 66) was an extension of Study 160603 that evaluated the long-term tolerability and safety of IgHy10. The safety extension also followed patients after discontinuation of hyaluronidase to monitor for delayed adverse reactions.

Study 160603 consisted of 2 epochs. During epoch 1, patients received IVIg 10% for 12 weeks. Of the 89 patients who were enrolled in epoch 1, 87 (98%) received IVIg treatment. Subsequently, 83 (93%) of the patients from epoch 1 continued to epoch 2, in which patients received IgHy10 (75 U/g recombinant human hyaluronidase [rHuPH20] followed by SCIg 10%), administered at 108% of the monthly total IVIg dose every 3 or 4 weeks for 14 to 18 months. The primary end point in Study 160603 was the rate of acute serious bacterial infections, defined as the mean number of validated acute serious bacterial infections (VASBIs) per patient per year. The annual rate of all infections, IgG levels, antibiotic use, health care utilization, productivity, HRQoL, tolerability, and safety were also evaluated.

Patients in Study 160603 who were exposed to treatment had a median age of 35.0 years (range = 4 to 78), were primarily White (91%) and non-Hispanic or non-Latino (91%), and 51% were male. The most commonly diagnosed PID among patients was common variable immune deficiency (56%), followed by hypogammaglobulinemia (20%) and X-linked agammaglobulinemia (7%). All patients reported a medical history that included disorders of the hematopoietic or lymphatic system, and the majority also reported medical conditions relating to the eyes, ears, nose, and throat (98%) and respiratory system (87%). The median serum IgG trough level assessed up to 6 months before enrolment was 10.34 g/L (range = 4.05 to 32.00). There were no notable differences in the demographic characteristics of patients who continued into Study 160902.

Efficacy Results

The efficacy results have been summarized with a focus on the results reported during epoch 2 of Study 160603, when patients were treated with IgHy10. It is important to note that in Study 160603, treatment with IgHy10 (epoch 2) cannot be compared with IVIg treatment (epoch 1) because the study was not designed to assess this.

Infections

The primary end point of Study 160603 was analyzed based on the null hypothesis of 1 or more VASBIs per patient per year tested against the alternate hypothesis of fewer than 1 VASBI per patient per year, as per the regulatory guidance from the FDA.¹¹ No comparisons of IgHy10 with other IgRTs were available. A total of 2 VASBIs were reported during treatment with IgHy10 in epoch 2; both cases were episodes of bacterial pneumonia that were treated with oral antibiotics without hospitalization.¹² This corresponded to a rate of 0.025 VASBIs per year (upper limit of the 99% confidence interval [CI] = 0.046). The clinical experts for this review agreed that the reported rate of VASBIs was aligned with what would be expected from an IgRT treatment. The rate of VASBIs was not reported during treatment with IVIg in epoch 1. The rate of VASBIs per year before the safety follow-up period was similar among the 66 patients who continued to Extension Study 160902 (0.020; upper limit of the 99% CI = 0.045).

In Study 160603, the rate of all infections reported during treatment with IVIg in epoch 1 was 4.51 infections per year (95% CI, 3.50 to 5.69). During treatment with IgHy10 in epoch 2, the rate of all infections was 2.97 infections per year (95% CI, 2.51 to 3.47). In Extension Study 160902, the rate of all infections during treatment with IgHy10 was 2.86 infections per year (95% CI, 2.36 to 3.43).

Additionally, a post hoc analysis by Wasserman et al. (2016)¹³ evaluated patients from Study 160603 and Study 160902 from the first administration of IgHy10 through the end of treatment. The annual rate of infections and annual rate of VASBIs during IgHy10 treatment were reported by age group (< 18 and ≥ 18 years). For patients who were at least 18 years of age (n = 59), the rate of infections was 2.98 per year (95% CI, 2.56 to 3.44) and the rate of VASBIs was 0.01 per year (upper limit of the 99% CI = 0.02). The rate of infections and VASBIs were consistent with the results reported for each of the individual studies.

Immunoglobulin Levels

The pivotal study and extension study evaluated IgG trough levels. The clinical experts consulted by CADTH indicated that IgG trough levels were routinely assessed in clinical practice and used as an indicator for the ability to prevent infection and disease-related comorbidities. The published recommendations for treatment with IgRT suggest that IgG trough levels should exceed 5 g/L and, ideally, be greater than 7 g/L.⁵ At baseline in Study 160603, the median serum IgG trough level was approximately 10 g/L. While receiving IgHy10 during epoch 2, the median IgG trough level in patients younger than 12 years old was 9.95 g/L (95% CI, 7.87 to 15.00). In patients who were at least 12 years old, the median IgG trough level was 10.70 g/L (95% CI, 9.46 to 11.80). The IgG trough levels while patients were receiving IgHy10 during epoch 2 appeared similar to the IgG trough levels while patients were receiving IVIg in epoch 1.

In Extension Study 160902, patients were asked to increase the frequency of IgHy10 administration to a 2- or 3-week interval for a minimum of 4 months to evaluate the effect of varying dose intervals on IgG levels. In summary, the steady-state IgG trough levels were maintained at a median of at least 10 g/L at a dose administration interval of 2, 3, or 4 weeks. After 4 months, patients had the option of returning to their initial dose interval or staying on the 2- or 3-week interval (17 of 66 [25.8%] patients stayed on a 2-week interval for more than 4 months). The ratio of IgG trough levels measured at the end of the safety follow-up period compared with the IgG trough levels measured at the end of IgHy10 treatment was also reported, which indicated that IgG levels were maintained or increased following discontinuation of hyaluronidase over a period of approximately 1.5 years (mean duration of treatment was 565.9 days; standard deviation [SD] = 211.8). Although the clinical experts consulted by CADTH indicated that IgG levels are routinely assessed and useful as a reference point, they also noted that treatment decisions are based predominantly on clinical assessments of the patient as opposed to relying solely on laboratory values.

Antibiotic Use

Outcomes related to antibiotic use were identified as important to clinicians and patients. Antibiotic use was reported as a point estimate of the number of days per month on antibiotics. Based on this, it was estimated that during treatment with IgHy10 in Study 160603, patients were on antibiotics for 1.68 days per month (95% CI, 1.29 to 2.16). In the extension study (Study 160902), the point estimate for days on antibiotics was reported annually. While receiving treatment with IgHy10 before the safety follow-up period, patients were on antibiotics for 64.03 days per year (95% CI, 45.16 to 87.54). The clinical experts consulted by CADTH indicated that the rate of antibiotic use was higher than expected, noting it is atypical for patients to use antibiotics on a monthly basis. Patients who could not discontinue prophylactic antibiotic use were excluded from the trials and concomitant prophylactic antibiotic use was not permitted during the trials. This is likely to overestimate the use of antibiotics in the trials; however, the magnitude of overestimation is difficult to determine, as the proportion of patients who were using antibiotics prophylactically before enrolment was not reported. Thus, there is significant uncertainty associated with the results for antibiotic use.

Health-Related Quality of Life

HRQoL was evaluated in Study 160603 and the extension study, Study 160902, using the Pediatric Quality of Life Inventory (PedsQL) and Short Form (36) Health Survey (SF-36) and reported by age group (2 to 7, 7 to 14, and at least 14 years old). Evidence of validity, reliability, and responsiveness was identified for both the PedsQL and SF-36; however, this did not include patients with immunodeficiencies. In Study 160603, using the SF-36 for patients aged at least 14 years, the mental and physical summary score was a median of 52.2 (range = 21.5 to 70.8) and 44.8 (range = 13.1 to 61.1), respectively. The HRQoL results were similar in the extension study, as the mental and physical summary score was a median of 51.0 (range = 25.3 to 56.9) and 48.7 (range = 11.6 to 52.9), respectively. The data for patients younger than 14 years of age were limited by sample size, and different outcome measures were used for patients between the age of 8 and 13 in the 2 studies. Although limited by methods of analysis and sample size, the evidence suggests there was no change in HRQoL following treatment with IgHy10.

Tolerability and Adherence

In Study 160603, 77 out of 87 patients (89%) and 350 out of 365 infusions (96%) did not require a reduction, interruption, or stoppage of infusion due to tolerability concerns while receiving IVIg in epoch 1. During treatment with IgHy10 in epoch 2, 68 out of 81 patients (84%) and 1,103 out of 1,129 infusions (98%) did not require a reduction, interruption, or stoppage of infusion due to tolerability concerns. The findings for patients receiving treatment with IgHy10 during Extension Study 160902 were similar to what was observed in Study 160603.

One of the key advantages that was anticipated for IgHy10 was the ability to administer treatment at home and less frequently than cSCIg, thereby improving the convenience and minimizing the impact of treatment on a patient’s life. The clinical experts consulted by CADTH indicated they expected the majority of patients (more than 90%) would be able to self-administer IgHy10 at home, similar to what they had observed with cSCIg in clinical practice. In epoch 2 of Study 160603, 282 out of 1,129 infusions (25%) were administered at home. Of these, 231 (82% of the infusions administered at home or 20.5% of all infusions) were administered without nurse intervention, and the majority of IgHy10 infusions (847 out of 1,129 or 75.0%) were administered at the investigational site. Infusions were required to occur at the investigational site until at least 2 infusions at the maximum infusion interval were tolerated, but the proportion of infusions to which this applies is unknown, based on the data available. While receiving IgHy10 (before the safety follow-up period) in Extension Study 160902, 64% of patients and 52% of infusions required assistance with self-administration at home. The reasons given for being unable to continue self-administration of infusions at home were medical reason (9 of 63 or 14.3% of patients), because of a family member (10 of 63 or 15.9% patients), or other reasons (37 of 63 or 58.7% of patients). Additional information about the reasons for being unable to self-administer infusions at home was not provided. Further, whether the ability to self-administer IgHy10 improves over time is unknown.

Health Care Utilization and Productivity

Outcomes related to health care utilization and productivity were of importance to clinicians and patients. A point estimate of the number of acute care physician visits, days in hospital, and days in hospital due to infection were reported per month in Study 160603 and per year in Study 160902.

In Study 160603, patients reported a rate of acute care visits to a physician of approximately 0.40 visits per month (95% CI, 0.32 to 0.49) while receiving treatment with IgHy10. There was no substantial difference in the number of acute care physician visits reported during IgHy10 (after the ramp-up) and during epoch 1 while receiving IVIg (0.33 visits per month; 95% CI, 0.23 to 0.45). The monthly rate of days in hospital and days in hospital due to infection were similar in epoch 1 and epoch 2, with overlapping CIs for the reported point estimates. The rate of days spent in hospital per month was 0.06 (95% CI, 0.03 to 0.10) while receiving IVIg and 0.02 (95% CI, 0.01 to 0.03) while receiving IgHy10. Whether the days spent in hospital per month included time spent in hospital due to infusions is unknown. The monthly rate of days spent in hospital due to infection was 0.03 (95% CI, 0.01 to 0.05) while receiving IVIg and zero days per month while receiving treatment with IgHy10. No days spent in hospital is a treatment goal for patients with humoral immunodeficiency, and these results were considered a clinically meaningful result by the clinical experts consulted by CADTH. Overall, these results describing health care utilization and productivity suggest there was minimal disruption to the everyday life of patients, as the number of acute care physician visits, days in hospital, and days in hospital due to infection occurred at a rate of less than 1 day (or 1 visit) per month per patient. Similar assessments conducted in the extension study yielded comparable results, reported annually.

In Study 160603, the point estimate for days off school or work during treatment with IgHy10 (epoch 2 after the ramp-up period) and treatment with IVIg (during epoch 1) was less than 1 day per month, or approximately 0.28 days per month (95% CI, 0.20 to 0.37) and 0.23 days per month (95% CI, 0.15 to 0.34), respectively. This suggests that patients experienced minimal disruption during IgRT in the trial, based on days of missed work or school.

Harms Results

The overall rate of AEs while receiving IgHy10 was 13.40 per patient during epoch 2 of Study 160603 and 19.75 per patient before the safety follow-up of Extension Study 160902. For reference, exposure to IgHy10 in Study 160603 was a mean of 38 days (SD = 10) during the ramp-up period, plus 368 days (SD = 104) following the ramp-up period. In Study 160902, patients were exposed to IgHy10 for a mean of 566 days (SD = 212). The rate of AEs was 4.45 per patient during treatment with IVIg in Study 160603, and 7.78 per patient during the safety follow-up with IVIg or SCIg without hyaluronidase during the extension study. The most frequently reported AEs while on treatment with IgHy10 was infusion site pain, which occurred at a rate of 1.14 events per patient, as well as the following AEs that occurred at a rate of less than 1 event per patient: headache, sinusitis, upper respiratory tract infection, asthma, nausea, fatigue, myalgia, infusion site pruritus, and viral upper respiratory tract infection. During the safety extension study, Study 160902, the overall rate of AEs was 19.75 per patient while receiving IgHy10. The rate of local AEs was 2.62 per patient, and the rate of systemic AEs was 17.13 per patient (including infections) or 12.71 per patient (excluding infections).

Additionally, AEs were reported by patients during epoch 2 following the ramp-up period. Overall, 53.1% of patients reported a local AE. The most frequently reported local AEs were infusion site pain, infusion site discomfort, infusion site erythema, and infusion site pruritus. From the available safety evidence, it is unknown whether the local AEs were specifically related to hyaluronidase or SCIg. The most frequently reported systemic AEs were headache (30% of patients), asthma (17%), nausea (15%), pyrexia (15%), and fatigue (15%), and the following AEs were reported in less than 15% of patients: myalgia, vomiting, arthralgia, dizziness, and diarrhea. Additionally, a post hoc integrated analysis of safety outcomes from Study 160603 and Extension Study 160902 reported the overall rate of systemic and local AEs (both excluding infections) by age group (< 18 and ≥ 18 years).¹⁴ Among adult patients (≥ 18 years), 1,200 systemic AEs were reported, corresponding to a rate of 8.63 AEs per patient-year. For local AEs, a total of 429 AEs were reported among adult patients, corresponding to a rate of 3.08 AEs per patient-year.

A total of 2 deaths were reported between the pivotal and extension study; both occurred during Extension Study 160902. The deaths were caused by toxicity to various drugs (n = 1) and cardiac arrest (n = 1), and neither death was considered related to the study treatments. Serious AEs were reported infrequently; a combined total of 22 patients reported an SAE in Study 160603 and Study 160902. Two SAEs due to chronic obstructive pulmonary disease were reported and were the only SAEs reported more than once.

The majority of notable harms identified in the systematic review protocol were captured in the standard reporting of safety results. While receiving IgHy10 in Study 160603, the systemic effects included as notable harms occurred at a rate of less than 1 AE per patient, as previously described where overall AEs are summarized. Infusion site pain was the most frequently occurring infusion-related AE (1.14 AEs per patient) and other infusion-related events occurred at a rate of less than 1 AE per patient. For local reactions, swelling or edema, and contact dermatitis were reported at a rate of less than 1 AE per patient, as were infusion site hypersensitivity and thrombotic events. No cases of hypersensitivity, anaphylaxis, thrombocytopenia, acute kidney injury, or aseptic meningitis were reported for patients receiving IgHy10 during epoch 2.

Critical Appraisal

The evidence informing the safety and efficacy of IgHy10 is based on 2 single-group, open-label studies. Neither a historical control or concurrent comparator group were used and, consequently, there was no control for potential confounding variables. Additionally, it is not possible to infer causality for the reported outcomes that were assessed in the trials, such as the annual rate of infections, which lacks both context and a reference point for evaluation. The single-group study design was also a particular issue in the assessment of safety, in addition to the outcomes that were reported as a rate per patient or per infusion. While this may partly account for the varying duration of treatment in each of the reported observation periods, the proportion of patients experiencing a particular AE is unknown, with the exception of the AEs commonly reported during treatment with IgHy10 in Study 160603. Most of the outcomes of interest for this review, including the primary end point of the pivotal trial, were not expected to have been impacted by an open-label design; however, patient-reported outcomes, such as those related to HRQoL, tolerability and adherence, and safety outcomes, may have been impacted based on patient beliefs about IgHy10. The risk of attrition bias is a concern due to the overall discontinuation rate in Study 160603, where 21% of patients discontinued from the study primarily due to patient request for withdrawal or AEs. Further, 43% of the patients aged 2 to younger than 12 years (n = 14) in Study 160603 discontinued from the study either due to a requested withdrawal (29%) or an AE (14%). As a result, the reported study results are likely biased in favour of IgHy10, as the data analyzed are largely based on patients who did not discontinue from the study. Although the outcome measures selected for reporting in the studies were considered clinically relevant, the methods of analysis hindered the ability to meaningfully interpret the outcomes. Statistical testing was used only for the primary end point in Study 160603; therefore, multiplicity was not an issue. Within-group changes were generally not reported, as results were analyzed as a rate or summarized using descriptive statistics.

The clinical experts consulted by CADTH did not have any concerns regarding the generalizability of the evidence to the groups of patients excluded from the trials (such as pregnant females, patients with immunoglobulin A [IgA] deficiency, patients required to remain on prophylactic systemic antibacterial antibiotics, or patients with certain pre-existing conditions), or regarding patients living in Canada specifically, despite only 1 Canadian study site being included. There were also no concerns regarding the generalizability to patients with secondary humoral immunodeficiency, patients who were IgRT-naive, or patients with lower serum levels of IgG. Concomitant use of prophylactic antibacterial antibiotics and pre-medications used before the administration of IVIg or SCIg were avoided if possible during the studies, but their use is common in clinical practice. The clinical experts consulted for this review suggested that while an at-home training/support system would be implemented to facilitate administration of IgHy10 at home, the level of supervision in the trials was more intensive than what would be used in clinical practice. Lastly, IgHy10 was not studied in patients with secondary humoral immunodeficiency, despite a proposed indication and reimbursement request for this patient population. However, the clinical experts consulted by CADTH were comfortable with extrapolating evidence of efficacy from patients with primary humoral immunodeficiency to patients with secondary humoral immunodeficiency.

Indirect Evidence

Indirect evidence matching the inclusion and exclusion criteria of this review was not submitted by the sponsor or identified in the CADTH literature review.

Other Relevant Evidence

Sponsor-Submitted Study in Adult Patients Switching From cSCIg to IgHy10 (NCT02881437)

Description of Study

NCT02881437 was a phase IV, open-label, non-randomized, single-group prospective study¹⁷ that filled an important gap in the comparison of cSCIg with IgHy10. The primary objective was to examine the difference in steady-state IgG trough levels among adults (18 years or older) with a PID requiring IgRT during cSCIg treatment (primarily once weekly) compared with steady-state IgG trough levels after switching to IgHy10 administration every other week at equivalent doses. Among the 22 enrolled patients, the median age was 45.0 (interquartile range [IQR] = 32.0 to 54.0) years and 68.2% were female.

The study began with a 1-week ramp-up period (subcutaneous IgHy10 provided at 1-quarter of the usual monthly cSCIg dose) that started 1 week after the last cSCIg infusion before enrolment. Subcutaneous IgHy10 infusions then occurred every 2 weeks at 1-half of the initial monthly cSCIg dose, with follow-up measurements at 3 and 6 months.

Results

The mean change in steady-state IgG trough level when switching from cSCIg to IgHy10 was −0.30 g/L (SD = 1.54) after 3 months, and −0.29 g/L (SD = 1.35) after 6 months (n = 16). A total of 11 out of 19 patients (57.9%) had at least 1 infection in the first 3 months of follow-up and 8 out of 17 (47.1%) had at least 1 infection at between 3 and 6 months of follow-up. The mean change in the physical component summary of the SF-36 was −0.90 (SD = 4.37) from baseline to 3 months and −2.67 (SD = 5.17) from 3 to 6 months (n = 12); the mean change in the mental component summary was −2.67 (SD = 5.17) from baseline to 3 months and 1.33 (SD = 5.13) from 3 to 6 months (n = 14).

A total of 21 of 22 patients (95.5%) reported at least 1 local AE, and all reported at least 1 systemic AE between baseline and follow-up at 3 months; 12 of 22 (66.7%) reported at least 1 local AE and 16 of 22 patients (88.9%) reported at least 1 systemic AE between the 3-month and 6-month follow-ups. Commonly reported AEs were similar to those in the pivotal studies.

Critical Appraisal

There are several internal validity concerns that limit the certainty of the conclusions that can be drawn. The primary concern is that there is no control group and confounders are unaccounted for; thus, causal relationships cannot be established. Though the inclusion and exclusion criteria are clear, some details of the participant disposition are limited (i.e., number screened versus randomized). The open-label design is likely to have biased the subjective end points (direction unclear). A large number of patients were lost to follow-up (6 of 22; 37%), which reduces the reliability of the findings for HRQoL. The statistical analyses were not adjusted for multiplicity.

Despite some differences in setting (all of the study sites were in France) and a narrower eligible population than would be seen in clinical practice, the clinical experts consulted by CADTH did not express concern in generalizing the evidence to adult patients in Canada; the applicability of the findings to children is less clear. The exposure to study treatments appeared to match the product monograph, aside from the ramp-up phase (not described in the monograph). Outcomes were clinically relevant, though the clinical experts indicated they would not rely on IgG trough levels alone for clinical decision-making. The sample size and length of follow-up may have been inadequate to capture rare and/or long-term harms.

Sponsor-Submitted Study of Safety, Tolerability, and Immunogenicity of IgHy10 in Pediatric Patients (Study 161504, Interim Analysis)

Description of Study

Clinical Study 161504 was a phase IV, open-label, non-randomized, single-group prospective study¹⁸ that provided further post-authorization safety, tolerability, and immunogenicity data on IgHy10 among 42 pediatric patients (2 to < 18 years old) with primary humoral immunodeficiency requiring IgRT. The findings are based on a planned interim analysis after 75% of patients had completed 1 year of study in epoch 2.¹⁹ Those naive to facilitated SCIg (fSCIg) (n = 23, 54.8%) had a mean age of 10.3 years (SD = 3.8); the group was 78% male and 96% White. The characteristics of patients with prior fSCIg exposure (pre-treated) were similar.

Patients naive to fSCIg were enrolled in a maximum 6-week ramp-up period of introduction to IgHy10 infusions (epoch 1). In epoch 2, IgHy10 treatment continued for up to 3 years. After 1 year in epoch 2, patients with an anti-rHuPH20 titre of 160 or lower at any time proceeded to study completion; others continued on treatment for another 2 years. Patients with an anti-rHuPH20 titre of 160 or higher who experienced an SAE or severe AE continued in a safety follow-up (epoch 3) in which IgHy10 was discontinued and patients received IVIg or cSCIg. The exact details of the treatment regimens are not available. At the time of the interim analysis, 22 patients (52.3%) had completed the study, 17 (40.5%) were ongoing, and 3 (7.1%) had discontinued prematurely.

Results

The mean IgG trough level was 9.6 mg/dL (SD = 2.1) at enrolment and 8.2 mg/dL (SD = 2.9) at 12 months. A total of 31 out of 42 patients (73.8%) experienced at least 1 treatment-emergent infection. One patient (2.4%) had a serious acute bacterial infection.

Of 42 enrolled patients, 27 (64.3%) reported at least 1 AE. Eleven patients (26.2%) experienced at least 1 local AE, 24 (57.1%) experienced at least 1 systemic AE, and 4 (9.5%) experienced at least 1 SAE. Across all treatments (n not reported), 7.4% of infusions were stopped, interrupted, or adjusted due to an AE. No patients developed an anti-rHuPH20 antibody titre of 160 or greater.

Critical Appraisal

There are several internal validity concerns that limit the certainty of conclusions that can be drawn. The primary concern is that there is no control group and confounders are unaccounted for; thus, causal relationships cannot be established. No statistical hypothesis testing was conducted. Interim findings of safety and efficacy should be interpreted cautiously, as these findings could overestimate the benefits and/or underestimate the harms of a treatment.^20,21 Though the inclusion and exclusion criteria are clear, some details of the participant disposition are limited (i.e., number screened versus randomized). The open-label design is likely to have biased the subjective end points; however, the direction of the bias is unclear. It is not fully clear how outcomes were defined and collected, and “treatment-emergent infections” were not pre-specified in the study protocol. The small sample size may have negatively impacted the reliability of the findings.

Despite some differences in setting (all of the study sites were in Europe) and a narrower eligible population than would be seen in clinical practice, the clinical experts consulted by CADTH did not express concern in generalizing the evidence to pediatric patients in Canada; the applicability of the evidence to adults is less clear. Dosing information was not provided. Outcomes were clinically relevant, though the clinical experts indicated they would not rely on IgG trough levels alone for clinical decision-making. The sample size was likely too small to capture rare harms.

Sponsor-Submitted Study on the Safety of IgHy10 in Pregnant Women and Their Infants (Registry Study 161301)

Description of Study

Study 161301 was a registry study providing safety data on women who had previously been treated with IgHy10 and their infants — a population excluded from the pivotal studies. All pregnant women who had ever been treated with IgHy10 were eligible in 1 of 2 study arms: the IgHy10 arm, which continued IgHy10 during pregnancy, and the alternative program arm, which switched patients to another IgRT or an alternative treatment. Nine mothers were enrolled; they had a median age of 34.0 years (IQR = 32.0 to 36.0), were primarily non-Hispanic or non-Latino (8 out of 9; 88.9%), and all were White. Seven of the mothers’ infants were enrolled. Patients visited their own physicians and were treated according to routine medical practice. Data on IgHy10 treatment were available for 6 (85.7%) mothers in the IgHy10 arm. Among these, the median number of infusions was 4 (IQR = 1.5 to 5.75); infusions were received on a 3- or 4-week interval.

Results

Among the 9 mothers, 4 (44.4%) reported at least 1 AE, 3 (42.9%) mothers in the IgHy10 arm and 1 (50.0%) in the alternative product arm. There were no local or immunologic AEs. One (11.1%) mother in the IgHy10 arm reported SAEs. There were no AEs leading to death or withdrawals due to adverse events (WDAEs). Four (44.4%) mothers (2 in each arm) were assessed for anti-rHuPH20 antibodies, and all were negative (titre less than 160). Eight (88.9%) mothers provided data on pregnancy outcomes; all were live births. One birth in the IgHy10 arm was considered abnormal because it was a Caesarean section.

Infants were born at a median of 38.0 (IQR = 37.0 to 40.0) weeks of gestation; weight, length, and head circumference were normal for all. Two (40.0%) infants in the IgHy10 arm had congenital malformations. During follow-up, 6 infants (85.7%) experienced at least 1 AE: 5 (100%) in the IgHy10 arm and 1 (50.0%) in the alternative product arm; 2 (40.0%) infants in the IgHy10 arm experienced an SAE. There were no AEs leading to death or WDAEs.

Critical Appraisal

There are several internal validity concerns that limit the certainty of the conclusions that can be drawn. The primary concern is that there was no control group and confounders are unaccounted for; thus, causal relationships cannot be established. There was no statistical hypothesis testing. Selection bias is possible because very few (n = 9) mothers were enrolled, and it is not clear whether women from various centres would differ systematically. As this is an open-label study, the subjective end points may be biased; however, the direction of the bias is unclear. Most of the data were collected retrospectively, which may have negatively affected quality and completeness. In the IgHy10 arm, 29% of mothers were lost to follow-up, which may have biased AE data in favour of IgHy10.

Despite some differences in setting (all of the study sites were in Europe or the US) and a narrower eligible population than would be seen in clinical practice, the clinical experts consulted by CADTH did not express concern in generalizing the evidence to patients in Canada. The dosage and administration of IgHy10 appear to align with the Health Canada–approved dosing; however, pregnant women are not an indicated population in the product monograph. The harm outcomes seem to be clinically important, but no efficacy outcomes were collected. The sample size and length of follow-up were likely inadequate to capture rare and long-term AEs.

Post-Authorization Safety Studies and Patient Registry Study

Results from 2 post-authorization safety studies (PASSes), Global PASS (NCT02593188)²² and EU PASS (EUPAS5812),^23,24 and a patient registry study, FIGARO (NCT03054181),^25-27 were submitted by the sponsor as supportive evidence. Both the Global PASS (N = 264) and EU PASS (N = 106) were non-interventional, prospective, uncontrolled, open-label, multi-centre PASSes that evaluated the long-term safety of IgHy10 under clinical routine conditions in the US and Europe, respectively. The Global PASS study was conducted between 2015 and 2021 and enrolled patients with a PID. The EU PASS study was conducted between 2014 and 2021 and enrolled patients who had been prescribed treatment for a PID or SID. The Global PASS reported that 56% of 909 infusions were self-administered at home. The EU PASS reported the proportion of treatments that were administered at a clinical site and at home by year since the first fSCIg treatment. During the first, second, and third year, and after the third year, 91.2% (n = 83 patients; 909 infusions), 93.2% (n = 556 patients; 600 infusions), 93.2% (n = 28 patients; 237 infusions), and 85.2% (n = 12 patients; 54 infusions) of treatments were administered at home, respectively. FIGARO was a long-term observational study on the utilization and outcomes of IgHy10 under everyday clinical practice conditions. FIGARO was conducted in Europe between 2016 and 2021 and enrolled 156 patients with a PID or SID. Data were available for 154 patients, of which 13 were pediatric (younger than 18 years), 120 were adults (18 to 64 years), and 21 were older adults (at least 65 years); results were analyzed by patient age. FIGARO reported that 81.7% of adults and 57.1% of older adults infused at home.

The results provided by the sponsor for infusions administered at home in Global PASS, EU PASS, and FIGARO suggest that the ability to administer treatment at home was more successful in a real-world setting than in the clinical trial setting; however, the generalizability of this evidence to patients treated in Canadian clinical practice is unknown. Additionally, the interpretation of the additional evidence should take into consideration the limitations associated with real-world evidence studies.

Post Hoc Analysis

The sponsor submitted a post hoc analysis by Wasserman et al. (2021)²⁸ as supportive evidence. The analysis examined 3 consecutive, open-label, uncontrolled clinical studies of IgG therapy. Each of the studies included a subset of patients with primary immunodeficiency. Two of the 3 studies, Study 160603 and Study 160902, informed CADTH’s systematic review of HyQvia. The retrospective post hoc analysis included 30 patients who had received at least 1 infusion of each type of therapy, i.e., IVIg, cSCIg, and fSCIg, and was designed to evaluate the efficacy (rates of infection) and tolerability of the 3 routes of IgG administration. The duration of exposure, total number of infusions, and mean IgG dose received during a 4-week period differed between the 3 treatments. As noted in the publication, the limitations of the study include a small sample size; selection bias, as study participation was voluntary; and year-to-year variations in community infections and other factors that change over time, which cannot be accounted for in a sequential study design. The post hoc analysis concluded that across the 3 treatment modalities (IVIg, cSCIg, and fSCIg), the annualized rates of VASBIs (0, 0.09, and 0.04, respectively) and all infections (4.17, 3.68, and 2.42, respectively) were similarly low.

Conclusions

The pivotal trial (Study 160603) and related extension study (Study 160902) provided evidence on the efficacy and safety of IgHy10 as replacement therapy in patients with a PID requiring antibody replacement therapy. The rate of VASBIs was less than 1.0 infections per patient per year (P < 0.0001), which was aligned with expectations for treatment with IgRT in patients with a PID, according to the experts consulted by CADTH. The rate of all infections per patient per year was less than 3 during treatment with IgHy10 in both Study 160603 and Study 160902. Additionally, the monthly rate of days spent in hospital due to infection was minimal (0.03 days per month or less). This was considered clinically important, as per the feedback from the clinical experts consulted by CADTH. HRQoL is an outcome of importance to patients; however, the results provided in the included studies do not allow for conclusions regarding a change in HRQoL during IgHy10 treatment. Regarding the safety of IgHy10, 2 deaths deemed unrelated to treatment were reported during the extension study and SAEs were infrequent overall. Significant safety concerns were not identified for IgHy10.

The lack of comparative evidence (direct or indirect) for IgHy10 versus other IgRTs represents a major limitation in the context of this review. Conclusions cannot be drawn about how IgHy10 compares with other IgRTs, and the single-group study design hinders the ability to appropriately interpret the reported outcomes. Also of note, the available evidence excluded patients with secondary humoral immunodeficiency. The clinical experts consulted by CADTH did not express any issues with using evidence in patients with primary humoral immunodeficiency to inform treatment decisions for patients with secondary humoral immunodeficiency, although this still represents a gap in the evidence. In summary, there are many other SCIg and IVIg therapies available in Canada. Although IgHy10 offers a unique therapy because it comprises 2 drug products (IgG facilitated by rHuPH20), how IgHy10 differs from other immunoglobulin products in terms of safety and efficacy is currently unknown. Therefore, IgHy10 was viewed as another option for SCIg treatment.

Introduction

Disease Background

Immunodeficiencies are characterized by the inability to produce an adequate immune response because the components of the immune system are either absent or functionally inadequate. PIDs or inborn errors of immunity encompass a heterogeneous group of disorders that are genetically determined, resulting from inherited defects in the development and/or function of the immune system.¹ More than 450 different PIDs have been identified and the clinical presentation of PIDs is variable; however, most patients with a PID present as having an increased susceptibility to infection.¹ Living with a PID predisposes affected patients to an increase in the frequency and severity of infections, autoimmunity, and aberrant inflammation and malignancy.¹

PIDs are often categorized by mechanistic and clinical characteristics.⁴ The drug under review is indicated for primary and secondary humoral immunodeficiencies. Humoral immunodeficiencies result from B-cell defects that lead to antibody deficiencies and account for 50% to 60% of PIDs.³ The most common B-cell disorders include X-linked agammaglobulinemia, common variable immunodeficiency, and selective IgA deficiency.^1,3 The presentation of PIDs can occur at any age, and patients with B-cell (antibody deficiency) disorders typically present after 6 months of age with recurrent and often severe sinopulmonary infections such as otitis media, sinusitis and pneumonia, and gastrointestinal infections. Diarrhea, fatigue, autoimmune manifestations (such as autoimmune cytopenia), and hearing loss are also common.^1,4

Early diagnosis and treatment are essential for the prevention of significant disease-associated morbidity and for improving patient outcomes.¹ Despite this, patients living with a PID often go undiagnosed, as they present with “routine” infections of the sinuses, ears, and lungs, which require a high degree of suspicion and specialized testing to arrive at a diagnosis of PID.¹ Immunodeficiency Canada estimates that 1 in 1,200 people living in Canada live with a PID, noting that more than 70% remain undiagnosed.² Consultation with a clinical immunologist or other specialist experienced in managing PIDs is recommended for diagnosis.⁵ A diagnosis is made based on a combination of clinical presentation and screening/laboratory tests. Typically, these tests include an evaluation of serum antibody levels and a measurement of serum-specific antibody titres in response to vaccine antigens.^1,6 Serum antibody levels that are lower than reference values by age and/or a weak or absent antibody response to antigens are indicative of B-cell immunodeficiencies.^1,6 Genetic testing and flow cytometry may also be conducted to identify a specific cause of primary humoral immunodeficiencies⁶; however, this is not required to initiate treatment, according to the clinical experts consulted by CADTH.

Separate from the genetically determined PIDs are SIDs, which are acquired and much more common. Secondary immunodeficiencies are a consequence of extrinsic factors and may result from systemic disorders, immunosuppressive treatments, or prolonged serious illness. Additionally, patients who are critically ill, older, or hospitalized are susceptible to acquired or secondary immunodeficiency.^3,7 Secondary humoral immunodeficiency is a type of SID that occurs across a wide spectrum of diseases with a range in the level of susceptibility to infection.⁷ Hematological malignancies, such as chronic lymphocytic leukemia, lymphoma, and multiple myeloma, are commonly associated with secondary antibody deficiency, either due to the conditions themselves or the therapies used to treat them. The diagnosis of secondary antibody deficiency relies on the screening and monitoring of patients who are at risk of developing secondary antibody deficiency.⁷ The laboratory tests used to confirm a diagnosis are consistent with those used for PID. An estimation of the prevalence and incidence of SIDs was not identified.

Standards of Therapy

According to the clinical experts consulted by CADTH, in Canada, the treatment of primary and secondary humoral immunodeficiency is complex. Human immunoglobulin preparations for IV or subcutaneous administration are the cornerstone of treatment in patients with primary immunodeficiency diseases affecting the humoral immune system.¹ IgRT helps fight against infections and is typically a lifelong necessity for patients. The clinical experts also noted that IgRT may also have significant anti-inflammatory and immunomodulating effects. According to the clinical experts, the appropriate use of immunoglobulin can be life-saving and cannot be replaced by any other drug or non-drug treatment. The National Immunoglobulin Replacement Expert Committee recommends that IgRT use and associated changes in dosage, or changes in product or its mode of delivery, should be initiated directly by or in consultation with an immunologist with expertise in the field of PID.⁵

Dosing for IgRT is weight-based, with a recommended dose of 400 mg/kg to 600 mg/kg administered once every 3 to 4 weeks for IVIg, or 100 mg/kg to 150 mg/kg per week for SCIg.⁵ Further, the dose or frequency should be adjusted according to desired trough levels and catered to the needs of the individual patient. The clinical experts consulted for this review stated the administration schedule for SCIg can be safely adjusted and the interval shortened, but not more frequently than every 2 weeks. It is also recommended that serum IgG trough levels should be higher than 5 g/L and, ideally, more than 7 g/L, and they should be maintained as per the age-normalized range for optimal clinical response.⁵ Both IVIg and SCIg therapies have limitations, 1 of which is associated with AEs. The most common AEs include headache, flushing, chills, myalgia, wheezing, tachycardia, lower back pain, nausea, and hypotension.¹ AEs associated with SCIg tend to be local reactions, whereas systemic AEs are more commonly reported with IVIg.⁸ In addition to fewer systemic AEs, SCIg offers advantages such as more consistent serum levels of IgG and administration at home, and does not require venous access. Disadvantages of SCIg include a higher frequency of infusions, requirement for multiple injection sites, and compliance, in certain situations.⁸ Treatment with IVIg allows for the administration of larger volumes of IgG compared with SCIg, more frequent and direct contact with health care professionals, and less frequent administration.⁸

In addition to IgRT, early and aggressive treatment of infections with antimicrobial drugs is essential in patients with primary or secondary humoral immunodeficiency.^1,9 Antimicrobial or antifungal prophylaxis may be required as an additive treatment in select patients with chronic/recurrent severe infections not fully controlled with IgRT.¹ The clinical experts consulted by CADTH noted that disease-modifying therapy is available only for selected immunodeficiencies and entails the use of immunoglobulin for immunomodulating therapy, which requires a much higher dose than IgRT.¹

Non-drug approaches for the treatment of humoral immunodeficiencies include avoidance of some live vaccines for selected diseases, and close monitoring and co-treatment for comorbidities, including autoimmune diseases (inflammatory bowel disease, celiac disease, thyroid disease), respiratory status and function, and malignancies.⁹

IgRT is indicated also for the prevention of bacterial infections in patients with hypogammaglobulinemia and/or recurrent bacterial infections associated with B-cell malignancies and other secondary humoral immunodeficiencies affecting B cells, such as after a hematopoietic stem cell transplant or use of B cell–depleting biologics.⁴ In summary, the IgRT treatment approach for secondary humoral immunodeficiency is similar to the IgRT treatment approach for primary humoral immunodeficiency, as noted by the clinical experts consulted for this review.

The clinical experts consulted by CADTH described the treatment goals for patients living with primary or secondary humoral immunodeficiencies as similar to the goals prioritized by patients, such as an improvement in HRQoL, preserved function, and prevention of hospitalizations through the prevention of infections. The experts also identified treatment goals from the treating specialist’s perspective, which included a reduction in morbidity and mortality related to disease, such as organ damage. Additionally, the experts described an ideal treatment as 1 that is well tolerated by patients and has options for administration in terms of home and hospital settings. Reducing the number of missed days of school or work, reducing the time required for infusions, and reducing the caregiver and health care system burden were also identified as goals of treatment.

Drug

IgHy10 (HyQvia), a combination of normal immunoglobulin (human) 10% and rHuPH20, is the subject of this CADTH review. The sponsor has requested reimbursement of IgHy10 as per the indication, which is as replacement therapy for primary humoral immunodeficiency and secondary humoral immunodeficiency in adult patients.¹⁰

Both components of IgHy10 are provided as solutions and are administered by subcutaneous infusion. The immunoglobulin is provided as a 10% solution and hyaluronidase is provided as a solution containing 160 U/mL. The 2 components must be infused sequentially, beginning with hyaluronidase. The full therapeutic dose can be administered in 1 to 2 sites up to every 4 weeks. The frequency and number of infusion sites used to administer IgHy10 may be adjusted for volume, total infusion time, and tolerability to ensure the patient receives the same weekly dose equivalent of the required therapeutic dose. The recommended dose of IgHy10 varies by previous treatment experience, as follows:

• For patients naive to IgG treatment, administer IgHy10 gradually from a weekly equivalent dose to a 3 or 4 week interval at 300 mg/kg to 800 mg/kg. Adjust the dosage and treatment interval as necessary based on serum IgG trough levels and infection rates.

• For patients switching directly from IVIg, or who have had a previous IV dose of immunoglobulin that can be referenced, IgHy10 should be administered at the same dose and at the same frequency as their previous IVIg treatment. When switching from IV treatment, begin IgHy10 at 1 to 2 weeks after the last IV dose. If patients were previously on a 3-week dosing regimen, increasing the interval to 4 weeks can be accomplished by administering the same weekly equivalents.

• For patients currently being administered SCIg, the initial dose of IgHy10 is the same as for subcutaneous treatment but may be adjusted to a 3- or 4-week interval based on the weekly equivalents. The first infusion of IgHy10 should be given 1 week after the last treatment with the previous immunoglobulin.

Hyaluronidase is administered using a minimum of 75 U/g of IgG.¹⁴ As per the draft product monograph,¹⁰ the recommended infusion rates for immunoglobulin (10%) vary by BW. For patients with a BW under 40 kg, infusion rates should begin at 5 mL/hour per infusion site and can be increased to a maximum of 160 mL per hour per infusion site. For patients with a BW of 40 kg or more, infusion rates should begin at 10 mL/hour per infusion site and can be increased to a maximum of 300 mL/hour per infusion site. Hyaluronidase may be infused manually or using a pump at a rate of 1 mL/minute to 2 mL/minute per infusion site, or as tolerated.

The immunoglobulin (10%) component of IgHy10 provides the therapeutic effect, while hyaluronidase facilitates the dispersion and absorption of the immunoglobulin (10%).¹⁰ IgG is the most common antibody in the human immune system and protects against a wide variety of bacterial and viral infections. The role of these antibodies and the mechanism of action of IgG in the immunoglobulin (10%) solution component of IgHy10 have not been fully elucidated. The other component is a soluble recombinant form of human hyaluronidase that modifies the permeability of connective tissues through the hydrolysis of hyaluronan.¹⁰

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups. The original and complete patient input submission can be found in the Stakeholder Feedback section.

One patient group, CIPO, submitted input for the review of IgHy10. Information for the patient group submission was collected through an online survey of patients and caregivers (N = 246) and semi-structured telephone interviews with patients (N = 8) living with a PID. A total of 233 (95%) of the survey respondents were patients living with a PID and 13 (5%) were caregivers responding on behalf of patients. The telephone interviews were with patients currently receiving IgRT for a PID. None of the patients captured in the patient group submission had experience with IgHy10.

The patient group submission described living with a PID as being prone to a wide range of infections that are often severe, chronic, and debilitating. According to CIPO, the frequency of infections is dramatically reduced with IgRT. As many patients with a PID require lifelong therapy, the method of administration and setting where the treatment is administered are important factors that can significantly affect HRQoL. The patient preference is strongly considered when selecting SCIg or IVIg therapy, along with the efficacy of the specific therapy.

According to CIPO, patients want a treatment that minimizes disruptions to their career or personal life. It was noted that administering therapy at a lower frequency and reducing the need to travel to an infusion clinic would help minimize disruption to everyday life as well as reduce the risk of hospital-acquired infections. Telephone interview respondents indicated curiosity about trying IgHy10, but also described a desire for the same result from treatment, voiced concerns about having a negative experience due to switching therapies and wondered whether IgHy10 would be an appropriate treatment option for an individual patient seeking treatment.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of PID and SID in pediatric and adult patients.

Unmet Needs

The clinical experts stated that treatments for primary humoral immunodeficiency that reverse the course of disease are limited. The experts also noted that treatments for secondary humoral immunodeficiency are limited, but some etiologies can be reversed. Current options for IgRT are effective, but the clinical experts noted that other treatments are needed to improve adherence and new formulations are needed to improve convenience. Current treatments were described as time-consuming and having an adverse effect on daily function, as IVIg requires monthly hospital visits lasting several hours and SCIg infusions are administered weekly or every 2 weeks. The clinical experts also expressed the need for treatments that are better tolerated, noting IVIg is associated with systemic side effects, including headaches, fever, myalgia, arthralgia, nausea, and allergic reactions, and requires pre-medication with antipyretics and anti-nausea drugs as well as antihistamines or corticosteroids. Some patients were also reported as having experienced transient acute kidney injury, aseptic meningitis, and thrombotic- and hyperviscosity-related side effects with IVIg, according to the experts. Lastly, the experts reported that not all patients respond to currently available treatments. Further, it was noted that it is difficult to achieve target levels of immunoglobulin in selected patients with IVIg due to its pharmacokinetics (greater fluxes in peaks and troughs between infusions), which can translate to suboptimal clinical control of disease.

Place in Therapy

According to the clinical experts consulted for this review, IgHy10 would present an additional option to patients who are already on IgRT (either IVIg or cSCIg), either as first line for patients who were expected to benefit from SCIg or as second line (following IVIg or cSCIg) for those who do not tolerate their current IgRT. The clinical experts reported that when determining which treatment to use, both the availability and different types of IgRT are discussed with the patient. The experts noted that the decision to use IgHy10 would be similar to the decision to use other available products. It was noted that this is because IgHy10 is very similar and comparable to other SCIg products in terms of providing the same anti-infective, immunomodulatory IgG molecules. Both experts felt IgHy10 had the potential to cause a shift in the current treatment paradigm, particularly in terms of SCIg therapies, as it would expand the available treatment options for subcutaneous IgRT for patients with primary or secondary humoral immunodeficiency.

Patient Population

The clinical experts indicated that patients who need IgRT and who would be expected to benefit more from SCIg compared with IVIg would also be expected to benefit from treatment with IgHy10. This would include patients with certain comorbidities (e.g., renal failure, thrombophilia, hyperviscosity disorders or older patients), those who live far from or have limited access to health care facilities, those who had severe side effects to IVIg, have difficult venous access, or those who prefer not to miss school or work or are unable to adhere to weekly SCIg infusions. The clinical experts also noted that patients who require large doses or large volumes due to higher BW or the need for immunomodulation (such as patients who suffer from additional autoimmune or hyperinflammatory diseases similar to the immune dysregulation in PID), or those who have a needle phobia and want to avoid using multiple injection sites, or those who want to infuse SCIg less frequently, would especially benefit from IgHy10. Both of the experts stated there are clear guidelines for diagnosing and treating primary and secondary humoral immunodeficiency; therefore, the identification of patients who require IgRT is not a challenge. More specifically, the experts stated a diagnosis is made using laboratory tests that demonstrate a quantitative and/or qualitative defect in innate immunoglobulin manifesting in clinical sequelae, such as recurrent infections, autoimmune disease, and/or malignancy.

Patients identified by the clinical experts as being least suitable for treatment with IgHy10 included those who have little to no subcutaneous tissue (very low body fat) or who have severe skin conditions preventing the subcutaneous administration. The clinical experts also felt that patients who require frequent clinical and immunoglobulin monitoring, such as patients with complex conditions with severe disease manifestation that require regular in-person reassessment (potentially coordinated with other IV treatments) would be less suitable for treatment with IgHy10. This is because it is more appropriate to follow those patients with monthly hospital visits when IVIg can be administered, and potentially coordinated with, other IV treatments. Lastly, the clinical experts noted patients with a history of poor adherence to treatment, inappropriate compliance, or inappropriate support from a caregiver (particularly for pediatric patients) may also be less suitable for treatment with IgHy10.

Assessing Response to Treatment

The clinical experts indicated that patients with primary or secondary humoral immunodeficiency who are starting treatment with IgHy10 and who also have chronic or active infections would be expected to respond to treatment with an improvement in clinical state and normalized blood IgG levels (i.e., IgG target levels achieved). In terms of long-term outcomes to assess response to treatment, the clinical experts would expect patients to present with fewer infections (and a reduction in frequency and severity), which should result in fewer visits to outpatient clinics, a reduced rate of emergency visits and/or hospitalizations due to infections, a reduced need for antimicrobial treatments or prophylactic use, fewer missed days from school or work, improved overall health and HRQoL, and a reduced need to access health care facilities for the treatment of infections. The experts also noted that in some cases, primary humoral immunodeficiency–associated organ dysfunction (such as lung function deterioration or malignancies) and autoimmune/hyperinflammatory diseases may go into remission. The experts would also expect the overall burden on caregivers and the health care system to be reduced.

The clinical experts reported that the outcomes used to assess the response to treatment with IgRT have a high degree of objectivity and therefore are not expected to vary between physicians. The experts described a clinically meaningful response to treatment as 1 that would include maintenance of target steady-state serum IgG trough levels (at least 7g/L), reduced infection rate (i.e., no serious infections or a notable reduction in severe infections per year), no emergency room visits/hospital admissions due to infections, a significant reduction in days missed from work or school, improved survival and HRQoL, and improvement or remission of autoimmune and inflammatory diseases associated with inborn error of immunity, if present.

The clinical experts suggested that patients treated with IgHy10 should be assessed for response to treatment every 3 to 6 months depending on disease severity, which is consistent with current clinical practice for patients with primary or secondary humoral immunodeficiency.

Discontinuing Treatment

Feedback from the clinical experts indicated that discontinuation of treatment with IgRT would be considered if there is a lack of improvement in immunoglobulin replacement levels, or response to treatment is not observed despite increasing doses of IgRT. The experts also noted that a patient who is not able to adhere to therapy (identified by an inability to maintain therapeutic serum IgG levels) and who therefore requires frequent monitoring, may be discontinued from IgHy10, as they may be better served by IVIg replacement. Discontinuation from IgHy10 may also be considered based on patient preference or because the patient does not exhibit an improvement in HRQoL, as described by the clinical experts.

Prescribing Conditions

According to the clinical experts, IgHy10 can be administered at home after appropriate training by a patient support program, which is similar to current practice for other SCIg preparations. The clinical experts also noted that selected cases may warrant infusion of IgHy10 in a health care facility (infusion clinic, outpatient clinic, in-hospital medical day treatment unit), such as when the caregiver or patient is unable to administer the infusion.

The experts also felt that a specialist with appropriate knowledge and training in primary or secondary humoral immunodeficiency should be involved in the diagnosis and initiation of therapy. This may include immunologists, rheumatologists, and hematologists with training in IgRT.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by patient groups.

Input for the review of IgHy10 was received from 2 clinician groups, the CINC and the Medical and Scientific Advisory Committee of the CIPO. The CINC is a group of clinicians and researchers that was created to enhance clinical and research collaborations and promote clinical immunology and associated research in Canada. The CIPO Medical and Scientific Advisory Committee works with patient groups to ensure activities and health information are relevant and useful for patients and caregivers.

Unmet Needs

The unmet needs of patients living with primary and secondary humoral immunodeficiency described by clinician groups were consistent with the input from the clinical experts consulted by CADTH.

Place in Therapy

Similar to the input received from the clinical experts consulted by CADTH, the clinician group input described IgHy10 as an intervention that would complement other available treatment options due to its unique mechanism of action compared with the currently available immunoglobulin therapies. The clinician groups felt that IgHy10 would likely be used as a second-line treatment (following IVIg or cSCIg) for primary or secondary humoral immunodeficiency in general but could become a first-line treatment in certain subpopulations of patients with the greatest unmet need. That includes patients requiring significantly large volumes of immunoglobulin that require a high frequency of cSCIg infusions, those who have difficulty tolerating their required volume of cSCIg, those receiving IVIg that is associated with frequent and bothersome systemic symptoms, those receiving IVIg who would greatly benefit from not missing school/work on infusion days, and those patients living in remote areas without easy access to health care facilities.

Patient Population

The feedback from the clinician groups regarding the patient population best suited for treatment with IgHy10 was consistent with the input from the clinical experts consulted by CADTH.

Assessing Response to Treatment

In general, the feedback from the clinician groups in terms of assessing response to treatment with IgHy10 was consistent with the input from the clinical experts consulted by CADTH. Regarding a clinically meaningful response to treatment, the clinician group input further described the target for infection rate as fewer than 4 infections per year.

The clinician group input recommended that treatment response be assessed at least every 6 to 12 months, which is longer than the frequency of 3 to 6 months suggested by the clinical experts consulted by CADTH.

Discontinuing Treatment

The information submitted by the clinician groups regarding considerations for the discontinuation of treatment with IgHy10 was consistent with the input from the clinical experts consulted by CADTH.

Prescribing Conditions

In general, the clinician group input on the prescribing conditions for IgHy10 was consistent with the input from the clinical experts consulted by CADTH. The clinician group input also noted that the administration of IgHy10 in the outpatient setting would be an important improvement, as the infusions can be given very quickly without significant risk of the systemic side effects seen with IVIg or the local side effects seen with traditional SCIg. The clinician groups also mentioned allergists and oncologists as specialists qualified for care of patients with primary or secondary humoral immunodeficiency, in addition to those listed by the experts consulted by CADTH.

Additional Considerations

According to the clinical groups, SCIg has been an important development in the treatment of immunodeficiency, freeing patients from outpatient units and freeing outpatient units to treat other patients. They noted there are considerable benefits associated with the ability to treat patients at home, particularly in terms of rising capacity issues for both inpatient and outpatient beds and the increasing costs of medicines.

Drug Program Input

The drug programs provide input on every drug reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. Their implementation questions and the corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.

Clinical Evidence

The clinical evidence included in this part of the review of IgHy10 is presented in 3 sections. The first section, the systematic review, includes the pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence selected from the literature that met the selection criteria specified in the review; however, indirect evidence was not provided or identified in the literature. The third section includes sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of IgHy10 for the treatment of primary and secondary humoral immunodeficiency in adult and pediatric patients 2 years of age and older.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Of note, the systematic review protocol presented subsequently was established before the granting of a Notice of Compliance from Health Canada.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies tool.⁴⁰

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946‒) through Ovid and Embase (1974‒) through Ovid. All Ovid searches were run simultaneously as a multi-file search. Duplicates were removed using Ovid deduplication for multi-file searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were human immunoglobulin and recombinant human hyaluronidase. Clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, the WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. See Appendix 1 for the detailed search strategies.

The initial search was completed on July 22, 2021. Regular alerts updated the search until the meeting of the CADTH Canadian Plasma Protein Product Expert Committee on November 24, 2021.

A focused literature search for network meta-analyses dealing with immunoglobulins or immunodeficiencies was run in MEDLINE All (1946–) on July 21, 2021. No filters were applied to limit the retrieval by study type.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature tool.⁴¹ Included in this search were the websites of regulatory agencies (FDA and European Medicines Agency). Google was used to search for additional internet-based materials. See Appendix 1 for more information on the grey literature search strategy.

These searches were supplemented through contacts with appropriate experts. In addition, the manufacturer of the drug was contacted for information regarding unpublished studies.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

A total of 2 studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Description of Studies

The details of the included studies are summarized in Table 6. Two sponsor-provided Clinical Study Reports, funded by Baxter Health care Corporation, were included. Study 160603 (N = 89) was a phase III, open-label, non-randomized, single-group prospective study with enrolment from December 2008 to November 2010. A total of 15 study sites were included, with 14 located in the US and 1 in Canada. Study 160603 aimed to evaluate the efficacy and tolerability of IgHy10 in patients with a PID. The study also aimed to assess HRQoL for IgHy10, cSCIg, and IVIg.

An overview of the design of Study 160603 is presented in Figure 2. Patients were enrolled in 1 of 2 study arms (cohorts) in Study 160603 based on whether they had previously participated in Study 160601. Patients who participated in Study 160601 were enrolled in study arm 1. Patients in study arm 1 were not required to receive treatment with IVIg during epoch 1 of Study 160603 because data regarding the bioavailability and exposure to IVIg had already been obtained in Study 160601, which evaluated the pharmacokinetics, efficacy, and safety of IVIg and was considered equivalent to epoch 1 of Study 160603. Patients enrolled in study arm 2 included all other patients enrolled in Study 160603 and were entered into epoch 1. During epoch 1, patients in study arm 2 received treatment with IVIg (10%) for 3 months. All patients (in study arms 1 and 2) proceeded to epoch 2, where they received IgHy10 for 14 months to 18 months. The overall study duration was planned to be 17 months for each patient but could extend to a maximum of 21 months, pending approval of Study 160902.

Extension Study 160902¹⁶ (N = 66) aimed to assess the long-term safety, tolerability, and practicability of IgHy10. Patients who had previously completed Study 160603 proceeded directly into the open-label, non-randomized, single-group extension study. Patients maintained the same dose and infusion interval for IgHy10 for the first 3 infusions, after which they had the option of switching to a 2-week treatment interval using one-half of the 4-week dose for up to 4 months. The purpose of the switch to a shorter treatment interval was to evaluate whether this would result in improved immunoglobulin trough levels. On July 31, 2021, following a discussion between the sponsor and the FDA, all study patients entered the safety follow-up period where they stopped treatment with rHuPH20. This decision was based on the theoretical risk of exposure to anti-rHuPH20 antibodies. Patients were therefore treated with immunoglobulin (10%) alone via IV or subcutaneously for 24 to 48 weeks, depending on the levels of rHuPH20-binding antibody titre, to ensure a safe transfer off of the study drug. A total of 50 patients completed the safety follow-up; 3 of these had previously switched directly to the safety follow-up phase during epoch 2 of Study 160603.

Figure 2: Overview of Study 160603 Study Design

max = maximum; PK = pharmacokinetic; rHuPH20 = recombinant human hyaluronidase; SC = subcutaneous; w = weeks.

Source: Clinical Study Report.¹⁵

Populations

Inclusion and Exclusion Criteria

Study 160603 enrolled patients aged 2 years and older with a PID requiring antibody replacement as defined by WHO criteria.^42,43 Patients were eligible if they had completed or were about to complete Study 160601, or had been receiving regular IVIg treatment at mean intervals of 21 (SD = 3) days or subcutaneous treatment at mean intervals of 5 to 16 days for at least 3 months before enrolment at a minimum dose of 300 mg/kg every 4 weeks. The main criteria for exclusion were serious medical conditions or hypersensitivity to immunoglobulin, enrolment in another non-Baxter clinical study, pregnancy, or not employing birth control measures. A prerequisite to inclusion in Extension Study 160902 was completion of Study 160603.

Baseline Characteristics

Table 7 and Table 8 show a summary of the patient baseline characteristics. In Study 160603, 2 patients withdrew before treatment, leaving 87 patients in the safety population for whom baseline characteristics were described. Of these, 87 patients (31 from Study 160601 and 56 from epoch 1 of Study 160603) were included among those who received IVIg (10%), and 83 patients received IgHy10 in epoch 2. Patients were distributed approximately equally by sex (51% male), had a median age of 35.0 years (range = 4 to 78), and were primarily White, and non-Hispanic and non-Latino (91%).

The most commonly diagnosed PID disease was common variable immune deficiency (56%), followed by hypogammaglobinemia (20%), and X-linked agammaglobulinemia (7%). All patients reported a medical history that included disorders of the hematopoietic and lymphatic systems, and the majority also reported medical conditions relating to the eyes, ears, nose, and throat (98%) and respiratory system (n = 76 of 87; 87%). The median serum IgG trough level up to 6 months before enrolment (before Study 160601 for study arm 1 and before Study 160603 for study arm 2) was 10.34 g/L (range = 4.05 to 32.00). Also, 64 (74%) of patients were receiving IVIg every 28 days, 17 (20%) every 21 days, 3 (3%) every 30 days, and 3 (3%) every 10 days or less before enrolment in Study 160603. It is unclear whether patients who had experience with IVIg administered every 10 days also had experience with cSCIg. Additionally, 33 patients (38%) were naive to cSCIg before enrolment.

There were no notable differences in the demographic characteristics of patients who continued into Extension Study 160902 versus patients in the main study. The most commonly diagnosed PID among those in the extension was common variable immune deficiency (59%), followed by humoral immune deficiency (9%) and hypogammaglobulinemia (9%). Patient medical history was generally similar to that of the patients who participated in Study 160603.

Table 7: Summary of Baseline Demographic Characteristics in Study 160603 and Study 160902 (SAS)

SAS = safety analysis set.

Note: Baseline refers to the start of epoch 1 in Study 160603.

^aIncludes patients who received at least 1 dose of the study treatment.

Sources: Wasserman et al. (2012),¹² Wasserman et al. (2016a),⁴⁴ Wasserman et al. (2016b),¹³and Clinical Study Reports.^15,16

Table 8: Summary of Baseline Disease Characteristics in Study 160603 and Study 160902 (SAS)

IgE = immunoglobulin E; IgG = immunoglobulin G; IgM = immunoglobulin M; NA = not applicable; NR = not reported; SAS = safety analysis set.

Note: Baseline refers to the start of epoch 1 in Study 160603.

^aTwo patients withdrew before treatment and are excluded.

Sources: Wasserman et al. (2012),¹² Wasserman et al. (2016a),⁴⁴ Wasserman et al. (2016b),¹³ Clinical Study Reports.^15,16

Interventions

Study 160603

During epoch 1, all patients were treated with IV infusion of normal human immunoglobulin (10%) for 12 weeks, at their usual dose and frequency (≥ 300 mg/kg BW every 4 weeks with a 3- or 4-week interval). All infusions were administered at the study site. Infusions started at a rate of 0.5 mL/kg BW per hour and increased as tolerated up to a maximum of 5.0 mL/kg BW per hour. For patients who had previously received subcutaneous treatment, IV treatment in epoch 1 was administered at a 3- or 4-week interval, with a dose based on the weekly equivalent of subcutaneous treatment. If a patient experienced an AE of at least moderate severity, the infusion rate was reduced to the rate immediately below where the AE occurred. In the case of hypersensitivity reactions or AEs that continued after a reduction of the infusion rate, the infusion was stopped and treated according to the standard of care.

In epoch 2, patients were treated with IgHy10 for 14 to 18 months, which was delivered by portable IV pump or syringe pump at an infusion site chosen by the patient. Initial infusions were administered at the study site until at least 2 infusions at the maximum infusion interval were tolerated. Thereafter, home treatment was allowed following adequate training and in the presence of a home nurse. Patients first received rHuPH20 by subcutaneous infusion at a rate of 1 mL to 2 mL per minute and a dose of at least 75 U/g immunoglobulin. The maximum volume for the majority of patients was approximately 20 mL and was infused at a single site, though 2 sites could be used. This was followed, within 10 minutes, by infusion of subcutaneous normal human immunoglobulin (10%) at 108% of the weekly equivalent dose of IVIg.

Treatment intervals and doses for the initial subcutaneous infusions were gradually increased during the first weeks of treatment, referred to as the ramp-up period. The first dose was a single dose for a 1-week interval based on the pre-study IVIg dose. A dose was considered to be tolerated if there were no SAEs, no non-serious moderate or severe local AEs preventing completion of the infusion, and no non-serious moderate or severe systemic AEs during or within 60 minutes of the infusion. If tolerated, each week, the interval was increased by 1 week, with the dose of immunoglobulin calculated based on the weekly equivalent of the dose that should be received on a 4-week interval until the treatment interval was the same as the pre-study treatment interval for IVIg (every 3 or 4 weeks). The dose then remained constant throughout epoch 2 and was calculated based on immunoglobulin in grams per BW in kg. At that time, IgG trough levels were reviewed and, if the trough level ratio was not between 93% and 123%, the dose was corrected for the next infusion and further reviewed until the ratio fell within the desired range. The infusion rate varied by week and patient weight (Table 9) up to a maximum of 300 mL per hour. Generally, a single infusion site was used, but a second was allowed when the volume infused was above 600 mL or if a single site was not tolerated. If an AE occurred, the infusion rate could be adjusted, as described for epoch 1. Serum trough levels of IgG greater than 4.5 g/L had to be maintained throughout the study; if levels fell to 4.5 g/L or less, the dose was to be adjusted and trough levels re-evaluated at the next infusion.

Prior and concomitant therapies taken for up to 2 weeks before the start of Study 160603 were allowed and were recorded; prophylactic treatment with antibacterial antibiotics, other immunoglobulin products, and hyperimmune serum was not allowed. Pre-medication before IV infusions with antihistamines, antipyretics, and/or steroids was to be avoided unless the same AE had been observed during or following at least 2 infusions either before or during the study. Pre-medication before subcutaneous infusions was not allowed unless an AE of at least moderate severity that did not resolve with a reduction of the infusion rate occurred during or after at least 2 previous infusions.

Extension Study 160902

Treatment from epoch 2 of Study 160603 was continued (at the same dose as the last infusion) in Extension Study 160902, but patients had the option to switch from a 3- or 4-week to a 2-week treatment interval using 1-half of the calculated 4-week dose for a maximum of 4 months. Patients were requested to change their drug administration interval to evaluate whether a more frequent administration of IgHy10 improved IgG trough levels. In the subsequent safety follow-up period, patients discontinued use of hyaluronidase and were switched to either IVIg or SCIg alone for up to 48 weeks. Those who were switched to IV infusion received a weekly dose equivalent to 100% (± 5%) of the most recent IV dose at a 3- or 4-week interval; those continuing with subcutaneous infusions received a weekly dose equivalent to the most recent IV dose multiplied by 1.37 (± 5%) at 1-week intervals.

Table 9: Infusion Rates for Subcutaneous Normal Immunoglobulin (Human) 10%

SC = subcutaneous.

Sources: Wasserman et al. (2012),¹² Clinical Study Report.¹⁵

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 10. These end points are further summarized subsequently. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

Infections

In Study 160603 and during the treatment with IgHy10 in Extension Study 160902 (i.e., before the safety follow-up period), the primary efficacy end point was the rate of VASBIs per patient per year throughout the study period. These were reported as AEs and the number and type were determined. Serious acute bacterial infections included bacteremia/sepsis, bacterial meningitis, osteomyelitis/septic arthritis, bacterial pneumonia, and visceral abscesses caused by a recognized bacterial pathogen. Diagnostic criteria were according to the US Department of Health and Human Services, FDA Guidance for Industry, June 2008,^11,45 and included an evaluation of symptoms and physical and laboratory findings. Essential diagnostic features were as follows:

• Bacteremia required a positive blood culture.

• Sepsis was defined as 2 of the following in adults: temperature greater than 38°C oral or 39°C rectal or less than 36°C oral or less than 37°C rectal, heart rate greater than 90 beats per minute, respiratory rate greater than 20 breaths per minute, or partial pressure of carbon dioxide (PaCO₂) less than 32 mm Hg, white blood cell count greater than 12,000/mm³, less than 4,000/mm³, or greater than 10%. In children, sepsis was based on the criteria of the International Consensus Conference on Pediatric Sepsis.⁴⁶ Blood-borne infections related to an indwelling catheter or vascular access device were not included.

• Bacterial meningitis required a positive cerebrospinal fluid Gram stain and/or culture and/or positive cerebrospinal fluid bacterial antigen assay.

• Osteomyelitis or septic arthritis required a positive X-ray, nuclear medicine bone scan, MRI, or CT scan showing bony destruction with radiolucent areas.

• Bacterial pneumonia required pulmonary infiltrate with consolidation on chest X-ray.

• Visceral abscess required typical findings on ultrasound, CT scan, MRI, or radionuclide scan.

• The annual rate of all infections per patient during treatment with IgHy10 was also calculated.

Immunoglobulin Levels

Immunoglobulin trough levels were determined using standard assay methods for the determination of IgG, performed at a central laboratory. In Study 160603, samples were collected at baseline, on the day of each infusion, and at the end-of-study visit. In Extension Study 160902, assessments occurred every 12 weeks, monthly during the first 4 months of 2-week interval infusions, and at the end-of-study visit.

Antibiotic Use

In Study 160603 and before the safety follow-up of Extension Study 160902, days on antibiotics were collected throughout the studies using patient diaries that were transcribed to case report forms. The frequency of assessment was not reported.

Health-Related Quality of Life

Assessments of quality of life occurred at the time of the first subcutaneous infusion in epoch 2 of Study 160603 and at the end-of-study visit for all patients. In the extension study (Study 160902), assessments occurred at the start of the safety follow-up period. Quality of life among patients aged 2 to 13 years was assessed using the PedsQL.⁴⁷ Scores were self-reported by patients aged 8 to 13 years and reported by a parent or primary caregiver for children aged 2 to 7 years. The PedsQL 4.0 (most recent version) consists of 23 items in 4 multi-item scales: physical functioning (8 items), emotional functioning (5 items), social functioning (5 items), and school functioning (5 items). Each item asks how much of a problem the item has been in the past month, with responses ranging from 0 (never a problem) to 4 (almost always a problem). Scale scores are then a sum of the items divided by the total number of questions answered. Two summary scores can then be computed: the physical health summary (8 items) is the same as the physical functioning scale, while the psychological summary score (15 items) is the sum of all items in the remaining scales divided by the number of items for which a response was provided.

Quality of life among patients 14 years and older was self-reported using the SF-36. The tool consists of 3 domains (functional status, well-being, and overall evaluation of health) comprising a total of 8 health dimensions. Functional status includes questions related to physical functioning (10 questions), social functioning (2 questions), physical role limitations (4 questions), and emotional role limitations (3 questions); well-being includes questions related to mental health (5 questions), vitality (4 questions), and pain (2 questions); and overall evaluation of health includes questions related to general health perception (5 questions). Response options to each question include Likert-like scales and yes/no options; responses within each domain are summed to obtain total scores. The developer’s recommended minimal important difference threshold for improved quality of life is 3 points,⁴⁸ but a minimal important difference specific to patients with immunodeficiencies was not identified.

All scores on both the PedsQL and SF-36 were transformed to a scale of 0 to 100, where higher scores indicate better quality of life.

Tolerability and Adherence

In Study 160603, infusions were deemed tolerated if no serious adverse drug reactions, no non-serious moderate or severe local adverse drug reactions preventing completion of the infusion, and no non-serious moderate or severe systemic adverse drug reactions occurred within 60 minutes of completion of the infusion. In Study 160902, the number of patients and caregivers who were unable to continue with patient- or caregiver-administered home infusions and the reasons why they could not continue.

Health Care Utilization

In Study 160603 and during treatment with IgHy10 in Extension Study 160902 (before the safety follow-up), the number of acute care physician visits, number of days in hospital, and number of days in hospital due to infection were reported throughout each of the studies. Patient diaries that were transcribed to case report forms were used to obtain data informing health care utilization.

Productivity

In Study 160603 and during treatment with IgHy10 in Extension Study 160902 (before the safety follow-up), days off school or work were reported throughout each of the studies. Patient diaries that were transcribed to case report forms were used to obtain data informing productivity.

Safety

Data on AEs were assessed from the time consent forms were signed for Study 160603 to the end-of-study visit in Extension Study 160902. Observable swelling following SCIg infusion that did not cause discomfort was not considered an AE.

For each infusion scheduled to be given at the study site, vital signs (sitting blood pressure, pulse, respiratory rate, body temperature) were monitored and recorded pre-infusion (within 30 minutes before immunoglobulin infusion), 30 minutes after initiation of the infusion, hourly during the infusion, and post infusion (within 30 minutes of completion of the infusion). For infusions given at home or at an infusion centre, vital signs were to be monitored and recorded pre-infusion (within 30 minutes before immunoglobulin infusion) and post infusion (within 30 minutes of completion of the infusion). Any vital sign changes occurring during the infusion that were considered clinically significant by the investigator were recorded as an AE.

Statistical Analysis

Power Calculation and Data Handling

The sample size for Study 160603 was determined based on collecting safety data on a sufficient number of patients (approximately 30) who were naive to subcutaneous infusion, in addition to patients rolling over from Study 160601 (approximately 45). For the primary end point, a sample size of 80 was planned to provide 81% power to reject the null hypothesis of 1 or more VASBIs per year at the 1% level of statistical significance.

Primary Outcomes of the Studies

The primary end point in Study 160603 was serious acute bacterial infection rate, defined as the mean number of VASBIs per patient per year. Serious acute bacterial infections included: bacteremia/sepsis, bacterial meningitis, osteomyelitis/septic arthritis, bacterial pneumonia, and visceral abscesses caused by a recognized bacterial pathogen (as per the diagnostic criteria defined by the FDA).¹¹ The primary end point was analyzed in the full analysis set (FAS).

The mean rate of VASBIs per patient per year and its 99% upper confidence limit were calculated using a Poisson model accounting for the length of the observation period for each patient. The null hypothesis of 1 or more VASBIs per patient per year was to be tested against the alternate hypothesis of less than 1 VASBI per patient per year. The observation period started after the ramp-up period and ended on the day of the end-of-study visit. To handle over-dispersion, the exponential distribution dispersion parameter was assumed to be given by the deviance divided by the degrees of freedom, and all statistics were adjusted accordingly. To assess efficacy, the null hypothesis of 1 or more infections per patient per year was tested using a generalized linear model assuming the Poisson distribution against the 1-sided alternative hypothesis of less than 1 infection per patient per year at the 1% level of statistical significance.

The primary end point was also assessed using the per-protocol analysis set (PPS).

There was no adjustment for covariates in any of the analyses. Statistical techniques were not used to identify or exclude any observations as outliers. If data were considered spurious, the reasoning and analysis from which the data were excluded were documented. For the primary end point, imputation techniques were not required, as the statistical method used accounted for the length of the observation period for each patient.

Since the number of patients at each study centre was small, analyses of centre effects were not performed. There were no adjustments made for multiple comparisons, as only 1 outcome was tested statistically. In Study 160603, in addition to the FAS and PPS, the primary end point and some secondary end points were assessed in the subcutaneous-naive population.

Interim Analyses

In Study 160603, a planned interim analysis was conducted that included data from patients in study arm 1 who had completed epoch 2 by the end of May 2010. The purpose of the interim analysis was to monitor the safety and tolerability of the treatments and to share updates about the study externally. No changes to the study were made as a result of the interim analysis.

In the extension study (Study 160902), a planned interim analysis occurred when the last patient reached 48 weeks of therapy. The analysis included serious AEs, all infections per patient, occurrence of neutralizing antibodies to rHuPH20, percentage of infusions requiring adjustment, all AEs by severity and classified by Medical Dictionary for Regulatory Activities (MedDRA) terms and IgG trough levels.

Sensitivity Analyses

Two sensitivity analyses of the rate of infections were performed to address the potential effects of patients not completing the full year of subcutaneous treatment:

• Use multiple imputation for the infection rate in unobserved time periods:

  • For patients who terminated the study for increased frequency or severity of infections: Use twice the highest infection rate observed in patients who completed more than 2 months in the study in the same season to address concerns that these patients may have done worse than others in the study.

  • For patients who did not leave the study due to increased frequency or severity of infections: Use the patient’s infection rate in a season; if more than 2 months were observed, then use the rate observed in patients who completed 2 or more months in the study in the same season. Rubin multiple imputations were used, where the number of infections in an unobserved time period were imputed by random numbers from the Poisson distribution, with the Poisson parameter set differently by season and by reason for study termination. Five or more datasets were imputed and analyzed, then the point estimate and CI were calculated using the Rubin method.

• Analyze a full year in the subset of patients who completed a full year. To avoid ambiguity, the first 365 days following the first subcutaneous infusion was selected.

Secondary Outcomes of the Studies

Infections

The annual rate of VASBIs was evaluated during the observation phase of Extension Study 160902 (before the safety follow-up). The analyses were similar to the analysis of the primary outcome in Study 160603. The annual rate of all infections was included as a secondary outcome in both studies. The rate of VASBIs was calculated per patient using the same Poisson model, including the allowance for over-dispersion. Additionally, in Study 160603, a post hoc exploratory analysis was conducted to assess the apparent difference in infection rates for IVIg versus IgHy10. Because the length of treatment and season of administration differed, the role of seasonal imbalance was investigated. Therefore, the infection rates were analyzed using a general linear Poisson model for the days per patient where the treatments were on the same calendar days. This analysis eliminated seasonal effects but not the possibility of year-to-year variation.

Immunoglobulin Levels

In Study 160603, IgG trough levels were summarized by medians and their 95% non-parametric CIs.

In Extension Study 160902, IgG trough levels over time were calculated for 2-, 3-, and 4-week infusion intervals and for the following age groups: 2 to 11 years, 12 to 15 years, 16 to 64 years, and 65 years and older. Descriptive statistics were used for the change in IgG trough levels from the end of the study period before the safety follow-up, to the end of the safety follow-up, stratifying for mode of administration (IV versus subcutaneous) and treatment interval.

Antibiotic Use, Health Care Utilization, and Productivity

In Study 160603 and during the observation phase of Extension Study 160902 (before the safety follow-up), point estimates and 95% CIs for the monthly rates of days off school/work, days on antibiotics, number of acute care physician visits, and days in hospital per patient were calculated using a Poisson model and the same methodology, including the allowance for over-dispersion, as described for the primary end point in Study 160603.

Safety and Tolerability

For Study 160603, analyses of the safety end points were provided for both the IV and subcutaneous administrations at the dose used in epoch 2 after the ramp-up phase. For the ramp-up phase in epoch 2, tolerability was summarized descriptively by the number of patients who tolerated the dose of the first infusion, the dose of the second infusion, and the number of patients who did not tolerate the dose. The individual patient’s rate for each of the secondary safety end point events (e.g., AEs) was calculated by dividing the total number of events by the total number of IV or subcutaneous infusions, respectively.

In Extension Study 160902, the analyses of safety end points were stratified by age: 2 to 11 years, 12 to 15 years, 16 to 64 years, and 65 years and older. Analyses were conducted for the period of IgHy10 treatment, for the safety follow-up period, and for all periods combined. AEs were reported descriptively by category (MedDRA preferred term and seriousness) as a rate per patient and as a rate per infusion. Temporally associated AEs, defined as occurring during or within 72 hours of an infusion, were also reported descriptively by rate per patient and rate per infusion.

Exploratory Outcomes of the Studies

Health-Related Quality of Life

HRQoL was analyzed using descriptive statistics. In Study 160603, HRQoL was analyzed separately for the 2 to 7 years, 8 to 13 years, and 14 years of age and older groups. Patients younger than 14 years old were assessed using the PedsQL and patients who were 14 years of age and older were assessed using the SF-36.

Analysis Populations

The analysis sets included in Study 160603 are described subsequently.

The FAS included all patients who had been exposed to either or both study drugs and who provided data for the primary end point for any period of time.

The PPS was a subset of the FAS that included only patients who had completed at least 6 months of subcutaneous treatment after the ramp-up.

The safety analysis set (SAS) included all patients who were exposed to either or both study drugs.

The primary dataset used for the analysis of primary and secondary efficacy outcomes was the FAS. The SAS was used to analyze safety and tolerability outcomes as well as HRQoL outcomes.

In Extension Study 160902, the SAS included data obtained in Study 160902 on all patients who received at least 1 dose of the study drug in the context of Study 160902. All analyses were conducted using the SAS.

Results

Patient Disposition

Study 160603

Full details of the patient disposition in Study 160603 are shown in Table 11. Of the 89 potential patients who were screened, 2 (2%) failed screening and withdrew before treatment. The remaining 87 patients began IV treatment in epoch 1 or in Study 160601. Of the 87 patients treated, 31 (36%) were in arm 1 (those who had participated in Study 160601) and the remaining 56 were in arm 2. One patient in the 2 years to younger than 12 years group asked to withdraw during epoch 1, and 2 patients aged 12 years or older were withdrawn because they missed 2 consecutive treatments. Of the 87 patients who started treatment, 84 (97%) completed epoch 1.

One patient who completed epoch 1 did not receive any infusions in epoch 2; therefore, 83 (93%) patients began treatment in epoch 2. One patient began treatment in epoch 2 despite failing to meet an inclusion criterion (pre-study dose was 16mg/kg, which was too low due to weight gain); this was documented as a protocol deviation. Of those who started epoch 2, 5 patients aged from 2 years to younger than 12 years and 11 patients aged 12 years or older withdrew (reasons in Table 11). Of those who started treatment, 68 (78%) completed epoch 2.

There were 15 major protocol deviations detected during the study, the most common being the administration of an incorrect dose (n = 7) and failure to conduct pharmacokinetic assessments (n = 4). No patients were excluded from the per-protocol analysis due to deviations. An audit at 1 of the study sites detected significant departures from good clinical practice; however, the site was not censored, as it was judged that this would introduce bias in Baxter’s favour.

Table 11: Patient Disposition for Study 160603

^aIncludes patients who withdrew or discontinued from the study. A total of 16 patients discontinued from study and 3 switched to the safety follow-up period in Study 160902.

^bSubset of the FAS that included only patients who completed at least 6 months of subcutaneous treatment after the ramp-up.

^cAll patients exposed to either or both study drugs.

Source: Clinical Study Report.¹⁵

Extension Study 160902

Full details of the patient disposition in Extension Study 160902 are shown in Table 12. Out of the 66 patients who rolled over from Study 160603 into 160902, 63 (95%) were treated with SCIg (10%) plus rHuPH20 (IgHy10); 3 (5%) who had switched to the safety follow-up received IVIg (10%) alone. Of the 63 patients who were receiving IgHy10, 15 (23%) withdrew or were discontinued from the study (reasons in Table 12); 48 (91%) switched to the safety follow-up when protocol amendment 5 went into effect. Therefore, of those who started treatment in Study 160603, 48 (55%) completed the safety follow-up in Extension Study 160902.

There were 31 major protocol deviations during the study; the most common were described as a procedure not being done (n = 16) or other causes (n = 12). No patients were excluded from the analyses due to protocol deviations.

Table 12: Patient Disposition for Study 160902

IgHy10 = normal immunoglobulin (human) 10% and recombinant human hyaluronidase; IVIg = intravenous immunoglobulin; SAS = safety analysis set.

^a32 patients total: 29 patients who had completed the safety follow-up plus 3 patients who had completed IVIg (normal immunoglobulin [human] 10%) without hyaluronidase.

^bAll patients who received at least 1 dose of the study drug in the context of Study 160902.

^cThe data obtained in Study 160603 started with patients’ first exposure; for Study 160902, the data were for all patients who participated.

Source: Clinical Study Report.¹⁶

Exposure to Study Treatments

Study 160603

A total of 365 IV infusions of immunoglobulin and 1,359 subcutaneous infusions of IgHy10 (90% in the abdomen, 9% in the thighs, < 1% in both abdomen and thigh, and < 1% in another site) were administered during the study. The median duration of IVIg treatment in epoch 1 was 91.0 days for patients younger than 12 years of age and those aged 12 years and older. Patients received IgHy10 for a median of approximately 1 year in epoch 2 (excluding the ramp-up) in both the SAS and FAS. The median duration of exposure in epoch 2 (excluding the ramp-up) was slightly higher in the PPS (423.0 days and 378.0 days for patients aged < 12 years and ≥ 12 years, respectively). In the ramp-up period, patients were exposed to IgHy10 for a median of 42 days in both age groups and in all datasets.

In 78 of the 83 patients (94.0%) who began treatment in epoch 2, the dosing interval that was used for IV infusions was reached for subcutaneous infusions with rHuPH20 during the ramp-up. In 15 patients (18.1%), this was a 3-week interval and in 63 patients (75.9%), this was a 4-week interval.

Infusions of IVIg were initiated at a median flow rate of 13.3 mL/hour (range = 4.0 to 32.0) in patients younger than 12 years of age and 36.5 mL/hour (range = 10.0 to 240.0) in those aged 12 years and older. IgHy10 was given at a median initial infusion rate of 10.0 mL/hour in both age groups assessed in epoch 2 (excluding the ramp-up); this result was identical in all datasets. The initial infusion rate ranged from 5.0 mL/hour to 20.0 mL/hour in patients younger than 12 years of age and 5.0 mL/hour to 300.0 mL/hour in those aged 12 years and older in all datasets except the SAS, in which the initial infusion rate was always 10.0 mL/hour in patients younger than 12 years of age. In the ramp-up, the median initial infusion rate was 5.0 mL/hour (range = 5.0 to 10.0) in patients younger than 12 years of age in all datasets except the SAS (median = 10.0; range = 5.0 to 10.0 mL/hour) and 10.0 (range = 5.0 to 10.0) mL/hour in patients aged 12 years and older.

The median maximum infusion rate used in patients younger than 12 years old was 62.5 (range = 25.0 to 316.0) mL/hour for IVIg infusions (epoch 1), 160.0 (range = 80.0 to 300.0) mL/hour for IgHy10 infusions in epoch 2 (excluding the ramp-up), and 80.0 (range = 40.0 to 300.0) mL/hour for IgHy10 infusions during the ramp-up. Comparable results were obtained for the SAS.

Table 13: Exposure in Study 160603 (SAS)

IgHy10 = normal immunoglobulin (human) 10% and recombinant human hyaluronidase; IVIg = intravenous immunoglobulin; SAS = safety analysis set; SD = standard deviation.

Source: Clinical Study Report.¹⁵

Extension Study 160902

Prior to the safety follow-up period in Study 160902, 63 patients received IgHy10 for a median treatment duration of 669 days (range = 60 to 729). The mean dose received was 0.156 g/kg per week (SD = 0.051). The median duration of IgHy10 infusion was 1.42 hours (range = 0.3 to 44.6). The high maximum infusion time was due to 1 patient being unable to complete an infusion at home due to technical problems with the infusion pump. The treatment therefore had to be completed at the clinic and the duration of the infusion was reported to be 2 days.

Across all age groups, the median initial rate of IgHy10 infusion was 10 mL/hour (range = 5 to 300) (Table 14) and the median maximum rate of infusion achieved was 300 mL/hour (range = 10 to 350). Across all age groups and infusion intervals, a median of 1.09 infusions per month (range = 0.3 to 2.1) was administered. Patients following the 3-week infusion interval received a median of 1.45 infusions per month (range = 0.8 to 1.6), and those following a 4-week infusion interval received a median of 1.09 infusions per month (range = 0.3 to 1.3). During the 2-week infusion interval period, patients received a median of 2.18 infusions per month (range = 2.0 to 2.5). Treatment with IgHy10 required a median of 1.58 infusion sites per month (range = 0.3 to 2.4) across all age groups and infusion intervals. Patients following the 3-week infusion interval used a median number of 2.40 infusion sites per month (range = 0.8 to 3.0); those following a 4-week infusion interval used a median of 1.09 infusion sites per month (range = 0.3 to 2.6). During the 2-week infusion interval period, patients used a median of 2.18 infusion sites per month (range = 2.0 to 5.1).

At the first infusion of the study, 10 of 66 patients (15%) received IgHy10 on a 3-week interval basis and 53 of 66 patients (80%) on a 4-week interval basis. Three out of 66 patients (4.5%) did not receive any IgHy10 in Study 160902.

Of the patients initially treated with IgHy10, 15 of 66 patients (22.7%) terminated the study while on IgHy10 and 51 of 66 patients (77.3%) were switched to the safety follow-up period. Of the patients on a baseline infusion interval of 3 weeks, 3 of 66 (4.5%) switched to a 2-week infusion interval and none returned to a 3-week infusion interval. Of the patients starting on a 4-week interval, 15 of 66 (22.7%) switched to a 2-week infusion interval and 3 of 66 (4.5%) returned to a 4-week infusion interval. Of a total of 18 patients who were switched to the 2-week infusion interval, 1 of 66 (1.5%) stayed on this treatment interval for less than 4 months, and 17 of 66 (25.8%) stayed on this interval for more than 4 months.

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported subsequently. See Appendix 4 for detailed efficacy data.

Infections

Annual Rate of VASBIs

In Study 160603, the mean annual rate of VASBIs during IgHy10 treatment in epoch 2 was 0.025 per patient per year (upper limit of the 99% CI = 0.046) in the FAS, which was below 1.0 (P < 0.0001), the threshold suggested by FDA guidance. Two VASBIs were reported, occurring on the day of the first subcutaneous infusion at the final infusion interval after the ramp-up. Rates of VASBI in the PPS and SAS in Extension Study 160902 also fell below 1.0 VASBI per patient per year (P < 0.0001).

Annual Rate of All Infections

In Study 160603, the mean annual rate of all infections during treatment with IVIg (epoch 1) and IgHy10 (epoch 2) was 2.97 infections per patient per year (95% CI, 2.51 to 3.47) and 4.51 infections per patient per year (95% CI, 3.50 to 5.69), respectively. The annual rate of infections occurring in more than 5% of patients was also reported (Table 15).¹² The most frequently reported infections during both epoch 1 and epoch 2 included sinusitis, upper respiratory tract infection, and bronchitis.

Two sensitivity analyses for the rate of infections were performed to address the potential effects of patients not completing the full year of IgHy10 in epoch 2. When Rubin multiple imputation methods were employed for any patients who terminated the study after less than 1 year, the annualized rate of all infections was 3.24 infections per patient per year (95% CI, 2.65 to 3.96). The rate of all infections per year in the 41 patients in the FAS who had completed a full year of treatment was 2.75 infections per patient per year (95% CI, 2.09 to 3.54).

The rate of infections in Extension Study 160902 was similar to the FAS in Study 160603.

In a post hoc analysis, Wasserman et al. (2016)¹³ evaluated patients from Study 160603 and Study 160902 from the first administration of IgHy10 through the end of treatment. Exposure to IgHy10 exceeded 30 months for 48 of the 83 patients included in the analysis. The annual rate of infections and annual rate of VASBIs during IgHy10 treatment were reported by age group (< 18 and ≥ 18 years). For patients who were at least 18 years of age (n = 59), the rate of infections was 2.98 per year (95% CI, 2.56 to 3.44) and the rate of VASBIs was 0.01 per year (upper limit of the 99% CI = 0.02). The rate of infections and VASBIs were consistent with the results reported for each of the individual studies. The rate of infections during treatment with IgHy10 was also reported for 1-year periods by age group. The rate of infections per 1-year period ranged from 2.52 (95% CI, 1.69 to 3.59) to 3.61 (95% CI, 2.84 to 4.50).

Table 15: Rate of Infections in Study 160603

CI = confidence interval; IgHy10 = normal immunoglobulin (human) 10% and recombinant human hyaluronidase; IVIg = intravenous immunoglobulin; NR = not reported; rHuPH20 = recombinant human hyaluronidase; SC = subcutaneous; SCIg = subcutaneous immunoglobulin.

^aThe mean rate of infections per patient per year and its variance were calculated using a Poisson model accounting for the length of the observation period for each patient. To handle over-dispersion, the exponential distribution dispersion parameter was assumed to be given by the deviance divided by the degrees of freedom and all statistics were adjusted accordingly.

^bIn an exploratory analysis using the same calendar days per patient for the IVIg only and SCIg plus rHuPH20 treatment periods, the infection rate of 4.3 per year for IVIg was higher than the rate of 2.3 per year for SCIg plus rHuPH20 (P = 0.0021). This analysis accounted for potential seasonal effects but could not account for year-to-year variations in weather conditions. Sensitivity analyses addressing the potential effects of patients who did not complete the full year of treatment, using Rubin imputation methods, resulted in an annualized rate of infections of 3.24 (95% CI, 2.65 to 3.96). The point estimate of the rate of all infections per year in the 41 patients in the full analysis set who had completed a full year of treatment was 2.75 (95% CI, 2.09 to 3.54).

^cThere was no adjustment for multiple testing.

Source: Clinical Study Report¹⁵ and Wasserman et al. (2012).¹²

Table 16: Rate of Infections Before the Safety Follow-Up in Study 160902 (SAS)

CI = confidence interval; IgHy10 = normal immunoglobulin (human) 10% and recombinant human hyaluronidase; SAS = safety analysis set.

^aThe mean rate of infections per patient per year and its variance were calculated using a Poisson model accounting for the length of the observation period for each patient. To handle over-dispersion, the exponential distribution dispersion parameter was assumed to be given by the deviance divided by the degrees of freedom, and all statistics were adjusted accordingly.

^bThere was no adjustment for multiple testing.

Source: Clinical Study Report.¹⁶

Immunoglobulin Levels

While receiving IgHy10 in Study 160603 (Table 17), the median IgG trough level in patients younger than 12 years was 9.95 g/L (95% CI, 7.87 to 15.00). In patients who were at least 12 years old, the median IgG trough level was 10.70 g/L (95% CI, 9.46 to 11.80). Patients’ IgG trough levels while receiving IgHy10 (epoch 2) were similar to patients’ IgG trough levels while receiving IVIg (epoch 1). Results for IgG trough levels reported in the FAS were consistent with those reported using the PPS.

In Study 160902 (Table 18), the median IgG trough level for patients who received IgHy10 administered at a 2-week interval was 10.90 g/L (95% CI, 9.39 to 13.30). For patients who received IgHy10 administered at a 3-week interval and a 4-week interval, the median IgG trough level was 12.30 g/L (95% CI, 11.50 to 15.30) and 9.67 g/L (9.26 to 10.70), respectively. Study 160902 also reported IgG trough levels as a percent change for patients whose IgHy10 treatment was switched from a 3- or 4-week interval to a 2-week interval (Table 18). When receiving IgHy10 at a 2-week interval, the IgG trough level was 105.90% (SD = 0.03), and 113.23% (SD = 13.02) for patients who were previously on a 3- or 4-week interval.

Lastly, the ratio of IgG trough levels at the end of the safety follow-up period (treatment with IVIg or SCIg without hyaluronidase) compared with the end of the IgHy10 treatment period was analyzed in Study 160902 (Table 18). The IgG trough level in patients who received SCIg at the end of the safety follow-up period was 117.8% (95% CI, 104.4 to 145.7) of their IgG trough level while receiving IgHy10. The IgG trough level in patients who received IVIg at the end of the safety follow-up period was 102.5% (95% CI, 97.7 to 109.8) of their IgG trough level while receiving IgHy10. The ratio of IgG trough levels is also summarized by administration interval.

Table 17: IgG Trough Levels by Age in Study 160603

CI = confidence interval; IgG = immunoglobulin G; IgHy10 = normal immunoglobulin (human) 10% and recombinant human hyaluronidase; IVIg = intravenous immunoglobulin.

Source: Clinical Study Report.¹⁵

Table 18: IgG Trough Levels by Dose Frequency in Extension Study 160902 (SAS)

CI = confidence interval; IgG = immunoglobulin G; IgHy10 = normal immunoglobulin (human) 10% and recombinant human hyaluronidase; IVIg = intravenous immunoglobulin; NA = not applicable; SAS = safety analysis set; SCIg = subcutaneous immunoglobulin; SD = standard deviation.

Source: Clinical Study Report.¹⁶

Antibiotic Use

Days on antibiotics were reported in Study 160603 and Study 160902 (before the safety follow-up period) and are summarized in Table 19 and Table 20, respectively.

While receiving treatment with IgHy10, patients were on antibiotics at a rate of 1.68 days per month (95% CI, 1.29 to 2.16). While on treatment with IVIg, patients were on antibiotics at a rate of 3.15 days per month (95% CI, 2.19 to 4.35). In Extension Study 160902, patients had to take antibiotics at an annual rate of 64.03 days per year (95% CI, 45.16 to 87.54).

Table 19: Days on Antibiotics in Study 160603

CI = confidence interval; IgHy10 = normal immunoglobulin (human) 10% and recombinant human hyaluronidase; IVIg = intravenous immunoglobulin.

^aPoint estimates and 95% CIs for the monthly and yearly rates were calculated using a Poisson model and the same methodology, including the allowance for over-dispersion, as described for the primary end points.

Source: Clinical Study Report.¹⁵

Table 20: Days on Antibiotics Before the Safety Follow-Up in Extension Study 160902 (SAS)

CI = confidence interval; IgHy10 = normal immunoglobulin (human) 10% and recombinant human hyaluronidase; SAS = safety analysis set.

^aPoint estimates and 95% CIs for the monthly and yearly rates were calculated using a Poisson model and the same methodology, including the allowance for over-dispersion, as described for the primary end points.

Source: Clinical Study Report.¹⁶

Health-Related Quality of Life

HRQoL was evaluated in Study 160603 and Extension Study 160902 using the PedsQL and SF-36 (Table 21 and Table 22). The scores from the SF-36 and PedsQL were combined and summarized for all patients. The median mental/psychosocial health summary score was 56.2 (range = 20.0 to 86.7) while receiving SCIg (patients enrolled from Study 160601), 53.1 (range = 20.5 to 90.0) while receiving IVIg, and 53.6 (range = 21.5 to 96.7) during treatment with IgHy10. The median physical component and health summary score was 47.0 (range = 13.1 to 100.0) while receiving SCIg (patients enrolled from Study 160601), 51.0 (range = 18.8 to 84.4) while receiving IVIg, and 56.0 (range = 55.2 to 56.6) during treatment with IgHy10.

HRQoL was also reported by age group (2 to 7 years, 8 to 13 years, and at least 14 years old). For IgHy10, among patients who were between 2 and 7 years old, the psychosocial health summary score was a median of 88.3 (range = 59.6 to 96.7), and the physical health summary score was a median of 88.0 (range = 66.7 to 97.8). For patients aged 8 to 13 years, the psychosocial health summary score was a median of 66.7 (range = 36.7 to 95.0), and the physical health summary score was a median of 90.6 (range = 28.1 to 100.0). Using the SF-36 for patients who were at least 14 years old and received IgHy10, the mental component and physical component summary scores were a median of 52.2 (range = 21.5 to 70.8) and 44.8 (range = 13.1 to 61.1), respectively.

Table 21: Health-Related Quality of Life in Study 160603 (SAS)

IgHy10 = normal immunoglobulin (human) 10% and recombinant human hyaluronidase; IVIg = intravenous immunoglobulin; NR = not reported; PedsQL = Pediatric Quality of Life Inventory; SAS = safety analysis set; SCIg = subcutaneous immunoglobulin; SF-36 = Short Form (36) Health Survey.

^aThe range of both scales is 0 to 100, where higher scores indicate a better quality of life.

Source: Clinical Study Report.¹⁵

Table 22: Health-Related Quality of Life in Extension Study 160902 Assessed Before Safety Follow-Up (SAS)

IgHy10 = normal immunoglobulin (human) 10% and recombinant human hyaluronidase; PedsQL = Pediatric Quality of Life Inventory; SAS = safety analysis set; SF-36 = Short Form (36) Health Survey.

^aThe range of both scales is 0 to 100, where higher scores indicate a better quality of life.

Source: Clinical Study Reports.^15,16

Tolerability and Adherence

In Study 160603, all but 3 (3.7%) subcutaneous infusions of IgHy10 during the ramp-up were tolerated according to the predefined criteria. One of the 3 infusions that were not tolerated was in a patient younger than 12 years old, and the remaining 2 were in patients aged12 years or older. Two of the 3 infusions that were not tolerated were the first subcutaneous IgHy10 infusions administered to the respective patient. The median rate of IgHy10 infusions tolerated at the dose used in epoch 2 (excluding the ramp-up) was 100% (95% CI, 100 to 100) for both IVIg administration and subcutaneous infusions. This outcome was not reported in Extension Study 160902.

The rate of patients who had no infusions that required a reduction in flow rate or that had to be interrupted or stopped due to tolerability concerns or AEs, was similar for subcutaneous IgHy10 (84.0%) and IVIg administration (88.5%) (Table 23). Most (97.7%) subcutaneous infusions with IgHy10 were tolerated, as were most (95.9%) IVIg infusions. The findings for subcutaneous IgHy10 in the Extension Study 160902 were similar.

No patients required a dose correction due to IgG trough levels below 4.5 g/L in Study 160603. This outcome was not reported in Study 160902.

Table 23: Infusions Where the Rate Was Reduced or the Infusion Interrupted or Stopped Due to Tolerability Concerns or AEs in Study 160603 and Study 160902 (SAS)

AE = adverse event; IgHy10 = normal immunoglobulin (human) 10% and recombinant human hyaluronidase; IVIg = intravenous immunoglobulin; SAS = safety analysis set.

^aOutcomes calculated using descriptive statistics.

Source: Clinical Study Reports.^15,16

The location where IgHy10 was infused in Study 160603 is summarized in Table 24. Briefly, 847 (75.0%) infusions were administered at the investigational site and 282 (25.0%) were administered at home. Of those administered at home, 51 (4.5% of all infusions) required intervention by a nurse and 231 (20.5% of all infusions) were administered independently. Similarly, the reasons for not being able to continue home infusions in Extension Study 160902 have been summarized in Table 25. Overall, 63.5% of patients were unable to continue self-administration of IgHy10 at home. This was due to medical reasons (14.3%), a family member (15.9%), or other reasons (58.7%). Overall, 51.8% of infusions required assistance for self-administration of IgHy10 at home, with 14.1% due to a medical reason, 5.1% due to a family member, and 32.6% due to other reasons. A summary of patients and infusions requiring assistance for administration at home was also summarized by age (Table 25). Specific reasons for not being able to self-administer IgHy10 at home were not reported in Study 160603.

Table 24: Summary of IgHy10 Infusions Administered at Home in Study 160603 (SAS)

IgHy10 = normal immunoglobulin (human) 10% and recombinant human hyaluronidase; SAS = safety analysis set.

Source: Clinical Study Reports.¹⁵

Table 25: Reasons for Being Unable to Continue Self-Administration of Infusions at Home in Study 160902 (SAS)

SAS = safety analysis set.

^aOutcomes calculated using descriptive statistics.

Source: Clinical Study Reports.^15,16

Health Care Utilization

Days in Hospital and Number of Acute Care Physician Visits

The monthly rate of days in hospital and acute care physician visits reported in Study 160603 and Study 160902 (before the safety follow-up period) are summarized in Table 26 and Table 27, respectively.

While receiving treatment with IgHy10, patients reported acute care physician visits at a rate of 0.40 visits per month (95% CI, 0.32 to 0.49). While on treatment with IVIg, patients reported acute care physician visits at a rate of 0.33 visits per month (95% CI, 0.23 to 0.45). The rate of days spent in hospital per month was 0.06 (95% CI, 0.03 to 0.10) while receiving IVIg and 0.02 (95% CI, 0.01 to 0.03) while receiving IgHy10. The monthly rate of days spent in hospital due to infection was 0.03 days per month (95% CI, 0.01 to 0.05) while receiving IVIg, and zero days per month while receiving treatment with IgHy10.

In Extension Study 160902, patients reported acute care physician visits at a rate of 4.19 visits per year (95% CI, 3.14 to 5.45). Also in Study 160902, the rate of days in hospital was 0.83 days/year (95% CI, 0.42 to 1.45) and the rate of days in hospital due to infection was 0.11 days/year (95% CI, 0.06 to 0.18).

Table 26: Number of Days in Hospital and Acute Care Physician Visits in Study 160603

CI = confidence interval; IgHy10 = normal immunoglobulin (human) 10% and recombinant human hyaluronidase; IVIg = intravenous immunoglobulin.

^aPoint estimates and 95% CIs for the monthly and yearly rates were calculated using a Poisson model and the same methodology, including the allowance for over-dispersion, as described for the primary end points.

Source: Clinical Study Report.¹⁵

Table 27: Days in Hospital and Acute Care Physician Visits per Year Before the Safety Follow-Up in Extension Study 160902 (SAS)

CI = confidence interval; IgHy10 = normal immunoglobulin (human) 10% and recombinant human hyaluronidase.

^aPoint estimates and 95% CIs for the monthly and yearly rates were calculated using a Poisson model and the same methodology, including the allowance for over-dispersion, as described for the primary end points.

^bDefined as non-study outpatient visits.

Source: Clinical Study Report.¹⁶

Productivity

Days off school or work were reported in Study 160603 and Study 160902 (before the safety follow-up period) and are summarized in Table 28 and Table 29, respectively.

While receiving treatment with IgHy10, patients had to miss school or work at a rate of 0.28 days per month (95% CI, 0.20 to 0.37). While on treatment with IVIg, patients had to miss school or work at a rate of 0.23 days per month (95% CI, 0.15 to 0.34). In Extension Study 160902, patients missed school or work at an annual rate of 7.70 days per year (95% CI, 5.33 to 10.69).

Table 28: Days Off School or Work in Study 160603

CI = confidence interval; IgHy10 = normal immunoglobulin (human) 10% and recombinant human hyaluronidase; IVIg = IV immunoglobulin; SCIg = subcutaneous immunoglobulin.

^aPoint estimates and 95% CIs for the monthly and yearly rates were calculated using a Poisson model and the same methodology, including the allowance for over-dispersion, as described for the primary end points.

Source: Clinical Study Report.¹⁵

Table 29: Days Off School or Work Before the Safety Follow-Up in Extension Study 160902 (SAS)

CI = confidence interval; IgHy10 = normal immunoglobulin (human) 10% and recombinant human hyaluronidase; SAS = safety analysis set.

^aPoint estimates and 95% CIs for the monthly and yearly rates were calculated using a Poisson model and the same methodology, including the allowance for over-dispersion, as described for the primary end points.

^bDays off school or work due to fever was 0.72 (95% CI, 0.45 to 1.07) per year, due to infection was 2.81 (95% CI, 1.78 to 4.17) per year, and due to other illness was 4.18 (95% CI, 2.72 to 6.08) per year.

Source: Clinical Study Report.¹⁶

Functional Status

Outcomes related to functional status were not reported in the studies included in this review.

Harms

Only those harms identified in the review protocol are reported subsequently. The focus of the summary of harms is on harms that occurred while patients were receiving IgHy10 (during epoch 2 of Study 160603 and during the safety extension phase of Study 160902). See Table 30 and Table 31 for detailed harms data, which includes safety data corresponding to epoch 1 of Study 160603 (treatment with IVIg) and the safety follow-up phase of Study 160902 (treatment with SCIg or IVIg without hyaluronidase). Additional harms data have been reported in Table 35, Table 36, and Table 37. Note that safety data reported during epoch 2 exclude safety events that occurred during the ramp-up period (unless otherwise indicated), as safety outcomes evaluated during the ramp-up period were analyzed separately.

Adverse Events

The rate of AEs in Study 160603 and Study 160902 are summarized in Table 30. In Study 160603, the overall rate of AEs while receiving IgHy10 was 13.40 AEs per patient. The rate of local AEs was 2.90 AEs per patient and the rate of systemic AEs was 10.49 AEs per patient. The most frequently reported AEs while on treatment with IgHy10 was infusion site pain, which occurred at a rate of 1.14 events per patient, as well as the following AEs that occurred at a rate of less than 1 event per patient: headache, sinusitis, upper respiratory tract infection, asthma, nausea, fatigue, myalgia, infusion site pruritus, and viral upper respiratory tract infection. During the safety extension study (Study 160902), the overall rate of AEs was 19.75 per patient while receiving IgHy10. The rate of local AEs was 2.62 per patient and the rate of systemic AEs was 17.13 per patient (including infections) or 12.71 per patient (excluding infections).

In addition, a summary of the most commonly reported AEs (by proportion of patients reporting an AE) that occurred following the ramp-up period during epoch 2 (Study 160603) is provided in Table 31. Briefly, 53.1% of patients reported a local AE. The most frequently reported local AEs were infusion site pain, infusion site discomfort, infusion site erythema, and infusion site pruritus. The most frequently reported systemic AEs were headache (30% of patients), asthma (17%), nausea (15%), pyrexia (15%), and fatigue (15%), and the following AEs were reported in less than 15% of patients: myalgia, vomiting, arthralgia, dizziness, and diarrhea. The rate of AEs per infusion was also summarized in Table 31.

Additionally, a post hoc integrated analysis of safety outcomes from Study 160603 and Study 160902 reported the overall rate of systemic AEs and local AEs (both excluding infections) by age group (< 18 and ≥ 18 years).¹⁴ Among adult patients (≥ 18 years), 1,200 systemic AEs were reported, corresponding to a rate of 8.63 AEs per patient-year. For local AEs, a total of 429 AEs were reported among adult patients, corresponding to a rate of 3.08 AEs per patient-year.

A summary of the most commonly reported harms by rate of AEs per infusion in Study 160902 is available in Table 35. Additional harms data for Study 160603 and Study 160902, such as temporally associated AEs, are available in Table 36 and Table 37.

Serious Adverse Events

The SAEs reported in studies 160603 and 160902 are summarized in Table 30. In epoch 2 of Study 160603, a total of 14 SAEs occurred among 11 patients treated with IgHy10, including the ramp-up period. This included cervical dysplasia, grand mal convulsion, lobar pneumonia, status epilepticus with respiratory failure, back injury, acute adrenocortical insufficiency, headache, myocardial infarction, gastroenteritis, intervertebral disc degeneration, petit mal epilepsy, tonsillar hypertrophy, oral leukoplakia, and thrombosis. Three of the 11 patients reporting SAEs experienced the SAE during the ramp-up period. The SAEs reported for that period included intervertebral disc degeneration, lobar pneumonia, and oral leukoplakia.

In Study 160902, there were a total of 18 SAEs reported among 11 patients. Of the SAEs, 13 (72%) occurred during treatment with IgHy10, and 3 occurred during the safety follow-up. SAEs reported while receiving IgHy10 included: chronic obstructive pulmonary disease (2 events), hypertension, aortic valve incompetence, atrial fibrillation, adhesiolysis, appendicitis, cardiac failure congestive, cryptosporidiosis infection, cystocele, mental status change, pneumonia Pseudomonas aeruginosa, spinal meningeal cyst, toxicity to various drugs, and vaginal prolapse. During the safety follow-up, cellulitis, femur fracture, and transient ischemic attack were reported as SAEs.

The rate of SAEs per patient is also available in Table 30.

Withdrawals Due to Adverse Events

Withdrawals from treatment due to AEs were not reported. The number of patients who required that their infusion be stopped due to tolerability concerns or an AE was 2 (0.2%) during epoch 2 of Study 160603, 1 (0.1%) during the safety extension (Study 160902), and 1 (0.2%) during the safety follow-up of Study 160902 (Table 30). As described in the Results section of this report (under Patient Disposition), 6 (6.9%) patients withdrew from the study due to AEs during epoch 2 of Study 160603, including 2 of 14 patients (14.3%) who were younger than 12 years old and 4 of 73 patients (5.5%) who were at least 12 years old. In Study 160902, 1 patient (1.5%) withdrew from the study due to an AE; the patient was between 16 and 65 years old and experienced a severe anaphylactic reaction, which was considered to be related to the immunoglobulin (10%) treatment.

Mortality

No deaths were reported during Study 160603. Two deaths occurred during the Extension Study 160902, 1 patient died from toxicity to various drugs on study day 135, and 1 had a cardiac arrest approximately 4 weeks after they completed the study. None of the deaths were considered to be related to the study treatments.

Notable Harms

Notable harms for this review are summarized in Table 30 as the number of AEs and rate of AEs per patient. While receiving IgHy10 in Study 160603 (excluding the ramp-up period), systemic effects (including headache, fatigue, nausea, vomiting, pyrexia, arthralgia, and myalgia) occurred at a rate of less than 1 AE per patient, as previously described under AEs. Infusion site pain was the most frequently occurring infusion-related AE (1.14 AEs per patient). Infusion site discomfort, infusion site erythema, and infusion site pruritus occurred at a rate of less than 1 AE per patient. For local reactions, swelling/edema and contact dermatitis were reported at a rate of less than 1 AE per patient, as were infusion site hypersensitivity and thrombotic events. No cases of hypersensitivity, anaphylaxis, thrombocytopenia, acute kidney injury, or aseptic meningitis were reported for patients receiving IgHy10 during epoch 2.

While receiving IgHy10 during the safety extension Study 160902, the notable harms related to systemic effects, local reactions, drug hypersensitivity, hypersensitivity, and thrombocytopenia were reported at a rate of less than 1 AE per patient. Infusion-related AEs were also reported at a rate of less than 1 AE per patient, with the exception of infusion site pain, which occurred at a rate of 1.33 AEs per patient. No cases of infusion site hypersensitivity, anaphylaxis, thrombotic events, acute kidney injury, or aseptic meningitis were reported for patients receiving IgHy10 during the safety extension Study 160902.

Table 30: Summary of Harms in Study 160603 and Study 160902 (SAS)

AE = adverse event; IgHy10 = normal immunoglobulin (human) 10% and recombinant human hyaluronidase; IVIg = intravenous immunoglobulin; NA = not applicable; NR = not reported; SAE = serious adverse event; SC = subcutaneous; SCIg = subcutaneous immunoglobulin.

^aAE reported at a rate ≥ 0.40 per patient in any treatment group.

^bIncludes SAEs that occurred during the ramp-up period. In total, 11 patients experienced an SAE while receiving IgHy10; 3 of these SAEs occurred during the ramp-up period.

^cSAEs were reported using the IgHy10 plus safety follow-up (n = 66) dataset.

^dDeaths were reported using the IgHy10 plus safety follow-up (n = 66) dataset. One of the deaths occurred 4 weeks after completion of the study.

Source: Clinical Study Reports.^15,16

Table 31: Summary of the Most Commonly Reported Harms That Occurred After the Ramp-Up in Epoch 2 by Percentage of Patients and Rate of AEs per Infusion in Study 160603 (SAS)

AE = adverse event; IgHy10 = normal immunoglobulin (human) 10% and recombinant human hyaluronidase; NR = not reported; SAS = safety analysis set.

^aFrequency ≥ 10% of patients or ≥ 0.01 AEs per infusion.

Source: Clinical Study Report.¹⁵

Critical Appraisal

Internal Validity

The IgHy10 pivotal trial was a non-randomized, open-label, single-group, prospective study design. Due to the uncontrolled study design, randomization was not possible. Patients in Study 160603 were enrolled in 1 of 2 study arms based on participation in a prior pharmacokinetic study (Study 160601). Of the 87 patients included in the study, 31 had previously received IVIg and cSCIg through participation in Study 160601 and the data collected during that study were used for epoch 1 of Study 160603. The remaining 56 patients proceeded with IVIg treatment as part of epoch 1. Whether there are inherent differences between the patients included in study arms 1 and 2 or the care they received is unknown. Most of the outcomes of interest for this review, including the primary end point of Study 160603, were not expected to suffer from its open-label design; however, patient-reported outcomes such as those related to HRQoL, tolerability and adherence, and safety outcomes, may have been impacted based on patient beliefs about IgHy10. It is unknown whether knowledge of treatment would have caused bias in favour of or against IgHy10.

As a single-group study design, neither a historical control nor a concurrent comparator group was used in either Study 160603 or the subsequent Extension Study 160902. Consequently, there is substantial uncertainty associated with inferring causality associated with the outcomes reported in the trials. For example, it is unknown whether the number of VASBIs reported, which informed the primary end point, were solely the result of treatment with IgHy10, as potential confounding factors were not accounted for. Prior to receiving IgHy10 (epoch 2), patients had received treatment with IVIg in epoch 1, during which safety and efficacy data were collected; however, Study 160603 was not designed to compare IVIg with IgHy10 treatment, except for pharmacokinetics (IgG trough levels). Further, the duration of treatment with IVIg was much shorter (3 months) than with IgHy10 (14 to 18 months), which would have subjected any comparisons to limitations related to seasonality or year-to-year variation.

Missing data were not accounted for in either the pivotal study or the extension study. The statistical techniques employed in the 2 studies did not require imputation of missing data, as the methods used accounted for the length of time each patient spent in the study. Despite this, the risk of attrition bias is still a concern due to the overall discontinuation rate in Study 160603, where 21% of patients discontinued from the study. The impact of discontinuation rates was greater for patients in the 2 years to younger than 12 years group (N = 14) in Study 160603, where 43% of patients discontinued from the study either due to a requested withdrawal (29%) or an AE (14%). As a result, the reported study results are likely biased in favour of IgHy10, as the data analyzed is largely based on patients who did not discontinue from the study.

In general, the efficacy outcomes assessed in the pivotal study and extension study were considered appropriate based on feedback from the clinical experts consulted for this review. A validated definition of acute serious bacterial infections was used for the primary end point in Study 160603. In terms of clinical context, reporting of serious bacterial infections was restricted to VASBIs. This was seen as a limitation by the clinical experts, as non-acute infections were not specifically reported. Chronic infections that were considered clinically relevant, such as sinusitis, recurrent ear infections, and gastroenteritis, were likely captured under the secondary end point, annual rate of all infections; however, infections were not reported with that level of detail (acute versus chronic, or duration of infection). The clinical experts noted that the chronic infections described can be serious and require urgent intervention or a long course of antibiotics.

The other efficacy outcomes were objective/clinical (e.g., IgG trough levels, days on antibiotics) or based on validated measures, such as the HRQoL outcomes assessed using the PedsQL and SF-36. Evidence of validity, reliability, and responsiveness was identified for both the PedsQL and SF-36, but not specifically in patients with immunodeficiency.

Although the selection of outcome measures reported in the studies was considered appropriate, the methods of analysis used were associated with limitations that hindered the ability to meaningfully interpret the outcomes. The analysis of the primary end point, annual rate of VASBI, is an exception, as the analysis was aligned with FDA guidance for industry¹¹ that states “a statistical demonstration of a serious infection rate per person-year less than 1.0 is adequate to provide substantial evidence of efficacy.” Statistical testing was used only for the primary end point in Study 160603; therefore, multiplicity was not an issue. Within-group changes were generally not reported, as results were analyzed as a rate or descriptively summarized for the observation period.

Both the patient and clinician input received for this review highlighted HRQoL as an important consideration for the treatment of primary and secondary humoral immunodeficiencies. The HRQoL outcomes included in the 2 studies were exploratory outcomes reported as a median (range) for each treatment period that did not offer the ability to draw any conclusions about a change in HRQoL with IgHy10. The HRQoL outcomes were reported by subgroups based on age, although they were limited by a small sample size, particularly for patients younger than 14 years old (N < 10). Additionally, HRQoL was reported using different outcomes for patients aged 8 to 13 years; in Study 160603, the PedsQL was used, whereas the SF-36 was used in the extension study.

The assessment of safety in the 2 studies was also challenging to interpret in a clinically meaningful way. The proportion of patients who experienced at least 1 AE was not reported in Study 160603, but the proportion of patients experiencing a local AE was available. The proportion of patients experiencing an AE (as defined by MedDRA) was reported as well, but only for patients receiving IgHy10 after the ramp-up period in Study 160603. Also, the majority of the safety outcomes were reported as a rate per patient or per infusion. While this may account for varying duration of treatment in each of the reported observation periods, the proportion of patients experiencing a particular AE is unknown, with the exception of the AEs commonly reported during treatment with IgHy10 in Study 160603.

External Validity

The pivotal trial (Study 160603) and extension study (Study 160902) were primarily located in the US, with 1 study site located in Canada, and were conducted between 2008 and 2013. The clinical experts consulted by CADTH felt the studies conducted in the US were generalizable to patients in Canada and that the age of the study was not a concern. They did note, however, that there has been a recent shift in the use of IVIg compared with SCIg, with the latter being used more commonly.

The patients included in Study 160603 and 160902 were required to have been diagnosed with a PID that required antibody replacement therapy and to have been receiving regular IgRT for at least 3 months before enrolment, and their last documented serum IgG trough level had to be greater than 4.5 g/L. The clinical experts consulted by CADTH did not have any concerns regarding the safety and efficacy of IgHy10 in terms of generalizing the evidence to patients with secondary humoral immunodeficiency, IgRT-naive patients, or patients with lower serum IgG levels. The sponsor also noted the guidance from Health Canada regarding the regulatory requirements for IVIg states that indications for SID can be accepted based on the evidence for a PID therapy⁴⁹; however it is unclear whether this policy would apply to a novel, subcutaneous, combination product such as IgHy10.

Certain patient groups were excluded from the included trials, such as pregnant or lactating females, patients with IgA deficiency, patients who were required to remain on prophylactic systemic antibacterial antibiotics, and patients with various pre-existing conditions. The clinical experts indicated a significant proportion of patients with primary or secondary humoral immunodeficiency plus pre-existing conditions would be treated prophylactically with antibiotics; thus, the patient groups that were excluded from the trials would not be excluded from treatment with IgHy10. The clinical experts consulted by CADTH did not express concern with applying the results of the included studies to these patients.

Patients received IgHy10 (75 U/g rHuPH20 followed by SCIg 10%), administered at 108% of the monthly total IVIg dose used in epoch 1 every 3 or 4 weeks.¹⁰ The setting of the dose of SCIg to 108% of the dose of IVIg was based on a phase II pharmacokinetic study.¹⁴ This differs from the recommended dosing in the Health Canada product monograph, which is to follow the previous dose of IgRT administered. However, dose adjustments are made at the discretion of the treating physician in clinical practice; therefore, whether this is a major concern regarding the generalizability of the evidence is unknown. Prior to administration of IVIg or SCIg, concomitant use of prophylactic antibacterial antibiotics and pre-medications was avoided during the studies, if possible. However, because concomitant use of these medications is consistent with clinical practice, such avoidance may have exaggerated the reported tolerability and safety outcomes compared with what is expected in clinical practice. Administration of IgHy10 was either performed at home or an infusion centre, or under permanent medical supervision at the clinical study site. Patients who administered IgHy10 at home or at an infusion centre were observed by a health care professional until at least the fifth or sixth infusion, after which the ability to administer treatment without observation was evaluated. As per feedback from the clinical experts, an at-home training/support system would be implemented to facilitate the administration of IgHy10 at home, but the level of supervision in the trials exceeds expectations for clinical practice. The impact of this on the performance of IgHy10 and in relation to what would be expected in clinical practice is unknown.

The duration of treatment with IgHy10 in Study 160603 was 14 to 18 months, with a mean duration of treatment of approximately 1 year (368 days; SD = 104). This was sufficient to evaluate the primary outcome and most of the other outcomes assessed in the study. However, because IgRT is a lifelong treatment, there may not have been enough time to capture long-term outcomes, such as risk of malignancies. Study 160902 was designed as a long-term safety and tolerability study for IgHy10. Patients in the study received IgHy10 for a mean of 566 days (SD = 212), which was an acceptable duration of treatment to generate sufficient data to supplement the safety outcomes data reported in the pivotal trial.

Indirect Evidence

Indirect evidence matching the inclusion and exclusion criteria of this review was not submitted by the sponsor or identified in the CADTH literature review.

Other Relevant Evidence

This section includes 2 submitted phase IV single-arm studies and 1 pregnancy registry study. These were provided within the sponsor’s submission to CADTH that were considered to address important gaps in the evidence included in the systematic review. The single-arm phase IV trials provide further evidence on the safety and tolerability of IgHy10 in children, and an assessment of IgG trough levels among patients switching from SCIg to subcutaneous IgHy10 every other week. The pregnancy registry study provides information on the potential harms of IgHy10 in pregnant women and their infants.

Sponsor-Submitted Study in Adult Patients Switching From CSCIg to IgHy10 (NCT02881437)

Description of Study

NCT02881437 was a phase IV, open-label, non-randomized, single-group prospective study,¹⁷ which filled an important gap in the comparison of cSCIg to IgHy10. The primary objective was to examine the difference in steady-state IgG trough levels among adults (18 years or older) with a PID requiring IgRT during cSCIg treatment (primarily once weekly) compared with the steady-state IgG trough levels after switching to IgHy10 administration every other week at equivalent doses. Full details of the study are in Appendix 5, Table 39. Among the 22 enrolled patients, the median age was 45.0 years (IQR = 32.0 to 54.0), and 68.2% were female. Appendix 5 shows the full baseline characteristics (Table 40) and patient disposition (Table 41).

The study began with a 1-week ramp-up period (subcutaneous IgHy10 provided at 1-quarter of the usual monthly cSCIg dose) which started 1 week after the last cSCIg infusion before enrolment. Subcutaneous IgHy10 infusions then occurred every 2 weeks at 1-half of the initial monthly SCIg dosage, with follow-up measurements at 3 and 6 months. Full details of prior treatment with cSCIg and exposure to IgHy10 are shown in Appendix 6, Table 42 and Table 43.

Outcomes of interest were change in IgG trough level, HRQoL (SF-36), and AEs.

Results

Table 44 in Appendix 5 shows the full details of the change in steady-state IgG trough level when switching from cSCIg to IgHy10. The mean change in steady-state IgG trough level when switching from cSCIg to IgHy10 was –0.30 g/L (SD = 1.54) after 3 months, and –0.29 g/L (SD = 1.35) after 6 months (n = 16).

A total of 11 of 19 patients (57.9%) had at least 1 infection in the first 3 months of follow-up, corresponding to an incidence of 0.34 (95% CI, 0.22 to 0.54) infections per month. Infection was reported among 8 of 17 patients (47.1%) at between 3 and 6 months of follow-up, corresponding to an incidence of 0.22 (95% CI, 0.10 to 0.48) infections per month.

The mean change in the physical component summary of the SF-36 was −0.90 (SD = 4.37) from baseline to 3 months and −2.67 (SD = 5.17) from 3 to 6 months (n = 12); the mean change in the mental component summary was −2.67 (SD = 5.17) from baseline to 3 months and 1.33 (SD = 5.13) from 3 to 6 months (n = 14).

A detailed record of the reported AEs is provided in Table 45. A total of 21 of 22 patients (95.5%) reported at least 1 local AE, and all reported at least 1 systemic AE between baseline and 3 months of follow-up; 12 of 22 patients (66.7%) reported at least 1 local AE and 16 of 22 (88.9%) reported at least 1 systemic AE between 3 and 6 months follow-up. Commonly reported AEs were similar to those in the pivotal studies.

Critical Appraisal

There are several internal validity concerns that limit the certainty of the conclusions that can be drawn. The primary concern is that there is no control group and confounders are unaccounted for; thus, causal relationships cannot be established. Though the inclusion and exclusion criteria are clear, some details of the disposition of the participants are limited (i.e., number screened versus randomized). The open-label design is likely to have biased the subjective end points; however, the direction of bias is unclear. There were large losses to follow-up (6 of 22; 37%), which reduces the reliability of the findings for HRQoL. Statistical analyses were not adjusted for multiplicity.

Despite some differences in setting (all study centres were located in France) and a narrower eligible population than would be seen in clinical practice, the clinical experts consulted by CADTH did not express concern in generalizing the evidence to adult patients in Canada; the applicability of the evidence to children is less clear. Exposure to study treatments appeared to match the product monograph, aside from the ramp-up phase (not described in the monograph). Outcomes were clinically relevant, though the clinical experts indicated they would not rely on IgG trough levels alone for clinical decision-making. The sample size and length of follow-up may have been inadequate to capture rare or long-term harms.

Sponsor-Submitted Study of Safety, Tolerability, and Immunogenicity of IgHy10 in Pediatric Patients (Study 161504, Interim Analysis)

Description of Study

Clinical Study 161504 was a phase IV, open-label, non-randomized, single-group prospective study¹⁸ that provided further post-authorization safety, tolerability, and immunogenicity data on IgHy10 among 42 pediatric patients (2 to < 18 years old) with primary humoral immunodeficiency requiring IgRT. The findings are based on a planned interim analysis after 75% of patients had completed 1 year of study in epoch 2.¹⁹ Full details of the study are in Appendix 6, Table 46. Patients who were naive to SCIg (n = 23; 54.8%) had a mean age of 10.3 years (SD = 3.8); the group was 78% male and 96% White. The characteristics of patients with prior SCIg exposure (pre-treated) were similar.

Patients naive to fSCIg were enrolled in a maximum 6-week ramp-up period where they were introduced to IgHy10 infusions (epoch 1). In epoch 2, IgHy10 treatment continued for up to 3 years. After 1 year in epoch 2, patients with an anti-rHuPH20 titre of 160 or lower at any time proceeded to study completion; others continued on treatment for another 2 years. Patients with an anti-rHuPH20 titre of 160 or higher who experienced an SAE or severe AE continued in a safety follow-up (epoch 3), where IgHy10 was discontinued and patients continued with IVIg or cSCIg. The exact details of the treatment regimens are not available. At the time of the interim analysis, 22 patients (52.3%) had completed the study, 17 (40.5%) were ongoing, and 3 (7.1%) had discontinued prematurely. At the time of the interim analysis, patients had received a mean of 12.5 infusions (SD = 6.9), with a median of 1.2 infusions per month (range = 0.5 to 7.6). The median infusion volume was 95.0 mL per site and the maximum infusion rate was 200.0 mL per hour per site.

Outcomes of interest were change in IgG trough level, immunogenicity, and AEs. Serious acute bacterial infections were not pre-specified but were reported. Details of the statistical analyses were unavailable.

Results

The mean IgG trough level was 9.6 mg/dL (SD = 2.1) at enrolment and 8.2 mg/dL (SD = 2.9) at 12 months. Full details of treatment-emergent infections are in Table 47 in Appendix 6. In total, 31 out of 42 patients (73.8%) experienced at least 1 treatment-emergent infection. One patient (2.4%) had a serious acute bacterial infection.

A detailed account of recorded AEs is provided in Table 48. Of 42 enrolled patients, 27 (64.3%) reported at least 1 AE. Eleven patients (26.2%) experienced at least 1 local AE, 24 (57.1%) experienced at least 1 systemic AE, and 4 (9.5%) experienced at least 1 SAE. Across all treatments (n not reported), 7.4% of infusions were stopped, interrupted, or adjusted due to an AE. No patients developed an anti-rHuPH20 antibody titre of 160 or greater.

Critical Appraisal

There are several internal validity concerns that limit the certainty of the conclusions that can be drawn. The primary concern is that there is no control group and confounders are unaccounted for; thus, causal relationships cannot be established. No statistical hypothesis testing was conducted. Interim findings of safety and efficacy should be interpreted cautiously, as these findings could overestimate the benefits and/or underestimate the harms of a treatment.^20,21 Though the inclusion and exclusion criteria are clear, some details of the participant disposition are limited (i.e., number screened versus randomized). The open-label design is likely to have biased the subjective end points; however, the direction of the bias is unclear. It is not fully clear how outcomes were defined and collected, and “treatment-emergent infections” were not pre-specified in the study protocol. The small sample size may negatively impact the reliability of the findings.

Despite some differences in setting (all study sites were located in Europe) and a narrower eligible population than would be seen in clinical practice, the clinical experts consulted by CADTH did not express concern in generalizing the evidence to pediatric patients in Canada; the applicability of the evidence to adults is less clear. Dosing information was not provided. Outcomes were clinically relevant, though the clinical experts indicated they would not rely on IgG trough levels alone for clinical decision-making. The sample size was likely too small to capture rare harms.

Sponsor-Submitted Study on Safety of IgHy10 in Pregnant Women and Their Infants (Registry Study 161301)

Description of Study

Study 161301 was a registry study providing safety data on women who had previously received treatment with IgHy10 and their infants⁵⁰ — a population excluded from the pivotal studies. All pregnant women who had ever been treated with IgHy10 were eligible in 1 of 2 study arms: continued IgHy10 during pregnancy (IgHy10 arm) and switched to another IgRT or alternative treatment (alternative product arm). Full details of the study are in Table 49. Nine mothers were enrolled; they had a median age of 34.0 years (IQR = 32.0 to 36.0), were primarily non-Hispanic and non-Latino (8 of 9; 88.9%), and all were White/Caucasian. Seven of the mothers’ infants were enrolled. The detailed characteristics of the mothers and their infants are in Appendix 7 (Table 50 and Table 51; patient disposition is in Table 52). Patients visited their own physicians and were treated according to routine medical practice. Data on IgHy10 treatment were available for 6 mothers (85.7%) in the IgHy10 arm. Among these, the median number of infusions was 4 (IQR = 1.5 to 5.75); infusions were received on a 3- or 4-week interval. Full details of exposure to IgHy10 are in Appendix 7 (Table 53 and Table 54).

Outcomes of interest were AEs (mothers and infants) and the development of anti-rHuPH20 antibodies (mothers). In addition, outcomes related to pregnancy and infant development were assessed. Full details of the statistical analysis are in Appendix 7.

Results

A full description of the AEs reported during the study is in Appendix 7 (Table 55). Among the 9 mothers, 4 (44.4%) reported at least 1 AE; 3 (42.9%) mothers in the IgHy10 arm and 1 (50.0%) in the alternative product arm. There were no local or immunologic AEs. One (11.1%) mother in the IgHy10 arm reported SAEs. There were no AEs leading to death or WDAEs. Four (44.4%) mothers (2 in each arm) were assessed for anti-rHuPH20 antibody titres, and all were negative (titre of less than 160). Eight (88.9%) mothers provided data on pregnancy outcomes; all were live births. One birth in the IgHy10 arm was considered abnormal because it was a Caesarean section.

Infants were born at a median gestation of 38.0 weeks (IQR = 37.0 to 40.0); weight, length, and head circumference were normal for all. Two (40.0%) infants in the IgHy10 arm had congenital malformations. During follow-up, 6 infants (85.7%) experienced at least 1 AE: 5 (100%) in the IgHy10 arm and 1 (50.0%) in the alternative product arm. Two (40.0%) infants in the IgHy10 arm experienced an SAE. There were no AEs leading to death or a WDAE.

Critical Appraisal

There are several internal validity concerns that limit the certainty of the conclusions that can be drawn. The primary concern is that there is no control group and confounders are unaccounted for; thus, causal relationships cannot be established. There was no statistical hypothesis testing. Selection bias is possible, as very few mothers (n = 9) were enrolled, and it is not clear whether women from various centres would differ systematically. As this is an open-label study, subjective end points may be biased; however, the direction of the bias is unclear. Most of the data were collected retrospectively, which may have negatively affected quality and completeness. In the IgHy10 arm, 29% of mothers were lost to follow-up, which may have biased AE data in favour of IgHy10.

Despite some differences in setting (study sites were in Europe and the US) and a narrower eligible population than would be seen in clinical practice, the clinical experts consulted by CADTH did not express concern in generalizing the evidence to patients in Canada. The dosage and administration of IgHy10 appear to align with the Health Canada–approved dosing; however, pregnant women are not an indicated population in the product monograph. The harm outcomes seem to be clinically important, but no efficacy outcomes were collected. The sample size and length of follow-up were likely inadequate to capture rare and/or long-term AEs.

Post-Authorization Safety Studies and Patient Registry Study

Results from 2 PASSes, Global PASS (NCT02593188)²² and EU PASS (EUPAS5812),^23,24 and a patient registry study, FIGARO (NCT03054181),^25-27 were submitted by the sponsor as supportive evidence. Both the Global PASS (N = 264) and EU PASS (N = 106) were non-interventional, prospective, uncontrolled, open-label, multi-centre PASSes that evaluated the long-term safety of IgHy10 under clinical routine conditions in the US and Europe, respectively. The Global PASS study was conducted between 2015 and 2021 and enrolled patients with a PID. The EU PASS study was conducted between 2014 and 2021 and enrolled patients who had been prescribed treatment for a PID or SID. The Global PASS reported that 56% of 909 infusions were self-administered at home. The EU PASS reported the proportion of treatments that were administered at a clinical site and at home by year since the first fSCIg treatment. During the first, second, and third year, and after the third year, 91.2% (n = 83 patients; 909 infusions), 93.2% (n = 556 patients; 600 infusions), 93.2% (n = 28 patients, 237 infusions), and 85.2% (n = 12 patients; 54 infusions) of treatments were administered at home, respectively. FIGARO was a long-term observational study on the utilization and outcomes of IgHy10 under everyday clinical practice conditions. FIGARO was conducted in Europe between 2016 and 2021 and enrolled 156 patients with a PID or SID. Data were available for 154 patients, of which 13 were pediatric (younger than 18 years), 120 were adults (18 to 64 years), and 21 were older adults (at least 65 years); results were analyzed by patient age. FIGARO reported that 81.7% of adults and 57.1% of older adults infused at home.

The results provided by the sponsor for infusions administered at home in Global PASS, EU PASS, and FIGARO suggest that the ability to administer treatment at home was more successful in a real-world setting than in the clinical trial setting. However, the generalizability of this evidence to patients treated in Canadian clinical practice is unknown. Additionally, the interpretation of the additional evidence should take into consideration the limitations associated with real-world evidence studies.

Post Hoc Analysis

The sponsor submitted a post hoc analysis by Wasserman et al., 2021,²⁸ as supportive evidence. The analysis examined 3 consecutive, open-label, uncontrolled clinical studies of IgG therapy. Each of the studies included a subset of patients with primary immunodeficiency. Two of the 3 studies, Study 160603 and Study 160902, informed CADTH’s systematic review of HyQvia. The retrospective post hoc analysis included 30 patients who had received at least 1 infusion of each type of therapy, i.e., IVIg, cSCIg, and fSCIg, and was designed to evaluate the efficacy (rates of infection) and tolerability of the 3 routes of IgG administration. The duration of exposure, total number of infusions, and mean IgG dose received during a 4-week period differed between the 3 treatments. As noted in the publication, the limitations of the study include a small sample size; selection bias, as study participation was voluntary; and year-to-year variations in community infections and other factors that change over time, which cannot be accounted for in a sequential study design. The post hoc analysis concluded that across the 3 treatment modalities (IVIg, cSCIg, and fSCIg), annualized rates of VASBI (0, 0.09, and 0.04, respectively) and all infections (4.17, 3.68, and 2.42, respectively) were similarly low.

Discussion

Summary of Available Evidence

Two sponsor-submitted, phase III, open-label, non-randomized, single-group, prospective studies were included in this review. Study 160603 (N = 89) evaluated the efficacy and tolerability of IgHy10 in patients who were at least 2 years of age with a PID that required antibody replacement therapy. The patients who were enrolled in Study 160603 were between the age of 4 and 78 years, and the patients who continued to Study 160902 were between the ages of 9 and 80 years. All patients were also required to have a serum IgG trough level greater than 4.5 g/L and to have been receiving regular IgRT for at least 3 months before enrolment. Study 160902 (N = 66) was an extension of Study 160603 that evaluated the long-term tolerability and safety of IgHy10. The safety extension also followed patients for delayed adverse reactions following discontinuation of hyaluronidase.

Study 160603 consisted of 2 epochs. During epoch 1, patients received IVIg 10% for 12 weeks. In epoch 2, patients received IgHy10 (75 U/g rHuPH20 followed by SCIg 10%), administered at 108% of the monthly total IVIg dose every 3 or 4 weeks, for 14 to 18 months. The primary end point in Study 160603 was serious acute bacterial infection rate, defined as the mean number of VASBIs per patient per year. The annual rate of all infections, immunoglobulin levels, antibiotic use, health care utilization, productivity, HRQoL, tolerability, and safety were also evaluated. Safety outcomes, including those related to tolerability concerns and AEs, were evaluated in Study 160902; the efficacy outcomes that were evaluated in Study 160603 were also evaluated.

In addition to the 2 sponsor-submitted studies previously described, 2 phase IV single-arm studies and 1 pregnancy registry study were reviewed and critically appraised. The single-arm phase IV trials provided further evidence on the safety and tolerability of IgHy10 in children, and an assessment of immunoglobulin trough levels among patients switching from SCIg to subcutaneous IgHy10 every other week. The pregnancy registry study provided information on the potential harms of IgHy10 in pregnant women and their infants. The results are summarized in the Clinical Evidence section (under Other Relevant Evidence) of this report.

Interpretation of Results

Efficacy

Patients living with primary and secondary humoral immunodeficiency are unable to produce an adequate immune response because the components of the immune system, specifically the antibodies, are either absent or functionally inadequate. As a result, primary and secondary humoral immunodeficiency predispose affected patients to an increase in the frequency and severity of infections, autoimmunity, and malignancy. The standard of therapy for the treatment of these patients is the use of IgRT, with the goal of treatment being the prevention of infections leading to an improvement in HRQoL, preserved function, and prevention of hospitalizations. The goal of treatment is also to reduce morbidity and mortality related to disease and minimize disruptions to the patient’s life; the latter was identified as an outcome of strong importance to patients through the patient input received for this review.

Of note, the evidence summarized in this review does not include patients with secondary humoral immunodeficiency. The clinical experts consulted by CADTH did not express any issues with using evidence in patients with primary humoral immunodeficiency to inform treatment decisions for patients with secondary humoral immunodeficiency. Additionally, there was no comparative evidence for IgHy10 versus other available IgRTs.

In Study 160603, 2 VASBIs were reported during 14 to 18 months of treatment with IgHy10. Both cases were episodes of bacterial pneumonia that were treated with oral antibiotics without hospitalization.¹² This corresponded to a rate of VASBIs per year of 0.025 (upper limit of the 99% CI, 0.046), thus meeting the primary end point of the study. The clinical experts for this review agreed that the reported rate of VASBIs in patients with a PID was aligned with what would be expected for patients receiving IgRT treatment. The rate of VASBIs per year before the safety follow-up period was similar among the 66 patients who continued to extension Study 160902 (rate of 0.020; upper limit of the 99% CI = 0.045). The rate of VASBIs was not analyzed during treatment with IVIg, but the rate of all infections was reported. The rate of all infections per patient per year was 2.97 (95% CI, 2.51 to 3.47) and 2.86 (95% CI, 2.36 to 3.43) during treatment with IgHy10 in Study 160603 and 160902, respectively. This was lower than the rate of all infections reported during treatment with IVIg in the pivotal trial, which was 4.51 (95% CI, 3.50 to 5.69). While we cannot statistically compare the infection rates reported during treatment with IgHy10 and treatment with IVIg, as the study was not designed to assess this, the rates appear to be lower when patients were treated with IgHy10. It is unknown whether this is an artifact of the different time periods or the different characteristics of the population as confounders such as temporal factors were not accounted for. Additionally, the results of a post hoc analysis of the annual rate of infections and annual rate of VASBIs during IgHy10 treatment were reported by age group (< 18 years and ≥ 18 years old).¹³ The annual rate of infections and annual rate of VASBIs in adult patients (≥ 18 years old) were consistent with the results reported for each of the individual studies.

The pivotal study and extension study included assessments of IgG trough levels. The clinical experts consulted by CADTH indicated that IgG levels are routinely assessed and useful as a reference point; however, treatment decisions are predominantly based on clinical assessments of the patient as opposed to relying solely on laboratory values. The median serum IgG trough level at baseline was approximately 10 g/L, which is aligned with published recommendations for treatment with IgRT.⁵ In Study 160603, the median IgG trough levels were maintained in both pediatric patients and patients who were at least 12 years of age or older over approximately 1 year of treatment. In the extension study, IgG trough levels were analyzed by infusion interval. Of note, patients were asked to increase the frequency of IgHy10 administration to a 2-week or 3-week interval to assess IgG levels following a change in administration frequency. In summary, the steady-state IgG trough levels were maintained for approximately 4 months at a median of at least 10 g/L despite changes to the administration frequency, although this is based on a small sample size of patients. Further, the ratio of IgG trough levels measured at the end of the safety follow-up period compared with the IgG trough levels measured at the end of IgHy10 treatment indicated that, following discontinuation of hyaluronidase, IgG levels were maintained or increased, with the exception of a switch to IVIg following administration of IgHy10 at a 2-week interval, where IgG levels decreased. Most of the assessments were based on a small sample size (between 3 and 38 patients) and statistical testing was not conducted, preventing any further conclusions from being drawn.

Outcomes related to antibiotic use, health care utilization, and productivity were of importance to clinicians and patients and were included in studies 160603 and 160902. While receiving treatment with IgHy10 in Study 160603, the rate of days off per month from either work or school was less than 1 day per month; no patients were hospitalized during treatment with IgHy10, and the rate of acute care physician visits was less than 1 visit per month. These outcomes suggest minimal disruption to the everyday life of patients and few days spent in hospital, which were key outcomes of interest for this review; however, the lack of historical data for the patients enrolled in the studies and the lack of a comparator group make it difficult to appropriately interpret these outcomes. Similar assessments conducted in the extension study yielded comparable results. The rate of days on antibiotics while on treatment with IgHy10 was also reported, which was less than 2 days per month in Study 160603 and 64 days per year (approximately 5 days per month) during the extension study. The clinical experts consulted by CADTH indicated that the rate of antibiotic use during treatment with IgHy10 in both studies was higher than expected, noting that it is atypical for patients to use antibiotics every month.

Another outcome that was of importance to patients was HRQoL. Two age-appropriate, validated outcomes, the PedsQL and SF-36, were used to assess HRQoL at the end of each epoch or observation period in both of the included studies. A significant limitation of the HRQoL data are the failure to evaluate outcomes as a change over time (i.e., at the start and end of treatment with IgHy10), especially considering the study was not designed to assess a comparison between epoch 1 (treatment with IVIg) and epoch 2 (treatment with IgHy10), and there was no other comparison group. As a result, no conclusions regarding HRQoL can be drawn from the available evidence.

The evidence that has been summarized so far suggests that in a clinical trial setting, IgHy10 seems to result in a rate of VASBIs that is similar to what might be expected with any IgRT; IgHy10 therapy also seems to maintain trough IgG levels and results in few visits to health care and disruptions to patient lives. However, the absence of comparative evidence for IgHy10 is a major limitation in the context of this review, as other SCIg and IVIg products are currently available in Canada. There is significant uncertainty associated with inferring causality of the reported results in studies 160603 and 160902, and there is no evidence on how IgHy10 performs compared with other available IgRTs. One of the key advantages that was anticipated for IgHy10 was the ability to administer treatment at home and less frequently than cSCIg, thereby improving the convenience and minimizing the impact of treatment on a patient’s life. The clinical experts consulted by CADTH indicated they expected that the majority of patients (more than 90%) would be able to self-administer IgHy10 at home, a level similar to what they had observed with cSCIg in clinical practice. The results from the extension, Study 160902, did not indicate this, as 64% of patients and 52% of infusions required assistance and were unable to continue self-administration of infusions at home. Also of note, 75.0% of all infusions in Study 160603 were administered at an investigational site. Of the 25% of infusions that were administered at home, 82% (20.5% of all infusions) were administered without nurse intervention (as opposed to 4.5% that were administered at home with intervention by a nurse). Some of the infusions were required to be administered at the investigational site, but the proportion of infusions this applies to is unknown, based on the data available.

From an implementation perspective, clinicians and decision-makers were interested in understanding how the efficacy of IgHy10 compares with the other available forms of IgRT, and cSCIg in particular, to determine the place in therapy. Again, conclusions cannot be drawn based on the evidence identified for this review that does not include comparative studies. This is a major limitation of the evidence identified for this review. There are many other SCIg and IVIg drugs available, and IgHy10 was viewed as another SCIg option by the clinical experts.

Three other studies did not meet the inclusion criteria of the CADTH review but were considered relevant in terms of addressing gaps in the evidence. In 1 study, patients did not experience a clinically meaningful change in IgG levels or HRQoL (measured by the SF-36) over a 6-month period. The other 2 studies provided additional safety evidence and have been described in the following section of the report.

Harms

One of the putative features of IgHy10 was that it possesses the benefits of both cSCIg (i.e., a favourable safety profile, particularly in terms of minimal systemic AEs) and IVIg (i.e., less frequent administration schedule). A total of 2 deaths were reported across the pivotal and the extension study; both occurred during Study 160902. One death was caused by toxicity to various drugs and the other by cardiac arrest; neither death was considered related to the study treatments. SAEs were reported infrequently. A total of 22 of 89 patients reported an SAE in studies 160603 and 160902. Two SAEs due to chronic obstructive pulmonary disease were reported, which were the only SAEs that were reported more than once.

The overall rate of AEs while receiving IgHy10 was 13.40 per patient during Study 160603 and 19.75 per patient during the extension study, where the mean duration of treatment was approximately 1 year and 1.5 years, respectively. In contrast, the rate of AEs was 4.45 per patient during treatment with IVIg in Study 160603, and 7.78 per patient during the safety follow-up with IVIg or SCIg without hyaluronidase during the extension study. The overall rate of AEs was driven by the rate of systemic AEs during treatment with IgHy10, which was not aligned with the expectations of the clinical experts consulted by CADTH. A notable limitation of this evidence is that the proportion of patients reporting an AE is limited to epoch 2 of Study 160603. For patients receiving IgHy10 following the ramp-up period in Study 160603, 53% of patients experienced at least 1 local AE. The most common AEs were infusion site pain (33% of patients), infusion site erythema (12%), and infusion site discomfort (10%). The proportion of patients with at least 1 systemic AE was not reported, but headache (30% of patients), asthma (17%), nausea (14%), pyrexia (14%), and fatigue (14%) were the most frequently reported individual systemic AEs. Again, the clinical experts indicated that the rate and proportion of patients reporting systemic AEs with IgHy10 was much higher than what is observed in clinical practice with cSCIg treatment. This suggests that IgHy10 may not offer a safety profile similar to cSCIg, as was anticipated; however, this is unknown without comparative evidence. Additionally, a post hoc integrated analysis of safety outcomes from Study 160603 and Study 160902 reported systemic AEs and local AEs among adult patients (aged ≥ 18 years) specifically. The rate of AEs in adult patients was similar to what was reported for the overall population in the individual studies, which included patients younger than 18 years of age, as well.

It should also be noted that temporally associated AEs (summarized in Appendix 4) were aligned with the results that have been discussed, but limited to data for overall AEs, local AEs, and systemic AEs. As noted by the clinical experts, the majority of patients treated with cSCIg administer treatment at home or without supervision from a health care professional, which was not the case in the included studies. The increased level of supervision may have impacted the frequency of AEs reported during the trial; however, whether AEs were overestimated in the trial or the AEs were underreported in clinical practice is unknown.

Two of the 3 other relevant studies summarized in this review provided additional safety data in pediatric patients and pregnant patients and their infants. Study 161504 (N = 42) was a single-arm phase IV trial that was conducted to collect post-authorization safety, tolerability, and immunogenicity data on the use of IgHy10 in pediatric patients. The most frequently reported AEs were cough (29% of patients), infusion site pain (17%), and pyrexia (14%). Evidence of immunogenicity (anti-rHuPH20 antibodies) was not observed in any patients. Additionally, only 1 patient experienced a serious acute bacterial infection. Study 161301 was a post-marketing pregnancy registry study designed to collect clinical safety data on the course and outcome of pregnancy among women who had ever been treated with IgHy10, and their infants. Overall, no major safety signals were observed; however, this is based on a very small sample size (fewer than 20 patients). Lastly, NCT02881437 (previously described) did not suggest any new safety signals associated with IgHy10 following a switch from cSCIg, based on physician record data.

The 2014 FDA assessment of IgHy10 summarized the safety profile of IgHy10 as being acceptable.⁵¹ Further, the FDA described the short-term risks as acceptable, but the long-term risks associated with antibodies to rHuPH20 remain unknown. The FDA report noted that Study 160603, Study 160902, and Study 160601 included a total of 26 pediatric patients (defined as patients from 2 years old to younger than 12 years), but that safety had not been established in pediatric patients. The European Medicines Agency originally restricted the use of IgHy10 to adults with safety concerns similar to those of pediatric patients, but has since authorized the use of IgHy10 as a replacement therapy in adults, children, and adolescents (from 0 to 18 years old).^52,53 Specifically, IgHy10 is indicated for use in patients with PID syndromes with impaired antibody production and in specific populations with hypogammaglobulinemia due to an SID. In the US, HyQvia is currently restricted to the treatment of adults with a PID.

Conclusions

The pivotal trial (Study 160603) and related extension study (Study 160902) provided evidence on the efficacy and safety of IgHy10 as replacement therapy in patients with a PID requiring antibody replacement therapy. The rate of VASBIs was less than 1.0 infections per patient per year (P < 0.0001), which was aligned with expectations for treatment with IgRT in patients with a PID, according to the experts consulted by CADTH. The rate of all infections per patient per year was less than 3 during treatment with IgHy10 in Study 160603 and Study 160902. Additionally, the monthly rate of days spent in hospital due to infection was minimal (0.03 days per month or less), which was considered clinically important as per feedback from the clinical experts consulted by CADTH. HRQoL is an outcome of importance to patients; however, the results provided in the included studies do not allow for conclusions regarding a change in HRQoL during IgHy10 treatment. Regarding the safety of IgHy10, 2 deaths deemed unrelated to treatment were reported during the extension study, and SAEs were infrequent overall. Significant safety concerns were not identified for IgHy10.

The lack of comparative evidence (direct or indirect) for IgHy10 versus other IgRT represents a major limitation in the context of this review. Conclusions cannot be drawn about how IgHy10 compares with other IgRTs, and the single-group study design hinders the ability to appropriately interpret the reported outcomes. Also of note, the available evidence excluded patients with secondary humoral immunodeficiency. The clinical experts consulted by CADTH did not express any issues with using evidence in patients with primary humoral immunodeficiency to inform treatment decisions for patients with secondary humoral immunodeficiency, although this still represents a gap in the evidence. In summary, there are many other SCIg and IVIg therapies available in Canada. Although IgHy10 offers a unique therapy because it comprises 2 drug products (IgG facilitated by rHuPH20), how IgHy10 differs from other immunoglobulin products in terms of safety and efficacy is currently unknown. Therefore, IgHy10 was viewed as another option for SCIg treatment.

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Appendix 1: Literature Search Strategy

Note that this appendix has not been copy-edited.

Clinical Literature Search

Overview

Interface: Ovid

Databases:

• MEDLINE All (1946-present)

• Embase (1974-present)

• Note: Subject headings and search fields have been customized for each database. Duplicates between databases were removed in Ovid.

Date of search: July 22, 2021

Alerts: Bi-weekly search updates until project completion

Search filters applied: No filters were applied to limit the retrieval by study type.

Limits:

• Conference abstracts: excluded

Table 32: Syntax Guide

Multi-Database Strategy

1. (IgHy10* or IGHy* or fSCIG* or f-SCIG*).ti,ab,kf,ot,hw,rn,nm.

2. (rHuPH20 or rHuPH 20 or Enhanze* or 743QUY4VD8 or ((recombinant* or human* or facilitated) adj3 hyaluronidase)).ti,ab,kf,ot,hw,rn,nm.

3. Immunoglobulins/ or Immunoglobulins, Intravenous/ or Immunoglobulin G/ or gamma globulins/

4. (Immunoglobulin* or immune globulin* or gammaglobulin* or gamma globulin* or IgG* or IG or NHIG or HNIG or IVIG or IGIV or SCIG or SCIGG or IGSC or 66Y330CJHS).ti,ab,kf,ot,hw,rn,nm.

5. 3 or 4

6. 2 and 5

7. facilitated.ti,ab,kf,ot,hw,rn,nm.

8. (infusions, subcutaneous/ or injections, subcutaneous/ or subcutaneous tissue/) and (Immunoglobulins/ or Immunoglobulins, Intravenous/ or Immunoglobulin G/ or gamma globulins/)

9. (infusions, subcutaneous/ or injections, subcutaneous/ or subcutaneous tissue/) and (Immunoglobulin* or immune globulin* or gammaglobulin* or gamma globulin* or IgG* or IG or NHIG or HNIG or IVIG or IGIV or 66Y330CJHS).ti,ab,kf,ot,hw,rn,nm.

10. (((subcutaneous* or “sub cutaneous*” or subQ) adj3 (Immunoglobulin* or immune globulin* or gammaglobulin* or gamma globulin* or IgG* or IG or NHIG or HNIG or IVIG or IGIV or 66Y330CJHS)) or SCIG or SCIGG or SC IG or SC IGG or IGSC).ti,ab,kf,ot,hw,rn,nm.

11. 8 or 9 or 10

12. 7 and 11

13. 1 or 6 or 12

14. 13 use medall

15. (IgHy10* or IGHy* or fSCIG* or f-SCIG*).ti,ab,kw,dq.

16. recombinant hyaluronidase/

17. (rHuPH20 or rHuPH 20 or Enhanze* or ((recombinant* or human* or facilitated) adj3 hyaluronidase)).ti,ab,kw,dq.

18. 16 or 17

19. immunoglobulin/ or human immunoglobulin/ or immunoglobulin G/ or immunoglobulin G1/ or immunoglobulin G2/ or immunoglobulin G2a/ or immunoglobulin G2b/ or immunoglobulin G3/ or immunoglobulin G4/

20. (Immunoglobulin* or immune globulin* or gammaglobulin* or gamma globulin* or IgG* or IG or NHIG or HNIG or IVIG or IGIV or SCIG or SCIGG or IGSC).ti,ab,kw,dq.

21. 19 or 20

22. 18 and 21

23. facilitated.ti,ab,kw,dq.

24. subcutaneous immunotherapy/ or immunoglobulin/sc or human immunoglobulin/sc

25. subcutaneous drug administration/ and (immunoglobulin/ or human immunoglobulin/ or immunoglobulin G/ or immunoglobulin G1/ or immunoglobulin G2/ or immunoglobulin G2a/ or immunoglobulin G2b/ or immunoglobulin G3/ or immunoglobulin G4/)

26. subcutaneous drug administration/ and (Immunoglobulin* or immune globulin* or gammaglobulin* or gamma globulin* or IgG* or IG or NHIG or HNIG or IVIG or IGIV).ti,ab,kw,dq.

27. (((subcutaneous* or “sub cutaneous*” or subQ) adj3 (Immunoglobulin* or immune globulin* or gammaglobulin* or gamma globulin* or IgG* or IG or NHIG or HNIG or IVIG or IGIV)) or SCIG or SCIGG or SC IG or SC IGG or IGSC).ti,ab,kw,dq.

28. 24 or 25 or 26 or 27

29. 23 and 28

30. 15 or 22 or 29

31. 30 not conference abstract.pt.

32. 31 use oemezd

33. 14 or 32

34. remove duplicates from 33

Clinical Trials Registries

ClinicalTrials.gov

Produced by the US National Library of Medicine. Targeted search used to capture registered clinical trials.

[Search – IgHy10, IgHy, fSCIG, (facilitated OR hyaluronidase OR rHuPH20 OR Enhanze) AND (immunoglobulin OR immunoglobulins OR “immune globulin” OR “immune globulins” OR IVIG OR SCIG OR SCIGG OR IGSC OR IGIV)]

WHO ICTRP

International Clinical Trials Registry Platform, produced by the World Health Organization. Targeted search used to capture registered clinical trials.

[Search terms – IgHy10, IgHy, fSCIG, (facilitated, hyaluronidase, rHuPH20, Enhanze) AND (immunoglobulin*, “immune globulin,” “immune globulins,” SCIG)]

Health Canada’s Clinical Trials Database

Produced by Health Canada. Targeted search used to capture registered clinical trials.

[Search terms – IgHy10, ighy, immunoglobulin, immunoglobulins, immune globulin, immune globulins, scig, fscig]

EU Clinical Trials Register

European Union Clinical Trials Register, produced by the European Union. Targeted search used to capture registered clinical trials.

[Search terms – IgHy10, IgHy, fSCIG, (facilitated, hyaluronidase, rHuPH20, Enhanze) AND (immunoglobulin, immunoglobulins, “immune globulin,” “immune globulins,” IVIG, SCIG, SCIGG, IGIV, IGSC)]

Grey Literature

Search dates: July 14 to 22, 2021

Keywords: IgHy10, IgHy, fSCIG, (facilitated subcutaneous OR hyaluronidase facilitated OR recombinant human hyaluronidase) AND (immunoglobulin OR immunoglobulins OR immune globulin OR immune globulins OR IVIG OR SCIG)

Limits: None

Updated: Search updated prior to the completion of stakeholder feedback period

Relevant websites from the following sections of the CADTH grey literature checklist Grey Matters: A Practical Tool for Searching Health-Related Grey Literature were searched:

• Health Technology Assessment Agencies

• Health Economics

• Clinical Practice Guidelines

• Drug and Device Regulatory Approvals

• Advisories and Warnings

• Drug Class Reviews

• Clinical Trials Registries

• Databases (free)

• Health Statistics

• Internet Search

• Open Access Journals

Appendix 2: Excluded Studies

Note that this appendix has not been copy-edited.

Table 33: Excluded Studies

fSCIg = facilitated subcutaneous immunoglobulin; IgG = immunoglobulin; rHuPH20 = recombinant human hyaluronidase.

Appendix 3: Detailed Outcome Data

Additional Efficacy Data

Table 34: Pharmacokinetic Parameters for Immunoglobulin in Relation to Dose Frequency in Extension Study 160902 (SAS)

CI = confidence interval; IgG = immunoglobulin; rHuPH20 = recombinant human hyaluronidase; SC = subcutaneous; SD = standard deviation.

Source: Clinical Study Report.¹⁶

Additional Harms Data

Table 35: Summary of the Most Commonly Reported Harms by Rate of AEs per Infusion in Study 160902 (SAS)