CADTH Reimbursement Review

Somatrogon (Ngenla)

Sponsor: Pfizer Canada ULC

Therapeutic area: Growth hormone deficiency

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Executive Summary

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

Introduction

Growth hormone (GH) has been available for management of the short stature associated with growth hormone deficiency (GHD) for more than 60 years.¹ Recombinant human growth hormone (rhGH) is the primary treatment for GHD, as well as for the associated abnormalities in body composition, metabolic profile, exercise capacity, and quality of life. Challenges to effective treatment include difficulty in establishing a firm diagnosis of GHD and variable responsiveness to GH within the population diagnosed with GHD.²

GHD is a clinical diagnosis based on auxologic features (i.e., a comparison of a child’s growth pattern to established norms) and confirmed by biochemical testing. If GHD is congenital and complete, the diagnosis is relatively easy to confirm. Affected children present with early growth failure, delayed bone age, the central distribution of body fat, and generally low serum concentrations of GH, insulin-like growth factor I (IGF-I), and insulin-like growth factor-binding protein 3, the major binding protein of circulating IGF-I. IGF-I is a protein that is typically produced by the liver in response to GH stimulation. Both GH and IGF-I form part of the somatotropic axis, which is markedly active at the onset of puberty, and responsible for whole body growth and development.^3,4 Infants with GHD are prone to hypoglycemia, prolonged jaundice, micropenis (in males), and giant cell hepatitis. For children with milder manifestations of GHD, it may be more difficult to establish the diagnosis. Nonetheless, once the diagnosis is confirmed, such children can and should be treated with GH until linear growth ceases.⁵

The prevalence of GHD is estimated to be between 1 in 3,500 children and 1 in 4,000 children in the UK.⁶ According to a research paper published in 2012, approximately 20,000 children in the US have been diagnosed with GHD.⁷ Currently, there are no published data on the prevalence and incidence of GHD in Canada.

The drug under review is somatrogon, available as a single patient use, multi-dose, disposable pre-filled pen for subcutaneous (SC) injection, in 2 dose strengths: 24 mg in 1.2 mL sterile solution (20 mg/mL) or 60 mg in 1.2 mL sterile solution (50 mg/mL).⁸ The indication for somatrogon is long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous GH (GHD).⁹ The sponsor reimbursement request is long-term treatment of pediatric patients who have GHD.⁸

The objective of this report is to perform a systematic review of the beneficial and harmful effects of somatrogon for the long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous GH (GHD).

Stakeholder Perspectives

The information in this section is a summary of input provided by the clinical expert consulted by CADTH for the purpose of this review.

Clinician Input

Input From Clinical Expert Consulted by CADTH

The most important goals that the ideal treatment would address would be optimizing final adult height, restoring metabolic functions associated with GHD, and optimizing quality of life. Some children also have additional co-existing pituitary hormone deficiencies such as thyroid hormone deficiency, cortisol deficiency, and gonadotropin deficiency. These hormone deficiencies should also be appropriately replaced to optimize growth. GH is an important counter-regulatory hormone in the regulation of blood glucose. GH also helps improve muscular tone and has anabolic effects on bone. While not the primary indications for replacing GH, these additional benefits are appreciated by patients and prescribing physicians.

Adherence is a major limitation to experiencing the full benefits of rhGH therapy. Currently, rhGH formulations are given as SC injections on a daily or near-daily basis (6 days per week). These injections must be given throughout childhood and adolescence. This daily schedule can be inconvenient when patients want to leave their home for any reason (e.g., travelling, visiting, camping) because they have to think about how to transport and store the drug, remember to bring the accompanying supplies (e.g., needles, pen tips, alcohol swabs), and disrupt the activities that they are doing. Furthermore, some patients find the injections painful or anxiety-provoking. These nightly injections cause stress on the families from having to chase after their children and find them and then hold them down for their injections. An ideal rhGH treatment would provide benefits on growth and metabolic outcomes while minimizing pain and anxiety. At the moment, the unmet needs with current rhGH formulations pertain to suboptimal adherence due to the anxiety and pain of injections, the frequency of injections, and the inconvenience in storing and handling injections, or simply forgetting to administer the injection.

Somatrogon could be used as first-line treatment for pediatric GHD. Currently, there is no evidence available for somatrogon in patients who are younger than 3 years of age, so if GHD was diagnosed in infancy or early childhood, then the child would start with the daily rhGH formulations and could be switched to the once-weekly formulation after the age of 3 years.

The clinical expert consulted by CADTH indicated that patients who have been using rhGH daily are likely to derive similar benefit from somatrogon in terms of impact on growth. In addition, a patient’s quality of life may significantly improve with a switch from daily injections to once-weekly injections.

A positive change in height velocity that results in an increase in height standard deviation score (SDS) indicates a favourable response to treatment. An inadequate response after the initiation of rhGH therapy in patients with GHD is often defined by 1 or more of the following criteria: a change in height velocity of less than 2 cm per year, a height velocity SDS of less than 0, or a change in height SDS of less than 0.3 per year during the first 6 months to 12 months of therapy. With height being the major outcome of interest, treatment response should be monitored every 3 months to 4 months in younger children who are expected to grow more rapidly and then every 6 months in the elementary school-aged child who grows less rapidly, and then every 4 months to 6 months in the pubertal-aged child.

RhGH is generally very safe and well tolerated. Prescribers and nurses discuss potential side effects and adverse effects with their patients and their caregivers. In the rare instance where a patient might develop a slipped capital femoral epiphysis or pseudotumour cerebri, GH therapy is paused to allow for treatment or resolution of the adverse event. In cases of glucose intolerance or significantly high IGF-I levels, the dose of GH may need to be reduced. Reasons to stop treatment before growth is complete would be if the patient and caregiver do not adhere to treatment advice, for example, by neglecting to attend appointments, adjusting doses on their own, or refusing to follow through on recommended laboratory monitoring. Generally, in these cases, the prescriber would first try to determine barriers to care before discontinuing therapy altogether.

Somatrogon should be prescribed only by pediatric endocrinologists who have access to the resources needed to be able to diagnose GHD properly and to endocrine nurses who are knowledgeable in GHD and would be able to support patients who require treatment.

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH reimbursement review processes. The following were identified as key factors that could impact the implementation of a CADTH recommendation for somatrogon.

• When should somatrogon be stopped? The clinical expert consulted by CADTH was of the opinion that when growth plates are fused, rhGH therapy becomes contraindicated. Other considerations could be bone age older than 14 years in girls or bone age older than 16 years in boys or height velocity of less than 2 cm per year.

• Would somatrogon be prescribed off label? The clinical expert consulted by CADTH noted that patients with other non-GHD indications may request somatrogon to enable less frequent injections. It is unlikely that somatrogon would be covered by private insurance if it were prescribed off label. They felt that of all the indications, adult GHD may be the one most considered for off-label prescription of somatrogon.

Clinical Evidence

Pivotal Studies and Protocol Selected Studies

Description of Studies

Two phase III studies (CP-4-006 and CP-4-009) were included in the systematic review.

CP-4-006 (N = 224) was an open-label, multi-centre, randomized, active-controlled, parallel group study evaluating the efficacy and safety of weekly somatrogon to daily Genotropin. Patients enrolled in the CP-4-006 study were prepubertal children with GHD and ranged in age from 3 years to younger than 11 years for girls and younger than 12 years for boys. CP-4-009 was a 12-month, open-label, multi-centre, randomized, active-controlled, parallel group study conducted in Japan that compared the efficacy and safety of weekly somatrogon to daily Genotropin in Japanese prepubertal children with GHD who ranged in age from 3 years to younger than 11 years for girls and younger than 12 years for boys. In both studies, patients were randomized in a 1:1 method to receive weekly SC doses of somatrogon or daily SC of Genotropin for 12 months. In both studies, following the completion of the 12-month treatment period, eligible patients were enrolled in a single-arm, open-label extension (OLE) treatment phase with somatrogon. The OLE treatment phase of study CP-4-009 (CP-4-009-Japan-OLE) is summarized in the Other Relevant Evidence section of this report. The OLE treatment phase of study CP-4-006 was not available at the time of writing this report.

The primary efficacy outcome of the CP-4-006 and CP-4-009 trials was annualized height velocity after 12 months of treatment. The secondary efficacy outcomes of both studies were annualized height velocity at 6 months, a change in height SDS at 6 months and 12 months, and a change in bone maturation at 12 months.

Efficacy Results

In study CP-4-006, the primary objective was to demonstrate that annual (12 months) height velocity from weekly somatrogon administration is noninferior to daily Genotropin administration in children with GHD. The primary objective in study CP-4-009 was to demonstrate that annual (12 months) height velocity from weekly somatrogon administration is comparable to daily Genotropin administration in children with GHD. Noninferiority in study CP-4-006 was concluded if the lower bound of the 2-sided 95% CI for the mean treatment difference between somatrogon and Genotropin in annualized height velocity after 12 months of treatment was –1.8 cm per year or more. Comparability in study CP-4-009 was concluded if the mean treatment difference of somatrogon minus Genotropin in annualized height velocity after 12 months of treatment was –1.8 cm per year or more. In study CP-4-006, the least squares mean (LSM) treatment difference for the mean height velocity after 12 months of treatment was 0.33 cm per year (95% confidence interval [CI], –0.24 to 0.89). The lower bound of the 2-sided 95% CI for mean height velocity was greater than the pre-specified noninferiority margin of –1.8 cm per year, indicating that weekly somatrogon administration was noninferior to daily Genotropin administration. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. In study CP-4-009, the treatment difference (somatrogon minus Genotropin) in LSM height velocity (cm per year) was 1.79 cm per year with a 2-sided 95% CI (0.97 to 2.61). Since the point estimate of 1.79 cm per year was greater than the pre-established margin of –1.8 cm per year, weekly somatrogon was concluded to be comparable to daily Genotropin.

The LSM treatment difference for annualized height velocity at 6 months was |||| cm per year (95% CI, |||||||||||||) in CP-4-006 and |||| cm per year (95% CI, |||||||||||||) in study CP-4-009. The LSM treatment difference for change in height SDS from baseline to 6 months was |||| (95% CI, |||||||||||||) in CP-4-006 and |||| (95% CI, |||||||||||||) in study CP-4-009. The LSM treatment difference for change in height SDS from baseline to 12 months was 0.05 (95% CI, –0.06 to 0.16) in CP-4-006 and |||| (95% CI, |||||||||||||) in study CP-4-009. The statistical significance of these results cannot be interpreted due to the lack of reporting of P values.

In both studies, advancement in bone age ||||||||||| exceed advancement in chronological age; mean bone maturation (defined as the ratio of bone age to chronologic age) at 12 months was ||||||||||||| in both treatment groups, |||||||||||||||||||||||||||||||||||||| was reported.

Health-related quality of life (HRQoL) was assessed in CP-4-006 using the Quality of Life in Short Stature Youth (QoLISSY) questionnaire, which assesses the impact of short stature on children from the perspectives of both the patients and their parents. In addition, the number of successful injection attempts by patients using the somatrogon multi-dose, pre-filled pen was evaluated based on the Observer Assessment Tool (OAT) and Participant Assessment Tool (PAT). The OAT was used to record the observer’s assessment of an administration with the device after the patient or caregiver injected somatrogon. The PAT was used to record all of the patients’ or caregivers’ injections of somatrogon and was completed by the actual user of the pen or parent/legal guardian. However, the analyses for QoLISSY were performed in selected locations only and the analyses for other patient-reported outcome (PRO) responses were reported for the somatrogon treatment group only; analyses were conducted in observed case patients, there were substantial amounts of missing data that would introduce significant biases, and no minimal important difference (MID) was identified in the literature for QoLISSY, OAT, and PAT. Hence, the effect of these assessments in support of somatrogon are highly uncertain.

Harms Results

In CP-4-006, 87.2% and 84.3% of the patients in the somatrogon group and Genotropin group, respectively, reported at least 1 AE; in CP-4-009, |||% and ||||% of the patients in the somatrogon group and Genotropin group, respectively, reported at least 1 AE. In both studies, the most commonly occurring adverse events were injection site pain, nasopharyngitis, pyrexia, and headache. No deaths were reported in either of the studies. In CP-4-006, the most notable harm reported was an injection-related event that was reported in ||||% and ||||% of patients in the somatrogon treatment group and Genotropin treatment group, respectively. In CP-4-009, the most common notable harm reported was an injection-related event that was reported in 72.7% of patients in the somatrogon treatment group. The clinical expert did express concern that the injection site reaction in somatrogon was higher compared to Genotropin. As somatrogon is a once-weekly injection and Genotropin is a once-daily injection, these analyses may warrant further explanation. The long-term safety concerns from the CP-4-006 study remain unknown.

Critical Appraisal

Internal Validity

The clinical expert noted that the commonly used treatment for GHD in Canada is Humatrope. Both the CP-4-006 and CP-4-009 studies had only Genotropin as the active comparator, despite other approved comparators being available for treatment in Canada. No direct or indirect evidence against GHD used in clinical practice within Canada was identified; hence, the comparative efficacy and safety of somatrogon against other regimens such as somatropin are unknown.

No justification for the comparability criteria was provided in study CP-4-009. While study CP-4-009 met the pre-specified criteria for comparability, this should not be confused with the unequivocal demonstration of equivalence, noninferiority, or superiority.

The clinical expert consulted by CADTH noted that the imbalance in age and sex in study CP-4-009 could influence the efficacy results in favour of somatrogon. However, the difference in age would not impact outcomes observed within the first year, but would impact the final adult height.

The primary outcomes of CP-4-006 and CP-4-009 looked to establish the noninferiority and comparability of somatrogon with Genotropin, respectively. Once noninferiority was established, analyses of the secondary efficacy outcomes were conducted. However, these secondary end points were not part of a hierarchical statistical testing plan and were not controlled for multiplicity, and P values have not been reported. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||, and superiority was not tested in CP-4-009.

CP-4-006 reported HRQoL and other PRO responses. However, these tools were administered only in selected locations with a very small sample size; as the study was open label, this could bias the results of the efficacy outcomes. Moreover, only a complete case analysis was carried out for this data with different subsets of patients at each time point. This would be subjected to an increased risk of bias due to the complete case analysis approach. No MID was identified from literature for the QoLISSY questionnaire or the OAT and PAT instruments.

External Validity

The clinical expert noted that based on baseline demographic and disease characteristics, the study population was fairly generalizable to Canadian patients; however, the clinical expert was of the opinion that the age for inclusion within both studies (i.e., ≥ 3 years) was not reflective of Canadian practice since patients with GHD would be identified in infancy. It was also noted that in CP-4-006, 20% of the cohort was Asian, which is a higher level than that seen in Canada. The clinical expert also commented on how indigenous peoples who are treated in Canada are underestimated in both studies. The clinical expert also noted that the proportion of patients with a peak GH level of greater than 7 ng/dL was higher than what is observed in Canadian clinical practice.

GH therapies are long-term therapies, and even though the primary end point of each of the 2 studies was met, in the absence of long-term comparative efficacy and safety results, interpreting the long-term clinical meaningfulness of somatrogon is limited.

Indirect Comparisons

No indirect comparisons were identified or submitted by the sponsor.

Other Relevant Evidence

Description of C0311002 (Study 002)

The C0311002 study (N = 87) was a randomized, open-label, multi-centre, 2-period crossover study that enrolled children with GHD who ranged in age from 3 years to younger than 18 years. Patients were randomized in a 1:1 ratio to 1 of 2 sequences (sequence 1 or sequence 2). Patients randomized to sequence 1 received treatment with once-daily somatropin for 12 weeks, followed by 12 weeks of treatment with once-weekly somatrogon. Patients randomized to sequence 2 received treatment with once-weekly somatrogon for 12 weeks, followed by 12 weeks of treatment with once-daily somatropin.

The primary objective of C0311002 was to evaluate the treatment burden of a weekly injection of somatrogon and a daily injection of somatropin (Genotropin). Secondary objectives included an evaluation of patient and caregiver self-assessments of treatment experience, and an evaluation of the psychometric properties of the Dyad Clinical Outcome Assessment (DCOA) questionnaires.

Efficacy Results

In the C0311002 study, all of the domains of the Dyad Clinical Outcome Assessment 1 (DCOA 1) questionnaire were associated with numerically greater overall scores during treatment with Genotropin than during treatment with somatrogon, with 2 exceptions: the injection signs and symptoms domain (from patients ≥ 8 years) and the assessment of signs domain (from caregivers for children < 8 years). The reported overall score for these 2 domains did not suggest a preference for either treatment based on the reported overall scores. The primary end point of C0311002 demonstrated that the treatment burden of the once-weekly somatrogon injection schedule, as evaluated by the patient life interference questionnaire, was lower than that of the once-daily Genotropin injection schedule. The LSM for the total score of overall life interference was lower for the once-weekly somatrogon injection schedule than for the once-daily Genotropin injection schedule. The mean treatment difference (95% CI; P value) between somatrogon and Genotropin was –15.49 (95% CI, –19.71 to –11.27; P < 0.0001).

The results of the Dyad Clinical Outcome Assessment 2 (DCOA 2) questionnaire showed that the overall proportion of patients who responded to the questionnaire indicating preference for somatrogon was greater than the proportion of patients indicating preference for Genotropin. The proportion of patients who preferred somatrogon and Genotropin in terms of injecting the medicine was ||||% and ||||%, respectively.

Harms Results

Thirty-eight (44.2%) patients in the Genotropin group and 47 (54.0%) patients in the somatrogon group reported at least 1 adverse event during treatment. The most frequently reported adverse event was injection site pain. One patient stopped treatment due to adverse events, which occurred during treatment with somatrogon as a result of injection site pain. With regard to notable harms for this review, injection-related events were reported by ||||% and ||||% of patients during treatment with Genotropin and somatrogon, respectively.

Critical Appraisal

The primary objective of C0311002 evaluated the treatment experience and patient preference for treatment with once-weekly somatrogon compared to once-daily Genotropin using subjective PROs within an open-label study design, which has potential for significant bias in the results. Evidence of reliability was demonstrated; however, there was no evidence of validity or responsiveness, and an MID was not identified from the literature. Additionally, results for the DCOA 1 questionnaire included P values, but the statistical tests were not controlled for multiplicity and, consequently, were at risk of type I error. The other secondary outcomes were reported descriptively. Both of these factors and the lack of an established MID make it difficult to determine the clinical meaningfulness of the results.

C0311002 had concerns of generalizability to the Canadian patient population and the lack of an appropriate assessment period.

Description of CP-4-009-Japan-OLE

The CP-4-009 long-term open-label extension (LT-OLE) (N = 42) evaluated the long-term efficacy and safety of somatrogon in a single-arm trial in Japanese prepubertal children. Patients who were treated with Genotropin and completed 12 months of treatment during the CP-4-009 main study were switched to a somatrogon dosage of 0.66 mg/kg per week and somatrogon-treated patients who completed 12 months of treatment during the main study continued to receive somatrogon with the same mg/kg per week dosage in the OLE treatment phase. The OLE phase would continue until the marketing registration of somatrogon in Japan.

Efficacy Results

The efficacy outcomes reported were annualized height velocity at 24 months and bone maturation at 24 months. These efficacy outcomes were not part of a pre-specified statistical testing plan. The mean (SD) change from baseline of the open-label phase at month 24 for annualized height velocity in the somatrogon group (N = |||||||||) was ||||||||||||||| and in the Genotropin group (N = |||||||||) was |||||||||||||||. The mean (standard deviation [SD]) change from baseline at month 24 for height SDS in the somatrogon group (N = |||||||||) was |||||| |||||||| and in the Genotropin group (N = |||||||||) was |||||||||||||||. The mean (SD) change from baseline of the open-label phase at month 24 for bone maturation in the somatrogon group (N = |||||||||) was ||||||||||||||| and in the Genotropin group (N = |||||||||) was |||||||||||||||.

Harms Results

The most commonly reported adverse event was |||||||||% in the somatrogon group and ||||% in the Genotropin-followed-by-somatrogon treatment group. |||||||| patient reported ||||||||| as a serious treatment-related adverse event in the Genotropin-followed-by-somatrogon treatment group. There were no reports of any deaths or patients who stopped treatment due to adverse events.

Critical Appraisal

CP-4-009-OLE was conducted to evaluate the long-term efficacy and safety of once-weekly somatrogon. The efficacy results of the OLE phase were selectively reported. The analyses were not part of a statistical testing plan and, hence, the effect of somatrogon at the data cut-off date of March 13, 2020, is considered uncertain. No efficacy analyses for HRQoL or other PRO measures have been conducted; hence, the long-term effect of somatrogon on HRQoL is unknown. CP-4-009-OLE was conducted exclusively in Japanese prepubertal children and did not include any Canadian patients; this is not reflective of Canadian clinical practice. Hence, CP-4-009-OLE has noted generalizability issues. The CP-4-009-OLE study excluded patients younger than 3 years of age, so this also leads to a Canadian generalizability issue as the clinical expert consulted by CADTH stated that in clinical practice, patients with GHD are seen as early as in their infancy.

Conclusions

Two phase III randomized controlled trials were included in the CADTH systematic review of somatrogon for long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous GH. Both studies demonstrated that for the primary efficacy outcome of annualized height velocity at 12 months, treatment with somatrogon was noninferior (CP-4-006) or comparable (CP-4-009) to Genotropin. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Other relevant outcomes such as HRQoL and other PRO responses were not assessed in study CP-4-009 and were not properly assessed in study CP-4-006; as a result, the effect of somatrogon on HRQoL is uncertain. The results of the long-term open-label phase for CP-4-006 were not available; hence, interpretation of the sustained response of treatment to somatrogon is unknown. Key evidence gaps include absence of adherence analyses, limited evidence on switchover from somatrogon to somatropin or vice versa, and limited interpretation of HRQoL and other PRO responses.

The key safety issues with somatrogon were related to injections, with a low number of serious adverse events being reported in the somatrogon and Genotropin treatment groups in both studies. A higher number of patients in the somatrogon treatment group experienced injection site pain, nasopharyngitis, pyrexia, and headache. Conclusions regarding the long-term safety of somatrogon cannot be made in the absence of corresponding data.

Introduction

Disease Background

GH has been available for management of the short stature associated with GHD for more than 60 years.¹ Recombinant human growth hormone is the primary treatment for GHD as well as the associated abnormalities in body composition, metabolic profile, exercise capacity, and quality of life. Challenges to effective treatment include difficulty in establishing a firm diagnosis of GHD and variable responsiveness to GH within the population diagnosed with GHD.² GH therapy is also prescribed for several other specific indications in children and adolescents, including idiopathic short stature and short stature associated with small for gestational age (SGA), chronic kidney disease, Turner syndrome, Prader-Willi syndrome, mutations in the SHOX gene, and Noonan syndrome.

GH affects many of the metabolic processes carried out by somatic cells. Linear growth and skeletal development are tightly regulated processes that are highly dependent on GH signalling and action.¹² The best known effect is the effect of increasing body mass. GH increases total body protein content, decreases total body fat content, and increases fat deposition in the liver. Physiologic concentrations of GH also have beneficial effects on the plasma lipid profile (i.e., decreases serum low-density lipoprotein and increases high-density lipoprotein).^13,14 The effects on fat are due to stimulation of lipolysis and reciprocal antagonism of the lipogenic action of insulin in peripheral fat stores. GH also increases bone mass by stimulating skeletal IGF-I synthesis and causing the proliferation of pre-chondrocytes, the hypertrophy of osteoblasts, bone remodelling, and net mineralization.¹⁵ GH stimulates cartilage growth; this is most evident as a widening of the epiphyseal plate and is associated with an increase in amino acid incorporation into cartilage and bone.¹⁶

GHD is a clinical diagnosis based on auxologic features (i.e., a comparison of a child’s growth pattern to established norms) and confirmed by biochemical testing. If GHD is congenital and complete, the diagnosis is relatively easy to confirm. Affected children present with early growth failure, delayed bone age, the central distribution of body fat, and generally low serum concentrations of GH, IGF-I, and insulin-like growth factor-binding protein 3, the major binding protein of circulating IGF-I. IGF-I is a protein that is typically produced by the liver in response to GH stimulation. Both GH and IGF-I form part of the somatotropic axis, which is markedly active at the onset of puberty and responsible for whole body growth and development.^3,4 Infants with GHD are prone to hypoglycemia, prolonged jaundice, micropenis (in males), and giant cell hepatitis. For children with milder manifestations of GHD, it may be more difficult to establish the diagnosis. Nonetheless, once the diagnosis is confirmed, such children can and should be treated with GH until linear growth ceases.⁵

The prevalence of GHD is estimated to be between 1 in 3,500 children and 1 in 4,000 children in the UK.⁶ According to a research paper published in 2012, approximately 20,000 children in the US have been diagnosed with GHD.⁷ Currently, there are no published data on the prevalence and incidence of GHD in Canada.

Standards of Therapy

Once the diagnosis GHD is established in children, GH therapy is the recommended course of treatment. Therapy should be started as soon as possible to enhance growth velocity and normalize final adult height.^17,18 Patients prescribed GH treatment are injected subcutaneously on a daily basis, 6 to 7 times per week.^9,19,20 Various studies indicated that GH is effective in children with GHD and, if started in early childhood, will normalize final height.¹⁷

The clinical expert consulted by CADTH indicated that the most important goals that the ideal treatment would address would be optimizing final adult height, restoring metabolic functions associated with GHD, and optimizing quality of life. The clinical expert also noted that GHD is diagnosed based on multiple clinical, auxological, and laboratory and radiographic data. Once the diagnosis of GHD is made, rhGH is prescribed. RhGH for the long-term treatment of pediatric GHD is the only indication for which public health drug plans cover costs. The starting dosage is around 0.18 mg/kg per week, administered once daily as an SC injection, for 6 to 7 days per week. (One day is provided as a break for patients and parents or guardians. For those who experience hypoglycemia from multiple pituitary hormone deficiencies that include GHD, it is common practice to dose daily).

While on treatment, routine monitoring consists of clinic visits. The frequency of visits depends on the age of the child (infants are seen every 3 months while school-aged children are seen every 4 months to 6 months). During the visits, the child’s growth is measured, puberty is assessed, side effects are reviewed, adherence and treatment satisfaction are explored, and dosing adjustments are made. Approximately every 3 months to 6 months, laboratory measurements are taken of IGF-I, thyroid function, any other pituitary hormone deficiencies, and glucose tolerance. A bone age estimation may be done once per year.

Treatment with rhGH for GHD is generally continued until growth is completed (when fused epiphyses are observed) or near complete (growth of less than 2 cm per year or a bone age of > 14 years in girls or > 16 years in boys). Once growth is completed, the dosage is reduced to adult GHD prescribing recommendations until the age of 18 years.

Drug

Somatrogon is a modified long-acting analogue of human growth hormone (hGH). It is a new molecular entity with receptor-binding properties and a mechanism of action analogous to hGH.¹⁰ Somatrogon binds to the GH receptor and initiates a signal transduction cascade, culminating in changes in growth and metabolism. Consistent with GH signalling, somatrogon binding leads to the activation of the STAT5B signalling pathway and increases the serum concentration of IGF-I.⁸

The drug under review is somatrogon, available as a single patient use, multi-dose, disposable pre-filled pen for SC injection, in 2 dose strengths: 24 mg in 1.2 mL sterile solution (20 mg/mL) or 60 mg in 1.2 mL sterile solution (50 mg/mL).⁸ The Health Canada indication for somatrogon is long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous GH (GHD).⁹ The sponsor reimbursement request is long-term treatment of pediatric patients who have GHD.⁸

Health Canada’s recommended dosage is 0.66 mg/kg body weight administered once weekly by SC injection. If a patient’s growth rate fails to increase in the first year, assess for treatment adherence and other causes of growth failure (e.g., hypothyroidism, undernutrition, advanced bone age); discontinuation of somatrogon treatment should be considered. Treatment with somatrogon should be discontinued when there is evidence of closure of the epiphyseal growth plates.⁹

Somatrogon is administered using a delivery device (a pre-filled pen). Injection sites are to be rotated successively (left upper arm, right upper arm, left buttock, right buttock, left thigh, right thigh, left abdomen, and right abdomen) such that the same injection site is used only after all other injection sites have been rotated.⁹ Table 3 presents key characteristics of currently available GH therapies.

Stakeholder Perspectives

Patient Group Input

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

No patient input was received by CADTH for this submission.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding 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, providing guidance on the potential place in therapy). The following input was provided by 1 clinical specialist with expertise in the diagnosis and management of long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous GH.

Unmet Needs

The most important goals that ideal treatment would address would be optimizing final adult height, restoring metabolic functions associated with GHD, and optimizing quality of life. Final adult height depends on several factors, some of which are intrinsic to the patient while others are modifiable. Taller parental height, younger age at initiation of treatment, later onset of puberty, and greater magnitude of GHD are associated positively with final adult height. Longer duration of GH treatment, consistent adherence to therapy, and higher doses of GH therapy are also positively associated with final adult height and are modifiable variables. Some children also have additional co-existing pituitary hormone deficiencies such as thyroid hormone deficiency, cortisol deficiency, and gonadotropin deficiency. These hormone deficiencies should also be appropriately replaced to optimize growth.

GH also affects other metabolic processes. GH is an important counter-regulatory hormone in the regulation of blood glucose. When the level of blood glucose falls, GH increases to promote the breakdown of glycogen and the endogenous formation of new glucose. Thus, 1 of the reasons to treat a child with GHD using rhGH is to prevent hypoglycemia. GH also helps improve muscular tone and has anabolic effects on bone. While not the primary indications for replacing GH, these additional benefits are appreciated by patients and prescribing physicians.

Adherence is a major limitation to experiencing the full benefits of rhGH therapy. Currently, rhGH formulations are given as SC injections on a daily or near-daily basis (6 days per week). These injections must be given throughout childhood and adolescence, amounting to approximately 18 years of therapy. This daily schedule can be inconvenient when patients want to leave their home for any reason (e.g., travelling, visiting, camping) because they have to think about how to transport and store the drug, remember to bring the accompanying supplies (e.g., needles, pen tips, alcohol swabs), and disrupt the activities that they are doing. Furthermore, some patients find the injections painful or anxiety-provoking. Clinicians have heard from caregivers of their children running away from them whenever it comes time for their rhGH injections. These nightly injections cause stress on families from having to chase after their children and find them and then hold them down for their injections. An ideal rhGH treatment would provide proven benefits on growth and metabolic outcomes while minimizing pain and anxiety.

At the moment, the unmet needs with current rhGH formulations pertain to suboptimal adherence due to anxiety and pain of injections, frequency of injections, and inconvenience in storing and handling injections, or simply forgetting to administer the injection. Ideally, GH would be given as a pill rather than an injection. Over the years, GH manufacturers have provided options that look less like needles and syringes. They offer pens and pods that attempt to mitigate the anxiety provoked by seeing a syringe. However, the needles in these pens and pods still cause pain, and the possibility of pain continues to be a source of anxiety. Additional work can be put into finding ways to reduce anxiety before injections. At most children’s hospitals, there are child life specialists who can help children with their fear of needles, but the demand currently outnumbers the availability of these specialists. In other conditions where options for longer-lasting formulations are available (e.g., intramuscular Lupron administered once every 3 months compared to monthly intramuscular Lupron for pubertal suppression, weekly intramuscular testosterone compared to daily transdermal testosterone for hormone replacement in hypogonadism), patients often choose the less frequent option to reduce the episodes of anxiety, for convenience, or both. Thus, a longer-acting, less frequently injected formulation of rhGH could address suboptimal adherence from anxiety, pain, and inconvenience. There are also some rhGH formulations that are pre-mixed and ready to load and others that do not require refrigeration.

Place in Therapy

Somatrogon could be used as first-line treatment for pediatric GHD. Currently, there is no evidence available for somatrogon in patients younger than 3 years of age, so if GHD was diagnosed in infancy or early childhood, then the child would start with the daily rhGH formulations and could be switched to the once-weekly formulation after the age of 3. There are some unanswered questions about somatrogon, though — specifically, at what point to measure and then how to use information from IGF-I levels to adjust the dose.

Patient Population

The clinical experts indicated that patients who would be best suited for treatment with somatrogon are pediatric patients who have a confirmed diagnosis of GHD and are at least 3 years of age. Somatrogon can be initiated with pediatric patients with GHD who are treatment naive or have previously received GH replacement therapy. Treatment with rhGH is very long (lasting throughout childhood and adolescence), and if there is an option available that is associated with less pain and less anxiety for children, it would not be ethical to limit access to that option. In addition, most children with GHD have additional pituitary hormone deficiencies: thyroid hormone deficiency (replaced with thyroid hormone in tablet form), cortisol deficiency (replaced by hydrocortisone taken by mouth 3 times per day), diabetes insipidus (treated with by Ddavp [desmopressin acetate injection] taken by mouth 2 times to 3 times per day), and hypogonadism (in adolescence, testosterone is replaced with intramuscular injections every 1 week to 4 weeks while estrogen is replaced either via a daily tablet or a transdermal patch with progesterone replacement by mouth for 10 days to 12 days per month). Children with GHD may also have comorbidities such as cerebral palsy or blindness. Thus, strategies to reduce the burden of care are essential.

A patient’s quality of life may improve with a switch to once-weekly injections. GH therapy requires a long commitment (childhood through adolescence). Adherence decreases over time while treatment fatigue increases. Patients younger than 3 years of age, patients with any of the contraindications or relative contraindications listed in the somatrogon monograph, and patients with an allergy to somatrogon would be least suited for treatment with somatrogon.

Assessing Response to Treatment

There is no single measure of what constitutes a meaningful response to treatment. Consensus guidelines describe seeing improvements in height velocity SDS of 0.3 to 0.5 SD in the first year and catch-up growth that places the child closer to the child’s mid-parental target height. However, any increase in height might be construed by a patient as being positive. A positive change in height velocity that results in an increase in height SDS indicates a favourable response to treatment. An inadequate response after the initiation of rhGH therapy in patients with GHD is often defined by 1 or more of the following criteria: a change in height velocity of less than 2 cm per year, height velocity SDS of less than 0, or a change in height SDS of less than 0.3 per year during the first 6 months to 12 months of therapy. With height being the major outcome of interest, treatment response should be monitored every 3 months to 4 months in younger children who are expected to grow more rapidly and then every 6 months in the elementary school-aged child who grows less rapidly, and then every 4 to 6 months in the pubertal-aged child who again grows more rapidly.

Discontinuing Treatment

Those with GHD should receive GH replacement not only to grow, but also to gain the metabolic benefits of GH. They should not discontinue therapy if possible. The dose of GH may be reduced after the completion of growth to an adult GHD dose. Afterwards, the individual may decide whether to continue with GH replacement as an adult, though it is generally recommended to do so if the adult truly has GHD. In situations where an adverse event happens, GH injections may need to be temporarily stopped until resolution of the adverse outcome. For example, in the case of active malignancy or within a year of treatment, GH therapy should be paused. If the patient develops a slipped capital femoral epiphysis or pseudotumour cerebri, GH therapy is paused to allow for treatment or resolution of the adverse event. In cases of glucose intolerance or significantly high IGF-I levels, the dose of GH may need to be reduced. An additional consideration to stop treatment would be if the patient and caregiver do not adhere to treatment advice, for example, by neglecting to attend appointments, adjusting doses on their own, or refusing to follow through on recommended laboratory monitoring. Generally, in these cases, the prescriber would first try to determine barriers to care before discontinuing therapy altogether.

Prescribing Conditions

Somatrogon should be prescribed only by pediatric endocrinologists who have access to the resources needed to be able to diagnose GHD properly and to endocrine nurses who are knowledgeable in GHD, and would be able to support patients who require treatment. Patients should be monitored in pediatric endocrinology clinics. Those who live far from pediatric endocrinology clinics should have a pediatrician who can collaborate with a pediatric endocrinologist to monitor growth and side effects.

Additional Considerations

Rarely, there are patients who appear to have true GHD even though their stimulated GH peak exceeds traditional cut-offs. The combination of other clinical data (e.g., significant short stature, poor height velocity, delayed bone age, low IGF-I, abnormal pituitary MRI findings) can indicate GHD irrespective of the GH level. These patients may require GH therapy for adequate growth — thus, excessive emphasis should not be placed on only the results of the GH stimulation test when making a diagnosis of GHD or making recommendations for treatment under the indication of GHD.

Clinician Group Input

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

No clinician group input was identified by CADTH for this submission.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 5.

Clinical Evidence Selection

The clinical evidence included in the review of somatrogon is presented in 3 sections. The first section, the systematic review, includes 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 (if submitted) and indirect evidence selected from the literature that met the selection criteria specified in the review. 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 somatrogon (20 mg/mL or 50 mg/mL pre-filled pen for SC injection) for the long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous GH.

Methods

Studies selected for inclusion in the systematic review will include pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 6. 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 in Table 6 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 checklist.²⁴

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via 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 consisted of both controlled vocabulary, such as the US National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was somatrogon. Clinical trials registries were searched: the US National Institutes of Health’s ClinicalTrials.gov, the WHO’s International Clinical Trials Registry Platform 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 June 25, 2021. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee on October 27, 2021.

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 reference.²⁵ Included in this search were the websites of regulatory agencies (the US 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 by reviewing bibliographies of key papers and 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 7. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Description of Studies

Two phase III randomized controlled trials, CP-4-006 (C0311009) (N = 224) and CP-4-009 (C0311010) (N = 44) were included in the CADTH systematic review. The details of the 2 trials are provided in Table 7. In CP-4-006, a total of 84 study sites randomized 228 patients of which 224 received at least 1 dose of study drug. In CP-4-009, a total of 24 study sites randomized patients; ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. For CP-4-006, the last patient’s last visit was on August 23, 2019. For CP-4-009, the data cut-off date was March 13, 2020. The main body of the review report presents data of the randomized phase for both studies.

CP-4-006 was an open-label, multi-centre, randomized, active-controlled, parallel group study evaluating the efficacy and safety of weekly somatrogon to daily GH (Genotropin). The study had 2 parts: a main study phase and a long-term open-label phase. The main study phase had a screening period of up to 12 weeks, wherein patients who met the inclusion criteria were randomized in a 1:1 method to receive weekly SC doses of somatrogon or daily SC doses of Genotropin for 12 months. At the end of the screening period, patients were administered a starting dosage of 0.66 mg/kg per week of somatrogon or a starting dosage of 0.034 mg/kg per day of Genotropin (equivalent to 0.24 mg/kg per week divided equally into 7 daily injections, which aligned with Health Canada–approved guidelines). The doses of somatrogon and Genotropin were adjusted every 3 months based on the patient’s body weight and decreased for safety reasons based on predefined dose-adjustment criteria (this was based on the severity of adverse events or repeated, elevated levels of IGF-I SDS). Genotropin was administered as an SC injection in the evening or during bedtime hours once daily, using pre-filled cartridges with the Genotropin Pen delivery device, into the upper arms, buttocks, thighs, or abdomen (8 locations). Injection sites were to be rotated successively (left upper arm, right upper arm, left buttock, right buttock, left thigh, right thigh, left abdomen, and right abdomen), using the same injection site only after all other injection sites had been rotated. Both somatrogon and Genotropin were to be stored, refrigerated at 2°C to 8°C.¹⁰

Patients were centrally randomized by geographical region, peak GH levels at screening, and chronological age. Patients were randomized through an interactive web response system (IWRS). Details of the randomization stratification were as follows:

• geographical region (region 1 — Western Europe, Israel, Australia, New Zealand, Canada, and the US; region 2 — Central and Eastern Europe, Greece, Turkey, Latin America, and Asia, except for India and Vietnam; region 3 — India and Vietnam)

• GH peak levels at screening — 3 ng/mL or less, more than 3 ng/mL to a maximum of 7 ng/mL, and more than 7 ng/mL to a maximum of 10 ng/mL

• chronological age of 3 years to 7 years and 0 days, and older than 7 years and 0 days.

In the LT-OLE phase, patients who received somatrogon during the main study continued with the same dosage of somatrogon (mg/kg per week) during the LT-OLE phase. Patients who received Genotropin during the main study were switched to somatrogon and began treatment with a dosage of 0.66 mg/kg per week no less than 1 day after stopping Genotropin treatment. During the entire study (main study and LT-OLE phase), the doses of somatrogon and Genotropin (main study only) were adjusted every 3 months based on the patient’s body weight and may have been decreased for safety reasons, based on predefined dose-adjustment criteria (based on the severity of adverse events or repeated, elevated levels of IGF-I SDS). Patients were free to discontinue from the study at any time. Patients who had withdrawn from the study during the 12 months of treatment post−first dose were not replaced. Patients who had withdrawn after successfully completing screening, but before first dose, were replaced. The main study lasted 15 months (a 12-month treatment period, up to 12 weeks of screening, and a 1-month post-dosing end-of-study follow-up for patients who discontinued the study early or did not continue in the LT-OLE phase). The LT-OLE phase was to continue until marketing approval.

CP-4-009 was a 12-month, open-label, multi-centre, randomized, active-controlled, parallel group study conducted in Japan. It compared the efficacy and safety of weekly somatrogon to daily Genotropin in Japanese prepubertal children with GHD. The study had 2 parts: a main study phase and a long-term open-label phase. In the main study, after a screening period of 4 weeks, patients meeting the inclusion criteria were randomized in a 1:1 ratio to receive either weekly somatrogon SC injections for 12 months or daily Genotropin SC injections (0.025 mg/kg per day, which is equivalent to 0.175 mg/kg per week, divided equally into 7 daily injections over a week) for 12 months. The randomization was not stratified. Somatrogon was administered in 3 stepwise escalating doses (0.25 mg/kg per week, 0.48 mg/kg per week, and 0.66 mg/kg per week), each for 2 weeks sequentially. Then for the remaining 46 weeks, patients continued to receive somatrogon at a dosage of 0.66 mg/kg per week. The doses of somatrogon and Genotropin were adjusted every 3 months based on the patient’s body weight and decreased for safety reasons based on predefined dose-adjustment criteria (based on the severity of adverse events or repeated, elevated levels of IGF-I SDS). Patients were free to discontinue from the study at any time. Patients who had withdrawn from the study before completing 12 months of treatment were not replaced. Both somatrogon and Genotropin were injected subcutaneously using a pen device. Following the completion of the 12-month treatment period, eligible patients were enrolled in a single-arm OLE treatment phase with somatrogon. Eligible Genotropin-treated patients who completed 12 months of treatment during the main study were switched to a somatrogon dosage of 0.66 mg/kg per week and somatrogon-treated patients who completed 12 months of treatment during the main study continued to receive somatrogon with the same dosage in the OLE phase. The OLE phase was to continue until the marketing registration of somatrogon in Japan. The LT-OLE phase has been summarized in the Other Relevant Evidence section of this report.

Populations

Inclusion and Exclusion Criteria

CP-4-006 included prepubertal children who ranged in age from 3 years to younger than 11 years for girls or younger than 12 years for boys, with either isolated GHD or GH insufficiency as part of multiple pituitary hormone deficiency. Patients were treatment naive to other rhGH therapy. Patients included in the study had to have impaired height and height velocity, which were defined as annualized height velocity below the 25th percentile for chronological age (height velocity < –0.7 SDS) and sex, according to the sponsor’s calculator; the interval between 2 height measurements should have been at least 6 months but should not have exceeded 18 months before inclusion. The baseline IGF-I level had to have been at least 1 SD below the mean IGF-I level standardized for age and sex (IGF-I SDS ≤ –1). Key exclusion criteria included children with a prior history of leukemia, lymphoma, sarcoma, or any other form of cancer and history of radiation or chemotherapy. Patients requiring glucocorticoid therapy (e.g., for asthma) who were taking chronically a dose greater than 400 mcg per day of inhaled budesonide or equivalent were excluded. Patients with chromosomal abnormalities including Turner syndrome, Laron syndrome, Noonan syndrome, Prader-Willi syndrome, Russell-Silver syndrome, SHOX mutations/deletions, and skeletal dysplasias were also excluded. Detailed inclusion and exclusion criteria are shown in Table 7. For patients to move into the LT-OLE phase, patients had to complete 12 months of treatment on the main study, with adequate compliance to protocol and checked as per a review of diary cards.

CP-4-009 included prepubertal Japanese children who ranged in age from 3 years to younger than 10 years for girls or younger than 11 years for boys. Other key inclusion and exclusion criteria were similar to that of study CP-4-006.

Baseline Characteristics

The baseline characteristics for CP-4-006 and CP-4-009 are given in Table 8 and Table 9. In general, the baseline characteristics were similar between treatment groups within each of the included studies; however, there are a few differences to note. There was an imbalance between treatment groups in terms of age and sex in both studies, and mean (SD) and median (range) height and weight in CP-4-009. In CP-4-006, in the somatrogon treatment group, 60.6% of the patients were 7 years or older and 39.4% of the patients ranged in age from more than 3 years to a maximum of 7 years. In the Genotropin treatment group, 59.1% of the patients were 7 years or older and 40.9% of the patients ranged in age from more than 3 years to a maximum of 7 years. In CP-4-009 in the somatrogon treatment group, ||||||||% of the patients were |||||||| years or older and ||||||||% of the patients ranged in age from more than |||||||| years to a maximum of |||||||| years. In the Genotropin treatment group, ||||||||% of the patients were |||||||| years or older and ||||||||% of the patients ranged in age from more than |||||||| years to a maximum of |||||||| years. In CP-4-006, 75.2% of the patients were male in the somatrogon treatment group and 68.7% of the patients were male in the Genotropin treatment group. In CP-4-009, 40.9% of the patients were male in the somatrogon treatment group and 54.5% of the patients were male in the Genotropin treatment group. In CP-4-009, the mean (SD) height (cm) was |||||||| and |||||||| in the somatrogon treatment group and Genotropin treatment group, respectively. Similarly, the mean (SD) weight was 14.49 (3.33) kg and 17.87 (4.85) kg in the somatrogon treatment group and Genotropin treatment group, respectively.

In CP-4-006, |||||||| of the patients in the somatrogon treatment group and |||||||| of the patients in the Genotropin treatment group had any prior medication. The most frequently reported prior treatments were |||||||| and ||||||||. In the somatrogon treatment group, ||||||||% of the patients had a prior |||||||| and in the Genotropin treatment group, ||||||||% of the patients had a prior ||||||||. In CP-4-009, ||||||||% of the patients in the somatrogon treatment group and ||||||||% of the patients in the Genotropin treatment group had any prior medication. The most frequently reported prior treatments ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Interventions

In CP-4-006, somatrogon was provided as a solution for injection, containing 20 mg/mL or 50 mg/mL in a multi-dose, disposable pre-filled pen. The formulation included citrate, histidine, sodium chloride, metacresol, poloxamer 188, and pH = 6.6. Genotropin was provided in a 2-chamber cartridge for administration with the Genotropin Pen delivery device (Goquick Pen delivery device). The Genotropin Pen was used for daily (evening or bedtime) SC administration of Genotropin. Training on drug administration was provided for patients and parents or a legal guardian. The device was intended to assist self-injecting adult and pediatric patients, health care professionals, and caregivers with the daily SC injection, primarily self-administered at home or in a health care environment. The starting dose for somatrogon administration was 0.66 mg/kg per week. The starting dose regimen for Genotropin was 0.034 mg/kg per day (or 0.24 mg/kg per week divided equally into 7 injections over a week). If a patient on Genotropin missed a dose, they could resume the medication with the next scheduled dose. In case the prescribed dose could not be fully set for a single injection on a pen, the patient was instructed to split the dose into 2 injections. The partial dosing could occur in 2 cases:

• Do 2 injections using 1 pen — In the event that the prescribed dose was higher than the maximum dose, which could be selected according to the pen amount, the patient was instructed to subtract the dose already received from the prescribed dose and set the pen accordingly.

• Split dose between 2 pens, the current pen and a new pen — This could happen when a complete dose could not be fully administered from the pen in use; in this case, the patient was instructed to subtract the dose already delivered from the prescribed dose and set the new pen accordingly.

Whether from the same pen or from a new pen, it was important with the second injection that the patient replace the needle and rotate the injection. The doses of somatrogon and Genotropin (main study only) were assessed every 3 months based on a patient’s body weight. Doses were determined by the IWRS and included an automatic rounding to the closest pen increment (0.2 increments in 20 mg/mL pens and 0.5 increments in 50 mg/mL pens). Doses were decreased for safety reasons according to the predefined, dose-adjustment criteria (which were based on the severity of adverse events or repeated, elevated levels of IGF-I SDS). For patients on somatrogon, the dose was decreased based on 2 repeated day-4 levels of IGF-I greater than 2.0 SDS. For patients on Genotropin, the dose was decreased based on repeated IGF-I levels greater than 2.0 SDS. If a patient had an IGF-I level greater than 2.0 SDS, they were to return for an unscheduled visit within 4 weeks to 6 weeks after the greater than 2.0 SDS result, on day 4 post dose for somatrogon-treated patients or any day for Genotropin-treated patients. If their IGF-I level was still greater than 2.0 SDS, the most recent dose was to be reduced by 15% (i.e., to 0.56 mg/kg per week for somatrogon and 29 mcg/kg per day for Genotropin). The patient was to be treated with the new dose for at least 4 weeks before a subsequent IGF-I determination could result in a further dose modification. At the time of the next visit, if the IGF-I was still greater than 2.0 SDS, the dose was to be reduced by an additional 15% to 0.48 mg/kg per week for somatrogon and to 24.7 mcg/kg per day for Genotropin. If the IGF-I was still greater than 2.0 SDS following 2 dose reductions (at least 4 weeks after the second dose reduction), the course of treatment would be decided on an individual basis. If a patient on somatrogon treatment missed a dose by not more than 72 hours, then the patient had to take a full dose as soon as they remembered. If the dose was more than 72 hours late, the patient could not take a dose for the whole week and would continue taking the study medication on the regular day the following week.

In CP-4-009, somatrogon was provided as a solution for injection, containing 20 mg/mL or 50 mg/mL in a multi-dose, disposable pre-filled pen. The device used in this study had not been approved or certified in Japan. The formulation included citrate, histidine, sodium chloride, metacresol, poloxamer 188, and pH = 6.6. Genotropin was provided in a 2-chamber cartridge for administration with the Genotropin Pen delivery device (Goquick Pen delivery device). If a patient on somatrogon treatment missed a dose for not more than 72 hours, then the patient had to take a full dose as soon as they remembered. If the dose was more than 72 hours late, the patient could not take a dose for the whole week and would continue taking the study medication on the regular day the following week. The starting dosage regimen for Genotropin was 0.025 mg/kg per day (or 0.175 mg/kg per week divided equally to 7 injections over a week). If a patient on Genotropin missed a dose, they could resume the medication with the next scheduled dose. In case the prescribed dose could not be fully set for a single injection on a pen, the patient was instructed to split the dose into 2 injections. The partial dosing could occur in 2 cases:

• Do 2 injections using 1 pen — In the event that the prescribed dose was higher than the maximum dose (24 mg pen is 12 mg and the 60 mg pen is 30 mg), which could be selected according to the pen amount, the patient was instructed to subtract the dose already received from the prescribed dose and set the pen accordingly.

• Split dose between 2 pens, the current pen and a new pen — This could happen when a complete dose could not be fully administered from the pen in use; in this case, the patient was instructed to subtract the dose already delivered from the prescribed dose and set the new pen accordingly.

Whether from the same pen or from a new pen, it was important with the second injection that the patient replace the needle and rotate the injection. The doses of somatrogon and Genotropin (main study only) were assessed every 3 months based on a patient’s body weight. Doses were determined by the interactive response technology (IRT) and included an automatic rounding to the closest pen increment (0.2 increments in 20 mg/mL pens and 0.5 increments in 50 mg/mL pens). Doses were decreased for safety reasons according to the predefined, dose-adjustment criteria (which were based on the severity of adverse events or repeated, elevated levels of IGF-I SDS). For patients on somatrogon, the dose was decreased based on 2 repeated day-4 levels of IGF-I greater than 2.0 SDS. For patients on Genotropin, the dose was decreased based on repeated IGF-I levels greater than 2.0 SDS. If a patient had an IGF-I level greater than 2.0 SDS, they were to return for an unscheduled visit within 4 weeks to 6 weeks after the greater than 2.0 SDS result, on day 4 post dose for somatrogon-treated patients or any day for Genotropin-treated patients. If their IGF-I level was still greater than 2.0 SDS, the most recent dose was to be reduced by 15% (i.e., to 0.56 mg/kg per week for somatrogon and 21 mcg/kg per day for Genotropin). The patient was to be treated with the new dose for at least 4 weeks before a subsequent IGF-I determination could result in a further dose modification. At the time of the next visit, if the IGF-I was still greater than 2.0 SDS, the dose was to be reduced by an additional 15% to 0.48 mg/kg per week for somatrogon and to 18 mcg/kg per day for Genotropin. If the IGF-I was still greater than 2.0 SDS following 2 dose reductions (at least 4 weeks after the second dose reduction), the course of treatment would be decided on an individual basis.

In CP-4-006, in the somatrogon treatment group, |||||||||% of the patients received concomitant medications and in the Genotropin treatment group, |||||||||% of the patients received concomitant medications. The most frequent medications included ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. In CP-4-009, in the somatrogon treatment group, |||||||||% of the patients received concomitant medications and in the Genotropin treatment group, |||||||||% of the patients received concomitant medications. The most frequently reported concomitant medication included |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

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 as follows. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 3.

Height Velocity

The primary efficacy outcome evaluated the annual height velocity in cm per year at 12 months. This was based on the difference between the heights at 12 months and baseline. Height was to be measured using a calibrated wall-mounted stadiometer and this process was to be conducted at the same time of the day for each visit, preferably in the morning. To ensure the consistency of results, ideally the same auxologist would perform the measurements for each patient at each visit. Three independent readings were recorded for each visit.

Auxologic Response

Auxologic responses were the secondary outcomes, evaluated as annualized height velocity at 6 months, a change in height SDS at 6 months and 12 months, and a change in bone maturation at 12 months. Annualized heigh velocity at 6 months was estimated based on the difference between the heights at 6 months and baseline. Changes in height SDS at 6 months and 12 months were determined from the age and sex standards listed in the US’s 2000 Centers for Disease Control and Prevention growth charts in CP-4-006 and from the age and gender standards listed in the national survey in year 2000 in CP-4-009. Change in bone maturation was estimated at 12 months. Bone maturation was calculated as bone age divided by chronological age. The bone age was to be determined by an X-ray according to the Greulich-Pyle method.^10,11

Serum Biomarker Levels

Clinical evaluations of IGF-I and IGF-I SDS were performed at every study visit during the main study except visit 3, visit 6a, visit 6b, visit 8a, and visit 9. Descriptive statistics were used to summarize the results of serum biomarker levels.

Health-Related Quality of Life

CP-4-006 used the QoLISSY questionnaire to assess HRQoL. The questionnaire was designed for self-reported use by adolescents between the ages of 8 years and 18 years and observer-reported use by parents of children between the ages of 4 years and 18 years for assessment of HRQoL. Items from 3 core domains (physical, social, and emotional) are summed for a 22-item total score. The core domains are accompanied by 28 additional items reflecting coping (10 items), beliefs (4 items), and treatment (14 items). Items are answered using a 5-point Likert type scale; subscale scores are transformed to a score from 0 to 100 where higher values represent a higher HRQoL. The 3 dimensions of the QoLISSY questionnaire were calculated individually and as a combined core total score based on the QoLISSY scoring manual. The core score is calculated as the sum of the means of these 3 dimensions and divided by 3. MID is not estimated for QoLISSY. HRQoL using the QoLISSY was not reported in the CP-4-009 study. The QoLISSY questionnaire was ||||||||||||||||||||||||||| completed for the following countries using a validated translated tool: US, Australia, New Zealand, Belarus, Russia, Ukraine, UK, and Spain.

Absent or Delayed Sexual Development During Puberty

Absent or delayed sexual development during puberty was not reported as an outcome in either study but was identified by CADTH as an outcome of interest.

Other Patient-Reported Outcome Responses

In CP-4-006, the OAT was used to record the observer’s assessment of the use of the device by patients or caregivers to administer somatrogon by injection. The observer recorded whether an injection attempt was successful or not based on the question from the OAT, “…did the user successfully inject into an acceptable injection site without physical assistance?” The injection attempt was considered successful if the observer answered “yes” to the questions for all attempts on the form. Of note, the instructions for the OAT advised the observer as follows: “|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.” This introduces substantial subjectivity into the assessment of a successful injection administration.⁹

The PAT was also used to record the patient’s or caregiver’s injections of somatrogon, based on an assessment by the user of the pen or by the parent or legal guardian. The following questions were used to determine a successful injection attempt via the PAT: “Did the dose window show ‘0’ when you finished your injection?” and “Do you believe that a full dose was injected?” The injection attempt was considered successful if the subject answered yes to both questions for all attempts on the form.¹⁰ Other PRO responses were not reported in the CP-4-009 study.

Evidence of MID, validity, reliability, and responsiveness of the OAT and PAT were not identified during this review.

Statistical Analysis

CP-4-006 aimed to establish noninferiority of somatrogon compared to Genotropin by a noninferiority margin of −1.8 cm per year. Noninferiority was concluded if the lower bound of the 2-sided 95% CI for the mean treatment difference between somatrogon and Genotropin in the primary efficacy end point was greater than or equal to –1.8 cm per year or more. In CP-4-006, an estimated sample size of 100 patients per treatment group were required to achieve at least 80% power for the noninferiority test between the treatment groups with a 2-sided 0.05 level of significance and assumed 10% dropout rate for each treatment group. The between-patient SD of annual growth rate of 2.5 cm per year in both treatment groups was assumed. The true mean treatment difference in the primary efficacy end point was assumed to be –0.8 cm per year. It was planned that 110 patients would be randomized to each treatment group for a total of 220 patients.

The rationale for the choice of the noninferiority margin was based on:

• Historical data from MacGillivray et al. (1996)²⁶ and Wilton and Gunnarsson (1988)²⁷ height velocity response for the first year of daily GH ranged from 10.2 cm per year (SD = 2.5) to 11.4 cm per year (SD = 2.5). Using the SD of 2.5 from these references, a noninferiority margin of –1.8 cm per year was within 1 SD of the expected results, and approximately 23% of the reference treatment response distribution would be below this value.

• Assuming the height velocity response for daily GH treatment is 11.5 cm per year in the first year, a margin of –1.8 cm per year would show that 84% of the growth rate from the reference daily GH treatment effect on the approved active control is retained.

• Other studies of long-acting GH compared to daily GH have used noninferiority margins of –1.8 cm to –2.0 cm per year as used in a phase III pivotal trial (NCT02781727). The use of –1.8 cm per year is the more conservative value based on the precedent set with these other studies.

If the condition for noninferiority was met, an assessment of superiority was conducted on the primary end point. Superiority would be achieved if the lower bound of the 2-sided 95% CI for the mean height velocity difference of somatrogon minus Genotropin is greater than or equal to 0 cm per year or more. Due to the sequential tests, no correction for multiple comparisons was performed.

CP-4-009 aimed to establish comparability of somatrogon to Genotropin by a comparability margin of −1.8 cm per year. Comparability was concluded if the mean treatment difference between somatrogon and Genotropin in the primary efficacy end point was greater than or equal to –1.8 cm per year or more. In CP-4-009, an estimated sample size of 20 patients per treatment group was required to achieve at least 88% power to detect that the observed difference between the treatment groups was greater than –1.8 cm per year. The between-patient SD of annual growth rate of 2.5 cm per year in both treatment groups was assumed. The true mean treatment difference in the primary efficacy end point was assumed to be –0.8 cm per year.

In CP-4-009, statistical hypothesis testing for superiority was not planned.

For both studies, in the primary efficacy analysis of annualized height velocity at 12 months, the CI for the difference of means between the 2 treatments was derived from an analysis of covariance (ANCOVA) model using multiple imputations assuming missing not at random (MNAR) on the full analysis set population and imputing the missing results. The ANCOVA model included classification terms for treatment, age group (3 years to 7 years and 0 days or > 7 years and 0 days), sex (male or female), peak GH levels (≤ 3 ng/mL, > 3 to ≤ 7 ng/mL, and > 7 to ≤ 10 ng/mL), and region (region 1: Western Europe, Israel, Australia, New Zealand, Canada, and the US; region 2: Central and Eastern Europe, Greece, Turkey, Latin America, and Asia, except for India and Vietnam; region 3: India and Vietnam). The model also included baseline height SDS as a covariate. The determination of noninferiority was based on LSM for the 2 treatments from the ANCOVA model and the 95% CI of the differences between the treatments. If the primary end point of noninferiority of somatrogon in comparison to Genotropin was met, an assessment of superiority of somatrogon over Genotropin at 12 months was to be conducted. Superiority was achieved if the lower bound of the 2-sided 95% CI for the mean height velocity difference between somatrogon and Genotropin was 0 cm per year or more. The MNAR and fully conditional specification method using multiple imputations was applied for the primary efficacy outcome.

For both studies, a similar ANCOVA model that was used for the primary end point was used to analyze the auxologic responses (i.e., annualized height velocity at 6 months, and a change in height SDS at 6 months and 12 months), which were the secondary end points. LSM estimates for the 2 treatments and the 95% CI of the difference between the treatments will be presented. For bone maturation, descriptive statistics (including univariate 95% CI) were reported.

In CP-4-006, for serum biomarker levels, descriptive statistics were reported for observed factors and change from baseline for the biochemical end points at each visit. The number and percent of patients who had IGF-I SDS greater than 2 was summarized at each visit. The number and percent of patients who achieved IGF-I normalization (defined as IGF-I SDS between –0.5 and 1.5, inclusive) were summarized. The number and percent of patients who had IGF-I SDS greater than 2.0 were summarized at each visit. This was not reported in the CP-4-009 study.

In CP-4-006, HRQoL was analyzed using the QoLISSY tool. The QoLISSY questionnaire had 3 dimensions (physical, social, and emotional) that would be calculated individually and as a combined core total score based on the QoLISSY scoring manual. Scores for individual dimensions were transformed from raw scores to a scale of 0 to 100. The core score was calculated as the sum of the means of these 3 dimensions and divided by 3. This tool was not used in CP-4-009.

In CP-4-006, other PROs were summarized using descriptive statistics for the OAT and the PAT. The number and percentage of successful single injections for PAT was to be summarized overall. The number and percentage of successful single injections for OAT was to be summarized overall. The number and percentage of successful single injections for PAT and OAT was summarized by age group, sex, and race. The number and percentage of the number of attempts required to achieve a success was summarized for PAT and OAT. The OAT and PAT were performed only in the US. This tool was not used in CP-4-009.

Missing Data

In both studies, for the primary and secondary end point analyses performed by ANCOVA, multiple imputations assuming MNAR were used to impute missing results. The imputation was by treatment group. The imputation model included randomization stratification factors and baseline height SDS. A total of 100 imputed datasets were created and the seed was set using the database lock date. An ANCOVA model was used to calculate the LSM and 95% CI of the treatment difference for each imputed set. The number of imputed datasets was increased if necessary. For somatrogon, values below the limit of quantification at the baseline visit were treated as 0.

Sensitivity Analysis

The ANCOVA-based primary efficacy analysis was performed using the per-protocol (PP) set.

|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Subgroup Analysis

Although several subgroups were identified by the sponsor, only those subgroups identified in the protocol are presented (i.e., age, sex, risk of GHD, and prior use of GH therapy).

Analysis populations

The safety analysis set included all patients who had received at least 1 dose of study treatment. Patients were analyzed according to actual treatment received.

The efficacy analyses were based on the full analysis set, defined as patients who were randomized and had received at least 1 dose of study medication. Patients were analyzed according to randomized treatment group.

The PP set consisted of all randomized patients who did not have any major protocol deviations. Patients who had major protocol deviations were identified in a blinded review.

Results

Patient Disposition

Patient disposition and protocol violations for CP-4-006 and CP-4-009 are presented in Table 11. In CP-4-006, 0.9% of the patients discontinued in each of the treatment groups. In CP-4-009, 4.5% of the patients in the Genotropin treatment group discontinued from treatment. In the somatrogon treatment group, |||||||||% of the patients were continued over to the LT-OLE phase, and |||||||||% of the patients in the Genotropin treatment group continued over to the LT-OLE phase. Protocol violations were documented in both studies. In CP-4-006, |||||||||% and |||||||||% of patients reported major protocol violations in the somatrogon treatment group and Genotropin treatment group, respectively. In the somatrogon treatment group, |||||||||% of patients reported drug and dosing administration-related protocol violations while in the Genotropin treatment group, |||||||||% of patients reported the same. Patients with a major protocol violation were excluded from the PP set. In CP-4-009, |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Exposure to Study Treatments

The extent of exposure was evaluated in the safety analysis set. The extent of exposure in the study is presented in Table 12. In CP-4-006, the main study lasted up to 15 months (a 12-month treatment period, up to 12 weeks of screening, and a 1-month post-dosing end-of-study follow-up for patients who discontinued the study early or did not continue in the LT-OLE phase). In CP-4-009, the total duration of patient participation in the main study lasted up to 14 months (up to 5 weeks of screening, 12 months of active treatment, and 1 month of follow-up).

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported as follows. Absent or delayed sexual development during puberty was not an efficacy outcome analyzed in either CP-4-006 or CP-4-009.

Height Velocity

In study CP-4-006, the LSM treatment difference for the mean height velocity after 12 months of treatment was 0.33 cm per year (95% CI, –0.24 to 0.89). The lower bound of the 2-sided 95% CI for mean height velocity was greater than the pre-specified noninferiority margin of –1.8 cm per year, indicating that weekly somatrogon administration is noninferior to daily Genotropin administration. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. In study CP-4-009, the treatment difference (somatrogon minus Genotropin) in LSM height velocity (cm per year) was 1.79 cm per year with a 2-sided 95% CI (0.97 to 2.61). Since the point estimate of 1.79 cm per year was greater than the pre-established margin of –1.8 cm per year, it was concluded that weekly somatrogon was comparable to daily Genotropin. The results of the primary efficacy outcome are presented in Table 13. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Auxologic Response

The secondary efficacy outcome was the mean annualized height velocity at 6 months. In CP-4-006, the treatment mean difference was ||||||||||||||||||||||||||||||||||||||. In CP-4-009, the treatment mean difference was |||||||||||||||||||||||||||||||| in favour of somatrogon. The results of the mean annualized height velocity at 6 months are presented in Table 14.

Change in height SDS was evaluated at 6 months and 12 months. In CP-4-006, the treatment mean difference between the somatrogon treatment group and Genotropin treatment group at 6 months was ||||||||||||||||||||||||||||||||. In CP-4-009, the treatment mean difference between the somatrogon treatment group and Genotropin treatment group at 6 months was |||||||||||||||||||||||||||||| in favour of somatrogon. In CP-4-006, the treatment mean difference between the somatrogon and Genotropin treatment groups at 12 months was 0.05 (95% CI, –0.06 to 0.16). In CP-4-009, the treatment mean difference between the somatrogon and Genotropin treatment groups at 12 months was ||||||||||||||||||||||||||||||||| in favour of somatrogon. The results of a change in height SDS at 6 months and 12 months are presented in Table 15 and Table 16, respectively.

Change from baseline in bone maturation was evaluated at 12 months and was similar between the treatment groups of somatrogon and Genotropin. In CP-4-006, the mean (SD) change from baseline was 0.05 (0.09) and 0.06 (0.10) in the somatrogon group and Genotropin group, respectively. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. The results are presented in Table 17.

Serum Biomarker Levels

For the purposes of this review, serum biomarker levels were evaluated using IGF-I levels and IGF-I SDS. Results were reported as change from baseline at 6 months and 12 months. The mean absolute IGF-I and IGF-I SDS values were reported only in the CP-4-006 study. At 6 months, the mean (SD) change from baseline in IGF-I levels was ||||||||||||| in the somatrogon treatment group and ||||||||||||| in the Genotropin treatment group. At 12 months, the mean (SD) change from baseline in IGF-I levels was ||||||||||||| in the somatrogon treatment group and ||||||||||||| in the Genotropin treatment group. At 6 months, the mean (SD) change from baseline in IGF-I SDS was ||||||||||||| in the somatrogon treatment group and ||||||||||||| in the Genotropin treatment group. At 12 months, the mean (SD) change from baseline in IGF-I levels was ||||||||||||| in the somatrogon treatment group and ||||||||||||| in the Genotropin treatment group. Results of the serum biomarker levels are presented in Table 18 and Table 19.

Health-Related Quality of Life

The HRQoL was measured in CP-4-006 using the QoLISSY instrument. No MID was identified from literature for the QoLISSY instrument. The mean (SD) change from baseline in the total score of the QoLISSY tool was ||||||||||||| in the somatrogon treatment group and ||||||||||||| in the Genotropin treatment group. The results of the change from baseline in the 3 domains of the QoLISSY tool are presented in Table 20.

Other Patient-Reported Outcome Responses

In CP-4-006, other PRO responses were measured only in the somatrogon treatment group. The PRO instruments used were the PAT and OAT. These analyses were performed only in the US. The somatrogon injections were evaluated by subgroups (age, sex, and race). For the PAT, in the group of those patients ranging in age from 3 years to less than 7 years, ||||||||% of the administered injections were successful. And ||||||||% of the administered injections in the group of patients older than 7 years of age were successful. As well, ||||||||% of injections in male patients were successfully administered as compared to ||||||||% of injections in female patients. Lastly, ||||||||% of the somatrogon injections were successfully administered in patients who were Asian as compared ||||||||% of injections in patients who were White.

For the OAT, the somatrogon injection was successfully administered in |||||||| of all patient subgroups.

Sensitivity Analysis

To account for missing data, several sensitivity analyses were conducted for the primary efficacy end point. The sensitivity analysis results were aligned with the main analyses and established noninferiority of somatrogon over Genotropin in CP-4-006 and comparability of somatrogon to Genotropin in CP-4-009.

Subgroups

Subgroup analyses conducted in both studies that were identified as being of interest in the CADTH review protocol focused on age (prepubertal versus pubertal children) and sex (male versus female). Results were reported for the primary efficacy outcome and the secondary outcomes of annual height velocity at 6 months and annual height velocity SDS at 6 months and 12 months.

Harms

Only those harms identified in the review protocol are reported as follows. See Table 21 for detailed harms data. Information about harms in the CP-4-009-OLE phase has been reported in the Other Relevant Evidence section of this report.

Adverse Events

In CP-4-006, 87.2% and 84.3% of patients in the somatrogon group and Genotropin group, respectively, reported at least 1 adverse event. The most commonly occurring adverse events were injection site pain (39.4% and 25.2% of patients in the somatrogon group and Genotropin group, respectively), nasopharyngitis (22.9% and 25.2% of patients in the somatrogon group and Genotropin group, respectively), pyrexia (16.5% and 13.9% of patients in the somatrogon group and Genotropin group, respectively), and headache (16.5% and 21.7% of patients in the somatrogon group and Genotropin group, respectively).

In CP-4-009, ||||||||% and ||||||||% of the patients in the somatrogon group and Genotropin group, respectively, reported at least 1 adverse event. The most commonly occurring adverse events were injection site pain (72.7% and 13.6% of patients in the somatrogon group and Genotropin group, respectively), nasopharyngitis (54.5% and 50.0% of patients in the somatrogon group and Genotropin group, respectively), pyrexia (18.2% and 13.6% of patients in the somatrogon group and Genotropin group, respectively), and headache (9.1% and 15.8% of patients in the somatrogon group and Genotropin group, respectively).

Serious Adverse Events

In CP-4-006, 2.8% and 1.7% of patients in the somatrogon group and Genotropin group, respectively, reported at least 1 serious adverse event. The most commonly occurring serious adverse events were under the system organ class of infections and infestation (2.8% and 0.9% of patients in the somatrogon group and Genotropin group, respectively). In the Genotropin treatment group, 0.9% of patients reported ureterolithiasis as a serious adverse event.

In CP-4-009, 9.1% of patients in both the somatrogon group and Genotropin group reported at least 1 serious adverse event. In the somatrogon treatment group, 4.5% of patients reported a serious adverse event under the system organ class of infections and infestations. As well, 4.5% of patients in the somatrogon treatment group reported hypoparathyroidism and febrile convulsion as a serious adverse event. In the Genotropin treatment group, 4.5% of patients reported craniopharyngioma and asthma as a serious adverse event.

Withdrawals Due to Adverse Events

In CP-4-006, 1 patient permanently withdrew from the study due to an injection site erythema and injection site induration in the somatrogon treatment group and no patients permanently discontinued from the study due to an adverse event in the Genotropin group.

In CP-4-009, only 1 patient withdrew from the study due to a craniopharyngioma, in the Genotropin treatment group.

Mortality

Neither study had any mortalities.

Notable Harms

The notable harms identified in the CADTH review protocol included the following: injection-related events, glucose intolerance and/or insulin resistance, excess IGF-I levels, malignancies, benign intracranial hypertension, slipped capital femoral epiphysis, scoliosis, tonsillar hypertrophy, carpal tunnel, and peripheral edema. In CP-4-006, of the identified notable harms, 43.1% of patients and 25.2% of patients in the somatrogon group and Genotropin group, respectively, reported experiencing an injection-related event. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. In CP-4-009, of the identified notable harms, 72.7% of patients in the somatrogon group reported experiencing an injection-related event. One patient in the Genotropin treatment group reported for malignancies under the system organ class of neoplasms benign, malignant, and unspecified (including cysts and polyps). ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Critical Appraisal

Internal Validity

CP-4-006 and CP-4-009 were both open-label studies; however, the studies used an IWRS or IRT to randomize patients.

Randomization was stratified by age group, sex, peak GH levels, and region. In both studies, baseline characteristics were mostly well balanced, except for age, sex, and mean (SD) and median (range) height and weight in CP-4-009. There were low dropout rates in both studies, which limited selection bias. The clinical expert consulted by CADTH was of the opinion that an imbalance in age and sex in study CP-4-009 could influence the efficacy results in favour of somatrogon. The clinical expert noted that in CP-4-009, the difference in age would not impact outcomes observed within the first year, but it could impact the final adult height. The concomitant medications used in both studies were reasonable to expect from a Canadian clinical perspective.

The clinical expert consulted by CADTH expressed that the commonly used treatment for GHD in Canada is Humatrope. Both CP-4-006 and CP-4-009 had only Genotropin as the active comparator, despite other approved comparators being available for treatment in Canada. No direct or indirect evidence against GHD used in clinical practice within Canada was identified; hence, the comparative efficacy and safety of somatrogon against other regimens such as somatropin are unknown.

No justification for the comparability criteria was provided in study CP-4-009. While study CP-4-009 met the pre-specified criteria for comparability, this should not be confused with the unequivocal demonstration of equivalence, noninferiority, or superiority.

The chosen noninferiority margin of –1.8 cm per year or more was supported by historical studies,^26,27 1 of which had a higher dosing of somatropin than that used in CP-4-006 and CP-4-009. In MacGillivray et al. (1996),²⁶ the total weekly dose of somatropin was 0.3 mg/kg and in Wilton and Gunnarsson (1988),²⁷ the doses ranged from 0.3 IU/kg per week to 0.8 IU/kg per week.

The primary outcomes of CP-4-006 and CP-4-009 looked to establish noninferiority and comparability of somatrogon with Genotropin, respectively. Once noninferiority was established, analyses of the secondary efficacy outcomes was conducted. However, these end points were not part of a hierarchical statistical testing plan and were not controlled for multiplicity, and no P values were reported.

CP-4-006 reported HRQoL and other PRO responses; however, these tools were administered only in selected locations with a very small sample size and as the study was open label, this could have biased the results of the efficacy outcomes in favour of somatrogon. Moreover, only a complete case analysis was carried out for this data, with different subsets of patients at each time point. As it is not a true full analysis set population, both outcomes would be subjected to an increased risk of bias due to the complete case analysis approach. No MID was identified from literature for the QoLISSY questionnaire or the OAT and PAT instruments.

The clinical expert consulted by CADTH stressed that adherence to treatment was of concern. Given the absence of patient input, CADTH is unable to determine the rate of adherence for somatrogon. Since the PAT and OAT were conducted only in the US with very small patient populations, the results can be viewed only as supportive evidence.

In CP-4-006, multiple sensitivity analyses were conducted to account for missing data for the primary efficacy outcome, and they were supportive of the primary efficacy outcome. In CP-4-009, a sensitivity analysis was performed using the PP population and was supportive for the primary efficacy outcome. However, the clinical expert consulted by CADTH was of the opinion that the sample size of CP-4-006 was very small, thereby limiting the interpretation of overall results.

The clinical expert consulted by CADTH was of the opinion that the safety results were satisfactory, and they were comfortable with the overall results. However, a concern regarding injection site reaction was flagged. Given that somatrogon was administered once weekly and Genotropin was administered daily, a higher number of injection-related adverse events in somatrogon could not be explained.

External Validity

The clinical expert noted that, based on baseline demographic and disease characteristics, the study population was fairly generalizable to Canadian patients; however, they were of the opinion that the age for inclusion in both studies (i.e., ≥ 3 years) was not reflective of Canadian practice, since patients with GHD would be identified and treated in infancy. They also noted that in CP-4-006, 20% of the cohort was Asian, which is a higher level than that seen in Canada. The clinical expert also commented on how the numbers of indigenous peoples who are treated in Canada are underestimated in both studies. The clinical expert also noted that the proportion of patients with a peak GH level of greater than 7 ng/dL was higher than what is observed in Canadian clinical practice. The dosing of Genotropin was aligned with Health Canada–approved dosing.

Most of the outcomes assessed in both studies were relevant to clinical practice and results were clinically meaningful. The experts were satisfied with the timing of the assessment of the primary and secondary efficacy end points. According to the clinical expert consulted for this review, the HRQoL outcomes are not typically used in clinical practice as far as routine management of prepubertal children with GHD is concerned.

The clinical expert consulted by CADTH was of the opinion that GH therapies are long-term therapies, and even though the primary end point of each of the 2 studies was met, in the absence of long-term comparative efficacy and safety results, interpreting the long-term clinical meaningfulness of somatrogon is limited.

Indirect Evidence

A focused literature search for network meta-analyses dealing with somatrogon and GHD was run in MEDLINE All (1946 − ) on June 25, 2021. No limits were applied.

No indirect evidence was submitted by the sponsor or identified in our literature search that would match the inclusion and exclusion criteria of this review.

Other Relevant Evidence

This section includes submitted long-term extension studies and additional relevant studies included in the sponsor’s submission to CADTH that were considered to address important gaps in the evidence included in the systematic review.

Patient Perception of Treatment Burden Study (C0311002)

Study C0311002 (study 002) was included as a study relevant to this review for the evaluation of the patient perception of somatrogon, which was not assessed in the studies included in the systematic review. Study 002 was a randomized, open-label, multi-centre, 2-period crossover study of children aged 3 years to less than 18 years with GHD. The primary objective of this study was to evaluate the treatment burden of a weekly injection of somatrogon and a daily injection of somatropin (Genotropin). Secondary objectives included an evaluation of patient and caregiver self-assessments of treatment experience, and an evaluation of the psychometric properties of the DCOA questionnaires. The latter is not reviewed in this summary.

Methods

The study included a 30-day screening period, a 24-week treatment period, and a follow-up phone call 4 weeks after the last clinic visit. Patients were required to be stable on treatment with daily somatropin for a minimum of 3 months before enrolment.

Key inclusion and exclusion criteria for study 002 has been presented in Table 22. To be included in study 002, patients were required to be from 3 years to less than 18 years of age with isolated GHD or GH insufficiency as part of multiple pituitary hormone deficiencies, to have an IGF-I SDS less than 2, and to be on treatment with 1 of the following formulations of somatropin for at least 3 months: Genotropin Pen, Genotropin Goquick Pen, Humatropen (US only), or Omnitrope Pen (US only). Patients were excluded from study 002 if they had a history of cancer, radiation or chemotherapy, or diabetes mellitus. Patients were also excluded if they had psychosocial dwarfism, were born SGA, had other causes of short stature, had chromosomal abnormalities, had a history of exposure to long-acting hGH preparation, had treatment with regularly scheduled medications other than the somatropin formulations listed in the inclusion criteria, or had closed epiphyses.

Patients were randomized in a 1:1 ratio to 1 of 2 sequences as illustrated in Figure 2. Randomization was stratified by region (the US or EU) and the type of Genotropin injection device used (Genotropin Pen or Genotropin Goquick). Patients randomized to sequence 1 received treatment with once-daily somatropin for 12 weeks followed by 12 weeks of treatment with once-weekly somatrogon. Patients randomized to sequence 2 received treatment with once-weekly somatrogon for 12 weeks followed by 12 weeks of treatment with once-daily somatropin.

Study visits occurred at baseline and at week 6, week 12, week 18, and week 24, with a follow-up phone call at week 28. Patients and caregivers were asked to complete the DCOA questionnaires at the end of each 12-week treatment period (DCOA 1 at week 12 and DCOA 2 at week 24). The DCOA questionnaires are described in the outcomes section below.

Figure 2: Study Design for Study 002

DCOA-1 = Dyad Clinical Outcome Assessment 1; DCOA-2 = Dyad Clinical Outcome Assessment 2; PGIS-IDA = Patient Global Impression–Severity: Impact on Daily Activities; v = visit; w = week; wk = week.

Source: Study 002 Clinical Study Report (2020).²⁸

Populations

A summary of baseline characteristics for patients included in study 002 is provided in Table 23. Overall, the mean age of patients was 10.7 years (SD = 3.5 years). The majority of patients were male (82.8%) and White (93.1%), |||||||||||||||||||||||||||||||| lived in ||||. The mean height and weight of patients was |||||| cm (SD = |||||| cm) and |||||| kg (SD = |||||| kg), respectively. Most patients were using |||||||||||| before study start (|||||| using the Genotropin Pen and |||||| were using the Genotropin Goquick Pen). The remainder had been using |||||||||||||||||| or ||||||||||||||||||||||||.

In general, the treatment groups were well balanced by the baseline characteristics presented. Differences to note include the proportion of patients who were male (sequence 1 = 79.1% versus sequence 2 = 86.4%), and those with prior experience with the |||||||||||||||||||||||| (sequence 1 = |||||| versus sequence 2 = ||||||) and |||||||||||| (sequence 1 = |||||| versus sequence 2 = ||||||).

Interventions

The interventions used in study 002 were somatrogon and Genotropin. More specifically, somatrogon 60 mg/1.2 mL solution for injection was available as a multi-dose disposable pre-filled pen for SC self-injection. Somatrogon was administered once weekly at approximately the same time on a regularly scheduled day of the week.

Commercially available Genotropin was the comparator in study 002. The product varied by region. For patients in the US, Genotropin was available as a 5 mg dose or 12 mg dose 2-chamber cartridge administered using the corresponding Genotropin Pen 5 and Genotropin Pen 12 delivery devices. In the EU region, Genotropin was available as a 5.3 mg dose or 12 mg dose 2-chamber cartridge administered using the Genotropin Pen 5.3 and Genotropin Pen 12 delivery devices. These doses were also available for administration using the Genotropin Goquick pre-filled pen. Genotropin was administered daily by SC administration at the same time of day as they were injecting their daily GH at the time of screening.

Interventions were administered at the clinical site at the start of 2 treatment periods, then self-administered at home for the rest of the study. There were no washout periods as the treatments were required to be taken continually.

Outcomes

Dyad Clinical Outcome Assessment and Patient Life Interference Questionnaire

The DCOA was designed to measure the experience of patients taking rhGH GHD injections. The intention of the DCOA is to demonstrate significant benefit of a weekly injection compared to a daily injection in terms of adherence and acceptance. As this study assessed GH injections in children, the patient and caregiver answer the questions together (a dyadic approach). The DCOA comprises 2 main aspects — an assessment of treatment burden and preference. Treatment burden includes concepts of patient life interference, injection signs and symptoms, pen ease of use, ease and convenience of injection schedule, and caregiver life interference. Preference includes concepts of missed injection, patient satisfaction, and willingness to continue. The 9 items of the DCOA 1 questionnaire and corresponding number of questions and evaluation scale are summarized as follows:

• pen ease of use (5 questions, 5-point scale each)

• ease of the injection schedule (1 question, 5-point scale)

• convenience of the injection schedule (1 question, 7-point scale)

• satisfaction with overall treatment experience (1 question, 5-point scale)

• willingness to continue injection schedule (1 question, 5-point scale)

• injection signs and symptoms (from patients aged 8 years and older) (4 questions, 0 to 10 scale each)

• assessment of signs (from caregivers for children aged < 8 years) (2 questions, 0 to 10 scale each)

• caregiver life interference, including family life interference (13 questions, 5-point scale each)

• missed injections (1 question, enter number of daily administrations missed (0 to 31), or number of weekly administrations missed (0 to 5)).

Treatment burden was assessed as the difference in mean overall life interference total scores between the weekly injection schedule and daily injection schedule as determined by the patient life interference questionnaire (which is part of DCOA 1) completed by the patient/caregiver dyad at baseline and after each treatment schedule experience. The patient life interference questionnaire outcome consisted of 7 questions, including 5 questions related to life interference (with daily activities, social activities, recreation/leisure activities, spending the night away from home, and with travel), 1 question about life interference due to changes to life routine, and 1 question about life interference due to the bother of GH injections. Questions were answered using a 5-point scale that ranged from “never” (1) to “always” (5). A total score was reported, which ranged from 7 to 35, where a lower score for life interference was considered to be a better outcome.

The DCOA 2 questionnaire was completed at week 24 and evaluated the proportion of patient/caregiver dyads that selected the weekly injection schedule compared to the daily injection schedule. The DCOA 2 questionnaire was assessed by the following domains and corresponding number of questions:

• choice of injection pen (1 question)

• preferred injection schedule (1 question)

• convenience of injection schedule (1 question)

• easier to follow (1 question)

• pen ease of use (4 questions)

• patient life interference (6 questions)

• caregiver life interference, including family life interference (11 questions)

• benefit relating to the injection schedule (1 question)

• intention to comply (4 questions).

A recently published field study demonstrated evidence of validity and reliability of the DCOA.²⁹ Internal consistency reliability demonstrated for all domains (Cronbach’s alpha ≥ 0.70), with the exception of the injection signs reported by caregiver domain (alpha = 0.653) and the satisfaction and willingness to continue domain (alpha = 0.589). Test-retest reliability was assessed and demonstrated across domains based on an intraclass correlation coefficient (ICC) of 0.70 or more. Some evidence of construct validity was reported in the overall sample (including children, adolescents, and adults). Concurrent validity was not demonstrated in the subgroup for children. Evidence of responsiveness or an MID was not identified. Additional information about this outcome is available in Appendix 3.

Patient Global Impression–Severity: Impact on Daily Activities

The Patient Global Impression–Severity: Impact on Daily Activities (PGI-S: IDA) was based on a single question, ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. Raw scores were transformed onto a scale from 0 to 100, where lower scores represent less impact on daily activities.

Statistical Analysis

The primary end point in study 002 was treatment burden, measured as the difference between weekly injection schedule and the daily injection schedule based on the mean overall life interference total scores.²⁸ The primary end point was analyzed using a linear mixed-effects model. Sequence, period, and treatment were included as fixed effects, and subject within sequence and within-subject error were included as random effects in the model.

Treatment experience using the DCOA questionnaires and the PGI-S: IDA questionnaire were secondary end points in study 002. Treatment experience via the DCOA 1 questionnaire was assessed using the difference in mean scores between the experience with weekly injections and daily injections, based on each variable of the DCOA 1 questionnaire. Treatment experience via the DCOA 2 questionnaire was assessed based on the proportion of patient/caregiver dyads that selected the weekly injection schedule compared to the daily injection schedule. Lastly, the PGI-S: IDA was reported at baseline and at the end of week 12 and week 24.²⁸

Patient Disposition

A total of 87 patients were included in this study, with 43 patients randomized to sequence 1 (Genotropin first) and 44 patients randomized to sequence 2 (somatrogon first). Overall, 2 patients randomized to sequence 2 discontinued from the study. One patient discontinued due to adverse events while receiving somatrogon and 1 patient discontinued due to a protocol violation while receiving Genotropin.

Exposure to Study Treatments

The duration of treatment was a mean of ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Efficacy

The mean (SD) of the total scores for the overall life interference questionnaire was a score of |||||||||||||||||||||||||||||| during treatment with Genotropin and ||||||||||||||||||||||| during treatment with somatrogon. The reported difference in overall scores was –15.49 (95% CI, –19.71 to –11.27; P < 0.001) in favour of treatment with somatrogon, indicating a lower treatment burden during treatment with somatrogon.

The results of the DCOA 1 questionnaire presented as total scores for each domain are summarized in Table 25. All of the domains of the DCOA 1 questionnaire were associated with numerically greater overall scores during treatment with Genotropin than during treatment with somatrogon, with 2 exceptions: the injection signs and symptoms domain (from patients aged 8 years and older) and the assessment of signs domain (from caregivers for children < 8 years old). The reported overall score for these 2 domains did not suggest a preference for either treatment based on the reported overall scores.

The results of the DCOA 2 questionnaire are summarized in Table 26. Overall, the proportion of patients who responded to the questionnaire indicating preference for somatrogon was greater than the proportion of patients indicating preference for Genotropin. Of note, between 27.4% and 64.3% of patients indicated no preference in response to the 4 items included in the domain addressing the pen ease of use. Further, the proportion of patients who preferred somatrogon and Genotropin in terms of injecting the medicine was 36.9% and 33.3%, respectively.

As presented in Table 27, the overall mean PGI-S: IDA score was 20.6 (SD = 19.9) for patients while being treated with Genotropin and 5.9 (SD = 8.8) for patients while being treated with somatrogon. The between-groups difference was –14.6 (95% CI, –18.7 to –10.4; P < 0.0001).

Harms

A summary of harms reported during study 002 is presented in Table 28. Adverse events were reported by 44.2% of patients during treatment with Genotropin and 54.0% of patients during treatment with somatrogon. The most frequently reported adverse event was injection site pain, followed by injection site hematoma, nasopharyngitis, and headache. No serious adverse events or deaths were reported during study 002. One patient stopped treatment due to adverse events, which occurred during treatment with somatrogon as a result of injection site pain. With regard to notable harms for this review, injection-related events were reported by ||||||||||||||||||| and |||||||||| of patients during Genotropin treatment and during somatrogon treatment, respectively. Additionally, |||||||||||||||||||||| reported excess IGF-I levels during somatrogon treatment.

Critical Appraisal

Internal Validity

Study 002 was conducted to evaluate the treatment experience and patient preference for treatment with once-weekly somatrogon compared to once-daily Genotropin. This was evaluated using subjective PROs within an open-label study design, which has potential for significant bias in the results. Further, the primary and secondary end points were evaluated using outcomes derived from the DCOA questionnaires, which were developed by the sponsor and underwent an evaluation of the psychometric properties of the tool as part of study 002. Evidence of reliability was demonstrated; however, there was no evidence of validity or responsiveness. An MID was not identified from the literature. Additionally, results for the DCOA 1 questionnaire included P values, but the statistical tests were not controlled for multiplicity and, consequently, were at risk of type I error. The other secondary outcomes were reported descriptively. Both of these factors and the lack of an established MID make it difficult to determine the clinical meaningfulness of the results. Lastly, the assessment of patient preference and treatment burden following 12 weeks of treatment with somatrogon is likely to overestimate the results compared to what is expected with long-term treatment in clinical practice as a result of diminishing excitement or expectations for a new treatment option over time.

External Validity

Study 002 did not include any patients living in Canada and the majority of included patients were White. This demographic does not reflect the diversity of patients seen in clinical practice in Canada. Study 002 also excluded patients younger than 3 years of age, which was noted as a generalizability issue for an important population living with GHD (those younger than 3 years old), per feedback from the clinical expert on this review. Lastly, the preference and treatment burden of somatrogon was assessed based on a period of 12 weeks, which does not reflect use in clinical practice where patients require long-term treatment with GH therapy.

CP-4-009 – Long-Term Open-Label Extension Study

The CP-4-009 LT-OLE evaluated the long-term efficacy and safety of somatrogon in a single-arm trial.

Methods

Eligible patients treated with Genotropin who completed 12 months of treatment during the CP-4-009 main study were switched to a somatrogon dose of 0.66 mg/kg per week and somatrogon-treated patients who completed 12 months of treatment during the main study continued to receive somatrogon with the same mg/kg per week dose in the OLE phase. The OLE phase would continue until the marketing registration of somatrogon in Japan.

Populations

Pediatric patients with GHD who completed the main study (12 months of treatment) with adequate compliance and adherence to the visit schedule and without major protocol deviation according to the main study protocol were eligible to enter the OLE phase.

Interventions

Patients who had received Genotropin for 12 months during the main study were switched to receive a dose of 0.66 mg/kg per week of somatrogon in the OLE phase (no less than 1 day after cessation of the Genotropin treatment).

Outcomes

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Patient Disposition

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Efficacy

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Harms

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Critical Appraisal

Internal Validity

CP-4-009-OLE was conducted to evaluate the long-term efficacy and safety of once-weekly somatrogon. Patients who had completed the main study of CP-4-009 and were eligible for the long-term open-label phase, and had received daily Genotropin in the main study, switched over to once-weekly somatrogon. The efficacy results of the OLE phase are selectively reported. The analyses are not part of a statistical testing plan and, hence, the effect of somatrogon at the data cut-off date of March 13, 2020, is considered uncertain. No efficacy analyses for HRQoL or other PRO measures were conducted; hence, the long-term effect of somatrogon on HRQoL is unknown.

External Validity

CP-4-009-OLE was conducted exclusively in Japanese prepubertal children and did not include any Canadian patients. This is not reflective of Canadian clinical practice. Hence, CP-4-009-OLE has noted generalizability issues. The CP-4-009-OLE study excluded patients younger than 3 years of age; this also leads to a Canadian generalizability issue, as the clinical expert consulted by CADTH stated that in clinical practice, patients with GHD are seen as early as in their infancy.

Discussion

Summary of Available Evidence

Two phase III studies were included in the systematic review. The CP-4-006 and CP-4-009 studies included prepubertal children with GHD.

CP-4-006 was an open-label, multi-centre, randomized, active-controlled, parallel group study evaluating the efficacy and safety of weekly somatrogon to daily GH (Genotropin). Patients were randomized in a 1:1 method to receive weekly SC doses of somatrogon or daily SC doses of Genotropin for 12 months. Following the completion of the 12-month treatment period, in both studies, eligible patients were enrolled in a single-arm OLE treatment phase with somatrogon. C0311002 was a randomized, open-label, multi-centre, 2-period crossover study.

The primary objective of CP-4-006 was to establish noninferiority of somatrogon compared to Genotropin. The primary objective of CP-4-009 was to establish comparability of somatrogon to Genotropin. The secondary objectives of both studies were annualized height velocity at 6 months, a change in height SDS at 6 months and 12 months, and a change in bone maturation at 12 months. The primary objective of C0311002 was to evaluate the treatment burden of a weekly injection of somatrogon and a daily injection of somatropin (Genotropin). Secondary objectives included an evaluation of patient and caregiver self-assessments of treatment experience and an evaluation of the psychometric properties of the DCOA questionnaires.

CP-4-006 and CP-4-009 used appropriate randomization techniques and the primary and secondary end points were considered clinically meaningful. Patient dropout was low in both studies and missing data were accounted for appropriately. The main limitations were a lack of multiplicity controls for all end points, a lack of rationale for a noninferiority margin, concerns with age of inclusion of patients in the study, a lack of interpretation of HRQoL outcomes and no reported MID. C0311002 had concerns of generalizability to the Canadian patient population and lacked an appropriate assessment period.

In addition to CP-4-006 and CP-4-009, evidence from C0311002 — which included prepubertal and pubertal children with GHD and assessed the treatment burden of a weekly injection of somatrogon and a daily injection of somatropin (Genotropin) — was also included in the Other Relevant Evidence section of this report. In addition, the OLE phase of CP-4-009 was also included in the Other Relevant Evidence section.

Interpretation of Results

Efficacy

In CP-4-006 and CP-4-009, the primary end point was to establish the noninferiority of once-weekly somatrogon as compared to daily Genotropin. Noninferiority was concluded if the lower bound of the 2-sided 95% CI for the mean treatment difference between somatrogon and Genotropin in the primary efficacy end point was –1.8 cm per year or more. The studies statistically demonstrated that somatrogon was not inferior to Genotropin (CP-4-006) and was comparable to Genotropin (CP-4-009). |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. In CP-4-009, the CI of the primary efficacy outcome did not cross the null; however, due to the small sample size and imbalance in baseline characteristics, the true treatment effect cannot be established with certainty.

In CP-4-006 and CP-4-009, the secondary efficacy outcomes were annualized height velocity at 6 months, a change in height SDS at 6 months and 12 months, and a change in bone maturation at 12 months. In annualized height velocity at 6 months and a change in height SDS at 6 months and 12 months, the between–treatment group difference was higher for somatrogon. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. P values for these analyses were not reported; hence, the statistical significance of these results in favour of 1 treatment cannot be interpreted.

In CP-4-006, other efficacy outcomes that were described using descriptive statistics were serum biomarker levels (IGF-I and IGF-I SDS), HRQoL, and other PRO responses. CP-4-009 did not report on any of these outcomes. HRQoL and other PRO responses had no MID identified in the literature. All the analyses were done in observed case patients and there were substantial amounts of missing data, which would introduce significant biases. The analyses for HRQoL and other PRO responses (only in the somatrogon treatment group) were performed in selected locations only. Hence, the effects of these assessments in support of somatrogon are highly uncertain.

Results from the long-term open-label phase for CP-4-006 were not available at the time of writing this report. In the absence of the long-term open-label phase results, it is uncertain whether the response of somatrogon was sustained. For CP-4-009, the sample size of the population in the long term open-label phase is very small to make a conclusive assessment of the long-term response of somatrogon.

In C0311002, evidence of the reliability of the DCOA 1 questionnaire was demonstrated; however, evidence of validity was inconsistent and there was no evidence of responsiveness or an MID. Additionally, results for the DCOA 1 questionnaire included P values, but the statistical tests were not controlled for multiplicity and, consequently, were at risk of type I error. The other secondary outcomes were reported descriptively. Both of these factors and the lack of an established MID make it difficult to determine the clinical meaningfulness of the results. Lastly, the assessment of patient preference and treatment burden following 12 weeks of treatment with somatrogon is likely to overestimate the results compared to what is expected with long-term treatment in clinical practice.

Harms

In CP-4-006, 87.2% and 84.3% of the patients in the somatrogon group and Genotropin group, respectively, and in CP-4-009, ||||||||% and ||||||||% of the patients in the somatrogon group and Genotropin group, respectively, reported at least 1 adverse event. The most commonly occurring adverse events were injection site pain, nasopharyngitis, pyrexia, and headache. No deaths were reported in any of the studies. The clinical expert consulted by CADTH was impressed with the safety profile of somatrogon. The notable harms identified in the CADTH review protocol included the following: injection-related events, glucose intolerance and/or insulin resistance, excess IGF-I levels, malignancies, benign intracranial hypertension, slipped capital femoral epiphysis, scoliosis, tonsillar hypertrophy, carpal tunnel, and peripheral edema. In CP-4-006, of the identified notable harms, 43.1% and 25.2% of patients in the somatrogon group and Genotropin group, respectively, reported experiencing an injection-related event. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. In CP-4-009, of the identified notable harms, 72.7% of patients in the somatrogon group reported experiencing an injection-related event. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. The clinical expert did express concern that the injection site reaction in somatrogon was higher compared to Genotropin. As somatrogon is a once-weekly injection and Genotropin is a once-daily injection, these analyses may warrant further explanation.

In C0311002, 44.2% of patients during treatment with Genotropin and 54.0% of patients during treatment with somatrogon reported at least 1 adverse event.

||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Conclusions

Two phase III randomized controlled trials were included in the CADTH systematic review of somatrogon for long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous GH. Both studies demonstrated that for the primary efficacy outcome of annualized height velocity at 12 months, treatment with somatrogon was noninferior (CP-4-006) or comparable (CP-4-009) to Genotropin. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. Other relevant outcomes such as HRQoL and other PRO responses were not assessed in study CP-4-009 and were not properly assessed in study CP-4-006; as a result, the effect of somatrogon on HRQoL is uncertain. The results of the long-term open label phase for CP-4-006 were not available; hence, interpretation of sustained response of treatment to somatrogon is unknown. Key evidence gaps include the absence of adherence analyses, limited evidence on switchover from somatrogon to somatropin or vice versa, limited interpretation of HRQoL, and other PRO responses.

The key safety issues with somatrogon were related to injections, with a low number of serious adverse events being reported in the somatrogon treatment group and Genotropin treatment group in both studies. A higher number of patients in the somatrogon treatment group experienced injection site pain, nasopharyngitis, pyrexia, and headache. Conclusions regarding the long-term safety of somatrogon cannot be made in the absence of corresponding data.

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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: June 25, 2021

Alerts: Weekly search updates until project completion

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

Limits:

• Publication date limit: none

• Language limit: none

• Conference abstracts: excluded

Table 31: Syntax Guide

Multi-Database Strategy

1. (somatrogon* or Ngenla* or Lagova* or mod 4023 or mod4023 or "pf 06836922" or pf06836922 or pf 6836922 or pf6836922 or mod-401 or mod401 or 6D848RA61B).ti,ab,kf,ot,hw,nm,rn.

2. ((carboxy-terminal peptide* or C-terminal peptide* or CTP) adj5 (hgh or rhgh or human growth hormone*)).ti,ab,kf,ot,hw,nm,rn.

3. exp growth hormone/ and (carboxy-terminal peptide* or C-terminal peptide* or CTP).ti,ab,kf,ot,hw,nm,rn.

4. or/1-3

5. 4 use medall

6. *somatrogon/ or (somatrogon* or Ngenla* or Lagova* or mod 4023 or mod4023 or "pf 06836922" or pf06836922 or pf 6836922 or pf6836922 or mod-401 or mod401).ti,ab,kw,dq.

7. ((carboxy-terminal peptide* or C-terminal peptide* or CTP) adj5 (hgh or rhgh or human growth hormone*)).ti,ab,kw,dq.

8. exp growth hormone derivative/ and (carboxy-terminal peptide* or C-terminal peptide* or CTP).ti,ab,kw,dq.

9. or/6-8

10. 9 use oemezd

11. 10 not (conference review or conference abstract).pt.

12. 5 or 11

13. remove duplicates from 12

Clinical Trials Registries

ClinicalTrials.gov

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

[Search terms – somatrogon, growth hormone deficiency]

WHO ICTRP

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

[Search terms – somatrogon, growth hormone deficiency]

Health Canada’s Clinical Trials Database

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

[Search terms – somatrogon, growth hormone deficiency]

EU Clinical Trials Register

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

[Search terms – somatrogon, growth hormone deficiency]

Grey Literature

Search dates: June 21-25, 2021