CADTH Reimbursement Review

Somapacitan (Sogroya)

Sponsor: Novo Nordisk Canada Inc.

Therapeutic area: Growth hormone deficiency (GHD)

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

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

Table 1: Background Information of Application Submitted for Review

NOC = Notice of Compliance.

^aSogroya was approved by Health Canada on July 26, 2023. According to the indication specified in the product monograph (point 1.1), “Pediatrics (2.5 years old to epiphyseal fusion): The efficacy and safety of Sogroya in pediatric patients aged 2.5 years to 11 years experiencing growth failure due to growth hormone deficiency have been established in clinical trials. The efficacy and safety of Sogroya have not been established in patients younger than 2.5 years of age. Data on the efficacy and safety of Sogroya in patients aged from 12 to less than 18 years are limited. Pediatric patients with a history or presence of malignancy, including intracranial tumours, were not studied in clinical trials.”¹

Introduction

Growth hormone deficiency (GHD) is a rare disease caused by impaired secretion of growth hormone (GH) by the pituitary gland, which affects patients’ growth, body composition, metabolic profile, bone mineral density, and quality of life.^2,3 In a cohort of 850 children in Canada treated with GH, among whom 526 had GHD, 72% (379 out of 526) were diagnosed with predominantly organic rather than idiopathic GHD, particularly intracranial tumours and congenital pituitary abnormalities.⁴ Congenital causes of GHD can be linked to a number of gene mutations; some of these mutations may be located on GH1, HESX1, X-linked recessive genes such as SOX3 and BTK, and many others.² The physical manifestation of GHD can vary depending on the types of cells affected, the age of onset, and the combination of genetic mutations.⁵ Estimates for the prevalence of pediatric GHD are sparse, with no specific Canadian data, although studies across Europe, the US, and China suggest an estimated prevalence ranging from 1 in 30,000 to 1 in 5,600.^3,6-8 Estimates of pediatric GHD suggest a prevalence range of 1 in 4,000 to 10,000 children worldwide, suggesting a prevalence of approximately 1,600 children in Canada.^9,10

GH stimulation testing is considered the standard diagnostic tool for GHD. The treatment of GHD is injections of synthetic GH.¹¹ Canadian and US guidelines recommend treatment with GH in cases of extreme shortness in children and adolescents with GHD to attain normal adult height.¹² Treatment with GH should begin as soon as possible for patients to optimize their growth velocity and final adult height,^9,13 and be continued until a patient reaches their full adult height and bone maturity, or when their height velocity (HV) is less than 2 cm/year.^14-16 The clinical expert consulted for this review indicated that somatropin and somatrogon are administered as daily or weekly subcutaneous injections for the treatment of pediatric GHD. Somatropin, administered as a daily subcutaneous injection, has traditionally been the primary GH used for the treatment of GHD. In March 2022, somatrogon (Ngenla), a Health Canada–approved GH, received a reimbursement recommendation from CADTH for the treatment of pediatric GHD as a weekly subcutaneous injection,¹⁴ but received a negative funding recommendation from the Institut national d’excellence en santé et en services sociaux (INESSS) due to the potential for greater pain at the injection site and the need for higher doses.¹⁷ According to input from the sponsor and the clinical expert consulted by CADTH, treatment goals for GHD include optimizing final adult height, restoring metabolic functions associated with GHD, reducing injection burden, improving treatment adherence, and optimizing quality of life. According to clinical expert input, 1 of the limitations associated with current treatments is that they require injections and daily (or near daily) injections, which can lead to suboptimal adherence, resulting in suboptimal clinical outcomes, e.g., the treatment goal of improvement in height is affected.^3,18,19

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of somapacitan 5 mg/1.5 mL (3.3 mg/mL), 10 mg/1.5 mL (6.7 mg/mL), and 15 mg/1.5 mL (10 mg/mL) as a prefilled pen for subcutaneous use in the long term treatment of pediatric patients experiencing growth failure due to an inadequate secretion of endogenous GH.

Stakeholder Perspectives

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

Patient Input

Two patient groups, the Canadian Organization for Rare Disorders (CORD) and the MAGIC Foundation, provided input for the treatment of GHD. CORD recruited participants through a patient membership list and parents attending a European summit. It then conducted interviews, whereas the MAGIC Foundation gathered data from surveys. A total of 12 parents (6 from the list and 6 from the summit) participated in the interviews conducted by CORD. Among these 12 participants, 4 were from Canada (Ontario), 2 were from the US, and 6 were from Europe. All of the participants who responded to the MAGIC Foundation’s surveys were from the US, and none of their current members in Canada had experience with a long-acting GH (LAGH). The children represented in the CORD input ranged in age from 4 to 15 years old, and those from the MAGIC Foundation input were between 3 and 18 years of age.

When parents were asked by CORD about the impact of the disease on patients’ and caregivers’ day-to-day life and quality of life, they expressed going through a variety of emotions, such as denial, blame, sadness, acceptance, and compassion. Parents from both groups reported a variety of psychological and social impacts on the child and the family, particularly due to short stature. In the MAGIC Foundation’s input, parents mentioned that their children were shorter than their peers, were fatigued, lacked concentration and appetite, had poor stamina, and were often very sick before beginning GH treatment.

Patients from both groups were reported to have been on GH therapy. All patients in the CORD group were reported to have experience with daily subcutaneous injections of somatropin, and 4 patients were reported to have current experience with LAGH therapy (somatrogon, lonapegsomatropin, and somapacitan-beco) through clinical trials, compassionate access, or reimbursement or insurance. On the other hand, some patients from the MAGIC Foundation group were reported to have experience with both daily and weekly injections, whereas others were reported to be strictly on daily injections.

Parents from the CORD group described the daily administration of an injection every night as the most consistent challenge. These parents also recognized the importance of GH therapy, despite the challenges and worries about the future. Parents from the MAGIC Foundation group mentioned the high cost of GH treatment and dependence on insurance companies in getting the treatment for children in the US. When parents were asked by the CORD group about the outcomes to consider when evaluating new therapies, an injection that lasted longer and was easier to administer was a desired change. While describing the experience with the current drug under review, all 4 respondents having experience with LAGH therapy shared positive feedback, such as positive impact on the child’s and the family’s quality of life; some described this impact as “transformational” and “life-changing.”

Clinician Input

Input From the Clinical Expert Consulted by CADTH

The expert indicated that the current treatment paradigm for children with GHD is to offer recombinant GH. The treatment goals are: to restore height by improving HV (with the target of achieving a near-final adult height that is close to the patient’s midparental heights), to restore metabolic health, to address hypoglycemia (especially in the neonatal or infantile periods), and to restore well-being. The expert pointed out that several brands of somatropin are available to treat GHD. They noted that somapacitan can be used in the treatment of pediatric GHD by those who are willing to try it or who are using somatropin and want to switch to once-weekly injections. The expert noted that the patients most in need of somapacitan would be those who experience significant pain or anxiety from the injections to the extent that there is a threat to optimal adherence to daily somatropin. The expert indicated that treatment responses include change in absolute height and height standard deviation score (SDS), change in HV and HV SDS, and change in insulin-like growth factor 1 [IGF-1] level and IGF-1 SDS). According to the clinical expert, patients prescribed somapacitan should be under the care of pediatric endocrinologists and pediatric endocrine nurses in either community settings or academic referral centres.

Clinician Group Input

Clinician group input on the review of somapacitan was received from Canadian Pediatric Endocrinology Nurses. A total of 5 nurses provided input for this review.

Canadian Pediatric Endocrinology Nurses mentioned that daily somatropin injections are used as the current treatment paradigm for GHD. These injections are administered to increase growth, stabilize blood sugar levels, increase bone density, and increase muscle development. The Pediatric Endocrinology Nurses group described the treatment gaps or unmet needs of currently available treatments. Issues with current treatments include: poor compliance in patients with daily injections, anxiety with daily injections, lack of availability of GH, and the need for a treatment with improved compliance, better tolerance, and formulations with improved convenience. The group indicated that somapacitan could be used as a first-line treatment for GHD if approved or funded.

While describing which patients would be best suited for treatment with the drug under review, the clinician group mentioned those who experience needle anxiety, have compliance issues, are in a complex social situation, or have remote living conditions. The group added that patients with GHD can be identified by, for example, clinician examination, GH stimulation testing, bone age, and IGF-1 level. The group emphasized that without GH treatment (either daily or weekly), patients with GHD will not grow and could have hypoglycemia, decreased bone density, poor muscle development, and altered body composition. The clinician group pointed out that improved growth velocity and normalized glucose in infants would be considered a clinically meaningful response to treatment. The group also added that factors such as achieving final adult height, closed epiphyses, and a growth rate of less than 2 cm/year should be considered when deciding to discontinue treatment with the drug under review. The clinician group noted that the patients must be diagnosed, treated, monitored, and prescribed by a pediatric endocrinologist.

Drug Program Input

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

• relevant comparators

• considerations for initiation of therapy

• consideration for continuation or renewal of therapy

• considerations for discontinuation of therapy

• consideration for prescribing of therapy

• generalizability

• system and economic issues.

The clinical expert consulted by CADTH provided advice on the potential implementation issues raised by the drug program. Refer to Table 4 for more details.

Clinical Evidence

Systematic Review

Description of Studies

One pivotal phase III, open-label, randomized controlled trial (RCT) comparing somapacitan (0.16 mg/kg once weekly) with Norditropin (somatropin) (0.034 mg/kg once daily) via subcutaneous infusion in prepubertal children with GHD who had no prior exposure to GH therapy or IGF-1 treatment (N = 200) was identified. Patients were randomized to either somapacitan or Norditropin (somatropin) in a 2:1 ratio for a 52-week randomized controlled period. The primary end point was estimated mean at week 52 in HV (cm/year) at week 52. The key secondary end points were change from baseline in height SDS and HV SDS at week 52. The key exploratory end points were Growth Hormone Deficiency–Child Impact Measure (GHD-CIM) as well as estimated mean scores in Growth Hormone Deficiency–Child Treatment Burden (GHD-CTB) and Growth Hormone Deficiency–Parent Treatment Burden (GHD-PTB) at week 52. HV reflects the change rate in height over time and was converted to be expressed in cm/year in the current review. Height SDS and HV SDS are end points that reflect whether the auxologic parameters are within a normal range (usually −2 to 2) considering age and gender, and standards of these measurements have been developed and used in clinical settings. The GHD-CIM, GHD-CTB, and GHD-PTB are disease-specific questionnaires that measure the impact or burden of GH treatment on children with GHD and their caregivers in terms of symptoms, physical functioning, social well-being, emotional well-being, and interference in daily life activities. Each of these 3 questionnaires has subdomains and total scores that are presented on a normalized range of 0 to 100, with a lower score indicating a better health state.

At baseline, the mean age was 6.38 years (standard deviation [SD] = 2.23) in the somapacitan arm and 6.43 years (SD = 2.42) in the Norditropin (somatropin) arm. More male patients (74.5%) were enrolled than female patients (25.5%). The majority of patients were white (57%) followed by Asian (37%), and 88% had GHD that was idiopathic (cause unknown). The median peak level of GH was higher in the somapacitan arm (5.2 mcg/L) than in the Norditropin (somatropin) arm (3.9 mcg/L). In terms of concomitant medications at baseline, a lower proportion of patients used thyroid hormones in the somapacitan arm (8.3%) than in the Norditropin (somatropin) arm (14.7%). After initiation of randomization, overall, concomitant medications were used by a higher proportion of patients in the somapacitan arm (66.7%) than in the Norditropin (somatropin) arm (58.8%), based on the detailed documentation of patient records; the difference did not have a potential impact on study results.

Efficacy Results

The key efficacy results from the REAL 4 trial are summarized in Table 2. The full analysis set was used for the auxologic response outcomes, and the observation datasets were used for the patient-reported outcomes.

Auxologic Response

The mean HV at baseline was 4.3 cm/year (SD = 1.4) in the somapacitan arm and 4.1 cm/year (SD = 1.4) in the Norditropin (somatropin) arm. The estimated mean at week 52 in HV was 11.2 cm/year and 11.7 cm/year in the somapacitan and Norditropin (somatropin) arms, respectively, with an estimated treatment difference (ETD) of −0.5 cm/year (95% confidence interval [CI], −1.1 to 0.2), which demonstrated noninferiority of somapacitan to Norditropin (somatropin) based on a prespecified noninferiority margin of −1.8 cm/year.

The improvements in height SDS and HV SDS (supportive secondary end points that were measured as change from baseline scores at week 52) were comparable between the 2 treatment arms. The baseline mean height SDS was −2.99 (SD = 1.02) in the somapacitan arm and −3.47 (SD = 1.52) in the Norditropin (somatropin) arm. The ETD for height SDS was −0.05 (95% CI, −0.18 to 0.08). The estimated mean change from baseline scores was 1.25 and 1.30 in the somapacitan and Norditropin (somatropin) arms, respectively. The baseline mean HV SDS was −2.35 (SD = 1.51) in the somapacitan arm and −2.52 (SD = 1.55) in the Norditropin (somatropin) arm. The ETD for HV SDS was −0.78 (95% CI, −1.63 to 0.08). The estimated mean change from baseline scores was 8.05 and 8.82 in the somapacitan and Norditropin (somatropin) arms, respectively.

Patient-Reported Outcomes

The improvements were comparable between the treatment arms at week 52 in total GHD-CIM scores (ETD = 1.8 points; 95% CI, −2.9 to 6.6) and GHD-CTB scores (ETD = −2.4 points; 95% CI, −5.7 to 0.9). The result of the GHD-PTB total score was in favour of somapacitan compared with Norditropin (somatropin) at week 52, with an ETD of −6.0 points (95% CI, −10.0 to −2.1).

Harms Results

The key harm results from the randomized controlled period of the REAL 4 trial are summarized in Table 2. The full analysis set was used for all of the safety outcomes.

During the 52-week treatment period, adverse events (AEs) were reported by 71.2% of patients who received somapacitan compared with 60.3% of patients who received Norditropin (somatropin). The most frequently reported AEs were headache (12.1%), nasopharyngitis (11.4%), and pain in extremity (9.1%) in the somapacitan arm, and nasopharyngitis (10.3%), pyrexia (10.3%), and headache (8.8%) in the Norditropin (somatropin) arm.

No withdrawal from treatment due to treatment-emergent AEs or deaths were reported among patients in either arm.

The occurrences of the 2 notable harms were comparable between the treatment arms at week 52, with a relative risk of |||| |||| ||| |||| || ||||| for injection-site reactions (5.3% versus 5.9% in the somapacitan and Norditropin [somatropin] arms, respectively) and |||| |||| ||| |||| || |||||| for injection-site pain (1.5% in both arms). Of note, the relative risk and 95% CI for injection-site reactions and injection-site pain were not part of the statistical analysis plan and were requested by CADTH to allow for the imprecision of the findings to be assessed.

Other Results

The other outcome identified as relevant and important, treatment discontinuation (or adherence to therapy), is summarized in Table 2. One patient was discontinued from treatment with somapacitan due to a violation of the inclusion and/or exclusion criteria. No patients discontinued treatment in the Norditropin (somatropin) arm. The mean therapy adherence rate, measured with a patient e-diary device for electronic data recording, was higher in the somapacitan arm than in the Norditropin (somatropin) arm (96% versus 88%).

Critical Appraisal

Appropriate methods of randomization were used. The proportion of patients who used thyroid hormones was lower in the somapacitan arm than in the Norditropin (somatropin) arm (8.3% versus 14.7%); whether this difference might impact the study results was uncertain, according to the clinical expert consulted by CADTH. The efficacy and harms outcomes were analyzed using the full analysis set (FAS); all the patient-reported outcomes were analyzed for the observation datasets in countries where these outcomes were available; the impact of the missing data in 4 countries was unknown. The open-label study design could potentially increase the risk of bias for the subjective assessment of patient-reported outcomes, such as health-related quality of life, and AEs such as injection-site reactions (including pain, bruising, hematoma, and swelling) and injection-site pain. Ethnicity and race are significant predictors of HV; however, the REAL 4 trial did not stratify this factor (only Japan was separated from the rest-of-the-world region, possibly because of different peak GH levels used in GHD diagnosis). Whether the lack of adjustment by different regions in the analysis might affect the results was uncertain. The study sample size calculation in the REAL 4 trial was based on an assumption of an SD of 3.5 cm/year and a noninferiority margin of −1.8 cm/year for HV. Most of the patients enrolled in the REAL 4 trial were from the US (|||), Japan (|||), Russia (|||||), India (|||), Korea (||), and Ukraine (||), among others. ||| ||||||| (|||| of overall study population) ||| ||| allocated to the somapacitan group was from Canada and whether |||| ||||||| belonged to an Indigenous population was unknown. A total of 57.0% of the patients were white and 37.0% were Asian. At baseline, the patients were aged between 2.5 years and 11 years for boys, and 2.5 years and 10 years for girls. Overall, there was a greater difference in the proportion of boys (74.5%) than girls (25.5%) in the REAL 4 trial compared with the Genetic and Neuroendocrinology of Short-Stature International Study (GeNeSIS) study (63% male versus 37% female in the GHD cohort of patients in Canada).⁴ For context, the GeNeSIS study is a phase IV prospective observational study that evaluated the outcomes of GH treatment in pediatric patients in Canada that compared the findings for the American pediatric patients in the study versus the overall global population. The REAL 4 trial enrolled only patients who had no prior exposure to GH or IGF-1 treatment. The clinical expert commented that these differences between patients in the REAL 4 trial and those encountered in Canadian clinical practice are less likely to impact the trial results. The majority of the patients in the REAL 4 trial had idiopathic GHD (88.0%) versus organic (12%),²⁰ which was different from the GHD patient cohort in the GeNeSIS study (28% had idiopathic and 72% had organic GHD).⁴ The clinical expert indicated that idiopathic GHD may be accompanied by other conditions that might influence GHD; thus, it was uncertain whether the results would be impacted by the fact that this patient characteristic in the GeNeSIS trial differs from that in the REAL 4 trial. The clinical expert noted there were patients excluded from the trial that clinicians would want to treat with GH therapy, if needed, such as patients with cancerous brain tumours and patients with a condition that precludes them from a height evaluation (e.g., patients with cerebral palsy who cannot stand). According to the clinical expert consulted by CADTH, the concomitant medications, the comparator used, and the administration of the study treatments in the REAL 4 trial were reflective of those encountered in Canadian clinical practice.

Summary of Findings and Certainty of the Evidence Using the Grading of Recommendations Assessment, Development, and Evaluation Framework

Methods for Assessing the Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was used to assess the certainty of the evidence for outcomes considered most relevant to inform deliberations by CADTH’s expert committee; a final certainty rating was determined as outlined by the GRADE Working Group.^21,22 Following the GRADE approach, the evidence from the RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

The selection of outcomes for GRADE assessment was based on the sponsor’s summary of clinical evidence, consultation with clinical experts, and the input received from patient and clinician groups and the public drug plans. The following list of outcomes was finalized with the input of the members of the CADTH expert committee: HV (cm/year, measured as estimated mean at follow-up), height SDS, HV SDS and GHD-CIM (measured as change from baseline in these values), GHD-CTB and GHD-PTB (measured as estimated mean at follow-up), injection-site reactions and injection-site pain (measured as occurrence of these AEs), and treatment discontinuation (measured as the proportion of patients who discontinued the treatment).

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty-of-evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The target of the certainty-of-evidence assessment was the presence or absence of an important effect based on the thresholds for HV, height SDS, and HV SDS informed by the clinical expert consulted for this review. The target of the certainty-of-evidence assessment was the presence or absence of any (non-null) effect for GHD-CIM, GHD-CTB, GHD-PTB, injection-site reactions, injection-site pain, and treatment discontinuation due to the lack of a formal minimal important difference (MID) estimate.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for somapacitan versus Norditropin (somatropin) in prepubertal children with GHD.

Long-Term Extension Studies

REAL 4 Long-Term Safety Extension Phase

Description of Studies

The REAL 4 study design is described in the main body of this report. A summary of the long-term safety extension phase (week 52 to week 104) is presented in this section.²³ The results presented in the sponsor’s interim analysis reflect the data available as of December 22, 2022.

Interventions

Patients were randomized (2:1) to receive either once-weekly somapacitan 0.16 mg/kg or daily Norditropin (somatropin) 0.034 mg/kg for the 52-week main trial period. For the subsequent safety extension trial period, which was planned for an additional 3 years following the main trial period and up to 208 weeks, all patients were allocated to once-weekly somapacitan 0.16 mg/kg.

Table 2: Summary of Findings for Somapacitan Versus Norditropin (Somatropin) for Pediatric Patients With GHD

CI = confidence interval; GH = growth hormone; GHD = growth hormone deficiency; GHD-CIM = Growth Hormone Deficiency–Child Impact Measure; GHD-CTB = Growth Hormone Deficiency–Child Treatment Burden; GHD-PTB = Growth Hormone Deficiency–Parent Treatment Burden; MID = minimal important difference; NA = not applicable; NR = not reported; RCT = randomized controlled trial; RR = relative risk; SDS = standard deviation score; TB-CGHD-O = Treatment Burden Measure–Child Growth Hormone Deficiency–Observer; TB-CGHD-P = Treatment Burden Measure–Child Growth Hormone Deficiency–Parent; TRIM-CGHD-O = Treatment-Related Impact Measure–Child Growth Hormone Deficiency–Observer.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes. For all the outcomes in this table, statistical testing was not adjusted for multiplicity; there is an increased risk of type I error (false-positive results).

^aThe CADTH review team identified a potential risk of bias due to several factors, including a baseline imbalance in GH peak level at baseline that was higher in the somapacitan group (median 5.2 mcg/L) than in the Norditropin (somatropin) group (3.9 mcg/L), an imbalance in the thyroid hormone use at baseline that was lower in the somapacitan group (8.3%) than in the Norditropin (somatropin) group (14.7%), and a higher treatment adherence rate in the somapacitan group (96%) than in the Norditropin (somatropin) group (88%), as measured with a patient e-diary device to record dosing; however, the certainty of evidence was not rated down for risk of bias because it was uncertain whether these imbalances might raise the potential for bias in favour of somapacitan.

^bIndirectness did not result in the level of certainty being rated down. Differences between the patients in clinical practice and those included (e.g., GH therapy–naive, no intracranial tumour) or excluded (due to prepubertal age and potential exclusion of patients who could not physically stand up due to, for example, significant spinal abnormalities and congenital abnormalities) in the single RCT that informed the evidence were noted; however, these differences were not considered serious enough to result in important differences in the observed effect, according to the clinical expert consulted by CADTH.

^cImprecision did not result in the level of certainty being rated down. The point estimate and both the lower and upper boundaries of the 95% CI of the between-group comparison indicate trivial or no clinically meaningful difference, according to the clinical expert consulted by CADTH; for HV, the 95% CI excludes the noninferiority margin (−1.8 cm/year).

^dThe level of certainty was rated down by 1 level for serious imprecision. No specific threshold was established but, according to the clinical expert consulted by CADTH, the point estimate (−0.78) and the lower boundary of the 95% CI (−1.63) could be considered a clinical meaningful worse efficacy for somapacitan vs. Norditropin (somatropin), while the upper boundary of the 95% CI (0.08) suggests no clinically meaningful difference between the 2 groups.

^eThe level of certainty was rated down by 1 level for serious risk of bias due to the potential for bias in favour of somapacitan (once-weekly injections) compared with Norditropin (somatropin) (once-daily injections) arising from the open-label nature of the study and the subjective nature of the outcome. The impact of missing outcome data (31% of the patients) is unclear.

^fThe level of certainty was rated down by 1 level for serious imprecision. Based on the MID identified in the literature (5 points based on within-group data), the point estimate suggested little to no difference, while the upper bound of the 95% CI suggested an increase in the GHD-CIM score compared with Norditropin (somatropin).

^gThe level of certainty was rated down by 1 level for serious risk of bias due to potential for bias in favour of somapacitan (once-weekly injections) compared with Norditropin (somatropin) (once-daily injections) arising from the open-label nature of the study and the subjective nature of the outcome. The impact of missing outcome data (15.5% of the patients) is unclear.

^hThe level of certainty was rated down by 1 level for serious imprecision. The CADTH review team was unable to confirm with the clinical expert consulted by CADTH whether the MID identified in the literature (6 points based on the within-group data provided by the sponsor) would be suitable to assess a between-group difference; therefore, the null was used to assess certainty. The point estimate suggested a decrease in the GHD-CTB score, while the upper bound of the 95% CI suggested an increase in the GHD-CTB score compared with Norditropin (somatropin).

ⁱThe level of certainty was rated down by 1 level for serious risk of bias due to potential for bias in favour of somapacitan (once-weekly injections) compared with Norditropin (somatropin) (once-daily injections) arising from the open-label nature of the study and the subjective nature of the outcome. The impact of missing outcome data (12% of the patients) is unclear.

^jImprecision did not result in the level of certainty being rated down. The CADTH review team was unable to confirm with the clinical expert consulted by CADTH about whether the MID identified in the literature (7 points based on within-group data, provided by the sponsor) would be suitable to assess a between-group difference; therefore, the null was used to assess certainty.

^kThe RR and 95% CI were not part of the statistical analysis plan; they were requested by CADTH to allow for an assessment of the imprecision of the findings.

^lThe level of certainty was rated down by 1 level for serious risk of bias due to potential for bias in favour of somapacitan (once-weekly injections) compared with Norditropin (somatropin) (once-daily injections) arising from the open-label nature of the study and the subjective nature of the outcome.

^mImprecision did not result in the level of certainty being rated down. The clinical expert consulted by CADTH could not provide a threshold of important difference; however, the CADTH review team judged that the effect estimate and 95% CI were unlikely to include any important effect.

ⁿTreatment discontinuation is for any reason and not limited to adverse events. Treatment discontinuation due to adverse events in both treatment arms in the REAL 4 trial was 0. One patient in the main study discontinued somapacitan due to a violation of inclusion and/or exclusion criteria. A total of 132 patients in the somapacitan arm and 131 patients in the Norditropin (somatropin) arm completed the main treatment period.

^oRisk of bias did not result in the level of certainty being rated down. One patient from the somapacitan arm discontinued the treatment due to a violation of the study protocol; no patients in the Norditropin (somatropin) arm discontinued the treatment.

Source: REAL 4 Clinical Study Report (week 52).²⁰

Results

Patient Disposition: A total of 199 patients were exposed in the safety extension (following week 52). Four patients in the somapacitan to somapacitan group and 1 patient in the Norditropin (somatropin) to somapacitan group discontinued the trial product in the safety extension period (from week 52 to week 104). None of the discontinuations were due to AEs. All patients in the extension period who discontinued were withdrawn from the trial.

Exposure to Study Treatments: In the safety extension period (week 52 to 104), the mean duration of exposure to somapacitan and mean adherence were similar between the somapacitan to somapacitan group and the Norditropin (somatropin) to somapacitan group. The mean adherence in the somapacitan to somapacitan group was 94.2% from week 0 to 104, suggesting consistently high adherence throughout the entire study.

Efficacy

The sponsor’s interim analysis includes data for up to week 104 in the safety extension phase. The key efficacy outcomes evaluated in the REAL 4 main trial phase were evaluated descriptively for the long-term safety extension phase.

After 104 weeks of treatment, the HV observed in the patients who had been treated with somapacitan during the full trial period was similar to the HV observed in the patients who switched from Norditropin (somatropin) to somapacitan after week 52. After 104 weeks of treatment, the increase in change from baseline in height SDS and HV SDS observed in the patients treated with somapacitan during the full trial period was similar to the change observed in the patients who were switched from Norditropin (somatropin) to somapacitan at week 52. The mean observed change from baseline after 104 weeks in the IGF-1 SDS and the insulin-like growth factor binding protein 3 (IGFBP-3) SDS was similar in both groups.

The Growth Hormone Patient Preference Questionnaire (GH-PPQ) assessing GH treatment preference was used to evaluate the switch from Norditropin (somatropin) to somapacitan after the final visit in the main phase of the trial at week 52. The questionnaire was completed for patients by the parent or legally authorized representative (LAR) 4 weeks after the patient had switched from Norditropin (somatropin) to somapacitan (week 56). Parents for 50 of the 68 patients who were switched from Norditropin (somatropin) to somapacitan at week 52 responded to the questionnaire. Of these 50 respondents, 45 preferred somapacitan to somatropin, while 5 respondents answered that they had no preference. None of the respondents preferred Norditropin (somatropin). The majority of the respondents (38 out of 45) who preferred somapacitan had a strong or very strong preference for its once-weekly treatment regimen over daily Norditropin (somatropin) injections. The main reasons selected in the GH-PPQ for the preference included: “number of times needing to do injections,” “less worried about remembering to give the injections,” and “child [is] less worried or annoyed by getting injections.” Thirty-five of the 45 parents preferring somapacitan stated they expected higher adherence to the current once-weekly regimen versus the Norditropin (somatropin) regimen; 1 parent expected the patient to be more adherent to Norditropin (somatropin), while the remaining 9 parents had no preference with regard to expected adherence to either drug.

Harms

The safety profile of once-weekly somapacitan administered to children with GHD for up to 104 weeks was similar to the well-known safety profile for daily Norditropin (somatropin). No new safety or local tolerability issues were identified.

In patients with an IGF-1 SDS above 2, no trend was seen in the amount or type of AEs reported at 2 or more consecutive visits compared with the remaining patients in the relevant treatment groups. There were no dose reductions due to AEs for these patients. The majority of AEs were of mild severity.

Critical Appraisal

Internal Validity

REAL 4 is an open-label trial, which may influence the perception of improvement by patients and clinicians, particularly for outcomes that are subjective in measurement and interpretation (e.g., patient-reported outcomes, subjective AEs). In the REAL 4 trial, only prepubertal children were enrolled into the main trial to avoid the pubertal growth spurt interfering with the treatment effect.

The efficacy outcomes were presented using descriptive statistics, so no statistical inferences were possible. The safety profile with somapacitan from the main phase to the long-term extension phase was consistent in the REAL 4 trial.

External Validity

Because the patients who took part in the open-label long-term safety extension phase were originally from the REAL 4 trial and the eligibility criteria remained the same, it is reasonable to expect that the same limitations to generalizability are relevant to the open-label long-term safety extension phase.

Indirect Comparisons

Direct comparative evidence exists between somapacitan and Norditropin (somatropin) 0.034 mg/kg once daily from the REAL 3 and REAL 4 trials, but there is a gap in evidence comparing somapacitan with somatrogon. Indirect comparisons were required to address this gap. One indirect treatment comparison (ITC) was submitted by the sponsor, which has been summarized and appraised in this report.

Description of Studies

Based on a systematic literature review (SLR) conducted by the sponsor, network meta-analyses (NMAs) were conducted to indirectly compare somapacitan with somatrogon based on phase II and phase III RCTs. Data for somapacitan 0.16 mg/kg/week versus somatropin (Norditropin 0.034 mg/kg/day) was informed by the REAL 3 and REAL 4 trials, while data for somatrogon 0.66 mg/kg/week versus somatropin (Genotropin 0.034 mg/kg/day) was informed by the Opko II and Opko III trials in the base-case analyses and, additionally, by the Opko JPN trial (Genotropin 0.025 mg/kg/day) in a scenario analysis because it differed in study design, patient population, dose escalation of somatrogon, and dose of somatropin relative to all other included trials. In all included studies, patients were randomized to treatment with an LAGH or short-acting GH (SAGH) for at least 26 weeks. The trials enrolled treatment-naive prepubescent children with GHD and had mostly similar patient eligibility criteria. Patient baseline characteristics differed across trials with regard to age, percent male, racial distribution, peak GH, and height SDS; other characteristics such as IGF-1 SDS, HV SDS, GHD cause, body mass index (BMI) and height could not be compared due to lack of reporting.

Efficacy Results

The sponsor conducted NMAs assessing annualized HV (AHV), HV SDS, and height SDS. Data sufficient to form a network was available at week 26 and week 52 for AHV and height SDS, but only at week 26 for HV SDS. No statistically significant differences were identified between somapacitan and somatrogon for any outcome in the base-case analyses. Although some differences were identified for the lower dose of somatropin assessed in the Opko JPN trial, the lower dose is not considered relevant.

Quantitative comparisons were not conducted for longer-term outcomes (week 104 and week 156) because the Opko II and Opko III extensions were single-arm trials, so there was no direct comparative data available to inform the somatrogon node. The results were presented narratively but could not be compared.

Harms Results

Short-Term Outcomes (52 Weeks)

Quantitative comparisons were not performed for any harm outcomes, though justification was not provided by the sponsor for this decision. The proportion of patients experiencing at least 1 AE across trials varied from approximately 60% to 100% through 52 weeks of treatment. Serious AEs were observed in 0 to 3 patients per treatment arm in all cases except the somapacitan arm of the REAL 4 trial, in which 6 patients (4.5%) experienced serious AEs. Severe AEs did not occur in the REAL 3 trial, occurred in few patients in the REAL 4 trial (from 1.5% in the Norditropin [somatropin] arm to 3.0% in the somapacitan arm), and occurred in from 5.2% (somatropin arm) to 8.3% (somatrogon arm) in the OPKO III trial. Although very few AEs were observed in the REAL 3, Opko II, and Opko JPN trials, the sample sizes of each of the treatment arms were very small.

In the REAL trials, the number of injection-site pain events ranged from zero to very few in both the somapacitan and Norditropin (somatropin) arms. In the Opko III and Opko JPN trials, there were high rates of injection-site pain reported in the somatrogon arms (39.4% and 72.7%, respectively). However, in the Opko III and JPN trials, there were also more frequent events of injection-site pain in the somatropin arms (25.2% and 13.6%, respectively), which contrasts with the 0% and 1.5% event rates in somatropin-treated patients from the REAL 3 and REAL 4 trials, respectively. Severe injection-site pain did not occur in any patients in either the REAL 3 or 4 trials, regardless of treatment assignment, whereas 1 somatrogon-treated patient in the Opko II trial, and 4.6% of somatrogon-treated patients and 2.6% of somatropin-treated patients in the Opko III trial experienced severe injection-site pain.

Overall, rates of antibodies varied considerably across the trials. Analyses showed patients who were positive for antibodies did not experience reduced efficacy or safety issues compared with those without antibodies.

Long-Term Outcomes (Beyond 52 Weeks)

Overall, continued treatment with somapacitan and somatrogon was well generally tolerated, with no new safety signals identified. The proportion of patients experiencing at least 1 AE ranged from approximately 70% to 81% across the extensions of the REAL 3 (week 52 to 156), Opko II (week 52 to 208), and Opko III (week 52 to 104) trials. Most reported AEs were mild to moderate in severity.

In the REAL 3 trial extension (week 52 to 156), 3 patients (6.7%) treated with somapacitan and 1 patient (7.1%) treated with Norditropin (somatropin) experienced injection site–related AEs. All injection site–related AEs were considered to be mild in severity. No injection-site AE data were available from the extension trials of somatrogon.

Similar to results from the 52-week outcomes, neutralizing antibodies were observed with somatrogon but not with somapacitan. Where reported, analyses indicated the presence of antibodies did not have any impact with respect to efficacy outcomes.

Critical Appraisal

In the base-case NMAs, there were some between-trial imbalances between studies in race, gender, and mean age at baseline, and differences in eligibility criteria related to age range, peak GH, and bone age. The sponsor stated these were not expected to have modified any effects; however, it did not provide any support for this statement. Notably, height SDS and HV SDS are standardized for age and gender by definition; therefore, the potential effect of imbalances in age and gender (but not race) may be partially mitigated inherently in these outcomes, however, that was not the case for AHV. Ultimately, the potential magnitude and direction of bias is unknown, which obscures the interpretation of the results. The clinical expert consulted by CADTH identified that other potential prognostic factors and effect modifiers include the cause of GH deficiency (idiopathic versus organic), and isolated GHD versus multiple pituitary hormone deficiencies; however, these characteristics could not be compared between trials due to a lack of reporting.

The networks were sparse. To account for potentially high heterogeneity, the sponsor used informative priors, though acknowledged that it was potentially problematic because data informing the priors were not sourced externally from the included trials. The heterogeneity of the trials may therefore still bias the results. Additionally, the network had no closed loops, so assessing for consistency was not possible.

The sparse network, small sample sizes, between-trial heterogeneity, and wide credible intervals (CrIs) indicate inconclusive results. Ultimately, there is no evidence that there is a clinically meaningful difference between somatropin and somatrogon; however, whether somatropin and somatrogon can be said to be clinically equivalent is likewise inconclusive. Furthermore, there were no quantitative comparisons of safety, and concerning differences between trials in the rate of injection-site pain in the common comparator arm (somatropin 0.034 mg/kg once daily) that were not explained. As a result, no conclusions can be drawn regarding the comparative safety of somapacitan versus somatrogon.

Studies Addressing Gaps in the Evidence From the Systematic Review

One other relevant study (REAL 3) was a phase II, multicentre, open-label, dose-finding trial that compared somapacitan versus Norditropin (somatropin) after 156 weeks of treatment, with a long-term (additional 4 years in plan and 1 year of data available) single-arm extension phase. The CADTH review focused on data for somapacitan with a dosage of 0.16 mg/kg/week, as per the proposed product monograph.

Description of Studies

Fourteen patients were enrolled in the 0.16 mg/kg/week somapacitan arm and 14 patients were enrolled in the Norditropin (somatropin) arm. The mean age of these patients was 6 years; ||||| of them were males and ||||| were females (cohort 1). The majority of patients were Asian (|||) followed by white (|||), and had idiopathic GHD (|||). The median GH peak level was higher in the somapacitan arm (5.28 mcg/L) than in the Norditropin (somatropin) arm (4.55 mcg/L). Pediatric patients of other ages were also analyzed in the long term safety extension phase: cohort 2 enrolled patients younger than 2.5 years (N = 1) and cohort 3 enrolled patients of pubertal age and up to 17 years (N = 9 for patients exposed in the long term extension and N = 1 for those who completed). Similar outcomes were reported at week 26 (primary time point for the dose-finding trial phase) and week 52 (extension phase). Harms outcomes were reported at weeks 104 and 208 in the single-arm safety extension phase. For cohorts 2 and 3, only harms outcomes were reported.

Efficacy Results

The results showed comparable effects in AHV at week 26 (primary end point), with an ETD of 1.67 cm/year (95% CI, −0.22 to 3.56); and the estimated mean HVs for somapacitan and Norditropin (somatropin) were 13.08 cm/year and 11.41 cm/year, respectively. The difference was similar at week 52 (1.8 cm/year; 95% CI, 0.5 to 3.1), but was smaller at week 156 (0.8 cm/year; 95% CI, −0.4 to 2.1). The point estimates were in favour of somapacitan compared with Norditropin (somatropin) for other auxologic response outcomes, including height SDS, HV SDS, and height (cm) at both week 26 and 52.

As of the pharmacodynamic end points, there was an increase in IGF-1 SDS with somapacitan compared with Norditropin (somatropin) at week 26 (ETD = 1.17; 95% CI, 0.38 to 1.95) and at week 52 (ETD = 1.56; 95% CI, 0.66 to 2.46). There was an increase in IGFBP-3 SDS at week 52 with an ETD of 0.93 (95% CI, 0.13 to 1.73).

The point estimates were in favour of somapacitan compared with Norditropin (somatropin) for the patient-reported outcomes of GHD-CIM, GHD-CTB, and GHD-PTB at week 52, but the 95% CI of the differences included the null.

Harms Results

During the 156-week treatment period, AEs were reported by 100% of patients in both the somapacitan and Norditropin (somatropin) arms. The most frequently reported AEs were pyrexia (29%), nasopharyngitis (21%), and vomiting (21%) in the somapacitan arm, and nasopharyngitis (21%), influenza (21%), and rhinitis (21%) in the Norditropin (somatropin) arm.

No patients in the somapacitan arm compared with 14% of patients in the Norditropin (somatropin) arm withdrew from treatment due to treatment-emergent AEs (2 patients in the Norditropin [somatropin] treatment arm discontinued treatment due to AEs that included nephrotic syndrome and drug hypersensitivity). No deaths were reported among patients in either arm.

The occurrence of 2 notable harms was comparable between the treatment arms at week 156: injection-site reactions were 7% in both arms, and injection-site pain was 7% in the somapacitan arm and 0 in the Norditropin (somatropin) arm.

No new safety issues were identified in the long term safety extension phase for any of the cohorts.

Other Outcomes

A comparable proportion of patients discontinued treatment with somapacitan (|||||) and Norditropin (somatropin) (|||||) at week 156, with reasons that included AEs (|||||| |||||), study protocol violation (|||| ||||||), and withdrawn by parent or guardian (|||| ||||||) in the somapacitan and Norditropin (somatropin) arms. Adherence to therapy was 92.2% in the somapacitan arm and 87.2% in the Norditropin (somatropin) arm at week 156.

Critical Appraisal

In general, internal validity and external validity for the REAL 3 trial were similar to those for the REAL 4 trial. Although the treatment and follow-up duration was up to 3 years for both efficacy and harms outcomes, with an additional 4 years of follow-up for safety, and patients of a wider range of age were enrolled (cohorts 2 and 3) in the REAL 3 trial, the generalizability of the study was limited by its small sample size. The use of an open-label design may bias the reporting of patient-reported outcomes (e.g., health-related quality of life) and AEs such as injection-site reactions (including pain, bruising, hematoma, and swelling) and injection-site pain. Furthermore, because of the lack of a control arm in the extension phases, the interpretation of the results is limited.

Conclusions

One phase III, multicentre, open-label study (REAL 4) compared the subcutaneous injection of somapacitan 0.16 mg/kg once weekly with Norditropin (somatropin) 0.034 mg/kg once a day in prepubertal children (aged 2.5 years to 10 years for girls and 2.5 years to 11 years for boys) with GHD at week 52. Somapacitan results in little to no difference in HV and height SDS (high certainty), and likely results in a smaller improvement from baseline in HV SDS (moderate certainty) when compared with Norditropin (somatropin). Somapacitan may result in little to no difference in disease-specific functioning when compared with Norditropin (somatropin) (low certainty). Somapacitan was associated with a reduction in child treatment burden (low certainty) and caregiver treatment burden (moderate certainty), compared with Norditropin (somatropin). Somapacitan results in little to no difference in treatment discontinuation when compared with Norditropin (somatropin) (moderate certainty). The evidence shows that somapacitan likely results in little to no difference in the notable harms, injection-site reactions and injection-site pain, when compared with Norditropin (somatropin) (moderate certainty). No new safety signals were identified from the longer-term single-arm studies; however, long-term comparative data were not available.

In the NMAs, there were no statistically significant differences identified between somapacitan and somatrogon (0.66 mg/kg/week) for the outcomes of AHV, height SDS, or HV SDS at week 26, nor in AHV or height SDS at week 52; however, the interpretation of the NMA is limited by the sparse network, small sample sizes, between-trial heterogeneity, and wide CrIs across all assessed outcomes. Disease-specific functioning, child treatment burden, and safety-related outcomes were not assessed in the NMAs.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of somapacitan 5 mg/1.5 mL (3.3 mg/mL), 10 mg/1.5 mL (6.7 mg/mL), 15 mg/1.5 mL (10 mg/mL) as a prefilled pen for subcutaneous use in the long term treatment of pediatric patients experiencing growth failure due to an inadequate secretion of endogenous GH (i.e., GHD).

Disease Background

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following have been summarized and validated by the CADTH review team.

Overview of the Condition

GHD is a rare disease caused by impaired secretion of GH by the pituitary gland, which affects patients’ growth, body composition, metabolic profile, bone mineral density, and quality of life.^2,3 GHD can be congenital (genetic and/or associated with brain malformations) or organic, also referred to as acquired (due to damage caused by tumours, physical trauma, inflammation, brain infections, or radiotherapy), and may occur in isolation (isolated GHD) or in conjunction with other pituitary hormone deficits (multiple pituitary hormone deficiency).² The majority of patients with GHD (up to 70%) have isolated GHD with no known cause (idiopathic).²⁴ This statistic seems different from the Canadian context; in a cohort of 850 children in Canada treated with GH, 526 of which had GHD, 72% (379 out of 526) were diagnosed with predominantly organic (particularly intracranial tumours and congenital pituitary abnormalities) rather than idiopathic GHD.⁴ Congenital causes of GHD can be linked to a number of gene mutations; some of these mutations may be located on GH1, HESX1, or X-linked recessive genes such as SOX3 and BTK, and many others.²

The clinical manifestation of GHD can vary, depending on the types of hypothalamic-pituitary lesions, the age of onset, and the combination of genetic mutations.⁵ For example, infants with GHD may not initially display obvious signs of the condition, but they may experience poor weight gain and lethargy, whereas GHD in adolescents may be associated with growth retardation and delayed puberty.² The key clinical features of GHD include delayed dentition, an immature face, a prominent forehead and depressed midfacial development, a high-pitched voice, increased fat mass that is predominantly centrally distributed, male hypogenitalism, decreased muscle mass, and delayed puberty.^2,25,26 In children and adolescents, GH is responsible for increasing bone length and density and is involved in regulating body composition.^2,27 GH also has antagonizing effects on insulin and glucose metabolism, affecting whole-body lipid metabolism. GH has the ability to induce insulin resistance, which is important for preventing hypoglycemia.^28,29 These regulatory processes mediated by GH contribute to the overall growth and maturation of children and adolescents into adults.

Estimated Disease Prevalence

Estimates for prevalence of pediatric GHD are sparse, with no specific Canadian data, although studies across Europe, the US, and China suggest an estimated prevalence ranging from 1 in 30,000 to 1 in 5,600.^3,6-8 Estimates of pediatric GHD suggest a prevalence of 1 in 4,000 to 10,000 children worldwide, suggesting a prevalence of approximately 1,600 children in Canada.^9,10

Diagnosis of the Condition

Diagnostic Testing Requirements

While there is no gold-standard diagnostic test for GHD, a multifaceted approach, including comprehensive clinical and auxological assessments, is used to diagnose children with GHD.³⁰ Typically, other potential causes of short stature, such as genetic, hormonal, metabolic, and/or psychogenic causes, will need to be explored and excluded before the evaluation of GHD in children with short stature.³¹ The Growth Hormone Research Society consensus guidelines recommend that assessments of GHD include a detailed medical history (gestational age, birth history, family history), anthropometric measures, static biochemical tests (IGF-1, IGFBP-3), imaging studies (bone age, MRI examination of the sella), and molecular genetics.^12,25,32 The Canadian Pediatric Endocrine Group consensus criteria for GH testing in Canada specifically includes the following measurements of auxologic and bone age:

• growth velocity of less than 25% of bone age documented over a 12-month period

• short stature, defined as being less than 2 SDs from midparental height (defined as a child’s estimated adult height based on the parent’s height), or bone age delayed by 2 SDs compared with chronological age, or the presence of other significant features associated with GH deficiency.³³

GH stimulation tests are performed to support the diagnosis of GHD and to measure the ability of the body to produce GH. A GH stimulation test involves administering a pharmacologic drug (e.g., arginine, glucagon, clonidine) to stimulate the pituitary gland to release GH and subsequently measuring GH levels.³⁴ Patients undergo 2 GH stimulation tests, which may be conducted consecutively on the same day or across multiple days. Specifically, the Canadian Pediatric Endocrine Group Consensus Criteria for the Diagnosis of Growth Hormone Deficiency in Canada indicates the criteria for a diagnosis of GHD involves 2 pharmacologic stimulation tests with peak GH concentrations of less than 10 mcg/L, or 1 pharmacologic test with peak GH concentrations of less than 3 mcg/L with abnormality present on MRI.³³ Thresholds for confirmation of GHD may vary based on the type of assay used for testing; however, the assays used in Canada for GH stimulation tests may typically range from 5.6 mcg/L to 8 mcg/L.

Availability of Diagnostic Testing

GH stimulation testing is a key diagnostic tool for GHD and usually occurs in hospital settings in Canada. According to the clinical expert consulted by CADTH, patients living in rural or geographically remote areas have a greater challenge in going to the specialty centres to have the GH stimulation testing done. The testing is done by pediatric endocrinologists who have access to or privileges at children’s hospitals (or, less commonly, in community hospitals) that have the qualified nurses, protocols, and facilities to conduct them properly. Two GH stimulation tests are usually required and are conducted consecutively on the same day. A single pharmacologic test may be sufficient for someone known to have multiple pituitary hormone deficiencies or a hypoplastic anterior pituitary or ectopic pituitary. GH stimulation testing is considered the standard of care for the diagnosis of GHD.

Health Care Resources

Treatment Phase

Patients receiving somapacitan (Sogroya) will be initiated with a dose of 0.16 mg/kg body weight once weekly. Maintenance dosing of somapacitan can be adjusted based on the patient and their response.¹

Patients who switch from another daily GH treatment to somapacitan should choose the preferred day to begin the weekly dose and stop daily GH treatment 8 to 24 hours before their first dose of somapacitan. Patients who switch from another GH therapy administered weekly are recommended to continue their weekly schedule. According to the product monograph, patients should be prescribed somapacitan by a health care provider but will self-administer or receive treatment with the help of a caregiver or guardian with proper training.¹

A key indicator of GHD is HV. The determination of HV should be made through serial measurements occurring at approximately 6-month intervals; the frequency of clinical visits may depend on the age of the child, with infants being seen more frequently at every 3 months, while adolescents may be seen every 4 to 6 months.^2,25 During these routine clinical visits, in addition to the measurement of height, additional assessments may occur, including the assessment of puberty, side effects from treatment, need for potential dose adjustments, adherence, and treatment satisfaction. Additional laboratory measurements will also need to take place approximately every 3 to 6 months to assess for proper physiological development and any hormone deficiencies (i.e., IGF-1 levels, thyroid function, pituitary hormone deficiencies, and glucose tolerance). Assessments of bone age may also occur every year.³⁵

Standards of Therapy

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following have been summarized and validated by the CADTH review team.

The primary treatment of GHD is injections of synthetic GH, which has been available since 1985.¹¹ Canadian and US guidelines recommend treatment with GH to normalize extreme shortness in children and adolescents with GHD to attain normal adult height.¹² Treatment with GH should begin as soon as possible for patients to achieve their optimal growth velocity and final adult height,^9,13 and be continued until a patient reaches their full adult height and bone maturity, or when their HV is less than 2 cm/year.^14-16 Somatropin, administered as a daily subcutaneous injection, has traditionally been the primary GH used for treatment of GHD. In March 2022, somatrogon (Ngenla), a Health Canada–approved GH, received CADTH’s reimbursement recommendation for treatment of pediatric GHD as a weekly subcutaneous injection,¹⁴ but received a negative funding recommendation by INESSS due to the potential for greater pain at the injection site and higher doses.¹⁷

If left untreated, GHD may become permanent upon reaching adulthood. Other complications from untreated GHD may also include insulin resistance, increase in adipose tissue and decreased lean body mass, decreased bone strength, and increased blood pressure.³⁶ According to the sponsor and clinical expert input, treatment goals for GHD include optimizing final adult height, restoring metabolic functions associated with GHD, reducing injection burden, improving treatment adherence, and optimizing quality of life.

The clinical expert consulted for this review indicated that all products in Table 3 may be used as treatments for pediatric GHD administered as daily or weekly subcutaneous injections. The choice of synthetic GH for treatment of GHD may be based on several factors, such as consideration of patient preference, cost, and financial and device support offered by the sponsor of the GH therapy.

According to the clinical expert input, 1 of the limitations associated with current treatments is that they require injections and daily (or near daily) injections, which can lead to suboptimal adherence, resulting in suboptimal clinical outcomes, e.g., the treatment goal of improvement in height is affected.^3,18,19 The daily dosing frequency can be burdensome to both patients and caregivers, and can cause anxiety around injection (e.g., needle phobia) and associated pain for patients.³⁷ Caregivers of pediatric patients may also feel uneasy about administering therapy, as parents often worry about causing their child pain.³⁷ Storage and administration of treatment can influence treatment adherence as can the patient’s and caregiver’s lives. Devices with less burdensome storage requirements that are easy to use and have advanced design in size, weight, and strength required to administer the injection (which is of particular importance for pediatric patients who self-administer treatment) may improve patient adherence to the treatment.^19,38

Drug Under Review

Indication and Reimbursement Request

The dossiers for somapacitan (Sogroya) were submitted to CADTH as a pre–Notice of Compliance submission, with the Notice of Compliance issued on July 26, 2023. Somapacitan underwent a standard review at Health Canada for the long-term treatment of pediatric patients experiencing growth failure due to an inadequate secretion of endogenous GH (GHD).

Dosing and Administration

Somapacitan is recommended to be initiated at a dose of 0.16 mg/kg body weight once weekly for treatment-naive patients and patients switching from daily GH (somatropin), under the supervision of an experienced health care provider. The dose of somapacitan is to be individualized and adjusted based on the patient’s response to treatment. Treatment with somapacitan may be administered at any time of day and is to be injected subcutaneously in the abdomen, thighs, buttocks, or upper arms. It is recommended that the injection site be rotated every week.¹

Patients switching from daily human GH to once-weekly somapacitan should choose the preferred day for the weekly dose and end daily treatment the day prior, or at least 8 hours before taking the first dose of once-weekly somapacitan. Patients switching from a weekly human GH to once-weekly somapacitan are recommended to continue their once-weekly dosing schedule. When GHD persists after growth completion, it is recommended that GH treatment be continued to achieve full somatic adult development, including lean body mass and bone mineral accrual.¹

Mechanism of Action

Somapacitan is a 23.3 kDa human GH derivative (99% similarity to endogenous GH) linked to a small noncovalent albumin-binding moiety that facilitates reversible endogenous albumin binding to delay somapacitan elimination. The mechanism of action of somapacitan is either directly via the GH receptor and/or indirectly through the IGF-1 produced in tissues throughout the body. When GH deficiency is treated with somapacitan, a normalization of body composition (i.e., decreased body fat mass, increased lean body mass) and of metabolic action is achieved. Somapacitan stimulates skeletal growth in pediatric patients with GHD as a result of its effects on the growth plates (epiphyses) of bones.¹

Prescribing

According to the Health Canada product monograph, somapacitan treatment should be initiated and monitored by physicians who are appropriately qualified and experienced in the diagnosis and management of patients with the condition for which somapacitan is indicated. Switching a patient from another type or brand of GH should be done by a physician who has experience in the diagnosis and management in GHD.¹

Key characteristics of somapacitan are summarized in Table 3, along with other treatments available for GHD.

Table 3: Key Characteristics of Somapacitan (Sogroya), Somatropin (Norditropin, Nutropin AQ, Humatrope, Genotropin, Omnitrope, Saizen), and Somatrogon (Ngenla)

GH = growth hormone; GHD = growth hormone deficiency; IGF-1 = insulin-like growth factor 1; NA = not applicable; PWS = Prader-Willi syndrome; SC = subcutaneous.

^aHealth Canada–approved indication.

Source: Product monographs.^1,39-45

Stakeholder Perspectives

Patient Group Input

This section was prepared by the CADTH review team based on the input provided by patient groups. The full original patient inputs received by CADTH have been included in the stakeholder section of this report.

Two patient groups, CORD and the MAGIC Foundation, provided input for the treatment of GHD. CORD recruited participants through patient membership list and parents attending a European summit and then conducted interviews, whereas the MAGIC Foundation gathered data from surveys. A total of 12 parents (6 from the list and 6 from the summit) participated in the interviews conducted by CORD. Among these 12 participants, 4 were from Canada (Ontario), 2 were from the US, and 6 were from Europe. All participants responding to the MAGIC Foundation’s surveys were from the US, and none of their current members in Canada had experience with an LAGH. The children represented in the CORD input ranged in age from 4 to 15 years, and those from the MAGIC Foundation input were between 3 and 18 years of age.

When parents were asked by CORD about the impact of the disease on patients’ and caregivers’ day-to-day life and quality of life, they expressed going through a variety of emotions, such as denial, blame, sadness, acceptance, and compassion. Parents from both groups reported a variety of psychological and social impacts on the child and the family, particularly due to short stature. In the MAGIC Foundation’s input, parents mentioned that their children were shorter than their peers, were fatigued, lacked concentration and appetite, had poor stamina, and were often very sick before beginning GH treatment.

Patients from both groups were reported to have been on GH therapy. All patients in the CORD group were reported to have experience with daily subcutaneous injections of somatropin, and 4 patients were reported to have current experience with an LAGH (somatrogon, lonapegsomatropin, and somapacitan-beco) obtained through clinical trials, compassionate access, or reimbursement or insurance. On the other hand, some patients from the MAGIC Foundation group were reported to have experience with both daily and weekly injections, whereas others were reported to be strictly on daily injections.

Parents from the CORD group described the daily administration of an injection every night as the most consistent challenge. These parents also recognized the importance of GH therapy despite the challenges and worries about the future. Parents from the MAGIC Foundation group mentioned the high cost of GH treatment and dependence on insurance companies in getting the treatment for children in the US. When parents were asked about the outcomes to consider when evaluating new therapies by the CORD group, an injection that lasted longer and was easier to administer was a desired change. While describing the experience with the current drug under review, all 4 respondents who had experience with LAGH therapy shared positive feedback, such as having a positive impact on the child’s and the family’s quality of life; some described this impact as “transformational” and “life-changing.”

Clinician Input

Input From the Clinical Expert Consulted by CADTH

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

Unmet Needs

The clinical expert indicated that the current treatment paradigm for patients with GHD is to offer recombinant GH (i.e., somatropin), generally with a starting dose of 0.18 mg/kg/week by daily injection (if hypoglycemia is a concern) or, commonly, 6 out of 7 days per week (to provide 1 day per week as a break from injections). According to the clinical expert, the treatment goals are: to restore height by improving HV (with the target of achieving a near-final adult height that is close to the patient’s midparental target heights), to restore metabolic health, to address hypoglycemia (especially in the neonatal or infantile periods), and to restore well-being.

Place in Therapy

According to the clinical expert, several brands of somatropin currently on the market are available to treat GHD. They noted that somapacitan can be used in the treatment of pediatric GHD by those who are willing to try it or who are already using somatropin and want to switch to once-weekly injections because they can no longer tolerate daily injections.

The clinical expert noted that using the ethical principle of justice, it could be appropriate to recommend that patients try somatropin first, especially if somapacitan is significantly more expensive than somatropin. The clinical expert did not believe that all patients should be required to use somatropin before somapacitan. According to the clinical expert, the ethical principle of beneficence requires that physicians prevent harm; if there is an available option that reduces the pain and anxiety of daily injections and is similar in treatment and safety outcomes to the conventional version, then physicians should prescribe the option that reduces harm. Nonetheless, the clinical expert highlighted that somapacitan can be prescribed for treatment-naive patients.

Patient Population

The clinical expert noted that patients who are similar to the ones enrolled in the REAL 4 trial (prepubertal, younger children) are most likely to respond to treatment with somapacitan, although uncertainties remain as to whether patients with other conditions that can affect growth would respond as well, since they were excluded from the trial. According to the clinical expert, an active control, Norditropin (somatropin), was used as the comparison in the REAL 4 trial; hence somapacitan probably confers greater benefit to those with more severe GHD, those with initial lower pretreatment levels of IGF-1, and those with a lower HV SDS.

The clinical expert noted that patients with GHD who were most in need of intervention would be those who experience significant pain or anxiety from the injections to the extent that there is a threat to optimal adherence to daily somatropin.

The clinical expert pointed out that although there are limitations in the diagnosis of GHD using examinations of IGF-1 level and peak GH, the likelihood of overdiagnosis in Canada is probably lower than in other countries, based on findings of the GeNeSIS study,⁴ which means that pediatric endocrinologists in Canada tend to be more stringent in diagnosing GHD. The clinical expert noted that underdiagnosis of GHD may happen more within the subgroup of children who acquire GHD after treatment for cancer.

The clinical expert noted that although no confirmed predictors have been identified, children who have more severe GHD, initiate GH treatment at a younger age, stay on therapy for a longer duration, and are adherent to therapy are more likely to respond to somapacitan, based on extrapolation from the results of the somatropin studies.

Assessing the Treatment Response

According to the clinical expert, the main outcomes that are used in clinical practice to determine whether a patient is responding to GH therapy include: change in absolute height and height SDS, change in HV and HV SDS, and change in IGF-1 level (and IGF-1 SDS).

Discontinuing Treatment

The clinical expert pointed out that GH therapy is necessary for children with GHD and, therefore, a concerted effort should be made to understand the cause of suboptimal growth before discontinuing somapacitan (or any other GH therapy), including excluding causes that are not related to the GH therapy itself, such as the lack of adherence to therapy for multiple reasons, other comorbid causes of suboptimal growth (nutrition, celiac disease, additional pituitary hormone deficiencies), and injection-technique issues.

According to the clinical expert, a contraindication that precludes ongoing use of somapacitan (or any other GH therapy) is when the epiphyses are closed. Adverse effects such as glucose intolerance, IGF-1 levels that exceed 2 SDS, raised intracranial pressure, slipped caput femoral epiphyses, and avascular necrosis would pause treatment but not necessarily discontinue it. When a patient develops a cancer (primary or secondary), GH therapy would be discontinued (but potentially restarted in the future).

Prescribing Considerations

The clinical expert indicated that somapacitan should be prescribed by board-certified pediatric endocrinologists who can diagnose, treat, and monitor the patients. A pediatric endocrine nurse should be involved in initiating recombinant GH, providing ongoing support, and double-checking that the patient is adhering to prescribed therapy. According to the clinical expert, treatment with somapacitan could happen in community settings or academic referral centres.

Clinician Group Input

This section was prepared by the CADTH review team based on the input provided by clinician groups. The full original clinician group input received by CADTH has been included in the stakeholder section of this report.

Clinician group input on the review of somapacitan was received from the Canadian Pediatric Endocrinology Nurses group. A total of 5 nurses provided input for this review.

Canadian Pediatric Endocrinology Nurses mentioned that daily somatropin injections are being used as the current treatment paradigm for GHD. These injections are administered to increase growth, stabilize blood sugar levels, and increase bone density and muscle development. The group described the treatment gaps or unmet needs of currently available treatments. Issues with current treatments include: poor compliance in patients with daily injections, anxiety with daily injections, lack of availability of GH, and the need for a treatment with improved compliance, better tolerance, and formulations with improved convenience. The group indicated that the drug under review could be used as a first-line treatment for GHD if approved and funded.

While describing which patients would be best suited for treatment with the drug under review, the clinician group mentioned those who experience needle anxiety, have compliance issues, are in a complex social situation, or have remote living conditions. The group also added that patients with GHD can be identified by, for example, clinician examination, GH stimulation testing, bone age, IGF-1 level, and so forth. The group emphasized that without GH (either daily or weekly), patients will not grow and could have hypoglycemia, decreased bone density, poor muscle development, and altered body composition. The clinician group pointed out that improved growth velocity and normalized glucose in infants would be considered a clinically meaningful response to treatment. They also added that factors such as achieving final adult height, closed epiphyses, and a growth rate of less than 2 cm/year should be considered when deciding to discontinue treatment with the drug under review. The clinician group noted the patients must be diagnosed, treated, monitored, and prescribed by a pediatric endocrinologist.

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 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

CDEC = CADTH Canadian Drug Expert Committee; GH = growth hormone; NIHB = Non-Insured Health Benefits.

Clinical Evidence

The objective of CADTH’s Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of somapacitan 5 mg/1.5 mL (3.3 mg/mL), 10 mg/1.5 mL (6.7 mg/mL), 15 mg/1.5 mL (10 mg/mL) as a prefilled pen for subcutaneous use in the long term treatment of pediatric patients experiencing growth failure due to an inadequate secretion of endogenous GH (i.e., GHD). The focus will be placed on comparing somapacitan with relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of somapacitan is presented in 4 sections, with CADTH’s critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. CADTH’s assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The second section includes sponsor-submitted long-term extension studies. The third section includes indirect evidence from the sponsor.

Included Studies

Clinical evidence from the following is included in the CADTH review and appraised in this document:

• one pivotal study (RCT) identified and included in systematic review

• one long-term extension study

• one ITC

• one additional study addressing gaps in evidence.

Systematic Review

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the CADTH review team.

Description of Studies

Characteristics of the included study are summarized in Table 5. Refer to Appendix 1 for the detailed patient inclusion and exclusion criteria.

One pivotal multicentre, multinational, randomized, open-label, active-controlled, phase III trial (REAL 4) met the inclusion criteria for the sponsor’s systemic review, in which a total of 86 sites randomized 200 patients (Table 5). The REAL 4 trial investigated the efficacy and safety of a once-weekly dosing of somapacitan compared with a once-daily dosing of Norditropin (somatropin) in patients with GHD who were at least 2.5 years of age and younger than 11 years for boys and younger than 10 years for girls. The trial consisted of a 52-week main treatment period that ended on November 10, 2021,²⁰ plus a 156-week (3-year) safety extension period. The total trial duration was 4 years (the 3-year extension period was still ongoing as of the March 18, 2022, cut-off) and the follow-up period was a minimum of 30 days (Figure 1). The main body of this report presents data from the main trial phase for the REAL 4 trial up to week 52. Data from the safety extension phase (week 52 to 104) are presented in the clinical evidence section under long-term extension studies.

Table 5: Details of Study Included in the Systematic Review

CDC = Centers for Disease Control and Prevention; FPFV = first patient first visit; G-DAT = Growth Hormone Device Assessment Tool; GH = growth hormone; GHD = growth hormone deficiency; GHD-CIM = Growth Hormone Deficiency–Child Impact Measure; GHD-CTB = Growth Hormone Deficiency–Child Treatment Burden; GHD-PTB = Growth Hormone Deficiency–Parent Treatment Burden; IGF-1 = insulin-like growth factor 1; IGFBP-3 = insulin-like growth factor binding protein 3; LPLV = last patient last visit; SD = standard deviation; SDS = standard deviation score; TB-CGHD-O = Treatment Burden Measure–Child Growth Hormone Deficiency–Observer; TB-CGHD-P = Treatment Burden Measure–Child Growth Hormone Deficiency–Parent; TRIM-CGHD-O = Treatment-Related Impact Measure–Child Growth Hormone Deficiency–Observer; WHO = WHO.

Note: 1 additional report was included (Miller et al., 2022⁴⁶).

^aActual key study date.

^bPlanned key study date.

Source: REAL 4 trial week 52²⁰ and week 104²³ Clinical Study Reports.

Patients were randomized 2:1 to receive either somapacitan or Norditropin (somatropin) during the 52-week main trial period. Randomization was stratified by region (Japan versus the rest of the world, possibly because of different peak GH levels used in GHD diagnosis), age group (< 6 years versus ≥ 6 years at randomization), gender (boys versus girls), and GH peak level (< 7.0 ng/mL versus ≥ 7.0 ng/mL). During the subsequent 3-year safety extension trial period, all patients were treated with once-weekly somapacitan. Both trial products were administered as subcutaneous injections. The trial was open-label; no blinding was conducted.

Figure 1: Study Design for the REAL 4 Trial

GH = growth hormone; GHD growth hormone deficiency.

Note: Reprinted from Miller et al., 2022. Creative Commons Attribution License 4.0.⁴⁶

Source: Miller et al., 2022,⁴⁶ and the week 52²⁰ and week 104²³ Clinical Study Reports for the REAL 4 trial.

Populations

Inclusion and Exclusion Criteria

REAL 4 included prepubertal children who were at least 2.5 years old and younger than 11 years for boys and younger than 10 years for girls who had a diagnosis of GHD confirmed by 2 different GH stimulation tests performed in the last 12 months before screening, defined as a peak GH level of 10.0 ng/mL or lower, who had impaired height (at least 2 SD below the mean) and impaired HV (below the 25th percentile) for chronological age and gender, and who had a mean IGF-1 level at least 1 SD below the standardized mean for age and gender. Patients were naive to other GH therapies or IGF-1 treatments. Key exclusion criteria included children with any clinically significant abnormality likely to affect growth or the ability to evaluate growth using standing or length measurements, concomitant administration of other treatments that may have an effect on growth, and a prior history or presence of malignancy and/or intracranial tumour. Additional exclusion criteria are shown in Table 5. Of note, for study sites in Japan, the confirmed diagnosis of GHD was determined by 1 GH stimulation test for patients with intracranial organic disease or symptomatic hypoglycemia and 2 different GH stimulation tests for patients in other countries, defined as peak GH level of 6 ng/mL or lower by assay using recombinant GH standard within 12 months before screening.

Interventions

Somapacitan was provided in a liquid formulation in the PDS290 pen-injector device and administered subcutaneously. In the REAL 4 trial, somapacitan was administered at a dose of 0.16 mg/kg/week throughout the main 52-week trial period and the 3-year extension period. Injections were given subcutaneously and 3 PDS290 pen-injector strengths (5 mg/1.5 mL, 10 mg/1.5 mL, and 15 mg/1.5 mL) were used in the trial based on the patient’s body weight.

The active control, Norditropin (somatropin), was provided in a liquid formulation in the FlexPro pen-injector device at a dose of 0.034 mg/kg/day for subcutaneous administration and was administered for the 52-week main trial period.

In the REAL 4 trial, when patients self-administered the trial product at home, compliance with trial-product administration was assessed and documented at each visit.

If AEs with a probable relationship to the trial product were persistent but allowed continuation in the trial, as judged by the investigator, dose reduction in consecutive steps of 25% of the current dose was considered at the investigator’s discretion. If after consecutive dose-reduction steps the AEs persisted, the patient’s treatment was discontinued according to the treatment discontinuation or withdrawal criteria. When the AE was resolved, the dose could be resumed to the original planned dose at the investigator’s discretion.

If IGF-1 SDS exceeds 2.5 SDS at 2 consecutive visits, Novo Nordisk would inform the investigator. The current dose would then have to be reduced by 25%.

No prior exposure to GH therapy and/or IGF-1 treatment was permitted in either of the pivotal trials.

At visit 2, the patients were provided with an e-diary device for the electronic recording of data. Information about the injection of the trial product was recorded in the e-diary device to provide data on adherence to therapy.

Outcomes

A list of the efficacy end points assessed is provided in Table 6, followed by descriptions of the outcome measures and their measurement properties in Table 7. Summarized end points are based on outcomes included in the sponsor’s summary of clinical evidence as well as any outcomes identified as important to this review, according to the clinical expert consulted by CADTH and the stakeholder input from the patient and clinician groups and public drug plans. Using the same considerations, the CADTH review team selected outcome measures considered to be most relevant to inform CADTH’s expert committee deliberations and finalized this list of outcome measures in consultation with members of the expert committee. All summarized efficacy outcome measures were assessed using GRADE and included HV, height SDS and HV SDS. Patient-reported outcomes that reflect patient quality of life or burden from disease and treatment, including GHD-CIM, GHD-CTB, and GHD-PTB, were considered important by the patient groups and were assessed using GRADE. Select notable harms outcomes and treatment discontinuations (or adherence to therapy) that were considered important for informing the deliberations of CADTH’s expert committee were also to be assessed using GRADE. Two notable harms were selected for GRADE assessment: injection-site reactions and injection-site pain, which were recognized as important by the clinical expert consulted by CADTH and could be associated with treatment adherence, which plays a role in GH therapy efficacy in terms of growth. Also, these harms provide the source for a key input in the sponsor’s pharmacoeconomic model.

Table 6: Outcomes Summarized From the REAL 4 Trial

GHD-CIM = Growth Hormone Deficiency–Child Impact Measure; GHD-CTB = Growth Hormone Deficiency–Child Treatment Burden; GHD-PTB = Growth Hormone Deficiency–Parent Treatment Burden; SDS = standard deviation score; TB-CGHD-O = Treatment Burden Measure–Child Growth Hormone Deficiency–Observer; TB-CGHD-P = Treatment Burden Measure–Child Growth Hormone Deficiency–Parent; TRIM-CGHD-O = Treatment-Related Impact Measure–Child Growth Hormone Deficiency–Observer.

Source: REAL 4 trial Clinical Study Report (week 52).²⁰

Height Velocity

The primary efficacy end point was change in HV at week 52 measured in cm/year using the following equation:

HV is derived from the height measurement that reflects the rate of change in human stature over time, and an AHV (over 1 year) is commonly used as a measure of growth.^47,48 In the REAL 4 trial, the calculation of HV was based on the difference between the heights at week 52 and baseline and the value was converted to be expressed in cm/year using the preceding formula. Standing height was measured by a trained person blinded to treatment allocation using a calibrated wall-mounted stadiometer, preferably using the same stadiometer at the same time of day (± 2 hours, compared with baseline). The average of the standing height, measured 3 consecutive times in centimetres or inches and rounded to 1 decimal, was used to determine the patient’s height during the visit.

Other Auxologic Response

Other auxologic responses were secondary end points in the REAL 4 trial, evaluated as change from baseline to week 52 in height SDS and HV SDS. SDS-related measurements are typically used as end points for outcomes such as height and HV because they are influenced by age and gender. Standards of these measurements have been developed and used by clinicians treating GHD.¹²

Height SDS was derived using the Centers for Disease Control and Prevention’s 25 standards, and HV SDS was derived using Prader standards as reference data.

Patient-Report Outcomes

The following patient-reported outcome questionnaires were completed:

• the GHD-CIM, previously called the Treatment-Related Impact Measure–Child Growth Hormone Deficiency–Observer (TRIM-CGHD-O)

• the GHD-CTB, previously called the Treatment Burden Measure–Child Growth Hormone Deficiency–Observer (TB-CGHD-O)

• the GHD-PTB, previously called the Treatment Burden Measure–Child Growth Hormone Deficiency–Parent (TB-CGHD-P)

• the Growth Hormone Device Assessment Tool (G-DAT).

These 4 questionnaires were completed only in countries where they were available.

The TRIM-CGHD-O is a disease-specific questionnaire that measures the impact of GH treatment on symptoms, physical health, and social and emotional well-being of children with GHD. Based on the responses, an overall score as well as domain-specific scores can be derived. The updated name of the TRIM-CGHD-O questionnaire is GHD-CIM. A lower score indicates a better health state. The scores of the GHD-CIM range from 0 to 100. Anchor-based patient and clinician ratings of severity of disease suggest a preliminary MID of 5 points for the overall score, 5 points for the physical functioning domain score, 7 points for the emotional well-being domain score, and 5 points for the social well-being domain score.⁴⁹

The TB-CGHD-O is a disease-specific questionnaire that measures the physical burden of GH treatment as well as its burden on emotional well-being and interference in the activities of daily life of children with GHD. Based on the responses, an overall score as well as domain-specific scores can be derived. The updated name of the TB-CGHD-O questionnaire is the GHD-CTB. The scores of the GHD-CTB range from 0 to 100, with a lower score indicating a better health state. Anchor-based patient and clinician ratings of severity of disease suggest a preliminary MID of 6 points for the physical domain score, 9 points for the emotional domain score, and 6 points for the interference domain score.⁵⁰

The TB-CGHD-P is a disease-specific questionnaire that measures the burden of GH treatment on the emotional well-being of the parent or guardian as well as the interference in the activities of daily life of the parent or guardian. Based on the responses, an overall score and domain-specific scores can be derived. The updated name of the TB-CGHD-O questionnaire is the GHD-PTB. The scores of the GHD-PTB range from 0 to 100, with a lower score indicating a better health state. Anchor-based patient and clinician ratings of severity of disease suggest a preliminary MID of 10 points for the emotional domain score, and 6 points for the interference domain score.⁵⁰

The G-DAT is a questionnaire that includes 6 questions completed by the parent or LAR to gather information on how the parents feel about their child’s GH device. The final question was “Overall, how difficult or easy is it to use the device?” Answers were scored on a 5-level scale from “very difficult” to “very easy.”

Safety

AE recording and laboratory measurements for safety were conducted when patients fulfilled the prespecified study visits at weeks 4, 13, 26, 39, and 52.^46,51 An AE was defined as any untoward medical event that occurred during the period when a patient was receiving a product but that did not necessarily have a causal relationship with the treatment. An injection-site reaction is defined as “an injection site reaction considered clinically significant by the investigator.” Digital photos were required to be taken of the injection-site reaction at the time of identification as frequently as judged necessary by the investigator, and then evaluated by an external dermatologist. Pain (general or at the injection site) was assessed as part of the injection-site reactions noted during the visual and manual inspection performed by the investigator at each visit.⁵¹

Table 7: Summary of Outcome Measures and Their Measurement Properties

G-DAT = Growth Hormone Device Assessment Tool; GHD-CIM = Growth Hormone Deficiency–Child Impact Measure; GHD-CTB = Growth Hormone Deficiency–Child Treatment Burden; GHD-PTB = Growth Hormone Deficiency–Parent Treatment Burden; LAR = legally authorized representative; MID = minimal important difference; TB-CGHD-O = Treatment Burden Measure–Child Growth Hormone Deficiency–Observer; TB-CGHD-P = Treatment Burden Measure–Child Growth Hormone Deficiency–Parent; TRIM-CGHD-O = Treatment-Related Impact Measure–Child Growth Hormone Deficiency–Observer.

Statistical Analysis

Clinical Trial End Points

Different estimand strategies for the FDA and European Medicines Agency (EMA) were used based on recommendations from the health authorities (Table 8). For the FDA, the treatment policy strategy was to use the calculated treatment difference in mean AHV at week 52 between somapacitan and Norditropin (somatropin) for all randomized patients with GHD, regardless of treatment adherence or initiation of ancillary therapy. For the EMA, the hypothetical strategy (no ancillary therapy available) used the treatment difference between somapacitan and Norditropin (somatropin) in mean AHV at week 52 when ancillary therapy had not been available before week 52, i.e., assuming no initiation of ancillary therapy in children with GHD. For the FDA strategy, the primary analysis of the primary end point was based on the FAS. For the EMA strategy, the primary analysis of the primary end point was based on the FAS, but the data assessed after the discontinuation of randomized treatment were disregarded. A tipping-point analysis was conducted for the EMA strategy, since 1 patient discontinued treatment. As there were no missing values at week 52 for the FDA strategy, no imputations were done.

The following 2 observation periods were used in the trial:

• “On-treatment” period: Including first administration and up until the last trial contact, visit 7, or 14 days after last administration, whichever came first.

• “In-trial” period: Including first administration and up until visit 7 or the last trial contact, whichever came first.

The secondary efficacy end points (bone age, height SDS, HV SDS) were analyzed based on the in-trial observation period during the main trial period. Data were analyzed as the change from screening (week 0) to visit 7 (week 52). The time interval used for the derivation of the baseline HV was defined as the period from the date of the pretrial height assessment (a minimum of 6 months and a maximum of 18 months before screening) to the date of the randomization visit.

Change in height SDS and HV SDS were analyzed using the same analysis model that was used for analyzing the primary end point for the primary estimand (treatment policy strategy), except that baseline height SDS and baseline HV SDS, respectively, were used as covariates in the model instead of baseline height. The estimate for the treatment difference at week 52 was reported with the corresponding 95% CI and P value.

Change in bone age was analyzed using an analysis of covariance (ANCOVA) model on the change in bone age or chronological age assessed at week 52. The model included treatment, gender, age group, region, GH peak group, and gender by age group by region interaction term as factors and bone age or chronological age at screening as a covariate. The treatment difference estimate was reported with the corresponding 95% CI and P value. Patients for whom no postrandomization data were available for the analyzed end point were not included in the analysis.

The pharmacodynamic end points (IGF-1 SDS and IGFBP-3 SDS) were analyzed based on the on-treatment observation period and the in-trial observational period using the mixed-model for repeated measures (MMRM). The patient-reported outcomes were analyzed based on the “on-treatment” observational period using an MMRM.

The supportive secondary safety end points (fasting plasma glucose, homeostatic model assessment, hemoglobin A1C levels) were analyzed using descriptive statistics based on the on-treatment observation period and the in-trial observation period. Data were measured as a change from screening (visit 1) to visit 7 (week 52). Homeostasis model assessment (HOMA) was reported as steady-state beta cell function (HOMA-B) and insulin resistance (HOMA-IR).

According to the protocol, the missing week 52 values were planned to be imputed. The missing week 52 values were imputed using a Markov chain Monte Carlo method. This imputation was carried out for each treatment group separately and 100 copies of the dataset were generated (seed = 5,297). The number of copies was increased if the estimation process did not result in robust estimates.

Sample Size and Power Calculation

The sample size was determined based on the primary end point of HV using a noninferiority margin of −1.8 cm/year and a 1-sided 2-group t test with a significance level of 2.5% for a 2:1 randomization ratio between somapacitan and Norditropin (somatropin). Previous trials that have allowed ancillary therapy or the retrieval of landmark data included in the analysis are limited; therefore, a conservative SD of 3.5 cm/year for HV at week 52 was chosen. With an SD of 3.5 cm/year and 90% power for the primary analysis, a sample size of 192 patients was calculated under the assumption of a true difference in AHV of 0 cm/year between the 2 treatment groups and no true difference in AHV between retrieved patients (i.e., subjects discontinuing randomized treatment but have landmark visit data) and patients staying on randomized treatment at the landmark visit. The sample size for the EMA was determined using the same assumptions as for the estimand for the FDA; for a total of 192 patients, the power was 88%.

Statistical Testing

The noninferiority of somapacitan was confirmed when the lower boundary of the 2-sided 95% CI was above −1.8 cm/year or equivalent when the P value for the 1-sided test of H₀ (D ≤ −1.8 cm/year) versus H_A (D > −1.8 cm/year) was less than 2.5%, where D was the mean treatment difference (somapacitan minus Norditropin [somatropin]). If noninferiority was confirmed, superiority was considered confirmed if the lower boundary of the 2-sided 95% CI was above 0 cm/year. If superiority was confirmed, the P value from the 2-sided superiority test was also reported. A tipping-point analysis was conducted for the primary outcome (and estimands) and based on a penalty for imputed values in the somapacitan arm of 1.8 cm/year, giving a power of 87% (adjusted treatment effect = 0.9 × 0 minus 0.05 × 1.8 = −0.09), under the assumption that landmark visit data (corresponding to an analysis that performs an imputation under the noninferiority null method) is not available for 5% of patients.

Subgroup Analyses

No subgroup analyses were planned or conducted.

Table 8: Statistical Analysis of Efficacy End Points for the REAL 4 Trial

ANCOVA = analysis of covariance; G-DAT = Growth Hormone Device Assessment Tool; GH = growth hormone; GHD-CIM = Growth Hormone Deficiency–Child Impact Measure; GHD-CTB = Growth Hormone Deficiency–Child Treatment Burden; GHD-PPQ = Growth Hormone Patient Preference Questionnaire; GHD-PTB = Growth Hormone Deficiency–Parent Treatment Burden; MMRM = mixed-model for repeated measures; NA = not applicable; SDS = standard deviation score; TB-CGHD-O = Treatment Burden Measure–Child Growth Hormone Deficiency–Observer; TB-CGHD-P = Treatment Burden Measure–Child Growth Hormone Deficiency–Parent; TRIM-CGHD-O = Treatment-Related Impact Measure–Child Growth Hormone Deficiency–Observer.

Source: REAL 4 trial Clinical Study Report (week 52).²⁰

Analysis Populations

The efficacy end points in the REAL 4 trial were analyzed based on the FAS, which included all randomized patients as randomized (Table 9). The safety population included all randomized patients who received at least 1 dose of treatment, analyzed as treated.

Results

Patient Disposition

In the REAL 4 trial, 200 patients were randomized. One patient discontinued treatment with somapacitan due to a violation of the inclusion and/or exclusion criteria. Refer to Table 10 for the data.

Table 9: Analysis Populations of REAL 4

FAS = full analysis set.

Source: REAL 4 trial Clinical Study Report (week 52).²⁰

Table 10: Summary of Patient Disposition From REAL 4 (Week 52)

FAS = full analysis set; IGF-1 = insulin-like growth factor 1; PP = per protocol.

Source: REAL 4 trial Clinical Study Report (week 52).²⁰

Baseline Characteristics

The baseline characteristics outlined in Table 11 are limited to those considered to be most relevant to this review or which were believed to affect the outcomes or interpretation of the study results.

In general, the patient demographics and disease characteristics were similar between groups. The mean age of patients enrolled in the REAL 4 trial was 6.38 years (SD = 2.23) and 6.43 years (SD = 2.42) in the somapacitan and Norditropin (somatropin) groups, respectively. Overall, the proportion of boys (74.5%) was higher than that of girls (25.5%); most patients were white (57%), with fewer patients who were Asian (37%) or Black (1 patient, 0.5% of total), or who were either of another race or their race was unknown (0.8% to 5.3%).

The mean BMI values of patients were 15.7 kg/m² (SD = 1.59) and 15.59 kg/m² (SD = 1.38) in the somapacitan and Norditropin (somatropin) groups, respectively. The proportion of idiopathic GHD in the somapacitan group (87.1%) was slightly lower than in the Norditropin (somatropin) group (89.7%). Most of the growth-related parameters in the somapacitan group (higher GH peak level, greater HV, less divergence from the normal range of −2 to 2 in HV SDS and height SDS) were slightly superior to those in the Norditropin (somatropin) group.

Exposure to Study Treatments

In the REAL 4 trial, 1 patient from the somapacitan group discontinued treatment during the 52-week duration (Table 10). The majority of patients received the planned treatment, with a mean adherence of 95.8% among patients receiving somapacitan and 88.3% among patients receiving Norditropin (somatropin), indicating possibly more missing doses among patients on Norditropin (somatropin). The mean and median duration of on-treatment days were similar between treatment groups (Table 12).

Table 11: Summary of Baseline Characteristics From the REAL 4 Trial (Full Analysis Set)

BMI = body mass index; GH = growth hormone; GHD = growth hormone deficiency; IGF-1 = insulin-like growth factor 1; IGFBP-3 = insulin-like growth factor binding protein 3; SD = standard deviation; SDS = standard deviation score.

Source: REAL 4 trial Clinical Study Report (week 52).²⁰

Table 12: Summary of Patient Exposure From the REAL 4 Trial (Full Analysis Set)

^aRepresents adherence according to diary: Number of administered dosings reported in diary divided by the number of planned dosings multiplied by 100.

Source: REAL 4 trial Clinical Study Report (week 52).²⁰

Concomitant Medications and Co-Interventions

Fewer patients in the somapacitan group (38.6%) than in the Norditropin (somatropin) group (41.2%) received concomitant medication at baseline, whereas more patients in the somapacitan group (66.7%) initiated concomitant medication than in the Norditropin (somatropin) group (58.8%) after randomization. The most frequently used medications at baseline included thyroid hormones (8.3% versus 14.7% in the somapacitan and Norditropin (somatropin) arms, respectively), and vitamin D and analogues (6.8% versus 5.9%). After randomization, the most frequently used medications were anilides (18.9% versus 16.2%) and propionic acid derivatives (13.6% versus 13.2%). Refer to Table 13 for the most frequently reported concomitant medications.

Table 13: Summary of Concomitant Medications From the REAL 4 Trial by ATC (Full Analysis Set)

ACT = anatomic therapeutic chemical classification; NR = not reported.

Source: REAL 4 trial Clinical Study Report (week 52).²⁰

Efficacy

Height Velocity

There was a −0.5 cm/year difference (95% CI, −1.1 to 0.2) in the estimated mean at follow-up between the somapacitan and Norditropin (somatropin) groups from baseline to week 52 (Figure 2), confirming that the noninferiority as the lower boundary of the 95% CI was above the prespecified noninferiority margin of −1.8 cm/year.

Height SDS

The change in the height SDS values from baseline to week 52 for somapacitan and Norditropin (somatropin) were nearly identical, with an ETD of −0.05 (95% CI, −0.18 to 0.08). The observed mean “height SDS” values in both treatment groups increased consistently from week 0 to week 52. The estimated versus the observed mean changes in height SDS from baseline to week 52 were similar: the estimated mean changes were 1.25 for somapacitan and 1.30 for Norditropin (somatropin), and the observed mean changes were 1.21 (SD = 0.54) for somapacitan and 1.37 (SD = 0.69) for Norditropin (somatropin).

Figure 2: HV at Week 52 in the REAL 4 Trial (FAS)

CI = confidence interval; ETD = estimated treatment difference; HV = height velocity; FAS = full analysis set.

Note: Figure was based on the estimated mean. HV at week 52 was analyzed using an analysis of covariance model with treatment, gender, age group, region, growth hormone peak group, and gender by age group by region interaction term as factors, and baseline height as covariate. There were no missing values at week 52, so no multiple imputation was done.

Source: REAL 4 trial Clinical Study Report (week 52).²⁰

Height Velocity SDS

There was a −0.78 difference in the increase in HV SDS between somapacitan and Norditropin (somatropin) at week 52 (95% CI, −1.63 to 0.08). The observed mean (i.e., HV SDS values for the 2 treatment groups using in-trial data) increased from week 0 to week 26, changing from −2.35 (SD = 1.51) to 8.95 (SD = 4.39) and from −2.52 (SD = 1.55) to 9.73 (SD = 4.62); overall, these increases were maintained to week 52 with values of 7.97 (SD = 3.36) and 8.97 (SD = 4.38) for the somapacitan and Norditropin (somatropin) groups, respectively.

A summary of the key efficacy results is shown in Table 14.

Table 14: Summary of Key Efficacy Results From the REAL 4 Trial (FAS)

ANCOVA = analysis of covariance; CI = confidence interval; GH = growth hormone; NA = not applicable; NR = not reported; SD = standard deviation; SDS = standard deviation score.

Note: In-trial period results are reported.

^aAnalysis conducted using an ANCOVA model, with treatment, gender, age group, region, GH peak group, and gender by age group by region interaction term as factors, and baseline assessment as a covariate.

^bSuperiority was not confirmed. Noninferiority was confirmed; the noninferiority margin is −1.8 cm/year.

Source: REAL 4 trial Clinical Study Report (week 52).²⁰

Patient-Reported Outcomes

GHD-CIM (Previously TRIM-CGHD-O)

Improvements were observed for the 3 domain scores and the total score for both treatment groups at the end of the main trial period of 52 weeks, and all of these changes from the baseline scores were similar between somapacitan and Norditropin (somatropin) (Table 15, Figure 3).

Table 15: Summary of GHD-CIM (TRIM-CGHD-O) Scores From the REAL 4 Trial (Full Analysis Set)

CI = confidence internal; GH = growth hormone; GHD-CIM = Growth Hormone Deficiency–Child Impact Measure; MMRM = mixed-model for repeated measures; SD = standard deviation; TRIM-CGHD-O = Treatment-Related Impact Measure–Child Growth Hormone Deficiency–Observer.

^aAnalysis conducted using an MMRM model, with treatment, gender, age group, region, GH peak group, and gender by age group by region interaction term as factors and baseline value as a covariate, all nested within week as a factor.

Source: REAL 4 trial Clinical Study Report (week 52).²⁰

Figure 3: Forest Plot of Change From Baseline in GHD-CIM (TRIM-CGHD-O) From the REAL 4 Trial at Week 52 (FAS)

CI = confidence internal; GHD-CIM = Growth Hormone Deficiency–Child Impact Measure; TRIM-CGHD-O = Treatment-Related Impact Measure–Child Growth Hormone Deficiency–Observer.

Note: The figure depicts REAL 4 trial results for the on-treatment period.

Source: REAL 4 trial Clinical Study Report (week 52).²⁰

GHD-CTB (Previously TB-CGHD-O)

Improvements were observed for the 3 domains (physical, emotional, interference) and the total score for both treatment groups at the end of the main trial period of 52 weeks, and all of the changes from baseline scores were similar between somapacitan and Norditropin (somatropin) (Table 16, Figure 4).

Table 16: Summary of GHD-CTB (TB-CGHD-O) Scores From the REAL 4 Trial (Full Analysis Set)

CI = confidence interval; GH = growth hormone; GHD-CTB = Growth Hormone Deficiency–Child Treatment Burden; MMRM = mixed-model for repeated measures; SD = standard deviation; TB-CGHD-O = Treatment Burden Measure–Child Growth Hormone Deficiency–Observer.

Note: The figure depicts REAL 4 trial results for the on-treatment period.

^aAnalysis conducted using an MMRM model, with treatment, gender, age group, region, GH peak group, and gender by age group by region interaction term as factors and baseline value as a covariate, all nested within week as a factor.

Source: REAL 4 trial Clinical Study Report (week 52).²⁰

GHD-PTB (Previously TB-CGHD-P)

The difference in the decrease (improved condition) in domain scores between somapacitan and Norditropin (somatropin) from baseline to week 52 was −5.3 (95% CI, −10.0 to −0.70) in the emotional domain, −6.7 (95% CI, −11.6 to −1.9) in the interference domain, and −6.0 (95% CI, −10.0 to −2.1) in the total score (Table 17 and Figure 4).

Table 17: Summary of GHD-PTB (TB-CGHD-P) Scores From REAL 4 (FAS)

CI = confidence interval; GH = growth hormone; GHD-PTB = Growth Hormone Deficiency–Parent Treatment Burden; MMRM = mixed-model for repeated measures; TB-CGHD-P = Treatment Burden Measure–Child Growth Hormone Deficiency–Parent.

Note: The figure depicts REAL 4 trial results for the on-treatment period.

^aAnalysis conducted using an MMRM model, with treatment, gender, age group, region, GH peak group, and gender by age group by region interaction term as factors and baseline value as a covariate, all nested within week as a factor.

Source: REAL 4 trial Clinical Study Report (week 52).²⁰

Growth Hormone Device Assessment Tool

The G-DAT questionnaire was used to evaluate and compare the ease of use for the somapacitan and Norditropin (somatropin) devices in the study at week 26. The somapacitan and Norditropin (somatropin) devices were evaluated as “easy” or “very easy” to use (96% and 96%, respectively) and store (95% and 94%, respectively).

Figure 4: Forest Plot of Change From Baseline in GHD-CTB (TB-CGHD-O) and GHD-PTB (TB-CGHD-P) From REAL 4 at Week 52 (FAS)

CI = confidence interval; GHD-CTB = Growth Hormone Deficiency–Child Treatment Burden; GHD-PTB = Growth Hormone Deficiency–Parent Treatment Burden; TB-CGHD-O = Treatment Burden Measure–Child Growth Hormone Deficiency–Observer; TB-CGHD-P = Treatment Burden Measure–Child Growth Hormone Deficiency–Parent.

Note: The figure depicts REAL 4 trial results for the on-treatment period.

Source: REAL 4 trial Clinical Study Report (week 52).²⁰

Harms

The REAL 4 trial reported the harms at the end of the main trial period at week 52. Overall, the safety profile of somapacitan was similar to the safety profile of once-daily Norditropin (somatropin) (Table 18). Ninety-four patients (71.2%) reported a total of 310 AEs in the somapacitan group compared with 41 patients (60.3%) reporting a total of 147 AEs in the Norditropin (somatropin) group. The AE reporting rates observed were 232.3 AEs per 100 patient-years (PYs) for somapacitan and 212.8 AEs per 100 PYs for Norditropin (somatropin). The most frequently reported AEs were headache (12%), nasopharyngitis (11%), and pain in extremity (9%) in the somapacitan group, and nasopharyngitis (10%), pyrexia (10%), and headache (9%) in the Norditropin (somatropin) group.

Serious Adverse Events

In the REAL 4 trial, 6 patients (4.5%) reported a total of 8 serious AEs (SAEs) in the somapacitan arm (6.0 SAEs per 100 PYs), and 2 patients (2.9%) reported a total of 3 SAEs in the Norditropin (somatropin) arm (4.3 SAEs per 100 PYs).

Withdrawal Due to Adverse Events

In the REAL 4 trial, no patients discontinued treatment or withdrew from the study due to AEs.

Mortality

No deaths were reported during the main REAL 4 trial period (up to week 52).

Notable Harms

Injection-Site Reactions

Comparably low proportions of children experienced injection-site reactions in the somapacitan group (5.3%) and the Norditropin (somatropin) group (5.9%) in the REAL 4 trial at week 52.

Antibodies

All antibody-positive samples were negative for in vitro neutralizing antibodies. Low-titre, non-neutralizing antibodies were detected in 20 somapacitan-treated patients (15.2%) and 7 patients (10.3%) treated with Norditropin (somatropin). Of these, 2 patients (1.5%) in the somapacitan group and 1 child (1.5%) in the Norditropin (somatropin) group had at least 2 consecutive antibody-positive samples.

IGF-1 SDS Greater Than 2

The mean IGF-1 SDS up to week 52 remained below 2.0 for both treatment groups. In the patients treated with somapacitan, 5 patients (3.8%) had an IGF-1 SDS above 2 at 2 or more consecutive visits during the 52-week treatment period. In the patients treated with Norditropin (somatropin), 2 patients (2.9%) had an IGF-1 SDS above 2.

No trend was seen in the amount or type of AEs reported in patients with an IGF-1 SDS above 2 at 2 or more consecutive visits compared with the remaining children in the relevant groups. None of the patients with an IGF-1 SDS above 2 at 2 or more consecutive visits had any treatment interruptions or dose reductions.

Injection-Site Infections

The incidence of injection-site infections was zero in the REAL 4 trial.

Injection-Site Pain

Two patients (1.5%) in the somapacitan group versus 1 patient (1.5%) in the Norditropin (somatropin) group experienced injection-site pain.

Dysglycemia and Glucose Metabolism

In the REAL 4 trial, 3 patients in each treatment arm (2.3% in the somapacitan group versus 4.4% in the Norditropin [somatropin] group) experienced dysglycemia.

There were no clinically relevant changes from baseline in mean fasting blood glucose or hemoglobin A1C levels and changes were similar for somapacitan and Norditropin (somatropin). Hemoglobin A1C mean values were similar between somapacitan (SD = 5.31%; SD = 0.28%) and Norditropin (somatropin) (5.31%; SD = 0.33%) at week 52. The increase in insulin from baseline was in line with what is expected following GH treatment in children with GHD and was similar between the somapacitan and Norditropin (somatropin) treatment groups. There were no reports of type 2 diabetes during the trial.

Critical Appraisal

Internal Validity

Randomization in the REAL 4 trial was performed using an appropriate methodology with adequate allocation concealment (i.e., web-based, interactive response system), and stratification was based on relevant prognostic factors, i.e., geographical region (Japan versus the rest of the world, with different diagnosis criteria for the 2 regions), sex (boys, girls), age (< 6 years, ≥ 6 years), and GH peak level (< 7.0 ng/mL, ≥ 7.0 ng/mL). Overall, baseline characteristics were generally similar and balanced between groups.

Table 18: Summary of Harms Results From the REAL 4 Trial at Week 52 (Full Analysis Set)

CI = confidence interval; GH = growth hormone; IGF-1 = insulin-like growth factor 1; NR = not reported; SAE = serious adverse event; SDS = standard deviation score.

^aIn the REAL 4 trial, SAEs occurred in 6 patients in the somapacitan treatment arm (1 patient had vomiting and dehydration; 1 patient had otitis media and adenoidal hypertrophy; asthma, headache, umbilical hernia, and cryptorchism occurred in 1 patient each) and 2 patients in the Norditropin (somatropin) treatment arm (1 patient had gastroenteritis and acute adrenocortical insufficiency; 1 patient had COVID-19).

^bInjection-site reaction (including bruising, pain, hematoma, hypersensitivity, and swelling).

^cThese analyses were not part of the statistical analysis plan and were requested by CADTH to allow for an assessment of the imprecision of the findings.

^dDysglycemia is defined as either fasting plasma glucose outside normal range (3.61 mmol/L to 5.83 mmol/L) or hemoglobin A1C in blood outside normal range (4% to 6%).

^eIn the REAL 4 trial, a number of events of dysglycemia were reported in the somapacitan treatment arm (1 hyperglycemia, 1 impaired fasting glucose, and 1 increased blood glucose) and in the Norditropin (somatropin) treatment arm (2 hyperglycemia and 1 increased hemoglobin A1C).

Source: REAL 4 trial Clinical Study Report (week 52).²⁰

The proportion of idiopathic GHD was slightly lower in the somapacitan arm (87.1%) than in the Norditropin (somatropin) arm (89.7%). The baseline growth-related parameters, such as height SDS, were closer to the normal range of −2 to 2 (−2.99 versus −3.47) in the somapacitan arm versus the Norditropin (somatropin) arm, respectively. The baseline median GH peak was higher in the somapacitan arm than in the Norditropin (somatropin) arm (5.2 mcg/L versus 3.9 mcg/L, respectively). ||||| |||||||||||||| |||||||||| ||||| |||| |||||| ||| ||||||| || |||||| || ||||||||||||

Most patients were included in the FAS for efficacy and harms outcomes. One patient (0.8%) in the somapacitan group discontinued from treatment in the REAL 4 trial due to a protocol violation versus no patients in the Norditropin (somatropin) group. The analysis set of patients was adequate.

All of the patient-reported outcomes were analyzed for the observation datasets in countries where these data were available. Patients in 4 participating countries (Latvia, Poland, Serbia, and Spain) did not complete the patient-reported outcome questionnaires; the impact of these missing data was unknown.

REAL 4 was an open-label study design, which could potentially increase the risk of bias, particularly for the subjective assessment of patient-reported outcomes (i.e., GHD-CIM, GHD-CTB, GHD-PTB, G-DAT) whereas the use of an open-label study design would not have affected the evaluation of treatment effect on height-related outcome measures. Height (cm) assessments were performed in an assessor-blinded manner. IGF-1 and IGFBP-3 were objective measures with standardized measurement or as measured by a central laboratory.

According to the sponsor’s Clinical Study Report for the REAL 4 trial, there were a limited number of previous trials that had allowed ancillary therapy or the retrieval of the landmark data included in the analysis, and no relevant data were available for children with GHD; thus, the noninferiority margin of −1.8 cm/year for the primary end point was chosen based on placebo-controlled trial results for children who were born small for gestational age (SGA) from the GHLIQUID-1424 trial.⁵² According to the sponsor, a noninferiority margin of −1.8 cm/year to −2.0 cm/year has been applied in previous trials on different brands of somatropin in children with GHD.²⁰ According to the clinical expert consulted by CADTH, the growth-related outcomes assessment at 1 year (52 weeks) was adequate because the best auxologic responses happen in the first year of a GH therapy.

Among the most frequently used medications at baseline, the proportion of patients who used thyroid hormones (8.3%) was lower in the somapacitan arm than in the Norditropin (somatropin) arm (14.7%). Whether this difference might impact the study results was uncertain, according to the clinical expert consulted by CADTH. After initiation of randomization, overall, a higher proportion of patients used a concomitant medication in the somapacitan arm (66.7%) than in the Norditropin (somatropin) arm (58.8%), based on the detailed documentation of patient records, but this difference would not have had an impact on the study results, according to the clinical expert.

The clinical expert noted that pediatric patients and their caregivers may have needle phobia, and caregivers may be under pressure when they administer the treatment. As noted in the patient and clinician group inputs for this review, patients and caregivers often prefer less frequent subcutaneous injections.

No significant protocol deviations were noted in either group in the REAL 4 trial. The sensitivity analyses and per-protocol analysis (these data are not included in this report) were completed and supported the conclusion of noninferiority for the primary end point.

Overall, the statistical methods used in both trials are appropriate. However, it is unknown what the impact of missing data would be on patient-reported outcome measures. The study stratified region into 2 categories (Japan versus the rest of the world) and included region in the various multivariate analyses. However, REAL 4 included Asian countries, such as Korea and India; moreover, the Asian population represented at least one-third of the total patients who received somapacitan. Ethnicity and race are significant predictors of HV; however, the REAL 4 trial did not stratify this factor (only Japan was separated from the rest-of-the-world region possibly because of different peak GH levels used in GHD diagnose). Whether the lack of adjustment by different regions in the analysis might affect the results was uncertain.

External Validity

The REAL 4 trial was conducted globally, and most patients were enrolled from the US (|||), Japan (|||), Russia (|||||), India (|||), Korea (||), and Ukraine (||), among others. ||| ||||||| (|||| of overall study population) ||| ||| allocated to the somapacitan group was from Canada; whether |||| ||||||| belonged to an Indigenous population was unknown. A total of 57.0% of the patients were white and 37.0% were Asian. At baseline, patient age ranged from 2.5 years to 11 years for boys and 2.5 years to 10 years for girls. Overall, there was a greater difference in the higher proportion of boys (74.5%) versus girls (25.5%) in the REAL 4 trial compared with the difference in proportions in the GeNeSIS study, which reported data on children treated with somatropin (63% male versus 37% female in the GHD cohort in Canada).⁴ The REAL 4 trial only enrolled patients who had no prior exposure to GH or IGF-1 treatment. The clinical expert commented that these differences between patients in the REAL 4 trial versus what is encountered in Canadian clinical practice are not likely to impact the trial results. About 58% of the patients who were screened entered the trial; the main reason for screening failure was that the patient did not meet the inclusion criterion of having an IGF-1 SDS of less than −1.0. This was not considered too significantly different from what would be seen in clinical practice, according to the clinical expert.

The majority of the patients in the REAL 4 trial (88.0%) had idiopathic GHD (and 12% had organic),²⁰ which was different from the GHD patient cohort in the GeNeSIS study (28% had idiopathic and 72% had organic).⁴ The clinical expert indicated that idiopathic GHD may be accompanied by other conditions that might influence GHD; thus, it was uncertain whether the results would be impacted when this patient characteristic in clinical practice is different from that in the REAL 4 trial. For example, it is uncertain whether the results would remain similar if, in clinical practice, there are more instances of organic GHD versus idiopathic. The clinical expert noted there were patients excluded from the trial that clinicians would want to treat with GH therapy, if needed, such as patients with cancerous brain tumours and patients with a condition that precludes them from a height evaluation (e.g., patients with cerebral palsy who cannot stand).

According to the clinical expert consulted by CADTH, the concomitant medications used in the REAL 4 trial were reflective of those encountered in Canadian clinical practice; the comparator used was appropriate in a Canadian clinical context, and the administration of the study treatments (dosages and settings) is in line with routine clinical practice in Canada. The clinical expert commented that the efficacy and safety outcomes used in the REAL 4 trial were generally clinically relevant and important to clinicians and patients in Canada.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For the pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined, as defined by the GRADE Working Group:^21,22

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as “very uncertain.”

Following the GRADE approach, the evidence from the RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty-of-evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or relative to the null. The target of the certainty-of-evidence assessment was the presence or absence of an important effect based on thresholds informed by the clinical expert consulted for this review for HV, height SDS, and HV SDS. The target of the certainty-of-evidence assessment was the presence or absence of any (non-null) effect for GHD-CIM, GHD-CTB, GHD-PTB, injection-site reactions, injection-site pain, and treatment discontinuation due to the lack of a formal MID estimate.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for somapacitan versus Norditropin (somatropin) in prepubertal children with GHD.

Long-Term Extension Studies

Contents within this section have been informed by materials submitted by the sponsor. The following were summarized and validated by the CADTH review team.

REAL 4 Long-Term Safety Extension Phase

Description of Studies

The REAL 4 study design is described in the main body of the sponsor’s Clinical Study Report.²³ A summary of the long-term safety extension phase (week 52 to week 104) is presented in this section of the CADTH Clinical Review Report. The results presented in the sponsor’s interim analysis of the REAL 4 trial reflect the data available as of December 22, 2022.

Populations

The inclusion and exclusion criteria for patients enrolled in the REAL 4 study were described in the main body of the sponsor’s report.

Interventions

Patients were randomized (2:1) to receive either once-weekly somapacitan 0.16 mg/kg or daily Norditropin (somatropin) 0.034 mg/kg for the 52-week main trial period. For the subsequent safety extension trial period, which was planned for an additional 3 years following the main trial period and up to 208 weeks, all patients have been allocated to once-weekly somapacitan 0.16 mg/kg.

Outcomes and Statistical Analysis

There were no primary or secondary efficacy growth-related end points (i.e., HV, HV SDS, height SDS, or bone age) defined after 52 weeks.

The following secondary efficacy outcomes were defined at week 104 and presented using descriptive statistics:

• change in IGF-1 SDS

• change in IGFBP-3 SDS.

The GH-PPQ at week 56 is also presented using descriptive statistics.

The 2 data observation periods (in-trial and on-treatment) that were utilized for the primary estimand, HV, and the 2 pharmacodynamic end points, IGF-1 SDS and IGFBP-3 SDS in the main Clinical Trial Report, were not defined past week 52 (visit 7). For completeness, observation periods similar to the main 52-week period were included for data in the safety extension period (weeks 52 to 104). As all patients discontinuing the trial product in the safety extension period were withdrawn from the trial, the results for the 2 observation periods from week 52 to 104 are nearly identical.

Results

Patient Disposition

Patient disposition for the long-term safety extension phase of the REAL 4 trial is presented in Table 19. A total of 199 patients were exposed in the safety extension (following week 52). Four patients in the somapacitan to somapacitan group and 1 patient in the Norditropin (somatropin) to somapacitan group discontinued the trial product in the safety extension period (from week 52 to week 104). None of the discontinuations were due to AEs. All patients who discontinued during the extension period were withdrawn from the trial.

Table 19: Patient Disposition in the REAL 4 Safety Extension Phase

^aPatient disposition presented for the safety extension period (week 52 to week 104).

Source: REAL 4 trial Clinical Study Report (week 104).²³

Exposure to Study Treatments

In the safety extension period (week 52 to 104), the mean duration of exposure to somapacitan and mean adherence were similar between the somapacitan to somapacitan group and the Norditropin (somatropin) to somapacitan group (Table 20). The mean adherence in the somapacitan to somapacitan group was 94.2% from week 0 to 104, suggesting consistently high adherence throughout the entire study.

Table 20: Exposure to Somapacitan in the Safety Extension Phase of the REAL 4 Trial From Week 52 to Week 104

SD = standard deviation.

Source: Week 104 Clinical Study Report for the REAL 4 trial.²³

Efficacy

The sponsor’s interim analysis includes data up to week 104 in the safety extension phase. The key efficacy outcomes evaluated in the REAL 4 main trial phase were evaluated descriptively for the long-term safety extension phase and are summarized in Table 21.

After 104 weeks of treatment, the HV observed in the patients treated with somapacitan for the full period is similar to the HV observed in the patients who switched from Norditropin (somatropin) to somapacitan after week 52. After 104 weeks of treatment, a similar increase in change from baseline in height SDS and HV SDS was observed in the patients treated with somapacitan for the full period and the patients who switched from Norditropin (somatropin) to somapacitan at week 52. The mean observed IGF-1 SDS and IGFBP-3 SDS change from baseline after 104 weeks was also similar in both groups.

Table 21: Summary of Efficacy End Points in the Safety Extension Phase of the REAL 4 Trial at Week 104

CI = confidence interval; IGF-1 = insulin-like growth factor 1; IGFBP-3 = insulin-like growth factor binding protein 3; SD = standard deviation; SDS = standard deviation score.

Note: In-trial period results are reported.

Source: REAL 4 trial Clinical Study Report (week 104).²³

The GH-PPQ, which assesses GH treatment preference, was used to evaluate the switch from Norditropin (somatropin) to somapacitan after the final visit in the main phase of the trial at week 52. The questionnaire was completed by the patient’s parent or LAR 4 weeks after the patient had switched from Norditropin (somatropin) to somapacitan (week 56). Parents of 50 of the 68 patients who were switched from Norditropin (somatropin) to somapacitan at week 52 responded to the questionnaire. Of these 50 respondents, 45 preferred somapacitan to Norditropin (somatropin), while 5 respondents answered that they had no preference. None of the respondents preferred Norditropin (somatropin). The majority (38 out of 45) of the respondents preferring somapacitan had a strong or very strong preference for the once-weekly (somapacitan) over the once-daily (Norditropin [somatropin]) treatment regimen. The main reasons selected in the GH-PPQ for the preference included: “number of times needing to do injections,” “less worried about remembering to give the injections,” and “child [is] less worried or annoyed by getting injections.” Thirty-five of the 45 parents who preferred somapacitan stated they expected higher adherence to the current once-weekly regimen than to Norditropin (somatropin); 1 parent expected the patient would be more adherent to Norditropin (somatropin), while the remaining 9 parents had no preference with regard to expected adherence to either drug.

Harms

A summary of harms for the REAL 4 safety extension phase is presented in Table 22.

Table 22: Summary of Harms Results From the REAL 4 Trial Safety Extension Phase Up to Week 104

GH = growth hormone; IGF-1 = insulin-like growth factor 1; SAE = serious adverse event; SDS = standard deviation score.

Source: REAL 4 trial Clinical Study Report (week 104).²³

The safety profile of once-weekly somapacitan administered to children with GHD for up to 104 weeks was similar to the well-known safety profile for daily Norditropin (somatropin). No new safety or local tolerability issues were identified.

In patients with an IGF-1 SDS above 2, no trend was seen in the amount or type of AEs reported at 2 or more consecutive visits compared with the remaining patients in the relevant treatment groups. There were no dose reductions due to AEs for these patients. The majority of AEs were of mild severity.

Critical Appraisal

Internal Validity

REAL 4 is an open-label trial, which may influence the perception of improvement by patients and clinicians, particularly for outcomes that are subjective in measurement and interpretation (e.g., patient-reported outcomes, subjective AEs). In the REAL 4 trial, only prepubertal children were enrolled into the main trial to avoid the pubertal growth spurt interfering with the treatment effect.

The efficacy outcomes were presented using descriptive statistics, so no statistical inferences were possible. The safety profile for somapacitan from the main trial phase to the long-term extension phase was consistent in the REAL 4 trial.

External Validity

The patients who took part in the open-label long-term safety extension phase were originally from the REAL 4 trial and the eligibility criteria remained the same; therefore, it is reasonable to expect that the same limitations to generalizability are relevant to the safety extension phase. In addition, the results in week 104 may be more representative of what might be observed in a long-term clinical setting. Of note, for example, the mean observed change in HV in both arms was not as high at week 104 as it was at week 52. It should also be noted that according to the clinical expert consulted by CADTH, the assessment of growth-related outcomes at 52 weeks was adequate because the best auxologic responses happen in the first year of a GH therapy.

Indirect Evidence

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the CADTH review team.

Objectives for the Summary of Indirect Evidence

Direct comparative evidence exists between somapacitan and somatropin (Norditropin 0.034 mg/kg once daily) from the REAL 3 and REAL 4 trials, but there is a gap in evidence comparing somapacitan with somatrogon. Indirect comparisons were required to address this gap. One ITC was submitted by the sponsor, which has been summarized and appraised in this report.

Description of the ITC

An SLR was conducted by the sponsor to identify evidence for inclusion in the ITC, as described in Table 23. One ITC was submitted by the sponsor comparing somapacitan with other LAGH treatments for GHD on height-related outcomes within the first year of treatment in prepubescent boys and girls. The sponsor also assessed the feasibility of conducting similar ITCs at time points beyond the first year of treatment, but concluded that it was infeasible.

Table 23: Study Selection Criteria and Methods for ITCs Submitted by the Sponsor

AE = adverse event; AHV = annualized height velocity; EPHPP = Effective Public Health Practice Project; GHD = growth hormone deficiency; HV = height velocity; IGF-1 = insulin-like growth factor 1; IGFBP-3 = insulin-like growth factor binding protein 3; ITC = indirect treatment comparison; LAGH = long-acting growth hormone; NICE = National Institute for Health and Care Excellence; NMA = network meta-analysis; SAGH = short-acting growth hormone; RCT = randomized controlled trial; SDS = standard deviation score; SLR = systematic literature review; STA = single technology appraisal.

^aThe reference lists of relevant SLRs and clinical guidance information were screened to ensure no relevant study was missed.

Source: Sponsor-submitted NMA report⁵³ and accompanying SLR report.⁵⁴

ITC Design

Objectives

The objective of the ITC was to generate evidence on the comparative effectiveness of somapacitan versus other LAGHs for GHD.

Study Selection Methods

The eligibility criteria for the SLR that informed the ITCs are detailed in Table 23. In summary, English-language clinical studies were included that evaluated LAGHs in pediatric patients with GHD from 2 to 12 years of age against any comparator and reported efficacy or safety results. Patients with indications for GHs other than height deficiency were not considered relevant. The databases searched were Embase, MEDLINE, and the Cochrane Library, in addition to several conferences and grey literature sources. Study screening was conducted in duplicate. Data extraction was conducted by 1 analyst and quality-checked by a different analyst. Quality assessments were performed using the tools described in Table 23 by 1 statistician.

The sponsor evaluated the feasibility of assessing outcomes at weeks 26, 52, 104, and 156. The sponsor-conducted ITC included Bayesian NMAs evaluating 3 efficacy outcomes (AHV, HV SDS, and height SDS) at weeks 26 and 52. However, longer-term outcomes were primarily informed by single-arm trials, so anchored analyses such as NMAs were not feasible. Longer-term efficacy outcomes and 2 safety outcomes (injection-site reactions and antibodies) were compared qualitatively only. Although the SLR included additional outcomes, the sponsor selected these as the most clinically relevant to compare for the purpose of addressing this data gap.

ITC Analysis Methods

Feasibility Assessment

The similarity of patient characteristics across 5 trials was assessed qualitatively. The assessment of patient characteristics focused on the following characteristics identified by the sponsor as potential prognostic factors:

• age

• gender

• race

• height SDS or AHV SDS

• peak GH

Network Structure

In trials with multiple doses of the same LAGH treatment, only the recommended dose (or intended dose if market authorization was pending) was used for analysis.

Within this network, multiple arms of somatropin were combined and considered as a single somatropin node, which was a common comparator for other treatments. A key assumption of this network was that the somatropin treatment arms (Genotropin and Norditropin) were considered similar enough to be combined into a single treatment node.

In the base-case network, somatropins of the same dose were pooled (0.034 mg/kg/day). An alternative network was conducted as a scenario analysis in which the trial where the somatropin dose differs (Opko JPN trial, 0.025 mg/kg/day) was connected, as a separate node, to the network through the common comparator somatrogon node.

Analysis Model and Implementation

All outcomes in the analysis were continuous. Height SDS was modelled in terms of the mean change in the outcome of interest from baseline, whereby it was assumed that the mean changes from baseline in trials follow a normal distribution. AHV and HV SDS were modelled in terms of the mean at the time point of interest, again assuming mean values at the time point of interest in trials follow a normal distribution. All analyses of continuous outcomes were performed using a normal likelihood, identity link model.

The programming language R (version 4.1.3) was used for implementation. Analysis was conducted utilizing function “nma” in version 0.4.2 of the publicly available package multinma.⁵⁵ Four chains of 10,000 iterations were run: 5,000 for burn-in and 5,000 for sampling.

Consistency of Evidence

As the network contains no loops, a formal assessment of consistency was not performed.

Prior Distributions

The prior represents the prior probability distribution; a vague prior contains no information about the parameters of interest. Vague priors are used for the study-specific treatment effect μi and treatment effect sizes relative to reference treatment 1 (d_1k) in the form of a normal distribution, with a mean of 0 and variance of 10,000, as recommended in NICE Technical Support Document 2.⁵⁶

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Measures of Model Complexity and Fit

Model comparisons (fixed effects [FE] versus random effects [RE]) were based on comparing the average residual deviance (i.e., residual deviance divided by the number of data points), in addition to the deviance information criterion (DIC), and the convergence of the models.⁵⁶ In general, a model is favoured if it has a lower DIC (a difference of 3 to 5 points or more between the DIC from the FE and RE models indicates a strong preference for the model with the lower DIC) and a posterior residual deviance closer to the number of data points. Model fit was assessed in the base-case network and the same model was applied to the alternative-scenario analysis network.

Data Selection and Transformation

A number of trials reported both arm- and trial-level data (e.g., treatment differences with measures of uncertainty); in such cases, arm-level data were used in the analysis. All trials reported mean change from baseline for height SDS, so no additional data transformation was needed. For HV SDS, posthoc analyses on Novo Nordisk trials were conducted to align with reported outcomes in other trials (having originally been modelled as mean change from baseline). The process of identifying and obtaining data has been described in detail in the statistical analysis plan.

Estimates of Treatment Effect and Credible Intervals

The results are presented as median treatment differences and an associated 95% CrI. The 95% CrI can be interpreted as an interval such that there is a 95% probability that the true value lies within the calculated interval.

For each end point in the base-case network, a plot of relative treatment estimates with the associated 95% CrI was presented, including the results of both the FE and RE models (Table 24).

Results of ITC

Summary of Included Studies

Overview

In total, the SLR identified 22 records comprising 10 unique studies. For the Canadian context, irrelevant comparators were excluded, so the final number of studies was smaller. Ultimately, the ITCs included 7 records informing 5 studies, 3 of which assessed somatrogon versus somatropin (the Opko II, Opko III, and Opko JPN trials), and 2 of which assessed somapacitan versus somatropin (REAL 3 and REAL 4 trials). The studies are summarized briefly in Table 25, and the evidence networks are displayed in Figure 5 (base case) and Figure 6 (alternative scenario, including somatotropin 0.025 mg/kg/day from the Opko JPN study).

The primary end point was AHV in all trials: 4 assessed the primary end point at 52 weeks, while 1 (REAL 3) assessed the primary end point at 26 weeks. Generally, when reported, the analysis of continuous end points was similar across trials, with trials considering treatment, age, sex, peak GH, region, and height in their analysis. However, 1 trial (Opko II) did not report on the use of methods such as ANCOVA.

Table 25: Trials Eligible to Inform Short-Term Efficacy Outcomes

AHV = annualized height velocity; ANCOVA = analysis of covariance; GH = growth hormone; MMRM = mixed-model for repeated measures; SDS = standard deviation score.

Source: Sponsor-submitted network meta-analysis⁵³ and accompanying SLR report.⁵⁴

Trial Design

In all trials, patients were randomized to treatment with an LAGH or an SAGH (somatropin) for at least 26 weeks. All randomized phases were open-label between LAGHs and somatropin; however, the REAL 3 trial was double-blinded within LAGH doses, and the REAL 3 and REAL 4 trials applied observer blinding to the primary end point. Four of the 5 trials evaluated somatropin at the same dose used in the Novo Nordisk–sponsored trials (0.034 mg/kg/day), while 1 trial (Opko JPN) evaluated somatropin at a lower dose and was therefore not included in the base-case analyses. Additionally, dose escalation for somatrogon-treated patients occurred in the first 6 weeks of the Opko JPN trial (0.25 mg/kg/week, 0.48 mg/kg/week, and 0.66 mg/kg/week; 2 weeks each) with the remaining 46 weeks at a dose of 0.66 mg/kg/week.

Across the trials, dose adjustments were made as needed based on IGF-1 assessments. There were some differences with respect to how much the dose was reduced, the criteria to justify a dose adjustment, and the timing of IGF-1 measurements.

The patient eligibility criteria are summarized in Table 26. The trials enrolled treatment-naive prepubescent children with GHD. Across the trials, there were slight differences in inclusion criteria for disease severity as defined by GH peak levels: the REAL 3 trial required 7 ng/mL or less; the REAL 4, Opko II, and Opko III trials all required 10 ng/mL or less; and the Opko JPN trial required 6 ng/mL or less. There were also slight differences in the age ranges of the patients enrolled, but the trials generally enrolled patients aged from 2 to 3 years to 10 to 11 years and all trials had different age caps for boys (1 year younger) than girls. Tanner development stages for testes and breasts were also described in the eligibility criteria for the REAL 3 and 4 trials, as previously described; this was not described in any of the included Opko trials. All trials required impaired height, but the Opko III trial uniquely did not require an SDS for height of less than −2 for patient eligibility. All trials required an AHV below the 25th percentile and excluded children born SGA.

Table 26: Patient Eligibility Criteria for the Studies Included in the ITCs

BMI = body mass index; GH = growth hormone; GHD = growth hormone deficiency; HV = height velocity; IGF-1 = insulin-like growth factor 1; ITC = indirect treatment comparison; NR = not reported; SD = standard deviation; SDS = standard deviation score.

^aAccording to standard growth charts by Prader et al.⁵⁷

^bAccording to the 2000 Centers for Disease Control and Prevention standards.⁵⁸

^cNot exhaustive.

Sources: Publications of the Opko II,⁵⁹ Opko III,⁶⁰ and Opko JPN⁶¹ trials.

Patient Baseline Characteristics

The baseline characteristics for the Opko II, Opko III, and Opko JPN trials are summarized in Table 27. For any studies that evaluated multiple doses of somatrogon (i.e., Opko II), only the 0.66 mg/kg/week dose is of interest, and so the cohorts randomized to other doses of somatrogon are not described here.

There was a large spread in the proportions of male patients across trials, from approximately 50% male in the Opko JPN trial to approximately 70% in the REAL 4 trial. There was also considerable variability with respect to race, with the Opko JPN trial exclusively enrolling Asian patients, while more than 90% of the patients enrolled in the Opko II trial were white. Additionally, the mean age in the Opko III trial was higher than in other trials, including REAL 4 (7.7 years versus 6.4 years, respectively). Height SDS and AHV SDS were slightly lower in the Opko II trial compared with other trials.

Table 27: Summary of Patient Baseline Characteristics in the Opko II, Opko III, and Opko JPN Trials

BMI = body mass index; GH = growth hormone; GHD = growth hormone deficiency; HV = height velocity; IGF-1 = insulin-like growth factor 1; IGFBP-3 = insulin-like growth factor binding protein 3; NR = not reported; SD = standard deviation; SDS = standard deviation score.

Sources: Publications of the Opko II,⁵⁹ Opko III,⁶⁰ and Opko JPN⁶¹ trials.

Summary of the Assessment of Homogeneity for the Sponsor-Submitted ITC

A summary of the assessment of homogeneity was not provided by the sponsor in its summary of clinical evidence. CADTH has summarized the details in Table 28.

Table 28: Assessment of Homogeneity for the Sponsor-Submitted ITC

AE = adverse event; CDC = Centers for Disease Control and Prevention; FAS full analysis set; GH = growth hormone; GHDS = growth hormone deficiency syndrome; HV = height velocity; IGF-1 = insulin-like growth factor 1; ITC = indirect treatment comparison; LAGH = long-acting growth hormone; NMA = network meta-analysis; SAGH = short-acting growth hormone; SAS = safety analysis set; SD = standard deviation; SDS = standard deviation score.

Source: Sponsor-submitted NMA report⁵³ and accompanying SLR report.⁵⁴

Results

Evidence Networks

The evidence networks are presented in Figure 5 for the base case and in Figure 6 for the alternative scenario that includes the Opko JPN trial. The availability of data by outcome and time point from each trial is summarized in Table 29.

Figure 5: Base-Case Scenario Evidence Network

d = day; QD = once daily; wk = week.

Source: Sponsor-submitted network meta-analysis.⁵³

Figure 6: Alternative Scenario Evidence Network

d = day; QD = once daily; wk = week.

Note: Trials not included in the base-case evidence network are in light grey.

Source: Sponsor-submitted network meta-analysis.⁵³

Table 29: Overview of Data Availability Across Included Trials for Each Outcome and Time Point

AHV = annualized height velocity; alt. = alternative scenario; HV = height velocity; SDS = standard deviation score.

Source: Sponsor-submitted network meta-analysis.⁵³

Annualized HV

Four of the 5 trials were included in the base-case network (all trials except Opko JPN), and all 5 trials were included in the alternative network (Table 30).

Results from the base-case NMA are presented in Table 31. While the difference in DIC and residual deviation between the FE and RE models did not indicate a strong model preference, there was a slight decrease with the RE model, suggesting a possible better model fit. Results from the RE model showed no differences between somapacitan and somatrogon or somatropin at week 26 or week 52. Results were generally similar with the FE model.

Results from the alternative network demonstrated that somapacitan improved AHV more than low-dose somatropin (0.025 mg/kg/day) at 52 weeks (difference of −1.61; 95% CrI, −3.23 to −0.16). No other differences between somatrogon and somapacitan were observed.

Table 30: Results From the Included Trials — AHV

AHV = annualized height velocity; CI = confidence interval; HV = height velocity; NR = not reported; SDS = standard deviation score; SE = standard error.

Source: Sponsor-submitted network meta-analysis.⁵³

Table 31: Results From the Base-Case NMA for AHV at 26 and 52 Weeks

AHV = annualized height velocity; CrI = credible interval; DIC = deviance information criteria; NMA = network meta-analysis.

Note: Results are presented as median treatment differences and an associated 95% CrI for comparators vs. somapacitan. Positive differences favour comparator treatments.

Source: Sponsor-submitted NMA report.⁵³

Table 32: Results From the Included Trials — HV SDS

AHV = annualized height velocity; CI = confidence interval; HV = height velocity; NR = not reported; SD = standard deviation; SDS = standard deviation score; SE = standard error.

Source: Sponsor-submitted network meta-analysis.⁵³

Results from the base case are presented in Table 33. While the difference in DIC and residual deviation between the FE and RE models did not indicate a strong model preference, there was a slight decrease with the RE model, suggesting a possible better model fit. Overall, no differences between somatrogon and somapacitan were observed in the RE analysis. Results were generally similar in the FE analysis.

Of note, results for the somapacitan versus somatrogon comparison differ in that the results numerically favoured somatrogon in the AHV analysis but favoured somapacitan in the HV SDS analysis. In either case, results did not indicate that somapacitan and somatrogon differed.

Height SDS

Four of the 5 trials were included in the base-case network (all trials except Opko JPN), and all 5 trials were included in the alternative network (Table 34).

Results from the base case are presented in Table 35. While the difference in DIC and residual deviation between the FE and RE models did not indicate a strong model preference, there was a slight decrease with the RE model, suggesting a possible better model fit. Overall, no differences between somatrogon and somapacitan were observed in the RE analysis. Results were generally similar in the FE analysis.

Results from the alternative network demonstrated that somapacitan improved height SDS more than low-dose somatropin (0.025 mg/kg/day) at 52 weeks (difference of −0.4; 95% CI, −0.72 to −0.11). No other differences between somatrogon and somapacitan were observed.

HV SDS

Data on HV SDS was available from 3 trials at week 52 (REAL 3, REAL 4, Opko II) and 2 trials at week 26 (REAL 3, REAL 4). A network for HV SDS at 26 weeks was determined to be not feasible. An alternative network was not constructed for HV SDS, as no data were available from the Opko JPN trial (Table 32).

Table 33: Results From the Base-Case NMA for Height Velocity SDS at 52 Weeks

CrI = credible interval; NMA = network meta-analysis; SDS = standardized deviation scores.

Results are presented as median treatment differences and an associated 95% CrI for comparators vs. somapacitan. Positive differences favour comparator treatments.

Source: Sponsor-submitted NMA report.⁵³

Table 34: Results From the Included Trials — Height SDS

AHV = annualized height velocity; CI = confidence interval; HV = height velocity; NR = not reported; SDS = standard deviation score; SE = standard error.

Source: Sponsor-submitted network meta-analysis.⁵³

Table 35: Results From Base Case for Height SDS at 26 and 52 Weeks

CrI = credible interval; SDS = standardized deviation score.

Results are presented as median treatment differences and an associated 95% CrI for comparators vs. somapacitan. Positive differences favour comparator treatments.

Source: Sponsor-submitted network meta-analysis.⁵³

Long-Term Efficacy Outcomes

Long-term efficacy data beyond 52 weeks was informed by the trials summarized in Table 36, and the results from each extension trial are summarized in Table 37. Quantitative ITCs were not feasible due to differences in study design and the lack of common comparator arms, given the single-arm nature of most of the long-term data.

Only the REAL 3 trial reported comparative data at week 104 and 156. The difference in AHV between the somapacitan and somatropin treatment arms at week 156 was 0.8 cm/year (95% CI, −0.4 to 2.1). Differences in the other 2 outcomes were not formally evaluated but were numerically similar for HV SDS and height SDS. Results were not provided by the sponsor for any additional efficacy outcomes.

Table 36: Trials Informing Long-Term Efficacy Outcomes at 104 or 156 Weeks

AHV = annualized height velocity; HV SDS = height velocity standard deviation score; NR = not reported; RCT = randomized controlled trial; SDS = standard deviation score.

Source: Sponsor-submitted network meta-analysis.⁵³

Table 37: Long-Term Efficacy Results From Included Trials

AHV = annualized height velocity; CI = confidence interval; HV = height velocity; NR = not reported; SD = standard deviation; SDS = standard deviation score; SE = standard error.

Note: Weeks indicate time on treatment (including time from randomized phase).

^aNo assessment of uncertainty in the Opko II trial for these outcomes was performed.

^bFor the Opko III trial at weeks 52 and 104, AHV is reported among those who continued on somatrogon 0.66 mg/kg/week from the main trial, while height SDS is reported among all patients entering the extension, regardless of the dose received in the main trial.

^cUnits were not provided by the sponsor but are assumed to represent mean (95% CI).

Source: Sponsor-submitted network meta-analysis.⁵³

Harms

Harms outcomes were not evaluated quantitatively in the indirect analysis. The sponsor summarized injection AEs and antibodies qualitatively.

Harms Outcomes at 52 Weeks

Overall AEs

The qualitative comparison of overall AEs (e.g., any AEs, serious AEs, severe AEs) at 52 weeks is summarized in Table 38. The proportion of patients experiencing at least 1 AE across trials varied from approximately 60% to 100% through 52 weeks of treatment. Serious AEs were observed in 0 to 3 patients per treatment arm in all cases except the somapacitan arm of the REAL 4 trial, in which 6 (4.5%) of 132 patients experienced serious AEs. Severe AEs did not occur in the REAL 3 trial, occurred in few patients in the REAL 4 trial (1.5% in the somatropin arm compared with 3.0% in the somapacitan arm), and 5.2% in the somatropin arm compared with 8.3% in somatrogon arm in the OPKO III trial. Although very few AEs were observed in the REAL 3, Opko II, and Opko JPN trials, the sample sizes of each of the treatment arms were very small.

Table 38: Overall AEs Through 52 Weeks of Treatment in the Included Trials

AE = adverse event.

Source: Sponsor-submitted network meta-analysis.⁵³

Injection-Site AEs

Injection-related AEs are summarized in Table 39. The studies varied in what kinds of AEs were reported. Injection-site AEs overall were not reported in the Opko trials but occurred in a similar number of patients in the REAL 4 trial between the somapacitan and somatropin arms. Injection-site pain was reported in the REAL 3 and 4 trials and in the Opko III and Opko JPN trials. In the REAL trials, the number of injection-site pain events was zero to very few in both the somapacitan and somatropin arms. In the Opko III and Opko JPN trials, there were high rates of injection-site pain reported in the somatrogon arms (39.4% and 72.7%, respectively). However, in the Opko III and JPN trials, there were also much more frequent events of injection-site pain in the somatropin arms (25.2% and 13.6%, respectively) which contrasts with the 0% and 1.5% event rates in the somatropin-treated patients from the REAL 3 and REAL 4 trials, respectively.

Severe injection-site pain did not occur in any patients in the REAL 3 or 4 trials, regardless of treatment assignment, whereas 1 somatrogon-treated patient in the Opko II trial, and 4.6% of somatrogon-treated patients and 2.6% of somatropin-treated patients in the Opko III trial, experienced severe injection-site pain.

Table 39: Injection AEs Through 52 Weeks of Treatment in the Included Trials

AE = adverse event; NR = not reported.

Source: Sponsor-submitted network meta-analysis.⁵³

Antibodies at 52 Weeks

In the REAL 3 trial, 1 patient (7.1%) treated with somatropin had persistent non-neutralizing anti–human GH (hGH) antibodies of low titre, and 2 patients (14.2%) treated with somapacitan 0.16 mg/kg/week had 1 single transient measurement of low-titre, non-neutralizing, anti-somapacitan antibodies during the 52-week treatment period. No neutralizing anti-hGH or anti-somapacitan antibodies were observed. In the REAL 4 trial, 2 patients (1.5%) treated with somapacitan, and 1 patient treated with somatropin (1.5%) had 2 or more consecutive positive non-neutralizing antibody samples during the 52-week treatment period. No neutralizing anti-hGH or anti-somapacitan antibodies were observed.

In the Opko II trial, 2 patients (14.3%) treated with somatrogon 0.66 mg/kg/week and 1 patient (9.1%) treated with somatropin had antidrug antibodies. There was no incidence of anti-CTP (cytidine triphosphate) antibodies. In the Opko III trial, 84 patients (77.1%) treated with somatrogon 0.66 mg/kg/week tested positive for antidrug antibodies compared with 18 patients (15.6%) treated with somatropin. In another trial of somatrogon (Opko JPN), 18 patients (81.8%) treated with somatrogon 0.66 mg/kg/week, and 4 patients (18.2%) treated with somatropin tested positive for antidrug antibodies; 2 patients (9.1%) treated with somatrogon tested positive for neutralizing antibodies at 1 visit.

Overall, the rates of antibodies varied considerably across the trials. Analyses showed patients who were positive for antibodies did not experience reduced efficacy or safety issues compared with those without antibodies.

Harms Outcomes in Extension Studies

Overall AEs

Overall, continued treatment with somapacitan and somatrogon was generally well tolerated, with no new safety signals identified. The proportion of patients experiencing at least 1 AE ranged from approximately 70% to 81% across the extensions of the REAL 3 (week 52 to 156), Opko II (week 52 to 208), and Opko III (week 52 to 104) trials. Most of the reported AEs were mild to moderate in severity.

In the extension of the REAL 3 (week 52 to 156) trial, serious AEs occurred in 4 (8.9%) of the pooled somapacitan-treated patients and 2 (14.3%) of the somatropin-treated patients. In the extension of the Opko II trial (week 52 to 208), serious AEs occurred in 3 (6.3%) of the somatrogon-treated patients. Serious AEs were not reported in the Opko III trial.

Severe AEs occurred in 0 of the somapacitan-treated patients and 1 (7.1%) of the somatropin-treated patients in the REAL 3 trial extension (week 52 to 156). Severe AEs were not reported in the Opko II and Opko III extension studies.

Injection-Site AEs

In the REAL 3 trial extension (week 52 to 156), 3 patients (6.7%) treated with somapacitan and 1 patient (7.1%) treated with somatropin experienced injection site–related AEs. All injection site–related AEs were considered to be mild in severity.

No data were available from the extension trials of somatrogon.

Antibodies

In the REAL 3 extension, over the entire 3 years of treatment (i.e., baseline to week 156), low-titre non-neutralizing antibodies were observed in 10 patients (22.2%) treated with somapacitan and 1 patient (7.1%) treated with somatropin. Seven patients (15.6%) treated with somapacitan experienced transient antibodies at a single time point, and 3 (6.7%) had more than 1 positive sample. The patient treated with somatropin experienced persistent anti-hGH antibodies of low titre from visit 4 to 16. All antibody samples were negative for neutralizing antibodies.

In the Opko II trial extension, 17 patients (35.4%) had low titres of anti-somatrogon antibodies, of which 3 had transient antibodies. All tests were negative for neutralizing antibodies. In the Opko III trial extension, among the patients in the somatrogon 0.66 mg/kg/week to somatrogon 0.66 mg/kg/week group, 84 of 109 patients (77%) had antidrug antibodies; 2 of these patients tested positive for neutralizing antibodies.

Similar to results from the 52-week outcomes, neutralizing antibodies were observed with somatrogon but not with somapacitan. Where reported, the analyses indicated that the presence of antibodies did not have any impact with respect to efficacy outcomes.

Critical Appraisal of Sponsor-Submitted ITC

An ITC was required to estimate the comparative effect estimates of somapacitan versus somatrogon; the choice of studies was appropriate to address the current gap in direct evidence. All studies had a common comparator (somatropin), albeit the somatropin arms in the REAL 3 and REAL 4 trials used a different brand (Norditropin) than that used in the Opko II, Opko III, and Opko JPN trials (Genotropin). The 2 brands were assumed to be equivalent and were pooled into 1 node in the NMA, given that they contain the same active ingredient. NICE previously noted there is no evidence of any difference between these brands,⁶² and this assumption was considered acceptable by the clinical expert consulted by CADTH. The Opko JPN trial differed from all other included trials in the study design, dose of the intervention and comparator, patient eligibility criteria, and patient characteristics at baseline, so it was appropriate that it was excluded from the base-case network and included in a separate, alternative-scenario network, where it informed an additional treatment node. Given the heterogeneity between the networks when the Opko JPN trial is included and given that the study population and dosages of treatments informed by the Opko JPN trial are not as relevant for the Canadian context, the results from this scenario analysis will not be discussed at length.

The ITC was conducted using NMA methodology, which was reasonable, given there were multiple studies informing multiple comparisons when the Opko JPN trial was included. However, since the target comparison is somapacitan versus somatrogon with a common comparator, simple Bucher analyses may have been preferable in the base case where the Opko JPN trial is excluded. A simple Bucher would be expected to generate results similar to the Bayesian FE model of the NMAs.

The sponsor quantitatively assessed the outcomes of AHV, height SDS, and HV SDS at 26 and 52 weeks in the NMAs. These outcomes were identified as the most important efficacy outcomes in this review, so the selection of efficacy outcomes was considered to be appropriate. However, the sponsor did not quantitatively assess any safety-related outcomes, and justification for this decision was not provided. It was not feasible to conduct quantitative ITCs for outcomes beyond 52 weeks due to a lack of comparative data and differences in the study designs of the relevant extension studies; therefore, a qualitative comparison was reported instead.

In the base-case NMAs, there were some between-trial imbalances between studies in race, gender, and mean age at baseline, and differences in eligibility criteria related to age range, peak GH, and bone age. The sponsor stated these were not expected to have any effect modification, but did not provide any support for this statement. Ultimately, the potential magnitude and direction of bias is unknown, which complicates the interpretation of the results. The clinical expert consulted by CADTH indicated that other potential prognostic factors or effect modifiers include the cause of GH deficiency (idiopathic versus organic), and isolated GHD versus multiple pituitary hormone deficiencies, but these characteristics could not be compared between trials due to a lack of reporting.

The networks were sparse. To account for potentially high heterogeneity, the sponsor utilized informative priors, but acknowledged that it was potentially problematic because the data informing the priors were not sourced externally from the included trials. The heterogeneity of the trials may therefore still bias the results. Additionally, the network had no closed loops, so assessing for consistency was not possible. The modelling of AHV and HV SDS was done in terms of the mean at the time point of interest, with an assumption by the sponsor that the mean values followed a normal distribution; however, it was not reported whether the sponsor tested whether this assumption holds. If the assumption does not hold, there is a concern that the results in mean difference were biased.

An important flag regarding the potential heterogeneity between trials is the differences in the trial outcomes for the arm used as a common comparator which, in this case, was somatropin 0.034 mg/kg/day. Among only somatropin-treated patients, there were substantial differences in the incidence of harms outcomes when comparing the REAL trials with the Opko trials. In the REAL 4 trial, 1 (1.5%) of the 68 somatropin-treated patients experienced injection-site pain while, in the Opko III trial, 29 (25.2%) of the 115 somatropin-treated patients experienced injection-site pain. Although the source of this difference is unknown, it may be related to differences in the treatment practices occurring at the treatment centres, different excipients in the different brands of somatropin used in the REAL versus Opko trials, and/or differences in how these events were recorded in the trials. Because the method of assessing injection-site pain was not reported in the REAL 3 and REAL 4 trials, it is unknown whether the cause of this difference is isolated to this outcome.

The sponsor’s conclusion that failure to detect a difference means that the efficacy is equivalent is somewhat uncertain. The sparse network, small sample sizes, and wide CrIs indicate inconclusive results, especially when considered together with the uncontrolled between-trial heterogeneity and inconsistency in AE results for the somatropin arms. Ultimately, there is no evidence that there is a clinically meaningful difference between somatropin and somatrogon, but whether the 2 drugs can be said to be clinically equivalent is likewise inconclusive.

Studies Addressing Gaps in the Systematic Review Evidence

Contents within this section have been informed by the materials submitted by the sponsor. The following have been summarized and validated by the CADTH review team.

One open-label, randomized, phase II trial (REAL 3) was identified as a study addressing gaps in the evidence. The characteristics of this study are summarized in Table 40. Refer to Appendix 1 for the detailed patient inclusion and exclusion criteria.

REAL 3 was a randomized, multinational, multiple-dose, dose-finding, open-label, parallel-group trial investigating the efficacy and safety of once-weekly somapacitan compared with once-daily Norditropin (somatropin) in GH treatment-naive children (aged ≥ 2.5 and ≤ 10.0 years) with GHD. A total of 29 study sites randomized 59 patients. The main trial period ended on September 13, 2018. The trial consisted of a 26-week main trial period followed by a 26-week extension trial period, a 104-week safety extension trial period, a 208-week long-term safety extension trial period, and a 30-day follow-up period (Figure 7). Patients received once-weekly somapacitan at 1 of 3 different dose levels or once-daily Norditropin (somatropin) for the 26-week main and extension trial periods in a 4-arm parallel-group design.

Figure 7: Study Design for the REAL 3 Trial

Note: Reprinted (and modified) from Sävendahl et al., 2020.⁶⁴ Creative Commons Attribution License 4.0.

Source: Sävendahl et al., 2020,^63,64 and the week 26,⁶⁷ week 156,⁶⁸ and week 208⁶⁹ Clinical Study Reports from the REAL 3 trial.

Table 40: Details of Studies Addressing Gaps in the Systematic Review Evidence