Efficacy and Safety Evaluation of Recombinant Human Growth Hormone (r-hGH), Saizen®, on a Population of Children With Hypochondroplasia, Treated at Least 3 Years or Until Near Final Height, When Applicable, in Comparison With a Historic Cohort of Non-treated Children

Study Overview
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Brief Summary
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This study is conducted to describe the efficacy and safety of recombinant human growth hormone (r-hGH) treatment Saizen® on children with hypochondroplasia.

Official Title
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Efficacy and Safety Evaluation of Recombinant Human Growth Hormone (r-hGH), Saizen®, on a Population of Children With Hypochondroplasia, Treated Over a Period of 3 Years or 5 Years if Applicable, in Comparison With a Historic Cohort of Non-treated Children With Hypochondroplasia

Conditions
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Hypochondroplasia

Intervention / Treatment
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* Drug: Recombinant human growth hormone (r-hGH)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female children with hypochondroplasia defined by a disproportional short limb height and a X-ray evidence of shortening of the long bones and failure of increase in the interpedicular distance between lumbar vertebrae L1 and L5 Result of genetic analysis for mutation of gene FGFR3 already known or ongoing analysis at the beginning of the study Chronological age greater than or equal to 3 years Height for chronological age less than or equal to - 2 SDS Bone age less than or equal to 11 years for girls and 13 years for boys A written informed consent at the beginning of the pre-treatment period must be obtained from the parent(s)/legal guardian(s). Children able to understand the trial should personally sign and date the written informed consent Additional inclusion criteria for each study prolongation: Bone age at Month 36 or Month 60 is compatible with treatment prolongation according to investigator opinion Subject is still under r-hGH treatment with Saizen® at Month 36 or Month 60 Height gain greater than or equal to + 1 SDS after the 2 first years of treatment for treatment prolongation at Month 36 and growth velocity greater than or equal to 5 centimeter (cm) per year, with bone age less than 14 years for females or less than 16 years for males for treatment prolongation at Month 60 According to investigator opinion, gene mutations of the subjects are not in connection with observed side effects during the 3 or 5 first years of treatment An updated written informed consent must be obtained from the parent(s)/legal guardian(s) before the start of each study prolongation. Children able to understand the trial should personally sign and date the written informed consent Exclusion Criteria: Turner's Syndrome in girls Active malignant neoplastic disease Severe congenital malformations Proliferative or preproliferative diabetic retinopathy Evidence of any progression or recurrence of an underlying intra-cranial space occupying lesion Severe psychomotor retardation Diabetes mellitus or history of significant glucose intolerance as defined by a fasting blood glucose greater than 6.4 millimole per liter (mmol/L) Known renal insufficiency as defined by serum creatinine level 1.0 milligram per deciliter (mg/dL) (88 micromole per liter [mcmol/L]) Known hepatic disease as defined by elevated liver enzymes or total bilirubin (* 2 Normal) Current congestive heart failure, untreated hypertension, serious chronic edema of any cause Chronic infectious disease History of intracranial hypertension with papilledema Previous or ongoing treatment with sex steroid therapy such as estrogens or testosterone Previous or ongoing treatment with any therapy that may directly influence growth, including Growth Hormone (GH), Growth Hormone Releasing Hormone (GHRH) and long duration corticosteroids therapy Known hypersensitivity to somatropin or any of the excipients Epiphyseal fusion Participation to any clinical study within the 30 days preceding study entry Pregnant females

Ages Eligible for Study
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Minimum Age: 3 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: r-hGH (Saizen®)<br> | Drug: Recombinant human growth hormone (r-hGH)<br>* Subjects will receive a single subcutaneous injection of recombinant human growth hormone (r-hGH) equivalent to a dose of 0.057 milligram per kilogram per day (mg/kg/day). The dose will be subsequently adjusted during the trial and subjects will be treated for at least 3 years or until near final height is reached.<br>* Other names: Saizen®, Somatropin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Height-Standard Deviation Score (H-SDS) of Recombinant Human Growth Hormone (r-hGH) Treated Subjects at Year 3 | Height was calculated in standardized units expressed as the standard deviation score (SDS), where SDS = (x - m)/sigma, in which x represents the height variable measured by sex and age, and m and sigma are the statistical parameters (mean and standard deviation) for the Sempe reference population. The reference population was the historical cohort consisting of non-treated subjects with Hypochondroplasia (HCH). SDS indicated how many standard deviations higher (in case of positive SDS) or lower (in case of negative SDS) a participant's value was relative to the mean of the reference population. The scores were centered around zero. Negative score indicated smaller height for the respective age/gender. | Baseline (Month 0), Year 3 | 
| Height-Standard Deviation Score (H-SDS) of Recombinant Human Growth Hormone (r-hGH) Treated Subjects at Year 4 | Height was calculated in standardized units expressed as the standard deviation score (SDS), where SDS = (x - m)/sigma, in which x represents the height variable measured by sex and age, and m and sigma are the statistical parameters (mean and standard deviation) for the Sempe reference population. The reference population was the historical cohort consisting of non-treated subjects with Hypochondroplasia (HCH). SDS indicated how many standard deviations higher (in case of positive SDS) or lower (in case of negative SDS) a participant's value was relative to the mean of the reference population. The scores were centered around zero. Negative score indicated smaller height for the respective age/gender. | Year 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Height-Standard Deviation Score (H-SDS) of Recombinant Human Growth Hormone (r-hGH) Treated Subjects | Height was calculated in standardized units expressed as the standard deviation score (SDS), where SDS = (x - m)/sigma, in which x represents the height variable measured by sex and age, and m and sigma are the statistical parameters (mean and standard deviation) for the Sempe reference population. The reference population was the historical cohort consisting of non-treated subjects with Hypochondroplasia (HCH). Data was reported by gender. Male subjects were analyzed till 9.5 years and female subjects were analyzed till 8.5 years. SDS indicated how many standard deviations higher (in case of positive SDS) or lower (in case of negative SDS) a participant's value was relative to the mean of the reference population. The scores were centered around zero. Negative score indicated smaller height for the respective age/gender. | Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 8.5 (only for female), 9 (only for male) and 9.5 (only for male) | 
| Change From Baseline in Height of Recombinant Human Growth Hormone (r-hGH) Treated Subjects With Hypochondroplasia (HCH) up to 9.5 Years | Body proportion was measured in terms of height. Data was reported by gender. Male subjects were analyzed till 9.5 years and female subjects were analyzed till 8.5 years. | Baseline (Month 0), Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 8.5 (only for female), 9 (only for male) and 9.5 (only for male) | 
| Change From Baseline in Upper Segment (Superior) of Recombinant Human Growth Hormone (r-hGH) Treated Subjects With Hypochondroplasia (HCH) up to 9.5 Years | Body proportion was measured in terms of upper segment for standing and sitting position. Data was reported by gender. Male subjects were analyzed till 9.5 years and female subjects were analyzed till 8.5 years. | Baseline (Month 0), Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 8.5 (only for female), 9 (only for male) and 9.5 (only for male) | 
| Change From Baseline in Weight of Recombinant Human Growth Hormone (r-hGH) Treated Subjects With Hypochondroplasia (HCH) up to 9.5 Years | The body weight was measured on a certified and calibrated hospital scale. Data was reported by gender. Male subjects were analyzed till 9.5 years and female subjects were analyzed till 8.5 years. | Baseline (Month 0), Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 8.5 (only for female), 9 (only for male) and 9.5 (only for male) | 
| Change From Baseline in Body Mass Index (BMI) of Recombinant Human Growth Hormone (r-hGH) Treated Subjects With Hypochondroplasia (HCH) up to 9.5 Years | Body proportion measured as BMI. It was calculated according to the formula BMI = Weight (kilogram)/Height square (meter square). Data was reported by gender. Male subjects were analyzed till 9.5 years and female subjects were analyzed till 8.5 years. | Baseline (Month 0), Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 8.5 (only for female), 9 (only for male) and 9.5 (only for male) | 
| Change From Baseline in Bone Mineral Density (BMD) of Recombinant Human Growth Hormone (r-hGH) Treated Subjects With Hypochondroplasia (HCH) up to 9 Years | Body composition measured as BMD. It was examined at the lumbar spine (L1-L4) and determined annually by dual-energy X-ray absorptiometry. Data was reported by gender. Male subjects were analyzed till 9 years and female subjects were analyzed till 8 years. | Baseline (Month 0), Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 9 (only for male) | 
| Change From Baseline in Percent Body Fat Mass of Recombinant Human Growth Hormone (r-hGH) Treated Subjects With Hypochondroplasia (HCH) up to 9 Years | Body composition measured as percentage of body fat mass. It was measured by Dual X-ray absorptiometry. Data was reported by gender. Male subjects were analyzed till 9 years and female subjects were analyzed till 8 years. | Baseline (Month 0), Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 9 (only for male) | 
| Change From Baseline in Lean Body Mass (LBM) of Recombinant Human Growth Hormone (r-hGH) Treated Subjects With Hypochondroplasia (HCH) up to 9 Years | Body composition measured as LBM. It was measured by Dual X-ray absorptiometry. Data was reported by gender. Male subjects were analyzed till 9 years and female subjects were analyzed till 8 years. | Baseline (Month 0), Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 9 (only for male) | 
| Growth (Height) Velocity of Recombinant Human Growth Hormone (r-hGH) Treated Subjects With Hypochondroplasia (HCH) From Year 1 up to 9.5 Years | Growth velocity was calculated in terms of height velocity. It corresponded to a difference in height between current and baseline values divided by the time interval between both evaluations. Data was reported by gender. Male subjects were analyzed till 9.5 years and female subjects were analyzed till 8.5 years. | Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 8.5 (only for female), 9 (only for male) and 9.5 (only for male) | 
| Head Circumference Values of Recombinant Human Growth Hormone (r-hGH) Treated Subjects With Hypochondroplasia (HCH) From Year 1 up to 9.5 Years | Body proportion was measured in terms of head circumference with a tape measure. Data was reported by gender. Male subjects were analyzed till 9.5 years and female subjects were analyzed till 8.5 years. | Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 8.5 (only for female), 9 (only for male) and 9.5 (only for male) | 
| Osteocalcin Values of Recombinant Human Growth Hormone (r-hGH) Treated Subjects With Hypochondroplasia (HCH) From Year 1 up to 9.5 Years | Osteocalcin as bone marker was analyzed with the Immunology system Elecsys. Data was reported by gender. Male subjects were analyzed till 9.5 years and female subjects were analyzed till 8.5 years. | Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 8.5 (only for female), 9 (only for male), 9.5 (only for male) | 
| C-terminal Telopeptide (CTX) Values of Recombinant Human Growth Hormone (r-hGH) Treated Subjects With Hypochondroplasia (HCH) From Year 1 up to 9.5 Years | CTX (Blood) as bone marker was analyzed with the Immunology system Elecsys. Data was reported by gender. Male subjects were analyzed till 9.5 years and female subjects were analyzed till 8.5 years. | Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 8.5 (only for female), 9 (only for male), 9.5 (only for male) | 
| Number of Subjects With Fibroblast Growth Factor Receptor (FGFR3) Mutation | Genetic analysis was performed to record FGFR3 gene mutation. Genomic DNA was extracted from lymphocytes of collected blood samples using standard procedures. A set of intronic primers was designed based on the genomic sequence of the human FGFR3 gene and used to amplify exons 2-19. Number of subjects with FGFR3 mutation were reported. | Baseline up to 3 years | 
| Number of Subjects With Adverse Event (AE) and Serious Adverse Event (SAE) | AEs: any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug , SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose. | Baseline up to 9.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypochondroplasia, Skeletal dysplasia, Growth, Growth Hormone, Recombinant-human Growth Hormone