rhGH and rhIGF-1 Combination Therapy in Children With Short Stature Associated With IGF-1 Deficiency

Study Overview
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Brief Summary
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IGF-1 (insulin-like growth factor-1) is a hormone that is normally produced in the body in response to another hormone called growth hormone. Growth Hormone is produced by a small gland at the base of the brain (the pituitary). Together IGF-1 and GH are large contributors to growth during infancy, childhood, and adolescence. Children with IGF Deficiency are short and have an imbalance in the levels of growth hormone and IGF-1 that their body produces. Their growth hormone levels are normal or even high, but IGF-1 levels do not increase normally in response to growth hormone. As a result, they have a type of growth hormone insensitivity and an inability to grow normally. This study is a test to see whether daily dosing with a combination of rhIGF-1 and rhGH will help children with IGFD grow taller more quickly than children treated with rhGH alone. The study medications, rhIGF-1 and rhGH, are approved by the US Food and Drug Administration (FDA) for use in some growth disorders in children, but the combination of rhIGF-1 and rhGH in children with IGF-1 deficiency (IGFD) is investigational.

Official Title
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Recombinant Human Growth Hormone (rhGH) and Recombinant Human Insulin-like Growth Factor-1 rhIGF-1) Combination Therapy in Children With Short Stature Associated With IGF-1 Deficiency: A Six-year, Randomized, Multi-center, Open-label, Parallel-group, Active Treatment Controlled, Dose Selection Trial

Conditions
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Insulin-like Growth Factor-1 Deficiency

Intervention / Treatment
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* Drug: NutropinAq® (Somatropin [rDNA origin])
* Drug: Increlex® (Mecasermin [rDNA origin] injection) + NutropinAq® (Somatropin [rDNA origin])
* Drug: Increlex® (Mecasermin [rDNA origin] injection) + NutropinAq® (Somatropin [rDNA origin])
* Drug: Increlex® (Mecasermin [rDNA origin] injection) + NutropinAq® (Somatropin [rDNA origin])


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Parents or legally authorized representatives must give signed informed consent before any trial-related activities IGF-1 SDS of ≤ -1 for age and gender Short stature, as defined by a height SDS of ≤ -2 for age and gender Chronological age ≥ 5 years Bone age ≤ 11 years in boys and ≤ 9 years in girls GH sufficiency, defined as a maximal stimulated GH response of greater than or equal to 10 ng/mL at Visit 2 (note: upon approval of the Medical Monitor, the result of a prior GH stimulation test may satisfy this requirement). Prepubertal status Adequate nutrition as evidenced by a body mass index (BMI) greater than or equal to the 5th percentile for age and gender Exclusion Criteria: Severe Primary IGFD (defined as height and IGF-1 SDS ≤ 3, and stimulated GH response greater than or equal to 10 ng/mL) Prior or current use of medications with the potential to alter growth patterns including GH, IGF-1, IGFBP-3, gonadotrophin agonists (e.g., Lupron), aromatase inhibitors, androgens and estrogens Known or suspected allergy to rhGH, rhIGF-1 or a constituent of their formulations Current use of medications for attention deficit disorder A chronic health condition that requires anti-inflammatory steroids or daily medication unless approved by the Medical Monitor

Ages Eligible for Study
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Minimum Age: 5 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1. rhGH Alone<br> | Drug: NutropinAq® (Somatropin [rDNA origin])<br>* rhGH (Somatropin) 45µg/kg once daily injection<br>* Other names: GH;|
| Experimental: 2. Combination Dose<br> | Drug: Increlex® (Mecasermin [rDNA origin] injection) + NutropinAq® (Somatropin [rDNA origin])<br>* rhGH (Somatropin) 45µg/kg and rhIGF-1 (Mecasermin) 50µg/kg once daily injections<br>* Other names: GH;|
| Experimental: 3. Combination Dose<br> | Drug: Increlex® (Mecasermin [rDNA origin] injection) + NutropinAq® (Somatropin [rDNA origin])<br>* rhGH 45µg/kg and rhIGF-1 100µg/kg once daily injections<br>* Other names: GH;|
| Experimental: 4. Combination Dose<br> | Drug: Increlex® (Mecasermin [rDNA origin] injection) + NutropinAq® (Somatropin [rDNA origin])<br>* rhGH 45µg/kg and rhIGF-1 150µg/kg once daily injection<br>* Other names: GH;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Height Velocity |  | First year of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Height Velocity |  | Second, third and fourth year | 
| Cumulative Change in Height Standard Deviation Score (SDS) | Height was measured standing and without shoes, and recorded as the mean of three measurements (the subject being repositioned each time) by the same observer using a Harpenden or other wall-mounted stadiometer which was to be calibrated prior to measurement of each subject and a calibration log kept. The SDS was calculated as: SDS=[(value /M)^L - 1] / LS; using power (L), Mean (M) and coefficient of variation (S). The reference values were dependent on gender in addition to age and were selected at the age the closest below subject's age. SDS scores were calculated using L, M and S as defined in the National Center for Health Statistics 2000 data as provided by the Center for Disease Control (Kuczmarski, Ogden et al. 2002) | First, second, third and fourth year | 
| Predicted Adult Height (PAH) | Predicted Adult Height calculated by method, Roche-Wainer-Thissen (RWT) and mid-parental target height SDS. The SDS was calculated as: SDS=[(value /M)^L - 1] / LS; using power (L), Mean (M) and coefficient of variation (S). The reference values were dependent on gender in addition to age and were selected at the age the closest below subject's age. SDS scores were calculated using L, M and S as defined in the National Center for Health Statistics 2000 data as provided by the Center for Disease Control (Kuczmarski, Ogden et al. 2002) | At baseline (Day 1), year 1,2,3 and 4 | 
| Total Change From Baseline (Day 1) in BMI SDS | BMI was calculated by weight divided by height squared and measured as kilogram per square meter (kg/m^2). The SDS was calculated as: SDS=[(value /M)^L - 1] / LS; using power (L), Mean (M) and coefficient of variation (S). The reference values were dependent on gender in addition to age and were selected at the age the closest below subject's age. SDS scores were calculated using L, M and S as defined in the National Center for Health Statistics 2000 data as provided by the Center for Disease Control (Kuczmarski, Ogden et al. 2002) | At year 1,2,3,4 and end of study (visit 23) versus baseline (day 1) | 
| Skeletal Maturation | Assessed by bone age. Bone age was determined by the radiograph. The SDS was calculated as: SDS=[(value /M)^L - 1] / LS; using power (L), Mean (M) and coefficient of variation (S). The reference values were dependent on gender in addition to age and were selected at the age the closest below subject's age. SDS scores were calculated using L, M and S as defined in the National Center for Health Statistics 2000 data as provided by the Center for Disease Control (Kuczmarski, Ogden et al. 2002) | At baseline(day 1), year 1,2,3 and 4 | 
| Changes From Baseline (Day 1) in Serum Concentrations of Growth Hormone (GH) |  | At Baseline (Day 1), Year 1,2,3 and 4 | 
| Changes From Baseline (Day 1) in Serum Concentrations of Insulin-Like Growth Factor-1 (IGF-1) |  | At Baseline (Day 1), Year 1,2,3 and 4 | 
| Changes From Baseline (Day 1) in Serum Concentrations of Insulin-Like Growth Factor Binding Protein-1 (IGFBP-1) |  | At Baseline (Day 1), Year 1,2,3 and 4 | 
| Changes From Baseline (Day 1) in Serum Concentrations of Insulin-Like Growth Factor Binding Protein-3 (IGFPB-3) |  | At Baseline (Day 1), Year 1,2,3 and 4 | 
| Changes From Baseline (Day 1) in Serum Concentrations of Acid-Labile Subunit (ALS) |  | At Baseline (Day 1), Year 1,2,3 and 4 | 
| Changes From Baseline (Day 1) in Serum Concentrations of Growth Hormone Binding Protein (GHBP) |  | At Baseline (Day 1), Year 1,2,3 and 4 | 
| Summary of Adverse Events With Number of Occurrences | A Data Monitoring Committee (DMC) was established to monitor subject safety | Approximately up to 4 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IGF-1 Deficiency, growth, ISS, Constitutional growth delay, Primary IGFD, Primary IGF Deficiency