Pediatric Growth Hormone Deficiency
Conditions
Brief summary
This is an open-label, randomized, multicenter, efficacy and safety study of weekly MOD-4023 compared to daily Genotropin therapy in pre-pubertal children with growth hormone deficiency.
Detailed description
The study consists of a 12 month, open-label, randomized, active controlled, parallel group study comparing the efficacy and safety of weekly MOD-4023 to daily growth hormone (GH), Genotropin. After 12 months, subjects will have the option to enter the long term open-label extension.
Interventions
DRUGMOD-4023
Once weekly subcutaneous injection using pre-filled pen device.
DRUGSomatropin
Once daily subcutaneous injection of Genotropin using pre-filled pen device.
Sponsors
OPKO Health, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
Main Study Inclusion Criteria: 1. Pre-pubertal children aged ≥3 years, and not yet 11 years for girls or not yet 12 years for boys with either isolated GHD, or GH insufficiency as part of multiple pituitary hormone deficiency. 2. Confirmed diagnosis of GHD by two different GH provocation tests defined as a peak plasma GH level of ≤10 ng/mL. 3. Bone age (BA) is not older than chronological age and should be less than 10 for girls and less than 11 for boys. 4. Without prior exposure to any r-hGH therapy (naïve patients). 5. Impaired height and height velocity defined as: * Annualized height velocity (HV) below the 25th percentile for CA (HV \< -0.7 SDS) and gender according to sponsor calculator * The interval between 2 height measurements should be at least 6 months, but should not exceed 18 months prior to inclusion 6. Baseline IGF-1 level of at least 1 SD below the mean IGF-1 level standardized for age and sex (IGF-1 SDS ≤-1) 7. Normal calculated GFR per updated bedside Schwartz formula for pediatric patients. 8. Children with multiple hormonal deficiencies must be on stable replacement therapies (no change in dose) for other hypothalamo-pituitary-organ axes for at least 3 months prior ICF signing. 9. Normal 46XX karyotype for girls. 10. Willing and able to provide written informed consent of the parent or legal guardian and written assent from patient. LT-OLE Inclusion Criteria: 11. Completion of the main study (12 months of treatment) with adequate compliance. 12. Willing and able to provide written informed consent of the parent or legal guardian and written assent from patient. 13. Agree to refrain from sexual activity. Main Study
Exclusion criteria
1. Children with prior history of leukemia, lymphoma, sarcoma or any other forms of cancer. 2. History of radiation therapy or chemotherapy. 3. Malnourished children defined as BMI \< -2 SDS for age and sex. 4. Children with psychosocial dwarfism. 5. Children born small for gestational age (SGA - birth weight and/or birth length \<-2 SDS for gestational age). 6. Presence of anti-hGH antibodies at screening. 7. Any clinically significant abnormality likely to affect growth or the ability to evaluate growth, such as, but not limited to, chronic diseases like renal insufficiency, spinal cord irradiation, etc. 8. T2 and T1 diabetic patients, who in the opinion of the investigator are not receiving standard of care treatment or are non-compliant with their prescribed treatment or who are in poor metabolic control. 9. Chromosomal abnormalities including Turner's syndrome, Laron syndrome, Noonan syndrome, Prader-Willi syndrome, Russell-Silver syndrome, SHOX mutations/deletions and skeletal dysplasias. 10. Concomitant administration of other treatments that may have an effect on growth such as anabolic steroids, or sex steroids, with the exception of ADHD drugs or hormone replacement therapies (thyroxin, hydrocortisone, desmopressin). 11. Children requiring glucocorticoid therapy (e.g. for asthma) that are taking chronically a dose greater than 400 μg/d of inhaled budesonide or equivalent. 12. Major medical conditions and/or presence of contraindication to r-hGH treatment. 13. More than one closed epiphyses. 14. Known or suspected HIV-positive patient, or patient with advanced diseases such as AIDS or tuberculosis. 15. Drug, substance, or alcohol abuse. 16. Known hypersensitivity to the components of study medication. 17. Other causes of short stature such as celiac disease, uncontrolled primary hypothyroidism and rickets. 18. Likely non-compliance in respect to study conduct. 19. Participation in any other trial of an investigational agent within 30 days prior to consent. 20. Study enrollment has been met or study is closed by sponsor prior to completion of screening process. LT-OLE
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annual Height Velocity in OLE Phase | Up to 60 months | Annualized Height Velocity (cm/year) in OLE Phase |
| Annual Height Velocity in Main Study Phase | 52 weeks | Annual Height Velocity in cm. Annual Height Velocity at 12 months is based on the difference between the heights at 12 months and baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Height Standard Deviation Score (SDS) in Main Study Phase | After 6 and 12 months | Change in height Standard Deviation Score (SDS) after 6 and 12 months is calculated based on the difference between the heights at 6 and 12 months and baseline. |
| Change in Bone Maturation (BM) in Main Study Phase | 52 weeks | Annual change in bone age measurements as per Gruelich-Pyle method |
| Change in Height Standard Deviation Score (SDS) in OLE Phase | 60 months | Change in height Standard Deviation Score (SDS) at each time point is calculated based on the difference between the time point and baseline. |
| Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in OLE Phase | 60 Months | — |
| Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in Main Study Phase | Baseline and at 12 months | Via central lab analysis |
| Height Velocity at 6 Months in Main Study Phase | After 6 months of treatment | Height velocity in cm measured after 6 months of treatment. Annualized Height velocity after 6 months is calculated based on the difference between the heights at 6 months and baseline. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Device | 6 weeks | Proportion of successful single injections out of total number of single injections using the MOD-4023 Pen in the USA |
Countries
Argentina, Australia, Belarus, Bulgaria, Canada, Colombia, Georgia, Greece, India, Israel, Mexico, New Zealand, Poland, Russia, South Korea, Spain, Taiwan, Ukraine, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MOD-4023 Once weekly subcutaneous injection of long acting r-hGH (MOD-4023)
MOD-4023: Once weekly subcutaneous injection using pre-filled pen device. | 109 |
| Genotropin Once daily subcutaneous injection of somatropin (r-hGH; Genotropin)
Somatropin: Once daily subcutaneous injection of Genotropin | 115 |
| Total | 224 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Main Study Phase | Adverse Event | 1 | 0 |
| Main Study Phase | Withdrawal by Subject | 0 | 1 |
| Open Label Extension (OLE) Year 1 | Adverse Event | 0 | 6 |
| Open Label Extension (OLE) Year 1 | Miscellaneous | 0 | 1 |
| Open Label Extension (OLE) Year 1 | Withdrawal by Subject | 2 | 2 |
| Open Label Extension (OLE) Year 2 | Adverse Event | 1 | 1 |
| Open Label Extension (OLE) Year 2 | Miscellaneous | 0 | 1 |
| Open Label Extension (OLE) Year 2 | Withdrawal by Subject | 2 | 2 |
| Open Label Extension (OLE) Year 3 | Adverse Event | 1 | 0 |
| Open Label Extension (OLE) Year 3 | Local Crisis | 1 | 0 |
| Open Label Extension (OLE) Year 3 | Prohibited Treatments | 0 | 1 |
| Open Label Extension (OLE) Year 3 | Withdrawal by Subject | 2 | 1 |
| Open Label Extension (OLE) Year 4 | Bone Age Reached | 3 | 1 |
| Open Label Extension (OLE) Year 4 | Local Crisis | 10 | 9 |
| Open Label Extension (OLE) Year 4 | Miscellaneous | 2 | 0 |
| Open Label Extension (OLE) Year 4 | Non-Compliance With Study Drug | 0 | 1 |
| Open Label Extension (OLE) Year 4 | Sponsor Discontinuation of Study | 27 | 21 |
| Open Label Extension (OLE) Year 4 | Withdrawal by Subject | 3 | 4 |
| Open Label Extension (OLE) Year 5 | Bone Age Reached, | 1 | 0 |
| Open Label Extension (OLE) Year 5 | Closure of Epiphyseal Plates | 1 | 0 |
| Open Label Extension (OLE) Year 5 | Local Crisis | 1 | 0 |
| Open Label Extension (OLE) Year 5 | Sponsor Discontinuation of Study | 2 | 6 |
| Open Label Extension (OLE) Year 5 | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Genotropin | MOD-4023 | Total |
|---|---|---|---|
| Age, Continuous | 7.61 years STANDARD_DEVIATION 2.37 | 7.83 years STANDARD_DEVIATION 2.66 | 7.72 years STANDARD_DEVIATION 2.51 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 11 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 102 Participants | 98 Participants | 200 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 21 Participants | 24 Participants | 45 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Multiracial | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 5 Participants | 3 Participants | 8 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 86 Participants | 81 Participants | 167 Participants |
| Region of Enrollment Argentina | 2 participants | 1 participants | 3 participants |
| Region of Enrollment Australia | 2 participants | 2 participants | 4 participants |
| Region of Enrollment Belarus | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Bulgaria | 2 participants | 2 participants | 4 participants |
| Region of Enrollment Canada | 2 participants | 3 participants | 5 participants |
| Region of Enrollment Colombia | 4 participants | 4 participants | 8 participants |
| Region of Enrollment Georgia | 1 participants | 5 participants | 6 participants |
| Region of Enrollment Greece | 0 participants | 3 participants | 3 participants |
| Region of Enrollment India | 14 participants | 12 participants | 26 participants |
| Region of Enrollment Israel | 8 participants | 7 participants | 15 participants |
| Region of Enrollment Mexico | 0 participants | 2 participants | 2 participants |
| Region of Enrollment New Zealand | 1 participants | 3 participants | 4 participants |
| Region of Enrollment Poland | 12 participants | 7 participants | 19 participants |
| Region of Enrollment Russia | 12 participants | 8 participants | 20 participants |
| Region of Enrollment South Korea | 4 participants | 8 participants | 12 participants |
| Region of Enrollment Spain | 9 participants | 10 participants | 19 participants |
| Region of Enrollment Taiwan | 2 participants | 0 participants | 2 participants |
| Region of Enrollment Turkey | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Ukraine | 11 participants | 13 participants | 24 participants |
| Region of Enrollment United Kingdom | 3 participants | 0 participants | 3 participants |
| Region of Enrollment United States | 25 participants | 17 participants | 42 participants |
| Sex: Female, Male Female | 36 Participants | 27 Participants | 63 Participants |
| Sex: Female, Male Male | 79 Participants | 82 Participants | 161 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 109 | 0 / 115 | 0 / 212 |
| other Total, other adverse events | 92 / 109 | 90 / 115 | 175 / 212 |
| serious Total, serious adverse events | 3 / 109 | 2 / 115 | 14 / 212 |
Outcome results
Primary
Annual Height Velocity in Main Study Phase
Annual Height Velocity in cm. Annual Height Velocity at 12 months is based on the difference between the heights at 12 months and baseline.
Time frame: 52 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MOD-4023 | Annual Height Velocity in Main Study Phase | 10.10 cm/year |
| Genotropin | Annual Height Velocity in Main Study Phase | 9.78 cm/year |
Primary
Annual Height Velocity in OLE Phase
Annualized Height Velocity (cm/year) in OLE Phase
Time frame: Up to 60 months
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MOD-4023 | Annual Height Velocity in OLE Phase | OLE Month 36 | 6.90 cm/year | Standard Deviation 1.8 |
| MOD-4023 | Annual Height Velocity in OLE Phase | OLE Month 0 | 10.27 cm/year | Standard Deviation 2.38 |
| MOD-4023 | Annual Height Velocity in OLE Phase | OLE Month 48 | 6.19 cm/year | Standard Deviation 1.62 |
| MOD-4023 | Annual Height Velocity in OLE Phase | OLE Month 24 | 7.78 cm/year | Standard Deviation 1.91 |
| MOD-4023 | Annual Height Velocity in OLE Phase | OLE Month 12 | 8.03 cm/year | Standard Deviation 1.81 |
| Genotropin | Annual Height Velocity in OLE Phase | OLE Month 0 | 9.72 cm/year | Standard Deviation 2.5 |
| Genotropin | Annual Height Velocity in OLE Phase | OLE Month 60 | 5.05 cm/year | Standard Deviation 1.1 |
| Genotropin | Annual Height Velocity in OLE Phase | OLE Month 12 | 8.21 cm/year | Standard Deviation 1.87 |
| Genotropin | Annual Height Velocity in OLE Phase | OLE Month 24 | 8.05 cm/year | Standard Deviation 1.77 |
| Genotropin | Annual Height Velocity in OLE Phase | OLE Month 36 | 7.14 cm/year | Standard Deviation 1.69 |
| Genotropin | Annual Height Velocity in OLE Phase | OLE Month 48 | 6.86 cm/year | Standard Deviation 2.08 |
Secondary
Change in Bone Maturation (BM) in Main Study Phase
Annual change in bone age measurements as per Gruelich-Pyle method
Time frame: 52 weeks
Population: 5 participants of MOD-4023 and 13 participants of Genotropin did not have bone age measurements at 12 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MOD-4023 | Change in Bone Maturation (BM) in Main Study Phase | 0.05 ratio of bone age to chronologic age | Standard Deviation 0.09 |
| Genotropin | Change in Bone Maturation (BM) in Main Study Phase | 0.06 ratio of bone age to chronologic age | Standard Deviation 0.1 |
Secondary
Change in Height Standard Deviation Score (SDS) in Main Study Phase
Change in height Standard Deviation Score (SDS) after 6 and 12 months is calculated based on the difference between the heights at 6 and 12 months and baseline.
Time frame: After 6 and 12 months
Population: Two subjects discontinued, one from each group.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| MOD-4023 | Change in Height Standard Deviation Score (SDS) in Main Study Phase | SDS at 6 months | 0.54 Standard Deviation Score |
| MOD-4023 | Change in Height Standard Deviation Score (SDS) in Main Study Phase | SDS at 12 months | 0.92 Standard Deviation Score |
| Genotropin | Change in Height Standard Deviation Score (SDS) in Main Study Phase | SDS at 6 months | 0.48 Standard Deviation Score |
| Genotropin | Change in Height Standard Deviation Score (SDS) in Main Study Phase | SDS at 12 months | 0.87 Standard Deviation Score |
Secondary
Change in Height Standard Deviation Score (SDS) in OLE Phase
Change in height Standard Deviation Score (SDS) at each time point is calculated based on the difference between the time point and baseline.
Time frame: 60 months
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MOD-4023 | Change in Height Standard Deviation Score (SDS) in OLE Phase | Baseline (from Main Study Phase) | -2.95 Standard Deviation Score | Standard Deviation 1.3 |
| MOD-4023 | Change in Height Standard Deviation Score (SDS) in OLE Phase | OLE Month 0 | 0.95 Standard Deviation Score | Standard Deviation 0.55 |
| MOD-4023 | Change in Height Standard Deviation Score (SDS) in OLE Phase | OLE Month 12 | 1.38 Standard Deviation Score | Standard Deviation 0.78 |
| MOD-4023 | Change in Height Standard Deviation Score (SDS) in OLE Phase | OLE Month 24 | 1.57 Standard Deviation Score | Standard Deviation 0.77 |
| MOD-4023 | Change in Height Standard Deviation Score (SDS) in OLE Phase | OLE Month 36 | 1.81 Standard Deviation Score | Standard Deviation 0.85 |
| MOD-4023 | Change in Height Standard Deviation Score (SDS) in OLE Phase | OLE Month 48 | 1.96 Standard Deviation Score | Standard Deviation 0.67 |
| Genotropin | Change in Height Standard Deviation Score (SDS) in OLE Phase | OLE Month 60 | 2.14 Standard Deviation Score | Standard Deviation 0.38 |
| Genotropin | Change in Height Standard Deviation Score (SDS) in OLE Phase | OLE Month 24 | 1.66 Standard Deviation Score | Standard Deviation 0.78 |
| Genotropin | Change in Height Standard Deviation Score (SDS) in OLE Phase | Baseline (from Main Study Phase) | -2.79 Standard Deviation Score | Standard Deviation 1.31 |
| Genotropin | Change in Height Standard Deviation Score (SDS) in OLE Phase | OLE Month 48 | 2.04 Standard Deviation Score | Standard Deviation 0.81 |
| Genotropin | Change in Height Standard Deviation Score (SDS) in OLE Phase | OLE Month 0 | 0.85 Standard Deviation Score | Standard Deviation 0.52 |
| Genotropin | Change in Height Standard Deviation Score (SDS) in OLE Phase | OLE Month 36 | 1.93 Standard Deviation Score | Standard Deviation 0.85 |
| Genotropin | Change in Height Standard Deviation Score (SDS) in OLE Phase | OLE Month 12 | 1.34 Standard Deviation Score | Standard Deviation 0.71 |
Secondary
Height Velocity at 6 Months in Main Study Phase
Height velocity in cm measured after 6 months of treatment. Annualized Height velocity after 6 months is calculated based on the difference between the heights at 6 months and baseline.
Time frame: After 6 months of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MOD-4023 | Height Velocity at 6 Months in Main Study Phase | 10.59 cm/year |
| Genotropin | Height Velocity at 6 Months in Main Study Phase | 10.04 cm/year |
Secondary
Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in Main Study Phase
Via central lab analysis
Time frame: Baseline and at 12 months
Population: 2 subjects in MOD-4023 and 5 subjects in Genotropin didn't have the measurements at 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MOD-4023 | Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in Main Study Phase | At 12 months | 0.65 Standard Deviation Score (SDS) | Standard Deviation 1.32 |
| MOD-4023 | Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in Main Study Phase | Baseline | -1.95 Standard Deviation Score (SDS) | Standard Deviation 0.89 |
| Genotropin | Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in Main Study Phase | Baseline | -1.72 Standard Deviation Score (SDS) | Standard Deviation 0.9 |
| Genotropin | Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in Main Study Phase | At 12 months | -0.69 Standard Deviation Score (SDS) | Standard Deviation 1.09 |
Secondary
Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in OLE Phase
Time frame: 60 Months
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MOD-4023 | Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in OLE Phase | Baseline (from Main Study Phase) | 77.91 Standard Deviation Score | Standard Deviation 46.11 |
| MOD-4023 | Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in OLE Phase | OLE Month 0 | 185.9 Standard Deviation Score | Standard Deviation 107.1 |
| MOD-4023 | Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in OLE Phase | OLE Month 12 | 255.9 Standard Deviation Score | Standard Deviation 120 |
| MOD-4023 | Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in OLE Phase | OLE Month 24 | 293.4 Standard Deviation Score | Standard Deviation 132.8 |
| MOD-4023 | Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in OLE Phase | OLE Month 36 | 315.6 Standard Deviation Score | Standard Deviation 139.7 |
| MOD-4023 | Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in OLE Phase | OLE Month 48 | 354.8 Standard Deviation Score | Standard Deviation 133.1 |
| Genotropin | Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in OLE Phase | OLE Month 60 | 397.5 Standard Deviation Score | Standard Deviation 85.27 |
| Genotropin | Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in OLE Phase | OLE Month 24 | 295.3 Standard Deviation Score | Standard Deviation 137.5 |
| Genotropin | Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in OLE Phase | Baseline (from Main Study Phase) | 83.10 Standard Deviation Score | Standard Deviation 41.17 |
| Genotropin | Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in OLE Phase | OLE Month 48 | 368.9 Standard Deviation Score | Standard Deviation 124.9 |
| Genotropin | Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in OLE Phase | OLE Month 0 | 69.96 Standard Deviation Score | Standard Deviation 59.92 |
| Genotropin | Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in OLE Phase | OLE Month 36 | 330.7 Standard Deviation Score | Standard Deviation 138 |
| Genotropin | Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in OLE Phase | OLE Month 12 | 248.6 Standard Deviation Score | Standard Deviation 111.9 |
Other Pre-specified
Device
Proportion of successful single injections out of total number of single injections using the MOD-4023 Pen in the USA at Week 1 based on the Observer Assessment Tool (OAT)
Time frame: 1 week
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MOD-4023 | Device | 17 Participants |
Other Pre-specified
Device
Proportion of successful single injections out of total number of single injections using the MOD-4023 Pen in the USA
Time frame: 6 weeks