Pediatric Growth Hormone Deficiency
Conditions
Keywords
GHD, r-hGH, Long-acting
Brief summary
This is a phase II, open label, active-controlled, randomized safety and dose finding study of different MOD-4023 dose levels compared to daily r-hGH therapy in pre-pubertal growth hormone deficient children.
Interventions
DRUGMOD-4023
Once weekly subcutaneous injection
DRUGSomatropin
Once daily subcutaneous injection of Genotropin
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
1. Pre-pubertal child aged ≥ 3 yrs old and not above 10 years for girls or 11 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 ≤7 ng/ml, determined by central laboratory using a validated assay . 3. Bone age (BA) is not older than chronological age and should be no greater than 9 years for girls and 10 years for boys. 4. Without prior exposure to any r-hGH therapy. 5. Normal birth size, birth weight and length for gestational age 6. Impaired height and height velocity defined as: 1. Height (HT) of at least 2.0 standard deviations (SD) below the mean height for chronological age (CA) and gender according to the standards from Prader et. al, 1989 , (HT SDS ≤ -2.0). 2. Annualized height velocity (HV) below the 25th percentile for CA (HV \<-0.7 SDS) and gender according to the standards of Prader et al (1989). The interval between two height measurements should be at least 6 months before inclusion. 7. BMI must be within ±2 SD of mean BMI for the chronological age and sex according to the 2000 CDC standards. 8. Baseline IGF-I level of at least 1 SD below the mean IGF-I level standardized for age and sex (IGF-I SDS ≤ -1.0) according to the central laboratory reference values; 9. 12\. Written informed consent of the parent or legal guardian of the patient and assent of the patient (if the patient can read).
Exclusion criteria
1. Children with past or present intracranial tumor growth as confirmed by an MRI scan (with contrast). 2. History of radiation therapy or chemotherapy. 3. Malnourished children defined as: 1. Serum albumin below the lower limit of normal (LLN) according to the reference ranges of central laboratory; 2. Serum iron below the lower limit of normal (LLN) according to the reference ranges of central laboratory; 3. BMI \< -2 SD for age and sex; 4. Children with psychosocial dwarfism. 5. Children born small for gestational age (SGA - birth weight and/or birth length \< -2 SD 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. Patients with diabetes mellitus. 9. Patients with impaired fasting sugar (based on WHO; fasting blood sugar \>110 mg/dl or 6.1 mmol/l) after repeated blood analysis. 10. Chromosomal abnormalities and medical syndromes (Turner's syndrome, Laron syndrome, Noonan syndrome, Prader-Willi Syndrome, Russell-Silver Syndrome, SHOX mutations/deletions and skeletal dysplasias), with the exception of septo-optic dysplasia. 11. Closed epiphyses. 12. Concomitant administration of other treatments that may have an effect on growth such as anabolic steroids and methylphenidate for attention deficit hyperactivity disorder (ADHD), with the exception of hormone replacement therapies (thyroxine, hydrocortisone, desmopressin (DDAVP)) 13. Children requiring glucocorticoid therapy (e.g. asthma) who are taking a dose of greater than 400 µg/d of inhaled budesonide or equivalents for longer than 1 month during a calendar year. 14. Major medical conditions and/or presence of contraindication to r-hGH treatment. 15. Known or suspected HIV-positive patient, or patient with advanced diseases such as AIDS or tuberculosis. 16. Drug, substance, or alcohol abuse. 17. Known hypersensitivity to the components of study medication. 18. Other causes of short stature such as coeliac disease, hypothyroidism and rickets. 19. The patient and/or the parent/legal guardian are likely to be non-compliant in respect to study conduct. 20. Participation in any other trial of an investigational agent within 30 days prior to Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annual Height Velocity | 12 months of treatment | Annual Height Velocity in cm/year measured after 12 months of treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Height Velocity at 6 Months | After 6 months of treatment | Annualized Height Velocity in cm/year measured after 6 months of treatment |
| Change in Height Standard Deviation Score (SDS) | After 6 and 12 months of treatment | Change in height standard deviation score from baseline (compared to normal population of same age group and sex). Height SDS was calculated as height minus reference mean height divided by SD of the reference mean height |
| Change in IGF-1 Standard Deviation Score | Once monthly on day 4 after the last dose | Change in IGF-1 standard deviation score from reference population mean of same age group and sex (WHO source). IGF-1 SDS was calculated as IGF-1 result minus reference mean IGF-1 result divided by SD of the reference mean IGF-1 value. |
Countries
Greece, Hungary, Slovakia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MOD-4023 Low Dose Once weekly subcutaneous injection of long acting r-hGH (MOD-4023) | 13 |
| MOD-4023 Middle Dose Once weekly subcutaneous injection of long acting r-hGH (MOD-4023) | 15 |
| MOD-4023 High Dose Once weekly subcutaneous injection of long acting r-hGH (MOD-4023) | 14 |
| Genotropin Once daily subcutaneous injection of Somatropin (r-hGH; Genotropin) | 11 |
| Total | 53 |
Baseline characteristics
| Characteristic | MOD-4023 Low Dose | MOD-4023 Middle Dose | MOD-4023 High Dose | Genotropin | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 13 Participants | 15 Participants | 14 Participants | 11 Participants | 53 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 3 Participants | 6 Participants | 5 Participants | 3 Participants | 17 Participants |
| Sex: Female, Male Male | 10 Participants | 9 Participants | 9 Participants | 8 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 13 | 10 / 15 | 10 / 14 | 8 / 11 |
| serious Total, serious adverse events | 0 / 13 | 0 / 15 | 0 / 14 | 0 / 11 |
Outcome results
Primary
Annual Height Velocity
Annual Height Velocity in cm/year measured after 12 months of treatment
Time frame: 12 months of treatment
Population: Per Protocol Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MOD-4023 Low Dose | Annual Height Velocity | 10.4 cm/year | Standard Deviation 2.6 |
| MOD-4023 Middle Dose | Annual Height Velocity | 11.0 cm/year | Standard Deviation 2.3 |
| MOD-4023 High Dose | Annual Height Velocity | 11.9 cm/year | Standard Deviation 3.5 |
| Genotropin | Annual Height Velocity | 12.5 cm/year | Standard Deviation 2.1 |
Secondary
Change in Height Standard Deviation Score (SDS)
Change in height standard deviation score from baseline (compared to normal population of same age group and sex). Height SDS was calculated as height minus reference mean height divided by SD of the reference mean height
Time frame: After 6 and 12 months of treatment
Population: Per Protocol Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MOD-4023 Low Dose | Change in Height Standard Deviation Score (SDS) | After 6 months of treatment | 0.65 score on a scale | Standard Deviation 0.36 |
| MOD-4023 Low Dose | Change in Height Standard Deviation Score (SDS) | After 12 months of treatment | 1.09 score on a scale | Standard Deviation 0.53 |
| MOD-4023 Middle Dose | Change in Height Standard Deviation Score (SDS) | After 12 months of treatment | 1.19 score on a scale | Standard Deviation 0.49 |
| MOD-4023 Middle Dose | Change in Height Standard Deviation Score (SDS) | After 6 months of treatment | 0.75 score on a scale | Standard Deviation 0.25 |
| MOD-4023 High Dose | Change in Height Standard Deviation Score (SDS) | After 6 months of treatment | 0.90 score on a scale | Standard Deviation 0.39 |
| MOD-4023 High Dose | Change in Height Standard Deviation Score (SDS) | After 12 months of treatment | 1.45 score on a scale | Standard Deviation 0.61 |
| Genotropin | Change in Height Standard Deviation Score (SDS) | After 6 months of treatment | 1.00 score on a scale | Standard Deviation 0.35 |
| Genotropin | Change in Height Standard Deviation Score (SDS) | After 12 months of treatment | 1.51 score on a scale | Standard Deviation 0.47 |
Secondary
Change in IGF-1 Standard Deviation Score
Change in IGF-1 standard deviation score from reference population mean of same age group and sex (WHO source). IGF-1 SDS was calculated as IGF-1 result minus reference mean IGF-1 result divided by SD of the reference mean IGF-1 value.
Time frame: Once monthly on day 4 after the last dose
Population: No data were scheduled to be collected for Week 23 in the Genotropin Arm/Group
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MOD-4023 Low Dose | Change in IGF-1 Standard Deviation Score | Week 14 | -1.07 score on a scale | Standard Deviation 0.553 |
| MOD-4023 Low Dose | Change in IGF-1 Standard Deviation Score | Week 1 | -1.86 score on a scale | Standard Deviation 0.817 |
| MOD-4023 Low Dose | Change in IGF-1 Standard Deviation Score | Week 18 | -0.815 score on a scale | Standard Deviation 0.733 |
| MOD-4023 Low Dose | Change in IGF-1 Standard Deviation Score | Month 9 | -0.119 score on a scale | Standard Deviation 0.921 |
| MOD-4023 Low Dose | Change in IGF-1 Standard Deviation Score | Week 26 | -0.725 score on a scale | Standard Deviation 0.801 |
| MOD-4023 Low Dose | Change in IGF-1 Standard Deviation Score | Week 10 | -1.03 score on a scale | Standard Deviation 0.902 |
| MOD-4023 Low Dose | Change in IGF-1 Standard Deviation Score | Month 12 | -0.458 score on a scale | Standard Deviation 1.194 |
| MOD-4023 Low Dose | Change in IGF-1 Standard Deviation Score | Week 23 | -1.70 score on a scale | Standard Deviation 0.741 |
| MOD-4023 Low Dose | Change in IGF-1 Standard Deviation Score | Week 22 | -0.958 score on a scale | Standard Deviation 0.673 |
| MOD-4023 Middle Dose | Change in IGF-1 Standard Deviation Score | Week 1 | -1.94 score on a scale | Standard Deviation 0.899 |
| MOD-4023 Middle Dose | Change in IGF-1 Standard Deviation Score | Week 10 | -0.279 score on a scale | Standard Deviation 0.891 |
| MOD-4023 Middle Dose | Change in IGF-1 Standard Deviation Score | Week 14 | -0.275 score on a scale | Standard Deviation 0.772 |
| MOD-4023 Middle Dose | Change in IGF-1 Standard Deviation Score | Week 18 | 0.189 score on a scale | Standard Deviation 0.707 |
| MOD-4023 Middle Dose | Change in IGF-1 Standard Deviation Score | Week 22 | -0.188 score on a scale | Standard Deviation 0.684 |
| MOD-4023 Middle Dose | Change in IGF-1 Standard Deviation Score | Week 23 | -1.48 score on a scale | Standard Deviation 0.653 |
| MOD-4023 Middle Dose | Change in IGF-1 Standard Deviation Score | Week 26 | 0.088 score on a scale | Standard Deviation 0.803 |
| MOD-4023 Middle Dose | Change in IGF-1 Standard Deviation Score | Month 9 | 0.184 score on a scale | Standard Deviation 0.905 |
| MOD-4023 Middle Dose | Change in IGF-1 Standard Deviation Score | Month 12 | -0.029 score on a scale | Standard Deviation 1.296 |
| MOD-4023 High Dose | Change in IGF-1 Standard Deviation Score | Month 9 | 0.261 score on a scale | Standard Deviation 1.108 |
| MOD-4023 High Dose | Change in IGF-1 Standard Deviation Score | Week 22 | 0.023 score on a scale | Standard Deviation 0.964 |
| MOD-4023 High Dose | Change in IGF-1 Standard Deviation Score | Week 10 | -0.001 score on a scale | Standard Deviation 1.164 |
| MOD-4023 High Dose | Change in IGF-1 Standard Deviation Score | Week 23 | -1.47 score on a scale | Standard Deviation 0.865 |
| MOD-4023 High Dose | Change in IGF-1 Standard Deviation Score | Week 26 | -0.011 score on a scale | Standard Deviation 1.084 |
| MOD-4023 High Dose | Change in IGF-1 Standard Deviation Score | Week 1 | -2.13 score on a scale | Standard Deviation 0.887 |
| MOD-4023 High Dose | Change in IGF-1 Standard Deviation Score | Week 14 | -0.058 score on a scale | Standard Deviation 1.067 |
| MOD-4023 High Dose | Change in IGF-1 Standard Deviation Score | Month 12 | 0.358 score on a scale | Standard Deviation 0.709 |
| MOD-4023 High Dose | Change in IGF-1 Standard Deviation Score | Week 18 | -0.083 score on a scale | Standard Deviation 1.299 |
| Genotropin | Change in IGF-1 Standard Deviation Score | Week 26 | -0.235 score on a scale | Standard Deviation 0.919 |
| Genotropin | Change in IGF-1 Standard Deviation Score | Week 22 | -0.495 score on a scale | Standard Deviation 1.108 |
| Genotropin | Change in IGF-1 Standard Deviation Score | Week 18 | -0.310 score on a scale | Standard Deviation 0.896 |
| Genotropin | Change in IGF-1 Standard Deviation Score | Month 9 | 0.124 score on a scale | Standard Deviation 1.071 |
| Genotropin | Change in IGF-1 Standard Deviation Score | Week 14 | -0.557 score on a scale | Standard Deviation 1.216 |
| Genotropin | Change in IGF-1 Standard Deviation Score | Week 1 | -2.12 score on a scale | Standard Deviation 0.813 |
| Genotropin | Change in IGF-1 Standard Deviation Score | Month 12 | -0.015 score on a scale | Standard Deviation 1.485 |
| Genotropin | Change in IGF-1 Standard Deviation Score | Week 10 | -0.515 score on a scale | Standard Deviation 1.238 |
Secondary
Height Velocity at 6 Months
Annualized Height Velocity in cm/year measured after 6 months of treatment
Time frame: After 6 months of treatment
Population: Per Protocol Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MOD-4023 Low Dose | Height Velocity at 6 Months | 11.8 cm/year | Standard Deviation 3.6 |
| MOD-4023 Middle Dose | Height Velocity at 6 Months | 12.5 cm/year | Standard Deviation 2.4 |
| MOD-4023 High Dose | Height Velocity at 6 Months | 13.5 cm/year | Standard Deviation 5 |
| Genotropin | Height Velocity at 6 Months | 15.0 cm/year | Standard Deviation 2.9 |