Small Gestational Age (SGA)
Conditions
Brief summary
Multicentric, open-label, randomized, pilot comparative study in parallel groups comparing 1 group of subjects receiving 0.057 milligram/kilogram/day (mg/kg/day) or 0.40 mg/kg/week of Saizen® during 1 year to 1 group receiving 0.035 mg/kg/day (0.24 mg/kg/week) of Saizen® during 1 year after an initial 3-year treatment of recombinant human growth hormone (r-hGH) therapy with 0.057 mg/kg/day in both groups.
Interventions
DRUGSaizen®
Saizen® \[somatropin (recombinant deoxyribonucleic acid \[rDNA\] origin) for injection\], a r-hGH, is indicated for the treatment of children with growth failure due to inadequate secretion of endogenous growth hormone.
Sponsors
Merck Serono S.A.S., an affiliate of Merck KGaA, Darmstadt, Germany
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
To be eligible for inclusion / randomization into this study, the subjects must fulfill all of the following criteria (if there is no inclusion phase, the inclusion criteria will be considered as inclusion criteria for randomization): * Written consent form signed by the parents / legal guardian, and child if possible * Subject born SGA and receiving a r-hGH therapy for this pathology * Recombinant human growth hormone (r-hGH) started at the maximal chronological age of 7 years for girls and 8 years for boys * Treatment with r-hGH started for at least 30 months and less than 36 months at 0.057 mg/kg/day * Height gain during the first 2 years of GH treatment \> 1 SD compared with the initial value
Exclusion criteria
To be eligible for inclusion in this study the subjects must not meet any of the following criteria: * Known hypersensitivity to Somatropin or any of the excipients * Active neoplasia (either newly diagnosed or recurrent) * Intracranial hypertension * Known diabetes mellitus * Proliferative or preproliferative diabetic retinopathy * Evidence of any progression or recurrence of an underlying intra-cranial space occupying lesion * Obesity defined as degree 1 on the corpulence curves * Precocious puberty * Pubertal status: Tanner breast development stage \> 2 for girls, and testicular volume \> 4 milliliter (mL) or testicular length \> 3 centimeter (cm) and/or testosterone value \>1 nanomole/liter \[nmol/L\] (0.29 gram/mL \[g/mL\]) for boys For girls \> 9 years and Tanner breast development stage 1: uterine size \> 35 millimeter (mm) * Severe chronic concomitant illness such as chronic renal failure, cystic fibrosis * Concomitant corticoid treatment or levothyroxine treatment other than substitutive treatment, topical or inhaled treatment * Participation to any clinical study within the 30 days preceding study entry
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Height Velocity | Month 12 | Height Velocity (HV) is the change in height since the previous year´s measurement and more precisely: HV = {(h-hp)/(d-dp)} \* 365.25 \[centimeter (cm)/year\] where h is current height in cm, hp is previous height in cm, closest to 1 year previous, d is the current date and dp is the date of measurement of previous height, closest to 1 year previous. Additionally, d and dp have to be within 0.6 years and 1.5 years. HV is the mean height velocity over the interval between d and dp but is displayed as HV at d. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Height Velocity-Standard Deviation Score (HV-SDS) | Month 6 and Month 12 | Height Velocity-Standard Deviation Score (HV-SDS) was calculated as height velocity minus reference mean height velocity divided by SD of the reference mean height velocity. Greater HV-SDS indicates greater height velocity. |
| Change From Baseline in Height at Month 6 | Baseline (randomization) and Month 6 | — |
| Change From Baseline in Bone Age at Month 12 | Baseline (randomization) and Month 12 | Bone age was assessed by a left wrist X-Ray and evaluated by the investigator according to the Greulich and Pyle method. |
| Change From Baseline in Height-Standard Deviation Score (H-SDS) at Month 6 and Month 12 | Baseline (randomization), Month 6 and Month 12 | Height-Standard Deviation Score (H-SDS) was calculated as height minus mean (age-and sex-matched reference) divided by standard deviation (SD) \[age and sex-matched reference\]. Greater H-SDS indicates greater height. |
| Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) Levels | Baseline (randomization), Month 6 and Month 12 | — |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Baseline (randomization) until Month 12 | Adverse Events (AEs): Any untoward medical occurrence in the form of signs, clinically significant abnormalities in laboratory findings, diseases, symptoms, or worsening of complications. TEAEs: AEs that occur during treatment with the Investigational Medicinal Product (IMP). |
| Insulin Like Growth Factor-1 (IGF-1) Levels | Baseline (randomization), Month 6 and Month 12 | — |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Saizen® 0.057 mg/kg/Day Saizen® (recombinant human growth hormone, r-hGH) subcutaneously administered at the daily dose of 0.057 milligram/kilogram (mg/kg) or 0.40 mg/kg/week for duration of 12 months. | 10 |
| Saizen® 0.035 mg/kg/Day Saizen® (r-hGH) subcutaneously administered at the daily dose of 0.035 mg/kg or 0.24 mg/kg/week for duration of 12 months. | 12 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Technical problem | 0 | 1 |
Baseline characteristics
| Characteristic | Saizen® 0.057 mg/kg/Day | Saizen® 0.035 mg/kg/Day | Total |
|---|---|---|---|
| Age, Continuous | 8.00 years STANDARD_DEVIATION 1.49 | 7.90 years STANDARD_DEVIATION 0.9 | 8.00 years STANDARD_DEVIATION 1.17 |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Male | 6 Participants | 8 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 10 | 1 / 12 |
| serious Total, serious adverse events | 0 / 10 | 0 / 12 |
Outcome results
Primary
Height Velocity
Height Velocity (HV) is the change in height since the previous year´s measurement and more precisely: HV = {(h-hp)/(d-dp)} \* 365.25 \[centimeter (cm)/year\] where h is current height in cm, hp is previous height in cm, closest to 1 year previous, d is the current date and dp is the date of measurement of previous height, closest to 1 year previous. Additionally, d and dp have to be within 0.6 years and 1.5 years. HV is the mean height velocity over the interval between d and dp but is displayed as HV at d.
Time frame: Month 12
Population: Full Analysis (FA) set included all the participants who received at least 1 dose of study medication and had at least 1 height evaluation post randomization. Last observation carried forward (LOCF) was used to impute missing values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saizen® 0.057 mg/kg/Day | Height Velocity | 6.40 centimeter (cm)/year | Standard Deviation 1.35 |
| Saizen® 0.035 mg/kg/Day | Height Velocity | 4.40 centimeter (cm)/year | Standard Deviation 1.15 |
Comparison: Month 12: Analysis of co-variance (ANCOVA) method with covariates height and age at baseline was used to calculate presented p-value.p-value: 0.001ANCOVA
Secondary
Change From Baseline in Bone Age at Month 12
Bone age was assessed by a left wrist X-Ray and evaluated by the investigator according to the Greulich and Pyle method.
Time frame: Baseline (randomization) and Month 12
Population: FA set included all participants who received at least 1 dose of study medication and had at least 1 height evaluation post randomization. 'N' (Number of participants analyzed) signified those participants who were evaluable for this measure and n = number of participants analyzed at that particular time point for each arm group respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saizen® 0.057 mg/kg/Day | Change From Baseline in Bone Age at Month 12 | Change at Month 12 (n=9,7) | 1.40 years | Standard Deviation 0.79 |
| Saizen® 0.057 mg/kg/Day | Change From Baseline in Bone Age at Month 12 | Baseline (randomization) (n = 9,10) | 7.50 years | Standard Deviation 0.82 |
| Saizen® 0.035 mg/kg/Day | Change From Baseline in Bone Age at Month 12 | Baseline (randomization) (n = 9,10) | 7.00 years | Standard Deviation 1.85 |
| Saizen® 0.035 mg/kg/Day | Change From Baseline in Bone Age at Month 12 | Change at Month 12 (n=9,7) | 1.40 years | Standard Deviation 0.89 |
Comparison: Change at Month 12: ANCOVA method with covariates height and age at baseline was used to calculate presented p-value.p-value: 0.972ANCOVA
Secondary
Change From Baseline in Height at Month 6
Time frame: Baseline (randomization) and Month 6
Population: FA set included all the participants who received at least 1 dose of study medication and had at least 1 height evaluation post randomization. LOCF was used to impute missing values.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saizen® 0.057 mg/kg/Day | Change From Baseline in Height at Month 6 | Baseline (randomization) | 121.10 cm | Standard Deviation 7.99 |
| Saizen® 0.057 mg/kg/Day | Change From Baseline in Height at Month 6 | Change at Month 6 | 3.60 cm | Standard Deviation 1.31 |
| Saizen® 0.035 mg/kg/Day | Change From Baseline in Height at Month 6 | Baseline (randomization) | 119.20 cm | Standard Deviation 5.29 |
| Saizen® 0.035 mg/kg/Day | Change From Baseline in Height at Month 6 | Change at Month 6 | 2.50 cm | Standard Deviation 0.99 |
Comparison: Change at Month 6: ANCOVA method with covariates height and age at baseline was used to calculate presented p-value.p-value: 0.029ANCOVA
Secondary
Change From Baseline in Height-Standard Deviation Score (H-SDS) at Month 6 and Month 12
Height-Standard Deviation Score (H-SDS) was calculated as height minus mean (age-and sex-matched reference) divided by standard deviation (SD) \[age and sex-matched reference\]. Greater H-SDS indicates greater height.
Time frame: Baseline (randomization), Month 6 and Month 12
Population: FA set included all the participants who received at least 1 dose of study medication and had at least 1 height evaluation post randomization. LOCF was used to impute missing values.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saizen® 0.057 mg/kg/Day | Change From Baseline in Height-Standard Deviation Score (H-SDS) at Month 6 and Month 12 | Baseline (randomization) | -1.30 standard deviation score | Standard Deviation 0.42 |
| Saizen® 0.057 mg/kg/Day | Change From Baseline in Height-Standard Deviation Score (H-SDS) at Month 6 and Month 12 | Change at Month 6 | 0.30 standard deviation score | Standard Deviation 0.22 |
| Saizen® 0.057 mg/kg/Day | Change From Baseline in Height-Standard Deviation Score (H-SDS) at Month 6 and Month 12 | Change at Month 12 | 0.30 standard deviation score | Standard Deviation 0.3 |
| Saizen® 0.035 mg/kg/Day | Change From Baseline in Height-Standard Deviation Score (H-SDS) at Month 6 and Month 12 | Baseline (randomization) | -1.50 standard deviation score | Standard Deviation 0.37 |
| Saizen® 0.035 mg/kg/Day | Change From Baseline in Height-Standard Deviation Score (H-SDS) at Month 6 and Month 12 | Change at Month 6 | 0.10 standard deviation score | Standard Deviation 0.1 |
| Saizen® 0.035 mg/kg/Day | Change From Baseline in Height-Standard Deviation Score (H-SDS) at Month 6 and Month 12 | Change at Month 12 | -0.10 standard deviation score | Standard Deviation 0.24 |
Comparison: Change at Month 6: ANCOVA method with covariates height and age at baseline was used to calculate presented p-value.p-value: 0.012ANCOVA
Comparison: Change at Month 12: ANCOVA method with covariates height and age at baseline was used to calculate presented p-value.p-value: 0.002ANCOVA
Secondary
Height Velocity-Standard Deviation Score (HV-SDS)
Height Velocity-Standard Deviation Score (HV-SDS) was calculated as height velocity minus reference mean height velocity divided by SD of the reference mean height velocity. Greater HV-SDS indicates greater height velocity.
Time frame: Month 6 and Month 12
Population: FA set included all the participants who received at least 1 dose of study medication and had at least 1 height evaluation post randomization. Here n signifies number of participants analyzed at that particular time point for each arm group respectively. LOCF was used to impute missing values.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saizen® 0.057 mg/kg/Day | Height Velocity-Standard Deviation Score (HV-SDS) | Month 6 (n= 10,11) | 0.60 standard deviation score | Standard Deviation 0.44 |
| Saizen® 0.057 mg/kg/Day | Height Velocity-Standard Deviation Score (HV-SDS) | Month 12 (n=10,12) | 0.30 standard deviation score | Standard Deviation 0.29 |
| Saizen® 0.035 mg/kg/Day | Height Velocity-Standard Deviation Score (HV-SDS) | Month 6 (n= 10,11) | 0.10 standard deviation score | Standard Deviation 0.22 |
| Saizen® 0.035 mg/kg/Day | Height Velocity-Standard Deviation Score (HV-SDS) | Month 12 (n=10,12) | -0.10 standard deviation score | Standard Deviation 0.24 |
Comparison: Month 6: ANCOVA method with covariates height and age at baseline was used to calculate presented p-value.p-value: 0.022ANCOVA
Comparison: Month 12: ANCOVA method with covariates height and age at baseline was used to calculate presented p-value.p-value: 0.002ANCOVA
Secondary
Insulin Like Growth Factor-1 (IGF-1) Levels
Time frame: Baseline (randomization), Month 6 and Month 12
Population: FA set included all participants who received at least 1 dose of study medication and had at least 1 height evaluation post randomization. 'N' (Number of participants analyzed) signified those participants who were evaluable for this measure and n = number of participants analyzed at that particular time point for each arm group respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saizen® 0.057 mg/kg/Day | Insulin Like Growth Factor-1 (IGF-1) Levels | Baseline (randomization) (n= 10,11) | 319.60 microgram/liter (mcg/L) | Standard Deviation 146.27 |
| Saizen® 0.057 mg/kg/Day | Insulin Like Growth Factor-1 (IGF-1) Levels | Month 6 (n= 9,7) | 369.30 microgram/liter (mcg/L) | Standard Deviation 120.13 |
| Saizen® 0.057 mg/kg/Day | Insulin Like Growth Factor-1 (IGF-1) Levels | Month 12 (n=10,10) | 414.30 microgram/liter (mcg/L) | Standard Deviation 176.7 |
| Saizen® 0.035 mg/kg/Day | Insulin Like Growth Factor-1 (IGF-1) Levels | Baseline (randomization) (n= 10,11) | 275.40 microgram/liter (mcg/L) | Standard Deviation 98.82 |
| Saizen® 0.035 mg/kg/Day | Insulin Like Growth Factor-1 (IGF-1) Levels | Month 6 (n= 9,7) | 262.40 microgram/liter (mcg/L) | Standard Deviation 65.52 |
| Saizen® 0.035 mg/kg/Day | Insulin Like Growth Factor-1 (IGF-1) Levels | Month 12 (n=10,10) | 263.00 microgram/liter (mcg/L) | Standard Deviation 120.7 |
Comparison: Month 6: ANCOVA method with covariates height and age at baseline was used to calculate presented p-value.p-value: 0.058ANCOVA
Comparison: Month 12: ANCOVA method with covariates height and age at baseline was used to calculate presented p-value.p-value: 0.026ANCOVA
Secondary
Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) Levels
Time frame: Baseline (randomization), Month 6 and Month 12
Population: FA set included all participants who received at least 1 dose of study medication and had at least 1 height evaluation post randomization. 'N' (Number of participants analyzed) signified those participants who were evaluable for this measure and n = number of participants analyzed at that particular time point for each arm group respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saizen® 0.057 mg/kg/Day | Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) Levels | Month 6 (n= 9,7) | 3.00 milligram/L (mg/L) | Standard Deviation 0.84 |
| Saizen® 0.057 mg/kg/Day | Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) Levels | Baseline (randomization) (n= 10,10) | 3.40 milligram/L (mg/L) | Standard Deviation 0.7 |
| Saizen® 0.057 mg/kg/Day | Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) Levels | Month 12 (n= 9,10) | 3.60 milligram/L (mg/L) | Standard Deviation 1.02 |
| Saizen® 0.035 mg/kg/Day | Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) Levels | Baseline (randomization) (n= 10,10) | 3.40 milligram/L (mg/L) | Standard Deviation 0.6 |
| Saizen® 0.035 mg/kg/Day | Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) Levels | Month 6 (n= 9,7) | 3.30 milligram/L (mg/L) | Standard Deviation 0.81 |
| Saizen® 0.035 mg/kg/Day | Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) Levels | Month 12 (n= 9,10) | 3.50 milligram/L (mg/L) | Standard Deviation 0.77 |
Comparison: Month 6: ANCOVA method with covariates height and age at baseline was used to calculate presented p-value.p-value: 0.793ANCOVA
Comparison: Month 12: ANCOVA method with covariates height and age at baseline was used to calculate presented p-value.p-value: 0.055ANCOVA
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Adverse Events (AEs): Any untoward medical occurrence in the form of signs, clinically significant abnormalities in laboratory findings, diseases, symptoms, or worsening of complications. TEAEs: AEs that occur during treatment with the Investigational Medicinal Product (IMP).
Time frame: Baseline (randomization) until Month 12
Population: The safety population included all the participants who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saizen® 0.057 mg/kg/Day | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 2 participants |
| Saizen® 0.035 mg/kg/Day | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 1 participants |