Neuromuscular Changes In Small For Gestational Age Children During Somatropin Therapy

Study Overview
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Brief Summary
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The planned study focuses on the effect of a one year Somatropin treatment (0.035 mg/kg/d or 0.067 mg/kg/d) in short children born SGA on neuromuscular function and cognitive performance.

Official Title
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Neuromuscular Changes In Small For Gestational Age (SGA) Children During Somatropin Therapy - A Prospective Randomized, Controlled, Open-Label Multicenter Trial

Conditions
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Growth Hormone Therapy, Infant, Small for Gestational Age

Intervention / Treatment
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* Drug: Somatropin
* Drug: Somatropin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pre-pubertal boys between 6 and 10 years of age or girls between 6 and 9 years of age. Birth length- and/or birth weight-SDS adjusted to gestational age < -2.0 (Voigt et al. 2002, Voigt et al. 2006 or Lawrence et al. 1989). Current height-SDS < -2.5 (Brandt/Reinken 1992) and parental adjusted height-SDS below -1 (Hermanussen and Cole 2003). Growth velocity SDS < 0 during the last year before inclusion (Brandt/Reinken 1988). Exclusion Criteria: Severe SGA (birth weight or length < -4 SD) and clinically relevant dysmorphic features. Severe pre-maturity (GA < 32 weeks of gestation). Severe perinatal complications like asphyxia, sepsis, necrotizing enterocolitis (NEC), respiratory distress syndrome, if associated with long-term sequelae (like short bowel syndrome, bronchopulmonary dysplasia (BPD), cerebral palsy etc). Inability to perform one- or two leg jumps from a standing position. Prior GH treatment.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 10 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: Treatment Group<br>Somatropin for 12 months | Drug: Somatropin<br>* Patients will be randomized at baseline in a 1:1 ratio into treatment group or control group. After six months the control group will undergo GH therapy with a higher dose of 0.067 mg/kg/day, too. All patients are treated with growth hormone for 12 months.<br>|
| Other: Control Group<br>In the first 6 months no intervention, afterwards Somatropin for 12 months | Drug: Somatropin<br>* Patients will be randomized at baseline in a 1:1 ratio into treatment group or control group. After six months the control group will undergo GH therapy with a higher dose of 0.067 mg/kg/day, too. All patients are treated with growth hormone for 12 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Peak Jump Power Standard Deviation Score (PJP-SDS; Two-leg-jump) in Full Analysis Set (FAS) Population at Month 6 | Peak jump power (PJP) was defined as the peak of the calculated power (force multiplied by velocity). It was measured by Leonardo Jumping Platform during two-leg jump. The participant performs 3 jumps and the highest peak (PJP) of the 3 recordings was selected for further calculations. The SDS indicates how similar the participant was to the reference population. | Baseline and Month 6 | 
| Change From Baseline in Peak Jump Power Standard Deviation Score (PJP-SDS; Two-leg-jump) in Per Protocol (PP) Population at Month 6 | PJP was defined as the peak of the calculated power (force multiplied by velocity). It was measured by Leonardo Jumping Platform during two-leg jump. The participant performs 3 jumps and the highest peak (PJP) of the 3 recordings was selected for further calculations. The SDS indicates how similar the participant was to the reference population. | Baseline and Month 6 | 
| Change From Baseline in Peak Jump Force Standard Deviation Score (PJF-SDS; Two-leg-jump) in Full Analysis Set (FAS) Population at Month 6 | PJF was defined as the maximum of force of the ascending part of the jump which the participant performed as a counter-movement jump with freely moving arms and as high as possible with the head and chest. It was measured by Leonardo Jumping Platform during two-leg jump. The SDS indicates how similar the participant was to the reference population. | Baseline and Month 6 | 
| Change From Baseline in Peak Jump Force Standard Deviation Score (PJF-SDS; Two-leg-jump) in Per Protocol (PP) Population at Month 6 | PJF was defined as the maximum of force of the ascending part of the jump which the participant performed as a counter-movement jump with freely moving arms and as high as possible with the head and chest. It was measured by Leonardo Jumping Platform during two-leg jump. The SDS indicates how similar the participant was to the reference population. | Baseline and Month 6 | 
| Change From Baseline in Maximum Jump Velocity (Vmax; Two-leg-jump) in Full Analysis Set (FAS) Population at Month 6 | Vmax was measured by Leonardo Jumping Platform during two-leg jump. | Baseline and Month 6 | 
| Change From Baseline in Maximum Jump Velocity (Vmax; Two-leg-jump) in Per Protocol (PP) Population at Month 6 | Vmax was measured by Leonardo Jumping Platform during two-leg jump. | Baseline and Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Intellectual Performance of Children Using Kaufmann-Assessment Battery for Children (K-ABC) Test Global Scales at Month 6 | K-ABC was assessed in children between 2.5-12.5 years. Comprised of 16 subtests; 10 mental processing (intelligence) and 6 achievement subtests. Achievement subtests: expressive vocabulary, faces&places, arithmetic, riddles, reading/decoding, reading/comprehension. Sixteen subtests were weighted accordingly to form 5 global scales: sequential processing, simultaneous processing, achievement, non-verbal and mental processing composite. Scores were rated as upper extreme [greater than (>) 131], above average (116-130), average (85-115), below average (70-84), lower extreme [less than (<) 69]. | Baseline and Month 6 | 
| Change From Baseline in Intellectual Performance of Children Using Kaufmann-Assessment Battery for Children (K-ABC) Test Global Scales at Months 12 and 18 | K-ABC was assessed in children between 2.5-12.5 years. Comprised of 16 subtests; 10 mental processing (intelligence) and 6 achievement subtests. Achievement subtests: expressive vocabulary, faces&places, arithmetic, riddles, reading/decoding, reading/comprehension. Sixteen subtests were weighted accordingly to form 5 global scales: sequential processing, simultaneous processing, achievement, non-verbal and mental processing composite. Scores were rated as upper extreme [greater than (>) 131], above average (116-130), average (85-115), below average (70-84), lower extreme [less than (<) 69]. | Baseline, Month 12 and Month 18 | 
| Change From Baseline in Intellectual Performance of Children Using Kinderversion Der Testbatterie Zur Aufmerksamkeitsprüfung für Kinder (KITAP) Test at Month 6 | The KITAP is a computer aided standardized neuro-cognitive development test which allows examination of a wide range of attention and executive functions such as shift of attention (Distractibility); simple reaction time (Alertness); Sustained Attention, change of reaction (Flexibility); Divided Attention, controlled reaction disposition (Go/No go) and Vigilance. It has been designed appropriately for children between the age of 6 to 10 years to allow optimal motivation during testing and to increase validity of results. | Baseline and Month 6 | 
| Change From Baseline in Intellectual Performance of Children Using Kinderversion Der Testbatterie Zur Aufmerksamkeitsprüfung für Kinder (KITAP) Test at Months 12 and 18 | The KITAP is a computer aided standardized neuro-cognitive development test which allows examination of a wide range of attention and executive functions such as shift of attention (Distractibility); simple reaction time (Alertness); Sustained Attention, change of reaction (Flexibility); Divided Attention, controlled reaction disposition (Go/No go) and Vigilance. It has been designed appropriately for children between the age of 6 to 10 years to allow optimal motivation during testing and to increase validity of results. | Baseline, Month 12 and Month 18 | 
| Change From Baseline in Intellectual Performance of Children Using Non-verbal Learning Test (NVLT) at Month 6 | NVLT was assessed for visual memorization that was difficult to verbalize. Test recorded instability index, T-scores[sum of differences of correct {C} - incorrect {IC} Yes answers(1);sum of C Yes answers(2);sum of IC Yes answers(3);sum of differences of C-IC Yes answers with high associative items{ 87%-95%}(4);sum of differences of C-IC Yes answers with low associative items{ 54%-64%}(5); difference between difference values for high and low associative items(6)].Scores were rated as below average(<40), average(40-60), above average(>60) and working time ranging between 9-12 minutes. | Baseline and Month 6 | 
| Change From Baseline in Intellectual Performance of Children Using Non-verbal Learning Test (NVLT) at Months 12 and 18 | NVLT was assessed for visual memorization that was difficult to verbalize. Test recorded instability index, T-scores[sum of differences of correct {C} - incorrect {IC} Yes answers(1);sum of C Yes answers(2);sum of IC Yes answers(3);sum of differences of C-IC Yes answers with high associative items{ 87%-95%}(4);sum of differences of C-IC Yes answers with low associative items{ 54%-64%}(5); difference between difference values for high and low associative items(6)].Scores were rated as below average(<40), average(40-60), above average(>60) and working time ranging between 9-12 minutes. | Baseline, Month 12 and Month 18 | 
| Change From Baseline in Intellectual Performance of Children Using Child Behavior Checklist 4-18 Years (CBCL 4-18) at Months 6, 12 and 18 | CBCL was standardized for children ages 4 to 18 years and measured child internalizing and externalizing behaviors and total problems. The 4-18 years' checklist contains 140 questions and responses were recorded on a Likert scale: 0 = Not True, 1 = Somewhat or Sometimes True, 2 = Very True or Often True. The range of possible values was 0-280 (0=good to 280=worst). | Baseline, Month 6, Month 12 and Month 18 | 
| Change From Baseline in Peak Jump Power Standard Deviation Score (PJP-SDS; One-leg-jump) at Months 6, 12 and 18 | PJP was defined as the peak of the calculated power (force multiplied by velocity). It was measured by Leonardo Jumping Platform during one leg jump. The participant performs 3 jumps and the highest peak (PJP) of the 3 recordings was selected for further calculations. The SDS indicates how similar the participant was to the reference population. | Baseline, Month 6 , Month 12 and Month 18 | 
| Change From Baseline in Peak Jump Force Standard Deviation Score (PJF-SDS; One-leg-jump) at Months 6, 12 and 18 | PJF was defined as the maximum of force of the ascending part of the jump which the participant performed as a counter-movement jump with freely moving arms and as high as possible with the head and chest. It was measured by Leonardo Jumping Platform during one leg jump. The SDS indicates how similar the participant was to the reference population. | Baseline, Month 6, Month 12 and Month 18 | 
| Change From Baseline in Maximum Jump Velocity (Vmax; One-leg-jump) at Months 6, 12 and 18 | Vmax was measured by Leonardo Jumping Platform during one leg jump. | Baseline, Month 6, Month 12 and Month 18 | 
| Change From Baseline in Five-chair Rising Test- Peak Jump Power (PJP) at Month 6 | The Chair rising test is a performance test (total power output) to measure neuromuscular function of complex movement in standing up. Test allows diagnostics of movement deficits using Leonardo jump plate. Five stand up test: five repetitions of rising from a chair on jump plate as quickly as possible with arms crossed over the chest (time to perform the tasks, maximal PJP, maximal velocity and maximal PJF). PJP is defined as the peak of the calculated power (force multiplied by velocity). | Baseline and Month 6 | 
| Change From Baseline in Five-chair Rising Test-Peak Jump Power (PJP) at Months 12 and 18 | The Chair rising test is a performance test (total power output) to measure neuromuscular function of complex movement in standing up. Test allows diagnostics of movement deficits using Leonardo jump plate. Five stand up test: five repetitions of rising from a chair on jump plate as quickly as possible with arms crossed over the chest (time to perform the tasks, maximal PJP, maximal velocity and maximal PJF). PJP is defined as the peak of the calculated power (force multiplied by velocity). | Baseline, Month 12 and Month 18 | 
| Change From Baseline in Five-chair Rising Test-Peak Jump Force (PJF) at Month 6 | The Chair rising test is a performance test (total power output) to measure neuromuscular function of complex movement in standing up. Test allows diagnostics of movement deficits using Leonardo jump plate. Five stand up test: five repetitions of rising from a chair on jump plate as quickly as possible with arms crossed over the chest (time to perform the tasks, maximal PJP, maximal velocity and maximal PJF). PJF is the maximum force of the ascending part of the jump which the participant performed as a counter-movement jump with freely moving arms as high as possible with the head and chest. | Baseline and Month 6 | 
| Change From Baseline in Five-chair Rising Test-Peak Jump Force (PJF) at Months 12 and 18 | The Chair rising test is a performance test (total power output) to measure neuromuscular function of complex movement in standing up. Test allows diagnostics of movement deficits using Leonardo jump plate. Five stand up test: five repetitions of rising from a chair on jump plate as quickly as possible with arms crossed over the chest (time to perform the tasks, maximal PJP, maximal velocity and maximal PJF). PJF is the maximum force of the ascending part of the jump which the participant performed as a counter-movement jump with freely moving arms as high as possible with the head and chest. | Baseline, Month 12 and Month 18 | 
| Change From Baseline in Five-chair Rising Test-Maximum Jump Velocity (Vmax) at Month 6 | The Chair rising test is a performance test (total power output) to measure neuromuscular function of complex movement in standing up. Test allows diagnostics of movement deficits using Leonardo jump plate. Five stand up test: five repetitions of rising from a chair on jump plate as quickly as possible with arms crossed over the chest (time to perform the tasks, maximal PJP, maximal velocity and maximal PJF). Vmax is defined as the maximum jump velocity. | Baseline and Month 6 | 
| Change From Baseline in Five-chair Rising Test-Maximum Jump Velocity (Vmax) at Months 12 and 18 | The Chair rising test is a performance test (total power output) to measure neuromuscular function of complex movement in standing up. Test allows diagnostics of movement deficits using Leonardo jump plate. Five stand up test: five repetitions of rising from a chair on jump plate as quickly as possible with arms crossed over the chest (time to perform the tasks, maximal PJP, maximal velocity and maximal PJF). Vmax is defined as the maximum jump velocity. | Baseline, Month 12 and Month 18 | 
| Change From Baseline in Five-chair Rising Test (Time to Perform the Tasks) at Month 6 | Chair rising test is performance test (total power output) to measure neuromuscular function of complex movement in standing up. Test allows diagnostics of movement deficits using Leonardo jump plate. Five stand up test: 5 repetitions of rising from a chair on jump plate as quickly as possible with arms crossed over chest (time to perform tasks, maximal PJP, maximal velocity and maximal PJF). Time to perform task includes: Average (avg) rise time which is avg time to perform 1 rise, avg time per test is the avg time to perform 1 test (rise and sitting down) and total time to perform 5 tests. | Baseline and Month 6 | 
| Change From Baseline in Five-chair Rising Test (Time to Perform the Tasks) at Months 12 and 18 | Chair rising test is performance test (total power output) to measure neuromuscular function of complex movement in standing up. Test allows diagnostics of movement deficits using Leonardo jump plate. Five stand up test: 5 repetitions of rising from a chair on jump plate as quickly as possible with arms crossed over chest (time to perform tasks, maximal PJP, maximal velocity and maximal PJF). Time to perform task includes: Average (avg) rise time which is avg time to perform 1 rise, avg time per test is the avg time to perform 1 test (rise and sitting down) and total time to perform 5 tests. | Baseline, Month 12 and Month 18 | 
| Change From Baseline in One-chair Rising Test-Peak Jump Power (PJP) at Months 6, 12 and 18 | The Chair rising test is a performance test (total power output) to measure neuromuscular function of complex movement to stand up. Test allows diagnostics of movement deficits using Leonardo jump plate. One stand up test: rising from a chair on the jump plate as quickly as possible with arms crossed over the chest (analysis of time, PJP, PJF and time of fastest rising). PJP is defined as the peak of the calculated power (force multiplied by velocity). | Baseline, Month 6 , Month 12 and Month 18 | 
| Change From Baseline in One-chair Rising Test-Peak Jump Force (PJF) at Months 6, 12 and 18 | The Chair rising test is a performance test (total power output) to measure neuromuscular function of complex movement to stand up. Test allows diagnostics of movement deficits using Leonardo jump plate. One stand up test: rising from a chair on the jump plate as quickly as possible with arms crossed over the chest (analysis of time, PJP, PJF and time of fastest rising). PJF is the maximum force of the ascending part of the jump which the participant performed as a counter-movement jump with freely moving arms as high as possible with the head and chest. | Baseline, Month 6 , Month 12 and Month 18 | 
| Change From Baseline in One-chair Rising Test (Time to Perform the Tasks) at Months 6, 12 and 18 | The Chair rising test is a performance test (total power output) to measure neuromuscular function of complex movement to stand up. Test allows diagnostics of movement deficits using Leonardo jump plate. One stand up test: rising from a chair on the jump plate as quickly as possible with arms crossed over the chest (analysis of time, PJP, PJF and time of fastest rising). | Baseline, Month 6 , Month 12 and Month 18 | 
| Change From Baseline in Maximal Isometric Grip Force-Standard Deviation Score (MIGF-SDS) at Month 6 | MIGF was assessed using standard adjustable Jamar dynamometer. MIGF (in Newtons) was calculated by multiplying the dynamometer reading (in kilograms) by a factor of 9.81. The SDS indicates how similar the participant was to the reference population. | Baseline and Month 6 | 
| Change From Baseline in Maximal Isometric Grip Force-Standard Deviation Score (MIGF-SDS) at Months 12 and 18 | MIGF was assessed using standard adjustable Jamar dynamometer. MIGF (in Newtons) was calculated by multiplying the dynamometer reading (in kilograms) by a factor of 9.81. The SDS indicates how similar the participant was to the reference population. | Baseline, Month 12 and Month 18 | 
| Mean Upper Arm Circumference |  | Baseline, Month 6, Month 12 and Month 18 | 
| Mean Thigh Circumference | Thigh measurements were taken as a mean of 3 consecutive measurements at upper thigh about an inch down from the crotch line. | Baseline, Month 6, Month 12 and Month 18 | 
| Mean Calf Circumference | Calf measurements were taken as a mean of 3 consecutive measurements at largest part of calf muscle, usually about 4 inches down from below the knee. | Baseline, Month 6, Month 12 and Month 18 | 
| Mean Height at Month 6 | Standing height was taken as a mean of 3 consecutive measurements using a wall mounted stadiometer. | Month 6 | 
| Mean Height at Months 12 and 18 | Standing height was taken as a mean of 3 consecutive measurements using a wall mounted stadiometer. | Month 12 and Month 18 | 
| Mean Growth Velocity at Month 6 | Growth velocity measures the annual rate of increase in height. | Month 6 | 
| Mean Growth Velocity at Months 12 and 18 | Growth velocity measures the annual rate of increase in height. | Month 12 and Month 18 | 
| Mean Height-Standard Deviation Score (SDS) at Month 6 | Standing height was taken as a mean of 3 consecutive measurements using a wall mounted stadiometer. The SDS indicates how similar the participant was to the reference population. | Month 6 | 
| Mean Height-Standard Deviation Score (SDS) at Months 12 and 18 | Standing height was taken as a mean of 3 consecutive measurements using a wall mounted stadiometer. The SDS indicates how similar the participant was to the reference population. | Month 12 and Month 18 | 
| Mean Growth Velocity-Standard Deviation Score (SDS) at Month 6 | Growth velocity measures the annual rate of increase in height. The SDS indicates how similar the participant is to the reference population. | Month 6 | 
| Mean Growth Velocity-Standard Deviation Score (SDS) at Months 12 and 18 |  | Month 12 and Month 18 | 
| Change From Baseline in Height-Standard Deviation Score (SDS) at Month 6 | Standing height was taken as a mean of 3 consecutive measurements using a wall mounted stadiometer. The SDS indicates how similar the participant was to the reference population. | Baseline and Month 6 | 
| Change From Baseline in Height-Standard Deviation Score (SDS) at Months 12 and 18 | Standing height was taken as a mean of 3 consecutive measurements using a wall mounted stadiometer. The SDS indicates how similar the participant was to the reference population. | Baseline, Month 12 and Month 18 | 
| Change From Baseline in Growth Velocity-Standard Deviation Score (SDS) at Month 6 | Growth velocity measures the annual rate of increase in height. The SDS indicates how similar the participant is to the reference population. | Baseline and Month 6 | 
| Change From Baseline in Growth Velocity-Standard Deviation Score (SDS) at Months 12 and 18 | Growth velocity measures the annual rate of increase in height. The SDS indicates how similar the participant is to the reference population. | Baseline, Month 12 and Month 18 | 
| Sitting Height-Standard Deviation Score (SDS) | Sitting height was measured using a stadiometer with a specialized chair. The SDS indicates how similar the participant was to the reference population. | Baseline, Month 6, Month 12 and Month 18 | 
| Body Mass Index-Standard Deviation Score (BMI-SDS) | The BMI was used to measure body fat based on height and weight. It was calculated by body weight (kg) divided by the height (m) squared. The SDS indicates how similar the participant was to the reference population. | Baseline, Month 6, Month 12 and Month 18 | 
| Change From Baseline in Head Circumference at Months 6, 12 and 18 | The maximum head circumference (usually horizontal just above the eyebrow ridges), was measured from just above the glabella area to the area near the top of the occipital bone (opisthocranion). | Baseline, Month 6, Month 12 and Month 18 | 
| Change From Baseline in Head Circumference-Standard Deviation Score (SDS) at Months 6, 12 and 18 | The maximum head circumference (usually horizontal just above the eyebrow ridges), was measured from just above the glabella area to the area near the top of the occipital bone (opisthocranion). The SDS indicates how similar the participant was to the reference population. | Baseline, Month 6, Month 12 and Month 18 | 
| Change From Baseline in Skinfold Thickness-Standard Deviation Score (SDS) at Month 6 | Triceps, supra-iliac and subscapular skinfolds were measured on the right side of the body to the nearest 0.1 mm with a Holtain skinfold caliper. The measurement was performed at the left side of the participant. Triceps skinfold thickness was measured halfway down the left upper arm, while the arm was hanging relaxed at the participant's side. Suprascapular skinfold was measured laterally just below the angle of the left scapula. Suprailiac skinfold was measured just above the iliac crest in the middle-axillary line. SDS indicates how similar the participant was to the reference population. | Baseline and Month 6 | 
| Change From Baseline in Skinfold Thickness-Standard Deviation Score (SDS) at Months 12 and 18 | Triceps, supra-iliac and subscapular skinfolds were measured on the right side of the body to the nearest 0.1 mm with a Holtain skinfold caliper. The measurement was performed at the left side of the participant. Triceps skinfold thickness was measured halfway down the left upper arm, while the arm was hanging relaxed at the participant's side. Suprascapular skinfold was measured laterally just below the angle of the left scapula. Suprailiac skinfold was measured just above the iliac crest in the middle-axillary line. SDS indicates how similar the participant was to the reference population. | Baseline, Month 12 and Month 18 |