Somatropin Therapy In Children Born Preterm But Appropriate For Gestational Age

Study Overview
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Brief Summary
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Safety and efficacy of Somatropin will be evaluated in short children born with a list weight below 1500 g and that did not catch up to normal height at the age of 4.

Official Title
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Somatropin Therapy For Short Children Born Of Premature Gestation, A Controlled, Prospective Randomized, Multicenter Study With An Untreated Control Group.

Conditions
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Growth Hormone Therapy, Infant, Very Low Birth Weight

Intervention / Treatment
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* Drug: Somatropin
* Other: Control Arm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the trial: Prepubertal caucasian boys between 4 and 10 years of age and girls between 4 and 9 years of age. Girls: Tanner stage 1 breast development Boys: Testis volume <= 3ml Tanner stage 1 pubic hair development (to exclude confounding effect of adrenarche on growth velocity, insulin sensitivity and body composition). (In case of any signs or symptoms of gonadal puberty a GnRH-Test must decide if the subject is still pubertal.) Height <=-2 SD for chronological age (Brandt/Reinken). Growth velocity SDS below 0 SD for chronological age (Brandt/Reinken based on 12+/- 3 months observation period before screening). Premature born defined as <=1500 g birth weight. GH sufficiency (GH level > 7 ug/l following any routine GH stimulation test). Written informed consent of both parents (legal guardians) and oral/written consent of subject due to age specific information. Exclusion Criteria: Subjects presenting with any of the following will not be included in the trial: Other endocrine diseases except for well substituted hypothyroidism. Severe chronic diseases or medication that might influence linear growth or insulin sensitivity (e.g. Glucocorticoids). Positive GAD and IA-2 antibodies (for type 1 diabetes). History of malignancy Children who meet all of the following 4 criteria: actual body height < -2,5 SDS (Brandt/Reinken) and parent adjusted target height < -1 SDS (Hermanussen and Cole, 2003) length and/or body weight retardations adjusted to gestational age at birth < -2,0 SDS (Lawrence et al., 1989, Voigt et al., 1996) children with chronological age > = 4 years and growth velocity < 0 SDS during the last year before inclusion. Chromosomal aberrations or syndromes. Suspected non-compliance or impossibility to follow the two or three year treatment schedule, respectively (e.g. social implications). Severe hemiparesis and severe CNS defects Retinopathia > third degree or laser treatment as newborns. Participation in any other clinical trial during active treatment phase. Other severe acute or chronic medical or psychiatric condition or clinically relevant laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgement of the investigator, would make the subject inappropriate for entry into this trial.

Ages Eligible for Study
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Minimum Age: 4 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 Arm<br> | Drug: Somatropin<br>* Controlled, prospective, randomized, multicenter study with an untreated (control) group during the first year. The children will be randomized into treatment or untreated (control) group. After one year the control group will undergo GH-therapy, too. Children randomized to the control group will get the possibility to continue treatment for a further year. The study will end after 2 and 3 years of observation, respectively.<br>Other: Control Arm<br>* Controlled, prospective, randomized, multicenter study with an untreated (control) group during the first year. The children will be randomized into treatment or untreated (control) group. After one year the control group will undergo GH-therapy, too. The study will end after 2 and 3 years of observation, respectively. Children randomized to the control group will get the possibility to continue treatment for a further year.<br>|
| No Intervention: Control Arm<br> | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Height Standard Deviation Score (SDS) After 1 Year | Change in Height SDS after 1 year where SDS=height minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference). | Baseline to 1 year (Month 12) | 
| Change in Growth Velocity Standard Deviation Score (SDS) After 1 Year | Change in Growth Velocity (GV) SDS after 1 year where SDS=GV minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference). | Baseline to 1 year (Month 12) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Growth Velocity After 1 Year and After 2 Years | Growth velocity measured as centimeters per year. | Baseline, Month 12, Month 24 | 
| Change From Baseline in Growth Velocity SDS After 2 Years | Change in Growth Velocity SDS after 2 years (24 months) where SDS = growth velocity minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference). | Baseline, Month 24 | 
| Change From Baseline in Height After 1 Year and After 2 Years |  | Baseline, Month 12, Month 24 | 
| Change From Baseline in Height SDS After 2 Years | Change in Height SDS after 2 years (24 months) where SDS = height minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference). | Baseline, Month 24 | 
| Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Triceps | Body composition measured as skinfold thickness at tricep in millimeters (mm); measured halfway down the left upper arm with arm hanging in relaxed position at participant's side. | Baseline, Month 12, Month 24 | 
| Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Subscapular | Body composition measured as subscapular skinfold thickness in millimeters (mm); measured laterally just below the angle of the left scapula. | Baseline, Month 12, Month 24 | 
| Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Suprailiac | Body composition measured as suprailiac skinfold thickness in millimeters (mm); measured just above the iliac crest in the middle-axillary line. | Baseline, Month 12, Month 24 | 
| Change From Baseline in Volumetric Cortical Bone Mineral Density (BMD) Using Peripheral Quantitative Computed Tomography (pQCT) After 1 Year and After 2 Years | Volumetric Cortical BMD measured as milligrams per cubic millimeter (mg/mm3). BMD (proximal radius) SDS (number of standard deviations a participant's BMD differs from the average BMD of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for participant's age and sex; negative values are below the average. | Baseline, Month 12, Month 24 | 
| Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Cortical Cross-sectional Area (CSA) | Bone structure Cortical CSA measured as millimeters squared (mm2). CSA (proximal radius) SDS (number of standard deviations a participant's CSA differs from the average CSA of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for participant's age and sex; negative values are below the average. | Baseline, Month 12, Month 24 | 
| Change From Baseline in Bone Structure Using Peripheral Quantitative Computed Tomography (pQCT) After 1 Year and 2 Years: Total Cross-sectional Area (CSA) | Bone structure Total CSA measured as millimeters squared (mm2). Total CSA (proximal radius) SDS (number of standard deviations a participant's CSA differs from the average CSA of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for participant's age and sex; negative values are below the average. | Baseline, Month 12, Month 24 | 
| Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Muscle Cross-sectional Area (CSA) | Bone structure Muscle CSA measured as millimeters squared (mm2). CSA (proximal radius) SDS (number of standard deviations a participant's CSA differs from the average CSA of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for participant's age and sex; negative values are below the average. | Baseline, Month 12, Month 24 | 
| Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Cortical Thickness (CT) | Cortical Thickness measured as millimeters (mm). CT (proximal radius) SDS (number of standard deviations a participant's CT differs from the average CT of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for participant's age and sex; negative values are below the average. | Baseline, Month 12, Month 24 | 
| Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Marrow Area (MA) | Marrow Area measured as millimeters squared (mm2). MA (proximal radius) SDS (number of standard deviations a participant's MA differs from the average MA of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for participant's age and sex; negative values are below the average. | Baseline, Month 12, Month 24 | 
| Change From Baseline in Bone Stability Using pQCT After 1 Year and After 2 Years: Strength-strain Index (SSI) | Bone stability expressed as polar SSI in cubic millimeters (mm3). SSI (proximal radius) SDS (number of standard deviations a participant's SSI differs from the average SSI of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for participant's age and sex; negative values are below the average. | Baseline, Month 12, Month 24 | 
| Change From Baseline in Muscle Strength: Hand Grip SDS After 1 Year and After 2 Years | Muscle strength determined by measuring grip force (kilograms) using hand grip dynamometer for participants ≥6 years of age. Baseline and post-baseline SDS values transformed to age and sex specific z-score. Change in hand grip calculated as SDS where SDS = hand grip minus mean (age- and sex-matched reference) divided by SD (age- and sex-matched reference). Positive values are above the average for participant's age and sex; negative values are below the average. | Baseline, Month 12, Month 24 | 
| Number of Participants With Change in Insulin Sensitivity: Somatropin | Insulin sensitivity calculated as incidence of pathological glucose intolerance assessed prior to randomization (Screening Day -3 to Baseline Day 0) and at final visit (final visit: Somatropin treatment group=Month 24). Pathological glucose intolerance (oral glucose tolerance test) measured as venous (blood or plasma) with range minimum 120 milligrams per deciliter (mg/dL) to >140 mg/dL; capillary (blood) with range minimum 120 mg/dL to >120 mg/dL; or method not known with range minimum 120 mg/dL to >120 mg/dL. | Baseline, Month 24 | 
| Number of Participants With Change in Insulin Sensitivity: Control Arm | Insulin sensitivity calculated as incidence of pathological glucose intolerance assessed prior to randomization (Screening Day -3 to Baseline Day 0) and at final visit (final visit: Control Arm=Month 36). Pathological glucose intolerance (oral glucose tolerance test) measured as venous (blood or plasma) with range minimum 120 milligrams per deciliter (mg/dL) to >140 mg/dL; capillary (blood) with range minimum 120 mg/dL to >120 mg/dL; or method not known with range minimum 120 mg/dL to >120 mg/dL. | Baseline, Month 36 | 
| Growth Curve Comparison Based on Height SDS | Growth curve comparison with height SDS in centimeters as the dependent variable; SDS = height minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference). | Month 12, Month 24 | 
| Growth Curve Comparison Based on Height SDS: Control Arm | Growth curve comparison with height SDS in centimeters as the dependent variable; SDS = height minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference). Control Arm final visit=Month 36. | Month 36 | 
| Growth Curve Comparison Based on Height | Growth curve comparison with height in centimeters as the dependent variable. | Month 12, Month 24 | 
| Growth Curve Comparison Based on Height: Control Arm | Growth curve comparison with height in centimeters as the dependent variable. | Month 36 |