Somatropin Treatment to Final Height in Turner Syndrome

Study Overview
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Brief Summary
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A randomized, controlled trial in girls with Turner syndrome at least 7 years old and younger than 13 at study entry, to determine the efficacy and safety of Humatrope (somatropin) treatment in promoting linear growth to final height.

Detailed Description
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A randomized, controlled trial of Humatrope (somatropin) treatment in girls with Turner syndrome at least 7 years old and younger than 13 at study entry. Core study objectives are to determine the efficacy of Humatrope in promoting linear growth to final height in girls with Turner syndrome, and to assess the safety of this treatment. Core study completion criteria (protocol final height) are that the patient has both a height velocity < 2 cm per year and a bone age of 14 years or greater. Addendum 1 provides the option of Humatrope treatment to patients who were randomized to the Control arm of the Core study and who discontinued from the study on or after December 19, 1997. Addendum 2 objectives are: 1) to collect true final height data; 2) to evaluate hearing, tympanic membrane function and other specific areas of interest with respect to the safety of growth hormone therapy in Turner syndrome; 3) to evaluate pancreatic beta cell function (glucose metabolism) in patients previously enrolled in the Core study. Addendum 3 objective is to determine the parental origin of the retained X chromosome of an appropriate subset of patients currently or previously enrolled in the Core study, and to determine whether this parental origin holds any predictive value for spontaneous growth or for response to growth hormone therapy.

Official Title
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Humatrope Treatment to Final Height in Turner's Syndrome

Conditions
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Turner Syndrome

Intervention / Treatment
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* Drug: Somatropin
* Drug: Ethinyl estradiol
* Drug: Medroxyprogesterone acetate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: girl with Turner syndrome prepubertal, Tanner stage I breast height velocity less than 6 cm/year and height less than or equal to the tenth percentile for sex and age in general population at least 6 months (preferably 12 months) of accurate height measurements available for calculation of pre-study height velocity if thyroxine deficient, to have received replacement therapy, and for six months prior to enrollment have had normal thyroid function tests Exclusion Criteria: prior treatment with growth hormone presence of a Y component in karyotype with gonads in situ diabetes mellitus

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 13 Years

Sexes Eligible for Study
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Female

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 |
| --- | --- |
| No Intervention: Control<br>Control arm; untreated with Humatrope. Ethinyl estradiol (escalating doses to 20 mcg daily) after age 13, and medroxyprogesterone acetate (10 mg tablets ten days monthly) after age 15. Subject continues until Core study completion criteria are met (protocol final height). | Drug: Ethinyl estradiol<br>* escalating doses 2.5-20.0 mcg tablets daily after age 13 and at least one year on study, continuing until Core study completion criteria are met.<br>Drug: Medroxyprogesterone acetate<br>* 10 mg tablets, ten days monthly, after age 15, continuing until Core study completion criteria are met.<br>|
| Experimental: Humatrope<br>Humatrope (0.05 mg/kg/dose) by subcutaneous injection 6 times per week. Ethinyl estradiol (escalating doses to 20 mcg daily) after age 13, and medroxyprogesterone acetate (10 mg tablets ten days monthly) after age 15. Subject continues until Core study completion criteria are met (protocol final height). | Drug: Somatropin<br>* 0.05 mg/kg/dose by subcutaneous injection 6 times per week, until Core study completion criteria are met (protocol final height).<br>* Other names: Growth hormone;Drug: Ethinyl estradiol<br>* escalating doses 2.5-20.0 mcg tablets daily after age 13 and at least one year on study, continuing until Core study completion criteria are met.<br>Drug: Medroxyprogesterone acetate<br>* 10 mg tablets, ten days monthly, after age 15, continuing until Core study completion criteria are met.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Height Standard Deviation Score (SDS) (National Center for Health Statistics [NCHS]), Change From Baseline to Last Measurement, As Randomized Population | Value analyzed is change from baseline to the most mature height measurement available. The terms Standard Deviation Score (SDS) and National Center for Health Statistics (NCHS) were defined in baseline characteristics. Greater height SDS values indicate greater height; positive values of change from baseline indicate increased height. | Baseline, and end of 4-year addendum | 
| Height Standard Deviation Score (SDS) (National Center for Health Statistics [NCHS]), Last Measurement After Attainment of Final Height | SDS report the number of standard deviations from the mean for age and sex for an individual measurement (normal range: -2 to +2 SDS). Height SDS [NCHS] uses the NCHS US general female population reference height values for age (Kuczmarski RJ et al. 2000) as the population mean and standard deviation. Calculation of Height SDS is provided in Height SDS [Lyon] description (Baseline). Since data reported by Kuczmarski RJ et al provides US general female population standards, values of Height SDS [NCHS] for untreated patients with Turner syndrome tend to be below zero e.g, -2.0 to -4.0 SDS. | at completion of core study, or at end of 4-year addendum | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Height Standard Deviation Score (SDS) (National Center for Health Statistics [NCHS]), Change From Baseline, As-Treated Population | Value analyzed is change from baseline to the most mature height measurement available. The terms Standard Deviation Score (SDS) and National Center for Health Statistics (NCHS) were defined in baseline characteristics. Greater height SDS values indicate greater height; positive values of change from baseline indicate increased height. | every 3 months during core study, and at start and end of 4-year addendum | 
| Height (Centimeters [cm]) | Most mature measurement available, at or after attainment of Final Height. | every 3 months during core study, and at start and end of 4-year addendum | 
| Number of Participants With an Abnormal Pure Tone Audiometry, Audiologist Assessment |  | at completion of core study or beginning of addendum | 
| Number of Participants With Abnormal Speech Audiometry, Audiologist Assessment |  | at completion of core study or beginning of addendum | 
| Number of Participants With Abnormal Impedance Tympanometry, Audiologist Assessment |  | at completion of core study or beginning of addendum | 
| Number of Participants With Hearing Loss, Audiologist Assessment | Sensorineural Hearing Loss (SNHL)=air conduction threshold >20 dB HL and air-bone gap ≤10 dB HL; Conductive Hearing Loss (CHL)= air conduction threshold >20 dB HL, bone conduction threshold ≤20 dB HL and air-bone gap >10 dB HL; Mixed Hearing Loss (MHL) = evidence of SNHL as defined above and CHL as defined above, in the same ear; Unspecified Hearing Loss (UHL)= abnormal hearing with none of SNHL, CHL, or MHL present. | at completion of core study or beginning of addendum | 
| Fasting Glucose, Change From Baseline | Change from core study baseline to addendum 2 maximum. | At core study baseline, and at end of 4-year addendum | 
| Maximum Fasting Glucose Value | Maximum measured value over addendum. In special cases an additional measurement is taken at 2 years. | At start and through end of 4-year addendum (up to an additional 2 years) | 
| Number of Participants With Any Abnormal Fasting Glucose Value | Indicates if patient had any measured value exceeding threshold of normality at any visit during addendum. Abnormal Fasting Glucose=Fasting Glucose >=100 milligrams per deciliter (mg/dL). | At start and through end of 4-year addendum | 
| Maximum Fasting Insulin Values | Maximum measured value over addendum. In special cases an additional measurement is taken at 2 years. | At start and through end of 4-year addendum (up to an additional 2 years) | 
| Number of Participants With Any Abnormal Fasting Insulin Value | Indicates if patient had any measured value exceeding threshold of normality at any visit during addendum. Abnormal Fasting Insulin = Fasting Insulin >=35 micro International Units per milliliter (uIU/mL). | At start and through end of 4-year addendum | 
| Minimum Fasting Glucose/Insulin Ratio Values | Minimum measured value over addendum. In special cases an additional measurement is taken at 2 years. | At start and through end of 4-year addendum (up to an additional 2 years) | 
| Number of Participants With Any Abnormal Fasting Glucose/Insulin Ratio Value | Indicates if patient had any measured value below threshold of normality at any visit during addendum. Abnormal Fasting Glucose/Insulin Ratio = Fasting Glucose/Insulin Ratio <=4.5 milligrams per 10^-4 Units (mg/10^-4U). | At start and through end of 4-year addendum | 
| Glycosylated Hemoglobin, Change From Baseline | Change from core study baseline to addendum 2 maximum. | At core study baseline, and at end of 4-year addendum | 
| Maximum Glycosylated Hemoglobin | Maximum measured value over addendum. In special cases an additional measurement is taken at 2 years. | At start and through end of 4-year addendum (up to an additional 2 years) | 
| Number of Participants With Any Abnormal Glycosylated Hemoglobin (HbA1c) Value | Indicates if patient had any measured value exceeding threshold of normality at any visit during addendum. Abnormal Glycosylated Hemoglobin = HbA1c ≥6.8% (up until 11-May-1998); and then HbA1c ≥6.1% (from 19-May-1998 onwards). | At start and through end of 4-year addendum | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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syndrome, Turner, Turner's, height, growth, growth hormone, somatropin, short stature, short, hearing, glucose metabolism