Androgen Effect on Klinefelter Syndrome Motor Outcome

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effects of low-dose androgen on the motor and cognitive development of boys with Klinefelter syndrome.

Detailed Description
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Klinefelter syndrome (KS), a genetic disorder that affects males only, is characterized by having an extra X chromosome. The phenotype - or physical and learning features - includes testicular failure, tall stature, and specific cognitive and behavioral attributes such as diminished motor function, language-based learning difficulties, poor self-image, and shyness. The KS phenotype may be the result of androgen deficiency in utero, infancy, and childhood. For individuals with KS, androgen replacement is standard treatment in adolescence and adulthood but has not been used earlier in childhood or included in the standard medical care of KS children ages 4 to 12. The purpose of this study is to examine the effects of androgen on learning and development in boys with KS. Researchers also want to determine if low-dose androgen replacement at an early age will improve some of the learning difficulties associated with the disorder. The overall goal of this study is to address questions regarding the relationship of early androgen deficiency to learning and motor function. Participants in the study will be randomized to one of two treatment groups, receiving either oxandrolone (low-dose androgen) or placebo, for two years. All participants will be evaluated for safety at the beginning of the study and at 3, 6, 12, 18, and 24 months. Also at the beginning of the study and every 3 to 6 months thereafter (for a total of 6 visits), the researchers will perform a careful history and physical examination and a bone age X-ray, and obtain a blood sample. Participation in the trial will last two years and includes 6 clinic visits.

Official Title
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Androgen Effect on Motor/Cognitive Outcome in Klinefelter Syndrome

Conditions
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Klinefelter Syndrome

Intervention / Treatment
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* Drug: androgen oxandrolone
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Karyotype diagnosis of Klinefelter syndrome Chronological age of 4-12 years No treatment with androgen in the past year Exclusion Criteria: Major liver, kidney or other systemic disease Variant karyotypes including 47,XYY males Evidence of spontaneous onset of puberty, defined as testicular size > 4ml

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 12 Years

Sexes Eligible for Study
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Male

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Oxandrolone<br>Androgen oxandrolone: Oxandrolone, 0.6 > mg/kg/day, orally, for 2 years. | Drug: androgen oxandrolone<br>* Oxandrolone ,06 >mg/kg/day, orally, for 2 years<br>|
| Placebo Comparator: Placebo<br>An inactive substance. | Other: placebo<br>* an inactive substance<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Motor Function/Strength | Outcome measures were tested using the following assessments: Bruininks-Osertesky Test of Motor Proficiency (BOT) subscales of (1) Visual Motor Control, (2) Upper limb Speed, and (3) Strength, Physical and Neurological Evaluation for Soft Signs (PANESS), and Hand Strength Dynamometer. BOT assess the child's motor development and includes standard scores (mean=100, SD=15) and subtest scores and is normed for sex and age (4-14.5 years). PANESS assesses the time required to press thumb to 4 fingers 20 times for the dominant and nondominant hands and includes standard scores (mean=100, SD=15) with age-specific norms (4-18 years). Hand strength dynamometer assess hand strength in the dominant and nondominant hands and includes standard scores (mean=100, SD=15). Data is expressed as standard scores with mean of 100 and SD of 15. The minimum standard score is 50; the maximum standard score is 145. Higher scorers imply better function. | 2 years per subject | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive Function and Language | Outcome measures were tested using the Differential Ability Scales - 2nd edition (DAS-II). DAS-II provides an age- and sex-standardized assessment of intellectual functioning (General Concept Ability subscale similar to IQ) in children ages 2-17 years of age (mean=100, SD=15). The Verbal Cluster measures the child's ability to define words and perform verbal reasoning tasks. The Nonverbal Cluster measures the child's inductive and sequential reasoning abilities. The Spatial Cluster measures visuospatial construction ability, spatial memory, and spatial reasoning. Data is expressed as standard scores with mean of 100 and SD of 15. The minimum standard score is 50; the maximum standard score is 145. Higher scores imply better function. | 2 years per subject | 
| Working Memory/Attention | Outcome measures were tested using the following cognitive assessments: Digit Span Backward, A Neuropsychological Assessment (NEPSY) subscales of (1) Phonemic Fluency and (2) Semantic Fluency, and Connors' Continuous Performance Test (CPT-II) subscales (1) Omissions, (2) Commissions, (3) Hit Reaction, (4) Variability, and (5) Preservations. Digit Span Backward tests working memory and is normed for children ages 5-16 years. Phonemic Fluency measures the number of words that the child can name beginning with the letters F and S (ages 6-12). Semantic Fluency measures the number of words the child can name in the categories food and drink (ages 4-12). CPT-II measures the ability to maintain attention over an extended period of time. All scores are reported as standard scores with a mean of 100 and SD of 15. The minimum standard score is 50; the maximum standard score is 145. Higher scores imply better function. | 2 years per participant | 
| Psychosocial and Behavior Domain | Outcome measures were tested using the following social assessments: The Child Behavior Checklist (CBCL) and The Children's Depression Inventory (CDI). The CBCL is standardized measure of behavior problems and social competency normed for children ages 4-16. Higher scores indicate more problems, with the cutoff for the clinical range at a t score greater than or equal to 67. The CDI assess cognitive, affective and behavioral signs of depression in children ages 6-17. The CDI total score reflects the presence of overall depressive symptoms. All scores are expressed as t-scores with a mean of 50 and SD of 10. Lower scores imply better function and higher scores indicate more problem behaviors. | 2 years per participants | 
| Psychosocial and Behavior Domain | Outcome measures were tested using The Piers-Harris Self Concept Scale. Scoring provides a total standard score and scores on six subscales: physical appearance and attributes, freedom from anxiety, intellectual and school status, behavioral adjustment, happiness and satisfaction, and popularity. Subscales are summed and standardized to provide the total standard score with a mean of 100 and SD of 15. The minimum standard score is 50; the maximum standard score is 145. Higher scores imply better function. | 2 years per subject | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Klinefelter syndrome, androgen, androgen oxandrolone