Study of Psychological and Motor Effects of Testosterone in Adolescents With XXY/Klinefelter Syndrome

Study Overview
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Brief Summary
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The purpose of this study is to determine if testosterone replacement therapy leads to changes in psychological factors and/or motor skills in adolescent males with 47,XXY (also called Klinefelter syndrome). This study will also evaluate whether certain genetic factors of the X chromosome affect the psychological or motor features of XXY/Klinefelter syndrome.

Detailed Description
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Klinefelter syndrome (47,XXY) is the most common chromosomal abnormality in humans and occurs in approximately 1 in 650 males. Testosterone deficiency develops during adolescence in the majority of individuals with XXY. However, there are no previous studies that evaluate the psychological and motor effects of testosterone replacement therapy in adolescents with XXY. The study researchers are interested in learning if testosterone therapy initiated in early puberty in XXY (KS) will lead to improvements in psychological and/or motor skills. They are also interested in learning if genetic variations of the androgen receptor gene or the parent-of-origin of the extra X chromosome influence the response to testosterone therapy. Specific psychological factors to be studied include verbal and nonverbal cognitive skills, attention, executive function (organization, problem-solving skills, inhibition), anxiety, language, self-esteem, and other behavioral factors. Motor skills to be studied include gross and fine motor skills, motor coordination, and motor planning. Participants in the study will be randomized to one of two treatment groups, receiving either testosterone gel or placebo, for 12 months. 60% of the study group will receive testosterone, and 40% will receive placebo. The research participants, parents/caregivers, and the members of the study team will be blinded to the treatment group, and will not know whether they are receiving testosterone gel or placebo treatments. The supervising endocrinologist for the study will not be blinded and will know which patients are in the testosterone and placebo groups. This will allow him to monitor results to determine if participants in the placebo group may develop a significant need for testosterone therapy during the study period. If this occurs, the patient will be switched to the testosterone group and will continue to be monitored in the study. All participants will be evaluated at the beginning of the study and at 1, 3, 6, and 12 months. Travel costs are included. Evaluations will include a combination of psychological and motor skills testing, questionnaires completed by the parent/caregiver and study participant, physical examinations, and blood draws for safety monitoring and genetic studies. Participation in the trial will last one year and includes 5 clinic visits to the eXtraordinarY Kids Clinic at Children's Hospital Colorado in Denver.

Official Title
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Psychological and Motor Effects of Testosterone Therapy in Adolescents With XXY/Klinefelter Syndrome

Conditions
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XXY Syndrome, Klinefelter Syndrome

Intervention / Treatment
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* Drug: Testosterone gel 1%
* Drug: Placebo gel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males with 47,XXY Participants must be in early puberty (Tanner stage II-III) Age 8 - 18 will be considered, but eligibility will be determined by review of laboratory results, bone age X-ray, and physical examination to determine stage of puberty All racial and ethnic groups Exclusion Criteria: Other genetic variations of Klinefelter syndrome (48,XXXY, 48,XXYY, 49,XXXXY). The investigator has other studies for these groups and we encourage interested individuals with these disorders to contact us about other available studies. 47,XXY plus another genetic disorder Non-English speaking individuals (because the psychological tests are administered in English) Participants with a medical history of blood clotting problems, blindness, deafness, or cancer

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 18 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 |
| --- | --- |
| Experimental: Testosterone gel 1%<br>Testosterone gel 1% applied to skin once per day for 1 year. Starting dose 1.25mL per day, titrated in 1.25mL increments for 1st 6 months of study after each study visit up to maximum of 5.0mL per day. Titration based on testosterone levels with target level in mid-range of normal for Tanner stage. | Drug: Testosterone gel 1%<br>* Testosterone gel will be administered on a daily basis. The gel will be dispensed in a syringe, and the specific amount of gel to be applied each day will be determined by the study endocrinologist after reviewing labs.<br>* Other names: Androgel 1%;|
| Placebo Comparator: Placebo gel<br>Placebo gel applied to skin once per day for 1 year. Starting dose 1.25mL per day. Dose randomly adjusted in 1.25mL increments for 1st 6 months of study after each study visit up to maximum of 5.0mL per day. | Drug: Placebo gel<br>* The placebo gel will be administered on a daily basis. The gel will be dispensed in a syringe, and the specific amount of gel to be applied each day will be determined by the study endocrinologist.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline on the Delis-Kaplan Executive Function System | A collection of subtests from the Delis-Kaplan Executive Function System will be used to evaluate different domains of executive functions including planning, problem solving, fluency, inhibition, and working memory. Possible scaled scores range from 0-20 (mean of 10), with higher scores indicating better performance. The value of the change in scaled score from baseline is reported. | Visit 1 (baseline) and Visit 5 (1 year) | 
| Change From Baseline on the Bruininks-Oseretsky Test of Motor Development - 2 | This test evaluates many aspects of motor functioning including fine and gross motor skills, visual motor integration, motor planning, and motor coordination. Possible scores range from 20-80, with higher scores indicating a better outcome. | Visit 1 (baseline) and Visit 5 (1 year) | 
| Change From Baseline on the Conners Parent Rating Scales: DSM Attention | This questionnaire allows parents to rate many aspects of behavior including attention, hyperactivity, anxiety, social skills, and emotional lability. The range of possible scores is 0 to 100 (Mean T-score 50), with higher scores indicating a worse outcome. | Visit 1 (baseline) and Visit 5 (1 year) | 
| Change From Baseline on the Conners Parent Rating Scales: DSM Hyperactivity | This questionnaire allows parents to rate many aspects of behavior including attention, hyperactivity, anxiety, social skills, and emotional lability. The range of possible scores is 0 to 100 (Mean T-score 50), with higher scores indicating a worse outcome. | Visit 1 (baseline) and Visit 5 (1 year) | 
| Change From Baseline on the Conners Parent Rating Scales: Anxiety | This questionnaire allows parents to rate many aspects of behavior including attention, hyperactivity, anxiety, social skills, and emotional lability. The range of possible scores is 0 to 100 (Mean T-score 50), with higher scores indicating a worse outcome. | Visit 1 (baseline) and Visit 5 (1 year) | 
| Change From Baseline on the Conners Parent Rating Scales: Social Skills | This questionnaire allows parents to rate many aspects of behavior including attention, hyperactivity, anxiety, social skills, and emotional lability. The range of possible scores is 0 to 100, with higher scores indicating a worse outcome. | Visit 1 (baseline) and Visit 5 (1 year) | 
| Change From Baseline on the Conners Parent Rating Scales: Emotional Lability | This questionnaire allows parents to rate many aspects of behavior including attention, hyperactivity, anxiety, social skills, and emotional lability. The range of possible scores is 0 to 100, with higher scores indicating a worse outcome. | Visit 1 (baseline) and Visit 5 (1 year) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline on the Vineland Adaptive Behavior Scales - 2nd Edition | The Vineland-2 is an interview evaluating adaptive skills in the areas of communication, daily living skills, social skills, and motor skills. Possible scores range from 20 to 160 (mean 100), with higher scores indicating a better outcome. | Visit 1 (baseline) and Visit 5 (1 year) | 
| Change From Baseline on the Wechsler Intelligence Scale for Children - Fourth Edition | This standardized assessment of cognitive functioning allows for evaluation of verbal and nonverbal cognitive skills, working memory, and processing speed. Possible full scale IQ scores range from 40-180 (mean 100), with higher scores indicating a better outcome. | Visit 1 (baseline) and Visit 5 (1 year) | 
| Change From Baseline on the Comprehensive Test of Phonological Processing | This standardized test evaluates reading and language skills. Possible scores range from 20-200 (Mean Standard Score 100), with higher scores indicating a better outcome. | Visit 1 (baseline) and Visit 5 (1 year) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Klinefelter syndrome, XXY syndrome, Sex Chromosome Abnormality, Testosterone replacement therapy