Klinefelter Syndrome
Conditions
Keywords
Klinefelter syndrome, androgen, androgen oxandrolone
Brief summary
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
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.
Interventions
Oxandrolone ,06 \>mg/kg/day, orally, for 2 years
an inactive substance
Sponsors
Study design
Eligibility
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Motor Function/Strength | 2 years per subject | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cognitive Function and Language | 2 years per subject | 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. |
| Working Memory/Attention | 2 years per participant | 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. |
| Psychosocial and Behavior Domain | 2 years per participants | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Oxandrolone androgen oxandrolone: Oxandrolone ,0.6 \>mg/kg/day, orally, for 2 years. | 46 |
| Placebo placebo: an inactive substance | 47 |
| Total | 93 |
Baseline characteristics
| Characteristic | Oxandrolone | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 46 Participants | 47 Participants | 93 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 6.9 years STANDARD_DEVIATION 2.2 | 8.5 years STANDARD_DEVIATION 2.6 | 7.7 years STANDARD_DEVIATION 2.5 |
| BMI Standard Deviation Score (SDS) | 0.40 kg/m^2 STANDARD_DEVIATION 1.15 | 0.58 kg/m^2 STANDARD_DEVIATION 1.17 | 0.49 kg/m^2 STANDARD_DEVIATION 1.16 |
| Diastolic blood pressure | 52.3 mm Hg STANDARD_DEVIATION 6.9 | 56.9 mm Hg STANDARD_DEVIATION 7.3 | 55 mm Hg STANDARD_DEVIATION 8.5 |
| Diastolic blood pressure > 90th percentile for age and height | 0 Participants | 0 Participants | 0 Participants |
| Fasting blood glucose > 110 mg/dL | 1 Participants | 0 Participants | 1 Participants |
| Fasting blood glucose, mg/dL | 84.8 mg/dL STANDARD_DEVIATION 8.4 | 85.2 mg/dL STANDARD_DEVIATION 6.7 | 85.2 mg/dL STANDARD_DEVIATION 7.6 |
| HDL cholesterol | 46 mg/dL STANDARD_DEVIATION 10.4 | 44.8 mg/dL STANDARD_DEVIATION 10.1 | 45.7 mg/dL STANDARD_DEVIATION 10 |
| HDL cholesterol < 50 mg/dL | 31 Participants | 31 Participants | 62 Participants |
| LDL cholesterol | 106 mg/dL STANDARD_DEVIATION 31 | 104 mg/dL STANDARD_DEVIATION 24 | 104.4 mg/dL STANDARD_DEVIATION 25.4 |
| Race/Ethnicity, Customized Ethnicity African American | 6 Participants | 6 Participants | 12 Participants |
| Race/Ethnicity, Customized Ethnicity Asian/Pacific Islander | 2 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized Ethnicity Hispanic | 5 Participants | 3 Participants | 8 Participants |
| Race/Ethnicity, Customized Ethnicity Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Ethnicity White | 33 Participants | 34 Participants | 67 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 46 Participants | 47 Participants | 93 Participants |
| Systolic blood pressure | 87.2 mm Hg STANDARD_DEVIATION 9.7 | 90.9 mm Hg STANDARD_DEVIATION 9.4 | 88.7 mm Hg STANDARD_DEVIATION 9.6 |
| Systolic blood pressure > 90th percentile for age and height | 0 Participants | 0 Participants | 0 Participants |
| Tanner 1 pubic hair | 43 Participants | 38 Participants | 81 Participants |
| Total cholesterol | 167 mg/dL STANDARD_DEVIATION 33 | 162 mg/dL STANDARD_DEVIATION 27 | 164 mg/dL STANDARD_DEVIATION 29 |
| Triglycerides | 75.4 mg/dL STANDARD_DEVIATION 58.2 | 67.7 mg/dL STANDARD_DEVIATION 32.6 | 70.7 mg/dL STANDARD_DEVIATION 46 |
| Triglycerides > 100 mg/dL | 9 Participants | 6 Participants | 15 Participants |
| Waist circumference percentile >75 percentile | 17 Participants | 22 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 46 | 0 / 47 |
| other Total, other adverse events | 36 / 46 | 38 / 47 |
| serious Total, serious adverse events | 0 / 46 | 0 / 47 |
Outcome results
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.
Time frame: 2 years per subject
Population: Some participants were not able to complete all test and/or it was determined by the investigator that their results do reflect their ability and they were removed from the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oxandrolone | Motor Function/Strength | PANESS SS- dominant hand | 91 score on a scale | Standard Deviation 3 |
| Oxandrolone | Motor Function/Strength | BOT Visual-motor control SS | 86 score on a scale | Standard Deviation 1 |
| Oxandrolone | Motor Function/Strength | BOT Upper limb speed SS | 92 score on a scale | Standard Deviation 1 |
| Oxandrolone | Motor Function/Strength | BOT Strength SS | 88 score on a scale | Standard Deviation 1 |
| Oxandrolone | Motor Function/Strength | Hand Dynamometer SS- dominant hand | 123 score on a scale | Standard Deviation 2 |
| Placebo | Motor Function/Strength | Hand Dynamometer SS- dominant hand | 118 score on a scale | Standard Deviation 2 |
| Placebo | Motor Function/Strength | BOT Strength SS | 85 score on a scale | Standard Deviation 1 |
| Placebo | Motor Function/Strength | BOT Visual-motor control SS | 81 score on a scale | Standard Deviation 1 |
| Placebo | Motor Function/Strength | PANESS SS- dominant hand | 91 score on a scale | Standard Deviation 3 |
| Placebo | Motor Function/Strength | BOT Upper limb speed SS | 89 score on a scale | Standard Deviation 2 |
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.
Time frame: 2 years per subject
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oxandrolone | Cognitive Function and Language | DAS: General Concept Ability | 96 score on a scale | Standard Deviation 2 |
| Oxandrolone | Cognitive Function and Language | DAS: Nonverbal Cluster | 102 score on a scale | Standard Deviation 2 |
| Oxandrolone | Cognitive Function and Language | DAS: Spatial Cluster | 96 score on a scale | Standard Deviation 2 |
| Oxandrolone | Cognitive Function and Language | DAS: Verbal Cluster | 92 score on a scale | Standard Deviation 2 |
| Placebo | Cognitive Function and Language | DAS: Spatial Cluster | 94 score on a scale | Standard Deviation 2 |
| Placebo | Cognitive Function and Language | DAS: General Concept Ability | 94 score on a scale | Standard Deviation 2 |
| Placebo | Cognitive Function and Language | DAS: Verbal Cluster | 90 score on a scale | Standard Deviation 2 |
| Placebo | Cognitive Function and Language | DAS: Nonverbal Cluster | 101 score on a scale | Standard Deviation 2 |
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.
Time frame: 2 years per participants
Population: Some participants were not able to complete all assessments and/or it was determined by the investigator that their results do reflect their ability and they were removed from the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oxandrolone | Psychosocial and Behavior Domain | CBCL: behavior total t-score | 56 score on a scale | Standard Deviation 1 |
| Oxandrolone | Psychosocial and Behavior Domain | CBCL: internalizing total t-score | 54 score on a scale | Standard Deviation 1 |
| Oxandrolone | Psychosocial and Behavior Domain | CBCL: externalizing total t-score | 51 score on a scale | Standard Deviation 2 |
| Oxandrolone | Psychosocial and Behavior Domain | CDI: total t-score | 45 score on a scale | Standard Deviation 2 |
| Placebo | Psychosocial and Behavior Domain | CDI: total t-score | 47 score on a scale | Standard Deviation 2 |
| Placebo | Psychosocial and Behavior Domain | CBCL: behavior total t-score | 59 score on a scale | Standard Deviation 1 |
| Placebo | Psychosocial and Behavior Domain | CBCL: externalizing total t-score | 54 score on a scale | Standard Deviation 1 |
| Placebo | Psychosocial and Behavior Domain | CBCL: internalizing total t-score | 57 score on a scale | Standard Deviation 1 |
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.
Time frame: 2 years per subject
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oxandrolone | Psychosocial and Behavior Domain | 105 units on a scale | Standard Deviation 3 |
| Placebo | Psychosocial and Behavior Domain | 100 units on a scale | Standard Deviation 2 |
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.
Time frame: 2 years per participant
Population: Some participants were not able to complete all assessments and/or it was determined by the investigator that their results do reflect their ability and they were removed from the analysis .
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oxandrolone | Working Memory/Attention | Digit span backward | 96 score on a scale | Standard Deviation 2 |
| Oxandrolone | Working Memory/Attention | CPT: commissions | 101 score on a scale | Standard Deviation 2 |
| Oxandrolone | Working Memory/Attention | Semantic fluency | 99 score on a scale | Standard Deviation 4 |
| Oxandrolone | Working Memory/Attention | CPT: hit reaction time | 84 score on a scale | Standard Deviation 3 |
| Oxandrolone | Working Memory/Attention | CPT variability | 86 score on a scale | Standard Deviation 2 |
| Oxandrolone | Working Memory/Attention | Phonemic fluency | 95 score on a scale | Standard Deviation 3 |
| Oxandrolone | Working Memory/Attention | CPT: preservations | 76 score on a scale | Standard Deviation 5 |
| Oxandrolone | Working Memory/Attention | CPT: omissions | 88 score on a scale | Standard Deviation 4 |
| Placebo | Working Memory/Attention | CPT: preservations | 74 score on a scale | Standard Deviation 5 |
| Placebo | Working Memory/Attention | Semantic fluency | 94 score on a scale | Standard Deviation 3 |
| Placebo | Working Memory/Attention | CPT: hit reaction time | 80 score on a scale | Standard Deviation 3 |
| Placebo | Working Memory/Attention | Digit span backward | 92 score on a scale | Standard Deviation 2 |
| Placebo | Working Memory/Attention | CPT: omissions | 83 score on a scale | Standard Deviation 4 |
| Placebo | Working Memory/Attention | CPT: commissions | 100 score on a scale | Standard Deviation 2 |
| Placebo | Working Memory/Attention | CPT variability | 86 score on a scale | Standard Deviation 2 |
| Placebo | Working Memory/Attention | Phonemic fluency | 91 score on a scale | Standard Deviation 2 |