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Androgen Effect on Klinefelter Syndrome Motor Outcome

Androgen Effect on Motor/Cognitive Outcome in Klinefelter Syndrome

Status
Completed
Phases
Phase 2
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00348946
Enrollment
93
Registered
2006-07-06
Start date
2006-07-31
Completion date
2017-11-30
Last updated
2021-07-08

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Klinefelter Syndrome

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

DRUGandrogen oxandrolone

Oxandrolone ,06 \>mg/kg/day, orally, for 2 years

OTHERplacebo

an inactive substance

Sponsors

National Institute of Neurological Disorders and Stroke (NINDS)
CollaboratorNIH
Thomas Jefferson University
Lead SponsorOTHER

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender
MALE
Age
4 Years to 12 Years
Healthy volunteers
No

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

MeasureTime frameDescription
Motor Function/Strength2 years per subjectOutcome 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

MeasureTime frameDescription
Cognitive Function and Language2 years per subjectOutcome 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/Attention2 years per participantOutcome 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 Domain2 years per participantsOutcome 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

ArmCount
Oxandrolone
androgen oxandrolone: Oxandrolone ,0.6 \>mg/kg/day, orally, for 2 years.
46
Placebo
placebo: an inactive substance
47
Total93

Baseline characteristics

CharacteristicOxandrolonePlaceboTotal
Age, Categorical
<=18 years
46 Participants47 Participants93 Participants
Age, Categorical
>=65 years
0 Participants0 Participants0 Participants
Age, Categorical
Between 18 and 65 years
0 Participants0 Participants0 Participants
Age, Continuous6.9 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 pressure52.3 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 height0 Participants0 Participants0 Participants
Fasting blood glucose > 110 mg/dL1 Participants0 Participants1 Participants
Fasting blood glucose, mg/dL84.8 mg/dL
STANDARD_DEVIATION 8.4
85.2 mg/dL
STANDARD_DEVIATION 6.7
85.2 mg/dL
STANDARD_DEVIATION 7.6
HDL cholesterol46 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/dL31 Participants31 Participants62 Participants
LDL cholesterol106 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 Participants6 Participants12 Participants
Race/Ethnicity, Customized
Ethnicity
Asian/Pacific Islander
2 Participants3 Participants5 Participants
Race/Ethnicity, Customized
Ethnicity
Hispanic
5 Participants3 Participants8 Participants
Race/Ethnicity, Customized
Ethnicity
Other
0 Participants1 Participants1 Participants
Race/Ethnicity, Customized
Ethnicity
White
33 Participants34 Participants67 Participants
Sex: Female, Male
Female
0 Participants0 Participants0 Participants
Sex: Female, Male
Male
46 Participants47 Participants93 Participants
Systolic blood pressure87.2 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 height0 Participants0 Participants0 Participants
Tanner 1 pubic hair43 Participants38 Participants81 Participants
Total cholesterol167 mg/dL
STANDARD_DEVIATION 33
162 mg/dL
STANDARD_DEVIATION 27
164 mg/dL
STANDARD_DEVIATION 29
Triglycerides75.4 mg/dL
STANDARD_DEVIATION 58.2
67.7 mg/dL
STANDARD_DEVIATION 32.6
70.7 mg/dL
STANDARD_DEVIATION 46
Triglycerides > 100 mg/dL9 Participants6 Participants15 Participants
Waist circumference percentile >75 percentile17 Participants22 Participants39 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
deaths
Total, all-cause mortality
0 / 460 / 47
other
Total, other adverse events
36 / 4638 / 47
serious
Total, serious adverse events
0 / 460 / 47

Outcome results

Primary

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.

ArmMeasureGroupValue (MEAN)Dispersion
OxandroloneMotor Function/StrengthPANESS SS- dominant hand91 score on a scaleStandard Deviation 3
OxandroloneMotor Function/StrengthBOT Visual-motor control SS86 score on a scaleStandard Deviation 1
OxandroloneMotor Function/StrengthBOT Upper limb speed SS92 score on a scaleStandard Deviation 1
OxandroloneMotor Function/StrengthBOT Strength SS88 score on a scaleStandard Deviation 1
OxandroloneMotor Function/StrengthHand Dynamometer SS- dominant hand123 score on a scaleStandard Deviation 2
PlaceboMotor Function/StrengthHand Dynamometer SS- dominant hand118 score on a scaleStandard Deviation 2
PlaceboMotor Function/StrengthBOT Strength SS85 score on a scaleStandard Deviation 1
PlaceboMotor Function/StrengthBOT Visual-motor control SS81 score on a scaleStandard Deviation 1
PlaceboMotor Function/StrengthPANESS SS- dominant hand91 score on a scaleStandard Deviation 3
PlaceboMotor Function/StrengthBOT Upper limb speed SS89 score on a scaleStandard Deviation 2
p-value: 0.005ANCOVA
Comparison: BOT upper limb speedp-value: 0.17ANCOVA
Comparison: BOT strengthp-value: 0.17ANCOVA
Comparison: Hand dynamometerp-value: 0.06ANCOVA
Comparison: PANESSp-value: 0.87ANCOVA
Secondary

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

ArmMeasureGroupValue (MEAN)Dispersion
OxandroloneCognitive Function and LanguageDAS: General Concept Ability96 score on a scaleStandard Deviation 2
OxandroloneCognitive Function and LanguageDAS: Nonverbal Cluster102 score on a scaleStandard Deviation 2
OxandroloneCognitive Function and LanguageDAS: Spatial Cluster96 score on a scaleStandard Deviation 2
OxandroloneCognitive Function and LanguageDAS: Verbal Cluster92 score on a scaleStandard Deviation 2
PlaceboCognitive Function and LanguageDAS: Spatial Cluster94 score on a scaleStandard Deviation 2
PlaceboCognitive Function and LanguageDAS: General Concept Ability94 score on a scaleStandard Deviation 2
PlaceboCognitive Function and LanguageDAS: Verbal Cluster90 score on a scaleStandard Deviation 2
PlaceboCognitive Function and LanguageDAS: Nonverbal Cluster101 score on a scaleStandard Deviation 2
Comparison: DAS: General concept abilityp-value: 0.44ANCOVA
Comparison: DAS: Verbal Clusterp-value: 0.57ANCOVA
Comparison: DAS: Nonverbal Clusterp-value: 0.55ANCOVA
Comparison: DAS: Spatial Clusterp-value: 0.65ANCOVA
Secondary

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.

ArmMeasureGroupValue (MEAN)Dispersion
OxandrolonePsychosocial and Behavior DomainCBCL: behavior total t-score56 score on a scaleStandard Deviation 1
OxandrolonePsychosocial and Behavior DomainCBCL: internalizing total t-score54 score on a scaleStandard Deviation 1
OxandrolonePsychosocial and Behavior DomainCBCL: externalizing total t-score51 score on a scaleStandard Deviation 2
OxandrolonePsychosocial and Behavior DomainCDI: total t-score45 score on a scaleStandard Deviation 2
PlaceboPsychosocial and Behavior DomainCDI: total t-score47 score on a scaleStandard Deviation 2
PlaceboPsychosocial and Behavior DomainCBCL: behavior total t-score59 score on a scaleStandard Deviation 1
PlaceboPsychosocial and Behavior DomainCBCL: externalizing total t-score54 score on a scaleStandard Deviation 1
PlaceboPsychosocial and Behavior DomainCBCL: internalizing total t-score57 score on a scaleStandard Deviation 1
Comparison: CBCL: Behavior totalp-value: 0.16ANCOVA
Comparison: CBCL: Internalizing totalp-value: 0.1ANCOVA
Comparison: CBCL: externalizing totalp-value: 0.24ANCOVA
Comparison: CDI: Totalp-value: 0.5ANCOVA
Secondary

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

ArmMeasureValue (MEAN)Dispersion
OxandrolonePsychosocial and Behavior Domain105 units on a scaleStandard Deviation 3
PlaceboPsychosocial and Behavior Domain100 units on a scaleStandard Deviation 2
p-value: 0.15ANCOVA
Secondary

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 .

ArmMeasureGroupValue (MEAN)Dispersion
OxandroloneWorking Memory/AttentionDigit span backward96 score on a scaleStandard Deviation 2
OxandroloneWorking Memory/AttentionCPT: commissions101 score on a scaleStandard Deviation 2
OxandroloneWorking Memory/AttentionSemantic fluency99 score on a scaleStandard Deviation 4
OxandroloneWorking Memory/AttentionCPT: hit reaction time84 score on a scaleStandard Deviation 3
OxandroloneWorking Memory/AttentionCPT variability86 score on a scaleStandard Deviation 2
OxandroloneWorking Memory/AttentionPhonemic fluency95 score on a scaleStandard Deviation 3
OxandroloneWorking Memory/AttentionCPT: preservations76 score on a scaleStandard Deviation 5
OxandroloneWorking Memory/AttentionCPT: omissions88 score on a scaleStandard Deviation 4
PlaceboWorking Memory/AttentionCPT: preservations74 score on a scaleStandard Deviation 5
PlaceboWorking Memory/AttentionSemantic fluency94 score on a scaleStandard Deviation 3
PlaceboWorking Memory/AttentionCPT: hit reaction time80 score on a scaleStandard Deviation 3
PlaceboWorking Memory/AttentionDigit span backward92 score on a scaleStandard Deviation 2
PlaceboWorking Memory/AttentionCPT: omissions83 score on a scaleStandard Deviation 4
PlaceboWorking Memory/AttentionCPT: commissions100 score on a scaleStandard Deviation 2
PlaceboWorking Memory/AttentionCPT variability86 score on a scaleStandard Deviation 2
PlaceboWorking Memory/AttentionPhonemic fluency91 score on a scaleStandard Deviation 2
Comparison: Digit Span backwardp-value: 0.23ANCOVA
Comparison: Phonetic fluencyp-value: 0.36ANCOVA
Comparison: Semantic fluencyp-value: 0.37ANCOVA
Comparison: CPT: omissionsp-value: 0.41ANCOVA
Comparison: CPT: commissionsp-value: 0.73ANCOVA
Comparison: CPT: hit reaction timep-value: 0.4ANCOVA
Comparison: CPT: variabilityp-value: 0.95ANCOVA
Comparison: CPT: preservationsp-value: 0.78ANCOVA

Source: ClinicalTrials.gov · Data processed: Mar 10, 2026