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Completed

NCT Number: NCT03325647

TESTO: Testosterone Effects on Short-Term Outcomes in Infants With XXY

This research study in infant males with Klinefelter syndrome (47,XXY) will learn more about the effect of testosterone on early health and development. The study is a total of three visits over 6 months with assessments of motor skills, body composition (muscle and fat), and hormone levels. This is a randomized, placebo-controlled study but all infants will receive testosterone treatment during the study period. The investigators will learn how testosterone treatment in infancy effects short term outcome measures on health and development.

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Key information

Conditions

Klinefelter Syndrome Chromosome Disorders Congenital Abnormalities Congenital, Hereditary, and Neonatal Diseases and Abnormalities Disorders of Sex Development Endocrine System Diseases Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Genetic Diseases, Inborn Gonadal Disorders Hypogonadism Male Urogenital Diseases Sex Chromosome Disorders Sex Chromosome Disorders of Sex Development Urogenital Abnormalities Urogenital Diseases

Age range

31 day–90 day

Sex eligibility

Male

Study type

Interventional

Phase

Phase 4

Primary location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

About this study

XXY (also known as Klinefelter syndrome) is the most common chromosomal abnormality in males, affecting 1/600 boys. The extra X chromosome leads to insufficient development of the testicles and subsequent testosterone deficiency. Males with XXY also have a high risk for developmental delays, learning disabilities, and cardiovascular disease. An essential question is how much of this risk is because of testosterone deficiency and could therefore be reduced by testosterone supplementation, particularly during critical periods of development.

In typical male development, there is a surge of testosterone in the first few months of life, commonly known as the "mini-puberty period of infancy." This testosterone surge may be critical for neurodevelopmental and cardiometabolic programming throughout life. Recently there has been increased off-label use of testosterone in infants with XXY, however neither the short or long term safety or efficacy have been evaluated. This study aims to quantify the short term effects of testosterone treatment in infants with XXY on neurodevelopment, growth, body composition, testicular function, and safety parameters. This is a double blind randomized placebo controlled trial of testosterone injections 25 mg every 4 weeks for 3 doses in boys with XXY enrolled between 1 and 3 months of age. Outcomes including body fat percentage, scaled motor developmental scores, growth velocity, testicular hormone concentrations, specific metabolites, and safety parameters will be assessed 12 weeks into the study. The groups will then cross-over (all subjects will receive testosterone during the study period) and the outcomes will be reassessed 24 weeks into the study. The secondary questions the investigators will answer with this cross-over is 1) whether benefits in the treatment group at 12 weeks are sustained at 24 weeks, and 2) whether the same benefits are seen if treated after the mini-puberty period.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Male infants with 47,XXY karyotype identified prenatally who are 4-12 weeks old (31 to 90 days of age). 47,XXY must be from a diagnostic test such as Chorionic Villus Sampling (CVS), amniocentesis, or post-natal blood/tissue. Non-invasive prenatal screening results alone will not be accepted.

Exclusion criteria

  • >20 percent mosaicism for a normal cell line
  • Gestational age at birth <36 weeks
  • Birth weight <2.5th percentile or >97.5 percentile for age (small or large for gestational age)
  • History of thrombosis in self or a first degree relative
  • Exposure to androgen therapy outside the study protocol
  • Use of medications known to affect body composition, such as growth hormone or insulin
  • Known allergy to the testosterone cypionate solution components including benzyl benzoate, benzyl alcohol, or cottonseed oil

Treatment and study plan

Testosterone Cypionate 200 Milligram/Milliliter Injectable Solution

Drug

Subjects in one arm will be randomized to receive testosterone cypionate 200 mg/ml intramuscularly every 4 weeks for a total of three doses after visit 1, and receive placebo injectable saline for the same duration starting at visit 2. Subjects in the other arm will be randomized to receive placebo injectable saline every 4 weeks for a total of 3 doses after visit 1, and testosterone cypionate 200 mg/ml intramuscularly for the same duration starting at visit 2.

Placebo injectable saline

Drug

Subjects in one arm will be randomized to receive testosterone cypionate 200 mg/ml intramuscularly every 4 weeks for a total of three doses after visit 1, and receive placebo injectable saline for the same duration starting at visit 2. Subjects in the other arm will be randomized to receive placebo injectable saline every 4 weeks for a total of 3 doses after visit 1, and testosterone cypionate 200 mg/ml intramuscularly for the same duration starting at visit 2.

Primary outcomes

  1. Change in Body Fat Percentage

    Time frame: Baseline and 3 months

    Body fat percentage will be measured using air displacement plethysmography (PEA POD) at the beginning and end of the study period

  2. Change in Composite Motor Score on Alberta Infant Motor Scale

    Time frame: 3 months

    Motor development will be assessed using the standardized Alberta Infant Motor Scale

  3. Change in C14:1 Long Chain Acylcarnitines (LCAC) through targeted metabolomics

    Time frame: Baseline and 3 months

    Plasma will be processed and stored until batch analysis using electrospray tandem mass spectroscopy per standard protocols to quantify acylcarnitines (short, medium, and long-chain) and Branched-Chain Amino Acids (BCAA--leucine/isoleucine and valine) at baseline and 12 weeks.

Secondary outcomes

  1. Change in height

    Time frame: 6 months

    Physical exam measurements will be measured by a physician at each visit

  2. Change in weight

    Time frame: 6 months

    Physical exam measurements will be measured by a physician at each visit

  3. Change in weight-for-length

    Time frame: 6 months

    Physical exam measurements will be measured by a physician at each visit

  4. Change in waist circumference

    Time frame: 6 months

    Physical exam measurements will be measured by a physician at each visit

  5. Change in serum leptin

    Time frame: 6 months

    Serum will be collected and measured at each study visit.

  6. Change in lipids

    Time frame: 6 months

    Serum will be collected and measured at each study visit.

  7. Change in insulin

    Time frame: 6 months

    Serum will be collected and measured at each study visit.

  8. Change in serum Luteinizing Hormone (LH)

    Time frame: 6 months

    Serum will be collected at each study visit. Ultrasensitive LH will be measured.

  9. Change in serum Follicle Stimulating Hormone (FSH)

    Time frame: 6 months

    Serum will be collected at each study visit. Follicle Stimulating Hormone (FSH) will be measured.

  10. Change in Inhibin B (INHB)

    Time frame: 6 months

    Inhibin B levels will be measured.

  11. Change in Anti-Mullerian Hormone (AMH)

    Time frame: 6 months

    Serum will be collected at each study visit. AMH levels will be measured.

  12. Change in Total Testosterone (Total T)

    Time frame: 6 months

    Serum will be collected at each study visit. Total testosterone by mass spectroscopy will be measured.

  13. Change in Gross Motor Scores on the Peabody Developmental Motor Scales 2

    Time frame: 6 months

    Gross motor development will be assessed using the standardized Peabody Developmental Motor Scales 2. The Peabody Developmental Motor Scales 2 measures gross motor development using the subscale of the Gross Motor Quotient, which measures the ability to utilize the large muscle systems. High scores on this composite are made by children with well-developed gross motor abilities.

  14. Change in Gross Motor Scores on the Alberta Infant Motor Scales

    Time frame: 6 months

    Gross motor development will be assessed using the standardized Alberta Infant Motor Scales (AIMS). The Alberta Infant Motor Scales is a performance-based and norm-referenced measure of infant gross motor maturation from birth to 18 months. The AIMS total score is calculated by summing the scores for the 58 items, with the score ranging between 0 and 58. Higher scores indicate more mature motor development. The infant's score can then be converted to a percentile and compared with age-equivalent peers from the normative sample.

  15. Change in Fine Motor Scores

    Time frame: 6 months

    Fine motor development will be assessed using the standardized Peabody Developmental Motor Scales 2. The Peabody Developmental Motor Scales 2 measures fine motor development using subscale of the Fine Motor Quotient, which measures a child's ability to use his or her hands and arms to grasp objects, stack blocks, draw figures, and manipulate objects. High scores on this composite are made by children with well-developed fine motor abilities.

  16. Change in Cognitive and Language Composite Scores on the Bayley III

    Time frame: 6 months

    Cognition and language will be assessed by a trained administrator of developmental tests using the standardized Bayley Scales of Infant and Toddler Development III: cognitive and language domains. In each subscale, age-standardized scores are calculated using test norms. Developmental delay is determined by calculating how many standard deviations a child scores from the mean in that subscale. Typically, the more standard deviations below the mean, the more severe the delay.

  17. Change in Adaptive Functioning

    Time frame: 6 months

    Adaptive Functioning will be assessed using the Adaptive Behavior Assessment System, 3rd edition, completed by the parent about their child.

  18. Change in Number and Type of Adverse Events

    Time frame: 6 months

    Adverse events will be measured by verbal questionnaire and parent-report, to determine safety.

  19. Change in Serum BCAA, other LCAC

    Time frame: 6 months

    BCAA and other LCAC will be measured through targeted metabolomics from serum collection at each visit.

  20. Change in Pathway analysis

    Time frame: 3 months

    Serum Pathways will be measured through untargeted/unbiased metabolomics

Sponsors and collaborators

Lead sponsor

University of Colorado, Denver

Other

Collaborators

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Registry information

Acronym: TESTO

Important dates

Study start
2017
Primary completion
2021
Study completion
2021
First posted
Oct 30, 2017
Registry last updated
May 6, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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