Klinefelter Syndrome and Testosterone Treatment in Puberty (TiPY)

Klinefelter Syndrome - the Effect of Testosterone Treatment in Puberty. a Randomized, Double-blind Placebo-controlled Intervention Study: 'The TiPY Study'

The goal of this randomized clinical trial is to study the effect of testosterone replacement therapy during puberty in boys with Klinefelter syndrome (KS, 47,XXY).

The main questions to answer are how treatment with testosterone will affect body fat mass, lipid and glucose metabolism, growth and body proportions, bone mineralization as well as effects on neurocognitive development and emotional and social difficulties.

Participants will be randomized to two years treatment with testosterone or placebo.

Study Overview

• Status: Recruiting
• Conditions: Klinefelter Syndrome
• Intervention / Treatment: Drug: Testosterone gel; Other: Placebo

Detailed Description

Klinefelter syndrome (KS, 47,XXY) is the most frequent sex chromosome disorder with a prevalence of 1:660 boys. Patients with KS are hypogonadal due to a progressive testicular destruction starting already in childhood. Consequently, the adult male with KS is characterized by small testes, signs of incomplete virilization (e.g. lack of voice deepening, sparse face and body hair, gynecomastia, low muscle mass, reduced penile length), hypergonadotropic hypogonadism, infertility and increased risk of metabolic syndrome, diabetes, cardiovascular disease, osteoporosis and psychosocial and neurodevelopmental challenges. Adults with KS have a poor health and a prevention of the major co-morbidities associated with KS and thereby an improvement in the general health would have an enormous impact on the life of a large cohort of males worldwide.

Sufficient testosterone is not only important in the adult but also during puberty and adolescence for a normal virilization and to improve body composition and body proportions, as well as to maximize peak bone mass acquisition. It has therefore been internationally accepted and makes biological sense to consider testosterone replacement therapy (TRT) during puberty in KS. However, there are no evidence based recommendations, and during recent years TRT in puberty has been questioned and is no longer recommended in some countries. There is a need on an international level for evaluating the effect of this treatment. We therefore aim at evaluating the effect of 2 years TRT during early puberty in boys with KS aged 10 to 14 years in this national, multi-center, randomized, double-blind, placebo-controlled intervention study. The primary endpoint is to evaluate the effect on body fat mass. The secondary endpoints are to evaluate effects on lipid and glucose metabolism, growth and body proportions, bone mineralization as well as effects on neurocognitive development and emotional and social difficulties.

• Study Type: Interventional
• Enrollment (Estimated): 32
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Lise Aksglaede, MD; Phone Number: +45 35455064; Email: lise.aksglaede@regionh.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Copenhagen University Hospital, Rigshospitalet
    • Contact: Lise Aksglaede, MD; Phone Number: +45353550564; Email: lise.aksglaede@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 47,XXY Klinefelter syndrome
• Age 10-14 years at inclusion
• Luteinizing Hormone > +2 standard deviations (SD) by ultrasensitive luteinizing hormone assay
• Free Testosterone<+2 standard deviations
• Signed consent from parents

Exclusion Criteria:

• Previous or ongoing T treatment except for TRT because of micropenis
• Contraindications to testosterone treatment known hypersensitivity to testosterone or to any other constituent of the gel known or suspected prostatic cancer or breast carcinoma
• Participation in any other clinical trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Testosterone; Testosterone gel applied to the skin	Drug: Testosterone gel; Two years treatment with testosterone; Other Names: Testosterone
Placebo Comparator: Placebo; Placebo gel applied to the skin	Other: Placebo; Two years treatment with placebo; Other Names: Testosterone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in body fat mass	Evaluation of body fat percentage by whole body dual energy x-ray absorptiometry (DEXA) scan	Baseline and 1 and two years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pubertal development and virilization	Tanner genital (G) staging from G1 to G5. G1 is the prepubertal stage and G5 is the fully develloped stage.	Every three months for two years
Pubertal development and virilization	Tanner pubic hair (PH) staging from PH1 to PH6. PH1 is the prepubertal stage and PH6 is the fully develloped stage.	Every three months for two years
Pubertal development and virilization	Measurement of voice frequency using the app "Voice Analyst" (Speechtools Ltd.).	Every three months for two years
Pubertal development and virilization	Evaluation of testicular volume by palpation with orchidometer	Every three months for two years
Pubertal development and virilization	Presence of gynecomastia (yes/no)	Every three months for two years
Pubertal development and viriliztion	Measurement of luteinizing hormone (LH) (IU/L) in serum	Every three months for two years
Pubertal development and viriliztion	Measurement of serum concentration of testosterone (nmol/L)	Every three months for two years
Pubertal development and viriliztion	Measurement of folliclestimulating hormone (FSH) (IU/L) in serum	Every three months for two years
Pubertal development and viriliztion	Measurement of serum concentration of estradiol (pmol/L)	Every three months for two years
Pubertal development and viriliztion	Measurement of serum concentration of inhibin B (ng/L)	Every three months for two years
Pubertal development and viriliztion	Measurement of serum concentration of anti mullerian hormone (AMH) (pmol/L)	Every three months for two years
Anthropometry	Measurement of height (cm)	Every three months for two years
Anthropometry	Measurement of weight (kg)	Every three months for two years
Anthropometry	Measurement of sitting height (cm)	Every three months for two years
Anthropometry	Measurement of head circumference (cm)	At base line, and at 1 and 2 years
Anthropometry	Measurement of arm span (cm)	At base line, and at 1 and 2 years
Bone health	Measurement of whole body bone mineral content (BMC) evaluated by whole body DXA scan	At baseline and at 1 and two years
Bone health	Evaluation of bone health index (BHI) from X-ray of left hand and evaluated using the software BoneXpert version 3 (Hørsholm, Denmark)	At base line, and at 1 and 2 years
Measurement of bone turnover markers	Measurement of 25-OH-vitamin D in blood sample	At base line, and at 1 and 2 years
Measurement of bone turnover markers	Measurement of calcium in blood sample	At base line, and at 1 and 2 years
Measurement of bone turnover markers	Measurement of phosphate in blood sample	At base line, and at 1 and 2 years
Measurement of bone turnover markers	Measurement of parathyroid hormone (PTH) in blood sample	At base line, and at 1 and 2 years
Measurement of bone turnover markers	Measurement of carboxy terminal telopeptide of collagen type I (CTX) in blood sample	At base line, and at 1 and 2 years
Measurement of bone turnover markers	Measurement of alkaline phosphatase in blood sample	At base line, and at 1 and 2 years
Measurement of bone turnover markers	Measurement of osteocalcin in blood sample	At base line, and at 1 and 2 years
Measurement of bone turnover markers	Measurement of procollagen type I N-terminal peptide (PINP) in blood sample	At base line, and at 1 and 2 years
Changes in growth	Evaluation of bone age by X-ray of left hand and evaluated using the software BoneXpert version 3 (Hørsholm, Denmark)	Base line and at 1 and 2 years
Measurement of serum concentrations of growth factors	Measurement of IGF1, IGF2, IGF1BP-1-6 and acid-labile subunit (ALS)) (microg/L)	At base line, and at 1 and 2 years
Muscle strength	Measurement of standing jump length (cm)	Every three months for two years
Muscle strength	Measurement of hand grip strength using a digital hand dynamometer (Baseline BIMS, digital hand dynamometer, functional model)	Every three months for two years
Changes i QTc	Evaluation of QT Interval with electrocardiogram (ECG)	Base line and at 1 and 2 years
Changes in markers of lipids	Measurement of cholesterol in blood sample	Base line and at 1 and 2 years
Changes in markers of metabolism	Measurement of adiponectin in blood sample	Base line and at 1 and 2 years
Changes in markers of metabolism	Measurement of leptin in blood sample	Base line and at 1 and 2 years
Changes in markers of metabolism	Measurement of glucose in blood sample	Base line and at 1 and 2 years
Changes in markers of metabolism	Measurement of insulin in blood sample	Base line and at 1 and 2 years
Changes in markers of metabolism	Measurement of HbA1C in blood sample	Base line and at 1 and 2 years
Changes in markers of inflammation	Measurement of CRP in blood sample	Base line and at 1 and 2 years
Neuropsychological evaluation	The Weschler Intelligence Scale for Children - Fifth Edition (WISC-V). The result is based on a combination of seperate index scores. A higher score generally indicates stronger cognitive abilities.	Baseline and after two years
Neuropsychological evaluation	The Test of Variables of Attention, version 9 (T.O.V.A) is a computerized, performance-based assessment tool used to measure attention and impulsivity. The result is based on a combination of scores.	Baseline and after two years
Neuropsychological evaluation	The Test of Memory and Learning, Second Edition (Tomal-2). The results are presented as standard scores, scaled scores, percentile ranks, and index scores. A higher score is a better outcome.	Baseline and after two years
Neuropsychological evaluation	The Judgement of Line Orientation Test. The result is based on a combination of scores. Higher scores indicate better visual-spatial judgment.	Baseline and after two years
Neuropsychological evaluation	The Mental Rotation Test	Baseline and after two years
Neuropsychological evaluation	The Beery-Buktenica Developmental Test of Visual-Motor Integration	Baseline and after two years
Neuropsychological evaluation	The Baseline Speed subtask of the Amsterdam Neuropsychological Tasks program (ANT)	Baseline and after two years
Neuropsychological evaluation	The Children's Communication Checklist (CCC-2). The result is evaluated based on 10 subscores. Higher scores indicate stronger communication skills.	Baseline and after two years
Neuropsychological evaluation	The Social Responsiveness Scale-2 (SRS-2) is a standardized questionnaire used to assess social behavior and autism-related traits. Higher scores indicate greater social difficulties, while lower scores suggest stronger social skills.	Baseline and after two years
Neuropsychological evaluation	The Delis-Kaplan Executive Function System (D-KEFS). Higher scores indicate better executive functioning, while lower scores may suggest difficulties with problem-solving, impulse control, or flexibility.	Baseline and after two years
Neuropsychological evaluation	The Behavior Rating Inventory of Executive Function, Second Edition rating scale , parent version (BRIEF-2) assesses executive functioning. The result is based on a combination of scores. Higher scores indicate greater executive function difficulties.	Baseline and after two years
Neuropsychological evaluation	Behavior Assessment System for Children, Third Edition (BASC-3), parent and self-report version. The result is based on a combination of scores. A higher score indicates more difficulties.	Baseline and after two years
Neuropsychological evaluation	Self-report version of The Multidimensional Anxiety Scale for Children - 2nd edition (MASC-2). The result is based on a combination of scores. Higher scores suggest greater levels of anxiety and more severe symptoms.	Baseline and after two years
Neuropsychological evaluation	The parent version of the ADHD-rating scale. The result is based on a combination of scores. Higher scores on the inattention and hyperactivity/impulsivity subscales suggest more significant ADHD symptoms.	Baseline and after two years
Neuropsychological evaluation	The Adaptive Behavior Assessment System, Third Edition (ABAS-III) is a comprehensive tool used to assess adaptive functioning. The result is based on a combination of scores. A higher score indicates better adaptive functioning.	Baseline and after two years
Neuropsychological evaluation	The Beck Youth Self-Concept Inventory is a tool designed to assess self-concept and self-esteem in children and adolescents. A high percentile rank (above 70) indicates a strong self-concept, while a low percentile rank (below 30) suggests low self-esteem or dissatisfaction.	Baseline and after two years
Neuropsychological evaluation	PedsQL Multidimentional Fatigue Scale, parent, and self-report versions is a tool designed to assess fatigue levels in children and adolescents. The result is based on a combination of scores. A higher score indicates less fatigue (better energy levels and functioning). A lower score indicates more fatigue, suggesting that fatigue is significantly affecting the child's daily activities.	Baseline and after two years
Cryopreservation of spermatozoa	If the patient is able and willing he will have the possibility to deliver a semen sample for cryopreservation of potential spermatozoa	After 2 years
Pubertal development	Measurement of the concentration of luteinizing hormone (LH) and follicle stimulating hormone (FSH) in the first, fasting, morning voiding. Measured in IU/L.	At base line, and at 1 and 2 years
Epigenetic	The effects on epigenetics will be evaluation by evaluating changes in DNA methylation patterns. This will be analyzed on DNA from white blood cells by applying Illumina methylation arrays.	At base line, and at 1 and 2 years
Genetic effects	DNA will be analyzed using a selected set of genetic polymorphisms in target genes with established or theoretic effects on hormone production and hormone receptor sensitivity. They will be analysed either by PCR genotyping or targeted sequencing (max. 200 selected genes). SNP arrays that exclusively target common variants, and not any rare variants, will be used to determine the influence of common genetic variation on the observed associations.	At base line, and at 1 and 2 years
Small non-coding RNA	RNA analysis of circulating, small, non-coding RNA will be performed as a biomarker for the circulating concentrations of reproductive hormones and for overweight.	At base line, and at 1 and 2 years

Collaborators and Investigators

• Sponsor: Lise Aksglæde
• Investigators: Principal Investigator: Lise Aksglaede, MD, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): August 15, 2024
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: February 21, 2024
• First Submitted That Met QC Criteria: March 5, 2024
• First Posted (Actual): March 6, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 14, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Body composition; Puberty; Klinefelter syndrome
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Pathologic Processes; Male Urogenital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genetic Diseases, Inborn; Disease; Gonadal Disorders; Congenital Abnormalities; Disorders of Sex Development; Urogenital Abnormalities; Sex Chromosome Disorders; Chromosome Disorders; Sex Chromosome Disorders of Sex Development; Hypogonadism; Syndrome; Klinefelter Syndrome; Antineoplastic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Anabolic Agents; Androgens; Methyltestosterone; Testosterone 17 beta-cypionate; Testosterone; Testosterone undecanoate; Testosterone enanthate
• Other Study ID Numbers: 2023-505854-16-00

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No