KLIN-HEALTH: Sex Steroids Balance for Metabolic and Reproductive Health in Klinefelter Syndrome

Sponsor

Georgios Papadakis (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05586802

Collaborator

(none)

120

Enrollment

Arms

37.9

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

The study seeks primarily to determine whether modulation of systemic and testicular sex steroids balance by aromatase inhibitors will positively affect the metabolic health and spermatogenesis of men with Klinefelter syndrome (KFS) as compared to the current state of the art for each issue.

Secondary objectives of this study are (i) to unravel the heterogeneity of the reproductive and metabolic phenotype of men with KFS by performing a multi-omic analysis in a large cohort at baseline; (ii) to evaluate the efficacy of semaglutide-induced weight loss to achieve metabolic and reproductive benefit in men with Klinefelter syndrome as compared to standard testosterone replacement; (ii) to assess whether addition of hCG to aromatase inhibitors further increases intratesticular testosterone and promotes spermatogenesis in men with KFS.

Condition or Disease	Intervention/Treatment	Phase
Klinefelter Syndrome	Drug: Anastrozole Drug: Semaglutide Drug: human chorionic gonadotropin Drug: Testosterone gel	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Two designs according to the presence of fertility desire (Design 1) or high metabolic risk (Design 2)Two designs according to the presence of fertility desire (Design 1) or high metabolic risk (Design 2)

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Dissecting the Importance of Sex Steroids Balance for Metabolic and Reproductive Health in Men With Klinefelter Syndrome: a Randomized Controlled Study

Anticipated Study Start Date :

Jan 1, 2023

Anticipated Primary Completion Date :

Mar 1, 2026

Anticipated Study Completion Date :

Mar 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Design 1 (Fertility) - positive micro-dissection testicular sperm extraction (mTESE) biopsy 1 Men with Klinefelter syndrome seeking fertility or interested in fertility preservation that undergo mTESE biopsy after wash-out of testosterone replacement therapy and have positive sperm retrieval (detectable spermatozoids)
Experimental: Design 1 (Fertility) - negative mTESE biopsy 1, then randomized to Group A Men with Klinefelter syndrome seeking fertility or interested in fertility preservation that undergo mTESE biopsy after wash-out of testosterone replacement therapy and have negative sperm retrieval (no detectable spermatozoids), subsequently randomized to receive an hormonal stimulation for 26 weeks	Drug: Anastrozole This will be an experimental treatment for 26 weeks in Design 1 Group A and Group B as well for Design 2 Group D Other Names: Anastrozole Teva
Experimental: Design 1 (Fertility) - negative mTESE biopsy 1, then randomized to Group B Men with Klinefelter syndrome seeking fertility or interested in fertility preservation that undergo mTESE biopsy after wash-out of testosterone replacement therapy and have negative sperm retrieval (no detectable spermatozoids), subsequently randomized to receive an hormonal stimulation for 26 weeks	Drug: Anastrozole This will be an experimental treatment for 26 weeks in Design 1 Group A and Group B as well for Design 2 Group D Other Names: Anastrozole Teva Drug: human chorionic gonadotropin This will be an experimental treatment for 26 weeks in addition to anastrozole in Design 1 -Group B Other Names: Choriomon
Active Comparator: Design 2 (Metabolic Risk) - randomized to Group C Men with Klinefelter syndrome not interested in fertility that present with high metabolic risk and consent to a wash-out of testosterone replacement therapy. They are subsequently randomized to receive an hormonal treatment to improve metabolic health. This arm will receive an active comparator by a testosterone gel	Drug: Testosterone gel This will be an active comparator for 26 weeks in Design 2 - Group C Other Names: Tostran
Experimental: Design 2 (Metabolic Risk) - randomized to Group D Men with Klinefelter syndrome not interested in fertility that present with high metabolic risk and consent to a wash-out of testosterone replacement therapy. They are subsequently randomized to receive an hormonal treatment to improve metabolic health. This arm will receive an an experimental treatment	Drug: Anastrozole This will be an experimental treatment for 26 weeks in Design 1 Group A and Group B as well for Design 2 Group D Other Names: Anastrozole Teva
Experimental: Design 2 (Metabolic Risk) - randomized to Group E Men with Klinefelter syndrome not interested in fertility that present with high metabolic risk and consent to a wash-out of testosterone replacement therapy. They are subsequently randomized to receive an hormonal treatment to improve metabolic health. This arm will receive an an experimental treatment	Drug: Semaglutide This will be an experimental treatment for 26 weeks in Design 2 Group E Other Names: Ozempic

Outcome Measures

Primary Outcome Measures

Design 1 : sperm retrieval rate at mTESE biopsy [mTESE biopsy 26 weeks after hormonal intervention]
Sperm retrieval rate at mTESE biopsy (Group A and B)
Design 2 : change in insulin resistance index (HOMA-IR) [From baseline to week 26 of intervention]
HOMA-IR calculated using fasting glucose and insulin levels

Eligibility Criteria

Criteria

Ages Eligible for Study:

16 Years to 65 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Inclusion Criteria:

-Diagnosis of Klinefelter syndrome (47,XXY or mosaicism)

Design 1:

Age range: 16-40 years old
Intention to become parent or interest in fertility preservation
Confirmed azoospermia (lack of spermatozoids) after centrifugation of 2 semen samples

Design 2:

Age range: 18-65 years old
No interest in fertility or fertility preservation
Hypogonadism at diagnosis or after wash-out of testosterone replacement therapy
High metabolic risk defined as severe overweight (BMI ≥ 28 kg/m2) or BMI 25-28 kg/m2 with insulin resistance (HOMA-IR > 2.6)

Exclusion Criteria:

Contraindications to testosterone-rising therapies (prostate or breast cancer, PSA > 4 µg/l, active liver disease, symptomatic heart disease)
Decreased life expectancy due to terminal disease
Known or suspected non-compliance, drug or alcohol abuse
Inability to follow the procedures of the study (language problems, severe psychological or mental disorders)