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

Georgios Papadakis

Status and phase: Enrolling; Phase 3

Conditions: Klinefelter Syndrome

Treatments: Drug: Testosterone gel; Drug: Anastrozole; Drug: human chorionic gonadotropin; Drug: Semaglutide

Study type: Interventional

Funder types: Other

Identifiers

NCT05586802

PZ00P3_202151

Details and patient eligibility

About

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.

Enrollment: 150 estimated patients

Sex: Male

Ages: 16 to 65 years old

Volunteers: No 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 one semen sample

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 overweight (BMI 25-28 kg/m2) and 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)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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150 participants in 6 patient groups

Group 1 (Fertility) - positive micro-dissection testicular sperm extraction (mTESE) biopsy 1

No Intervention group

Description:

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)

Group 1 (Fertility) - negative mTESE biopsy 1, then randomized to Arm A

Experimental group

Description:

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

Treatment:

Drug: Anastrozole

Group 1 (Fertility) - negative mTESE biopsy 1, then randomized to Arm B

Experimental group

Description:

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

Treatment:

Drug: Anastrozole

Drug: human chorionic gonadotropin

Group 2 (Metabolic Risk) - randomized to Arm C

Active Comparator group

Description:

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

Treatment:

Drug: Testosterone gel

Group 2 (Metabolic Risk) - randomized to Arm D

Experimental group

Description:

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

Treatment:

Drug: Anastrozole

Group 2 (Metabolic Risk) - randomized to Arm E

Experimental group

Description:

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

Treatment:

Drug: Semaglutide