FSH Receptor Polymorphism p.N680S and Efficacy of FSH Therapy

NCT ID: NCT02349945

Last Updated: 2016-07-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 88 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-01-31
• Study Completion Date: 2015-12-31

Brief Summary

CONDITION: Idiopathic male infertility In men with idiopathic infertility, the sperm DNA fragmentation index (DFI) within 12 weeks of FSH therapy and 12 weeks follow-up improves depending on the FSHR genotype as assessed by the non-synonymous SNP rs6166 (wild type or p.N680S).

This is a phase II b, multicenter, prospective, open label, one arm, clinical trial stratified according to the patient's genotype.

INTERVENTION: FSH therapy (150 I.U. sc every other day for 12 weeks) in infertile men who are homozygous for the wild-type FSHR or the p.N680S allele of the FSHR. Duration of intervention per patient: 12 weeks

Primary efficacy endpoint: Sperm DFI. Number of patients with an improvement in DFI > 60% Key secondary endpoint(s): pregnancy, semen parameters, serum levels of inhibin B and AMH.

Detailed Description

Male factor infertility is responsible for about 50% of cases of involuntary couple infertility and remains idiopathic in about half of the cases. At present, there are no consistently effective treatments for male idiopathic infertility. Since follicle-stimulating hormone (FSH) is fundamental for spermatogenesis, recombinant hFSH is empirically used for male infertility treatment. The response to FSH, however, is highly variable and while sperm parameters improve in some patients, about 50% of the subjects do not clearly respond to FSH. Several studies were performed in the past and a recent Cochrane meta-analysis showed that FSH treatment of male idiopathic infertility overall significantly improves pregnancy rate. Nevertheless, no predictive marker of response to FSH, allowing a stratified therapeutic approach, was identified so far.

The sperm DNA fragmentation index (DFI) provides an estimation of genetic integrity of spermatozoa and was shown to improve significantly after FSH treatment. Therefore, DFI could be used as a pharmacodynamic marker of FSH in the male.

In women, the response to FSH varies depending on the FSH receptor (FSHR) genotype, as determined by the non-synonymous SNP rs6166, which exchanges the amino acid Asn to Ser in codon 680. This SNP is very common, with a minor allele frequency of 0.4. Women homozygous for Ser at amino acid position 680 of the FSHR are less sensitive to endogenous and exogenous FSH compared to those homozygous for Asn and require more FSH for multiple follicular growth and maturation in assisted reproduction. The investigators hypothesize that the variable response to FSH in unselected infertile men is due to a different individual sensitivity to FSH as determined by the common FSHR polymorphism rs6166. In particular the investigators will test the hypothesis that men homozygous for Asn at 680 (wild type) will respond better to exogenous FSH treatment in terms of sperm DFI compared to men homozygous for Ser, assessing sperm DFI as pharmacodynamic parameter of FSH.

Men with idiopathic infertility and normal serum FSH levels, candidate for treatment with FSH, will be recruited. Men with a sperm DFI > 15% will be included in the trial if carriers of the homozygous Asn/Asn or Ser/Ser at aminoacid position 680. The FSHR genotype will be assessed centrally and the physician will only receive the information whether the patient is eligible for entering the trial (i.e. homozygous) but both the physician and the patient will remain blind to the genotype. Human recombinant FSH (Gonal-f, Merck Serono) will be self-administered sc at the dose of 150 IU every other day for 12 weeks, followed by 12 weeks of observation (follow up). Changes in sperm DFI will be the primary end point and compared between the two arms. In addition, the effects on pregnancy rate and other clinical and hormonal parameters will be evaluated.

Should this pilot, proof-of-principle trial demonstrate that the response to FSH in male idiopathic infertility depends on FSHR genotype, larger interventional trials aiming at assessing the effects on pregnancy rate will be justified.

Conditions

Male Infertility

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Arm 1

FSHR A680G SNP homozygous for allele N treated with follitropin alpha

Group Type: EXPERIMENTAL

follitropin alpha

Intervention Type: DRUG

All subjects included in the study will receive recombinant FSH therapy (follitropin alpha: Gonal-f 150 I.U. s.c. every other day for 12 weeks). Follow up: 12 further weeks after end of treatment.

Previous studies included in the Cochrane meta-analysis used: hMG/hCG, 150 IU three times a week for 13 weeks; purified FSH, 150 IU/day for 12 weeks; rec hFSH, 150 IU/day for 12 weeks; rec hFSH, 100 IU on alternate days for 3 months. Therefore any dosage > 100 IU on alternate days is eligible. The duration of treatment is based on the duration of one spermatogenetic cycle.

Arm 2

FSHR A680G SNP homozygous for allele S treated with follitropin alpha

Group Type: EXPERIMENTAL

follitropin alpha

Intervention Type: DRUG

All subjects included in the study will receive recombinant FSH therapy (follitropin alpha: Gonal-f 150 I.U. s.c. every other day for 12 weeks). Follow up: 12 further weeks after end of treatment.

Previous studies included in the Cochrane meta-analysis used: hMG/hCG, 150 IU three times a week for 13 weeks; purified FSH, 150 IU/day for 12 weeks; rec hFSH, 150 IU/day for 12 weeks; rec hFSH, 100 IU on alternate days for 3 months. Therefore any dosage > 100 IU on alternate days is eligible. The duration of treatment is based on the duration of one spermatogenetic cycle.

Interventions

follitropin alpha

All subjects included in the study will receive recombinant FSH therapy (follitropin alpha: Gonal-f 150 I.U. s.c. every other day for 12 weeks). Follow up: 12 further weeks after end of treatment.

Previous studies included in the Cochrane meta-analysis used: hMG/hCG, 150 IU three times a week for 13 weeks; purified FSH, 150 IU/day for 12 weeks; rec hFSH, 150 IU/day for 12 weeks; rec hFSH, 100 IU on alternate days for 3 months. Therefore any dosage > 100 IU on alternate days is eligible. The duration of treatment is based on the duration of one spermatogenetic cycle.

Intervention Type: DRUG

Other Intervention Names

Gonal f

Eligibility Criteria

Inclusion Criteria

• age 20-50 years
• idiopathic male factor infertility for at least one year;
• homozygous FSHR allele at codon 680 (wild type: Asn/Asn or Ser/Ser);
• sperm DFI > 15%;
• normal serum FSH levels (< 8 IU/L)
• normal serum LH, testosterone, prolactin and estradiol levels
• normal ovulatory female partner These men might have impaired ejaculate parameters (decreased sperm count and/or decreased proportion of sperm with progressive motility and/or decreased proportion of sperm with normal morphology) of unknown aetiology.

Exclusion Criteria

• azoospermia
• all known aetiologies of male infertility (endocrine disorders, genetic disorders, chromosome abnormalities, congenital bilateral absence of the vas deferens, microdeletions within the AZF regions of the Y chromosome, varicocele, cryptorchidism, infections, immunological infertility, and obstructive infertility)
• all known aetiologies of female infertility in the partner (tubal blockage, endocrine abnormalities including anovulation and PCO, anatomical abnormalities, infections)
• heterozygous FSHR allele at codon 680
• drug abuse and major systemic diseases
• testicular insufficiency

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

University of Roma La Sapienza

OTHER

Sponsor Role: collaborator

University of Halle Medical Faculty

OTHER

Sponsor Role: collaborator

Istituto Clinico Humanitas

OTHER

Sponsor Role: collaborator

University of Padova

OTHER

Sponsor Role: collaborator

University of Florence

OTHER

Sponsor Role: collaborator

Azienda USL Modena

OTHER

Sponsor Role: lead

Responsible Party

Manuela Simoni

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Manuela Simoni, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Azienda USL Modena

Locations

Zentrums für Reproduktions-medizin und Andrologie Universitätsklinikum Halle (Saale), Martin-Luther-Universität Halle-Wittenberg

Halle, , Germany

Dipartimento di Ginecologia e Medicina della Riproduzione IRCCS Istituto Clinico Humanitas,

Rozzano, Milan, Italy

Andrology Unit Department of Clinical Physiopathology

Florence, , Italy

AziendaUSLModena

Modena, , Italy

University of Padova Department of Histology, Microbiology and Medical Biotechnologies Clinical Pathology Section & Centre for Male Gamete Cryopreservation

Padua, , Italy

Department of Medical Pathophysiology, University of Rome La Sapienza, Lab of Seminology & Immunology of Reproduction

Rome, , Italy

Countries

Germany; Italy

Other Identifiers

EudraCT 2010-020240-35

Identifier Type: -

Identifier Source: org_study_id