Male InfertilityPhase 2/3NCT02349945
FSH Receptor Polymorphism p.N680S and Efficacy of FSH Therapy
A Phase 2/3 study testing follitropin alpha in people with Male Infertility, run by Azienda USL Modena at 6 sites in 2 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 20 to 50 years, men only
- Conditions the study is for
- Male Infertility
- What is being tested?
- follitropin alpha
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 88 participants
- Where
- 6 sitesin 2 countries
- Study dates
- Jan 2011to Dec 2015
- Phase
- Phase 2/3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 to 50 years
- Men only
- No healthy volunteers
- Adult
Who may be able to join
- 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.
Who cannot join
- 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
Trial locations and contacts
6 sites in 2 countries.
6 sites in 2 countries
Italy5 sites
Andrology Unit Department of Clinical Physiopathology
Florence, 50139
AziendaUSLModena
Modena, 41126
University of Padova Department of Histology, Microbiology and Medical Biotechnologies Clinical Pathology Section & Centre for Male Gamete Cryopreservation
Padova, 35121
Department of Medical Pathophysiology, University of Rome La Sapienza, Lab of Seminology & Immunology of Reproduction
Rome
Dipartimento di Ginecologia e Medicina della Riproduzione IRCCS Istituto Clinico Humanitas,
Rozzano, Milan, 20089
Germany1 site
Zentrums für Reproduktions-medizin und Andrologie Universitätsklinikum Halle (Saale), Martin-Luther-Universität Halle-Wittenberg
Halle, 06120
About this study
Official title: Significance of the FSH Receptor Polymorphism p.N680S for the Efficacy of FSH Therapy of Idiopathic Male Infertility: a Pharmacogenetic Approach
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.
Read more
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.
Read the 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
- Being tested
- follitropin alpha
- Medical subject headings
- Infertility, Male
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
follitropin alphaDrug
Also called Gonal f
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.
| Study group | Role | What they receive |
|---|---|---|
| Arm 1 | Experimental | FSHR A680G SNP homozygous for allele N treated with follitropin alpha Receives: Drug: follitropin alpha |
| Arm 2 | Experimental | FSHR A680G SNP homozygous for allele S treated with follitropin alpha Receives: Drug: follitropin alpha |
What is being measured
The primary outcome is the main question the study is designed to answer.
Sperm DFI
Measured: "after 12 weeks"
Secondary outcomes (2)
Sperm DFI (DNA Fragmentation Index)
Measured: "Baseline"
Sperm DFI
Measured: "after 24 weeks"
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Jan 2015 (estimated)
- Study startJan 2011
- Primary completionDec 2014
- Study completionDec 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Male InfertilityStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Care provider
- Enrolment
- 88 participants (actual)
Sponsor and investigators
- Lead sponsor
- Azienda USL Modena
- Sponsor type
- University, hospital or other
- Collaborators
- University of Roma La Sapienza, University of Halle Medical Faculty, Istituto Clinico Humanitas, University of Padova, University of Florence
- Responsible party
- Principal investigator, Manuela Simoni, Azienda USL Modena
- Investigators
- Manuela Simoni, MD, PhD, Principal investigator, Azienda USL Modena
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02349945
- Sponsor's protocol ID
- EudraCT 2010-020240-35
- Status last verified
- Jul 2016
- First submitted
- 16 Jan 2015
- Last updated
- 12 Jul 2016
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 12 Jul 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Significance of the FSH Receptor Polymorphism p.N680S for the Efficacy of FSH Therapy of Idiopathic Male Infertility: a Pharmacogenetic Approach
- ClinicalTrials.gov ID
- NCT02349945
- Acronym / sponsor ID
- EudraCT 2010-020240-35
- Conditions
- Male Infertility
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 88 participants (actual)
- Lead sponsor
- Azienda USL ModenaUniversity, hospital or other
- Collaborators
- University of Roma La Sapienza, University of Halle Medical Faculty, Istituto Clinico Humanitas, University of Padova, University of Florence
- Study start
- Jan 2011
- Primary completion
- Dec 2014 (actual)
- Study completion
- Dec 2015 (actual)
- First posted
- 29 Jan 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (care provider)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Arm 1 | Experimental | Drug: follitropin alphaFSHR A680G SNP homozygous for allele N treated with follitropin alpha |
| Arm 2 | Experimental | Drug: follitropin alphaFSHR A680G SNP homozygous for allele S treated with follitropin alpha |
Who may qualify
- Ages
- 20 to 50 years
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- 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)
Key exclusion criteria (6 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| follitropin alphaAlso: Gonal fAll 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. | Drug | Arm 1, Arm 2 |
Primary outcome
Sperm DFI
Time frame: "after 12 weeks"
2 secondary outcomes
Sperm DFI (DNA Fragmentation Index)
Time frame: "Baseline"
Sperm DFI
Time frame: "after 24 weeks"
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Jul 2016.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Manuela Simoni, MD, PhD principal investigator
Azienda USL Modena
6 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing follitropin alpha in people with Male Infertility, run by Azienda USL Modena at 6 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Jul 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in Italy, Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Sperm DFI (time frame: "after 12 weeks"). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Jul 2016.