Trial document





This study has been imported from ClinicalTrials.gov without additional data checks.
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  DRKS00009485

Trial Description

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Title

Significance of the FSH Receptor Polymorphism p.N680S for the Efficacy of FSH Therapy of Idiopathic Male Infertility: a Pharmacogenetic Approach

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Trial Acronym

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URL of the Trial

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Brief Summary in Lay Language

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.

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Brief Summary in Scientific Language

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.

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Do you plan to share individual participant data with other researchers?

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Description IPD sharing plan:

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Organizational Data

  •   DRKS00009485
  •   2015/10/23
  •   2015/01/16
  •   yes
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Secondary IDs

  •   2010-020240-35 
  •   NCT02349945  (ClinicalTrials.gov)
  •   EudraCT 2010-020240-35  (Azienda USL Modena)
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Health Condition or Problem studied

  •   Male Infertility
  •   N46 -  Male infertility
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Interventions/Observational Groups

  •   Drug: follitropin alpha
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Characteristics

  •   Interventional
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  •   Non-randomized controlled trial
  •   Blinded
  •   caregiver
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  •   Treatment
  •   Parallel
  •   II-III
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Primary Outcome

- Sperm DFI; time frame: "after 12 weeks"

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Secondary Outcome

- Sperm DFI (DNA Fragmentation Index); time frame: "Baseline"
- Sperm DFI; time frame: "after 24 weeks"

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Countries of Recruitment

  •   Germany
  •   Italy
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Locations of Recruitment

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Recruitment

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  •   2011/01/31
  •   88
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Male
  •   20   Years
  •   50   Years
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Additional 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.

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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

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Addresses

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    • Azienda USL Modena
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    • University of Roma La Sapienza
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    • University of Halle Medical Faculty
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    • Istituto Clinico Humanitas
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    • University of Padova
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    • University of Florence
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    • Azienda USL Modena
    • Manuela Simoni, MD, PhD 
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    • Azienda USL Modena
    • Manuela Simoni, MD, PhD 
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Sources of Monetary or Material Support

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    • Bitte wenden Sie sich an den Sponsor / Please refer to primary sponsor
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Status

  •   Recruiting complete, follow-up continuing
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Trial Publications, Results and other Documents

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Additional Trial Attributes

  • Urological disease 
  • If other, please specify 
  • Study recommendations 
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  • German director of clinical investigation 
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  • Further contact 
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  • Function of contact 
  • Non-interventional study 
  • Stage 
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  • Onset of therapy 
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The parameters in ClinicalTrials.gov and DRKS are not identical. Therefore the data import from ClinicalTrials.gov required adjustments. For full details please see the DRKS FAQs .
  •   3
  •   2016/01/14
* This entry means the parameter is not applicable or has not been set.