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Male InfertilityPhase 3FOLFIVNCT01407432

Impact of Folates in the Care of the Male Infertility

A Phase 3 study testing Folic acid in people with Male Infertility, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

Unexplained male infertility is increasing, and, nowadays, the investigators only can propose palliative treatment, as In VITRO Fertilization (IVF). The folate metabolism is a key for the maintenance of genome integrity. Read more about this study

Who is it for?
Ages 18 to 60 years
Conditions the study is for
Male Infertility
What is being tested?
Folic acid
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
162 participants
Where
1 siteFrance
Study dates
Nov 2011to Apr 2016
Phase
Phase 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 18 to 60 years
  • All sexes
  • No healthy volunteers
  • Adult

Who may be able to join

  • Couple whose man is from 18 to 60 years old
  • Couple whose man presents an infertility indicating a care in VITRO fertilization with or without intracytoplasmic sperm injection (IVF +/- ICSI)
  • Couple whose spouse is from 18 to 38 years old
  • Couple whose spouse do not present particular factors of infertility
  • Couple Taken care in IVF +/- ICSI
  • Couple with social insurance
  • 2 members of the couple having signed the consent

Who cannot join

  • Etiology of not genetic known male infertility : infertility of neoplastic origine, infertility of definitive obstructive origin
  • Presence of a factor of feminine infertility : A definitive infertility tubal, Turned out ovarian incapacity (FSH > 9 and/or CFA <= 8)
  • Male infertility requiring the appeal to some sperm testicular or in some frozen sperm- Men or women attend of HIV or hepatitis B or C
  • Epileptic men
  • Men under anti-folic treatment
  • Men presenting a big sensibility to the folic acid or to one of the constituents of the drug
  • Couple of which one of the partners refuses to participate in the study

Trial locations and contacts

1 site in 1 country.

France1 site

  • Service of gynaecology-obstetrics and medicine of the reproduction, Tenon Hospital - APHP

    Paris, 75020

Other trials in France

About this study

Unexplained male infertility is increasing, and, nowadays, the investigators only can propose palliative treatment, as In VITRO Fertilization (IVF). The folate metabolism is a key for the maintenance of genome integrity. A dysfunction in this pathway can be responsible of spermatogenesis defects, and further, of infertility. Few assays have shown that folate treatment can improve sperm parameters and fertility, till 30% in some of theses studies. The purpose of the investigators study is to demonstrate the impact of folates treatment on improvement of sperm parameters and on the rate of success of in VITRO fertilization procedures.

Read the detailed description

The folate impact in the treatment of male infertility will be reviewed by this large multicentric randomized controlled double-blind study comparing 2 parallel groups of 184 patients. In each group: folic acid 15mg/day versus placebo, orally for at least 3 months (duration of a cycle of spermatogenesis). This assay will evaluate the effectiveness of treatment with folic acid compared to its placebo in infertile men with the outcome of IVF+/-ICSI techniques (pregnancy rate). It will also assess the impact of folate therapy on sperm parameters, and further, the impact on abnormal sperm DNA methylation profiles.

Being tested
Folic acid, placebo of folic acid
Keywords
Male infertility, folic acid, in VITRO fertilization, sperm parameters, MTHFR genotype
Medical subject headings
Infertility, Male

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Folic acidDrug

    Taking of folic acid 15 mg per day by hanging oral route during 3 at 4 months

  • placebo of folic acidDrug

    Taking of placebo of folic acid by hanging oral route during 3 at 4 months

Study groups in NCT01407432
Study groupRoleWhat they receive
Folic acidExperimentaltablets of 5 mg of folic acid
Receives: Drug: Folic acid
PlaceboPlacebo comparatorTablets of placebo of folic acid
Receives: Drug: placebo of folic acid

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. The rates of pregnancy in IVF +/- ICSI and spontaneous pregnancy according to the arm of treatment

    Estimate the efficiency of the treatment by folic acid at infertile men on the improvement of improvement of the pregnancy rates in IVF +/- ICSI and spontaneous pregnancy before IVF +/- ICSI

    Measured: 3 months

Secondary outcomes (4)

  1. The rate of improvement of the sperm parameters with acid folic treatment

    Estimate the efficiency of the treatment by folic acid on the sperm parameters

    Measured: 3 months

  2. The rate of improvement of the nuclear quality of gametes with acid folic treatment

    Estimate the efficiency of the treatment by folic acid on the nuclear quality of gametes

    Measured: 3 months

  3. The rate of pregnancy of couple with infertile men treated by folic acid according to the methylene-tetrahydrofolate reductase (MTHFR) genotype

    Estimate the impact of the methylene-tetrahydrofolate reductase (MTHFR) genotype of the patients on the rates of pregnancy according to the arm of treatment

    Measured: 3 months

  4. The difference between the methylene-tetrahydrofolate reductase (MTHFR) genotype of the patients on sperm parameters according to the arm of treatment

    Estimate the impact of methylene-tetrahydrofolate reductase (MTHFR) genotype of the patients on sperm parameters according to the arm of treatment

    Measured: 3 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Aug 2011 (estimated)
  2. Study startNov 2011
  3. Primary completionApr 2016
  4. Study completionApr 2016

Resources

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 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
162 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01407432
Sponsor's protocol ID
P 100108
Acronym
FOLFIV
Status last verified
May 2016
First submitted
28 Jun 2011
Last updated
9 Jun 2016
Results posted
No
Data monitoring committee
No

Publications

  • Bentivoglio G, Melica F, Cristoforoni P. Folinic acid in the treatment of human male infertility. Fertil Steril. 1993 Oct;60(4):698-701. doi: 10.1016/s0015-0282(16)56225-6.

    PubMed 8405528

  • Bezold G, Lange M, Peter RU. Homozygous methylenetetrahydrofolate reductase C677T mutation and male infertility. N Engl J Med. 2001 Apr 12;344(15):1172-3. doi: 10.1056/NEJM200104123441517. No abstract available.

    PubMed 11302150

  • Blount BC, Mack MM, Wehr CM, MacGregor JT, Hiatt RA, Wang G, Wickramasinghe SN, Everson RB, Ames BN. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3290-5. doi: 10.1073/pnas.94.7.3290.

    PubMed 9096386

  • Boxmeer JC, Smit M, Weber RF, Lindemans J, Romijn JC, Eijkemans MJ, Macklon NS, Steegers-Theunissen RP. Seminal plasma cobalamin significantly correlates with sperm concentration in men undergoing IVF or ICSI procedures. J Androl. 2007 Jul-Aug;28(4):521-7. doi: 10.2164/jandrol.106.001982. Epub 2007 Feb 7.

    PubMed 17287458

  • Boxmeer JC, Macklon NS, Lindemans J, Beckers NG, Eijkemans MJ, Laven JS, Steegers EA, Steegers-Theunissen RP. IVF outcomes are associated with biomarkers of the homocysteine pathway in monofollicular fluid. Hum Reprod. 2009 May;24(5):1059-66. doi: 10.1093/humrep/dep009. Epub 2009 Feb 15.

    PubMed 19221098

  • Boxmeer JC, Smit M, Utomo E, Romijn JC, Eijkemans MJ, Lindemans J, Laven JS, Macklon NS, Steegers EA, Steegers-Theunissen RP. Low folate in seminal plasma is associated with increased sperm DNA damage. Fertil Steril. 2009 Aug;92(2):548-56. doi: 10.1016/j.fertnstert.2008.06.010. Epub 2008 Aug 22.

    PubMed 18722602

  • Chen J, Ma J, Stampfer MJ, Palomeque C, Selhub J, Hunter DJ. Linkage disequilibrium between the 677C>T and 1298A>C polymorphisms in human methylenetetrahydrofolate reductase gene and their contributions to risk of colorectal cancer. Pharmacogenetics. 2002 Jun;12(4):339-42. doi: 10.1097/00008571-200206000-00011.

    PubMed 12042673

  • Choi SW, Mason JB. Folate and colorectal carcinogenesis: is DNA repair the missing link? Am J Gastroenterol. 1998 Nov;93(11):2013-6. doi: 10.1111/j.1572-0241.1998.02013.x. No abstract available.

    PubMed 9820367

  • Doerksen T, Benoit G, Trasler JM. Deoxyribonucleic acid hypomethylation of male germ cells by mitotic and meiotic exposure to 5-azacytidine is associated with altered testicular histology. Endocrinology. 2000 Sep;141(9):3235-44. doi: 10.1210/endo.141.9.7661.

    PubMed 10965894

  • Ebisch IM, van Heerde WL, Thomas CM, van der Put N, Wong WY, Steegers-Theunissen RP. C677T methylenetetrahydrofolate reductase polymorphism interferes with the effects of folic acid and zinc sulfate on sperm concentration. Fertil Steril. 2003 Nov;80(5):1190-4. doi: 10.1016/s0015-0282(03)02157-5.

    PubMed 14607573

  • Eskenazi B, Kidd SA, Marks AR, Sloter E, Block G, Wyrobek AJ. Antioxidant intake is associated with semen quality in healthy men. Hum Reprod. 2005 Apr;20(4):1006-12. doi: 10.1093/humrep/deh725. Epub 2005 Jan 21.

    PubMed 15665024

  • Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, Rozen R. Human methylenetetrahydrofolate reductase: isolation of cDNA mapping and mutation identification. Nat Genet. 1994 Aug;7(4):551. No abstract available.

    PubMed 7951330

  • Heijmans BT, Gussekloo J, Kluft C, Droog S, Lagaay AM, Knook DL, Westendorp RG, Slagboom EP. Mortality risk in men is associated with a common mutation in the methylene-tetrahydrofolate reductase gene (MTHFR). Eur J Hum Genet. 1999 Feb-Mar;7(2):197-204. doi: 10.1038/sj.ejhg.5200283.

    PubMed 10196703

  • Kelly TL, Li E, Trasler JM. 5-aza-2'-deoxycytidine induces alterations in murine spermatogenesis and pregnancy outcome. J Androl. 2003 Nov-Dec;24(6):822-30. doi: 10.1002/j.1939-4640.2003.tb03133.x.

    PubMed 14581508

  • Kelly TL, Neaga OR, Schwahn BC, Rozen R, Trasler JM. Infertility in 5,10-methylenetetrahydrofolate reductase (MTHFR)-deficient male mice is partially alleviated by lifetime dietary betaine supplementation. Biol Reprod. 2005 Mar;72(3):667-77. doi: 10.1095/biolreprod.104.035238. Epub 2004 Nov 17.

    PubMed 15548731

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Folic acid in people with Male Infertility, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.

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 7 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 9 Jun 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in France. 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. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

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?

The rates of pregnancy in IVF +/- ICSI and spontaneous pregnancy according to the arm of treatment (time frame: 3 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01407432, which also lists 30 linked publications.

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 9 Jun 2016.

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