search
Back to results

Impact of Folates in the Care of the Male Infertility (FOLFIV)

Primary Purpose

Male Infertility

Status
Completed
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Folic acid
placebo of folic acid
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Male Infertility focused on measuring Male infertility, folic acid, in VITRO fertilization, sperm parameters, MTHFR genotype

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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

Sites / Locations

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

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Folic acid

Placebo

Arm Description

tablets of 5 mg of folic acid

Tablets of placebo of folic acid

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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
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
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
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

Full Information

First Posted
June 28, 2011
Last Updated
June 8, 2016
Sponsor
Assistance Publique - Hôpitaux de Paris
search

1. Study Identification

Unique Protocol Identification Number
NCT01407432
Brief Title
Impact of Folates in the Care of the Male Infertility
Acronym
FOLFIV
Official Title
Impact of Folates in the Care of the Male Infertility
Study Type
Interventional

2. Study Status

Record Verification Date
May 2016
Overall Recruitment Status
Completed
Study Start Date
November 2011 (undefined)
Primary Completion Date
April 2016 (Actual)
Study Completion Date
April 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief 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. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Male Infertility
Keywords
Male infertility, folic acid, in VITRO fertilization, sperm parameters, MTHFR genotype

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
162 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Folic acid
Arm Type
Experimental
Arm Description
tablets of 5 mg of folic acid
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Tablets of placebo of folic acid
Intervention Type
Drug
Intervention Name(s)
Folic acid
Intervention Description
Taking of folic acid 15 mg per day by hanging oral route during 3 at 4 months
Intervention Type
Drug
Intervention Name(s)
placebo of folic acid
Intervention Description
Taking of placebo of folic acid by hanging oral route during 3 at 4 months
Primary Outcome Measure Information:
Title
The rates of pregnancy in IVF +/- ICSI and spontaneous pregnancy according to the arm of treatment
Description
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
Time Frame
3 months
Secondary Outcome Measure Information:
Title
The rate of improvement of the sperm parameters with acid folic treatment
Description
Estimate the efficiency of the treatment by folic acid on the sperm parameters
Time Frame
3 months
Title
The rate of improvement of the nuclear quality of gametes with acid folic treatment
Description
Estimate the efficiency of the treatment by folic acid on the nuclear quality of gametes
Time Frame
3 months
Title
The rate of pregnancy of couple with infertile men treated by folic acid according to the methylene-tetrahydrofolate reductase (MTHFR) genotype
Description
Estimate the impact of the methylene-tetrahydrofolate reductase (MTHFR) genotype of the patients on the rates of pregnancy according to the arm of treatment
Time Frame
3 months
Title
The difference between the methylene-tetrahydrofolate reductase (MTHFR) genotype of the patients on sperm parameters according to the arm of treatment
Description
Estimate the impact of methylene-tetrahydrofolate reductase (MTHFR) genotype of the patients on sperm parameters according to the arm of treatment
Time Frame
3 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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 Exclusion Criteria: 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Emmanuelle MATHIEU - D'ARGENT, MD
Organizational Affiliation
TENON Hospital - APHP
Official's Role
Principal Investigator
Facility Information:
Facility Name
Service of gynaecology-obstetrics and medicine of the reproduction, Tenon Hospital - APHP
City
Paris
ZIP/Postal Code
75020
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
8405528
Citation
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.
Results Reference
background
PubMed Identifier
11302150
Citation
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.
Results Reference
background
PubMed Identifier
9096386
Citation
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.
Results Reference
background
PubMed Identifier
17287458
Citation
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.
Results Reference
background
PubMed Identifier
19221098
Citation
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.
Results Reference
background
PubMed Identifier
18722602
Citation
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.
Results Reference
background
PubMed Identifier
12042673
Citation
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.
Results Reference
background
PubMed Identifier
9820367
Citation
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.
Results Reference
background
PubMed Identifier
10965894
Citation
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.
Results Reference
background
PubMed Identifier
14607573
Citation
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.
Results Reference
background
PubMed Identifier
15665024
Citation
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.
Results Reference
background
PubMed Identifier
7951330
Citation
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.
Results Reference
background
PubMed Identifier
10196703
Citation
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.
Results Reference
background
PubMed Identifier
14581508
Citation
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.
Results Reference
background
PubMed Identifier
15548731
Citation
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.
Results Reference
background
PubMed Identifier
8988912
Citation
Kim YI, Pogribny IP, Basnakian AG, Miller JW, Selhub J, James SJ, Mason JB. Folate deficiency in rats induces DNA strand breaks and hypomethylation within the p53 tumor suppressor gene. Am J Clin Nutr. 1997 Jan;65(1):46-52. doi: 10.1093/ajcn/65.1.46.
Results Reference
background
PubMed Identifier
9192787
Citation
Koury MJ, Horne DW, Brown ZA, Pietenpol JA, Blount BC, Ames BN, Hard R, Koury ST. Apoptosis of late-stage erythroblasts in megaloblastic anemia: association with DNA damage and macrocyte production. Blood. 1997 Jun 15;89(12):4617-23.
Results Reference
background
PubMed Identifier
9990116
Citation
Kundu TK, Rao MR. CpG islands in chromatin organization and gene expression. J Biochem. 1999 Feb;125(2):217-22. doi: 10.1093/oxfordjournals.jbchem.a022276.
Results Reference
background
PubMed Identifier
9122232
Citation
Lengauer C, Kinzler KW, Vogelstein B. DNA methylation and genetic instability in colorectal cancer cells. Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2545-50. doi: 10.1073/pnas.94.6.2545.
Results Reference
background
PubMed Identifier
9067278
Citation
Ma J, Stampfer MJ, Giovannucci E, Artigas C, Hunter DJ, Fuchs C, Willett WC, Selhub J, Hennekens CH, Rozen R. Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res. 1997 Mar 15;57(6):1098-102.
Results Reference
background
PubMed Identifier
9399898
Citation
Matsushita S, Muramatsu T, Arai H, Matsui T, Higuchi S. The frequency of the methylenetetrahydrofolate reductase-gene mutation varies with age in the normal population. Am J Hum Genet. 1997 Dec;61(6):1459-60. doi: 10.1086/301640. No abstract available.
Results Reference
background
PubMed Identifier
18990381
Citation
Oliva A, Dotta A, Multigner L. Pentoxifylline and antioxidants improve sperm quality in male patients with varicocele. Fertil Steril. 2009 Apr;91(4 Suppl):1536-9. doi: 10.1016/j.fertnstert.2008.09.024. Epub 2008 Nov 5.
Results Reference
background
PubMed Identifier
19657388
Citation
Ravel C, Chantot-Bastaraud S, Chalmey C, Barreiro L, Aknin-Seifer I, Pfeffer J, Berthaut I, Mathieu EE, Mandelbaum J, Siffroi JP, McElreavey K, Bashamboo A. Lack of association between genetic polymorphisms in enzymes associated with folate metabolism and unexplained reduced sperm counts. PLoS One. 2009 Aug 6;4(8):e6540. doi: 10.1371/journal.pone.0006540.
Results Reference
background
PubMed Identifier
11781870
Citation
Rosenberg N, Murata M, Ikeda Y, Opare-Sem O, Zivelin A, Geffen E, Seligsohn U. The frequent 5,10-methylenetetrahydrofolate reductase C677T polymorphism is associated with a common haplotype in whites, Japanese, and Africans. Am J Hum Genet. 2002 Mar;70(3):758-62. doi: 10.1086/338932. Epub 2002 Jan 4.
Results Reference
background
PubMed Identifier
10190487
Citation
Rozen R, Fraser FC, Shaw G. Decreased proportion of female newborn infants homozygous for the 677 C-->T mutation in methylenetetrahydrofolate reductase. Am J Med Genet. 1999 Mar 12;83(2):142-3. doi: 10.1002/(sici)1096-8628(19990312)83:23.0.co;2-y. No abstract available.
Results Reference
background
PubMed Identifier
16997330
Citation
Skjelbred CF, Svendsen M, Haugan V, Eek AK, Clausen KO, Svendsen MV, Hansteen IL. Influence of DNA repair gene polymorphisms of hOGG1, XRCC1, XRCC3, ERCC2 and the folate metabolism gene MTHFR on chromosomal aberration frequencies. Mutat Res. 2006 Dec 1;602(1-2):151-62. doi: 10.1016/j.mrfmmm.2006.08.009. Epub 2006 Sep 25. Erratum In: Mutat Res. 2007 Nov 1;624(1-2):133.
Results Reference
background
PubMed Identifier
10528242
Citation
Stegmann K, Ziegler A, Ngo ET, Kohlschmidt N, Schroter B, Ermert A, Koch MC. Linkage disequilibrium of MTHFR genotypes 677C/T-1298A/C in the German population and association studies in probands with neural tube defects(NTD). Am J Med Genet. 1999 Nov 5;87(1):23-9.
Results Reference
background
PubMed Identifier
14669450
Citation
Szymanski W, Kazdepka-Zieminska A. [Effect of homocysteine concentration in follicular fluid on a degree of oocyte maturity]. Ginekol Pol. 2003 Oct;74(10):1392-6. Polish.
Results Reference
background
PubMed Identifier
11872201
Citation
Wong WY, Merkus HM, Thomas CM, Menkveld R, Zielhuis GA, Steegers-Theunissen RP. Effects of folic acid and zinc sulfate on male factor subfertility: a double-blind, randomized, placebo-controlled trial. Fertil Steril. 2002 Mar;77(3):491-8. doi: 10.1016/s0015-0282(01)03229-0.
Results Reference
background
PubMed Identifier
35506389
Citation
de Ligny W, Smits RM, Mackenzie-Proctor R, Jordan V, Fleischer K, de Bruin JP, Showell MG. Antioxidants for male subfertility. Cochrane Database Syst Rev. 2022 May 4;5(5):CD007411. doi: 10.1002/14651858.CD007411.pub5.
Results Reference
derived

Learn more about this trial

Impact of Folates in the Care of the Male Infertility

We'll reach out to this number within 24 hrs