Study Results
Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.
View full resultsBasic Information
Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.
COMPLETED
NA
2370 participants
INTERVENTIONAL
2013-06-30
2019-06-30
Brief Summary
Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.
1. To estimate the effect of folic acid and zinc dietary supplementation on semen quality parameters, including but not limited to concentration, motility, morphology, and sperm DNA integrity, relative to the placebo group.
2. To estimate the effect of folic acid and zinc dietary supplementation on fertility treatment outcomes \[fertilization, embryo quality, implantation/human Chorionic Gonadotropin (hCG) confirmed pregnancy, clinical pregnancy, live birth\], relative to the placebo group.
3. To estimate the association between semen quality parameters, sperm DNA integrity and fertility treatment outcomes (fertilization, embryo quality, clinical pregnancy, live birth) and to identify the best combination of semen quality parameters for prediction of clinical pregnancy and live birth.
4. To estimate the effect of folic acid and zinc dietary supplementation on fertilization rates among couples undergoing assisted reproductive technology procedures, relative to the placebo group.
5. To estimate the effect of folic acid and zinc dietary supplementation on embryonic quality among couples undergoing assisted reproductive technology procedures, relative to the placebo group.
Detailed Description
Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.
The Epidemiology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development intends to conduct a multi-site double-blind, randomized controlled clinical trial to evaluate the effect of folic acid and zinc dietary supplementation on semen quality and conception rates among male partners of couples seeking assisted reproduction. Randomization will be stratified (with random sequences of block sizes) by site and assisted reproduction technique (IVF, non-IVF receiving fertility treatment at a study site, and non-IVF receiving fertility treatment at a nonstudy site) to ensure that balance between the treatment groups is maintained within site and within fertility treatment type over the enrollment period.
The study is designed with a sample size of 2,400 randomized participants based on obtaining adequate power to detect meaningful differences in the live birth rate between cohorts. Since the comparison of sperm parameters are differences between continuous assay measurements, this sample size will be more than sufficient for the primary sperm parameter comparisons. Additionally, calculations were done to demonstrate adequate statistical power when stratified analysis is to be performed (i.e., sample size distributions among the strata and their corresponding live birth RRs detected at 80% statistical power, with an alpha level of 0.05 and a total sample size of 2400 couples divided among the folic acid/zinc and placebo arms of the trial).
Data collection will include screening male and female partners for eligibility, administering baseline questionnaires, and collecting biospecimens in both partners of the couple, body measurements for both partners, daily journal reporting for male partners, medical record abstraction related to required treatment and outcome data, and semen quality of four samples collected at baseline, two, four, and six months following study enrollment. A data coordinating center (DCC) will support the trial.
The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two cohorts based on the randomized assignment, both overall and by treatment strata (IVF, non-IVF receiving fertility treatment at a study site, and non-IVF receiving fertility treatment at a nonstudy site).This approach will be applied to the two primary endpoints (semen parameters and live birth rate) as well as designated secondary endpoints (number of follicles, number and proportion of oocytes fertilized).
The DCC will perform periodic safety analyses and present interim reports to the Data and Safety Monitoring Board (DSMB) as requested, during the recruitment phases of the trial. It is anticipated that safety analyses will be performed every 6-12 months. The final analysis will be performed upon completion of data collection and editing in the follow-up and close-out phase of the trial. Also one full formal interim analysis is planned and the power calculations with considerations for the choice of optimal time for the analysis have been conducted.
Conditions
See the medical conditions and disease areas that this research is targeting or investigating.
Keywords
Explore important study keywords that can help with search, categorization, and topic discovery.
Study Design
Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.
RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
Review each arm or cohort in the study, along with the interventions and objectives associated with them.
Folic acid and zinc supplementation
5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months.
5 mg folic acid and 30 mg elemental zinc
Placebo
Matching placebo, taken orally daily for 6 months.
Placebo Comparator: Placebo
Interventions
Learn about the drugs, procedures, or behavioral strategies being tested and how they are applied within this trial.
5 mg folic acid and 30 mg elemental zinc
Placebo Comparator: Placebo
Eligibility Criteria
Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.
Inclusion Criteria
2. Couples actively trying to conceive.
3. Couples who are planning ovulation induction (OI), natural fertility optimization methods, or intrauterine insemination (IUI) should be willing to be on the study dietary supplement for at least 3 weeks before starting the next assisted reproduction cycle.Women with regular periods may initiate their fertility therapy at the start of the woman's menstrual cycle following randomization if randomization occurred within the first 10 days of the cycle, but must wait one menstrual cycle if the visit occurred after day 10 of the cycle). For women with irregular periods or amenorrhea, the male must be on the study supplement for 3 weeks prior to initiation of any ovulation induction medication (e.g., clomid, letrozole, gonadotropins).
1. Willing to provide semen samples according to the proposed schedule at baseline, 2, 4, and 6 months of follow-up.
2. Able to complete regular study questionnaires and daily journals aimed at capturing ejaculation, sexual intercourse and lifestyle factors considered to affect male fecundity (e.g., cigarette smoking, fever, high temperature environment and other environmental exposures) and other data collection instruments (e.g., physical activity, food frequency questionnaire, stress).
Exclusion Criteria
2. Couples using donor, cryopreserved sperm, or sperm obtained via microsurgical or percutaneous epididymal sperm aspiration.
3. Couples attempting to conceive with a gestational carrier (surrogate).
4. Positive urine pregnancy test at screening.
1. Age \<18 years.
2. Unwilling to abstain from use of non-study approved dietary supplements or medications containing folic acid or oral preparations containing zinc throughout the study.
3. Unwilling to abstain from use of testosterone supplementation throughout the study.
4. Diagnosis of Vitamin B12 deficiency or pernicious anemia.
5. Consuming a vegan diet.
6. A known genetic cause of male factor subfertility, including chromosomal disorders related to subfertility (e.g., Y chromosome deletions).
7. Males currently using and unwilling (or unable) to discontinue the following drugs known to interact with folic acid or interfere with the biosynthesis of folic acid will be excluded.
1. Dihydrofolate reductase inhibitors: Trimethoprim, Triamterene, Bactrim, Iclaprim
2. Sulfonamides: Hydrochlorothiazide (HCTZ), Metolazone, Indapamide, Lasix, Bumex, Torsemide, Chlorthalidone, Acetazolamide, Mefruside, Xipamide
3. Sulfonylureas: Glipizide, Glyburide
4. Cox-2 inhibitors: Celecoxib
5. Others: Valproic acid, Probenecid, Sulfasalazine, Sumatriptan, Mafenide, Ethoxzolamide, Sulfiram, Zonisamide, Dorzolamide (optic), Dichlorphenamide, Fluorouracil, Capecitabine, Methotrexate
8. History of organ transplantation.
9. Physician diagnosed:
1. Current poorly controlled chronic diseases such as heart disease, diabetes mellitus, hypertension, cancer, inflammatory diseases, autoimmune, thyroid disease, endocrine dysfunction, liver disease, kidney disease, or HIV/AIDS or other immune-insufficient related illnesses.
2. Crohn's disease, celiac disease, ulcerative colitis, gastric bypass surgery, lap band surgery or history of intestinal surgery to remove a portion of small bowel. History of diseases/symptoms that require folic acid dietary supplementation, such as megaloblastic anemia, homocystinemia, and homocystinuria.
3. History of alcohol dependency disorder and/or other drug/substance dependency in the past 180 days.
4. History of psychoses or other mental conditions that would result in cognitive impairment and inability to participate in any part of this study including the informed consent process, as diagnosed by a physician within the past year.
10. History of vasectomy without reversal, obstructive azoospermia such as Congenital Bilateral Aplasia of Vas Deferens (CBAVD), or ejaculatory duct obstruction.
11. Known allergy to folic acid or zinc dietary supplements.
Age \<18 or \>45 years.
18 Years
45 Years
ALL
Yes
Sponsors
Meet the organizations funding or collaborating on the study and learn about their roles.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
NIH
Responsible Party
Identify the individual or organization who holds primary responsibility for the study information submitted to regulators.
Principal Investigators
Learn about the lead researchers overseeing the trial and their institutional affiliations.
Enrique F. Schisterman, PhD
Role: STUDY_DIRECTOR
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Sunni L. Mumford, PhD
Role: STUDY_DIRECTOR
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
C. Matthew Peterson, MD
Role: PRINCIPAL_INVESTIGATOR
University of Utah
Jared C. Robins, MD
Role: PRINCIPAL_INVESTIGATOR
Northwestern University
Ginny L. Ryan, MD, MA
Role: PRINCIPAL_INVESTIGATOR
University of Iowa
Bradley J. Van Voorhis, MD
Role: PRINCIPAL_INVESTIGATOR
University of Iowa
Locations
Explore where the study is taking place and check the recruitment status at each participating site.
Northwestern University
Chicago, Illinois, United States
University of Iowa
Iowa City, Iowa, United States
Center for Reproductive Medicine
Minneapolis, Minnesota, United States
University of Utah
Salt Lake City, Utah, United States
Countries
Review the countries where the study has at least one active or historical site.
References
Explore related publications, articles, or registry entries linked to this study.
DiTosto JD, Caniglia EC, Hinkle SN, Sealy N, Schisterman EF, Johnstone E, Mendola P, Mills J, Hotaling J, Ryan G, Mumford SL. Target trial emulation of preconception serum vitamin D status on fertility outcomes: a couples-based approach. Fertil Steril. 2025 Feb;123(2):300-312. doi: 10.1016/j.fertnstert.2024.08.332. Epub 2024 Aug 20.
DeVilbiss EA, Sjaarda LA, Peterson CM, Hotaling JM, Mills JL, Mendola P, Carrell DT, Johnstone E, Chen Z, Perkins NJ, Ryan G, Schisterman EF, Mumford SL. Longitudinal semen parameter assessments and live birth: variability and implications for treatment strategies. Fertil Steril. 2022 Nov;118(5):852-863. doi: 10.1016/j.fertnstert.2022.08.012. Epub 2022 Oct 1.
Jenkins T, Aston K, Carrell D, DeVilbiss E, Sjaarda L, Perkins N, Mills JL, Chen Z, Sparks A, Clemons T, Chaney K, Peterson CM, Emery B, Hotaling J, Johnstone E, Schisterman E, Mumford SL. The impact of zinc and folic acid supplementation on sperm DNA methylation: results from the folic acid and zinc supplementation randomized clinical trial (FAZST). Fertil Steril. 2022 Jan;117(1):75-85. doi: 10.1016/j.fertnstert.2021.09.009. Epub 2021 Oct 14.
Schisterman EF, Sjaarda LA, Clemons T, Carrell DT, Perkins NJ, Johnstone E, Lamb D, Chaney K, Van Voorhis BJ, Ryan G, Summers K, Hotaling J, Robins J, Mills JL, Mendola P, Chen Z, DeVilbiss EA, Peterson CM, Mumford SL. Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment: A Randomized Clinical Trial. JAMA. 2020 Jan 7;323(1):35-48. doi: 10.1001/jama.2019.18714.
Provided Documents
Download supplemental materials such as informed consent forms, study protocols, or participant manuals.
Document Type: Study Protocol and Statistical Analysis Plan
Related Links
Access external resources that provide additional context or updates about the study.
The FAZST trial home page
Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
FAZST
Identifier Type: -
Identifier Source: org_study_id