Folic Acid and Zinc Supplementation Trial (FAZST)
Condition: Pregnancy; Live Birth; Spontaneous Abortion
MeSH terms: Abortion, Spontaneous
Study type: Interventional

Summary: 
      The overarching goal of this trial is to determine if an intervention comprising folic acid
      and zinc dietary supplementation improves semen quality and indirectly fertility outcomes
      (i.e., live birth rate) among couples trying to conceive and seeking assisted reproduction.
      The following study objectives underlie successful attainment of the overarching research
      goal:

        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: 
      Two micronutrients fundamental to the process of spermatogenesis, folic acid (folate) and
      zinc, are of particular interest for fertility as they are of low cost and wide availability.
      Though the evidence has been inconsistent, small randomized trials and observational studies
      show that folate and zinc have biologically plausible effects on spermatogenesis and improved
      semen parameters. These results support the potential benefits of folate on spermatogenesis
      and suggest that dietary supplementation with folate and zinc may help maintain and improve
      semen quality, and perhaps, fertility rates.

      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.
    

Intervention name(s): 5 mg folic acid and 30 mg elemental zinc; Placebo Comparator: Placebo
Intervention type(s): Dietary Supplement; Drug
Intervention MeSH terms: Folic Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Folic Acid; Zinc; Semen; In vitro fertilization; Assisted reproductive technology; Ovulation induction; Intrauterine insemination; Pregnancy; Live Birth; Abortion, spontaneous