Folic Acid and Zinc Supplementation Trial (FAZST)

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2013 by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Sponsor:
Information provided by (Responsible Party):
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier:
NCT01857310
First received: May 13, 2013
Last updated: May 15, 2014
Last verified: April 2013
  Purpose

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.

Condition Intervention
Pregnancy
Live Birth
Spontaneous Abortion
Dietary Supplement: 5 mg folic acid and 30 mg elemental zinc
Drug: Placebo Comparator: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Folic Acid and Zinc Supplementation Trial: A Multi-center, Double-blind, Block-randomized, Placebo-controlled Trial

Resource links provided by NLM:


Further study details as provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):

Primary Outcome Measures:
  • Live birth [ Time Frame: At delivery ] [ Designated as safety issue: No ]
    Live birth assessment will be based on hospital delivery records.

  • Change in semen quality [ Time Frame: Semen quality will be assessed at baseline, 2 months, 4 months, 6 months ] [ Designated as safety issue: No ]
    Semen quality will be assessed via standardized quantification of volume, concentration, motility, morphology, sperm count, and sperm DNA fragmentation index.


Secondary Outcome Measures:
  • Human chorionic gonadotropin (hCG) detected pregnancy (implantation) [ Time Frame: For IVF, 12 days post embryo transfer for day 5 embryo transfers, and 14 days post embryo transfer for day 3 embryo transfers; For couples undergoing OI/IUI, after self-report of positive pregnancy test ] [ Designated as safety issue: No ]
    A quantitative hCG evaluation in serum > 5 milli-international units per milliliter (mIU/ml)

  • Clinical intrauterine pregnancy [ Time Frame: 6.5 weeks ] [ Designated as safety issue: No ]
    Visualized gestational sac in the uterus on ultrasound.

  • Ectopic pregnancy [ Time Frame: 6.5 weeks ] [ Designated as safety issue: No ]
    Either visualization of no gestational sac in the uterus with a suspicious mass in the adnexa on ultrasound, an hCG level more than 1500 mIU/ml without visualization of an intrauterine gestational sac on ultrasound, or a slowly rising or plateauing serum hCG level without visualization of an intrauterine gestation on ultrasound.

  • Early pregnancy loss [ Time Frame: Up to first 20 weeks of pregnancy ] [ Designated as safety issue: No ]
    hCG pregnancy loss will be defined as a serum hCG > 5 mIU/ml followed by a decline. Clinically recognized pregnancy losses will be defined as visualization of an intrauterine gestational sac followed by a loss prior to 20 weeks gestation.

  • Other specific pregnancy outcomes [ Time Frame: Delivery ] [ Designated as safety issue: No ]
    Cesarean section, preeclampsia, gestational diabetes, growth restriction, gestational age, preterm birth, birth weight (small for gestational age), major neonatal complications (including death) and severe post-partum maternal morbidity. Outcomes will be determined based on hospital records and medical chart abstraction.

  • Early embryonic development parameters: [ Time Frame: Couples will be followed for up to 9 months of fertility treatment ] [ Designated as safety issue: No ]
    Fertilization rates, method of fertilization, number of cells and embryo morphology on day 3 and day 5, number of good quality embryos on day 5, proportion of good quality embryos on day 5, number of embryos transferred, quality of embryos transferred, number of embryos cryopreserved, and sperm penetration assay results.When available, information regarding the chromosomal complement of embryo will be assessed.

  • Reproductive hormones and other measured biomarkers [ Time Frame: Semen quality will be assessed at baseline, 2 months, 4 months, 6 months ] [ Designated as safety issue: No ]
    Measured urinary, serum, and salivary concentrations (collected at baseline and month 2, 4, and 6 clinic visits) of reproductive hormones, particularly androgens, proteomic analysis of human sperm and cardiometabolic risk factors and markers of oxidative stress, as well as measures of trace elements in toenails (collected at month 4 clinic visit).


Estimated Enrollment: 2400
Study Start Date: June 2013
Estimated Primary Completion Date: November 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Folic acid and zinc supplementation
5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months.
Dietary Supplement: 5 mg folic acid and 30 mg elemental zinc
Placebo Comparator: Placebo
Matching placebo, taken orally daily for 6 months.
Drug: Placebo Comparator: Placebo

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.

  Eligibility

Ages Eligible for Study:   18 Years to 45 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Couples Inclusion Criteria:

  1. Heterosexual couples in a committed relationship with a female partner aged 18-45 years and male partner aged 18 years and older attempting to conceive and seeking assisted reproduction at participating fertility clinics.
  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).

Couples Exclusion Criteria:

  1. Female partner unwilling to participate (e.g., no abstraction of her assisted fertility treatment record or unwilling to complete baseline visit).
  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.

Male Inclusion Criteria:

  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).

Male Exclusion Criteria:

  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. Diagnosis of anemia at screening. All participants will be screened at baseline for anemia and any men that screen positive (Hemoglobin <13 gm/dL) will be excluded.
  4. Diagnosis of Vitamin B12 deficiency or pernicious anemia.
  5. Any other diagnosis of anemia within the last 5 years that has not been successfully treated.
  6. Consuming a vegan diet.
  7. A known genetic cause of male factor subfertility, including chromosomal disorders related to subfertility (e.g., Y chromosome deletions).
  8. 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
  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.

Female Exclusion Criteria:

Age <18 or >45 years.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01857310

Contacts
Contact: C. Matthew Peterson, MD (801) 581-3834 c.matthew.peterson@hsc.utah.edu
Contact: Bruce Campbell, MD (612) 863-8833 Bruce.Campbell@ivfmn.com

Locations
United States, Minnesota
Center for Reproductive Medicine Active, not recruiting
Minneapolis, Minnesota, United States, 55407
United States, Utah
University of Utah Recruiting
Salt Lake City, Utah, United States, 84132
Principal Investigator: C. Matthew Peterson, MD         
Sponsors and Collaborators
Investigators
Study Director: Enrique F Schisterman, PhD Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study Director: Sunni L Mumford, PhD Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Principal Investigator: C. Matthew Peterson, MD University of Utah
  More Information

Additional Information:
No publications provided

Responsible Party: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier: NCT01857310     History of Changes
Other Study ID Numbers: FAZST
Study First Received: May 13, 2013
Last Updated: May 15, 2014
Health Authority: United States: Institutional Review Board
United States: Federal Government

Keywords provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):
Folic Acid
Zinc
Semen
In vitro fertilization
Assisted reproductive technology
Ovulation induction
Intrauterine insemination
Pregnancy
Live Birth
Abortion, spontaneous

Additional relevant MeSH terms:
Folic Acid
Vitamin B Complex
Abortion, Spontaneous
Pregnancy Complications
Hematinics
Zinc
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Hematologic Agents
Therapeutic Uses
Trace Elements

ClinicalTrials.gov processed this record on July 28, 2014