Folic Acid and Zinc Supplementation Trial (FAZST)
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:
- 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.
- 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.
- 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.
- 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.
- 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.
Dietary Supplement: 5 mg folic acid and 30 mg elemental zinc
Drug: Placebo Comparator: Placebo
|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|
- 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.
- 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).
|Study Start Date:||June 2013|
|Estimated Primary Completion Date:||November 2016 (Final data collection date for primary outcome measure)|
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|
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.
|Contact: C. Matthew Peterson, MD||(801) email@example.com|
|Contact: Bruce Campbell, MD||(612) 863-8833||Bruce.Campbell@ivfmn.com|
|United States, Minnesota|
|Center for Reproductive Medicine||Recruiting|
|Minneapolis, Minnesota, United States, 55407|
|Principal Investigator: Bruce Campbell, MD|
|United States, Utah|
|University of Utah||Recruiting|
|Salt Lake City, Utah, United States, 84132|
|Principal Investigator: C. Matthew Peterson, MD|
|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|