Folic Acid and Zinc Supplementation Trial: A Multi-center, Double-blind, Block-randomized, Placebo-controlled Trial
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 2,370
- 试验地点
- 4
- 主要终点
- Sperm Motility
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
- •Couples actively trying to conceive.
- •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).
排除标准
- •Female partner unwilling to participate (e.g., no abstraction of her assisted fertility treatment record or unwilling to complete baseline visit).
- •Couples using donor, cryopreserved sperm, or sperm obtained via microsurgical or percutaneous epididymal sperm aspiration.
- •Couples attempting to conceive with a gestational carrier (surrogate).
- •Positive urine pregnancy test at screening.
- •Male Inclusion Criteria:
- •Willing to provide semen samples according to the proposed schedule at baseline, 2, 4, and 6 months of follow-up.
- •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:
- •Age <18 years.
- •Unwilling to abstain from use of non-study approved dietary supplements or medications containing folic acid or oral preparations containing zinc throughout the study.
- •Unwilling to abstain from use of testosterone supplementation throughout the study.
- •Diagnosis of Vitamin B12 deficiency or pernicious anemia.
- •Consuming a vegan diet.
- •A known genetic cause of male factor subfertility, including chromosomal disorders related to subfertility (e.g., Y chromosome deletions).
- •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.
- •Dihydrofolate reductase inhibitors: Trimethoprim, Triamterene, Bactrim, Iclaprim
- •Sulfonamides: Hydrochlorothiazide (HCTZ), Metolazone, Indapamide, Lasix, Bumex, Torsemide, Chlorthalidone, Acetazolamide, Mefruside, Xipamide
- •Sulfonylureas: Glipizide, Glyburide
- •Cox-2 inhibitors: Celecoxib
- •Others: Valproic acid, Probenecid, Sulfasalazine, Sumatriptan, Mafenide, Ethoxzolamide, Sulfiram, Zonisamide, Dorzolamide (optic), Dichlorphenamide, Fluorouracil, Capecitabine, Methotrexate
- •History of organ transplantation.
- •Physician diagnosed:
- •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.
- •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.
- •History of alcohol dependency disorder and/or other drug/substance dependency in the past 180 days.
- •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.
- •History of vasectomy without reversal, obstructive azoospermia such as Congenital Bilateral Aplasia of Vas Deferens (CBAVD), or ejaculatory duct obstruction.
- •Known allergy to folic acid or zinc dietary supplements.
- •Female Exclusion Criteria:
- •Age <18 or >45 years.
研究组 & 干预措施
Folic acid and zinc supplementation
5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months.
干预措施: 5 mg folic acid and 30 mg elemental zinc (Dietary Supplement)
结局指标
主要结局
Sperm Motility
时间窗: 6 months
% motile (including percentage of progressive motile sperm and percentage of nonprogressive motile sperm) Assessed utilizing the World Health Organization (WHO) semen analysis procedure 5th edition World Health Organization. WHO laboratory manual for the Examination and processing of human semen. 5th Edition ed. Switzerland: 2010.
Live Birth
时间窗: At delivery
Based on hospital delivery records
Sperm Morphology
时间窗: 6 months
% normal morphology Assessed utilizing the World Health Organization (WHO) semen analysis procedure 5th edition World Health Organization. WHO laboratory manual for the Examination and processing of human semen. 5th Edition ed. Switzerland: 2010.
Semen Volume
时间窗: 6 months
Volume of the ejaculate, mL Assessed utilizing the World Health Organization (WHO) semen analysis procedure 5th edition World Health Organization. WHO laboratory manual for the Examination and processing of human semen. 5th Edition ed. Switzerland: 2010.
Sperm Concentration
时间窗: 6 months
Number of spermatozoa per unit of volume of semen Assessed utilizing the World Health Organization (WHO) semen analysis procedure 5th edition World Health Organization. WHO laboratory manual for the Examination and processing of human semen. 5th Edition ed. Switzerland: 2010.
DNA Fragmentation Index
时间窗: 6 months
Comet assay used to measure sperm DNA integrity based on excess DNA strand breaks Assessed utilizing the World Health Organization (WHO) semen analysis procedure 5th edition World Health Organization. WHO laboratory manual for the Examination and processing of human semen. 5th Edition ed. Switzerland: 2010.
Total Motile Sperm Count
时间窗: 6 months
Calculated as semen volume (mL) \* sperm concentration (10\^6 spermatozoa/mL) \* motility (% motile)
次要结局
- Cesarean Delivery(Delivery)
- Clinical Intrauterine Pregnancy(approximately 6.5 weeks gestation)
- Ectopic Pregnancy(approximately 6.5 weeks gestation)
- Early Pregnancy Loss(hcG-detected pregnancy until 20 weeks of pregnancy)
- Human Chorionic Gonadotropin (hCG) Detected Pregnancy (Implantation)(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)
- Preeclampsia or Gestational Hypertension(Delivery)
- Gestational Diabetes(Delivery)
- Preterm Delivery(Delivery)
- Small for Gestational Age(Delivery)
- Gestational Age(Delivery)
- Birth Weight(Delivery)
- Cells on Day 3 Per Embryo Per Cycle, Categorical(Up to 9 months of fertility treatment post-randomization)
- Method of Fertilization Per Cycle(Up to 9 months of fertility treatment post-randomization)
- Cells on Day 5 Per Embryo Per Cycle, Categorical(Up to 9 months of fertility treatment post-randomization)
- Stillbirth(Delivery)
- Neonatal Mortality(Delivery)
- Major Neonatal Complications(Delivery)
- Fertilization Rate Per Cycle, %(Up to 9 months of fertility treatment post-randomization)
- Number of Good Quality Embryos on Day 5 Per Cycle(Up to 9 months of fertility treatment post-randomization)
- Number of Embryos Transferred Per Cycle(Up to 9 months of fertility treatment post-randomization)
- Structural Malformations(Delivery)
- Percentage of Good Quality Embryos on Day 5 Per Cycle(Up to 9 months of fertility treatment post-randomization)
- Number of Embryos Cryopreserved Per Cycle(Up to 9 months of fertility treatment post-randomization)
- Embryo Morphology on Day 3 Per Cycle, Categorical(Up to 9 months of fertility treatment post-randomization)
- Embryo Morphology on Day 5 Per Cycle, Categorical(Up to 9 months of fertility treatment post-randomization)
- Quality of Embryos Transferred Per Cycle, Categorical(Up to 9 months of fertility treatment post-randomization)
- Severe Maternal Morbidity(Delivery)
- Cells on Day 3 Per Embryo Per Cycle(Up to 9 months of fertility treatment post-randomization)
- Chromosomal Complement of Embryo Per Cycle(Up to 9 months of fertility treatment post-randomization)
- Sperm Penetration Per Cycle, %(Up to 9 months of fertility treatment post-randomization)