Males, Antioxidants, and Infertility Trial (MOXI)

Males, Antioxidants, and Infertility (MOXI) Trial

The objective of the Males, Antioxidants, and Infertility (MOXI) Trial is to examine whether treatment of infertile males with an antioxidant formulation improves male fertility. The central hypothesis is that treatment of infertile males with antioxidants will improve sperm structure and function, resulting in higher fertilization rates and improved embryo development, leading to higher pregnancy and live birth rates. Findings from this research will be significant in that they will likely lead to an effective, non-hormonal treatment modality for male infertility. An effective treatment for men would also reduce the treatment burden on the female partner, lower costs, and provide effective alternatives to couples with religious or ethical contraindications to ART (Assisted Reproductive Technology). If antioxidants do not improve pregnancy rates, but do improve sperm motility and DNA integrity, they could allow for couples with male factor infertility to use less intensive therapies such as intrauterine insemination. Male fertility specialists currently prescribe antioxidants based on the limited data supporting their use. A negative finding, lack of any benefit, would also alter current treatment of infertile males.

Study Overview

• Status: Completed
• Conditions: Male Infertility
• Intervention / Treatment: Other: Placebo; Drug: Antioxidant Supplement

• Study Type: Interventional
• Enrollment (Actual): 171
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90089
      • Keck School of Medicine of University of Southern California
    • San Francisco, California, United States, 94115
      • University of California San Francisco
    • Sunnyvale, California, United States, 94087
      • Stanford University
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Augusta University
  • Michigan
    • Southfield, Michigan, United States, 48034
      • Wayne State University
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Carolinas Medical Center - Women's Institute
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Pennsylvania State University
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:Couple

• 12 or more months of infertility (primary or secondary)
• Heterosexual
• Cohabitating and able to have regular intercourse

Male:

• ≥ 18 years of age

• At least one abnormal semen parameter on a semen analysis within the past 6 months:

  • Sperm concentration ≤15 Million/ml
  • Total motility ≤40%
  • Normal morphology (Kruger) ≤4%
  • DNA fragmentation (SCSA, DNA fragmentation index) >25%

Female:

• ≥18 years of age and ≤40 years of age
• For women ≥ 35 years of age, evidence of normal ovarian reserve as assessed by menstrual cycle day 3 (+/-2 days) FSH ≤10 IU/L with estradiol ≤ 70 pg/mL, AMH ≥ 1.0 ng/mL, OR antral follicle count >10 within one year prior to study initiation.
• Evidence of at least one patent fallopian tube as determined by an hysterosalpingogram or laparoscopy showing at least one patent fallopian tube or a saline infusion sonogram showing spillage of contrast material
• Regular cycles defined as ≥25 days and ≤35 days in duration
• Evidence of ovulation including biphasic basal body temperatures, positive ovulation predictor kits, or progesterone level ≥3 ng/ml.

Exclusion Criteria:

• Couple:

  • Previous sterilization procedures (vasectomy, tubal ligation). The prior procedure may affect study outcomes.
  • Planning in vitro fertilization in the next 6 months

Male:

• Sperm concentration < 5 million/mL on screening semen analysis
• Current use of a medication or drug that would affect reproductive function or metabolism (see Appendix C for list)
• Current multivitamin or herb use (requires 1 month wash-out)
• Current serious medical illnesses, such as cancer, heart disease, or cirrhosis
• Current use of anticoagulants
• Untreated hypothyroidism
• Uncontrolled diabetes mellitus

Female:

• History of surgically or medically confirmed moderate or severe endometriosis
• Body mass index >35 kg/m2
• Currently pregnant
• History of polycystic ovarian syndrome
• Current serious medical illnesses, such as cancer, heart disease, or cirrhosis
• History of systemic chemotherapy or pelvic radiation
• Current use of a medication or drug that would affect reproductive function or metabolism

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo; Placebo
Active Comparator: Antioxidant Supplement; Tablet: Vitamin C, 500 mg; Vitamin D3, 1000 IU; Vitamin E, 400 IU; Folic Acid 1000 mcg; Zinc, 20 mg; Selenium 200 mcg; Lycopene, 10 mg; Capsule: Vitamin D3, 1000 IU, L-Carnitine, 1000 mg	Drug: Antioxidant Supplement; An antioxidant combination including Vitamin C, Vitamin E, folic acid, selenium, zinc, and L-carnitine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Live Birth Rate	up to 15 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pregnancy Rate		up to 7 months
Miscarriage Rate	miscarriages per total number of pregnancies	up to 9 months
Time to Pregnancy	Time to pregnancy will be the chronologic time from randomization to pregnancy detection in days, in which the pregnancy is defined as a human Chorionic Gonadotropin (hCG) value over 5 on 2 separate occasions.	up to 7 months
Change in Total Motile Sperm Count	Samples will be assessed using a standard semen analysis	baseline and 3 months
Change in Deoxyribonucleic Acid (DNA) Fragmentation Index (DFI)	DFI is the ratio of damaged sperm to total sperm. It is measured using Sperm Chromatin Structure Analysis (SCSA) which was performed on 5000 sperm per sample.	Baseline and 3 months
Change in Semen Total Motility	Samples assessed using a standard semen analysis	baseline and 3 months
Change in Sperm Concentration	Samples assessed using a standard semen analysis	baseline and 3 months
Change in Normal Morphology of Semen, Using World Health Organization (WHO) 5 Criteria	Samples assessed using a standard semen analysis	baseline and 3 months
Change in Total Sperm Count	Samples assessed using a standard semen analysis	baseline and 3 months

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: University of Pennsylvania; University of Oklahoma; University of California, San Francisco; Penn State University; Augusta University; University of North Carolina
• Investigators: Study Chair: Nanette Santoro, MD, University of Colorado, Denver; Study Director: Marcelle Cedars, MD, University of California, San Francisco; Study Director: Esther Eisenberg, MD, Eunice Kennedy Shriver National Institue of Child Health and Human Development; Principal Investigator: Anne Z Steiner, MD, University of North Carolina; Study Director: Michael P Diamond, MD, Augusta University; Study Director: Richard S Legro, MD, Penn State University; Study Director: Karl R Hansen, MD, University of Oklahoma

Publications and helpful links

General Publications

• Spitzer TL, Trussell JC, Coward RM, Hansen KR, Barnhart KT, Cedars MI, Diamond MP, Krawetz SA, Sun F, Zhang H, Santoro N, Steiner AZ. Biomarkers of Stress and Male Fertility. Reprod Sci. 2022 Apr;29(4):1262-1270. doi: 10.1007/s43032-022-00853-x. Epub 2022 Feb 1.
• Steiner AZ, Hansen KR, Barnhart KT, Cedars MI, Legro RS, Diamond MP, Krawetz SA, Usadi R, Baker VL, Coward RM, Huang H, Wild R, Masson P, Smith JF, Santoro N, Eisenberg E, Zhang H; Reproductive Medicine Network. The effect of antioxidants on male factor infertility: the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial. Fertil Steril. 2020 Mar;113(3):552-560.e3. doi: 10.1016/j.fertnstert.2019.11.008. Epub 2020 Feb 25.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2015
• Primary Completion (Actual): June 11, 2018
• Study Completion (Actual): December 1, 2018

Study Registration Dates

• First Submitted: March 19, 2015
• First Submitted That Met QC Criteria: April 15, 2015
• First Posted (Estimate): April 21, 2015

Study Record Updates

• Last Update Posted (Actual): September 4, 2019
• Last Update Submitted That Met QC Criteria: August 12, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infertility; Infertility, Male; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Antioxidants
• Other Study ID Numbers: MOXI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: IPD will be shared with other researchers through the NICHD DASH system. It will be available 6 months after publication of the primary results.
• IPD Sharing Time Frame: Following publication of the primary publication and when the de-identified data have been put into a format that is acceptable for DASH submission.