Anne SteinerREI, Duke University
- Duke University
- United States of America
We would like to thank the medical advisory board of Theralogix for their interest in the MOXI trial. We understand that the findings might be disconcerting to Theralogix as the company currently markets and sells a product containing this antioxidant formulation “to promote sperm structure and function” (https://theralogix.com/products/conceptionxr-motility-support-supplement).
We appreciate that the medical advisory board read the pre-published version of paper that was provided by the RMN as a courtesy to Theralogix. It appears that some of the commentary (internal pilot sample size) is also based on the protocol, which is publically available on clinicaltrials.gov (https://clinicaltrials.gov/ct2/show/NCT02421887?term=MOXI&draw=2&rank=2). While we appreciate that the medical advisory board of Theralogix has an opinion about the quality of the MOXI trial, we do not share that opinion. We would like to point out that this protocol was vetted through peer review by study section, an advisory board at the NIH, and a DSMB. In addition, an IND was obtained from the FDA. The trial was designed to mimic how antioxidants are currently being marketed and prescribed by physicians, and used by patients.
Regarding the issues put forth by the medical advisory board for Theralogix:
- Motility endpoint:
As noted in your letter, the protocol called for 120 subjects to be included in the internal pilot. Based on the assumption that 50% of men would have low motility, we needed 30 men in each group (total 60) to achieve >80% power at an alpha of 0.05. MOXI ultimately enrolled 171 (51 men were enrolled while the internal pilot samples and data were being analyzed). There were 74 men enrolled in the trial with low motility. Thus this published study was adequately powered to look at changes in semen parameters among men with low motility.
- DNA fragmentation:
The power analysis was not based on the assumption that the change in DNA fragmentation would be observed only among men with abnormal DNA fragmentation at baseline, but on all subjects.
- SCSA not TUNEL:
We assessed DNA fragmentation by TUNEL in addition to SCSA. The data was not presented due to space limitations. There was no significant difference between the two groups in change in DNA fragmentation (assessed by TUNEL). Change in DNA fragmentation by TUNEL (%) is 2.3 (-3.4 to 7.8) and -0.7 (-5.7 to 6.0) for anti-oxidant group and placebo group, respectively (p=0.283).
- Improvement in placebo arm (Table 4)
Among men with abnormal semen parameters, all semen parameters improved between baseline and visit 3. This improvement was observed among both the placebo and antioxidant groups (although more commonly “statistically significant” in the placebo group). This is likely due to regression to the mean. This is one reason why placebos are needed in clinical trials (aka “placebo effect”). It should be pointed out, though, that these subgroups have very small numbers and “improvements” should be interpreted with caution. Additionally, there were no significant differences in change in semen parameters between groups.
However, in the full cohort, change in concentration did significantly differ between the placebo and antioxidant group, favoring the placebo. Of note, better semen parameters and lower DNA fragmentation was also observed among the placebo group in the FAZST trial (1) which randomized 2370 men to the antioxidants, folic acid and zinc, or placebo.
- Comparison of findings to other trials on antioxidants
While we note the cited systematic review published in the Arab Journal of Urology (2), we would note that our trial findings are consistent with the Cochrane systematic review (3), which found no benefit on live birth when studies at high risk of bias were removed from the analysis. In addition, it is consistent with the FASZT trial, which showed that antioxidants did not improve live birth among the 2370 men enrolled in that RCT (1).
Anne Z. Steiner, MD, MPH
Karl Hansen, MD, PhD
Kurt Barnhart, MD
Marcelle Cedars, MD
Richard Legro, MD
Michael Diamond, MD
Matthew Coward, MD
Nanette Santoro, MD
Esther Eisenberg, MD, MPH
Heping Zhang, PhD
For the Reproductive Medicine Network
- Schisterman EF, Sjaarda LA, Clemons T, et al. Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment: A Randomized Clinical Trial. JAMA. 2020;323(1):35–48.
- Majzoub A & Agarwal A. Systematic review of antioxidant types and doses and male infertility: Benefits on semen parameters, advanced sperm function, assisted reproduction and live birth rate. Arab J Urol 2018;16(1):113-124.
- Smits RM, Mackenzie‐Proctor R, Yazdani A, Stankiewicz MT, Jordan V, Showell MG. Antioxidants for male subfertility. Cochrane Database of Systematic Reviews 2019, Issue 3. Art. No.: CD007411. DOI: 10.1002/14651858.CD007411.pub4