- Tulane University School of Medicine
- United States of America
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Recent Comments
Making Sense of the MOXI Study
The MOXI trial attempted to determine whether antioxidant treatment of subfertile men would lead to an increase in pregnancy and birth rate. The study was designed with an internal pilot phase, which measured changes in the 3-month semen parameters of the first 120 men enrolled. The results of the pilot phase were intended to determine whether the fully powered, 790-couple study—with live birth as its endpoint—would proceed. “Success” in the pilot phase required statistically significant improvements in both motility and DNA Fragmentation Index (DFI) among those first 120 subjects.
Study design is arguably the most important aspect of any scientific manuscript, as it determines the level of evidence and conclusions that can be drawn from the data. It also helps determine how the data can be extrapolated and provides a template for reproducibility. In the MOXI study, couples were enrolled in the pilot study on the basis of a single S/E [semen evaluation], which demonstrated any abnormality in one of 4 parameters: 1) count; 2) motility; 3) morphology; 4) or % DFI (as determined by Sperm Chromatin Structural Assay [SCSA]).
The FDA provides guidance in regard to investigational agents used for the treatment of male factor infertility. Drug exposure must be for at least 26 weeks (i.e., two consecutive spermatogenesis cycles or longer), with semen analysis every 13 weeks, and at least two semen collections per time point.1
Given this primary inclusion criteria (“any abnormality at all on a single S/E”), it is unclear how the investigators could prospectively predict the relative frequency or severity of the different baseline semen abnormalities which would occur in the study subjects. This fact, along with other factors in the study’s design and methodology, raise important questions about its conclusions.
As mentioned, the full study’s primary endpoint was live birth. The power calculation for that endpoint required enrollment of 790 couples in order to demonstrate a statistically significant difference between the antioxidant and placebo arms. However, the study only enrolled 171 couples, of which only 144 of those completed the study. Not surprisingly, there was no statistical difference between the placebo and antioxidant arms for the live birth endpoint. Given that less than 20% of the required enrollment was achieved, it is unclear why the authors state any conclusion about this endpoint.
The pilot design required the antioxidant group to show a statistically significant improvement in both motility and DFI percentages after three months of treatment. As neither parameter showed significant improvement, the study was ended. However, several issues confound the pilot phase data:
Over the years, many studies have demonstrated the ability of antioxidant supplementation to reduce seminal oxidative stress and improve semen parameters in sub-fertile men.3-4 Studies seeking to determine whether those improvements translate into higher birth rates and, in which clinical settings (i.e. IUI, IVF, natural conception, etc.), that might be the case, have presented unique challenges and yielded mixed results. We do not believe that the MOXI study was able to answer that question. Unfortunately, that puzzle remains unsolved, since a careful review of the MOXI data appears to raise more questions than it resolves.
The antioxidant supplement and placebo used in the MOXI study were provided by Theralogix, LLC at the investigator’s request. The authors provided the company with a prepublication copy of the manuscript, which, as members of the Medical Advisory Board at Theralogix, we had the opportunity to review. Our review of that manuscript forms the basis for the concerns expressed in this communication.
Respectfully,
Marc Goldstein, MD, FACS
Wayne Hellstrom, MD, FACS
Glenn Schattman, MD, FACOG
Robert Stillman, MD, FACOG
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