The overlooked impact of background diet and adherence in nutrition trials

Abstract Randomized controlled trials in nutrition (RCTN) face unique challenges, including the considerable influence of the background diet and the challenge of assuring intervention adherence by participants. The impact of these factors on the outcome of RCTNs has been difficult to quantify, but nutritional biomarkers represent a valuable tool to address these challenges. Using flavanols as a model dietary intervention and a set of recently validated flavanol biomarkers, we here investigated the impact of background diet and adherence on the outcomes of the COcoa Supplement and Multivitamin Outcomes Study (COSMOS, NCT 02422745). We found that 20% of participants in the placebo and cocoa-extract intervention arms had a flavanol background intake as high as the intervention, and only 5% did not consume any flavanols. Approximately 33% of participants in the intervention group did not achieve expected biomarker levels from the assigned intervention – more than the 15% estimated with pill-taking questionnaires usually implemented in RCTN. Taking these factors into account resulted in a larger effect size for all observed endpoints (HR (95% CI)) estimated using intention-to-treat vs. per-protocol vs. biomarker-based analyses: total cardiovascular disease (CVD) events 0.83 (0.65; 1.07); 0.79 (0.59; 1.05); 0.65 (0.47; 0.89) – CVD mortality 0.53 (0.29; 0.96); 0.51 (0.23; 1.14); 0.44 (0.20; 0.97) – all-cause mortality 0.81 (0.61; 1.08); 0.69 (0.45; 1.05); 0.54 (0.37; 0.80) –– major CVD events 0.75 (0.55; 1.02); 0.62 (0.43; 0.91); 0.48 (0.31; 0.74). These results highlight the importance of taking background diet and adherence into consideration in RCTN to obtain more reliable estimates of outcomes through nutritional biomarker-based analyses. Competing Interest Statement J.I.O. and H.S. are employed by Mars, Incorporated, a company engaged in flavanol research and flavanol-related commercial activities. H.D.S. has received investigator-initiated research support from Mars Edge, Pure Encapsulations, and Pfizer Inc., and honoraria and/or travel for lectures from the Council for Responsible Nutrition, BASF, NIH, and American Society of Nutrition during the conduct of the study. J.E.M. has received investigator-initiated research support from Mars Edge. G.G.C.K. has received an unrestricted grant from Mars. COSMOS is supported by an investigator-initiated grant from Mars Edge, a segment of Mars dedicated to nutrition research and products, which included infrastructure support and the donation of study pills and packaging. Clinical Trial NCT02422745 Funding Statement COSMOS is supported by an investigator-initiated research grant from Mars Edge (JEM, HDS), a segment of Mars dedicated to nutrition research and products, which included infrastructure support and the donation of study pills and packaging. Pfizer Consumer Healthcare (now Haleon) provided support through the partial provision of study pills and packaging (JEM, HDS). COSMOS is also supported in part by grants AG050657, AG071611, EY025623, and HL157665 from the US National Institutes of Health (NIH), Bethesda, MD. The Women's Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, NIH, US Department of Health and Human Services through contracts 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, and 75N92021D00005. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The COSMOS trial and ancillary studies were reviewed and approved by Institutional Review Boards at Brigham and Women's Hospital/Mass General Brigham. The COSMOS website is www.cosmostrial.org. All participants provided informed consent. No identifiable information were used in this study I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Expanded on methodology and revised figures Data Availability Code is available from https://gitlab.act.reading.ac.uk/xb901875/biomarker-based-intervention. Data and associated documentation will be available to users only under a data-sharing agreement. Details on the availability of the study data to other investigators will be on our study website at https://cosmostrial.org/.