Randomized controlled trial of intermittent calorie restriction in people with multiple sclerosis

Background and objectives: Calorie restriction (CR) ameliorates preclinical models of multiple sclerosis (MS) through reduction of inflammation via multiple mechanisms including reduced adiposity and changes in pro-inflammatory adipokine levels. Daily and intermittent CR (iCR) have been tested in people with MS (pwMS) with benefits shown on fatigue and wellbeing measures. The aim of this trial was to study the effects of 12-week iCR on metabolic, immunological and clinical outcomes in pwMS. Methods: Participants with relapsing-remitting MS were randomly assigned to iCR or a control group for 12 weeks. Anthropometric measures, clinical and patient-reported outcomes, and blood samples were collected at baseline, 6 and 12 weeks. Oral glucose tolerance test and dual-energy X-ray absorptiometry were performed at baseline and week 12. Primary outcome of the study was change in leptin serum levels; secondary outcomes included changes in anthropometric and body composition measures, peripheral blood metabolic and immunologic profiling, and clinical measures. Mixed effects linear regression models were used to evaluate differences in the outcomes of interest between and within groups over time. Results: Forty-two pwMS were randomized, 34 completed the study (17 iCR and 17 control). Leptin levels decreased over the course of the study in the iCR group and were significantly lower in the iCR than the control group at 6 (mean difference 11.49 ug/dL, 95% CI 32.54, 9.54; P=0.01) and 12 weeks (6.97 ug/dL, 95% CI 28.02, 14.06; P=0.03). Adiponectin increased from baseline in the iCR, but not in the control cohort. We observed a significant reduction of weight, body mass index and body adiposity measures over the 6 and 12-weeks in participants randomized to iCR. Immune profiling showed a significant increase in CD45RO+ regulatory T cell numbers after 6 weeks of iCR. Lysophosphatidylcholine, lysophophatidylethanolamine and phosphatidylinositol lipids species were significantly increased after 12 weeks in the iCR group compared to baseline, and all three were higher at 12 weeks compared to controls. Exploratory cognitive testing demonstrated improvement in the symbol digit modality test score in the iCR group. Conclusions: Short term iCR is safe, feasible and can benefit metabolic and immunologic profiles in pwMS. ### Competing Interest Statement L.P. has received research funding from the National MS Society, the NIH, the Department of Defense and Fondazione Italiana Sclerosi Multipla; she has been funded by Alector and Biogen for a project not related to the one included in this manuscript. She is one of the Editor-in Chief of Journal of Neuroimmunology. AHC received compensation for consulting for Biogen, EMD Serono, Bristol Myers Squibb, TG Therapeutics, Octave, Genentech, Roche, Novartis, Horizon and Janssen (J&J). AHC was supported by the Manny & Rosalyn Rosenthal-Dr. John L. Trotter MS Center Chair in Neuroimmunology during this study. GFW received compensation for consulting for EMD Serono, Genzyme, Novartis, Sangamo, Roche, Alumis, and the US Department of Justice. He has received research grant funding from the NIH, National MS Society, Doris Duke Foundation, US Department of Veterans Affairs, Biogen, EMD Serono, and Genentech. He serves on the editorial boards of Neurology: Neuroimmunology & Neuroinflammation and the Journal of Neuroimmunology. He serves on advisory boards for Progentec and Genentech. RTN has consulted for Alexion Pharmaceuticals, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, EMD Serono, Horizon Therapeutics, Novartis, TG Therapeutics. Amber Salter receives research funding from Multiple Sclerosis Society of Canada, National Multiple Sclerosis Society, CMSC and the Department of Defense Congressionally Directed Medical Research Program and is a member of editorial board for Neurology. She serves as a consultant for Gryphon Bio, LLC and Abata Therapeutics, LLC. She is a member of the Data and Safety Monitoring Board for Premature Infants Receiving Milking or Delayed Cord Clamping (PREMOD2), Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS), Ocrelizumab for Preventing Clinical Multiple Sclerosis in Individuals With Radiologically Isolated Disease (CELLO) and Methotrexate treatment of Arthritis caused by Chikungunya virus (MARCH). She holds the Kenney Marie Dixon‐Pickens Distinguished Professorship in Multiple Sclerosis Research. ### Clinical Trial The study was registered at ClinicalTrials.gov ([NCT03539094][1]). ### Funding Statement This study was funded by the National MS Society (grant # RG-1607-25158 to L.P.). ### 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 study was approved by the Washington University School of Medicine Institutional Review Board (#201707010). Written informed consent was signed by all participants. 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 All data produced in the present study are available upon reasonable request to the authors. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03539094&atom=%2Fmedrxiv%2Fearly%2F2024%2F01%2F29%2F2024.01.28.24301860.atom