Physical Activity and Fatigue in Multiple Sclerosis: Secondary Outcomes from a Double-blinded Randomized Controlled Trial of Cocoa Flavonoid Drinks

Physical Activity and Fatigue in Multiple Sclerosis: Secondary Outcomes from a Double-blinded Randomized Controlled Trial of Cocoa Flavonoid Drinks Maedeh Mansoubi()1,2, Shelly Coe1,2,3, Jo Cossington1, Johnny Collet1,2, Miriam Clegg4, Jacqueline Palace5, Ana Cavey5, Gabriele C DeLuca5, Martin Ovington1 and Helen Dawes1,2,6  1Center for Movement, Occupational and Rehabilitation Sciences, Oxford Institute of Nursing, Midwifery and Allied Health Research, Oxford Brookes University, Oxford, United Kingdom 2Oxford Clinical Allied Technology and Trial Services Unit (OxCATTS), Oxford, United Kingdom 3Oxford Brookes Center for Nutrition and Health, Oxford Brookes University, Oxford, United Kingdom 4Hugh Sinclair Unit of Human Nutrition, Department of Food and Nutritional Sciences, University of Reading, Reading, United Kingdom 5Department of Neurology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom 6Oxford Health NHS Foundation Trust, United Kingdom © The Authors   Abstract Fatigue is a common and pervasive symptom reducing physical activity in people with multiple sclerosis (pwMS). Exercise may reduce fatigue, although evidence to guide optimal prescription is limited. Specifically, supportive evidence for the timing of exercise for fatigue management or the impact of dietary supplements is unavailable. We performed intensive phenotyping of the interrelation of time of day, physical activity levels, and fatigue to evidence exercise prescription in 40 pwMS participating in a six week randomized controlled trial of morning flavonoid intake (n=19) or a control (n=21). Physical activity was measured over seven days by using an accelerometer at baseline, week three and week six. Participants self-reported their fatigue on a 1–10 rating scale at 10 am, 3 pm, and 8 pm daily. Physical activity levels were calculated for 2.5 h before and after fatigue was reported. Generalized estimating equations were used to explore the time of day fatigue profiles, the relationship of physical activity to fatigue, and the effect of morning flavonoids on this relationship. Participants experienced higher fatigue at 8 pm (4.64±2.29) than at 3 pm (4.39±2.28) and 10 am (3.90±2.10) (P<0.001). Higher fatigue was shown to predict subsequent lower physical activity behavior (P=0.015), but physical activity did not predict higher subsequent fatigue (P>0.05). Morning flavonoid cocoa consumption reduced the relationship of fatigue to physical activity (P=0.049) and fatigue to time of the day (P<0.001). Fatigue levels increased during the day and higher fatigue reduced physical activity in pwMS, but physical activity did not increase fatigue. In addition, morning cocoa reduced daytime fatigue and the relationship of fatigue to subsequent physical activity levels. Therefore morning exercise prescription is indicated; in combination with dietary flavonoids, it may optimize exercise and physical activity potential in pwMS. Trial registration: ISRCTN69897291, https://doi.org/10.1186/ISRCTN69897291 Registration name: A study to determine whether the daily consumption of flavonoid-rich pure cocoa has the potential to reduce fatigue in people with relapsing-remitting multiple sclerosis (RRMS). Consort Statement: In this study, we adhered to CONSORT guidelines. As this paper is a secondary analysis, we therefore did not repeat some parts in the methods, results, diagrams, or tables that have been published in the first paper authored by Coe et al. 2019.