PROJECT SUMMARY Consistent with the research priorities of the National Institute on Aging, this R01 application will investigate the optimal intervention sequence to achieve weight loss in older adults with obesity and ≥ 2 Medicare-defined multiple chronic conditions (MCC). The growing prevalence of obesity in older adults, particularly in those with common chronic conditions such as diabetes, hypertension, or arthritis, increases the risk of functional decline, nursing home placement, and early mortality. Weight loss interventions can mitigate such adverse outcomes; however, differential response to treatment is often observed due to a patient’s clinical heterogeneity. Clinicians lack guidance on the most effective lifestyle-based intervention, and which intervention to try if the first one fails. An innovative Sequential, Multiple Assignment, Randomized Trial (SMART) design will be conducted to identify optimal intervention approaches for weight loss in older adults with MCC, tailoring strategies for non-responders to weight loss. During the 52-week, two-stage trial, 180 older adults with obesity and MCC will be enrolled to compare two weight loss interventions: a prescriptively focused, medically tailored, weight loss intervention (prescriptive), and a behaviorally focused, health coaching intervention (behavioral). Consistent with a SMART design, at 8-weeks, early non-responders (weight loss of <2.5%) will be randomized to: (a) more sessions of the original assignment; (b) a combination of prescriptive and behavioral interventions; or (c) a switch to a prescriptive, medically tailored strategy (initial, first-line behavioral arm participants) or to a behaviorally focused health coach-delivered strategy (initial prescriptive arm participants). The SMART will enable the identification of the treatment combinations that maximize weight loss at 52-weeks. To this end, the proposal aims to: 1) test the superiority of an initial (first-line) prescriptive or behavioral intervention using an adaptive strategy for early non-responders; 2) assess the patterns of initial weight loss and compare strategies for non-responders; and 3) examine the cost-effectiveness from a societal perspective for maintaining weight loss of the proposed treatment sequences at 78-weeks (26-weeks post-intervention completion). The primary outcome is percent weight loss at 52-weeks; secondary outcomes include global health and physical function, anthropometry, behavioral treatment targets and risk factors, and clinical indices. Based on preliminary data, it is hypothesized that older adults with obesity and MCC will achieve greater weight loss with a prescriptive, medically tailored intervention, and the estimated adaptive intervention strategy tailored to a patient’s characteristics will lead to better outcomes than a fixed intervention. If the trial is successful, the adaptive strategy will be compared to a fixed prescriptive or behavioral strategy in a future comparative ef...