Project Summary/Abstract Severe obesity in children is a highly prevalent, serious and chronic disease that directly leads to severe obesity in adults and the subsequent enormous social and financial burden on society. Lifestyle therapy is the cornerstone of pediatric obesity treatment, but this intervention when used alone is often insufficient for achieving clinically significant and durable BMI reduction. Adjunct anti-obesity medications may improve outcomes of this disease, but the pharmacological options used for obesity in children are extremely limited. Thus there is an urgency to identify anti-obesity medications for use in the pediatric population, which are safe, effective, easily administered and affordable. Psychostimulants, the second most commonly prescribed class of medications in children, have a long-standing safety profile and because of their favorable effect on weight, may serve as a useful adjunct to lifestyle therapy for the treatment of severe obesity in this population. Thus, the goal of this pilot and feasibility clinical trial is to estimate the treatment effect of a common psychostimulant, lisdexamfetamine, for the treatment of severe obesity in children. Specifically, 44 children ages 6 to <12 years with severe obesity (BMI ≥120% of the 95th percentile) will be randomized, 1:1, to lisdexamfetamine plus lifestyle therapy or placebo plus lifestyle therapy for 24 weeks of treatment. The primary outcome of the main aim will be change in BMI, and secondary outcomes will include changes in body composition, cardiometabolic health, and quality of life. The second aim will be to identify participant tolerability of the recommended starting dose of lisdexamfetamine and the emergence of clinically significant increases in blood pressure and heart rate. Potential mechanisms by which lisdexamfetamine reduces BMI will also be explored including changes in executive functioning, reward processing, appetite, resting energy expenditure, and health behaviors (diet, eating behaviors, and physical activity). The results of this pivotal pilot trial will directly inform the conduct of the larger, fully powered, definitive study, which ultimately, by identifying a safe, effective and scalable treatment, will improve the outcomes of the millions of children affected by this serious, chronic disease.