Background: Autosomal dominant polycystic kidney disease (ADPKD) has been associated with metabolic disturbances characterized by downregulation of AMP-activated protein kinase (AMPK), a critical sensor of the cellular energy status. Therapeutic activation of AMPK by metformin could inhibit cyst enlargement by inhibition of both the mammalian target of rapamycin (mTOR) pathway and fluid secretion via the CFTR chloride channel. Methods: We designed a Phase 2 randomized, placebo controlled clinical trial to assess the safety, tolerability, and efficacy of metformin on total kidney volume in non-diabetic adults (age 18-60 years) with ADPKD and eGFR>50 ml/min/1.73m 2. There were no eligibility criteria relating to kidney volume. In addition to demographics and clinical/family history, baseline parameters included eGFR, total kidney and liver volumes measured by MRI and patient-reported outcomes ascertained by the Medical Outcomes Study Short-Form 36 (MOS-SF36), the Gastrointestinal Safety Rating Scale (GSRS) and the HALT-PKD pain questionnaire. Results: We successfully randomized 97 participants recruited from two university-based clinical sites in Baltimore and Boston. Mean age was 41.9 years, 72% were female, and Caucasians comprised 94% of participants. The majority of study participants had early stage disease with a mean estimated GFR of 86.8 ± 19.0 ml/min/1.73m 2. Approximately half of study participants (47.9%) were classified as high risk for progression (Mayo imaging classes 1C, 1D, or 1E). There was no correlation between kidney and/or liver size and health related quality of life nor gastrointestinal symptom severity. Conclusions: We report successful recruitment in this ongoing novel clinical trial of metformin in ADPKD, with a study sample comprising patients with early-stage disease and nearly one-half of participants considered at high estimated risk for progression. Participants reported a low gastrointestinal symptom burden at baseline, and HRQoL similar to that of the general population, with no differences in symptoms or HRQoL related to organomegaly.