Background: Metformin inhibits cyclic AMP generation and activates AMP-activated protein kinase (AMPK), which inhibits the cystic fibrosis transmembrane conductance regulator and Mammalian Target of Rapamycin pathways. Together these effects may reduce cyst growth in autosomal dominant polycystic kidney disease (ADPKD). Methods: A phase II, double-blinded randomized placebo-controlled trial of 26 months duration. Participants will include nondiabetic adults (n = 96) aged 18–60 years, with an estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73 m2 and ADPKD, recruited from university-based practices in Baltimore and Boston. Participants will be randomized in 1: 1 ratio to metformin or placebo at 500 mg once daily, increased every 2 weeks to a maximum of 1,000 mg twice daily as tolerated. Dose is decreased if eGFR falls to 30–45 mL/min/1.73 m2 and discontinued at eGFR < 30 mL/min/1.73 m2. Results: The primary outcomes are safety, assessed by the rates of hypoglycemia, elevated lactic acid levels, adverse events, and tolerability assessed by the Gastrointestinal Severity Rating Scale and maximum tolerated dose of study medication. Secondary outcomes include changes in total kidney and liver volumes, pain, and health-related quality of life, and changes in urinary metabolomic biomarkers. Conclusions: Results of this trial will provide important information on the feasibility, safety, and tolerability of long-term use of metformin in patients with ADPKD and provide preliminary information regarding its efficacy in slowing disease progression. Furthermore, results may support or refute the hypothesis that metformin effects on disease progression are mediated through the activation of the AMPK pathway. These results will be essential for the justification and design of a full-scale efficacy trial.
Tolvaptan use in children and adolescents with autosomal dominant polycystic kidney disease: rationale and design of a two-part, randomized, double-blind, placebo-controlled trial