@article{88cce749d1d1460a9cabeb39958f0ebd,
title = "Primary results of the randomized trial of metformin administration in polycystic kidney disease (TAME PKD)",
abstract = "Autosomal dominant polycystic kidney disease (ADPKD) is characterized by growth of kidney cysts and glomerular filtration rate (GFR) decline. Metformin was found to impact cystogenesis in preclinical models of polycystic disease, is generally considered safe and may be a promising candidate for clinical investigation in ADPKD. In this phase 2 two-year trial, we randomly assigned 97 patients, 18-60 years of age, with ADPKD and estimated GFR over 50 ml/min/1.73 m2, in a 1:1 ratio to receive metformin or placebo twice daily. Primary outcomes were medication safety and tolerability. Secondary outcomes included estimated GFR decline, and total kidney volume growth. Thirty-eight metformin and 39 placebo participants still received study product at 24-months. Twenty-one participants in the metformin arm reduced drug dose due to inability to tolerate, compared with 14 in the placebo arm (not significant). Proportions of participants experiencing serious adverse events was similar between the groups. The Gastrointestinal Symptoms Rating Scale score was low at baseline and did not significantly change over time. The annual change for estimated GFR was -1.71 with metformin and -3.07 ml/min/1.73m2 per year with placebo (mean difference 1.37 {-0.70, 3.44} ml/min/1.73m2), while mean annual percent change in height-adjusted total kidney volume was 3.87% in metformin and 2.16% per year in placebo, (mean difference 1.68% {-2.11, 5.62}). Thus, metformin in adults with ADPKD was found to be safe and tolerable while slightly reducing estimated GFR decline but not to a significant degree. Hence, evaluation of efficacy requires a larger trial, with sufficient power to detect differences in endpoints.",
keywords = "autosomal dominant polycystic kidney disease, clinical trial, estimated glomerular filtration rate, metformin, total kidney volume",
author = "Perrone, {Ronald D.} and Abebe, {Kaleab Z.} and Watnick, {Terry J.} and Althouse, {Andrew D.} and Hallows, {Kenneth R.} and Lalama, {Christina M.} and Miskulin, {Dana C.} and Seliger, {Stephen L.} and Cheng Tao and Harris, {Peter C.} and Bae, {Kyongtae Ty}",
note = "Funding Information: The authors wish to thank the following research staff for their tireless efforts in the conduct this clinical trial: Charalett Diggs and Ashley Hargrove at the University of Maryland; Carly Tucker, Margaret Reilly, Raabia Malik, and Victoria Himaras at Tufts Medical Center; and Linda Whiting, Susan Spillane, and Suzanne Burdin at the University of Pittsburgh). We thank Michelle Woods (University of Pittsburgh) for creation of the visual abstract. We want to express our gratitude to the study participants and the ADPKD community who were instrumental for the success of this clinical trial. This study was supported by the Department of Defense contract W81XWH-15-1-0663, by the National Center for Advancing Translational Sciences , National Institutes of Health Award Numbers UL1TR002544 and 1UL1TR003098 . This work also used resources developed by the Maryland Polycystic Kidney Disease Research and Translation Core Center P30 DK090868 and U54 DK126114. Mutation analysis by PCH was supported by the Mayo Translational PKD Center P30 DK090728 and NIH R01 DK058816. Funding Information: RDP has received research funding from Otsuka, Kadmon Corporation, Sanofi-Genzyme, and Reata and is a consultant to Palladiobio, Reata, Sanofi-Genzyme, Navitor, and Otsuka. TW has received research funding from Otsuka, Kadmon Corporation, Palladio Biosciences, Sanofi, and Reata. KRH has received research funding from Otsuka and Esperion Therapeutics. DCM has received research funding from Regulus and Dialysis Clinics, Inc. SLS has received research funding from Otsuka, Kadmon Corporation, Palladio Biosciences, Sanofi, and Reata. KTB is a consultant to Kadmon, Otsuka, and Sanofi. PCH reports research funding from Otsuka Pharmaceuticals, Navitor, and Acceleron; consulting for Otsuka Pharmaceuticals, Mitobridge, and Regulus; and is on the Advisory Board for Vertex Pharmaceuticals. All other authors declared no competing interests. Funding Information: The authors wish to thank the following research staff for their tireless efforts in the conduct this clinical trial: Charalett Diggs and Ashley Hargrove at the University of Maryland; Carly Tucker, Margaret Reilly, Raabia Malik, and Victoria Himaras at Tufts Medical Center; and Linda Whiting, Susan Spillane, and Suzanne Burdin at the University of Pittsburgh). We thank Michelle Woods (University of Pittsburgh) for creation of the visual abstract. We want to express our gratitude to the study participants and the ADPKD community who were instrumental for the success of this clinical trial. This study was supported by the Department of Defense contract W81XWH-15-1-0663, by the National Center for Advancing Translational Sciences, National Institutes of Health Award Numbers UL1TR002544 and 1UL1TR003098. This work also used resources developed by the Maryland Polycystic Kidney Disease Research and Translation Core Center P30 DK090868 and U54 DK126114. Mutation analysis by PCH was supported by the Mayo Translational PKD Center P30 DK090728 and NIH R01 DK058816. Publisher Copyright: {\textcopyright} 2021 International Society of Nephrology",
year = "2021",
month = sep,
doi = "10.1016/j.kint.2021.06.013",
language = "English (US)",
volume = "100",
pages = "684--696",
journal = "Kidney International",
issn = "0085-2538",
publisher = "Nature Publishing Group",
number = "3",
}