title: Design of a phase 2 clinical trial of an ASK1 inhibitor, GS-4997, in patients with diabetic kidney disease.
abstract: BACKGROUND
  Most patients with diabetic kidney disease (DKD) experience disease progression despite receiving standard care therapy. Oxidative stress is associated with DKD severity and risk of progression, but currently approved therapies do not directly attenuate the pathologic consequences of oxidative stress. GS-4997 is a once daily, oral molecule that inhibits Apoptosis Signal-regulating Kinase 1 (ASK1), which is a key mediator of the deleterious effects of oxidative stress.
  
  
  METHODS
  We describe the rationale and design of a Phase 2 placebo-controlled clinical trial investigating the effects of GS-4997 in patients with T2DM and stage 3/4 DKD receiving standard of care therapy. Approximately, 300 subjects will be randomized in a stratified manner, based on the estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio, to one of four arms in this dose-ranging study. The primary endpoint is change in eGFR at 48 weeks, and the key secondary endpoint is change in albuminuria.
  
  
  CONCLUSIONS
  Guided by the biology of oxidative stress signaling through ASK1, the biology of DKD pathogenesis, and solid statistical methods, the decisions made for this Phase 2 study regarding delineating study population, efficacy outcomes, treatment period and statistical methods represent innovative attempts to resolve challenges specific to DKD study design.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Lin
authors.forename: Jenny J
authors.initials: JJ
authors.lastname: Zhang
authors.forename: Shao-Lee
authors.initials: SL
authors.lastname: Lin
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Chertow
mesh_terms: D000328:Adult; D000368:Aged; D000419:Albuminuria / Q000188:drug therapy / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000503:physiopathology; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human