title: Pyridoxamine dihydrochloride in diabetic nephropathy (PIONEER-CSG-17): lessons learned from a pilot study.
abstract: OBJECTIVE
  Pyridoxamine dihydrochloride (Pyridorin™) blocks pathogenic oxidative pathways in the progression of diabetic nephropathy. The pyridoxamine pilot study was designed to test entry criteria and outcomes. Subjects had SCr 1.3-3.5 mg/dl, protein-to-creatinine ≥1,200 mg/g and used a surrogate outcome of ΔSCr over 52 weeks. Subjects had to be on a maximally tolerated dose of ACE/ARB for 3 months; stable other antihypertensive doses for 2 months; stable diuretic dose for 2 weeks, and BP ≤160/90 mm Hg; or enter a Pharmaco-Stabilization Phase (PSP). This pilot failed to detect an effect on ΔSCr in intent-to-treat analysis.
  
  
  METHODS
  We queried the locked clinical trial database for subgroups in which there was a treatment effect.
  
  
  RESULTS
  Subjects not requiring PSP and those with entry SCr <2.0 mg/dl had a treatment effect. Subjects entering PSP required more changes in antihypertensive medications and experienced larger ΔSCr over 52 weeks. PSP subjects with BP >140/90 mm Hg had no treatment effect, but those ≤140/90 mm Hg did.
  
  
  CONCLUSIONS
  Time required for acute effects of ACE/ARB to stabilize is unknown, but these data suggest >3 months. Thus, subjects in the pivotal trial must be on ACE/ARB for 6 months. Frequent antihypertensive adjustment could engender SCr changes unrelated to CKD progression. Thus, we will require subjects to have BP ≤150/90 mm Hg and on stable antihypertensives for 26 weeks, or ≤140/90 mm Hg and on stable antihypertensives for 13 weeks. Since ΔSCr over 52 weeks is limited as a surrogate outcome, the pivotal trial uses a time-to-event analysis of baseline SCr to at least a 50% increase in SCr or ESRD as the primary outcome. This substantial ΔSCr is protected from noise and is clinically relevant. The pyridoxamine pilot provided critical information to inform the design of PIONEER-CSG-17, which we conducted under the SPA agreement with FDA.
authors.forename: Jamie P
authors.initials: JP
authors.lastname: Dwyer
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Greco
authors.forename: Kausik
authors.initials: K
authors.lastname: Umanath
authors.forename: David
authors.initials: D
authors.lastname: Packham
authors.forename: J Wesley
authors.initials: JW
authors.lastname: Fox
authors.forename: Robert
authors.initials: R
authors.lastname: Peterson
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Broome
authors.forename: Laura E
authors.initials: LE
authors.lastname: Greene
authors.forename: Mohammed
authors.initials: M
authors.lastname: Sika
authors.forename: Julia B
authors.initials: JB
authors.lastname: Lewis
mesh_terms: D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage; D000959:Antihypertensive Agents / Q000008:administration & dosage; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use*; D003404:Creatinine / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D003928:Diabetic Nephropathies / Q000097:blood / Q000188:drug therapy*; D004232:Diuretics / Q000008:administration & dosage; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D010865:Pilot Projects; D011733:Pyridoxamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D000975:Antioxidants; D004232:Diuretics; D011733:Pyridoxamine; D003404:Creatinine; C570561:pyridoxamine dihydrochloride