Design and baseline characteristics for the aminoguanidine clinical trial in overt type 2 diabetic nephropathy (ACTION II)

Advanced glycosylation endproduct (AGE) formation has been implicated in th e development and progression of nephropathy in type 2 diabetes mellitus. I n diabetic animals, aminoguanidine inhibits AGE-mediated cross-linking of p roteins in vascular and renal tissue and slows the progression of renal dis ease. ACTION II is a randomized, double-blind, placebo-controlled trial comparing two dose levels of aminoguanidine with placebo on the progression of nephr opathy in 599 type 2 diabetic patients with renal disease from 84 centers i n the United States and Canada. The primary endpoint is time to doubling of serum creatinine concentration. Secondary endpoints include the effect of aminoguanidine on time to all-cause mortality, end-stage renal disease (ESR D), cardiovascular morbidity and mortality, rate of change in indices of re nal function (iothalamate, Cockcroft and Gault [C&G] calculated creatinine and measured creatinine clearances), proteinuria, retinopathy, circulating and urinary AGE levels, and estimation of the relationship between plasma a minoguanidine concentrations and primary and secondary efficacy endpoints a nd adverse events. Progression of macrovascular disease was monitored and f undus photography performed. Type 2 diabetic patients aged 30 to 70 years w ere eligible for the trial if their blood pressure was less than or equal t o 180 mm Hg systolic and less than or equal to 120 mm Hg diastolic, serum c reatinine concentration greater than or equal to 1.0 mg/dL (in women) or gr eater than or equal to 1.2 mg/dL (in men), C&G clearance greater than or eq ual to 40 mL/min, and proteinuria greater than or equal to 500 mg/d with di abetic retinopathy or diabetic nephropathy on renal biopsy. Recruitment began in July 1995 and terminated in December 1996. The trial r andomized a total of 599 subjects. At baseline, the mean (standard deviatio n [SD]) age was 58 (7.7) years, diabetes duration 16.5 (7.5) years,body mas s index 32 kg/m(2) (10-90% range 26-42), arterial blood pressure 105 (12) m m Hg, C-pep tide concentration 2.55 (1.71) ng/mL, serum glucose concentrati on 201 (89) mg/dL, hemoglobin A1c 8.7% (1.6), serum creatinine concentratio n 1.6 (0.5) mg/dL, iothalamate clearance 52 (25) mL/min/1.73 m(2), proteinu ria 4.1 (4.2) g/d, triglycerides 259 (214) mg/dL, and LDL cholesterol 144 ( 40) mg/dL. Patients are 72% male, 68% white, 16% black, and 16% Asian Ameri can and Native American. At baseline, 76% were receiving concomitant angiot ensin-converting enzyme (ACE) inhibitors and 43% lipid-lowering agents. fol low-up in ACTION II was scheduled to continue through December 1998, so tha t follow-up was to be 2 years after the date of randomization of the final enrolled patient. The trial in fact ended in March 1998. This trial will co ntribute to our understanding of the natural history of type 2 diabetes mel litus-associated nephropathy and determine whether aminoguanidine will slow the progression of established diabetic renal disease. (C) Elsevier Scienc e Inc. 1999.