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Principal Investigator:  Oliver M. Bautista, Ph.D.

The Biostatistics Center served as the Biostatistical Analysis Center for A Clinical Trial in Overt Nephropathy (ACTION); two multi- center clinical trials on the pharmacological inhibition of the formation of advanced glycated endproducts (AGE) in diabetics with chronic renal disease using pimagedine. ACTION I was conducted in insulin dependent diabetes mellitus (IDDM) participants; ACTION II was conducted in non-insulin dependent diabetes mellitus (NIDDM) participants.

ACTION I and II were double-masked, multiple-dose, placebo-controlled, randomized clinical trials designed to evaluate the safety and efficacy of advanced glycosylated endproduct inhibition (AGEi) using pimagedine in retarding the rate of progression of renal disease in participants with overt diabetic nephropathy. In ACTION I and II, one-third of the participants were randomized to placebo and two-thirds were randomized to either a low or high dose of pimagedine. The primary endpoint in both ACTION I and II is the time from randomization to the doubling of baseline serum creatinine. Efficacy is evaluated by comparing the placebo group versus the combined low and high pimagedine dose groups with respect to the primary outcome. In addition to the progression of renal disease, ACTION included evaluations of fundus photographs and a pharmacoeconomic evaluation.

During 31 months from February 1994 to September 1996, 56 clinical sites in the US and Canada randomized a total of 690 participants into ACTION I. Randomized participants were followed with quarterly visits until the scheduled administrative censoring period during the third quarter of 1998. With over 1,700 participant-years of follow-up accumulated in ACTION I, the combined pimagedine dose group showed a tendency of having a lower risk of doubling of serum creatinine. However, the observed difference between the placebo group and the combined pimagedine dose group with respect to the primary outcome did not reach statistical significance. The combined pimagedine dose group was also observed to have statistically significant lower levels of triglycerides, LDL cholesterol, and urine protein.

During 17 months from July 1995 to December 1996, 84 clinical sites in the US and Canada enrolled a total of 599 participants into ACTION II. Participants were followed with quarterly visits, with administrative censoring scheduled during the third quarter of 1999. On March of 1998, having accumulated 50% of the total information anticipated for ACTION II, the ACTION I and II External Safety Monitoring Committee (ESMC) recommended the early termination of the ACTION II trial due to safety concerns and apparent lack of efficacy.

Funding for ACTION I and II was provided by Alteon, Inc., 1993- 1998; IND 29,629.)