Fine tuning brings its own risks

The FDA's decisions to halt and restart - all within one week - ProCyte Corp.'s Phase III trials of its Iamin peptide-copper compound to treat diabetic foot ulcers illustrates one of the tradeoffs in pivotal trial design - generating greater statistical significance can mean moving into sicker patients who are more likely to die or experience adverse events.

PRCY's original decision to do the Phase III studies in patients with larger ulcers (>100 mm 2) was dictated by statistical considerations. "The drug worked equally well in all size ulcers, but the best statistics were in large ulcers," said Leonard Patt, director of pharmaceutical research. There were 59 patients with plantar ulcers ranging in size from 25 mm2 to 2700 mm2 in the company's Phase II study. The mean percent of wound closure in the 27 who were treated immediately with 2 percent Iamin was 73 percent versus 10.3 percent in the 32 given placebo (p=0.015). But the statistics looked better in the subgroup of patients with ulcers of >100mm2 at entry. While the treatment group looked the same - 72.2 percent closure in 14 patients, the wounds in the 16 patients in the placebo group enlarged by 13.4 percent, resulting in a greater difference between the two groups (p=0.002). Thus in the Phase III trials, PRCY tightened the criteria to enroll only patients with plantar ulcers of >100mm2 in area, whereas the Phase II study enrolled patients with plantar, venous stasis and other lower-limb ulcers without the limitations on size. But the tradeoff was moving into sicker patients. "You see more deaths in patients with large wounds," said Karen Hedine, vice president of administration. "Those patients have more immunocompromised systems, more advanced disease. The underlying condition causes both the cardiovascular events and the ulcers. The patients have poor blood flow, which is why they have the wound and the cardiovascular disease. The real issue is the population you're treating." There have been seven cardiovascular-related deaths and 21 adverse cardiovascular events in the Phase III study, spread among the treatment and placebo groups. There was one death from pneumonia and nine cardiovascular events in the Phase II trial. A total of 339 patients have been enrolled to date in the Phase III trial; there were 181 patients in the earlier study. Hedine said that serum copper levels were normal in all the patients who died and that cardiovascular events are normal and expected in studies in diabetes. ...