Tiopinac in rheumatoid arthritis: a three-phase dose-ranging, efficacy, and aspirin-withdrawal protocol

We designed a clinical trial to obtain dose-ranging, efficacy, and aspirin-withdrawal data on tiopinac in patients with rheumatoid arthritis. To accomplish this without exposing the patients to risk of disease exacerbation and avoiding type II error, we used a 3-phase protocol adding tiopinac to current therapy. The 3 phases-open-label dose ranging, double-blind tiopinac versus placebo, and aspirin withdrawal-began after a single-blind run-in period. The manufacturer withdrew tiopinac from investigation because of toxicity at higher doses, but with only 13 patients we found that tiopinac (up to 300 mg/day) decreased walking time, painful joints, and morning stiffness and increased grip strength (p less than 0.05). Both the global evaluation by the investigators and patient ratings of their activity showed superiority of tiopinac (tiopinac: 5 better, 1 worse; placebo: 1 better, 6 worse; p = 0.028 by Fisher's exact test). Complete aspirin withdrawal could be accomplished in only 3 patients, although in 10 of 13 the dose could be reduced 50% of baseline or less. The 3-phase protocol indicated effectiveness, a dose range, and partial aspirin replacement with minimal patient risk.