1. ¹University of California, San Diego, CA, USA
2. ²New York University School of Medicine, New York, NY, USA
3. ³Pivotal Research Centers, Peoria, AZ, USA
4. ⁴Merck Research Laboratories, West Point, PA, USA

Correspondence: Dr CR Lines, Merck Research Laboratories, 10 Sentry Parkway, Blue Bell, PA 19422, USA. Tel: +1 484 344 2595; Fax: +1 484 344 4940; E-mail: chris_lines@merck.com

⁵Members of the Rofecoxib Protocol 078 study group are listed in Acknowledgments

Received 8 March 2004; Revised 16 December 2004; Accepted 29 December 2004; Published online 2 March 2005.

Abstract

Inflammatory mechanisms have been implicated in Alzheimer's disease (AD) and might be mediated via the COX-2 enzyme. Previous studies with the selective COX-2 inhibitors, rofecoxib and celecoxib, have shown that they do not alter the progression of AD. We conducted a double-blind study to investigate whether rofecoxib could delay a diagnosis of AD in patients with mild cognitive impairment (MCI), a group with an expected annual AD diagnosis rate of 10–15%. MCI patients 65 years were randomized to rofecoxib 25 mg (N=725) or placebo (N=732) daily for up to 4 years. The primary end point was the percentage of patients with a clinical diagnosis of AD. The estimated annual AD diagnosis rate was lower than the anticipated 10–15%: 6.4% in the rofecoxib group vs 4.5% in the placebo group (rofecoxib : placebo hazard ratio=1.46 (95% CI: 1.09, 1.94), p=0.011). Analyses of secondary end points, including measures of cognition (eg the cognitive subscale of the AD Assessment Scale (ADAS-Cog)) and global function (eg the Clinical Dementia Rating (CDR)), did not demonstrate differences between treatment groups. There was also no consistent evidence that rofecoxib differed from placebo in post hoc analyses comparing ADAS-Cog and CDR-sum of boxes scores in overlapping subgroups of patients who had Mini Mental State Exam scores of 24–26 in the present MCI study and in a previous AD treatment study with a similar design. The results from this MCI study did not support the hypothesis that rofecoxib would delay a diagnosis of AD. In conjunction with the lack of effects observed in previous AD studies, the findings suggest that inhibition of COX-2 is not a useful therapeutic approach in AD.