Results of a follow-up study to the randomized Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT)

Abstract

Objectives: The Alzheimer's Disease Anti-inflammatory Prevention Trial Follow-up Study (ADAPT-FS) was designed to evaluate the efficacy of naproxen and celecoxib for the primary prevention of Alzheimer's disease (AD) several years after cessation of treatment in ADAPT.

Methods: ADAPT was a randomized, double-masked, multicenter clinical trial of naproxen or celecoxib vs placebo (1:1:1.5 assignment ratio) at six U.S.-based clinics. The trial enrolled 2528 people between 2001 and 2004. Treatments were discontinued in December 2004 and participants were monitored regularly until 2007. In 2010 and 2011, ADAPT-FS screened 1537 participants by telephone and, if indicated, examined them in person using standardized clinical assessments. The primary outcome was time to diagnosis of AD. Death index searches were performed for participants not located.

Results: Eighty-nine additional AD events were identified (24 celecoxib, 25 naproxen, and 40 placebo) yielding a total of 161 events (48 [6.6% of randomized participants] celecoxib, 43 [6.0%] naproxen, and 70 [6.5%] placebo) across ADAPT and ADAPT-FS. Adjusted hazard ratios (HRs) comparing each treatment with placebo showed no overall reduction in risk of AD: HR celecoxib vs placebo, 1.03 (95% confidence interval [CI], 0.72-1.50; P = .86); HR naproxen vs placebo, 0.92 (95% CI, 0.62-1.35; P = .66). There were 349 deaths (110 [15.2%] celecoxib, 96 [13.4%] naproxen, and 143 [13.2%] placebo). Risk of death was similar for the naproxen- and placebo-assigned groups (HR, 0.99; 95% CI, 0.76-1.28; P = .93) and slightly higher for celecoxib compared with the placebo-assigned group (HR, 1.15; 95% CI, 0.90-1.48; P = .27).

Conclusions: These results acquired during a follow-up of approximately 7 years (which included a median of less than 1.5 years of treatment) do not support the hypothesis that celecoxib or naproxen prevent AD in adults with a family history of dementia.

Keywords: Alzheimer's disease; Celecoxib; Clinical trial; Naproxen; Nonsteroidal anti-inflammatory drug; Prevention.

Fig. 1

Participant flow in the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) and the Alzheimer's Disease Anti-inflammatory Prevention Trial Follow-up Study (ADAPT-FS). *Numbers available only for those randomized, not those screened for eligibility. ^†Participants considered to have terminated study drug if study drug had been started but was no longer issued prior to December 17, 2004. Does not include temporary interruptions. The number of participants who never took the study drug is updated from previous publications. ^‡Participants were eligible but did not have an assessment. ^§Participants' status was considered unknown after final death sweep.

Fig. 2

Cumulative incidence of Alzheimer's disease (AD) over the Alzheimer's Disease Anti-inflammatory Prevention Trial and the Alzheimer's Disease Anti-inflammatory Prevention Trial Follow-up Study. Cel, celecoxib; Plb, placebo; Nap, naproxen.

Fig. 3

Cumulative incidence of death the Alzheimer's Disease Anti-inflammatory Prevention Trial and the Alzheimer's Disease Anti-inflammatory PreventionTrial Follow-up Study. Cel, celecoxib; Plb, placebo; Nap, naproxen.