Recruitment of a multi-site randomized controlled trial of aerobic exercise for older adults with amnestic mild cognitive impairment: The EXERT trial.

INTRODUCTION: Effective strategies to recruit older adults with mild cognitive impairment (MCI) into nonpharmacological intervention trials are lacking. METHODS: Recruitment for EXERT, a multisite randomized controlled 18-month trial examining the effects of aerobic exercise on cognitive trajectory in adults with amnestic MCI, involved a diverse portfolio of strategies to enroll 296 participants. RESULTS: Recruitment occurred September 2016 through March 2020 and was initially slow. After mass mailings of 490,323 age- and geo-targeted infographic postcards and brochures, recruitment rates increased substantially, peaking at 16 randomizations/month in early 2020. Mass mailings accounted for 52% of randomized participants, whereas 25% were recruited from memory clinic rosters, electronic health records, and national and local registries. Other sources included news broadcasts, public service announcements (PSA), local advertising, and community presentations. DISCUSSION: Age- and geo-targeted mass mailing of infographic materials was the most effective approach in recruiting older adults with amnestic MCI into an 18-month exercise trial.

Reliability of monitoring the clinical dementia rating in multicenter clinical trials.

CONTEXT: The Clinical Dementia Rating (CDR) is quickly becoming a criterion standard in multicenter clinical trials in Alzheimer disease. An abbreviated version, with formal monitoring for consistency across sites and raters, is currently used in the Alzheimer's Disease Cooperative Study (ADCS). OBJECTIVE: To demonstrate the degree of agreement on CDR scoring of clinical monitors working independently from ADCS-CDR worksheets. DESIGN: Three members of the ADCS who are experienced and highly trained with respect to the CDR independently reviewed the ADCS-CDR worksheets of 15 subjects, assigning box and global CDR scores according to the prescribed algorithm. SETTING: The ratings were assigned during a single, 3-hour session in a closed room. PARTICIPANTS: Two clinical monitors and one project director/clinical monitor supervisor. MAIN OUTCOME MEASURES: Percent agreement, Kendall's tau-b, and Cohen's kappa were used to assess the degree of agreement of the raters with the previously established gold standard assessment on global and box scores for the 15 subjects. RESULTS: Raters, blinded to patient groupings, were in agreement with the Gold Standard global CDR assessment on 87% of ratings. Kappa values indicated good (kappa = 0.66, orientation and judgment & problem solving boxes) to excellent (kappa = 0.83, global CDR) agreement. CONCLUSIONS: The ADCS-CDR worksheets were reliably and consistently scored by clinical monitors, who may be considered proxy gold standards for CDR assessment.

Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial.

CONTEXT: Laboratory evidence that inflammatory mechanisms contribute to neuronal injury in Alzheimer disease (AD), along with epidemiological evidence, suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) may favorably influence the course of the disease. OBJECTIVE: To determine whether treatment with a selective cyclooxygenase (COX) -2 inhibitor (rofecoxib) or a traditional nonselective NSAID (naproxen) slows cognitive decline in patients with mild-to-moderate AD. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to study medications. SETTING: Forty ambulatory treatment centers affiliated with the Alzheimer's Disease Cooperative Study consortium. PARTICIPANTS: Participants with mild-to-moderate AD (Mini-Mental State Examination score of 13-26) were recruited from December 1999 to November 2000 using clinic populations, referrals from community physicians, and local advertising. Stable use of cholinesterase inhibitors, estrogen, low-dose aspirin, and vitamin E was allowed. Participants with inflammatory diseases that might respond to the study medications were excluded. Of 474 participants screened, 351 were enrolled. INTERVENTIONS: Once-daily rofecoxib, 25 mg, or twice-daily naproxen sodium, 220 mg, or placebo. MAIN OUTCOME MEASURES: The primary outcome measure was the 1-year change in the Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score. Secondary outcome measures included the Clinical Dementia Rating scale sum-of-boxes, the Neuropsychiatric Inventory, the Quality of Life-AD, and the time to attainment of significant end points (4-point decline from baseline ADAS-Cog score, 1-step worsening on the global Clinical Dementia Rating scale, 15-point decline on the ADCS activities of daily living inventory, institutionalization, or death). RESULTS: The 1-year mean (SD) change in ADAS-Cog scores in participants treated with naproxen (5.8 [8.0]) or rofecoxib (7.6 [7.7]) was not significantly different from the change in participants treated with placebo (5.7 [8.2]). Results of secondary analyses showed no consistent benefit of either treatment. Fatigue, dizziness, and hypertension were more commonly reported in the active drug groups, and more serious adverse events were found in the active treatment group than in the placebo group. CONCLUSION: The results of this study indicate that rofecoxib or low-dose naproxen does not slow cognitive decline in patients with mild-to-moderate AD.