Background: Eighteen-month-long randomized, placebo-controlled clinical trials are common for phase II and phase III drug development for Alzheimer's disease (AD). Yet, no 18-month trial has shown statistically significant outcomes favoring the test drug. We examined characteristics and underlying assumptions of these trials by assessing the placebo groups.
Methods: We searched the clinicaltrials.gov registry for randomized, placebo-controlled clinical trials for AD of at least 18-month duration and extracted demographic, clinical, and trials characteristics, and change in main outcomes from the placebo groups. We obtained additional information from presentations, abstracts, publications, and sponsors.
Results: Of 23 trials identified, 11 were completed and had baseline data available; nine had follow-up data available; 17 were phase III. General inclusion criteria were very similar except that minimum Mini-Mental State Examination (MMSE) scores varied from 12 to 20. Sample sizes ranged from 402 to 1,684 for phase III trials and 80 to 400 for phase II. Cholinesterase inhibitor use was from 53% to 100%, and memantine use was from 13.5% to 78%. The AD Assessment Scale-cognitive (ADAS-cog) was the co-primary outcome in all trials; and activities of daily living, global severity, or global change ratings were the other co-primaries. APOE epsilon4 genotype carriers ranged from 58% to 67%; mean baseline ADAS-cog was 17.8 to 24.2. ADAS-cog worsening in the placebo groups during 18 months ranged from 4.34 to 9.10, with standard deviations from 8.17 to 9.39, increasing during 18 months.
Conclusions: Inclusion criteria are essentially similar to earlier 6-month and 12-month trials in which cholinesterase inhibitors were not allowed, as were mean ADAS-cog rates of change. Yet increasing variability and relatively little change overall in the ADAS-cog placebo groups, eg, about 25% of patients do not worsen by more than 1 point, might make it more unlikely than previously assumed that a modestly effective drug can be reliably recognized, especially when the drug might work only to attenuate decline in function and not to improve function. These observations would be strengthened by pooling individual trials data, and pharmaceutical sponsors should participate in such efforts.