Controversy About Lack of Placebo Group Decline in Alzheimer's Trials
Lack of measureable decline in memory and thinking processes among placebo groups in Alzheimer's disease clinical trials might reduce the ability to show the effectiveness of new Alzheimer therapies, according to new research reported today at the 2008 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2008) in Chicago.
Alzheimer clinical trials seek to show that those who received the treatment improved over the course of the study when compared to those who received the placebo, or that they got worse to a lesser degree. A complication that is emerging in Alzheimer clinical trials is the perception that participants with Alzheimer's in the placebo arms of the trials are showing less worsening over the time period of current studies. It has been speculated that this may be due to:
Inadequate sensitivity of the standard scales used for measuring cognition in these trials.
Differences in disease severity and co-existing medical conditions between the populations being recruited now compared with previous trials.
The relatively common use of the currently approved Alzheimer drugs (cholinesterase inhibitors and memantine) by populations involved in the clinical trials.
"In Alzheimer trials, if the placebo group does not worsen over the course of the trial then it might be very difficult, or even impossible, to show that a drug is effective," said William Thies, PhD, vice president for Medical & Scientific Relations at the Alzheimer's Association.
Two scientific presentations from ICAD 2008 address the issue head on – one through a review of 87 Alzheimer clinical trials conducted between 1991 and 2005, and the second by specifically looking at trials of the drug donepezil from 1990 to 1999.
Analysis of Multiple Studies Reveals Process to Ensure Placebo Group Decline
Lon S. Schneider, MD, professor of psychiatry and neurology at the University of Southern California Keck School of Medicine, and professor of gerontology at the USC Leonard Davis School of Gerontology and colleagues searched published and unpublished sources for six months or longer randomized, double-blind, placebo-controlled Alzheimer clinical trials. They found 103 trials conducted between 1991 and 2005 and obtained information from 87. From these they extracted information about trial size, countries, number of sites, treatment allocation ratios, enrollment dates, age, gender, and scores on two standard measures of cognition – the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog).
The researchers found no changes in amounts of cognitive decline across the 15-year time period of the trials. They found that smaller placebo groups were associated with less likelihood of cognitive worsening over the course of the trial. Placebo group sample sizes less than 100 had a 37 percent chance of not showing significant change, while samples greater then 200 all showed significant worsening at six months. In 12-month studies, 95 percent of placebo group sample sizes greater then 100 showed significant decline.
Several other factors were found to be associated with whether or not there was cognitive decline in the placebo group. Studies with non-English speaking trial sites were associated with less cognitive worsening over the course of the clinical trial. Use of more frequent cognitive assessments reduced the amount of variance in the amount of worsening. Use of cholinesterase inhibitors was not associated with less cognitive decline during clinical trials.
"Experts have no need to worry that people with Alzheimer's in clinical trials are less likely to worsen than they have before, or that cholinesterase inhibitors are lessening decline of placebo treated patients in recent trials," Schneider said. "Based on our analysis, the most reliable approach to maximize the likelihood for demonstrating efficacy is to have a placebo group size greater than 200 and to use the ADAS-cog at least four times and in English."
Scientific Review of Donepezil Trials Shows Slowing Rates of Placebo Group Decline
Professor Roy Jones, Director of RICE – The Research Institute for the Care of Older People, based at the Royal United Hospital in Bath, England, and colleagues conducted a meta-analysis using individual patient data from randomized, double-blind, placebo-controlled studies of donepezil (Aricept) for Alzheimer's between 1990 and 1999. The work stemmed from discussions and analyses undertaken through an expert working group initiated and funded by Eisai and Pfizer, makers and marketers of donepezil.
"Our results indicate that patients with Alzheimer's entering the later clinical trials appear to be experiencing a slower rate of decline in memory and thinking processes," Jones said. "These observations are potentially important for the future design of clinical trials in people with Alzheimer's. For example, it may be necessary to conduct longer duration research studies – more than 24 weeks – to ensure any effects of treatment can be fully evaluated."
Data were available from 3,403 patients who participated in 13 randomized, double-blind, placebo-controlled Alzheimer trials. Data were grouped according to the year of initiation of the trials. Group 1: studies initiated in 1990-1994; Group 2: studies initiated in 1996-1999. This cut-off was associated with the timing of donepezil registration. Changes from baseline MMSE and ADAS-cog scores up to week 24 were compared between groups 1 and 2 for placebo only, and then between donepezil and placebo.
Decline on the MMSE from baseline to week 24 was significantly greater among placebo patients in group 1 (-1.28 points) compared with group 2 (-0.56 points; P = 0.024). Placebo decline on the ADAS-cog was also greater in group 1 than group 2, but the difference was nonsignificant.
The 2008 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2008) is the largest gathering of international leaders in Alzheimer research and care ever convened. At ICAD 2008, more than 5,000 researchers from 60 countries will share groundbreaking information and resources on the cause, diagnosis, treatment and prevention of Alzheimer's and related disorders. As a part of the Association's research program, ICAD serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community. ICAD 2008 will be held in Chicago at McCormick Place, Lake Side Center from July 26–31.
About the Alzheimer's Association
The Alzheimer's Association, the nonprofit world leader in Alzheimer's research and support, is the first and largest U.S. voluntary health organization dedicated to finding prevention methods, treatments and an eventual cure for Alzheimer's. For more than 25 years, the donor-supported Alzheimer's Association has provided reliable information and care consultation; created supportive services for families; increased funding for dementia research; and influenced public policy changes. For more information, call (800) 272-3900 or visit www.alz.org.