Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study
Feldman HH, Ferris S, Winblad B, Sfikas N, Mancione L, He Y, et al.;
Commented by , 22 May 2007
Aim of the study
To assess the effects of the cholinesterase inhibitor rivastigmine in patients with mild cognitive impairment (MCI) on the time to clinical diagnosis of Alzheimer's disease (AD) and the rate of cognitive decline.
Method
Double-blind randomized (1:1) controlled trial comparing for 48 months rivastigmine 3-12mg/day (using a 18-week titration period) to placebo in patients with MCI defined as cognitive symptoms, global clinical dementia rating (CDR) stage 0.5, <9 on the NYU delayed paragraph recall test, not demented clinically.
The primary outcomes were time to a clinical diagnosis of AD (e.g. dementia) and change in performance on a 10-test cognitive battery. Secondary outcomes were performance on ADAS-cog, MMSE, ADCS-ADL, GDS, CDR, Beck depression inventory, NPI, quality of life, rate of volumetric changes in whole brain, ventricles, hippocampi from MRI.
Correlations were made with gender, apoE and BCHE genotypes. Progression to dementia was made by clinicians at scheduled 3-monthly visits with verification by a four-member diagnosis monitoring committee.
Results
1526 patients were screened, 1018 were randomized, 197 progressed to dementia over 4 years (19%). 500 participated in the ApoE genotyping study, 207 carrying one or two copies of ApoE ε4 (41%), and 490 in the BCHE study, 156 showing the K variant (32%).
There was no statistically significant differences in the primary analysis between rivastigmine and placebo treated groups, nor when ApoE status was taken into consideration. Phamacogenomic post-hoc analysis showed fewer progression from MCI to AD in rivastigmine-treated women who were homozygous for the wid-type BCHE genotype compared to placebo (HR 0.46 [95% CI 0.233-0.911], p=0.026), and the ventricular volume expansion was reduced in this group (p=0.012).
Despite adverse events (AE) being equal in frequency, total discontinuation rates due to AE were 12.2% on drug and 6.7% on placebo.
Professor Gauthier's comments
The InDDEx study was made at a time when there was hope of delaying the time of progression from MCI to clinical AD, e.g. early dementia caused by AD, using cholinesterase in hibitors. A study done with donepezil has already been published (ref. 1) and the study with galantamine will be submitted for publication shortly. All failed in the primary analysis to show a significant delay in progression.
These negative results should not be deter investigators and sponsors to work in MCI populations, since there is a good possibility of modifying the pathophysiological processes in the pre-dementia stage of AD.
Much has been learned from the three pivotal trials with rivastimine, donepezil and galantamine in terms of entry criteria that allow for higher rates of progression per year, the importance of ApoE genotype in rate of progression (future trials should stratify for carrier status before randomization), means of diagnosing early dementia.
The new generation of amyloid-modifying drugs, including tramiprosate and R-flurbiprofen) may be the best candidates for future "delay of progression from pre-dementia AD to AD" trials.
References
1. Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. New England Journal of Medicine 2005; 352(23); 2379-2388. Free full text article