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Treatment of MCI With Rivastigmine: Results From the InDDEx Study: Presented at AAT

By Chris Berrie

GENEVA, SWITZERLAND -- April 24, 2006 -- Although rivastigmine does not appear to promote significant overall benefits for patients with amnestic mild cognitive impairment (aMCI), 2 subpopulations do appear to be revealed with respect to their nonprogression or progression to Alzheimer's disease (AD), according to research presented here at the 9^th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy (AAT).

The randomised, placebo-controlled, double-blind trial, which investigated the acetylcholinesterase and butyrylcholinesterase inhibitor rivastigmine, was presented on April 21^st on behalf of the InDDEx (Investigation to Delay the Diagnosis of AD with Exelon) Study Group.

MCI appears to represent a transition state between normal aging and dementia, with aMCI potentially being a useful diagnostic construct to reduce the intrinsic heterogeneity of the MCI condition, explained coinvestigator Howard Feldman, MD, chairman, Diagnostic Monitoring Committee, and head, division of neurology, Clinic for Alzheimer's Disease and Related Disorders, University of British Columbia, Vancouver, British Columbia, Canada.

"So, [amnestic MCI] would be quite suitable in the first instance to begin to test drugs that will delay progression to the time of AD, and the cholinesterase inhibitors seem to be suitable candidates."

This originally 36-month study was increased to 48 months to allow further conversions from aMCI to AD to occur, and it was designed as an 18-week dose titration from 0.5 mg rivastigmine BID that a mean daily dose of 5.7 mg. As Dr Feldman stressed, "One of the major problems that comes up in this study is that the mean dose of rivastigmine used in the rivastigmine arm is under 6 mg per day," and thus below what might now be accepted as being an effective therapeutic dose.

Inclusion criteria were clinical dementia rating (CDR) of 0.5 or greater and a New York University (NYU) Delayed Paragraph Recall Test score less than 9. Patients were excluded if they met various specified criteria for AD, and if they had major or active depression, other unstable, advanced, or severe comorbid medical illnesses, and neurodegenerative or cardiac disease. Those with a known hypersensitivity to AChE inhibitors were also excluded.

Coprimary outcomes were time to clinical diagnosis of AD and change in cognitive function. The latter was measured by a composite Z score using a battery of 10 individual cognitive tests. A comparison of a range of secondary outcomes was also included.

The 1018 subjects enrolled were randomised in 2 equal groups to placebo (mean age, 70.6 years; male, 49%) and rivastigmine (mean age, 70.3 years; male, 47%). Baseline characteristics were similar across these 2 groups, except that the apolipoprotein E (APOE) epsilon-4 genotype -- which was previously shown to be a potent predictor of progression to AD -- was low in the rivastigmine arm (36.5%) compared with the placebo arm (46.4%).

After the full 48 months, although the coprimary endpoint of mean time to AD was not significantly different between the placebo (1289 days) and rivastigmine (1318 days) arms, it did show a tendency towards a benefit from rivastigmine (hazard ratio, 0.85; 95% confidence interval, 0.64-1.12; P =.242).

The researchers found no significant differences in Z score measures of cognitive function, with mean changes from baseline of -1.03 for placebo versus -1.10 for rivastigmine (P =.726). Similarly, none of the secondary outcome measures showed significant differences, except for the ventricular volume changes that showed a significant benefit for rivastigmine over placebo in the first 2 years (year 1, P =.009; year 2, P =.019).

However, significant differences were found when the study cohort was evaluated according to progression or nonprogression to AD in various areas: mean age (placebo, 74.0 vs 69.8 years; rivastigmine, 74.0 vs 69.5 years), MMSE scores (placebo, 27.5 vs 24.7; rivastigmine, 27.4 vs. 25.1), CRD sum of boxes (placebo, 1.3 vs. 1.9; rivastigmine, 1.4 vs 1.9), GDS (placebo 2.3 vs 2.7; rivastigmine, 2.4 vs 2.7), hippocampal volume (placebo, 3.7 vs 3.1 cm^3; rivastigmine, 3.8 vs 3.1 cm³) and, in particular, lower APOE epsilon-4 genotype (placebo, 43.2% vs 59.0%; rivastigmine, 36.5% vs 55.0%).

Overall frequencies of adverse events were similar in the 2 treatment arms, as for serious adverse events. However, there was a higher overall treatment discontinuation rate in the rivastigmine arm (25.3% vs 12.2% for placebo) that potentially arose from the increased nausea (rivastigmine, 49.3%; placebo 14.3%), vomiting (32.5% vs 7.3%), dizziness (24.8% vs 15.3%), diarrhoea (23.2% vs 9.2%) and headache (21.4% vs 15.1%).

After also reporting on some further exploratory analyses from this study, Dr. Feldman concluded, "Those subjects that progressed to Alzheimer's disease are systematically more impaired, with higher proportions for the APOE epsilon-4 genotyping, and we were not able to remove the heterogeneity [of MCI] in this study."

Novartis Pharma AG provided financial support for this study.


[Presentation title: Treatment of MCI With Rivastigmine: Results From the InDDEx Study. Abstract 28]

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