GCR: Alzheimer's Disease

Cholinesterase Inhibitors

Assessment of Efficacy

How is the efficacy of CHE-I assessed in clinical trials?
One of the difficulties that investigators and the FDA faced prior to the approval of tacrine was how to determine appropriate assessment instruments and clinical endpoints for cognitive-enhancing medications. To evaluate treatment effect, it was also necessary to estimate the rate of disease progression in untreated patients.

The current primary outcome measures utilized by the FDA for the evaluation of any drug for treatment of AD includes

Study design is double blind, placebo controlled with parallel groups
Statistically significant differences between active treatment and placebo groups on both
- Alzheimer's Disease Assessment Scale Cognitive Portion (ADAS-Cog)
- Clinical Interview Based Impression of Change with Caregiver Input (CIBIC-Plus)

The ADAS-Cog subscale is an instrument that measures multiple domains of cognitive functioning.^¹

More sensitive indicator of cognitive decline than the MMSE. An example of estimated equivalent ADAS-Cog scores is shown in below.

MMSE	ADAS-Cog
10	48.1
15	36.1
20	24.0
30	0

Assesses language, memory, praxis and response to commands
Scored from 0-70; lower scores indicate milder disease
Typical deterioration in untreated patients with mild-moderate AD is 7-10 points/year ²
Decrease of 4 points is thought to represent a clinically significant effect of treatment³

The CIBIC-Plus is a global assessment of overall clinical effect based on evaluation of cognition, behavior, and ADL functioning as observed by the clinician-evaluator and caregiver.⁴ This scale rates global function from 1-7 in following manner

Score of 1 represents marked clinical improvement
Score of 4 represents no change
Score of 7 represents marked worsening

Since the initial CHE-I clinical trials, investigators have begun including other rating instruments in clinical trials after realizing that these agents impact important domains not measured by the standard scales. The Progressive Deterioration Scale (PDS) measures change in IADL and ADL functioning.⁵ The Neuropsychiatric Inventory (NPI) is being increasingly utilized in dementia trials to quantitate the severity and frequency of common behavioral symptoms in AD as reported by caregiver interview.⁶

The appropriate length of CHE-I trials continues to be debated. The standard length of CHE-I is 6 months, however, data from a limited number of extended longitudinal trials is available. Longer-term studies are essential to elucidate the effects of these medications on cognition, behavior, function, and the overall course of AD.

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