Characteristics and performance of a modified version of the ADCS-CGIC CIBIC+ for mild cognitive impairment clinical trials.
BACKGROUND
The Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) was modified for use in mild cognitive impairment (MCI) trials and tested in the ADCS MCI randomized clinical trial of donepezil, vitamin E, and placebo. We assessed feasibility for its use by determining whether or not: (1) it distinguished a medication effect at 6 months and 12 months, (2) baseline demographic or clinical characteristics predicted change, (3) there was an association between MCI-CGIC and change in other clinical measures in order to evaluate external or concurrent validity.


METHODS
We used a generalized estimating equations approach for ordinal outcome data to test the effects of treatment, baseline characteristics, and change in clinical measures on the MCI-CGIC over 12 months, and ordinal logistic regression to assess the association between MCI-CGIC and change in clinical measures at 6 months and 12 months.


RESULTS
On the MCI-CGIC overall, 12.9% and 10.6% were rated as having improved, and 31.6% and 39.8% as having worsened over 6 months and 12 months, respectively. The MCI-CGIC did not distinguish the donepezil or vitamin E groups from placebo at 6 and 12 months treatment. Variables at screening or baseline that were associated with worse CGIC scores over 6 and 12 months included white race, greater years of education, worse depression, dementia severity rating, cognitive, and daily activities scores, and lower memory domain scores on a neuropsychological battery. Rate of worsening on the MCI-CGIC over 12 months was associated with change on the Alzheimer Disease Assessment Scale-cognitive and on executive function. Worsening at 6 months and 12 months, separately, were associated with the corresponding change in Alzheimer Disease Assessment Scale-cognitive, Activities of Daily Living, Beck Depression Inventory, Mini-Mental State Examination, Clinical Dementia Rating sum of boxes, memory, and executive function.


CONCLUSIONS
Change detected by the MCI-CGIC was associated with baseline clinical severity and with change in clinical ratings over 6 and 12 months, supporting the validity of a CGIC approach in MCI. The effect size of the donepezil-placebo difference was similar to that of other outcomes at 12 months. About 40% of MCI patients were judged worse and about 11% improved, consistent with clinical experience and other ratings.
Schneider
Lon S
LS
Departments of Psychiatry and Neurology, Keck School of Medicine, University of Southern California, 1510 San Pablo Street, Los Angeles, CA 90033, USA. lschneid@usc.edu
Raman
Rema
R
Schmitt
Frederick A
FA
Doody
Rachelle S
RS
Insel
Philip
P
Clark
Christopher M
CM
Morris
John C
JC
Reisberg
Barry
B
Petersen
Ronald C
RC
Ferris
Steven H
SH
D000203:Activities of Daily Living; D000544:Alzheimer Disease / Q000517:prevention & control; D000975:Antioxidants / Q000627:therapeutic use; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000188:drug therapy*; D018450:Disease Progression; D000077265:Donepezil; D006801:Humans; D007189:Indans / Q000627:therapeutic use*; D008568:Memory / Q000187:drug effects*; D009483:Neuropsychological Tests; D010880:Piperidines / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012720:Severity of Illness Index; D014810:Vitamin E / Q000627:therapeutic use
D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D014810:Vitamin E; D000077265:Donepezil