Table 1

 Selected review of short- and long-term completed clinical trials in MCI

Donepezil+vitamin E*DonepezilRivastigmine†Galantamine study 1 (GAL-INT-11)Galantamine study 2 (GAL-INT-18)RofecoxibPiracetam
*Memory Impairment Study (MIS); †the Investigation into the Delay to Diagnosis of AD with Exelon (InDDEx); amnestic MCI, defined according to generally accepted criteria10: by memory complaint, corroborated by an informant, abnormal memory function documented by a variant of a delayed recall test, normal general cognitive function as determined by CDR and MMSE, no or minimal impairment in ADL, and not clinically demented.
ADAS-Cog, Alzheimer’s Disease Assessment Scale, Cognitive subscale; ADCS, Alzheimer Disease Cooperative Study; ADL, Activities of Daily Living scale; AVLT, Auditory Verbal Learning Test; BDRS, Blessed Dementia Rating Scale; CBCS, Cognitive Battery Composite Score; CDR, Clinical Dementia Rating scale; CDR-SB, Clinical Dementia Rating Scale—Sum of Boxes; CGIC, Clinical Global Impression of Change scale; BSI, Brief Symptoms Inventory; CIBIC-plus, Clinician’s Interview-Based Impression of Change with caregiver input; CSF, cerebrospinal fluid; Del Pg Rec, delayed paragraph recall; donep, donepezil; DS backw, Digit Symbol backwards; DSST, Digit Symbol Substitution Test; FE, fully available population; galantam, galantamine; GDS, Global Deterioration Scale; HDRS, Hamilton Depression Rating Scale; MMSE, Mini Mental State Examination; MRI, magnetic resonance imaging; NIA, National Institute on Aging; NINCDS-ADRDA criteria, National Institute of Neurological Disorders and Communicative Disorders-Alzheimer’s Disease and Related Disorders criteria; NP tests, neuropsychological tests; NPI, Neuropsychiatric Inventory; NYU Pg Rec, New York University Paragraph Recall; PET, positron emission tomography; PGA, Patient Global Assessment; plac, placebo; QL, quality of life; QOL-AD, Quality of Life—Alzheimer’s Disease; RCT, randomised clinical trial; rivastig, rivastigmine; Symb Dig Modalities, Symbol Digit Modalities; WMS-R, Wechsler Memory Scale-Revised.
SponsorNIA, Pfizer, Eisai,PfizerNovartisJohnson & JohnsonJohnson & JohnsonMerckUCB Pharma
Sites (start year)Multicentre, 69 ADCS centres in US and Canada (1999)Multicentre, USMulticentre, 69 centres in 14 countries: US, Canada, Europe, Latin America, South Africa (1999)Multicentre, 8 European countries, Canada, and US (2001)Multicentre, 4 European countries, Canada, US, Argentina, and Australia (2001)MulticentreMulticentre, 69 sites in 16 European countries (2000)
Study designRCT, placebo controlled, double blind, three armsRCT, placebo controlled, double blind, parallel groupRCT, placebo controlled, double blind, parallel groupRCT, placebo controlled, double blind, parallel groupRCT, placebo controlled, double blind, parallel groupRCT, placebo controlled, double blind, parallel groupRCT, placebo controlled, double blind, three arms
Daily doseVitamin E (1000 IU/bid), donepezil (10 mg/day)5 mg/day first 42 days, thereafter 10 mg/day3–12 mg/day16 or 24 mg/day, flexible dose16 or 24 mg/day, flexible dose25 mg/day4800 mg/day, 9600 mg/day
Trial duration3 years24 weeksPlanned 3 years, extended to 4 years24 months24 monthsPlanned 2–3 years, extended to 4 years12 months
Enrolment criteriaAmnestic MCI‡, (Del Pg Rec Logical Memory III from WMS-R), HDRS ⩽12, CDR 0.5 (⩾0.5 memory domain)Amnestic MCI‡ (Del Pg Rec Logical Memory II from WMS-R), CDR 0.5 (0.5–1.0 memory domain), MMSE ⩾24, HDRS ⩽12Amnestic MCI‡, (NYU Pg Rec Delayed Recall <9), CDR 0.5 (⩾0.5 memory domain), HDRS <13, HDRS item 1 ⩽1Amnestic MCI‡, (NYU Pg Rec Delayed Recall ⩽10), CDR 0.5 (⩾0.5 memory domain)Amnestic MCI‡, (NYU Pg Rec Delayed Recall ⩽10), CDR 0.5 (⩾0.5 memory domain)Amnestic MCI‡, (AVLT ⩽37), CDR 0.5 (⩾0.5 memory domain), MMSE ⩾24, BDRS ⩽3.5, HDRS ⩽12Amnestic MCI‡, CDR 0.5 (⩾0.5 memory domain), WMS-R Logical Memory immediate Recall <10 or difference between immediate and delayed recall >5, HDRS <18
No of subjects769269101899510621457675
Age (years)55–90 (mean 72.9)55–89 (mean 73)Mean 70.5>50>50⩾6550–89 (mean 68)
ApoE e458% donepezilNot available41% (determined in 49% of sample)26.4% galantamine24.4% galantamine35% rofecoxib43% (determined in 60% of sample)
55% vitamin E29.5% placebo23.5% placebo36% placebo
53% placebo
Primary outcomeTime to clinical diagnosis of AD (NINCDS-ADRDA criteria)Symptom change: NYU Pg Test Delayed Recall, CGIC-MCI(i) Time to clinical diagnosis of AD (NINCDS-ADRDA criteria); (ii) change from baseline on cognitive function as measured by a single score summed from weighted scores on a series of individual cognitive testsIncident dementia (CDR >1.0) at 24, ADAS-Cog/MCI, CDR-SB at 12 monthsIncident dementia (CDR >1.0) at 24, ADAS-Cog/MCI, CDR-SB at 12 monthsCDR >1.0 and incident AD (NINCDS-ADRDA criteria)Symptom change: CBCS
Secondary outcomeMMSE, ADAS-Cog, NP tests, CGIC, CDR, GDS, QL, ADL, outcome by APOE e4 statusADAS-Cog, NYU Pg Immediate Rec, DS-backw, Symb Dig Modalities, PGAADAS-Cog, MMSE, CDR, GDS, ADCS-ADL, NPI, QOL-AD, healthcare utilisation, outcome by APOE e4 status, volumetric MRI, and biomarkers (eg, CSF and blood levels of tau, amyloid-beta peptide)ADAS-Cog/MCI, CDR-SB, ADCS-ADL/MCI, DSST, ADAS-Cog/11, ADAS-Cog/13, MRI brain and hippocampal atrophyADAS-Cog/MCI, CDR-SB, ADCS-ADL/MCI, DSST, ADAS-Cog/11, and ADAS-Cog/13ADAS-Cog, MMSE, Selective Reminding Test, CDR, BDRSCIBIC-plus, change in separate tests of CBCS, ADL-MCI, MMSE, BSI, GDS
Conversion rates16%/year19.4%/3–4 years13% (galantam)17% (galantam)6.4% (rofecoxib)
18% (plac)/2 years21% (plac)/2 years4.5% (plac)/year
Dropout rate12%/year20%43%Not availableNot available45% (rofecoxib)27% (4800 mg)
45% (plac)21% (9600 mg)
24% (plac)
Adverse events88% (donep)96% (rivastig)90% (galantam)90% (galantam)90% (rofecoxib)72% (4800 mg)
73% (plac)93% (plac)88% (plac)86% (plac)92% (plac)68% (9600 mg)
76% (plac)
ResultsSignificant positive effect on conversion time and cognitive tests during first 18 months. In e4 carriers, positive treatment effect during 36 months. No effect in the vitamin E groupSignificant positive effect on ADAS-Cog in donep group FE population: immediate and delayed recall tests and DS backw, Symb Dig Modalities PGA. The study did not achieve its primary objectivesNo effect on conversion rate and ADAS-Cog, positive effect on CDR-CB, attention (DSST) at month 12, rate of atrophy of whole brain volume (not hippocampal), effect of symptom duration, and baseline severity (NYU Pg Rec)No effect on conversion rate, ADAS-Cog, or CDR-CB, positive effect on attention (DSST) at month 24. Effect of baseline severity (NYU Pg Rec) on conversion at month 24 (9% galantamine, 26% placebo)No change in primary or secondary efficacy parametersNo change in primary or secondary efficacy parameters