Selected review of short- and long-term completed clinical trials in MCI
| Donepezil+vitamin E* | Donepezil | Rivastigmine† | Galantamine study 1 (GAL-INT-11) | Galantamine study 2 (GAL-INT-18) | Rofecoxib | Piracetam | |
|---|---|---|---|---|---|---|---|
| *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. | |||||||
| Sponsor | NIA, Pfizer, Eisai, | Pfizer | Novartis | Johnson & Johnson | Johnson & Johnson | Merck | UCB Pharma |
| Sites (start year) | Multicentre, 69 ADCS centres in US and Canada (1999) | Multicentre, US | Multicentre, 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) | Multicentre | Multicentre, 69 sites in 16 European countries (2000) |
| Study design | RCT, placebo controlled, double blind, three arms | RCT, placebo controlled, double blind, parallel group | RCT, placebo controlled, double blind, parallel group | RCT, placebo controlled, double blind, parallel group | RCT, placebo controlled, double blind, parallel group | RCT, placebo controlled, double blind, parallel group | RCT, placebo controlled, double blind, three arms |
| Daily dose | Vitamin E (1000 IU/bid), donepezil (10 mg/day) | 5 mg/day first 42 days, thereafter 10 mg/day | 3–12 mg/day | 16 or 24 mg/day, flexible dose | 16 or 24 mg/day, flexible dose | 25 mg/day | 4800 mg/day, 9600 mg/day |
| Trial duration | 3 years | 24 weeks | Planned 3 years, extended to 4 years | 24 months | 24 months | Planned 2–3 years, extended to 4 years | 12 months |
| Enrolment criteria | Amnestic 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 ⩽12 | Amnestic MCI‡, (NYU Pg Rec Delayed Recall <9), CDR 0.5 (⩾0.5 memory domain), HDRS <13, HDRS item 1 ⩽1 | Amnestic 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 ⩽12 | Amnestic 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 subjects | 769 | 269 | 1018 | 995 | 1062 | 1457 | 675 |
| Age (years) | 55–90 (mean 72.9) | 55–89 (mean 73) | Mean 70.5 | >50 | >50 | ⩾65 | 50–89 (mean 68) |
| ApoE e4 | 58% donepezil | Not available | 41% (determined in 49% of sample) | 26.4% galantamine | 24.4% galantamine | 35% rofecoxib | 43% (determined in 60% of sample) |
| 55% vitamin E | 29.5% placebo | 23.5% placebo | 36% placebo | ||||
| 53% placebo | |||||||
| Primary outcome | Time 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 tests | Incident dementia (CDR >1.0) at 24, ADAS-Cog/MCI, CDR-SB at 12 months | Incident dementia (CDR >1.0) at 24, ADAS-Cog/MCI, CDR-SB at 12 months | CDR >1.0 and incident AD (NINCDS-ADRDA criteria) | Symptom change: CBCS |
| Secondary outcome | MMSE, ADAS-Cog, NP tests, CGIC, CDR, GDS, QL, ADL, outcome by APOE e4 status | ADAS-Cog, NYU Pg Immediate Rec, DS-backw, Symb Dig Modalities, PGA | ADAS-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 atrophy | ADAS-Cog/MCI, CDR-SB, ADCS-ADL/MCI, DSST, ADAS-Cog/11, and ADAS-Cog/13 | ADAS-Cog, MMSE, Selective Reminding Test, CDR, BDRS | CIBIC-plus, change in separate tests of CBCS, ADL-MCI, MMSE, BSI, GDS |
| Conversion rates | 16%/year | – | 19.4%/3–4 years | 13% (galantam) | 17% (galantam) | 6.4% (rofecoxib) | – |
| 18% (plac)/2 years | 21% (plac)/2 years | 4.5% (plac)/year | |||||
| Dropout rate | 12%/year | 20% | 43% | Not available | Not available | 45% (rofecoxib) | 27% (4800 mg) |
| 45% (plac) | 21% (9600 mg) | ||||||
| 24% (plac) | |||||||
| Adverse events | 88% (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) | |||||||
| Results | Significant 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 group | Significant 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 objectives | No 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 parameters | No change in primary or secondary efficacy parameters |