Petersen 2005.
Methods | 3‐arm, parallel group, randomised, controlled trial, duration 3 years | |
Participants |
Location: United States and Canada. Setting of recruitment and treatment: 69 ADCS sites in the United States and Canada, between March 1999 and January 2004. Sample size:
Participant baseline characteristics:
Inclusion criteria:
Exclusion criteria:
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Interventions |
Active intervention: 2000 IU of vitamin E and multivitamin containing 15 IU of vitamin E daily. Intial vitamin E dose was 1000 IU daily, increased to 2000 IU (1000 IU twice daily) after 6 weeks. Comparator group: Placebo vitamin E and multivitamin containing 15 IU of vitamin E daily. Note: There was a third arm in which participants received donepezil. Both groups of interest in this review received placebo donepezil. |
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Outcomes |
Outcomes of interest in the review: Progression to possible or probable Alzheimer’s disease, defined according to the clinical criteria of the National Institute of Neurological and Communicative Diseases and Stroke and the Alzheimer’s Disease and Related Disorders Association. Overall cognitive function: MMSE (also measured: ADAS‐cog). Specific cognitive subdomain: episodic memory: standardised composite z‐score incorporating ADAS immediate and delayed word‐recall scores and the New York University immediate and delayed paragraph‐recall scores. Specific cognitive subdomain: executive function: standardised composite z‐score incorporating the digits‐backward test, Symbol Digit Modalities Test, and number‐cancellation test. Clinical global impression: CDR sum of boxes, Global Deterioration Scale. Functional performance: ADCS Mild Cognitive Impairment Activities of Daily Living Scale. Adverse events: rates of adverse events that occurred in at least 5% of subjects in the donepezil or vitamin E group and at least two times in the placebo group during the double‐blind phase. |
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Source of Funding | Supported by a grant from the National Institute on Aging (UO1 AG10483) (50% of funding), and by Pfizer and Eisai (50% of funding). DSM Nutritional Products donated the vitamin E. | |
Declaration of Interest | Most authors were either employees of a pharmaceutical company funding the study, or had received fees for various engagements from pharmaceutical companies. | |
Notes | ||
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Low risk | Quote: "We used an adaptive allocation scheme for the treatment assignment, with the MMSE score, age, and APOE ϵ4 status as balancing covariates. Comment: Adequate sequence generation in the study. |
Allocation concealment (selection bias) | Low risk | Comment: Insufficient information given. Should be adequate in a large multicentre well designed study. |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: “In this multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group study, which was conducted between March 1999 and January 2004”. Comment: Insufficient information on the process of double‐blinding. Should be adequate in a large multicentre RCT. Placebos used and identical treatment regimens in all groups. |
Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "A data and safety monitoring board reviewed the blinded safety data every three months during the trial.".. "verification by a central review committee that a participant met these clinical criteria for Alzheimer’s disease..." Comment: Should be adequate in a large trial with safety and central review committees for main outcomes. |
Incomplete outcome data (attrition bias) All outcomes | High risk | Only 185/257 (72%) in intervention and 193/259 (75%) completed review. Comment: More than 25% dropout from each arm. |
Selective reporting (reporting bias) | High risk | No protocol identified. Cognitive results reported as composite z‐scores, individual test results not reported. Number of participants in each analysis not reported. |
Other bias | Low risk | No other potential biases detected. |