Sano 2011.
| Methods | Randomised, placebo‐controlled, double‐blind trial. Multicentre trial (45 sites) conducted by the ADCS, a consortium of US centres funded by the National Institute of Aging | |
| Participants | Individuals with probable AD according to NINCDS‐ADRDA criteria Inclusion criteria included aged > 50 years and MMSE score 12‐26. Mean (± SD) age 74.6 ± 9.3 years. Stable use (for at least 3 months) of cholinesterase inhibitors and memantine was allowed Duration of study: 18 months Mean (± SD) total cholesterol in the groups combined at study entry was 211.9 ± 30.8 mg/dL, mean (± SD) LDL‐C 126.0 ± 25.1 mg/dL, mean (± SD) HDL‐C 60.9 ± 16.4 mg/dL. 59.4% women |
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| Interventions | Intervention group: simvastatin 20 mg for 6 weeks and simvastatin 40 mg thereafter for the remainder of the 18‐month study Placebo group: matching placebo |
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| Outcomes | Primary outcome: change in ADAS‐Cog score Secondary outcomes: ADCG‐CGIC, MMSE, Dependence Scale, ADCS‐ADL, NPI 3 supplemental cognitive tests from the ADCS instrument protocol Quality of life ADCS Resource Use Instrument Adverse events |
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| Notes | Individuals were excluded if they had other neurological or psychiatric diagnosis that could interfere with cognitive function, if they were taking lipid‐lowering drugs or if they had conditions requiring cholesterol‐lowering treatment as defined by Adult Treatment Guidelines at that time. They were also excluded if they had LDL‐C < 80 mg/dL or triglycerides > 500 mg/dL, if they had recently taken drugs with significant central anticholinergic effects, sedatives, anti‐parkinsonian medications or any investigational treatment for AD. Other excluded medications were those that are specifically contraindicated with simvastatin as well as those that could interact with CYP 3A4 to either increase or decrease levels of simvastatin | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomisation carried out using a random permuted block treatment assignment stratified by site with equal probability of assignment to drug and placebo. Randomisation sequence generated by the ADCS data centre Comment: probably done |
| Allocation concealment (selection bias) | Low risk | Randomisation sequence generated by the ADCS data centre Comment: probably done |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | "Scratch‐off" code breakers were used so that instances of unblinding would be documented: all code breakers were collected at the end of the trial. Adequacy of the blinding was assessed by questionnaires completed by participants, carers, psychometrists and site investigators Comment: probably done |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Double blind Comment: probably done |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Flow of participants through the study detailed in a figure. 685 subjects screened, 406 randomised, 279 not randomised as did not meet criteria. 204 participants in treatment group, 15 lost to follow‐up before month 18, 145 completed month 18 on medication, 3 completed month 18 off medication. 202 participants in placebo group, 10 participants lost to follow‐up before month 18, 152 completed month 18 on medication, 4 completed month 18 off medication. Predominant reasons for early discontinuation were side effects (16 in placebo arm, 13 in treatment arm) and study partner's unwillingness or inability to continue (7 in placebo arm, 22 in treatment arm). There were no statistically significant differences in baseline characteristics between study participants who discontinued early and study completers (data not published, available by request from authors) |
| Selective reporting (reporting bias) | Unclear risk | Most cognitive and functional outcomes reported. CGIC data available upon request but not provided on contacting study author |