Table 1

Methodological shortcomings of 12 randomised controlled trials on donepezil

Author and yearDoseImbalance of groups at baseline with regard to% of missing patients in endpoint analyses—cholinesterase inhibitor (placebo)*Missing information in publicationNo correction for multiple comparisons†Calculation of mean values may bias resultsMissing information on blinding in reportOther shortcomings
Rogers et al 199651 mgWeight and heightCGIC—2 (0) ADAS-cog—not reportedCorrect: 1 significant resultADAS-cogYesInconsistent reports‡
3 mg—ADAS-cog—not reported
5 mg—CGIC—3 (0) ADAS-cog—not reportedADAS-cog: No of patients at end point
Rogers et al 1998a65 mg—ADAS-cog—1 (2) CIBIC-plus—3 (2)——ADAS-cog CIBIC-plusException: CIBIC-plus ratersDifferent dropout rates (P<0.05): placebo 7%; 10 mg: 18%; last observation carried forward
10 mgADAS-cog—2 (2) CIBIC-plus—4 (2)
Rogers et al 1998b75 mg—ADAS-cog—1 (6) CIBIC-plus—3 (6)--ADAS-cog CIBIC-plusException: CIBIC-plus ratersDifferent dropout rates (P<0.05): placebo 20%; 10 mg: 32%; last observation carried forward
10 mgAgeADAS-cog—5 (6) CIBIC-plus—5 (6)
Burns et al 199985 mg—Not reportedADAS-cog and CIBIC-plus: No of patients at end pointCorrect: 3 significant resultsADAS-cogYesLast observation carried forward
10 mg
Greenberg et al 200095 mgADAS-cog—20 (20)——ADAS-cog—Observed cases analysis only
Homma et al 2000105 mgADAS-cogADAS-cog—7 (14) J-CGIC—2 (2)Baseline characteristics of intention to treat population—ADAS-cogYes—
Feldman et al 20011110 mg—CIBIC-plus—3 (0)——CIBIC-plusYesYes
Mohs et al 20011210 mg—Dropout rate—28 (26) Missing patients in intention to treat population—3 (4)Some data reported only up to week 48——YesInconsistent report‡
Tariot et al 20011310 mgWeightNot reportedNeuropsychiatric inventory - nursing home version: No at end point—Neuropsychiatric inventory - nursing home versionYesInconsistent report‡
Winblad et al 20011410 mgSexGottfries-Brane-Steen scale—3 (0)——Gottfries-Brane-Steen scaleYesInconsistent report‡
AD2000 Collaborative Group 2004155 mg or 10 mg—Not reported adequately for the Bristol activities of daily living scale5 mg and 10 mg not analysed separately———Diverse problems, no clear duration of study, double randomisation
Holmes et al 20041610 mg————Neuropsychiatric inventoryYesSide effects of withdrawal, not efficacy of drug tested; last observation carried forward

  • ADAS-cog=Alzheimer's disease assessment scale—cognitive subscale.

  • CIBIC-plus=Clinician's interview based impression of change with caregiver input.

  • CGIC=Clinical global impression of change.

  • J-CGIC=Japanese version of the CGIC.

  • ↵* Refers to the intention to treat population.

  • ↵† This criterion is satisfied, when several primary end points were calculated without correction for multiplicity and the presented results after correction exceed the significance level of 5%. To adjust for multiple comparisons we used the Bonferroni method. As many trials do not report the number of attempted comparisons, the minimum number of reported independent tests concerning primary end points was used for adjustment. For example, in the study by Burns et al,8 two dose groups of donepezil and two primary outcome measures were specified: ADAS-cog and CIBIC-plus. Therefore four comparisons were assumed for Bonferroni adjustment, leading to a required level of 0.05/4=0.0125. This, in spite of an ambiguous definition of the evaluation procedure for the CIBIC-plus in the original publication, which allowed for much more methods of comparison, all of which are mentioned in the results section of the study: comparison of means and of fractions, applying various cut-points. Assuming four comparisons, one end point did not reach the adjusted level: the comparison of donepezil 5 mg with placebo on the CIBIC-plus scores ≥3 (P=0.015). The three other results remain significant after adjustment.

  • ↵‡ Data in tables and text, statements in text and abstract or study results, and abstracts of presentations at congresses are discrepant.