Herrmann 2016.

Study characteristics
Methods	8‐week randomised, double‐blind, placebo‐controlled pilot trial
Participants	Setting: 2 long‐term care facilities in Canada between July 2010 and August 2015 Sample size: 40 patients were randomised to ChEI continuation (N = 21) or placebo (N = 19); 32 male and 8 female Age: mean 89.2 years Inclusion criteria ≥ 55 years Probable AD, according to NINDS‐ADRDA criteria Primary degenerative dementia, according to DSM‐IV criteria SMMSE ≤ 15 Treated with donepezil, galantamine or rivastigmine (oral) for ≥ 2 years, with a stable dose for ≥ 3 months prior to study entry If patient was receiving a concomitant psychotropic, they were required to have been on a stable dose for ≥ 1 month prior to study entry Exclusion criteria Dementia unrelated to AD Treated with transdermal rivastigmine Any uncontrolled illness that would interfere with participation in the study Significant difficulty ingesting oral medication
Interventions	Patients were randomised with a 1:1 ratio balanced by ChEI to continue receiving their ChEI (continuation) at their current dose, or to receive an identical‐looking placebo substitution. Patients randomised to placebo were tapered off their ChEI for the first 2 weeks and continued on placebo for the remaining 6 weeks.
Outcomes	1. Clinician's global impression CGI and CGI‐C. CGI was measured at 0, 4 and 8 weeks, CGI‐C at 4 and 8 weeks 2. Cognition SMMSE at 0, 2, 4 and 8 weeks SIB at 0, 4 and 8 weeks 3. Side effects UKU‐SERS at 0, 2, 4 and 8 weeks 4. Neuropsychiatric status NPI‐NH at 0, 4 and 8 weeks CMAI at 0, 4 and 8 weeks 5. Apathy AES at 0, 4 and 8 weeks 6. Function ADCS‐ADL‐sev at 0, 4 and 8 weeks 7. Quality of life QUALID at 0 and 8 weeks 8. Safety Vital signs (blood pressure, pulse rate, weight) at 0, 4 and 8 weeks 9. Adverse events, measured at 2, 4 and 8 weeks
Source of funding	Alzheimer's Society of Canada and internal funding, Sunnybrook Health Sciences Centre, Toronto, Canada
Declaration of interest	None declared
Notes	AD: Alzheimer's Disease ADCS‐ADL‐sev: Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory modified for severe dementia AES: Apathy Evaluation Scale CGI: Clinical Global Impressions scale CGI‐C: Clinical Global Impression of Change scale ChEI: Cholinesterase Inhibitor CMAI: Cohen Mansfield Agitation Inventory NINCDS‐ADRDA: National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association NPI‐NH: Neuropsychiatric Inventory‐Nursing Home version QUALID:Quality of Life in Late‐Stage Dementia scale SIB: Severe Impairment Battery SMMSE: Standardised Mini‐Mental State Examination UKU‐SERS: Kliniske Undersøgelser (UKU) Side Effects Rating Scale
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomisation was completed independently by the pharmacy at Sunnybrook Health Sciences Center in permuted blocks using a computer generated code".
Allocation concealment (selection bias)	Unclear risk	Methods used to conceal the allocation sequence were not described; therefore it was not possible to determine whether intervention allocations could have been foreseen in advance of, or during, enrolment.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Patients, family members, nurses, clinicians, outcome assessors, and investigators were unaware of treatment group assignments or block size".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Patients, family members, nurses, clinicians, outcome assessors, and investigators were unaware of treatment group assignments or block size".
Incomplete outcome data (attrition bias) All outcomes	High risk	40 patients were randomised to ChEI continuation (N = 21) or placebo (N = 19), and all were included in the analysis. The authors reported that all baseline characteristics were comparable, with the exception that patients randomised to ChEI continuation had lower SMMSE scores (P = 0.03). Of the 40 randomised patients, 33 patients (82.5%) completed the study (85.7% continuation, N = 18; 78.9% placebo, N = 15); 1 died prior to study completion (unrelated to study; placebo); 1 was terminated early because of a serious adverse effect (continuation); 1 was lost to follow‐up (continuation); 1 had clinically significant cognitive decline (placebo); and 3 had clinically significant neuropsychiatric deterioration (2 placebo, 1 continuation). Data for the primary outcome (CGI‐C; worsening, improvement/no change) were available for 83% of participants (86% continuation, 79% placebo). Overall, the number of participants with the event of interest (worsening on the CGI‐C) was 13 (13/40 = 33%), while the number of participants with missing data was 7 (7/40 = 18%). There may be possible bias because: 1. the proportion of missing data in the 2 groups is different (14% continuation, 21% placebo), and 2. the number of participants with the event of interest is not relatively greater in comparison to the number with missing data (N = 13 vs. N = 7). There is no evidence in analysis methods that correct for bias, or sensitivity analyses. The authors stated that the primary assessment of efficacy was based on an ITT comparison of CGI‐C ratings at week 8. However, there was no information on imputation of missing data, despite Figure 1 clearly showing that there were dropouts after randomisation, and the results stating that "forty institutionalised patients with moderate to severe AD were randomised..... and all were included in the analyses". Although not stated anywhere in the paper, there may have been imputation of missing data using LOCF. Reasons for missing data could be related to participants' health status: death, adverse events, loss to follow‐up.
Selective reporting (reporting bias)	Unclear risk	The study's prespecified primary, secondary and other outcomes (as detailed in the clinical trials registration documentation) were reported, with the exception of the number of 'prn' (as needed) medications used to treat behavioural and psychological symptoms of dementia (BPSD) at 0, 2, 4 and 8 weeks. For the CGI outcome measure, it was not made explicit whether this was the CGI‐S measure which considers severity. The authors reported that the UKU‐SERS scale was completed by primary nurses, but the scores were not reported in the manuscript. The documentation on the clinical trials registration website indicated that the Cornell Depression Scale for Dementia (CDSD) was to be administered at 0, 4 and 8 weeks. While the authors did report that the CDSD was administered by primary nurses, it was not clear whether this was performed at baseline only or at all time points, and no data were reported in the manuscript.
Other bias	Low risk	The authors acknowledged in the results section that patients randomised to the continuation group had lower SMMSE scores, and adjusted for this baseline SMMSE in the between‐group comparison.