Study design and procedures
This study was a randomized, multicenter, open-label, parallel-group, prospective clinical trial conducted in six centers in South Korea between December 2014 and August 2016. The study duration was 12 weeks, and the dose-titration duration was the first 4 weeks from the baseline. Patients with moderate to severe AD dementia were consecutively enrolled and randomized into three groups; groups 1 and 2 are dose-titration groups during the first 4 weeks using two different titration methods, and group 3 is no-titration group with direct escalation to 23-mg donepezil. Concomitant use of cognitive enhancers (i.e., choline alfoscerate, Ginkgo biloba, or acetyl-l-carnitine) or memantine was permitted but maintained at a stable dose during the study period. Other AChEIs and investigational products for cognition were prohibited during the study period or should have been discontinued for ≥ 12 weeks before screening. Medications that might cause gastrointestinal (GI) problems or cholinergic side effects were permitted (including antiplatelet agents, antihypertensive drugs, antidepressant drugs including selective serotonin receptor inhibitors, and cholinergic agonists), but should be taken with a stable dose for at least 3 months prior to the screening and maintained during the study. Study drug was provided free of charge and was administered at any time of day. To determine drug compliance, unused drugs were counted and recorded at every visit in each center. The number of remaining drugs was divided by the number of initially prescribed drugs at every visit, and the mean drug compliance was measured.
Patients with moderate to severe AD dementia were recruited. Our inclusion criteria were as follows: (1) age ranged between 45 and 90, (2) patients diagnosed with probable AD dementia according to the NIA-AA criteria , (3) patients who had been receiving donepezil 10 mg/day for at least 3 months prior to screening, (4) moderate to severe AD (MMSE , 0–20; clinical dementia rating (CDR) score , 2 or higher), (5) existence of a reliable caregiver who was sufficiently familiar with the patient to provide the investigator with accurate information, and (6) patient and caregiver agreed with the study participation. Patients were excluded if they had the following: (1) any neurological or psychiatric disorders that might cause dementias not related to AD (i.e., Parkinson’s disease, active epilepsy, normal pressure hydrocephalus, stroke, Huntington’s disease, schizophrenia, bipolar disorders); previous history of major depressive disorder was permitted; (2) history of participation in a clinical trial within 3 months prior to screening; (3) any severe or unstable medical disease that may prevent the patient from participating all study requirements (i.e., severe pulmonary, cardiovascular, GI, hematologic, endocrine, hepatic, or renal disease); (4) patients treated with other anti-dementia medications within 3 months (memantine combination with a stable dose of donepezil was allowed); (5) substance or alcohol abuse history within the past 5 years; and (6) previous history of intolerance or hypersensitivity to AChEIs. Written informed consent was obtained from the subject before the initiation of the study.
We divided patients into three groups according to the dose escalation method: 15 mg of donepezil for 4 weeks before escalating to 23 mg (group 1), 10 mg and 23 mg on alternate days for 4 weeks before escalating (group 2), and direct escalation to 23 mg (group 3).
The study protocol and informed consent form were reviewed and approved by the institutional review board of each center. The study was conducted in accordance with the Declaration of Helsinki and principles of Good Clinical Practice.
Safety and tolerability outcome variables
Primary safety outcome variable was the incidence of treatment emergent adverse events of special interests (AESI). AESI included nausea, vomiting, diarrhea, anorexia, abdominal pain, headache, bradycardia, and weight loss. Nausea, vomiting, diarrhea, anorexia, abdominal pain, and headache were assessed by the patient’s and caregivers’ self-reports. Bradycardia was defined as a low pulse rate below 50 per minute at any time during the study period. Weight loss indicates ≥ 7% weight decrease compared with the baseline weight at any time during the study. Secondary safety outcome variables included dropout rates, mean drug compliance (number of actually taken drugs/total number of prescribed drugs), vital signs, changes in weight or electrocardiogram at week 12, blood laboratory findings at week 12 (including hematology, biochemistry, and electrolytes in each center), and any AE occurrence (incidence, symptoms, severity, and relationship with the study drug). The AE occurrence was recorded using both spontaneous reports from patients/caregivers at any time throughout the study period and open-ended questioning by study staff at all study visits. Severities of AEs were rated as mild, moderate, or severe: AEs causing minimal inconvenience and easily tolerated without interfering normal daily activities were rated as mild, AEs interfering with the participant’s daily activities/functioning were rated as moderate, and AEs interrupting the participant’s normal daily activities were rated as severe. Relationships between the study drug and AEs were rated as unrelated, possibly related, or probably related: AEs clearly not related to the study drug were considered to be unrelated, AEs which follow a reasonable temporal sequence from initiation of the study drug but could be caused by other factors were considered to be possibly related, and AEs which follow a reasonable temporal sequence from initiation of the study drug and confirmed by improvement on stopping the study drug and that could not reasonably explained by other known characteristics of the participant’s clinical status were considered to be probably related. We assessed physical examinations, weight, vital signs, concomitant medications, and AE at each study visit (baseline, weeks 4, 8, and 12). Laboratory tests were performed at baseline and week 12. Subjects who withdrew prematurely were asked to complete all end-point assessments at the time of early termination. A visit window for five calendar days was allowed for the follow-up visits.
Sample size and randomization
Sample size was calculated under the assumption that incidence of AESI in group 1 would be 15% (95% confidence interval, 3–18%). Because there was no previous study that had investigated safety of donepezil 23 mg after dose titration, we exploratively presumed that the incidence would be lower than that of previous studies without dose titration [8, 9, 15]. As a result, 60 patients in each group were needed for our study without considering dropout rates as the study aimed to investigate safety and tolerability.
Patients were consecutively randomized in a 1:1:1 ratio using web-based stratified block randomization in each center. Stratification was based on gender and weight, whether a patient’s weight at baseline is below 55 kg or 55 kg or more, considering even distribution of gender and weight.
Safety set population was defined as all randomized patients who had a baseline evaluation, took at least one study drug, and at least one post-baseline assessment, regardless of study completion or discontinuation. Per-protocol (PP) population was defined as patients who completed the study without any major protocol violations.
Baseline demographic and clinical characteristics were compared using the analysis of variance (ANOVA) or Kruskal-Wallis tests for continuous variables according to the normal distribution patterns. Dunnett’s methods were used for post hoc analyses. Chi-square tests were used for categorical variables in both safety set population and PP population. Safety outcomes were analyzed in the safety set population. Group comparisons for incidences of AEs were performed using chi-square tests or Fisher’s exact tests. Odds ratio of each AE was assessed using binary logistic regression analysis. Significance for all tests was set at α = 0.05, two-tailed. All statistical tests were conducted using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina, USA).