Study design and patient population
This study was a post-hoc analysis using data from a randomized, multicenter, open-label, parallel group, prospective clinical trial named Optimal Dose Escalation Strategy to Successful Achievement of High Dose Donepezil 23 mg (ODESA). Detailed study design and methods are described in a previous report.1 In brief, this study was conducted at 6 centers in South Korea between December 2014 and August 2016 to investigate the safety and tolerability of high-dose donepezil based on dose-escalation methods during the first 12 weeks. The study included consecutive patients with moderate to severe AD dementia. Inclusion criteria were as follows: 1) age between 45 and 90; 2) patients clinically diagnosed with probable AD dementia [16]; 3) patients who had been taking donepezil 10mg daily for at least 3 months prior to screening; 4) a score of 0-20 on the Korean version of the Mini-Mental State Examination (K-MMSE) [17]; 5) a clinical dementia rating (CDR) [18] score ≥2 or a global deterioration scale (GDS) [19] score ≥4. Patients with any neurological/ psychiatric disorders that might cause dementias not related to AD, severe medical conditions, and previous history of intolerance or hypersensitivity to AChEI were excluded. Participants were randomized into 3 groups: groups 1 and 2 were dose titration groups during the first 4 weeks using 2 different titration methods (group 1: 15mg of donepezil before the escalation; group 2: 10mg and 23mg on alternate days before the escalation), and group 3 had no dose titration and directly escalated to 23 mg donepezil. In the current study, the participants were divided into two groups according to the existence of AEs and baseline BW, regardless of the dose escalation methods.
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 outcome variables
Safety and tolerability were assessed at each visit during the study period (baseline and at weeks 4, 8, and 12). The primary safety outcome variable was the incidence of treatment emergent AE of special interests (AESI). We defined 8 most common cholinergic symptoms as AESIs: nausea, vomiting, diarrhea, anorexia, abdominal pain, headache, bradycardia, and weight loss. We assessed physical and neurologic examinations, weight, vital signs, and AE at every study visit. Nausea, vomiting, diarrhea, anorexia, abdominal pain, and headache were assessed by the patients’ and caregivers’ self-reports. Bradycardia indicates a pulse below 50 at any study visit, and weight loss indicates a ≥7% decrease compared with baseline BW at any time during the study. Other safety outcome variables included drop-out rates, drug compliance (ratio of drug taken to drug prescribed), AE gastrointestinal symptoms (including anorexia, nausea, vomiting, and diarrhea), and any AE occurrence. Subjects who discontinued the study before 12 weeks were asked to complete all end-point assessments at the time of early termination.
Statistical analyses
Baseline demographic and clinical characteristics were compared using an independent t-test or a Mann-Whitney U test for continuous variables and chi-square tests or Fisher’s exact tests for categorical variables. Group comparisons for incidences of AEs were performed using chi-square tests or Fisher’s exact tests; to adjust for confounding factors, we also used Cochran-Mantel-Haenzil tests. Relationships between the occurrence of AESIs and baseline characteristics were assessed using binary logistic regression analysis. Using univariable analysis, each baseline factor was assessed separately to measure the relationship. Using multivariable analysis, the five most relevant baseline factors were analyzed together to compare the relationships between baseline characteristics and the occurrence of AESIs. Significance for all tests was set at α = 0.05, two-tailed. All statistical analyses were performed using SPSS 19.0 (SPSS, Chicago, IL, USA).