PMID- 31039806 OWN - NLM STAT- MEDLINE DCOM- 20200508 LR - 20200508 IS - 1758-9193 (Electronic) VI - 11 IP - 1 DP - 2019 May 1 TI - Safety and tolerability of donepezil 23 mg with or without intermediate dose titration in patients with Alzheimer's disease taking donepezil 10 mg: a multicenter, randomized, open-label, parallel-design, three-arm, prospective trial. PG - 37 LID - 10.1186/s13195-019-0492-1 [doi] LID - 37 AB - BACKGROUND: High-dose donepezil is currently prescribed for patients with Alzheimer's disease (AD) who showed poor or waning response to a lower dose at the risk of increasing cholinergic side effects. However, the adverse events (AEs) depending on the method of dose escalation have not been clarified yet. This study aimed to find out whether dose titration before escalating to donepezil 23 mg is preferred. We investigated safety and tolerability of donepezil 23 mg during the first 12 weeks of dose escalation in patients with moderate to severe AD. METHODS: This study was a 12-week, multicenter, randomized, open-label prospective trial. We included patients with moderate to severe AD who were treated with a stable dose of donepezil 10 mg/day. Patients were randomized into 3 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 prior to escalation (group 2), and direct escalation to 23 mg (group 3). Safety analyses included incidence, severity, timing of AEs, relationship to the study drug, and premature study discontinuation due to AEs between the groups. RESULTS: Among 175 enrolled, 110 patients completed the study. Baseline characteristics were similar among the groups. Using safety population (N = 160), cholinergic gastrointestinal symptoms including anorexia and nausea were the most common AEs and titration groups showed significantly fewer cases of nausea as compared with those in no-titration group. CONCLUSIONS: In this study, dose titration before escalating to donepezil 23 mg/day showed better safety in terms of cholinergic AEs. We suggest that dose titration during the first 4 weeks can be recommended for patients with moderate to severe AD. TRIAL REGISTRATION: Clinicaltrials.gov , NCT02550665. Retrospectively registered on 15 Sep 2015. FAU - Hong, Yun Jeong AU - Hong YJ AUID- ORCID: 0000-0002-4996-4981 AD - Neurology, The Catholic University of Korea, Uijeongbu St. Mary's Hospital, Uijeongbu, South Korea. AD - Neurology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea. FAU - Han, Hyun Jeong AU - Han HJ AD - Neurology, Dementia and Neurocognitive Center, Hanyang University College of Medicine, Myongji Hospital, Ilsan, South Korea. FAU - Youn, Young Chul AU - Youn YC AD - Neurology, Chung-Ang University Hospital, Seoul, South Korea. FAU - Park, Kyung Won AU - Park KW AD - Neurology, Dong-A University College of Medicine, Busan, South Korea. FAU - Yang, Dong Won AU - Yang DW AD - Neurology, The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, South Korea. FAU - Kim, SangYun AU - Kim S AD - Neurology, Seoul National University College of Medicine & Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Seongnam, South Korea. FAU - Kim, Hwa Jung AU - Kim HJ AD - Preventive Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea. FAU - Kim, Ji Eun AU - Kim JE AD - Neurology, University of Ulsan College of Medicine, Gangneung Asan Hospital, Gangneung, South Korea. FAU - Lee, Jae-Hong AU - Lee JH AD - Neurology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea. jhlee@amc.seoul.kr. CN - ODESA study (Optimal Dose Escalation Strategy to Successful Achievement of High Dose Donepezil 23 mg) LA - eng SI - ClinicalTrials.gov/NCT02550665 GR - 2014-0576/Asan Institute for Life Sciences, Asan Medical Center/International PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20190501 PL - England TA - Alzheimers Res Ther JT - Alzheimer's research & therapy JID - 101511643 RN - 0 (Cholinesterase Inhibitors) RN - 8SSC91326P (Donepezil) SB - IM MH - Aged MH - Aged, 80 and over MH - Alzheimer Disease/*drug therapy MH - Cholinesterase Inhibitors/*adverse effects MH - Donepezil/*adverse effects MH - Dose-Response Relationship, Drug MH - Female MH - Humans MH - Male MH - Prospective Studies MH - Treatment Outcome PMC - PMC6492390 OTO - NOTNLM OT - Alzheimer's disease OT - Dose-titration OT - High-dose donepezil OT - Safety OT - Tolerability COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: 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. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2019/05/02 06:00 MHDA- 2020/05/10 06:00 PMCR- 2019/05/01 CRDT- 2019/05/02 06:00 PHST- 2018/12/10 00:00 [received] PHST- 2019/04/09 00:00 [accepted] PHST- 2019/05/02 06:00 [entrez] PHST- 2019/05/02 06:00 [pubmed] PHST- 2020/05/10 06:00 [medline] PHST- 2019/05/01 00:00 [pmc-release] AID - 10.1186/s13195-019-0492-1 [pii] AID - 492 [pii] AID - 10.1186/s13195-019-0492-1 [doi] PST - epublish SO - Alzheimers Res Ther. 2019 May 1;11(1):37. doi: 10.1186/s13195-019-0492-1.