A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase IIb Clinical Study to Evaluate the Safety and Efficacy of DHP1401 in Patients with Mild to Moderate Alzheimer’s Disease Treated with Donepezil: DHP1401 Randomized Trial in Mild to Moderate Alzheimer’s Disease (DRAMA)

Article type: Research Article

Authors: Shim, YongSoo^a | Han, Hyun Jeong^b | Park, Kyung Won^c | Kim, Byeong C.^d | Park, Kee Hyung^e | Park, Mee Young^f | Kim, Hee-Jin^g | Moon, So Young^h | Choi, Seong Hyeⁱ | Park, Kun Woo^j | Yang, Dong Won^k | Yoon, Soo Jin^l | Kim, Sang Yun^m | Youn, Young Chulⁿ | Choi, Hojin^o | Yoon, Koung Eun^p | Cho, Hyun Ju^p | Han, Seol-Heui^{q; *}

Affiliations: [a] Department of Neurology, The Catholic University of Korea Eunpyeong St. Mary’s Hospital, Seoul, Republic of Korea | [b] Department of Neurology, Myongji Hospital, Hanyang University College of Medicine, Goyang, Republic of Korea | [c] Department of Neurology, Dong-A University College of Medicine and Department of Translational Biomedical Sciences, Graduate School of Dong-A University, Busan, Republic of Korea | [d] Department of Neurology, Chonnam National University Medical School, Gwangju, Republic of Korea | [e] Department of Neurology, College of Medicine, Gachon University, Gil Medical Center, Incheon, Republic of Korea | [f] Department of Neurology, Yeungnam University College of Medicine, Daegu, Republic of Korea | [g] Department of Neurology, College of Medicine, Hanyang University, Seoul, Republic of Korea | [h] Department of Neurology, Ajou University School of Medicine, Suwon, Republic of Korea | [i] Department of Neurology, Inha University School of Medicine, Incheon, Republic of Korea | [j] Department of Neurology, Korea University Anam Hospital, Seoul, Republic of Korea | [k] Department of Neurology, The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul, Republic of Korea | [l] Department of Neurology, Daejeon Eulji Medical Center, Eulji University, Daejeon, Republic of Korea | [m] Department of Neurology, Seoul National University Bundang Hospital & Seoul National University College of Medicine, Seongnam, Republic of Korea | [n] Department of Neurology, Chung-Ang University College of Medicine, Seoul, Republic of Korea | [o] Department of Neurology, Hanyang University College of Medicine, Hanyang University Guri Hospital, Guri, Republic of Korea | [p] Clinical Trial Team, Daehwa Pharmaceutical Co., Ltd, Seoul, Republic of Korea | [q] Department of Neurology, Konkuk University Medical Center, Seoul, Republic of Korea

Correspondence: [*] Correspondence to: Seol-Heui Han, Department of Neurology, Konkuk University Medical Center, 120-1, Neungdong-ro, Gwangjin-gu, Seoul, 05030, Republic of Korea. Tel.: +82 2 2030 7751; E-mail: [email protected].

Abstract: Background:Preclinical studies in transgenic models of Alzheimer’s disease (AD) suggest that DHP1401 has neuroprotective and memory-enhancing effects. Objective:To evaluate the efficacy and safety of DHP1401 in AD patients treated with donepezil Methods:Methods: In a double-blind study, patients with mild-to-moderate AD were randomized (1:1:1) to receive a twice daily total dose of 500 mg or 1000 mg DHP1401 or placebo for 24 weeks. Tolerability and safety were monitored at baseline and weeks 12 and 24. Results:total of 180 patients were randomized to Active 1 (500 mg: n = 62), Active 2 (1000 mg: n = 53), and control groups (n = 65) in 16 sites in Korea. There was no significant difference in the Alzheimer’s Disease Assessment Scale (ADAS-cog) score, the primary efficacy endpoint, from baseline. However, in the subgroup with mild AD patients (MMSE, 20–26) who received the high dose of DHP1401 and the group that received donepezil 5 mg, the ADAS-cog scores improved. MMSE and K-TMT-e type B were significant in both active groups at week 24. The most frequently observed symptom was dizziness (2.78%), and the most commonly observed reactions were related to metabolism and nutrition disorders (5.00%). No remarkable adverse events were observed for 24 weeks. Conclusion:Although the effectiveness of DHP1401 was not proved to be superior as the primary efficacy endpoint, the secondary endpoints, MMSE and K-TMT-e type B, showed significant beneficial effects. Also, the subgroups showed that ADAS-cog scores significantly were improved. DHP1401 could be proven beneficial for the AD treatment by further clinical trials.

Keywords: Alzheimer’s disease, DHP1401, mild to moderate AD, randomized placebo-controlled clinical trial

DOI: 10.3233/JAD-215277

Journal: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 391-403, 2022