A 36-week multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial of sodium oligomannate for mild-to-moderate Alzheimer’s dementia

Springer Science and Business Media LLC - Tập 13 Số 1 - 2021
Shifu Xiao1, Piu Chan2, Tao Wang1, Zhen Hong3, Shuzhen Wang4, Weihong Kuang5, Jincai He6, Xiaoping Pan7, Yuying Zhou8, Yong Ji8, Luning Wang9, Yan Cheng10, Ying Peng, Qinyong Ye11, Xiaoping Wang12, Yun-Cheng Wu12, Qing Qu13, Shengdi Chen14, Shuhua Li15, Wei Chen16, Jun Xu17, Dantao Peng18, Zhao Zhi-gang19, Yansheng Li20, Junjian Zhang21, Yifeng Du22, Weixian Chen23, Dongsheng Fan24, Yongmin Yan25, Xiaowei Liu26, Wei Zhang27, Benyan Luo28, Wei Wu29, Lu Shen30, Chunfeng Liu31, Peixian Mao32, Qiumei Wang33, Qianhua Zhao3, Qihao Guo3, Yanjun Zhou2, Yi Li4, Lijun Jiang5, Wenwei Ren6, Yingjun Ouyang7, Yan Wang8, Shuai Liu8, Jianjun Jia9, Nan Zhang10, Zhonglin Liu34, Raoli He11, Tingyi Feng12, Wenhui Lu13, Huidong Tang14, Ping Gao15, Yingchun Zhang16, Lanlan Chen17, Lei Wang18, You Yin19, Qun Xu20, Jian‐Kang Xiao21, Cong Liu22, Xi Cheng23, Zhang Hui24, Dan Gao25, Minghua Xia26, Ting Lian27, Guoping Peng28, Xu Zhang29, Bin Jiao30, Hua Hu31, Xueyan Chen32, Yihui Guan3, Ruixue Cui33, Qiu Huang35, Xianliang Xin36, Hongjian Chen36, Yu Ding36, Jing Zhang36, Teng Feng36, Marc Cantillon36, Kewei Chen37, Jeffrey L. Cummings38, Jian Ding39, Meiyu Geng39, Zhenxin Zhang33
1Department of Geriatric Psychiatry, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, China
2Xuanwu Hospital Capital Medical University, Beijing, China
3Huashan Hospital, Fudan University, Shanghai, China
4Qilu Hospital of Shandong University, Ji’nan, China
5West China Hospital of Sichuan University, Chengdu, China
6The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
7Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
8Tianjin Huanhu Hospital, Huanhu Hospital Affiliated to Nankai University, Tianjin, China
9Department of Geriatric Neurology of PLA General Hospital, Beijing, China
10Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
11Fujian Medical University Union Hospital, Fuzhou, China
12Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
13Department of Neurology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
14Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
15Beijing Hospital, Beijing, China
16Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine and Key Laboratory of Medical Neurobiology of Zhejiang Province, Hangzhou, China
17Northern Jiangsu People’s Hospital, Yangzhou, China
18Department of Neurology, China-Japan Friendship Hospital, Beijing, China
19Shanghai Changzheng Hospital, Shanghai, China
20Renji Hospital Shanghai, Jiaotong University School of Medicine, Shanghai, China;
21Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, China
22Shandong Provinical Hospital affiliated to Shandong University, Ji’nan, China
23Jiangsu Province People’s Hospital, Nanjing, China
24Peking University Third Hospital, Beijing, China
25The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
26Department of Geriatric psychiatry, Wuxi Mental Health Center, Wuxi, China
27Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
28The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
29Tongji Hospital of Tongji University, Shanghai, China
30Xiangya Hospital, Central South University, Changsha, China
31The Second Affiliated Hospital of Soochow University, Suzhou, China
32Beijing An Ding Hospital, Capital Medical University, Beijing, China
33Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Beijing, 100730, China
34Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
35Med-X Research Institution, Shanghai Jiao Tong University, Shanghai, China
36Shanghai Green Valley Pharmaceutical Co. Ltd., No. 421, Niudun Road, Shanghai, China
37Banner Alzheimer's Institute, Phoenix, AZ, USA
38Chamberrs-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada, Las Vegas, USA
39State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu chong zhi Road, Nevada, China

Tóm tắt

Abstract Background

New therapies are urgently needed for Alzheimer’s disease (AD). Sodium oligomannate (GV-971) is a marine-derived oligosaccharide with a novel proposed mechanism of action. The first phase 3 clinical trial of GV-971 has been completed in China.

 Methods

We conducted a phase 3, double-blind, placebo-controlled trial in participants with mild-to-moderate AD to assess GV-971 efficacy and safety. Participants were randomized to placebo or GV-971 (900 mg) for 36 weeks. The primary outcome was the drug-placebo difference in change from baseline on the 12-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog12). Secondary endpoints were drug-placebo differences on the Clinician’s Interview-Based Impression of Change with caregiver input (CIBIC+), Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, and Neuropsychiatric Inventory (NPI). Safety and tolerability were monitored.

 Results

A total of 818 participants were randomized: 408 to GV-971 and 410 to placebo. A significant drug-placebo difference on the ADAS-Cog12 favoring GV-971 was present at each measurement time point, measurable at the week 4 visit and continuing throughout the trial. The difference between the groups in change from baseline was − 2.15 points (95% confidence interval, − 3.07 to − 1.23; p < 0.0001; effect size 0.531) after 36 weeks of treatment. Treatment-emergent adverse event incidence was comparable between active treatment and placebo (73.9%, 75.4%). Two deaths determined to be unrelated to drug effects occurred in the GV-971 group.

 Conclusions

GV-971 demonstrated significant efficacy in improving cognition with sustained improvement across all observation periods of a 36-week trial. GV-971 was safe and well-tolerated.

 Trial registration

ClinicalTrials.gov, NCT02293915. Registered on November 19, 2014

Từ khóa


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