A 36-week Multicenter, Randomised, Double-blind, Placebo-controlled, Parallel-group, Phase 3 Clinical Trial of Sodium Oligomannate for Mild-to-Moderate Alzheimer's Dementia
Authors: Xiao Shifu , Chan Piu , Wang Tao , Hong Zhen , Wang Shuzhen , Kuang Weihong , He Jincai , Pan Xiaoping , Zhou Yuying , Ji Yong , Wang Luning , Cheng Yan , Peng Ying , Ye Qinyong , Wang Xiaoping , Wu Yuncheng , Qu Qiumin , Chen Shengdi , Li Shuhua , Chen Wei , Xu Jun , Peng Dantao , Zhao Zhongxin , Li Yansheng , Zhang Junjian , Du Yifeng , Chen Weixian , Fan Dongsheng , Yan Yong , Liu Xiaowei , Zhang Wei , Luo Benyan , Wu Wenyuan , Shen Lu , Liu Chunfeng , Mao Peixian , Wang Qiumei , Zhao Qianhua , Guo Qihao , Zhou Yongtao , Li Yi , Jiang Lijun , Ren Wenwei , Ouyang Yingjun , Wang Yan , Liu Shuai , Jia Jianjun , Zhang Nan , Liu Zhonglin , He Raoli , Feng Tingyi , Lu Wenhui , Tang Huidong , Gao Ping , Zhang Yingchun , Chen Lanlan , Wang Lei , Yin You , Xu Qun , Xiao Jinsong , Cong Lin , Cheng Xi , Zhang Hui , Gao Dan , Xia Minghua , Lian Tenghong , Peng Guoping , Zhang Xu , Jiao Bin , Hu Hua , Chen Xueyan , Guan Yihui , Cui Ruixue , Huang Qiu , Xin Xianliang , Chen Hongjian , Ding Yu , Zhang Jing , Feng Teng , Cantillon Marc , Chen Kewei , Cummings Jeffrey L. , Ding Jian , Geng Meiyu , Zhang Zhenxin 
Published: November 2020

Abstract
Background: New therapies are urgently needed for Alzheimer’s disease (AD). Sodium oligomannate (GV-971) is a marine-derived oligosaccharide which reconstitutes gut microbiota, reduces neuroinflammation, decreases amyloid deposition, and improves cognition in AD animal models. 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: 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 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 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.