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

doi:10.1186/s13195-021-00795-7

Clinical Trial

. 2021 Mar 17;13(1):62.

doi: 10.1186/s13195-021-00795-7.

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

Shifu Xiao^#^{1

2}, Piu Chan^#³, Tao Wang^#^{4

5}, Zhen Hong⁶, Shuzhen Wang⁷, Weihong Kuang⁸, Jincai He⁹, Xiaoping Pan¹⁰, Yuying Zhou¹¹, Yong Ji¹¹, Luning Wang¹², Yan Cheng¹³, Ying Peng¹⁴, Qinyong Ye¹⁵, Xiaoping Wang¹⁶, Yuncheng Wu¹⁶, Qiumin Qu¹⁷, Shengdi Chen¹⁸, Shuhua Li¹⁹, Wei Chen²⁰, Jun Xu²¹, Dantao Peng²², Zhongxin Zhao²³, Yansheng Li²⁴, Junjian Zhang²⁵, Yifeng Du²⁶, Weixian Chen²⁷, Dongsheng Fan²⁸, Yong Yan²⁹, Xiaowei Liu³⁰, Wei Zhang³¹, Benyan Luo³², Wenyuan Wu³³, Lu Shen³⁴, Chunfeng Liu³⁵, Peixian Mao³⁶, Qiumei Wang³⁷, Qianhua Zhao⁶, Qihao Guo⁶, Yongtao Zhou³, Yi Li⁷, Lijun Jiang⁸, Wenwei Ren⁹, Yingjun Ouyang¹⁰, Yan Wang¹¹, Shuai Liu¹¹, Jianjun Jia¹², Nan Zhang¹³, Zhonglin Liu¹⁴, Raoli He¹⁵, Tingyi Feng¹⁶, Wenhui Lu¹⁷, Huidong Tang¹⁸, Ping Gao¹⁹, Yingchun Zhang²⁰, Lanlan Chen²¹, Lei Wang²², You Yin²³, Qun Xu²⁴, Jinsong Xiao²⁵, Lin Cong²⁶, Xi Cheng²⁷, Hui Zhang²⁸, Dan Gao²⁹, Minghua Xia³⁰, Tenghong Lian³¹, Guoping Peng³², Xu Zhang³³, Bin Jiao³⁴, Hua Hu³⁵, Xueyan Chen³⁶, Yihui Guan⁶, Ruixue Cui³⁷, Qiu Huang³⁸, Xianliang Xin³⁹, Hongjian Chen³⁹, Yu Ding³⁹, Jing Zhang³⁹, Teng Feng³⁹, Marc Cantillon³⁹, Kewei Chen⁴⁰, Jeffrey L Cummings⁴¹, Jian Ding⁴², Meiyu Geng⁴³, Zhenxin Zhang⁴⁴

Affiliations

¹ Department of Geriatric Psychiatry, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, China. xiaoshifu@msn.com.
² Alzheimer's Disease and Related Disorders Center, Shanghai Jiaotong University, 600 South Wan Ping Road, Shanghai, 200030, China. xiaoshifu@msn.com.
³ Xuanwu Hospital Capital Medical University, Beijing, China.
⁴ Department of Geriatric Psychiatry, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
⁵ Alzheimer's Disease and Related Disorders Center, Shanghai Jiaotong University, 600 South Wan Ping Road, Shanghai, 200030, China.
⁶ Huashan Hospital, Fudan University, Shanghai, China.
⁷ Qilu Hospital of Shandong University, Ji'nan, China.
⁸ West China Hospital of Sichuan University, Chengdu, China.
⁹ The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
¹⁰ Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
¹¹ Tianjin Huanhu Hospital, Huanhu Hospital Affiliated to Nankai University, Tianjin, China.
¹² Department of Geriatric Neurology of PLA General Hospital, Beijing, China.
¹³ Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China.
¹⁴ Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
¹⁵ Fujian Medical University Union Hospital, Fuzhou, China.
¹⁶ Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
¹⁷ Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
¹⁸ Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
¹⁹ Beijing Hospital, Beijing, China.
²⁰ Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine and Key Laboratory of Medical Neurobiology of Zhejiang Province, Hangzhou, China.
²¹ Northern Jiangsu People's Hospital, Yangzhou, China.
²² Department of Neurology, China-Japan Friendship Hospital, Beijing, China.
²³ Shanghai Changzheng Hospital, Shanghai, China.
²⁴ Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
²⁵ Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, China.
²⁶ Shandong Provinical Hospital affiliated to Shandong University, Ji'nan, China.
²⁷ Jiangsu Province People's Hospital, Nanjing, China.
²⁸ Peking University Third Hospital, Beijing, China.
²⁹ The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
³⁰ Department of Geriatric psychiatry, Wuxi Mental Health Center, Wuxi, China.
³¹ Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
³² The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
³³ Tongji Hospital of Tongji University, Shanghai, China.
³⁴ Xiangya Hospital Central South University, Changsha, China.
³⁵ The Second Affiliated Hospital of Soochow University, Suzhou, China.
³⁶ Beijing An Ding Hospital, Capital Medical University, Beijing, China.
³⁷ Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Beijing, 100730, China.
³⁸ Med-X Research Institution, Shanghai Jiao Tong University, Shanghai, China.
³⁹ Shanghai Green Valley Pharmaceutical Co. Ltd., No. 421, Niudun Road, Shanghai, China.
⁴⁰ Banner Alzheimer's Institute, Phoenix, AZ, USA.
⁴¹ Chamberrs-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada, Las Vegas, USA.
⁴² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu chong zhi Road, Nevada, China.
⁴³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu chong zhi Road, Nevada, China. mygeng@simm.ac.cn.
⁴⁴ Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Beijing, 100730, China. wuzhangzhenxin@163.com.

^# Contributed equally.

PMID: 33731209
PMCID: PMC7967962
DOI: 10.1186/s13195-021-00795-7

Free PMC article

Clinical Trial

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

Shifu Xiao et al. Alzheimers Res Ther. 2021.

Free PMC article

. 2021 Mar 17;13(1):62.

doi: 10.1186/s13195-021-00795-7.

Authors

Affiliations

¹ Department of Geriatric Psychiatry, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, China. xiaoshifu@msn.com.
² Alzheimer's Disease and Related Disorders Center, Shanghai Jiaotong University, 600 South Wan Ping Road, Shanghai, 200030, China. xiaoshifu@msn.com.
³ Xuanwu Hospital Capital Medical University, Beijing, China.
⁴ Department of Geriatric Psychiatry, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
⁵ Alzheimer's Disease and Related Disorders Center, Shanghai Jiaotong University, 600 South Wan Ping Road, Shanghai, 200030, China.
⁶ Huashan Hospital, Fudan University, Shanghai, China.
⁷ Qilu Hospital of Shandong University, Ji'nan, China.
⁸ West China Hospital of Sichuan University, Chengdu, China.
⁹ The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
¹⁰ Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
¹¹ Tianjin Huanhu Hospital, Huanhu Hospital Affiliated to Nankai University, Tianjin, China.
¹² Department of Geriatric Neurology of PLA General Hospital, Beijing, China.
¹³ Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China.
¹⁴ Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
¹⁵ Fujian Medical University Union Hospital, Fuzhou, China.
¹⁶ Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
¹⁷ Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
¹⁸ Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
¹⁹ Beijing Hospital, Beijing, China.
²⁰ Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine and Key Laboratory of Medical Neurobiology of Zhejiang Province, Hangzhou, China.
²¹ Northern Jiangsu People's Hospital, Yangzhou, China.
²² Department of Neurology, China-Japan Friendship Hospital, Beijing, China.
²³ Shanghai Changzheng Hospital, Shanghai, China.
²⁴ Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
²⁵ Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, China.
²⁶ Shandong Provinical Hospital affiliated to Shandong University, Ji'nan, China.
²⁷ Jiangsu Province People's Hospital, Nanjing, China.
²⁸ Peking University Third Hospital, Beijing, China.
²⁹ The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
³⁰ Department of Geriatric psychiatry, Wuxi Mental Health Center, Wuxi, China.
³¹ Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
³² The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
³³ Tongji Hospital of Tongji University, Shanghai, China.
³⁴ Xiangya Hospital Central South University, Changsha, China.
³⁵ The Second Affiliated Hospital of Soochow University, Suzhou, China.
³⁶ Beijing An Ding Hospital, Capital Medical University, Beijing, China.
³⁷ Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Beijing, 100730, China.
³⁸ Med-X Research Institution, Shanghai Jiao Tong University, Shanghai, China.
³⁹ Shanghai Green Valley Pharmaceutical Co. Ltd., No. 421, Niudun Road, Shanghai, China.
⁴⁰ Banner Alzheimer's Institute, Phoenix, AZ, USA.
⁴¹ Chamberrs-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada, Las Vegas, USA.
⁴² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu chong zhi Road, Nevada, China.
⁴³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu chong zhi Road, Nevada, China. mygeng@simm.ac.cn.
⁴⁴ Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Beijing, 100730, China. wuzhangzhenxin@163.com.

^# Contributed equally.

PMID: 33731209
PMCID: PMC7967962
DOI: 10.1186/s13195-021-00795-7

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, NCT0229391 5. Registered on November 19, 2014.

Keywords: Alzheimer’s disease; Clinical trial; Efficacy; Safety; Sodium oligomannate.

PubMed Disclaimer

Conflict of interest statement

Shifu Xiao and Zhenxin Zhang have been the provisional consultants of Pfizer, Lilly, Novartis, Roche, GSK, Johnson & Johnson, Lundbeck, Biogen, and Green Valley and received honorariums. Xianliang Xin, Hongjian Chen, Yu Ding, Jing Zhang, and Marc Cantillon were full-time employees of Shanghai Green Valley Pharmaceutical Co., Ltd. Kewei Chen was a full-time employee of Shanghai Green Valley Pharmaceutical Co., Ltd. at the time the [¹⁸F]-FDG-PET data was analyzed. Currently, he is a full-time employee of Banner Health to which Banner Alzheimer’s Institute belongs, and serves as a paid consultant to Shanghai Green Valley Pharmaceutical Co., Ltd. Jeffrey L. Cummings has provided consultation to Acadia, Actinogen, Alkahest, Alzheon, Avanir, Axsome, BiOasis Technologies, Biogen, Cerecin, CNS Innovations, Cortexyme, EIP, Eisai, Genentech, Green Valley, Grifols, Hisun, Idorsia, Merck, Otsuka, Resverlogix, Roche, Samus, Samumed, Sunovion, Suven, and United Neuroscience pharmaceutical and assessment companies.

Figures

**Fig. 1**
Enrollment, randomization, and completion. *Not treated n = 1, in GV-971 group

**Fig. 2**
Mean ADAS-Cog12 score change from baseline at weeks 4, 12, 24, and 36 (observed value). The mean change from baseline to week 36 on the ADAS-Cog12 (with scores ranging from 0 to 75 and higher scores indicating greater impairment) by full analysis set was showed. Error bars represent standard errors (SE). p values are obtained from the Wilcoxon rank sum tests

**Fig. 3**
Secondary outcome of CIBIC+ at week 36. p value is obtained from a stratified Cochran-Mantel-Haenszel (CMH) test, including stratification factors of MMSE at baseline, education level, and age group

**Fig. 4**
Analyses for the change in primary and secondary outcomes from baseline to week 36. *The direction of the ADCS-ADL change scores was reversed for consistency with the other outcomes

**Fig. 5**
Mean ADAS-Cog12 score change from baseline at weeks 4, 12, 24, and 36 (observed value) on the ADAS-Cog12 by the MMSE subgroup. Error bars represent standard errors (SE). p values are obtained from the Wilcoxon rank sum tests

See this image and copyright information in PMC

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References

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[1] Zhang Y, Xu Y, Nie H, Lei T, Wu Y, Zhang L, Zhang M. Prevalence of dementia and major dementia subtypes in the Chinese populations: a meta-analysis of dementia prevalence surveys, 1980-2010. J Clin Neurosci. 2012;19(10):1333–1337. doi: 10.1016/j.jocn.2012.01.029. - DOI - PubMed

[2] Zhang Y, Xu Y, Nie H, Lei T, Wu Y, Zhang L, Zhang M. Prevalence of dementia and major dementia subtypes in the Chinese populations: a meta-analysis of dementia prevalence surveys, 1980-2010. J Clin Neurosci. 2012;19(10):1333–1337. doi: 10.1016/j.jocn.2012.01.029. - DOI - PubMed

[3] Chan KY, Wang W, Wu JJ, Liu L, Theodoratou E, Car J, Middleton L, Russ TC, Deary IJ, Campbell H, et al. Epidemiology of Alzheimer’s disease and other forms of dementia in China, 1990-2010: a systematic review and analysis. Lancet. 2013;381(9882):2016–2023. doi: 10.1016/S0140-6736(13)60221-4. - DOI - PubMed

[4] Chan KY, Wang W, Wu JJ, Liu L, Theodoratou E, Car J, Middleton L, Russ TC, Deary IJ, Campbell H, et al. Epidemiology of Alzheimer’s disease and other forms of dementia in China, 1990-2010: a systematic review and analysis. Lancet. 2013;381(9882):2016–2023. doi: 10.1016/S0140-6736(13)60221-4. - DOI - PubMed

[5] Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Donepezil Study Group. Neurology. 1998;50(1):136–145. doi: 10.1212/WNL.50.1.136. - DOI - PubMed

[6] Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Donepezil Study Group. Neurology. 1998;50(1):136–145. doi: 10.1212/WNL.50.1.136. - DOI - PubMed

[7] Rosler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, Stahelin HB, Hartman R, Gharabawi M. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. BMJ. 1999;318(7184):633–638. doi: 10.1136/bmj.318.7184.633. - DOI - PMC - PubMed

[8] Rosler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, Stahelin HB, Hartman R, Gharabawi M. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. BMJ. 1999;318(7184):633–638. doi: 10.1136/bmj.318.7184.633. - DOI - PMC - PubMed

[9] Wilcock GK, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: multicentre randomised controlled trial. Galantamine International-1 Study Group. BMJ. 2000;321(7274):1445–1449. doi: 10.1136/bmj.321.7274.1445. - DOI - PMC - PubMed

[10] Wilcock GK, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: multicentre randomised controlled trial. Galantamine International-1 Study Group. BMJ. 2000;321(7274):1445–1449. doi: 10.1136/bmj.321.7274.1445. - DOI - PMC - PubMed

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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

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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

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