Human Umbilical Cord Mesenchymal Stem Cells to Treat Neuromyelitis Optica Spectrum Disorder (hUC-MSC-NMOSD): A Study Protocol for a Prospective, Multicenter, Randomized, Placebo-Controlled Clinical Trial
Authors: Yao Xiaoying , Xie Li , Cai Yu , Zhang Ying , Deng Ye , Gao Meichun , Wang Yishu , Xu Huiming , Gao Weiqiang , Ding Jie , Wu Yifan , Zhao Nan , Wang Ze , Song Yaying , Wang Liping , Xie Chong , Li Zezhi , Wan Wenbin , Lin Yan , Jin Haifeng , Qiu Huiying , Zhuang Lei , Jin Yuyan , Ni Liping , Yan Jiali , Guo Quan , Xue Jiahui , Chen Shengdi , Liu Jianrong , Liu Zhenguo , Wang Xiaoping , Zhao Yuwu , Liu Jianren , Qian Biyun , Guan Yangtai 
Published: December 2020

Abstract
Background：Neuromyelitis optica spectrum disorder (NMOSD) is a severe relapsing and disabling inflammatory autoimmune disease of the central nervous system. Despite the progress made in understanding the pathogenesis of the disease, the optimal first line treatment to reduce relapse rate and ameliorate neurological disability remains unclear. Mesenchymal stem cells (MSC) are known for having anti-inflammatory and regenerative properties and there are a number of studies on the use of human umbilical cord MSCs (hUC-MSCs) in NMOSD patients. Therefore, we will conduct a prospective, multicenter, randomized, placebo-controlled clinical trial to study the safety and effectiveness of hUC-MSCs in the treatment of NMOSD.Methods：The trial is planned to recruit 430 AQP4-IgG seropositive NMOSD patients. The multicenter study will be conducted in six clinical centers. The whole clinical trial consists of three consecutive stages. The first stage will be carried out in the leading center (Ren Ji Hospital) only and it will last 24 months. In the first stage the primary objective is to evaluate the safety of hUC-MSCs. Patients (n=30) will be treated with three different doses of hUC-MSC: the low dose group (n=10, 1×106 MSC / kg·weight), the medium dose group (n=10, 2×106 MSC / kg·weight) and the high dose group (n=10, 5×106 MSC / kg·weight). The second stage, which aims to find the optimal dosage, will last 24 months and will be carried out in six centers (one leading center and five branch centers). Patients (n=160) will be randomized into four groups by 1:1:1:1 allocation ratio: the low, medium, high dose groups and the controlled group (n=40). The third stage, which aims to evaluate the effectiveness, will lasts for 24 months and will be developed in six centers. Patients (n=320) will be 1:1 randomized into two groups: the optimal dose group (n=160) and the controlled group (n=160). HUC-MSC infusion will be given four times to the intervention groups and stem cell solution will be given four times to the control group every 3 months; besides the primary drugs will be provided to both groups. Primary endpoint is the first recurrent time and secondary endpoints are the recurrent times, EDSS scores, MRI lesion numbers, OSIS scores, Hauser walking index and SF-36 (quality of life short Form-36) scores. Exploratory endpoints will include: serum lymphocyte subsets, cytokines, complements, serum anti-AQP4 antibody titers etc. Endpoint events and side-effects will be evaluated at baseline and every 3 months for a total of 24 months follow-up.Discussion：Although hUC-MSC has shown promising treatment effect of NMOSD in preclinical study, there is still a lack of well-designed clinical trials to evaluate the safety and effectiveness of hUC-MSC among NMOSD patients. As far as we know, this trial will be the first one to systematically demonstrate the clinical safety and efficacy of hUC-MSC in treating NMOSD and might be able to determine the optimal dose of hUC-MSC for NMOSD patients.Trial registration：The study was registered with Chinese Clinical Trial Registry (CHICTR.org.cn) on Mar 2, 2016 (registration No. ChiCTR-INR-16008037), and the revised trial protocol (Protocol version 1.2.1) was released on March 16, 2020.