To assess the safety and therapeutic effects of allogeneic human dental pulp stem cells (DPSCs) in treating severe pneumonia caused by COVID-19. This is a single centre, two arm ratio 1:1, triple blinded, randomized, placebo-controlled, parallel group, clinical trial. Twenty serious COVID-19 cases will be enrolled in the trial from April 6th to December 31st 2020. Inclusion Criteria: hospitalised patients at Renmin Hospital of Wuhan University satisfy all criteria as below: Exclusion Criteria: Patients will be excluded from the study if they meet any of the following criteria. There will be two study groups: experimental and control. Both will receive all necessary routine treatment for COVID-19. The experimental group will receive an intravenous injection of dental pulp stem cells suspension (3.0x107 human DPSCs in 30ml saline solution) on day 1, 4 and 7; The control group will receive an equal amount of saline (placebo) on the same days. Clinical and laboratory observations will be performed for analysis during a period of 28 days for each case since the commencement of the study. 1. Primary outcome The primary outcome is Time To Clinical Improvement (TTCI). By definition, TTCI is the time (days) it takes to downgrade two levels from the following six ordered grades [(grade 1) discharge to (grade 6) death] in the clinical state of admission to the start of study treatments (hDPSCs or placebo). Six grades of ordered variables: 2. Secondary outcomes 2.1 vital signs: heart rate, blood pressure (systolic blood pressure, diastolic blood pressure). During the screening period, hospitalization every day (additional time points of D1, D4, D7 30min before injection, 2h ± 30min, 24h ± 30min after the injection) and follow-up period D90 ± 3 days. 2.2 Laboratory examinations: during the screening period, 30 minutes before D1, D4, D7 infusion, 2h ± 30min, 24h ± 30min after the end of infusion, D10, D14, D28 during hospitalization or discharge day and follow-up period D90 ± 3 days. 2.3 Blood routine: white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, neutrophils, lymphocytes, monocytes, eosinophils Acidic granulocyte count, basophil count, red blood cell, hemoglobin, hematocrit, average volume of red blood cells, average red blood cell Hb content, average red blood cell Hb concentration, RDW standard deviation, RDW coefficient of variation, platelet count, platelet specific platelet average Volume, platelet distribution width,% of large platelets; 2.4 Liver and kidney function tests: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transferase, prealbumin, total protein, albumin, globulin, white / globule ratio , Total bilirubin, direct bilirubin, cholinesterase, urea, creatinine, total carbon dioxide, uric acid glucose, potassium, sodium, chlorine, calcium, corrected calcium, magnesium, phosphorus, calcium and phosphorus product, anion gap, penetration Pressure, total cholesterol, triacylglycerol, high density lipoprotein cholesterol, Low density lipoprotein cholesterol, lipoprotein a, creatine kinase, lactate dehydrogenase, estimated glomerular filtration rate. 2.5 Inflammation indicators: hypersensitive C-reactive protein, serum amyloid (SAA); 2.6 Infectious disease testing: Hepatitis B (HBsAg, HBsAb, HBeAg, HBeAb, HBcAb), Hepatitis C (Anti-HCV), AIDS (HIVcombin), syphilis (Anti-TP), cytomegalovirus CMV-IgM, cytomegalovirus CMV-IgG; only during the screening period and follow-up period D90 ± 3. 2.7 Immunological testing: Collect peripheral blood to detect the phenotype of T lymphocyte, B lymphocyte, natural killer cell, Macrophage and neutrophil by using flow cytometry. Collect peripheral blood to detect the gene profile of mononuclear cells by using single-cell analyses. Collect peripheral blood serum to detect various immunoglobulin changes: IgA, IgG, IgM, total IgE; Collect peripheral blood serum to explore the changes of cytokines, Th1 cytokines (IL-1 β, IL-2, TNF-a, ITN-γ), Th2 cytokines (IL-4, IL-6, IL -10). 2.8 Pregnancy test: blood β-HCG, female subjects before menopause are examined during the screening period and follow-up period D90 ± 3. 2.9 Urine routine: color, clarity, urine sugar, bilirubin, ketone bodies, specific gravity, pH, urobilinogen, nitrite, protein, occult blood, leukocyte enzymes, red blood cells, white blood cells, epithelial cells, non-squamous epithelial cells , Transparent cast, pathological cast, crystal, fungus; 2.10 Stool Routine: color, traits, white blood cells, red blood cells, fat globules, eggs of parasites, fungi, occult blood (chemical method), occult blood (immune method), transferrin (2h ± 30min after the injection and not detected after discharge). Block randomization method will be applied by computer to allocate the participants into experimental and control groups. The random ratio is 1:1. Participants, outcomes assessors and investigators (including personnel in laboratory and imaging department who issue the sample report or image observations) will be blinded. Injections of cell suspension and saline will be coded in accordance with the patient’s randomisation group. The blind strategy is kept by an investigator who does not deliver the medical care or assess primary outcome results. Twenty participants will be randomized to the experimental and control groups (10 per group). Protocol version number, hDPSC-CoVID-2019-02-2020 Version 2.0, March 13, 2020. Patients screening commenced on 16th April and an estimated date of the recruitment of the final participants will be around end of July. . Registration: World Health Organization Trial Registry: ChiCTR2000031319; March 27,2020. ClinicalTrials.gov Identifier: NCT04336254; April 7, 2020 Other Study ID Numbers: hDPSC-CoVID-2019-02-2020 The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

中文翻译：

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同种异体人牙髓干细胞治疗重症 COVID-19 患者的安全性和有效性评估：随机对照试验研究方案的结构化摘要（I / II 期）。

评估同种异体人牙髓干细胞 (DPSCs) 治疗 COVID-19 引起的重症肺炎的安全性和治疗效果。这是一项单中心、两臂比例 1:1、三盲、随机、安慰剂对照、平行组、临床试验。20 例 COVID-19 重症病例将于 2020 年 4 月 6 日至 12 月 31 日入组。 纳入标准：武汉大学人民医院住院患者符合以下所有标准： 排除标准：符合条件的患者将被排除在研究之外以下任何标准。将有两个研究组：实验组和控制组。两人都将接受 COVID-19 的所有必要常规治疗。实验组第1天静脉注射牙髓干细胞悬液（3.0x107人DPSCs在30ml盐水溶液中），4和7；对照组将在同一天接受等量的生理盐水（安慰剂）。自研究开始以来，将在每个病例的 28 天内进行临床和实验室观察以进行分析。1. 主要结果 主要结果是临床改善时间 (TTCI)。根据定义，TTCI 是从入院临床状态到开始研究治疗（hDPSCs 或安慰剂）。六级有序变量： 2. 次要结果 2.1 生命体征：心率、血压（收缩压、舒张压）。筛查期间每天住院（追加时间点D1、D4、D7注射前30min、2h±30min、注射后24h±30min）和随访期D90±3天。2.2实验室检查：筛选期间，D1、D4、D7输液前30分钟，输液结束后2h±30min、24h±30min，住院或出院当日D10、D14、D28及随访期D90±3天。2.3 血常规：白细胞、中性粒细胞、淋巴细胞、单核细胞、嗜酸性粒细胞、嗜碱性粒细胞、中性粒细胞、淋巴细胞、单核细胞、嗜酸性粒细胞 酸性粒细胞计数、嗜碱性粒细胞计数、红细胞、血红蛋白、红细胞比容、平均红细胞体积、平均红细胞细胞Hb含量、平均红细胞Hb浓度、RDW标准差、RDW变异系数、血小板计数、血小板比血小板平均体积、血小板分布宽度、大血小板百分比；2.4 肝肾功能检查：丙氨酸氨基转移酶、天冬氨酸氨基转移酶、碱性磷酸酶、γ-谷氨酰转移酶、前白蛋白、总蛋白、白蛋白、球蛋白、白/球比、总胆红素、直接胆红素、胆碱酯酶、尿素、肌酐、总二氧化碳、尿酸葡萄糖、钾、钠、氯、钙、校正钙、镁、磷、钙和磷产物、阴离子间隙、渗透压、总胆固醇、三酰基甘油、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、脂蛋白 a、肌酸激酶、乳酸脱氢酶、估计肾小球过滤率。2.5 炎症指标：超敏C反应蛋白、血清淀粉样蛋白（SAA）；2.6 传染病检测：乙型肝炎（HBsAg、HBsAb、HBeAg、HBeAb、HBcAb）、丙型肝炎（抗HCV）、艾滋病（HIVcombin）、梅毒（抗TP）、巨细胞病毒CMV-IgM、巨细胞病毒CMV-IgG；仅在筛选期和随访期D90±3。 2.7 免疫学检测：采集外周血，用流式细胞仪检测T淋巴细胞、B淋巴细胞、自然杀伤细胞、巨噬细胞和中性粒细胞的表型。通过使用单细胞分析收集外周血以检测单核细胞的基因谱。采集外周血检测各种免疫球蛋白变化：IgA、IgG、IgM、总IgE；采集外周血清，探索细胞因子、Th1细胞因子（IL-1β、IL-2、TNF-a、ITN-γ）、Th2细胞因子（IL-4、IL-6、IL -10）的变化。2.8 妊娠试验：血β-HCG，筛查期和随访期检查绝经前女性受试者D90±3。 2.9 尿常规：颜色、透明度、尿糖、胆红素、酮体、比重、pH、尿胆原、亚硝酸盐、蛋白质、潜血、白细胞酶、红细胞、白细胞、上皮细胞、非鳞状上皮细胞、透明管型、病理管型、水晶、真菌；2.10 大便常规：颜色、性状、白细胞、红细胞、脂肪球、寄生虫卵、真菌、潜血（化学法）、潜血（免疫法）、转铁蛋白（注射后2h±30min未检出）出院后）。将通过计算机应用块随机化方法将参与者分配到实验组和对照组。随机比例为 1:1。参与者、结果评估人员和调查人员（包括出具样本报告或图像观察的实验室和影像科人员）将被蒙蔽。细胞悬液和生理盐水的注射将根据患者的随机分组进行编码。盲法策略由不提供医疗服务或评估主要结果结果的研究者保留。20 名参与者将被随机分配到实验组和对照组（每组 10 人）。协议版本号，hDPSC-CoVID-2019-02-2020 2.0 版，2020 年 3 月 13 日。患者筛查于 4 月 16 日开始，预计最终参与者的招募日期将在 7 月底左右。. 注册：世界卫生组织试验注册：ChiCTR2000031319；2020 年 3 月 27 日。ClinicalTrials.gov 标识符：NCT04336254；2020 年 4 月 7 日 其他研究 ID 号：hDPSC-CoVID-2019-02-2020 完整方案作为附加文件附加，可从试验网站访问（附加文件 1）。为了加快传播这种材料的兴趣，熟悉的格式已被删除；这封信是对完整协议关键要素的总结。