key: cord-0762247-3jnhboif authors: Tang, Wei; Cao, Zhujun; Han, Mingfeng; Wang, Zhengyan; Chen, Junwen; Sun, Wenjin; Wu, Yaojie; Xiao, Wei; Liu, Shengyong; Chen, Erzhen; Chen, Wei; Wang, Xiongbiao; Yang, Jiuyong; Lin, Jun; Zhao, Qingxia; Yan, Youqin; Xie, Zhibin; Li, Dan; Yang, Yaofeng; Liu, Leshan; Qu, Jieming; Ning, Guang; Shi, Guochao; Xie, Qing title: Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial date: 2020-05-14 journal: BMJ DOI: 10.1136/bmj.m1849 sha: b6fdefb90f73c979c57a6a54068cb1edd6b2096e doc_id: 762247 cord_uid: 3jnhboif OBJECTIVE: To assess the efficacy and safety of hydroxychloroquine plus standard of care compared with standard of care alone in adults with coronavirus disease 2019 (covid-19). DESIGN: Multicentre, open label, randomised controlled trial. SETTING: 16 government designated covid-19 treatment centres in China, 11 to 29 February 2020. PARTICIPANTS: 150 patients admitted to hospital with laboratory confirmed covid-19 were included in the intention to treat analysis (75 patients assigned to hydroxychloroquine plus standard of care, 75 to standard of care alone). INTERVENTIONS: Hydroxychloroquine administrated at a loading dose of 1200 mg daily for three days followed by a maintenance dose of 800 mg daily (total treatment duration: two or three weeks for patients with mild to moderate or severe disease, respectively). MAIN OUTCOME MEASURE: Negative conversion of severe acute respiratory syndrome coronavirus 2 by 28 days, analysed according to the intention to treat principle. Adverse events were analysed in the safety population in which hydroxychloroquine recipients were participants who received at least one dose of hydroxychloroquine and hydroxychloroquine non-recipients were those managed with standard of care alone. RESULTS: Of 150 patients, 148 had mild to moderate disease and two had severe disease. The mean duration from symptom onset to randomisation was 16.6 (SD 10.5; range 3-41) days. A total of 109 (73%) patients (56 standard of care; 53 standard of care plus hydroxychloroquine) had negative conversion well before 28 days, and the remaining 41 (27%) patients (19 standard of care; 22 standard of care plus hydroxychloroquine) were censored as they did not reach negative conversion of virus. The probability of negative conversion by 28 days in the standard of care plus hydroxychloroquine group was 85.4% (95% confidence interval 73.8% to 93.8%), similar to that in the standard of care group (81.3%, 71.2% to 89.6%). The difference between groups was 4.1% (95% confidence interval –10.3% to 18.5%). In the safety population, adverse events were recorded in 7/80 (9%) hydroxychloroquine non-recipients and in 21/70 (30%) hydroxychloroquine recipients. The most common adverse event in the hydroxychloroquine recipients was diarrhoea, reported in 7/70 (10%) patients. Two hydroxychloroquine recipients reported serious adverse events. CONCLUSIONS: Administration of hydroxychloroquine did not result in a significantly higher probability of negative conversion than standard of care alone in patients admitted to hospital with mainly persistent mild to moderate covid-19. Adverse events were higher in hydroxychloroquine recipients than in non-recipients. TRIAL REGISTRATION: ChiCTR2000029868. -Oral hydroxychloroquine treatment is superior to supportive therapy in change from baseline to day 4, day 7, day 10 of clinical symptoms (criteria for improvement of clinical symptoms: body temperature returned to normal, SaO2 returned to normal, respiratory symptoms were reduced by 50% from baseline); -Oral hydroxychloroquine treatment is superior to supportive therapy in change from baseline to day 4, day 7, day 10 of laboratory indicators (CRP decreased by 50% from baseline, erythrocyte sedimentation decreased by 50%, and absolute peripheral lymphocyte count returned to normal); -Oral hydroxychloroquine treatment is superior to supportive therapy in change from baseline to day 10 of improving rate of imaging (chest CT lesion absorption on day 10 of treatment is> 50% above The current study is an open-label randomized trial for the evaluation of efficacy and safety of HCQ sulphate in the treatment of 2019-nCov respiratory infection. HCQ sulphate has been approved for clinical application as anti-inflammation and anti-microorganisms with good reported efficacy and safety profiles. We therefore anticipate that the administration of HCQ will not bring additional major risks. Potential benefits： 1. Participants could benefit from the treatment group because the tested drug planned for investigation in this study is thought to offer potential benefits to individual subjects, based upon previous pre-clinical and several retrospective case-series investigations. With regard to control group, all patients were treated according to the latest guideline and therefore receive the best treatment at current stage. 2. For each participant, either assigned into treatment or control group, all the expenses for examination and treatment are covered by the sponsors. Confidential: Record of personal information will be kept private without publication according to legislation and laws. Results from this study, but not your identity, may be shared with local medical providers, government health organizations or international health workers to help them better understand 2019-nCoV infection. Since The disease course and prognosis can be largely improved by the effective inhibition of virus replication, whereas no such drug has yet been approved to treat human CoV [3] . One of the best solutions to this problem is to use approved drugs with potential anti-viral effects and good safety profiles; among them, hydroxychloroquine (HCQ) is a promising candidate. HCQ is a commonly used antimalarial drug, which together with chloroquine (CQ), belong to a class of drugs known as 4-aminoquinolines. After the first successful chemical synthesis of CQ in 1944, HCQ was generated by replacing ethyl with hydroxyethyl in the basic side chine of CQ. Comparing to CQ, HCQ is absorbed faster by the intestinal tract with a wider distribution in human body. Clinical applications of HCQ is first reported in antimalarial treatment and expands to systemic lupus erythematosus in 1955 and to rheumatoid arthritis in 1988. The immune modulatory effects, safety and treatment efficacy of HCQ has been widely acknowledged [4] . Although HCQ and CQ have similar treatment efficacy, HCQ is preferred due its reduced toxicity [5,6] and its clinical applications have been expanded from rheumatic diseases to dermatology, malignancies and other fields because of the multifaceted effects on immune modulation, anti-inflammation, inhibiting of malignant cell growth and viability, enhancing clearance of lipid, anti-thrombosis and reducing diabetes risk [7, 8] . In addition, CQ significantly reduces inflammatory response of SARS, possibly through the inhibition of TNFα and IL-6 [9] . Similarly, CQ is able to prevent an overexuberant inflammatory response in patients with human immunodeficiency virus (HIV) infection by inhibiting the HIV activated TLR-7 signaling pathway [10] . Treatment with HCQ (200-400 mg/day) for 8 weeks has been found to significantly reduce immune response, especially in patients with high viral load [11, 12] . More importantly, high dose of HCQ treatment demonstrates anti-viral effects in studies investigating SARS-CoV and Middle East Respiratory Syndrome Coronavirus, (MERS-CoV) [13, 14] . It has been proposed to use HCQ for the prophylaxis and treatment of SARS-CoV infection [13] . Animal studies demonstrate a survival rate of over 80% using CQ for the treatment of mice infected with MERS-CoV [14] . The main anti-viral mechanisms of HCQ include: 1) impairing the maturation of lysosomes and autophagosomes by increasing the pH of endosomal compartments; 2) interfering with cellular ferritin metabolism; 3) inhibiting posttranslational modification of virus protein by increasing the pH of Golgi apparatus. Moreover, CQ is able to inhibit p38 MAPK signaling pathway in HCoV-229e infected cell [14, 16, 17] . CQ is also reported to interfere with terminal glycosylation of the cellular receptor, angiotensin converting enzyme 2 in SARS-CoV, which negatively influence the virus-receptor binding and abrogate the infection [13] . Finally, animal studies have demonstrated good safety and tissue distribution of HCQ [18, 19] 。 The aim of current study was to evaluate the efficacy and safety of high dose HCQ in the treatment of patients with 2019-nCoV respiratory infection stratified into mild, moderate and severe group. A prospective, multicenter, randomized clinical trial was performed to evaluate the effects of HCQ on negative conversion rate of virus RNA, improvement of clinical symptom and laboratory parameters and prevention of disease progression. We hypothesized that HCQ could be an effective drug in the treatment of 2019-nCoV respiratory infection. The primary objective of this study is to evaluate the efficacy and safety of high dose of HCQ sulfate in patients with 2019-nCoV respiratory infection by comparisons between the HCQ plus standard-of-care (SOC) group and the SOC group. To evaluate the efficacy and safety of high dose of HCQ sulfate in patients with 2019-nCoV respiratory infection This trial was a prospective, multicenter, open-label, randomized trial of patients with 2019-nCoV. The trial enrolled 360 patients with 1:1 randomization ratio stratified by disease severity (mild/moderate/severe) to receive either HCQ plus SOC or SOC alone.  Dose adjustment: Treatment dose will be adjusted only when adverse events are related to the investigated drug as judged by investigators. In any case, investigator should perform evaluation carefully based on clinical experience. Treatment can be temporarily stopped or adjusted to a lower level of dose (switch from 400mg to 300mg), if the investigator considers a continued treatment with pre-defined dose will increase toxicity based on the individual safety and tolerance. Treatment can be restarted at original dose or at a lower level if the patients was recovered from 23 adverse events. The investigators should also evaluate the clinical benefits to decide whether continues treatment until Day14/21 in cases with disease progression. All standard drugs that are recommended by the guideline can be used for SOC, except for other drugs belongs to 4-aminoquinolines, e.g., CQ phosphate. Patients who have received CQ can be enrolled after 48h of withdrawal. Medications for diseases other than 2019-nCoV respiratory infection can be used during the study period. The trail can be terminated early if any of the following circumstance occurs: ① Treatment needs to be changed due to disease progression during study period after comprehensive assessment by investigators. ② Serious adverse events lead to disease progression ③ Patient is no longer willing to be treated with the investigated drug Primary endpoint: Negative conversion rate of virus nucleic acid within 28-day For severe disease subgroup, considering both virology conversion and clinical improvement.  Definition for clinical improvement：decline of two categories from enrollment status on a six-category ordinal scale of clinical status which ranging from 1 (discharged) to 6 (death) 2) Improvement rate of clinical symptoms within 28-day  Definition for clinical symptoms improvement: resolving from fever (axillary temperature ≤36.6℃，or oral temperature ≤37.2℃, or rectal/ear temperature ≤37.8℃), normalization of SpO2 (SpO2 >94% on room air), disappearance of respiratory symptom. 3) Improvement rate of laboratory parameters within 28-day  Definition for laboratory parameters improvement: 50% decline of C-reactive protein, erythrocyte sedimentation rate, IL-6 and TNF-α level from baseline and normalization of absolute blood lymphocyte count. 4) Improvement rate of chest radiology within 28-day  Definition for radiology improvement: Resolved more than 50% from baseline on chest CT Given that HCQ sulphate has been widely used in antimalarial and rheumatoid arthritis treatment, the side-effects of HCQ have been fully established as listed in Table 2 -3. Among all the sideeffects, gastrointestinal upset, particularly diarrhea, and retinopathy are relative common at a regular dose but usually resolve after treatment is stopped. ② Dropout rate will be applied to control family-wise type-I error which is 0.05, two-sided, in this study. The first interim analysis will occur after 40% of subjects (around 150 subjects) have been treated for 7 days or have discontinued. The goal is to evaluate efficacy and need of sample size re-estimation. p-value boundary for efficacy significance is 0.00079 (two-sided). Final analysis will be conducted after 248 events are observed. p-value boundary is 0.04974 (twosided). The actual α spent and p-value boundaries at each analysis will be calculated based on the exact observed number of events. Extended followup [13] Visit 12-lead electrocardiogram × [11] × × × CRP, ESR × [11] × × × × × × TNF-α，IL-6 × [11] × × × × × × CBC with differential [5] × [11] × × × × × × Urinalysis [6] × [11] × × × Blood chemistry [7] (hepatic and kidney panel, Myocardial enzyme) × [11] × × × × × × Coagulation panel [8] × [11] × × × × × × 2019-nCoV RT-PCR [9] × [12] 2. Epidemiological information includes recent travel history and exposure to epidemic area or infected patients; medical history includes present illness and past medical history including co-morbidity medications 3. Physical examination includes height, weight, general outlook, head, eye, ear, nose, throat, neck and thyroid, skin, cardiovascular system, Anterior chest and lung, abdomen, neuro system, skeletal muscle system and lymphatic system 4. Vital signs: body temperature, respiratory rate, pulse, blood pressure; record maximum temperature of the visiting day and use same measurement criteria throughout the study period. 5. CBC with differential includes: haptoglobin and absolute count of red blood cell, platelet, total white blood cell, neutrophil, lymphocyte, monocyte, eosinophil and basophil 6. Urinalysis: urinary pH, urinary red blood cell, urinary white blood cell, urinary protein, glucose and ketone 7. Blood chemistry includes alanine aminotransferase, aspartate aminotransferase, total bilirubin, albumin, γglutamyl transpeptidase, lactate dehydrogenase, creatine kinase, creatine kinase isoenzyme-MB, blood urea nitrogen and creatinine 8. Coagulation panel includes: Prothrombin time, activated partial thrombin time, thrombin time, fibrinogen and international normalized ratio. 9. RT-PCR results upon unplanned visit should also be recorded in CRF 10 . Record daily administration of tested drug including under use and over use 11 . These examinations can be exempted by the investigators if the participants can provide qualified examination results within 3-day prior to initiation of the study 12. RT-PCR results of 2019-nCoV within 5-day prior to initiation of the study can be used for screening 13 . For patients discharge alive, only medications and AE information will be collected via telephone contact. Extended follow-up [13] 12-lead electrocardiogram × [11] × × CRP, ESR × [11] × × × × × × TNF-α，IL-6 × [11] × × × × × × CBC with differential [5] × [11] × × × × × × Urinalysis [6] × [11] × × Blood chemistry [7] (hepatic and kidney panel, Myocardial enzyme) × [11] × × × × × × Coagulation panel [8] × [11] × × × × × × 2019-nCoV RT-PCR [9] × [12] × × × × × × Pulse oximetry(on room air) × × × × × × × Arterial blood gas analysis × [11] Optional (as per clinical needs) Urine hCG) × [11] × Chest CT × [11] 2. Epidemiological information includes recent travel history and exposure to epidemic area or infected patients; medical history includes present illness and past medical history including co-morbidity medications 3. Physical examination includes height, weight, general outlook, head, eye, ear, nose, throat, neck and thyroid, skin, cardiovascular system, Anterior chest and lung, abdomen, neuro system, skeletal muscle system and lymphatic system 4. Vital signs: body temperature, respiratory rate, pulse, blood pressure; record maximum temperature of the visiting day and use same measurement criteria throughout the study period. 5. CBC with differential includes: haptoglobin and absolute count of red blood cell, platelet, total white blood cell, neutrophil, lymphocyte, monocyte, eosinophil and basophil 6. Urinalysis: urinary pH, urinary red blood cell, urinary white blood cell, urinary protein, glucose and ketone 7. Blood chemistry includes alanine aminotransferase, aspartate aminotransferase, total bilirubin, albumin, γglutamyl transpeptidase, lactate dehydrogenase, creatine kinase, creatine kinase isoenzyme-MB, blood urea nitrogen and creatinine 8. Coagulation panel includes: Prothrombin time, activated partial thrombin time, thrombin time, fibrinogen and international normalized ratio. 9. RT-PCR results upon unplanned visit should also be recorded in CRF 10 . Record daily administration of tested drug including under use and over use 11 . These examinations can be exempted by the investigators if the participants can provide qualified examination results within 3-day prior to initiation of the study 12. RT-PCR results of 2019-nCoV within 5-day prior to initiation of the study can be used for screening For patients discharge alive, only medications and AE information will be collected via telephone contact. The current study is an open-label randomized trial for the evaluation of efficacy and safety of HCQ sulphate in the treatment of 2019-nCov respiratory infection. HCQ sulphate has been approved for clinical application as anti-inflammation and anti-microorganisms with good reported efficacy and safety profiles. We therefore anticipate that the administration of HCQ will not bring additional major risks. Participants could benefit from the treatment group because the tested drug planned for investigation in this study is thought to offer potential benefits to individual subjects, based upon previous pre-clinical and several retrospective case-series investigations. With regard to control group, all patients were treated according to the latest guideline and therefore receive the best treatment at current stage. For each participant, either assigned into treatment or control group, all the expenses for examination and treatment are covered by the sponsors. Confidential: Record of personal information will be kept private without publication according to legislation and laws. Results from this study, but not your identity, may be shared with local medical providers, government health organizations or international health workers to help them better understand 2019-nCoV infection. (肝功能、肾功能、心肌酶) × [11] × × × × × × 凝血功能 [8] × [11] × × × × × × 新型冠状病毒核酸检测 [9] × [12] 凝血功能 [8] × [11] × × × × × × 新型冠状病毒核酸检测 [9] × [12] This is the translated version of the final protocol originally written in Chinese. 2. Introduction was modified based on updating knowledge on 2019-nCoV and Hydroxychloroquine 3. The sample size of 200 cases in the original version was replaced by 360 cases in the newest version based on the alternative hypothesis of a 30% reduction of time to virus nucleic acid negativity. Under the exponential distribution, this benefit translates to a reduction in median time to virology negativity from 10 days to 7 days. A total of 248 events would provide a power of 80% to detect a 30% reduction of hazard ratio (control vs. treatment) of 0.70 with a Log-Rank test, assuming a twosided significance level of 5%. A 75-day accrual period and an additional 7-day follow-up are assumed. The sample size calculation has also taken into consideration an annual dropout rate of 20%. 4. In the original version of the protocol, patients with severe pneumonia were excluded. However, considering the anti-inflammatory property of HCQ favoring disease regression, we decided to change exclusion criteria in order to include patients with severe type of pneumonia. Stratified random sampling was then applied to stratify all eligible patients according to the disease severity (mild-to-moderate or severe) followed by random assignment (in a 1:1 ratio) in each stratum to ensure balanced distribution of disease severity between treatment (HCQ plus SOC) and control (SOC only) groups. 5. In the original version of the protocol, age of patients was restricted to 14 or higher. However, given no data available of COVID-19 in adolescents, we decided to focus on adult patients without risking younger patients and lifted the threshold of age limitation to 18 years. 6. Patients with severe liver disease and renal diseases were excluded due to safety concerns of using hydroxychloroquine in this population. 7. In the 4th version, "Onset of illness <12 days" was added to focus on as earlier stage of COVID-19 as possible. However, in hospitalized patients, this criterion would rule out too many patients that could previously participate in. We therefore remove this criterion in last version. 8. In the original version, the study drug was orally administrated 2 tablets/time of hydroxychloroquine (250mg/ tablet), twice a day, from Day1-Day3 followed by 1 tablet/time of hydroxychloroquine (250mg/ tablet) , twice a day, from Day4-Day10. In the newest version, the study drug changed to orally administrated hydroxychloroquine sulfate tablets (100mg/ tablet) 4 tablets /time, three times a day, from day 1 to day 3 followed by hydroxychloroquine sulfate (100mg/ tablet), 4 tablets/time, twice a day, from Day 4 ~ day 14( for mild-to-moderate patients), from Day 4 ~ day 21(for severe patients). 9. Concomitant anti-viral treatments were forbidden after randomization in the original version. However, considering the fact that these drugs are recommended as standard-of-care in the national guideline, we decided to remove this restriction in the later version. Moreover, usage of chloroquine was prohibited after randomization. If the subject had already used chloroquine medication prior to randomization, he or she can participate in this clinical study after 48 hours of chloroquine medication. 10 . In the newest version, addition to the secondary efficacy endpoint: time to negative of the novel coronavirus nucleic acid detection (day) and rate of negative percentage of the novel coronavirus detection of the treatment day 4, day 7, day 14 & day 21. 11. In the original version, the clinical symptom improvement as one of the secondary study endpoints was described as respiratory symptom reduction ≥50%. In the newest version, this was described as respiratory symptom disappearance. Add six-level classification scale for evaluation the clinical severity of subjects with severe type of 2019-nCoV pneumonia: Level specific description are as follows: Score 6: death; Score 5: ICU administration and/or requiring extracorporeal membrane pulmonary oxygenation (ECMO) and/or invasive mechanical ventilation (IMV); Score 4: ICU/ hospitalization requiring non-invasive mechanical ventilation (NIV)/high-flow nasal catheter oxygen therapy (HFNC); Score 3: Hospitalization, requiring oxygen therapy (non-niv /HFNC); Score 2: Hospitalization, no need of oxygen therapy; Score1:discharge from the hospital. 13 . Add details to safety end point in the newest version: Gastrointestinal reactions (especially diarrhea) and retinopathy are relatively common at clinically prescribed doses, but can be reversed after withdrawal. Long-term or high doses may cause irreversible retinal damage and the risk of visual impairment. 14. Add secondary endpoint for subject with severe type of 2019-nCoV pneumonia: All-cause mortality. 15. Add secondary endpoint for subject with severe type of 2019-nCoV pneumonia: clinical status on days 7, 14, 21 and 28. 16 . Add secondary endpoint for subject with severe type of 2019-nCoV pneumonia: duration of mechanical ventilation (IMV, NIV) (days), extracorporeal membrane oxygenation (days), oxygen therapy (nasal catheter or mask oxygen) (days), hospitalization (days). Version date. 20 February 2020 No amendment of this statistical analysis plan until the study completion. The eligible patients will be randomly assigned to one of the treatment arms with ratio 1:1. The randomization number will be generated by computer and implemented by random envelops. The stratification factor includes severity of disease (mild/moderate and severe). Extended follow-up [13] Visit × [11] × × × × × × Urinalysis [6] × [11] × × × Blood chemistry [7] (hepatic and kidney panel, Myocardial enzyme) × [11] × × × × × × Coagulation panel [8] × [11] × × × × × × 2019-nCoV RT-PCR [9] × [12] 28. Epidemiological information includes recent travel history and exposure to epidemic area or infected patients; medical history includes present illness and past medical history including co-morbidity medications 29. Physical examination includes height, weight, general outlook, head, eye, ear, nose, throat, neck and thyroid, skin, cardiovascular system, Anterior chest and lung, abdomen, neuro system, skeletal muscle system and lymphatic system 30. Vital signs: body temperature, respiratory rate, pulse, blood pressure; record maximum temperature of the visiting day and use same measurement criteria throughout the study period. 31. CBC with differential includes: haptoglobin and absolute count of red blood cell, platelet, total white blood cell, neutrophil, lymphocyte, monocyte, eosinophil and basophil 32. Urinalysis: urinary pH, urinary red blood cell, urinary white blood cell, urinary protein, glucose and ketone 33. Blood chemistry includes alanine aminotransferase, aspartate aminotransferase, total bilirubin, albumin, γ-glutamyl transpeptidase, lactate dehydrogenase, creatine kinase, creatine kinase isoenzyme-MB, blood urea nitrogen and creatinine 34. Coagulation panel includes: Prothrombin time, activated partial thrombin time, thrombin time, fibrinogen and international normalized ratio. 35. RT-PCR results upon unplanned visit should also be recorded in CRF 36. Record daily administration of tested drug including under use and over use 37. These examinations can be exempted by the investigators if the participants can provide qualified examination results within 3-day prior to initiation of the study 38. RT-PCR results of 2019-nCoV within 5-day prior to initiation of the study can be used for screening 39. For patients discharge alive, only medications and AE information will be collected via telephone contact. [11] × × electrocardiogram CRP, ESR × [11] × × × × × × TNF-α，IL-6 × [11] × × × × × × CBC with differential [5] × [11] × × × × × × × [11] × × Blood chemistry [7] (hepatic and kidney panel, Myocardial enzyme) × [11] × × × × × × Coagulation panel [8] × [11] × × × × × × 2019-nCoV RT-PCR [9] × [12] Arterial blood gas analysis × [11] Optional (as per clinical needs) Pregnancy Test (Serum or Urine hCG) × [11] × Chest CT × [11] Demographics include birth date, gender and ethnicity. 14. Epidemiological information includes recent travel history and exposure to epidemic area or infected patients; medical history includes present illness and past medical history including co-morbidity medications 15. Physical examination includes height, weight, general outlook, head, eye, ear, nose, throat, neck and thyroid, skin, cardiovascular system, Anterior chest and lung, abdomen, neuro system, skeletal muscle system and lymphatic system 16. Vital signs: body temperature, respiratory rate, pulse, blood pressure; record maximum temperature of the visiting day and use same measurement criteria throughout the study period. 17. CBC with differential includes: haptoglobin and absolute count of red blood cell, platelet, total white blood cell, neutrophil, lymphocyte, monocyte, eosinophil and basophil 18. Urinalysis: urinary pH, urinary red blood cell, urinary white blood cell, urinary protein, glucose and ketone 19. Blood chemistry includes alanine aminotransferase, aspartate aminotransferase, total bilirubin, albumin, γ-glutamyl transpeptidase, lactate dehydrogenase, creatine kinase, creatine kinase isoenzyme-MB, blood urea nitrogen and creatinine 20. Coagulation panel includes: Prothrombin time, activated partial thrombin time, thrombin time, fibrinogen and international normalized ratio. 21. RT-PCR results upon unplanned visit should also be recorded in CRF 22. Record daily administration of tested drug including under use and over use 23. These examinations can be exempted by the investigators if the participants can provide qualified examination results within 3-day prior to initiation of the study 24. RT-PCR results of 2019-nCoV within 5-day prior to initiation of the study can be used for screening For patients discharge alive, only medications and AE information will be collected via telephone contact. (1) Negative conversion rate of virus nucleic acid within 28-day (2) For severe disease subgroup, considering both virology conversion and clinical improvement. • Definition for clinical improvement：decline of two categories from enrollment status on a six-category ordinal scale of clinical status which ranging from 1 (discharged) to 6 (death). Adverse Events，Laboratory values, ECG, vital signs and physical examination findings will be monitored and recorded. Approximately 360 subjects (180 per group) will be randomized in the study. The sample size for this study is based on the alternative hypothesis of a 30% reduction in the risk of virus nucleic acid negativity. Under the exponential distribution, this benefit translates to a reduction in median virology negativity from 10 days to 7 days. A total of 248 events would provide a power of 80% to detect a reduction of 30% (hazard ratio (control vs. treatment) of 0.70) with a log-rank test, assuming a two-sided significance level of 5%. A 75-day accrual period and an additional 7-day follow-up are assumed. The sample size calculation has also taken into consideration an annual dropout rate of 20%. Meanwhile, co-primary endpoint in the subgroup defined by severe disease is 28-day clinical improvement. Assume 50% patients have clinical improvement by day 28 in control group, 100 patients can detect a 25% improvement in treatment group with a power=70%. Intent-to-treat (ITT): is defined as subjects who have been randomly assigned to the treatment group or placebo group. Analyses of efficacy will be based on this population. The ITT analyses grouping will be based on treatment planned. Per Protocol Set (PPS)： Is a subset of ITT，defined as all subjects who have been randomly assigned to the study and received at least 11-day treatment(mild/moderate disease) /16-day treatment(severe disease)，and have no major PD which significantly impact primary endpoint. The analyses grouping will be according to treatment planned. Safety Set(SS): is defined as subjects who have received at least 1 administration of any study treatment (partial or complete). This population will be used for all safety analyses. The safety analyses grouping will be according to treatment actually received. All patients in control arm will be included in SS and randomization date is used as substitute for treatment date. All analyses will be conducted in SAS 9.2(or higher version). In general, continuous variables will be summarized using descriptive statistics such as mean, standard deviation (SD), median and range. Categorical variables will be summarized using frequency and percentage. For time-to-event variables, the Kaplan-Meier method will be used for descriptive summaries. In listing, list results that tests/evaluation actually happened. Unless otherwise specified, listing follows the order: treatment, patient ID, visit, parameters. Study month=number of days/30.4375。 Unless otherwise specified, display of mean and median will have one more digit than original data, standard deviation have 1 more digit than mean. All numerical display do not show more than 3 digits. Percentage has 1 digit and no percentage display if frequency is 0. In general, denominator in percentage is number of patients in the corresponding header. Primary efficacy analysis is on ITT and supportive efficacy analysis is on PPS. Safety analysis is SS. (1) If a lab value was recorded as ＜normal value，≤normal value，＞normal value or ≥normal value, the value will be treated as =normal value in the summary tables, but listed as-is in the listings. (2)Missing/Partial Date of Birth If the end date of an adverse event is missing completely or partially, the following imputation rules will be used. ➢ If month and year are present and the day of the month is missing, the last day of the month is imputed. ➢ If only a year is present, the 31st of December is used. ➢ If the imputed date is later than the date of death (if available), the date of death will be used as the imputed date instead. (4) If the relevance of an AE with the study drug is missing or not evaluable, the AE will be counted in "relevant". Unless otherwise specified，baseline values is defined as values at visit "V1". The change from baseline is defined as the values-baseline value. An overview of subject disposition by treatment group will be provided. The overview includes a summary of total number of subjects who are randomized to each treatment group, the number and percentage of subjects who are randomized but not treated and number and percentage of subjects who are treated. The number and percentage of subjects who discontinued study treatment including reason for discontinuation as indicated by the investigators will be summarized. The similar summaries will be presented for all randomized subjects who discontinued from study participation. A listing of subjects who discontinued study treatment including reasons for discontinuation will be provided. A similar listing will be provided for subjects who discontinued study participation. Major protocol deviations will be summarized for the ITT population by the following types of deviation for each treatment group: Entered but did not satisfy inclusion/exclusion criteria Developed withdrawal criteria but not withdrawn Received an excluded concomitant treatment Other -protocol non-compliance A list of subjects with major protocol deviations including subject ID, type of deviation, and reasons for deviation will be provided. Unless specified otherwise, all demographic and baseline characteristics variables will be summarized for the ITT population. No statistical comparisons between the 2 treatment groups are planned. Parameters relevant to the study disease will be summarized in ITT by treatment group, including time from the first positive test to the randomization, time from the first onset of symptoms to the randomization, exposure history, SpO2, onset of fever, onset of respiratory symptom, medication allergy history, etc. Pre-existing conditions and medical history will be coded by MedDra (version 22.0 or higher) and summarized by SOC and PT. A listing of subjects who had pre-existing conditions and medical history will be provided. Historical medications and concomitant medications will be coded based on WHO DD(the lastest version). Historical medication is defined as those medication the ending date of which is before randomization date. Concomitant medication is defined as those medication the ending date of which is after randomization date or missing. Historical/Concomitant Medication collected in the CRF page during the study will be summarized by therapeutic class, pharmacologic class, and drug name for each treatment group. Similar analytic approach as for historical/concomitant treatment(medications). Efficacy analysis will be done on both ITT and PPS. Results on ITT is primary. The frequency and proportion of virology negativity by day 4、7、10、14、21 will be reported for each group. Proportion is defined by cumulative # of patients who had negativity by the given day/number of ITT in each group. Conversion of virology negativity is defined as two consecutive testing results showing negativity (at least one day interval between two tests) and no result is positive before end of study(or early drop-out). If a planned test is done but result is pending, impute result as "positive". Unscheduled testing can be used to confirm negativity. The Kaplan-Meier method will be used to estimate the distribution of time to negativity for each treatment group. The median time to negativity with 95% CI will be provided. In addition, the number and percentage of subjects who had an event or were censored will be reported. The Kaplan-Meier curve will also be plotted by treatment group and will be compared by the stratified log-rank test. The stratification factor is the same as factor considered in the randomization. The primary treatment comparison of the distribution of overall negativity will be based on a stratified log-rank test. The p-value from a stratified log-rank test will be reported. Hazard ratio and its 95% confidence interval will be estimated based on a stratified Cox's regression model with treatment as the sole explanatory variable. Stratification factors used in the analyses include severity of disease. In addition, 4, 7, 10, 14, 21 and 28 day of negativity rate with 95% CI will be estimated by Kaplan-Meier method and reported for each treatment group. Determination of dates of event and dates for censoring is summarized in Table 1 . • In the severe disease subgroup ， report the clinical state change at each time point. Summarize duration (days) of mechanical ventilation, extracorporeal membrane oxygenation, supplemental oxygenation and hospital stay. • In the mild/moderate subgroup, report progression rate at each time point.。 Safety analysis will be conducted among SS set. Compliance is defined as the actual dose/planned dose*100%. Summarize compliance the treatment duration. The treatment duration for study drug is defined by the last day of drug use-the first day of drug use and the treatment duration for control group is defined by the last day in study-randomization date. The general rule when AE is analyzed: ➢ Adverse events will be coded using the latest version of Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary and will be recorded in standard medical terminology and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) ➢ AE will be summarized by actual treatment received. ➢ If a patient had the same AE for multiple times, in the table summarizing prevalence at patient-level, the highest grade of AE will be summarized. In the table summarizing prevalence at incidence-level, The same AE on the same patient on the same date, the highest grade will be summarized. ➢ Summary of AE events does not come alone with percentage. ➢ When summarizing a subgroup of AE which prevalence is greater than a given percentage, search the AE within SOC/PT. The incidence and prevalence of AEs will be summarized overall, by treatment group, by MedDRA system organ class (SOC) and preferred term, by toxicity grade, and by relationship to study treatment administration. Specifically, the following AE summaries will be presented by meaningful) and post-baseline value will be provided. ECG will be summarized by visit and by treatment group. Shift table for baseline value (normal vs abnormal but not clinical meaningful vs. abnormal and clinical meaningful) and post-baseline value may be provided. Vital signs (systolic and diastolic blood pressure, heart rate, and temperature) values and change from baseline will be summarized by visit and by treatment group. Shift table for baseline value (normal vs abnormal but not clinical meaningful vs. abnormal and clinical meaningful) and postbaseline value may be provided. Physical examination findings will be summarized by visit and by treatment group. Shift table for baseline value (normal vs abnormal but not clinical meaningful vs. abnormal and clinical meaningful) and the worst post-baseline value may be provided. An Independent Data Monitoring Committee (IDMC) will be established to review data at 1 interim analyses prior to the primary endpoint analysis. The following cumulative α-spending function (O'Brien-Fleming type by Lan-DeMets algorimth) (Lan-Demets，1983)will be applied to control family-wise type-I error (0.05) where， is the cumulative information at the time of kth analysis，Φ is standard normal distribution，Φ −1 quantile function. The cumulative alpha spending function α( ) is a function of cumulative information, therefore, the significance level (p-value boundary) is a function of cumulative information, i.e., the observed number of events. The first interim analysis will occur after 40% of subjects (around 150 subjects) have been treated for at least 7 days or have discontinued. The goal is to evaluate efficacy and need of sample size re-estimation. P-value boundary for efficacy significance is 0.00079(two-sided). Final analysis will be conducted after 248 events are observed. P-value boundary is 0.04974(two-sided). The actual alpha spent and p-value boundaries at each analysis will be calculated based on the exact number of events. TFL shells will be provided in a separate file. Mild & Common type CONFIDENTIAL The information contained here relates to trade secrets and business information. These business information terms confidential content or proprietary information, except as required by regulations, shall not be disclosed by any person. Any individual who has access to the document shall be aware of its proprietary or confidential nature and shall not disclose the document without authorization. The restrictions on the confidentiality of the above documents will apply to any information provided to you in the future that is marked as proprietary or confidential. 1. The case report form shall be recorded by an authorized person, and each page in the CRF shall be carefully checked and signed. 2. The trial physicians should be familiar with the trial protocol and master the GCP principles. 3. Please write clearly and legibly with a sign pen in blue or black ink, preferably in capital letters for English, for example：CASE REPORT FORM 4. When filling in Numbers in open squares, fill in one number in each box；If the number of digits is less than the corresponding number of squares, please fill with zero. Spaces are not allowed. For example：56Kg，fill in the blanks as follows:| 0 | 5 | 6 |. | 0 | 0 |Kg. 5. The date is in the international ISO8601 date format：yyyymmdd. For example, December 21, 2007 was written as| 2 |0 | 0 | 7 |YEAR| 1 | 2 |Month| 2 | 1 |DAY。 6. For the items with "□"in the form, please type "×"in the corresponding box, , or fill in the relevant Numbers. If not done or the data is not available, please fill in ND(Not Done) or NK(not known) in the corresponding space; NA is not applicable. Each item must be filled in accurately, do not arbitrarily alter, do not use correction fluid or other ways to cover the original data. If you find any errors, please cross out the wrong record with a single 9. Do not change the format of the case report form. If you find that there is no place in the form to fill in the information the recorder wishes to record, please contact the responsible CRA. 10. Upon completion of the case report form, the principal investigator shall examine each page of the case report form and sign at the investigator's statement. If any adverse events have occurred since the signing of the informed consent, please fill in the form of "adverse events"; If there is medication combination, please fill in the form "previous/combined medication"; If there is combined non-drug therapy, please fill in the "previous/combined non-drug therapy" form; If there is an out-of-plan inspection, please fill in the "out-of-plan inspection" form; If there is IMV/NIV, ECMO, HFNC, oxygen therapy, please fill in the "IMV/NIV, ECMO, HFNC, oxygen therapy" form. Protocol Number：KY2020-29 If any adverse events have occurred since the last visit, please fill in the "Adverse Events Form". If there is medication combination, please fill in the "Previous/Combined medication Form"; If there is combined non-drug therapy, please fill in the " Comined Non-Drug Therapy Form"; If there is an out-of-plan inspection, please fill in the "Out-Of-Plan Inspection Form". If the subject has been discharged from the hospital, the following contents may not be carried out, please leave blank; If the subject is not discharged, please conduct the following examinations. □1 U/L □2Other：_____ □1 □2 □3 □0 Glutamic-oxalacetic transaminease(AST) □1 U/L □2Other：_____ □1 □2 □3 □0 Total Bilirubin(TBIL) □1 μmol/L □2Other：_____ □1 □2 □3 □0 Albumin(ALB) □1 g/L □2Other：_____ □1 □2 □3 □0 γ-glutamyl transpeptidas (GGT) □1 U/L □2Other：_____ □1 □2 □3 □0 Lactic dehydrogenase (LDH) □1 U/L □2Other：_____ □1 □2 □3 □0 Creatine kinase(CK) □1 U/L □2Other：_____ □1 □2 □3 □0 Creatine kinase isoenzyme(CK-MB) □1 U/L □2Other：_____ □1 □2 □3 □0 Blood urea nitrogen (BUN) □1 mmol/L □2Other：_____ □1 □2 □3 □0 Urea(Urea) □1 mmol/L □2Other：_____ □1 □2 □3 □0 Serum creatinine(CR) □1 μmol/L □2Other：_____ □1 □2 □3 □0 Urine If the subject has been discharged from the hospital, the following contents may not be carried out, please leave blank; If the subject is not discharged, please conduct the following examinations. Severe type CONFIDENTIAL The information contained here relates to trade secrets and business information. These business information terms confidential content or proprietary information, except as required by regulations, shall not be disclosed by any person. Any individual who has access to the document shall be aware of its proprietary or confidential nature and shall not disclose the document without authorization. The restrictions on the confidentiality of the above documents will apply to any information provided to you in the future that is marked as proprietary or confidential. 9. Do not change the format of the case report form. If you find that there is no place in the form to fill in the information the recorder wishes to record, please contact the responsible CRA. 10. Upon completion of the case report form, the principal investigator shall examine each page of the case report form and sign at the investigator's statement. Lactic dehydrogenase If any adverse events have occurred since the signing of the informed consent, please fill in the form of "adverse events"; If there is medication combination, please fill in the form "previous/combined medication"; If there is combined non-drug therapy, please fill in the "previous/combined non-drug therapy" form; If there is an out-of-plan inspection, please fill in the "out-of-plan inspection" form; If there is IMV/NIV, ECMO, HFNC, oxygen therapy, please fill in the "IMV/NIV, ECMO, HFNC, oxygen therapy" form. If any adverse events have occurred since the last visit, please fill in the "adverse events" form. If there is medication combination, please fill in the "previous/combined medication" form; If there is combined non-drug therapy, please fill in the "combined non-drug therapy" form; If there is an out-of-plan inspection, please fill in the "out-of-plan inspection" form. If any adverse events have occurred since the last visit, please fill in the "adverse events" form. If there is medication combination, please fill in the "previous/combined medication" form; If there is combined non-drug therapy, please fill in the "combined non-drug therapy" form; If there is an out-of-plan inspection, please fill in the "out-of-plan inspection" form. Protocol Number：KY2020-29 Protocol Number：KY2020-29 If any adverse events have occurred since the last visit, please fill in the "adverse events" form. If there is medication combination, please fill in the "previous/combined medication" form; If there is combined non-drug therapy, please fill in the "combined non-drug therapy" form; If there is an out-of-plan inspection, please fill in the "out-ofplan inspection" form; If there is IMV/NIV、ECMO、HFNC、oxygen therapy, please fill in the "IMV/NIV、ECMO、HFNC、oxygen therapy" form. Protocol Number：KY2020-29 If the subject has been discharged from the hospital, the following contents may not be carried out, please leave blank; If the subject is not discharged, please conduct the following examinations. Date |__|__|__|__|YEAR|__|__|MONTH|__|__|DAY Date：|__|__|__|__|YEAR|__|__|MONTH|__|__|DAY Protocol Number：KY2020-29 Extend Follow-Up If any adverse events have occurred since the last visit, please fill in the "adverse events" form. If there is medication combination, please fill in the "previous/combined medication" form; If there is combined non-drug therapy, please fill in the "combined non-drug therapy" form; If there is an out-of-plan inspection, please fill in the "out-of-plan inspection" form; If there is IMV/NIV、ECMO、HFNC、oxygen therapy, please fill in the "IMV/NIV、ECMO、HFNC、 oxygen therapy" form. Name of Treatment (please describe in professional medical terms) (1) (please describe in professional medical terms) (1) 自上次访视以来，受试者如有不良事件发生，请填写"不良事件"表；如有合并药物治疗，请填 写"既往/合并药物治疗"表；如有合并非药物治疗，请填写"既往/合并非药物治疗"表；如有计划 外检查，请填写"计划外检查"表。如有 IMV/NIV、ECMO、HFNC、氧疗，请填写在"IMV/NIV、 自上次访视以来，受试者如有不良事件发生，请填写"不良事件"表；如有合并药物治疗，请填 写"既往/合并药物治疗"表；如有合并非药物治疗，请填写"既往/合并非药物治疗"表；如有计划 外检查，请填写"计划外检查"表。如有 IMV/NIV、ECMO、HFNC、氧疗，请填写在"IMV/NIV、 自上次访视以来，受试者如有不良事件发生，请填写"不良事件"表；如有合并药物治疗，请填 写"既往/合并药物治疗"表；如有合并非药物治疗，请填写"既往/合并非药物治疗"表；如有计划 外检查，请填写"计划外检查"表。如有 IMV/NIV、ECMO、HFNC、氧疗，请填写在"IMV/NIV、 自上次访视以来，受试者如有不良事件发生，请填写"不良事件"表；如有合并药物治疗，请填 写"既往/合并药物治疗"表；如有合并非药物治疗，请填写"既往/合并非药物治疗"表；如有计划 外检查，请填写"计划外检查"表。如有 IMV/NIV、ECMO、HFNC、氧疗，请填写在"IMV/NIV、 自上次访视以来，受试者如有不良事件发生，请填写"不良事件"表；如有合并药物治疗，请填 写"既往/合并药物治疗"表；如有合并非药物治疗，请填写"既往/合并非药物治疗"表；如有计划 外检查，请填写"计划外检查"表。如有 IMV/NIV、ECMO、HFNC、氧疗，请填写在"IMV/NIV、 自上次访视以来，受试者如有不良事件发生，请填写"不良事件"表；如有合并药物治疗，请填 写"既往/合并药物治疗"表；如有合并非药物治疗，请填写"既往/合并非药物治疗"表；如有计划 外检查，请填写"计划外检查"表。如有 IMV/NIV、ECMO、HFNC、氧疗，请填写在"IMV/NIV、 □1 U/L □2Other：_____ □1 □2 □3 □0 Glutamic-oxalacetic transaminease(AST) □1 U/L □2Other：_____ □1 □2 □3 □0 Total Bilirubin(TBIL) □1 μmol/L □2Other：_____ □1 □2 □3 □0 Albumin(ALB) □1 g/L □2Other：_____ □1 □2 □3 □0 γ-glutamyl transpeptidas (GGT) □1 U/L □2Other：_____ □1 □2 □3 □0 Lactic dehydrogenase (LDH) □1 U/L □2Other：_____ □1 □2 □3 □0 Creatine kinase(CK) □1 U/L □2Other：_____ □1 □2 □3 □0 Creatine kinase isoenzyme(CK-MB) □1 U/L □2Other：_____ □1 □2 □3 □0 Blood urea nitrogen (BUN) □1 mmol/L □2Other：_____ □1 □2 □3 □0 Urea(Urea) □1 mmol/L □2Other：_____ □1 □2 □3 □0 Serum creatinine(CR) □1 μmol/L □2Other：_____ □1 □2 □3 □0 Protocol确认入选/排除标准 受试者是否满足所有入选标准且不满足所有排除标准？ □1 是 □0 否，请填写。 □1 不满足入选标准，入选标准编号(可多选) □ 1 □ 2 □ 3 □ 4 □ 5 □ 6 □ 7 □ 其他，请描述： □2 满足排除标准，排除标准编号(可多选) □ 1 □ 2 □ 3 □ 4 □ 5 □ 6 □ 7 □ 8 □ 9 □ 其他，请描述： 人口学资料 性 别 □1 男 □2 女 出 生 日 期 |__|__|__|__|年|__|__|月|__|__|日 如不能获得，请填写年龄：|__|__| 岁 民 族 □1 汉 □2白蛋白(ALB) □1 g/L □2 其他：_____ □1 □2 □3 □0 γ-谷氨酰转肽酶(GGT) □1 U/L □2 其他：_____ □1 □2 □3 □0 乳酸脱氢酶(LDH) □1 U/L □2 其他：_____ □1 □2 □3 □0 肌酸激酶(CK) □1 U/L □2 其他：_____ □1 □2 □3 □0 肌酸激酶同工酶(CK-MB) □1 U/L □2 其他：_____ □1 □2 □3 □0 血尿素氮(BUN) □1 mmol/L □2 其他：_____ □1 □2 □3 □0 尿素(Urea) □1 mmol/L □2 其他：_____ □1 □2 □3 □0 血肌酐(CR) □1 μmol/L □2 其他：_____ □1 □2 □3白蛋白(ALB) □1 g/L □2 其他：_____ □1 □2 □3 □0 γ-谷氨酰转肽酶(GGT) □1 U/L □2 其他：_____ □1 □2 □3 □0 乳酸脱氢酶(LDH) □1 U/L □2 其他：_____ □1 □2 □3 □0 肌酸激酶(CK) □1 U/L □2 其他：_____ □1 □2 □3 □0 肌酸激酶同工酶(CK-MB) □1 U/L □2 其他：_____ □1 □2 □3 □0 血尿素氮(BUN) □1 mmol/L □2 其他：_____ □1 □2 □3 □0 尿素(Urea) □1 mmol/L □2 其他：_____ □1 □2 □3 □0 血肌酐(CR) □1 μmol/L □2 其他：_____ □1 □2 □3白蛋白(ALB) □1 g/L □2 其他：_____ □1 □2 □3 □0 γ-谷氨酰转肽酶(GGT) □1 U/L □2 其他：_____ □1 □2 □3 □0 乳酸脱氢酶(LDH) □1 U/L □2 其他：_____ □1 □2 □3 □0 肌酸激酶(CK) □1 U/L □2 其他：_____ □1 □2 □3 □0 肌酸激酶同工酶(CK-MB) □1 U/L □2 其他：_____ □1 □2 □3 □0 血尿素氮(BUN) □1 mmol/L □2 其他：_____ □1 □2 □3 □0 尿素(Urea) □1 mmol/L □2 其他：_____ □1 □2 □3 □0 血肌酐(CR) □1 μmol/L □2 其他：_____ □1 □2 □3谷丙转氨酶(ALT) □1 U/L □2 其他：_____ □1 □2 □3 □0 谷草转氨酶(AST) □1 U/L □2 其他：_____ □1 □2 □3 □0 总胆红素(TBIL) □1 μmol/L □2 其他：_____ □1 □2 □3 □0 白蛋白(ALB) □1 g/L □2 其他：_____ □1 □2 □3 □0 γ-谷氨酰转肽酶(GGT) □1 U/L □2 其他：_____ □1 □2 □3 □0 乳酸脱氢酶(LDH) □1 U/L □2 其他：_____ □1 □2 □3 □0 肌酸激酶(CK) □1 U/L □2 其他：_____ □1 □2 □3 □0 肌酸激酶同工酶(CK-MB) □1 U/L□2谷丙转氨酶(ALT) □1 U/L □2 其他：_____ □1 □2 □3 □0 谷草转氨酶(AST) □1 U/L □2 其他：_____ □1 □2 □3 □0 总胆红素(TBIL) □1 μmol/L □2 其他：_____ □1 □2 □3 □0 白蛋白(ALB) □1 g/L □2 其他：_____ □1 □2 □3 □0 γ-谷氨酰转肽酶(GGT) □1 U/L □2 其他：_____ □1 □2 □3 □0 乳酸脱氢酶(LDH) □1 U/L □2 其他：_____ □1 □2 □3 □0 肌酸激酶(CK) □1 U/L □2 其他：_____ □1 □2 □3 □0 肌酸激酶同工酶(CK-MB) □1 U/L □2 其他：_____ □1 □2 □3 □0 血尿素氮(BUN) □1 mmol/L □2 其他：_____ □1 □2 □3 □0 尿素(Urea) □1 mmol/L □2 其他：_____ □1 □2 □3 □0 血肌酐(CR) □1 μmol/L □2 其他：_____ □1 □2 □3 Dear Sir or Madame: We invite you to participate in a randomized, controlled, open multicenter study of hydroxychloroquine sulfate in the treatment of COVID-19 infection clinical research. Before you agree to participate in this study, please read the following message carefully. You may also discuss it with your relatives and ask your doctor or researcher any questions you wish to know until you get a satisfied answer. If you agree to participate in this study, please sign the informed consent and keep a copy of the informed consent signed by both parties. Since This study was carried out in 20 centers across the country. After you participate in this study, we will follow up and observe your condition for 28 days, including 14 days or 21days according to the disease severity after treatment and 7 days after treatment. You will receive standard care according to Chinese guideline of COVID-19 pneumonia edition 6 or standard care and hydroxychloroquine sulfate orally. Routine consultation and physical examination, chest HRCT, vital signs monitoring, relevant blood examination and viral nucleic acid sampling will be done according to the protocol. To participate in this study, the doctor will treat your disease according to the current COVID -19 pneumonia Chinese guideline. Give fully active treatment, follow-up, and randomly with or without use of hydroxychloroquine sulfate orally (for 14-21 days according to the disease severity). Investigators will collect your demographic information, evaluate your clinical condition before the treatment, 4 days, 7 days, 10 days, 14 days and 21 days (for severe pneumonia) during the treatment. Laboratory examination and safety of the treatment were followed up along with the treatment and 7 days after treatment. Your participation in this study may contribute to your recovery from COVID 19 infection. You will not be at additional risk if you are enrolled in a routine medical program where all examinations are for diseases. The required examination and treatment in this study are completed according to the routine of diagnosis and treatment, and there will be no additional cost for you to participate in this study. This study is related to diseases of public health emergencies. There is no corresponding financial compensation. At the same time, the treatment you received after participating in this study is carried out in accordance with the standard management of diseases. The additional hydroxychloroquine sulfate tablets you received are commonly used as a routine clinical medication, but individual patients may still have individual adverse drug reactions. However, since the drug has been on the market for many years, investigators are familiar with the type and severity of adverse reactions, and will take corresponding treatment according to the condition if it happens. Corresponding measures will include stopping the use of the drug according to the severity of the adverse reactions. Your participation will make an important contribution to the treatment of covid-19 infection and provide help for the future treatment of similar patients. We appreciate your participation very much. This is a clinical observation study, if you are not willing to participate in this study, according to the routine management of the disease, will not affect your clinical treatment. Your medical records (including research medical records and physical and laboratory examination reports) will be kept in the hospital as required. In addition to investigators, ethics committees, supervision, auditing, pharmaceutical administration departments and other relevant personnel will be allowed to access your medical records, other personnel not related to the study will not have access to your medical records without permission. Public reports of the results of this study will not disclose your personal identity. We will do everything we can to protect the privacy of your personal medical information. Multifaceted effects of hydroxychloroquine in human disease Effects of chloroquine on viral infections: an old drug against today's diseases? The anti-HIV-1 activity of chloroquine Chloroquine and beyond: exploring anti-rheumatic drugs to reduce immune hyperactivation in HIV/AIDS Chloroquine could be used for the treatment of filoviral infections and other viral infections that emerge or emerged from viruses requiring an acidic pH for infectivity Chloroquine is a potent inhibitor of SARS coronavirus infection and spread Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine High-Throughput Screening and Identification of Potent Broad-Spectrum Inhibitors of Coronaviruses Inhibition of human coronavirus 229E infection in human epithelial lung cells (L132) by chloroquine: involvement of p38 MAPK and ERK Multifaceted effects of hydroxychloroquine in human disease Effects of chloroquine on viral infections: an old drug against today's diseases? The anti-HIV-1 activity of chloroquine Chloroquine and beyond: exploring anti-rheumatic drugs to reduce immune hyperactivation in HIV/AIDS Chloroquine could be used for the treatment of filoviral infections and other viral infections that emerge or emerged from viruses requiring an acidic pH for infectivity Chloroquine is a potent inhibitor of SARS coronavirus infection and spread Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine High-Throughput Screening and Identification of Potent Broad-Spectrum Inhibitors of Coronaviruses Inhibition of human coronavirus 229E infection in human epithelial lung cells (L132) by chloroquine: involvement of p38 MAPK and ERK Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate Tissue distribution of chloroquine, hydroxychloroquine, and Participation in the study is entirely voluntary. You may refuse to participate in the study or withdraw from the study without reason at any time during the study. This will not affect your relationship with your doctor, nor will it affect the loss of your medical or other benefits. In addition, your participation in this study may be terminated for the following reasons:1. You did not follow the study protocol.2. You fail to conduct follow-up observation on time. This study was reported to the human research ethics committee of Ruijin hospital affiliated to the school of medicine of Shanghai Jiao tong university, and was approved after a comprehensive review by the committee, including risk assessment of the subjects.I confirm that I have read and understood the informed consent of this study, voluntarily accepted the treatment in this study, and agreed to use my medical data for the publication of this study. I confirm that I have explained to the patient the details of the study, including its rights and possible benefits and risks, and given him a copy of the signed informed consent.Signature of investigator:Contact information: (mobile phone) date: