key: cord-0800279-iwsa760n authors: Zhu, Rui-fang; Gao, Ru-lu; Robert, Sue-Ho; Gao, Jin-ping; Yang, Shi-gui; Zhu, Changtai title: Systematic Review of the Registered Clinical Trials of Coronavirus Disease 2019 (COVID-19) date: 2020-03-03 journal: nan DOI: 10.1101/2020.03.01.20029611 sha: 6efe01046ce81279412ea440a4b246f942f29124 doc_id: 800279 cord_uid: iwsa760n Background: Since the outbreak of coronavirus disease 2019 (COVID-19), many researchers in China have immediately carried out clinical research scheme of the COVID-19. But, there is still a lack of systematic review of registered clinical trials. Therefore, we conducted a systematic review of the clinical trials of COVID-19 to summarize the characteristics of the COVID-19 registered clinical trials. Methods: This study is based on the recommendations of the PRISMA in the Cochrane handbook. The databases from the Chinese Clinical Registration Center and the ClinicalTrials.gov were searched to collect the registered clinical trials of COVID-19. The retrieval inception date is February 9, 2020. Two researchers independently selected the literature based on inclusion and exclusion criteria, extracted data and evaluated the risk of bias. Results: A total of 75 registered clinical trials (63 interventional studies and 12 observational studies) of COVID-19 were obtained. A majority of clinical trials were sponsored by Chinese hospitals. Only 11 trials have begun to recruit patients, and none of the registered clinical trials had been completed; 34 trials were early clinical exploratory trials or in a pre-experiment stage, 15 trials belonged to phrase Ⅲ and 4 trials were phrase Ⅳ. The methods of intervention included traditional Chinese medicine involving 26 trials, Western medicine involving 30 trials, and integrated traditional Chinese medicine and Western medicine involving 19 trials. The subjects were mainly non-critical adult patients (≥ 18 years old). The median sample size of the trials was 100 (IQR: 60 - 200), and the median execute time of the trials was 179 d (IQR: 94 - 366 d). The main outcomes were clinical observation and examinations. Overall, both the methodology quality of interventional trials and observational studies were low. Conclusions: Disorderly and intensive clinical trials of COVID-19 using traditional Chinese medicine and western medicine are ongoing or will being carried out in China. However, based on the low methodology quality and small sample size and long studies execute time, we will not be able to obtain reliable, high-quality clinical evidence about COVID-19 treatment in the near future. Improving the quality of study design, prioritizing promising drugs, and using different designs and statistical methods are worth advocating and recommending for the clinical trials of COVID-19 in China. This review presented a narrative synthesis. This study mainly analyzed and summarized the types of studies, intervention, host organization and address, sample size, research stage, research status, excepted completion time, inclusion and exclusion criteria, outcome measurement and observation time, methodology quality and describes the results with statistics and characteristics respectively. Nonparametric data was represented by median and 95% CI and the statistical analysis Up to February 9, 2020, we retrieved 57 clinical trials of COVID-19 from the Chinese clinical registration center, and 18 clinical trials of COVID-19 from the ClinicalTrails.gov, and a total of 75 clinical trials of COVID-19 were obtained (Table 1 and Table 2 ). The retrieval process is shown in Figure 3 . In addition to the two observational trials from France (NCT04262921, NCT04259892), the others were sponsored by Chinese organizations. These organizations are responsible for three or author/funder, who has granted medRxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) The copyright holder for this preprint . of traditional Chinese medicine, 2 preventive studies, 4 studies on prognosis, rehabilitation and devices). Most of the trials have passed the ethical review, most of the studies are still in the preparation stage, only 11 trials have started to recruit patients, and all the registered clinical trials have not been completed. The first to register was on January 3, 2020 was a randomized controlled trial of "Chinese medicine for severe pneumonia with severe coronavirus pneumonia" on January 3, 2020, which is sponsored by Dongzhimen Hospital of Beijing University of Traditional Chinese Medicine. In terms of trial stages, 20 trials are exploratory studies or in the preliminary experiment The common characteristics of inclusion criteria included: signing informed consent; age over 18 years; laboratory test (RT-PCR) confirmed infection of COVID-19 (diagnostic criteria for pneumonia diagnosis in line with "Protocol of Prevention and Control of Novel Coronavirus Pneumonia"); chest imaging confirmed lung involvement; participants were willing to be assigned to any designated treatment group randomly; agree not to participate in another study of the investigator until the study was completed. Most of the subjects were limited to light (ordinary subjects), and few of the studies included severe patients. The common characteristics of the exclusion criteria are: severe and critical patients with COVID-19; pregnant and lactating women; allergic patients; patients with serious heart, brain, kidney, tumor, hemoglobin disease and other diseases; patients with mental disorders, drug abuse or dependence history; those who do not get informed consent; the researchers think the subject is not suitable. The main intervention methods of registered clinical trials include traditional Chinese medicine treatment, western medicine treatment and integrated traditional and Western medicine treatment, etc.; the outcome of treatment observation mainly includes clinical rehabilitation time, the incidence of using mechanical ventilation, the incidence in ICU, mortality, all kinds of complications and virological detection indicators, etc.; the medication methods mainly include oral, injection, atomization inhalation, etc.; the majority of medication time is more than one week. . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.03.01.20029611 doi: medRxiv preprint There are 6 clinical registration trials of the combination of Chinese medicine and Western medicine, and the intervention means is to use the combination of the above Chinese herbs and Western medicine antiviral drugs. The observation outcomes included: cure rate, cure time, incidence of adverse outcomes, clinical improvement time, ratio of normal progression to severe disease, time to heavy progression, death, virus nucleic acid copies, coronavirus nucleic acid conversion time, pneumonia severity index, Murray lung injury score, chest CT, the survival rate and mortality of patients. Additionally, some laboratory tests novel coronavirus were also selected, including routine blood test, urine routine test, C-reactive protein, procalcitonin, erythrocyte sedimentation rate, muscle enzyme, troponin, myoglobin, D dimer, blood gas analysis, coagulation routine, new coronavirus nucleic acid examination, and T cell subgroup analysis, hospital length etc. The follow-up timing of the outcome measure is mostly 2-4 weeks, but some studies do not set forth a plan. According to the Cochrane bias risk assessment results ( Figure 5 ), the quality assessment of the interventional study methodology is generally low. Most trials reported randomization, while the other trials had high risk of biases in randomization (17 trials did not mention randomization and 6 trials were judged as non-randomized trials)； Few trials conducted distribution concealment; only nine trials implemented blinding of participants, personnel and outcome assessment; None of the 63 trials clarified drop-out and follow-up bias. However, other bias risks, such as the risk of conflict of interest among drug manufacturers, are unclear. The NOS scores of the observational trials are from 4 to 6 ( Table 3) . Most of the observational trials have high risk of biases in assessment outcome, follow-up of outcome and adequacy of follow up of cohorts ( Figure 6 ). Therefore, the overall quality of registered observational trials is low. . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.03.01.20029611 doi: medRxiv preprint COVID-19 is a new infectious disease, which is still poorly understood, so there is no recognized effective treatment. This sudden health incident has caused great harm to China and seriously threatened people's health [21] [22] [23] . In order to deal with the disease, researchers have carried out many clinical studies intensively. According to the search results, the current studies are At present, the treatment of this disease is mainly antiviral, improving patients' immunity, intervening in autoimmune damage (against immune storm caused by cytokines) and symptomatic treatment. According to the in vitro cell test, the antiviral effect of Western drugs is obviously superior to that of traditional Chinese medicine (the concentration value of the inhibitory effect is low). But considering that Chinese herbs have both antiviral and immunomodulatory effects, it has a certain application prospect in disease prevention and treatment; at present, the combination of Chinese and Western Medicine (Qingfeipaidutang and chloroquine phosphate, abidol, lopinavir/Rito) is considered as a better treatment method by experts, and has been listed in "Protocol of Prevention and Control of Novel Coronavirus Pneumonia", but there is still a lack of high-quality evidence, which needs clinical verification. According to the existing preliminary evidence, the antiviral drug Remdesivir (two three-phase clinical trials for light, moderate and heavy patients respectively, expected to end on April 27, 2020) has a promising application prospect. The reasons are as follows: i) cell test results both in vitro and in vivo showed that very low concentration can play an antiviral role 24-25 ; ii) animal test is safe 26 ; and iii) clinical test is anti-Ebola (the same as new coronavirus) RNA virus is effective 27-28 ; and iv) clinical case report is effective 29 . In addition, some of the validation drugs, such as Chloroquine Phosphate, Abidol, Darunavir, and Lopinavir/Ritonavir (Coriolus Versicolor), . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.03.01.20029611 doi: medRxiv preprint have been proved to be safe and have strong antiviral potential in vitro 25 . Therefore, these Western antiviral drugs have an application potential and need to be verified in clinical practice. In this review, we found that many trials used biological products for immunotherapy of the disease. In light of the experience and lessons of severe acute respiratory syndrome (SARS), 30-31 , steroid therapy has been used cautiously in the treatment of the disease, so there are few trials based on the retrieval results. From the perspective of inclusion and exclusion criteria, some people were excluded, such as children and adolescents, pregnant women, patients with serious liver and kidney damage. Therefore, this will lead to the lack of clinical evidence in this part of the population. The outcomes of clinical trial observation includes clinical observation outcomes, physical examination and laboratory test results, but some outcomes are subjective, which may cause measurement bias. Based on Cochrane risk of bias items and NOS, we evaluated the quality of intervention trials and observational trials, respectively. The evaluation results showed that the overall quality of registered clinical research was low. Therefore, it indicates that most of the registered clinical studies have a greater risk of bias, and the level of evidence is relatively low in the future, which belittles the practice significance of the research. We believed that the main reasons for the low quality of the registered clinical trial protocols are: i) the researchers' clinical research ability is not enough, and ii) the researchers lack experience in dealing with sudden health events. We believed that it is necessary to improve the quality of research and to the registered clinical research programmes in strict accordance with the guidelines for clinical trials 32- 35 . In addition, current clinical trials by different hospitals conducted spontaneously are not effectively organized and coordinated, so more scattered and disorderly. Some drugs that have not been tested in vitro or whose safety is of great concern are also being tested in clinical trials, which not only increase the risk of clinical trials, but also waste research resources. Hence, the National Administration of scientific research should strengthen their management and coordination and a small number of promising drugs, such as Remdesivir, should be prioritized for clinical trials and allowed to run smoothly. From these registered clinical studies, we found a serious limitation: most of the registered clinical research did not consider the "timeliness", and still followed the conservative traditional . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.03.01.20029611 doi: medRxiv preprint study design paradigm. The research duration was more than 5 months, and the median (days) of the intervention research was 180 (95% CI: 146.3 -328.9), which is very unfavorable for the current urgent situation. We believed that, in the current situation, we should pay more attention to "timeliness" in the design of clinical trials (otherwise, the epidemic situation may have ended after drug approval; the research also lost its social significance). Therefore, in response to this emerging public health event, we can refer to the "sequential design" for clinical trials; "sequential design" not only saves the sample size, but also significantly shortens the research period, so it is very conducive to the screening and discovery of some drugs with significant efficacy [36] [37] . In addition, a very difficult problem is the treatment of severe and critical patients with COVID-19. For these patients, we suggested that: based on the "compassionate use drug" principle, with safe and obvious antiviral potential drugs, to conduct a staged small batch and single-arm clinical trials is feasible. We believed that "compassionate use drug" can not only meet the special needs of patients but also carry out clinical effectiveness observation, research and analysis, so as to improve the research efficiency and benefit patients [38] [39] [40] [41] [42] . Also, given a large number of clinical cases have accumulated information, and using available existing data for statistics and analysis with the help of new statistical methods such as clinical data-mining [43] [44] [45] and real-world study 46-48 , etc ., can also quickly obtain some very valuable information and save research time. In brief, under the condition that there are a large number of cases to be selected at present, it is of great value for the treatment and prevention of COVID-19 to try to complete various clinical trial designs and data analysis scientifically and efficiently with a variety of clinical research designs and statistical analysis methods, and researchers should try in future. Disorderly and intensive clinical trials of COVID-19 using traditional Chinese medicine and Western medicine are ongoing or will be carried out in China. However, based on the poor quality and small sample size and long completion period, we will not be able to obtain reliable, high-quality clinical evidence about COVID-19 treatment for quite a long time in the future. In order to effectively deal with the current sudden health emergencies, the National Administration of scientific research should strengthen their management and coordination to improve the study quality based on the guidelines for clinical trials. Also, it is important to ensure that some . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.03.01.20029611 doi: medRxiv preprint promising projects are prioritized. In addition, we suggest that using a variety of study designs and statistical methods to scientifically and efficiently conduct the clinical trials, which has an extremely important value for the control of COVID-19. The authors declare that there is no conflict of interest. 1 . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) The copyright holder for this preprint . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) The copyright holder for this preprint . Table 3 The methodology quality of the observational trials using Newcastle-Ottawa scale. Note: A study can be awarded a maximum of one point for each numbered item within the Selection and Outcome categories. A maximum of two points can be given for Comparability. . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.03.01.20029611 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.03.01.20029611 doi: medRxiv preprint R e c o r d s i d e n t i f i e d t h r o u g h C h i C T R s e a r c h i n g ( n = 7 8 ) R e c o r d s i d e n t i f i e d t h r o u g h C l i n i c a l T r a i l s . g o v ( n = 3 3 ) . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.03.01.20029611 doi: medRxiv preprint Representativeness of the exposed cohort Selection of the non exposed cohort . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.03.01.20029611 doi: medRxiv preprint Optimal adaptive group sequential design with flexible timing of sample size determination Availability of Investigational Medicines Through the US Food and Drug Administration's Expanded Access and Compassionate Use Programs Compassionate Use of Cefiderocol as Adjunctive Treatment of Native Aortic Valve Endocarditis Due to Extremely Drug-resistant Pseudomonas aeruginosa Expanding Patient Access to Investigational Drugs: Single Patient Investigational New Drug and the "Right to Try Notes from the Field: Acquisition of Delamanid Under a Compassionate Use Program for Extensively Drug-Resistant Tuberculosis -United States Right now, in the right way: U. S. Food and Drug Administration's expanded access program and patient rights Clinical data mining Gaining Insights on Nasopharyngeal Carcinoma Treatment Outcome Using Clinical Data Mining Techniques Health social workers' assessments as part of a specialized pain rehabilitation: a clinical data-mining study Effectiveness and Patient Satisfaction with Budesonide/Formoterol Easyhaler((R)) Among Patients with Asthma or COPD Switching from Previous Treatment: a Real-World Study of Patient-Reported Outcomes Real-world study of direct oral anticoagulant dosing patterns in patients with atrial fibrillation Rifaximin improves survival in cirrhotic patients with refractory ascites: A real-world study