key: cord-0948194-vhfu020h authors: Yang, Ming; Shang, Ya-xi; Tian, Zi-yu; Xiong, Min; Lu, Chun-li; Jiang, Yue; Zhang, Yao; Zhang, Ying-ying; Jin, Xin-yan; Jin, Qiu-bai; Zhang, Ying; Willcox, Merlin L.; Liu, Jian-ping title: Characteristics of registered studies for Coronavirus disease 2019 (COVID-19): A systematic review date: 2020-05-20 journal: Integr Med Res DOI: 10.1016/j.imr.2020.100426 sha: edb31cf80285adf152e8661be420bfff4cfa898a doc_id: 948194 cord_uid: vhfu020h Abstract Background The World Health Organization characterized the Coronavirus disease 2019 (COVID-19) as a pandemic on March 11th. Many clinical trials on COVID-19 have been registered, and we aim to review the study characteristics and provide guidance for future trials to avoid duplicated effort. Methods Studies on COVID-19 registered before March 3rd, 2020 on eight registry platforms worldwide were searched and the data of design, participants, interventions, and outcomes were extracted and analyzed. Results Three hundred and ninety-three studies were identified and 380 (96.7%) were from mainland China, while 3 in Japan, 3 in France, 2 in the US, and 3 were international collaborative studies. Two hundred and sixty-six (67.7%) aimed at therapeutic effect, others were for prevention, diagnosis, prognosis, etc. Two hundred and two studies (51.4%) were randomized controlled trials. Two third of therapeutic studies tested Western medicines including antiviral drugs (17.7%), stem cell and cord blood therapy (10.2%), chloroquine and derivatives (8.3%), 16 (6.0%) on Chinese medicines, and 73 (27.4%) on integrated therapy of Western and Chinese medicines. Thirty-one studies among 266 therapeutic studies (11.7%) used mortality as primary outcome, while the most designed secondary outcomes were symptoms and signs (47.0%). Half of the studies (45.5%) had not started recruiting till March 3rd. Conclusions Inappropriate outcome setting, delayed recruitment and insufficient numbers of new cases in China implied many studies may fail to complete. Strategies and protocols of the studies with robust and rapid data sharing are warranted for emergency public health events, helping the timely evidence-based decision-making. Coronaviruses are a large family of viruses that cause illness ranging from the common cold to more severe diseases such as Middle East respiratory syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS). 1 Coronavirus disease 2019 occurred in December 2019 and the first case was reported in Wuhan, China. 2 On January 31, 2020, the World Health Organization (WHO) announced that the new coronavirus epidemic constituted a public health emergency of international concern and characterized COVID-19 as a pandemic on March 11. 3 As of April 28, 3, 138, 115 people were confirmed infected with COVID-19 worldwide in 210 countries and territories with cases. 4 While carrying out public health control and clinical management, Chinese government also encouraged speeding up clinical trials of new drugs, and it was necessary to promptly launch them into the frontline of treatment, improve cure and reduce death. 5 As there is no specific treatment for COVID-19, and the main management is for symptomatic treatment and supportive care, clinical evidence is urgently needed to support clinical decision-making. Researchers in China reacted quickly, and the first clinical trial was registered in the China clinical trials registry on January 23 2020. Following a short period, more than 200 clinical trials have been registered, involving a variety of therapeutic approaches. 6 Facing the increasing ongoing trials, it would be important to review the research questions and characteristics of these studies to inform clinical practice for the prevention and treatment of Therefore, our aim is to investigate the characteristics of the registered studies in J o u r n a l P r e -p r o o f 5 the early period after the outbreak of COVID-19, providing guidance for future trials and avoiding duplicated effort worldwide. All the clinical studies on COVID-19 registered before March 3rd 2020 on the trial registry platforms were retrieved, including the United States ClinicalTrials.gov Nine authors (MX, YJ, YZ, YYZ, YXS, ZYT, XYJ, QBJ, MY) abstracted data, including registration number and date, title, e-mail, leading institutions, country and province, setting, ethic information, funding, design, study objectives, anticipated start date, interventions and control, population, sample size, recruiting status and outcomes. We also checked the numbers of confirmed cases in China from the official website of the National Health Commission of the People's Republic of China. 7 All J o u r n a l P r e -p r o o f 6 abstracted data were entered into a pre-defined data extraction sheet. The quantitative description and figures were conducted by MY and YXS with Microsoft Excel 2016 and the GraphPad Prism 6. After searching on the registries, 406 records were retrieved and after removing duplicates, 393 were eligible and included in the analysis. Three hundred and twenty-one studies were from ChiCTR, 69 from the Clinicaltrials.gov, and 3 from Japanese Registry. No records were found from other registries. The countries hosting the trials were China (380 studies), Japan (3), France (3), the US (2), 3 international collaboration studies, and 2 studies with no country origin (Supplementary Figure 1) . Among those 380 studies in China, 36 studies were supposed to be conducted in more than 2 provinces, and 328 studies each in one province (26 provinces in total) and 16 studies did not provide information about the place. One study was an online survey investigating quality of life of Chinese residents during or after the outbreak of COVID-19. Table 1 The characteristics of the registered studies from eight registries Table 1 . One hundred and seventy-seven studies (66.5%) were testing Western medicine and others were for Chinese medicine (16 studies, 6.0%) or integrative therapy of both (73 studies, 27.4%). In terms of the comparisons, 122 therapeutic studies (45.9%) used conventional therapy as control intervention, following to the guidance issued by National Health Commission and National Administration of Traditional Chinese Medicine. Antiviral drugs, placebo, blank, multiple controls, and others were the comparisons used in the studies (Table 1 ). The therapeutic clinical trials contributed the largest proportion in the registrations with the number of 266 studies ( Table 2 ). Among the tested Western medicine, 47 studies tested on antivirals including arbidol, lopinavir-ritonavir, darunavir, interferon, ribavirin, and danoprevir. Apart from these antivirals in China, five RCTs registered for remdesivir, including two phase Ⅲ randomized, double-blind, placebo-controlled multicenter study for mild/moderate and severe patients, two phase Ⅲ RCTs comparing different duration with standard therapy, and one phaseⅡmulticenter, adaptive, randomized blinded controlled trial. Other trials tested antivirals not marketed in China including fapilavir, xofluza, azvudine, triazavirin, and ASC09F. As for the latest status, the two RCTs of remdesivir in China were suspended or terminated due to the lack of participants. Other clinical studies for Western treatments included 27 for stem cell and cord blood, 22 for chloroquine and derivatives, 15 for immunological agents and monoclonal antibodies, 8 for convalescent plasma therapy, 6 for inhalation therapy of oxygen, nitric oxide, and hydrogen-oxygen, 6 for glucocorticoids, 4 for psychological therapy, 3 for vitamins, and 3 for extracorporeal membrane oxygenation (ECMO). There were 8 studies for COVID-19 prevention testing Western medicine, such as arbidol, interferon spray, hydroxychloroquine and mask for doctors during gastroscopy. These studies had not started recruitment according to the registrations. The secondary category of interventions was Chinese medicine and integrated therapies of multiple drugs and non-pharmaceutical interventions. There were 46 studies using Chinese medicines without detailed information, and one tested Chinese medicine granule for people with common cold. The involved Chinese medicines, compositions, and rationale in 34 studies are presented in Table 3 In Table 4 , only 17 RCTs, 2 controlled clinical trials, and 12 observational studies used mortality as a primary outcome. Other clinical important outcomes such as exacerbation rate/time and length of intensive care unit (ICU) stay were also seldom used as primary outcomes. Symptoms and signs, viral nucleic acid/viral loads, and imaging examinations (chest CT, X radiograph, etc.) were the most used in the primary outcomes. Similarly, symptoms and signs, common laboratory tests (blood, urine routine, biochemical, etc.), and viral nucleic acid/viral loads were the most used in the secondary outcomes, and mortality and safety outcomes were also frequently mentioned in secondary outcomes. This study systematically reviewed available registered studies for COVID-19 with the analyses of their distributions and characteristics. Three hundred and ninety-three studies were registered in eight registries, aiming at the prevention, treatment, diagnosis and prognosis of COVID-19. Majority of the studies were randomized trials, followed by observational studies testing different interventions such as antiviral drugs, Chinese medicine, and integrated therapies. Except for 50 studies, clinical important outcomes such as mortality and exacerbation rate/time were not set as primary outcomes in majority trials. One hundred and seventy-nine studies had not started recruiting and would hardly be able to carry on in China due to insufficient patients. As a new communicable disease, direct evidence for the prevention of COVID-19 is not available. We found insufficient evidence to support the rationale for tested Western medicines, while based on historical records and human evidence of SARS and H1N1 influenza prevention, Chinese herbal formula is considered as an alternative approach for prevention of COVID-19 in high-risk population. 23 The therapeutic clinical studies made up the largest proportion of the registrations. Antivirals, the most promising category of Western medicine, accounted for 17.7% out of the therapeutic studies. In terms of Chinese medicines, 14 had clinical or laboratory evidence, showing the potential therapeutic effects on COVID-19 patients. Though two months have passed after the retrieving date (March 3rd) of our study, few trials released the results. Flaws in study design, such as the setting of the control and outcomes, and the lack of coordination were discovered from the registrations. Even in an outbreak, investigational products should be evaluated scientifically and ethically. 24 Do no harm is always the first rule for all human studies. Methodologically, double-blind randomized, placebo controlled trials are considered to be the gold standard for therapeutic clinical trials. 25 However, considering the emergency and the practical issues of ethics and informed consent, the implementation of RCT faces more challenges. In the context of COVID-19 pandemic, J o u r n a l P r e -p r o o f 14 the control interventions should be supportive care. As statistics shows, the mortality of COVID-19 was 4.3% in Wuhan, China, indicating severe life-threatening disease. 26 New studies on clinical characteristics of COVID-19 also reported outcomes on exacerbation, such as the median time from first symptom to dyspnea, acute respiratory distress syndrome (ARDS), transfer to the ICU due to complications and death of multiple organ failure, 26, 27 and other symptoms and laboratory findings for example neutrophilia, organ and coagulation dysfunction, which were potential risk factors for ARDS and elevated d-dimer as risk factors for mortality. 28, 29 On the contrary, clinical important outcomes such as mortality and exacerbation were only used as primary outcomes in 21.5% analyzed registrations, and the observational measures in clinical practice such as symptoms, signs, common laboratory tests and viral nucleic acid/viral load were used more frequently. Additionally, the most used primary and secondary outcomes were similar and clear measurements and time points were seldom available. The design of more than three primary outcomes in one trial may bring problems in the interpretation of research results. 6 Although the number of registered trials is increasing, only carefully conducted trials can show which measures work. 30 recently, aim to strengthen overall coordination, promote data integration, and improve research efficiency. 34 With the statistics of registered information, we will trace the trials for the update status regularly. Further research could be conducted to investigate the impact factors of a successful trial in the emergency of public events, and summarize valuable experience for the protocols of unexpected emergency events. In conclusion, from January 23rd to March 3rd 2020, 393 studies were registered for the prevention, treatment, diagnosis and prognosis of COVID-19. The limitations of design, delayed recruitment, and insufficient numbers of new cases in China make studies difficult to complete. International collaborations are important to achieve efficient research on global pandemics, and robust and rapid data sharing is urgently needed. Research protocols for public health emergency will be warranted and priority trials could be defined in shorter time, avoiding the waste of resources and duplication of research efforts. Authors would like to thank Dr. Junchao Chen for the retrieval of WHO Guid ance and Dr. Fei Dong for her searching suggestions. The authors declare that they have no conflict of interest. This research did not involve any human or animal experiment. All data generated and analysed during this study are included in this article. Table 1 The characteristics of the registered studies from eight registries Table 2 Proportion of different types of Western medicine and Chinese medicine Table 3 Compositions and rationale for tested Chinese herbal medicine Table 4 Number of the registered studies for therapeutic evaluation using primary and secondary outcomes However, high-quality evidence is warranted to support the application of CDDP in treating CHD. Origin and evolution of pathogenic coronaviruses Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia World Health Organization. Coronavirus (COVID-19) events as they happen Coronavirus Update (Live) Premier Li Keqiang presided over a meeting of the Central Leading Group for New Coronary Pneumonia Epidemic Situation, deployed further classification, effective prevention and control, required vivo Compound Danshen (Salvia miltiorrhiza) dripping pill for coronary heart disease: an overview of systematic reviews XueBiJing Injection Versus Placebo for Critically Ill Patients With Severe Community-Acquired Pneumonia: A Randomized Controlled Trial Tanreqing injection for acute bronchitis disease: A systematic review and meta-analysis of randomized controlled trials Efficacy and safety of Re-Du-Ning injection in the treatment of seasonal influenza: results from a randomized, double-blinded, multicenter, oseltamivir-controlled trial Expert consensus statement on Xiyanping Injection for respiratory system infectious diseases in clinical practice (adults) The protective effect of Shenfu injection against elderly severe pneumonia Honeysuckle-encoded atypical microRNA2911 directly targets influenza A viruses Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Epidemiologic and Clinical Characteristics of Novel Coronavirus Infections Involving 13 Patients Outside Wuhan Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Slew of trials launch to test coronavirus treatments in China World Health Organization. Consultation on Clinical Trial Design for Ebola Virus Disease World Health Organization Epimedii Folium (Yinyanghuo), etc. (No more information available) NA Bai-Du-Yin formula granules Coptidis Rhizoma (Huanglian) Gardeniae Fructus (Zhizi), Radix Platycodonis (Jiegeng), Scutellariae Radix (Huangqin), Anemarrhenae Rhizoma (Zhimu), Paeoniae Radix Rubra (Chishao), Scrophulariae Radix (Xuanshen), Fructus Forsythiae (Lianqaio) Moutan Cortex (Mudanpi), and along with a traditional Chinese mineral Chaihu Qingwen decoction ) (for suspected COVID-19 cases, ordinary patients, and the prevention for people Bupleuri Radix (Chaihu) Officinalis Flos (Houpohua), Armeniacae Semen Amarum Isatidis 37 exposed to patients) Radix (Banlangen) Phragmitis Rhizoma (Lugen) Viticis Fructus (Manjingzi) Qingfei Jiebiao decoction Platycodonis Radix (Jiegeng) Poria (Fuling), Saposhnikoviae Radix (Fangfeng) Trichosanthis Pericarpium (Gualoupi) Coicis Semen (Yiyiren) Paeoniae Radix Rubra Artemisiae Scopariae Herba (Yinchen), Platycladi Semen (Baiziren), Sepiae Endoconcha (Haipiaoxiao) Glycyrrhizae Radix et Rhizoma (Gancao), Amomi Fructus (Sharen), Curcumae Radix (Yujin) Imperatae Rhizoma (Baimaogen) Galli Gigerii Endothelium Corneum (Jineijin) Astragali Radix (Huangqi) NA Magnoliae Officinalis Cortex (Houpo Pogostemonis Herba (Huoxiang), (Caoguo), Ephedrae Herba (Mahuang) Rhizoma Zingiberis Recens (Shengjiang) Polygoni Cuspidate Rhizome et Ephedrae Herba (Mahung) Polygoni Cuspidate Rhizome et Radix (Huzhang), along with a traditional Chinese mineral SR, systematic review and /or meta-analysis CHD, coronary heart disease; RDNI, Reduning injection