key: cord-0686733-9yql0qbr authors: Chen, C.-P.; Lin, Y.-C.; Chen, T.-C.; Tseng, T.-Y.; Wong, H.-L.; Kuo, C.-Y.; Lin, W.-P.; Huang, S.-R.; Wang, W.-Y.; Liao, J.-H.; Liao, C.-S.; Hung, Y.-P.; Lin, T.-H.; Chang, T.-Y.; Hsiao, C.-F.; Huang, Y.-W.; Chung, W.-S.; Cheng, C.-Y.; Cheng, S.-H. title: A Multicenter, randomized, open-label, controlled trial to evaluate the efficacy and tolerability of hydroxychloroquine and a retrospective study in adult patients with mild to moderate Coronavirus disease 2019 (COVID-19) date: 2020-07-10 journal: nan DOI: 10.1101/2020.07.08.20148841 sha: 20b187befc8847946dec3859d4cc1a971a8ea2b7 doc_id: 686733 cord_uid: 9yql0qbr Objective In this study, we evaluated the efficacy of hydroxychloroquine (HCQ) against coronavirus disease 2019 (COVID-19) via a randomized controlled trial (RCT) and a retrospective study. Methods Subjects admitted to 11 designated public hospitals in Taiwan between April 1 and May 31, 2020, with COVID-19 diagnosis confirmed by pharyngeal real-time RT-PCR for SARS-CoV-2, were randomized at a 2:1 ratio and stratified by mild or moderate illness. HCQ 400 mg twice for 1 d and HCQ 200 mg twice daily for 6 days were administered. Both study group and controlled group received standard of care (SOC). Pharyngeal swabs and sputum were collected every other day. The proportion and time to negative viral PCR were assessed on day 14. In the retrospective study, medical records were reviewed for patients admitted before March 31, 2020. Results There were 33 and 37 cases in the RCT and retrospective study, respectively. In the RCT, the median times to negative rRT-PCR from randomization to hospital day 14 were 5 days (95% CI; 1-9 days) and 10 days (95% CI; 2-12 days) for the HCQ and SOC groups, respectively (p = 0.40). On day 14, 81.0% (17/21) and 75.0% (9/12) of the subjects in the HCQ and SOC groups, respectively, had undetected virus (p = 0.36). In the retrospective study, 12 (42.9%) in the HCQ group and 5 (55.6%) in the control group had negative rRT-PCR results on hospital day 14 (p = 0.70). Conclusions Neither study demonstrated that HCQ shortened viral shedding in mild to moderate COVID-19 subjects. Coronavirus Disease 2019 (COVID-19) is caused by severe acute respiratory syndrome 90 coronavirus 2 (SARS-CoV-2) and is an ongoing pandemic. The outbreak was first localized to 91 Wuhan, Hubei Province, People's Republic of China (PRC) on December 31, 2019 [1] . On 92 January 30, 2020, the World Health Organization (WHO) declared that the outbreak was a 93 public health emergency of international concern and thereafter recognized it as a pandemic 94 [2,3]. As of June 20, 2020, more than eight million cases of COVID-19 have been reported in 95 187 countries and territories. More than 450,000 deaths have been associated with this 96 infection [4]. Taiwan is a close neighbor of PRC and reported its first COVID-19 case on 97 January 21, 2020 [5] . As of June20, 2020, there were 446 confirmed COVID-19 cases in 98 Taiwan. As a result of the early implementation of social distancing, hand hygiene, and face 99 masks, Taiwan has had a low incidence of domestic COVID-19 cases [6] . Chloroquine phosphate is a well-known antimalarial drug that has been on the market for 110 several decades. An in vitro study showed that chloroquine is effective against SARS-CoV-2 111 at the entry and post-entry infection stages [8] . Chloroquine may either increase endosomal 112 pH by blocking the fusion of the virus and the host cell membrane [18] or by interfering with 113 cell receptor glycosylation [19] . Chloroquine may also repress proinflammatory signaling and 114 cytokine (IL-1, IL-6, and TNF) production by inhibiting lysosome activity in antigen- 115 presenting cells [20] . Compared to chloroquine, HCQ has an additional hydroxyl group, lower 116 toxicity, and similar antiviral efficacy. 117 118 HCQ received emergency approval by the US Food and Drug Administration (FDA) for used 119 in the treatment of COVID-19 [21] . However, the efficacy of HCQ against SARS-CoV-2 has 120 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 10, 2020. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 10, 2020. Clinical course 159 COVID-19 symptoms were recorded and followed up daily. Chest X-rays, 160 electrocardiography, and the biomarkers complete blood count, white blood cell differential 161 count, biochemistry, prothrombin time, activated partial thromboplastin time, ferritin, highly 162 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 10, 2020. . https://doi.org/10.1101/2020.07.08.20148841 doi: medRxiv preprint 7 active troponin I, C-reactive protein, and erythrocyte sedimentation rate were tested upon 163 admission and every 4 days after enrollment. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 10, 2020. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 10, 2020. . https://doi.org/10.1101/2020.07.08.20148841 doi: medRxiv preprint Clinical trial 231 Thirty-three cases were enrolled in the RCT (Fig. 1) . The mean age (SD) of the subjects was 232 32.9 (10.7) y. Males comprised 57.6% of all subjects. A few individuals presented with 233 underlying chronic illnesses. The initial presentation included anosmia (51.5%), cough 234 (48.5%), ageusia (30.0%), nasal obstruction (24.2%), and sore throat (21.2%). Of these, 235 12.1% of the cases had pneumonia according to the X-ray images ( Table 1) . . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 10, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 10, 2020. . https://doi.org/10.1101/2020.07.08.20148841 doi: medRxiv preprint Twenty-one cases were randomized to the HCQ group and 12 cases were randomized to the 246 SOC group. However, two in the HCQ group and one in the SOC group had withdrawn 247 consents before the first dose was administered. One (4.8%) in the HCQ group and two 248 (16.7%) in the SOC group were concomitantly administered azithromycin. 249 The median times to negative rRT-PCR assessment from randomization to hospital day 14 250 were 5 days (95% CI; 1-9 days) for the HCQ group and 10 days (95% CI; 2-12 days) for the 251 SOC group (p = 0.40) (Fig. 2; Table 2 ). By day 14, 81.0% (17/21) and 75.0% (9/12) of the 252 subjects in the HCQ and SOC groups, respectively, had undetected virus (p = 0.36) ( Table 2) . 253 Analysis of area under curve of Ct value in the study interval showed that least square mean 254 (SD) were 501.7 (18.0) for HCQ group and 496.6 (21.2) for SOC group. The treatment 255 difference (95% CI) was 5.1 (-37.1 -47.2) (p=0.81) ( Table 3) . For subjects presenting with 256 mild illness, the median times to negative rRT-PCR assessment from randomization were 5 257 days (95% CI; 1-11 days) for the HCQ group and 11 days (95% CI; 1-12 days) for the SOC 258 group (p = 0.31) (Supplemental Fig. 3 ; Table 4 ). CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 10, 2020. Retrospective observational study 284 Thirty-seven cases were enrolled in the observational study (Fig. 1) CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 10, 2020. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 10, 2020. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 10, 2020. . https://doi.org/10.1101/2020.07.08.20148841 doi: medRxiv preprint therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon 461 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 10, 2020. . https://doi.org/10.1101/2020.07.08.20148841 doi: medRxiv preprint This funding source played no role in 400 study design or conduction, data collection, analysis or interpretation, writing of the 401 manuscript, or decision to submit it for publication. The authors also thank for their donation of investigational products, the National Health Research Institutes Taiwan Centers for Disease Control, Taiwan Food and Drug Administration Taiwan for their technical assistance, and all study members participating in the 405 Group led by Shu-Hsing Cheng (shcheng@mail.tygh.gov.tw), namely Ministry of Health and Welfare, Chin-Feng Lin, Jiing-Chyuan Luo Hsiao from Taipei Hospital, Ministry of Health and Welfare Huei Lee and Sz-Rung Huang* from Miaoli General Hospital, Ministry of Health and 412 Chiu from Feng Yuan Hospital, Ministry of Health and Welfare Tzung-Fan Chuang Ming Huang from Nantou Hospital, Ministry of Health and Welfare Ministry of Health 419 and Welfare Wang from Pingtung Hospital, Ministry of Health and Welfare, and Chin-Fu Hsiao 422 from Institute of Population Health Sciences Naming the coronavirus disease (COVID-19) and the viral 431 that caused it guidance/naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it World Health Organization. Statement on the second meeting or the International Health 435 Emergency Committee regarding the outbreak of novel coronavirus 436 World Health Organization. WHO director-general's opening remarks at the media 440 briefing on COVID-19 World Health Organization. Novel coronavirus situation report-151 First case of 446 coronavirus disease 2019 (COVID-19) pneumonia in Taiwan Taiwan Centers for Disease Control. CECC confirmed 1 more imported COVID-19 450 case;case returns to Taiwan from Bangladesh First case of 454 2019 novel coronavirus in the United States Remdesivir and chloroquine 457 effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro Comparative 460 beta against MERS-CoV Favipiravir (T-705), a broad spectrum inhibitor of 464 viral RNA polymerase Lopinavir/ritonavir did not 467 shorten the duration of SARS CoV-2 shedding in patients with mild pneumonia in Taiwan A trial of lopinavir-ritonavir in 471 adults hospitalized with severe COVID-19 The FDA-approved drug 474 ivermectin inhibits the replication of SARS-CoV-2 in vitro SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human 478 ACE2 Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-482 label non-randomized clinical trial Complex immune dysregulation in COVID-19 patients with severe 486 respiratory failure IL-6 trans-signaling via the soluble IL-6 receptor: Importance for the pro-489 inflammatory activities of IL-6 Effects of chloroquine on viral 492 infections: An old drug against today's diseases International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted Chloroquine is a potent inhibitor of SARS coronavirus infection and spread Current targeted therapeutics against COVID-19: Based 498 on first-line experience in China Reply to request for emergency use authorization for 501 use of chloroquine phosphate or hydroxychloroquine sulfate supplied from the strategic 502 national stockpile for treatment of Retraction: Cardiovascular disease, 505 drug therapy, and mortality in Covid-19 Retraction-hydroxychloroquine or chloroquine with 508 or without a macrolide for treatment of COVID-19: A multinational registry analysis World Health Organization. Diagnostic detection of 2019-nCoV by real-time RT-PCR Chloroquine phosphate has shown apparent 514 efficacy in treatment of COVID-19 associated pneumonia in clinical studies Effect of 522 high vs low doses of chloroquine diphosphate as adjunctive therapy for patients 523 hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 524 infection: A randomized clinical trial Clinical and 527 microbiological effect of a combination of hydroxychloroquine CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity The authors thank the Hospital and Social Welfare Organizations Administration Commission, 399 CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)The copyright holder for this preprint this version posted July 10, 2020. . https://doi.org/10.1101/2020.07.08.20148841 doi: medRxiv preprintThe copyright holder for this preprint this version posted July 10, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)The copyright holder for this preprint this version posted July 10, 2020. . https://doi.org/10.1101/2020.07.08.20148841 doi: medRxiv preprint