key: cord-277203-14he8n3u authors: Chen, Chang; Zhang, Yi; Huang, Jianying; Yin, Ping; Cheng, Zhenshun; Wu, Jianyuan; Chen, Song; Zhang, Yongxi; Chen, Bo; Lu, Mengxin; Luo, Yongwen; Ju, Lingao; Zhang, Jingyi; Wang, Xinghuan title: Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial date: 2020-03-20 journal: nan DOI: 10.1101/2020.03.17.20037432 sha: doc_id: 277203 cord_uid: 14he8n3u Background No clinically proven effective antiviral strategy exists for the epidemic Coronavirus Disease 2019 (COVID-19). Methods We conducted a prospective, randomized, controlled, open-label multicenter trial involving adult patients with COVID-19. Patients were randomly assigned in a 1:1 ratio to receive conventional therapy plus Umifenovir (Arbidol) (200mg*3/day) or Favipiravir (1600mg*2/first day followed by 600mg*2/day) for 10 days. The primary outcome was clinical recovery rate of Day 7. Latency to relief for pyrexia and cough, the rate of auxiliary oxygen therapy (AOT) or noninvasive mechanical ventilation (NMV) were the secondary outcomes. Safety data were collected for 17 days. Results 240 enrolled COVID-19 patients underwent randomization; 120 patients were assigned to receive Favipiravir (116 assessed), and 120 to receive Arbidol (120 assessed). Clinical recovery rate of Day 7 does not significantly differ between Favipiravir group (71/116) and Arbidol group (62/120) (P=0.1396, difference of recovery rate: 0.0954; 95% CI: -0.0305 to 0.2213). Favipiravir led to shorter latencies to relief for both pyrexia (difference: 1.70 days, P<0.0001) and cough (difference: 1.75 days, P<0.0001). No difference was observed of AOT or NMV rate (both P>0.05). The most frequently observed Favipiravir-associated adverse event was raised serum uric acid (16/116, OR: 5.52, P=0.0014). Conclusions Among patients with COVID-19, Favipiravir, compared to Arbidol, did not significantly improve the clinically recovery rate at Day 7. Favipiravir significantly improved the latency to relief for pyrexia and cough. Adverse effects caused Favipiravir are mild and manageable. This trial is registered with Chictr.org.cn (ChiCTR2000030254). ≤ 36.6 °C; respiratory frequency ≤ 24 times/min; Oxygen saturation ≥ 98% without oxygen inhalation; mild or no cough. The armpit temperature, respiratory rate, oxygen saturation without oxygen, oxygen therapy and noninvasive positive pressure ventilation (NPPV) were recorded in daily All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.17.20037432 doi: medRxiv preprint follow-up. Repeated measurements were made at least twice in each follow-up. The measurements were taken after 15 minutes rest at room temperature (23±2 °C). Secondary outcomes included the time from randomization to fever reduction (patients with fever at the time of enrollment), the time from randomization to cough relief (patients with moderate or severe cough at the time of enrollment), the rate of auxiliary oxygen therapy or noninvasive mechanical ventilation during the trial, the all-cause mortality during the trial, the rate of respiratory failure during the trial (defined as SPO 2 ≤ 90% or PaO 2 /FiO 2 < 300 mmHg without oxygen inhalation, and requires oxygen therapy or higher respiratory support). Blood biochemistry, urine routine, coagulation function, C-reactive protein, nucleic acid and CT were examined on the third day (D3±1 day) and the seventh day (D7±1 day) after taking the drug, and the adverse events and concomitant medication were observed. Classification criteria of ordinary COVID-19 patients and critical COVID-19 patients: (1) Ordinary COVID-19 patients: has a fever, respiratory symptom, can be observed by imageology methods. (2) Critical COVID-19 patients: meeting any of the following case: a. dyspnea, RR > 30 times/min; b. the SpO 2 < 93% in the resting state; c. PaO 2 /FiO 2 < 300mmHg (1 mmHg = 0.133 kPa). PaO 2 /FiO 2 should be corrected according to the formula: PaO 2 /FiO 2 × [atmospheric pressure (mmHg)/760]. The pulmonary imaging showed that the lesions progressed more than 50% within 24-48 hours, and the patients were classified as critical patients. All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.17.20037432 doi: medRxiv preprint Sample size estimation: the expected clinical recovery rate of the experimental group is 70%, the clinical recovery of the control group is 50%, α = 0.025 (single side), β = 0.20, power = 0.80. According to the distribution ratio of 1:1 between the experimental group and the control group, the statistical sample size is 92 participants in each group. The sample size increased about 20% considering factors such as shedding/elimination. The trial was designed to include 240 participants in the group, including 120 in the experimental group and 120 in the control group. SAS9.4 software was used for statistical analysis. For the main efficacy indicator/primary outcome (clinical recovery rate after 7 days or the end of treatment), the comparison between the experimental group and the control group adopts the optimal test. We calculated the bilateral 95% CI of the difference between the clinical recovery rate of the experimental group and the control group. If the lower limit was > 0, it was considered the experimental group (favipiravir) is superior to the control group (arbidol). Log rank test was used to compare the "time" between the two groups. For the secondary efficacy indicators/secondary outcomes, t test or Wilcoxon rank sum test (if t-test was not applicable) was performed for safety indicators and continuous variables, Wilcoxon rank sum test was used for grade variables. Frequency or composition (%) were used for statistical description of classification indexes, and Chi-square test test or Fisher's exact test was used for comparison between groups. For all statistical tests, P value < 0.05 (bilateral) were considered as statistically significant. All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.17.20037432 doi: medRxiv preprint Comparison of duration of fever, cough relief time and auxiliary oxygen therapy or noninvasive mechanical ventilation rate between 2 groups Table 3 displayed duration of fever, cough relief time and auxiliary oxygen therapy or noninvasive mechanical ventilation rate between the favipiravir and arbidol groups. All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . patients. Favipiravir author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.17.20037432 doi: medRxiv preprint COVID-19) Situation Report. 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