Objective To evaluate whether favipiravir reduces the time to viral clearance as documented by negative SARS-CoV-2 RT-PCR in mild COVID-19 cases compared to placebo. Methods In this randomized, double-blinded, multicenter, and placebo-controlled trial, adults with PCR confirmed mild COVID-19 were recruited in an outpatient setting at seven medical facilities across Saudi Arabia. Participants were randomized in a 1:1 ratio to receive either favipiravir 1800 mg by mouth twice daily on day one followed by 800 mg twice daily (n=112) or a matching placebo (n=119), for a total of 5 to 7 days. The primary outcome was the effect of favipiravir on reducing the time to viral clearance (by PCR test) within 15 days of starting the treatment compared to the placebo group. The trial included the following secondary outcomes: symptom resolution, hospitalization, ICU admissions, adverse events, and 28-day mortality. Results 231 patients were randomized and began the study (median age, 37 [interquartile range: 32-44] years; 155 [67%] men), and 112 (48.5%) were assigned to the treatment group and 119 (51.5%) into the placebo group. The data and safety monitoring board (DSMB) recommended stopping enrollment because of futility at the interim analysis. The median time to viral clearance was 10 (IQR: 6-12) days in the favipiravir group and 8 (IQR: 6-12) days in the placebo group, with a hazard ratio of 0.87 for the favipiravir group (95% CI 0.571 to 1.326; p-value =0.51). The median time to clinical recovery was 7 days (IQR: 4-11) in the favipiravir group and 7 days (IQR: 5-10) in the placebo group. There was no difference between the two groups on the secondary outcome of hospital admission. There were no drug-related severe adverse events. Conclusion In this clinical trial, favipiravir therapy in mild COVID-19 patients did not reduce the time to viral clearance within 15 days of starting the treatment. Clinical Trial Registration ClinicalTrials.gov identifier ( NCT04464408 ): https://clinicaltrials.gov/ct2/show/NCT04464408 .

IntroductionA novel coronavirus, designated SARS-CoV-2, caused an international outbreak of a respiratory illness, termed COVID-19 in December 2019. There is a lack of specific therapeutic agents based on evidence for this novel coronavirus infection; however, several medications have been evaluated as a potential therapy. Therapy is required to treat symptomatic patients and decrease the virus carriage duration to limit the communitytransmission.Methods and analysisWe hypothesise that patients with mild COVID-19 treated with favipiravir will have a shorter duration of time to virus clearance than the control group. The primary outcome is to evaluate the effect of favipiravir on the timing of the PCR test conversion from positive to negative within 15 days after starting the medicine.Adults (>18 years, men or nonpregnant women, diagnosed with mild COVID-19 within 5 days of disease onset) are being recruited by physicians participating from the Ministry of National Guard Health Affairs and the Ministry of Health ethics committee approved primary healthcare centres. This double-blind, randomised trial comprises three significant parts: screening, treatment and a follow-up period. The treating physician and patients are blinded. Eligible participants are randomised in a 1:1 ratio to either the therapy group (favipiravir) or a control group (placebo) with 1800 mg by mouth two times per day for the first day, followed by 800 mg two times per day for 4–7 days. Serial nasopharyngeal/oropharyngeal swab samples are obtained on day 1 (5 days before therapy). On day5±1 day, 10±1 day, 15±2 days, extra nasopharyngeal/oropharyngeal PCR COVID-19 samples are requested.The primary analysis population for evaluating both the efficacy and safety outcomes will be a modified intention to treat population. Anticipating a 10% dropout rate, we expect to recruit 288 subjects per arm. The results assume that the hazard ratio is constant throughout the study and that the Cox proportional hazard regression is used to analyse the data.Ethics and disseminationThe study was approved by the King Abdullah International Medical Research Centre Institutional Review Board (28 April 2020) and the Ministry of Health Institutional Review Board (1 July 2020). Protocol details and any amendments will be reported to https://clinicaltrials.gov/ct2/show/NCT04464408. The results will be published in peer-reviewed journals.Trial registration numberNational Clinical Trial Registry (NCT04464408).

Background Patients’ race and ethnicity may play a role in mortality from Covid-19. Studies in China, the US, and Europe have been conducted on the predictors of Covid-19 mortality, yet in the EMR countries, such studies are scarce. Therefore, we aimed to describe the hospitalization rate, ICU-admission, and in-hospital mortality of Covid-19 and predictors of in-hospital mortality in Saudi Arabia. Methods E-medical records were examined for all Covid-19 patients diagnosed in five tertiary hospitals affiliated with the Saudi-National Guard-Health Affairs during March 21, 2020, and September 12, 2021, based on a positive SARS-CoV-2 RT-PCR test, (n = 35,284). Data were collected on patients’ characteristics, comorbidities, laboratory findings, hospitalization, ICU admission, and in-hospital and overall mortality. Logestic regressions were used to identify the independent predictors of in-hospital mortality. The best laboratory parameters cut-off values to predict in-hospital mortality were identified using the area under the receiver operating characteristic curve (AUC). Significance was considered at p < 0.05. Results Of all 35,284 Covid-19 patients, 81.8% were adults and 21.7% were hospitalized. Compared to non-hospitalized patients, hospitalized patients were more of female gender (52.1% versus 47.3%, p < 0.001) and had higher mean age (p < 0.001), higher mean BMI (p < 0.001), and higher rates of: diabetes (p < 0.001), hypertension (p < 0.001), ischemic heart disease (p < 0.001), cancer (p < 0.001), COPD (p < 0.001) and asthma (p = 0.011). The study showed 3.1% overall case-fatality, 20.3% ICU admission rate, and 9.7% in-hospital mortality. Predictors of in-hospital mortality among adult patients were; patients’ age ≥ 70 years (OR = 6.93, 95% CI 1.94–24.79), ischemic heart disease (OR = 1.80, 95% CI 1.05–3.09), ICU admission (OR = 24.38, 95% CI 15.64–38.01), abnormal C-reactive protein “CRP” (OR = 1.85, 95% CI 1.08–3.16), abnormal D-dimer (OR = 1.96, 95% CI 1.15–3.36), lymphopenia (OR = 2.76, 95% CI 2.03–3.3.76), high neutrophil count (OR = 2.10, 95% CI 1.54–2.87), and abnormal procalcitonin (OR = 3.33, 95% CI 1.88–5.90). The best laboratory parameters cut-off values to predict in-hospital mortality were CRP > 72.25 mg/L (AUC = 0.64), d-dimer > 1125 µg/L (AUC = 0.75), neutrophils count > 5,745 × 10^9/L (AUC = 0.70), lymphocytic count < 1.10 × 10^9/L (AUC = 0.72), and procalcitonin > 0.18 ng/mL (AUC = 0.76). Conclusions Rates of hospitalization, ICU-admission, in-hospital mortality and overall case fatality were nearly comparable to the rates in western countries. Early interventions are necessary for high-risk Covid-19 patients, especially elderly patients and those with cardiac diseases.