Background Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known. Methods We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15. Results A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P=0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, −5.0 percentage points; 95% CI, −9.8 to −0.3; P=0.03), as were new infections (5.9% vs. 11.2%; difference, −5.3 percentage points; 95% CI, −8.7 to −1.9; P=0.003). Conclusions Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579 .)

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Summary Background Influenza continues to have a significant socioeconomic and health impact despite a long established vaccine program and approved antivirals. Preclinical data suggest combination antivirals might be more effective than oseltamivir alone in the treatment of influenza. Methods We conducted a randomized, double-blinded, multicenter phase 2 trial of combination antivirals versus monotherapy for the treatment of influenza. Participants ≥18 years with influenza at increased risk of complications from influenza were randomized by an online computer-generated randomization system to receive either oseltamivir, amantadine, and ribavirin or oseltamivir alone for 5 days, and followed for 28 days. The primary endpoint was the percentage of participants with virus detectable by polymerase chain reaction in nasopharyngeal swab at Day 3. Among the secondary outcomes, there were safety and time to alleviation of influenza clinical symptoms. ClinicalTrials.gov Identifier: NCT01227967. Findings Between March 2011 and April 2016 we randomized 633 participants. Seven participants were excluded from analysis: 3 were given treatment without randomization, 3 withdrew before taking any medication, and 1 was lost to follow-up. The primary analysis included 394 participants, excluding 47 in the pilot phase, 172 without confirmed influenza, and 13 without an endpoint sample. 80 of 200 (40.0%) participants in the combination arm had virus detectable at Day 3 compared to 97 of 194 (50.0%) (95%C.I. 0.2–19.8%, p=0.046) in the control arm. There was no benefit, however, in multiple clinical secondary endpoints, such as median duration of symptoms (4.5 days in the combination arm vs 4.0 days in the oseltamivir arm; p = 0.21). Interpretation Although oseltamivir, amantadine, and ribavirin showed a statistically significant decrease in viral shedding at Day 3 relative to oseltamivir, this difference was not associated with improved clinical benefit. More work is needed to understand the lack of clinical benefit when a difference in virologic outcome was identified. Funding National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States.

A coordinated response and collaboration between law enforcement, the local public health, emergency medical services and Health Center staff, were all key interventions in preventing a more substantial public health outbreak resulting from use of a novel synthetic cannabinoid compound. Real time collaborations between toxicology laboratories, suppliers of analytical standards and the public health system may be useful in the face of future novel chemical exposures.