Efficacy and safety of baricitinib in patients with COVID-19 infection: Results from the randomised, double-blind, placebo-controlled, parallel-group COV-BARRIER phase 3 trial
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Abstract
Background
The efficacy and safety of baricitinib, an oral selective Janus kinase 1/2 inhibitor, in addition to standard of care (SOC) in hospitalised adults with COVID-19 is unknown.
Methods
In this phase 3, global, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America ( ClinicalTrials.gov NCT04421027 ). Hospitalised adults with COVID-19 receiving SOC were randomly assigned (1:1) to once-daily baricitinib 4-mg or placebo for up to 14 days. SOC included systemic corticosteroids in 79·3% of participants (dexamethasone ∼90%). The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28. All-cause mortality by days 28 and 60 were key secondary and exploratory endpoints, respectively. Efficacy and safety analyses included the intent-to-treat and safety populations, respectively.
Findings
Between June 11, 2020 and January 15, 2021, 1525 participants were randomly assigned to baricitinib 4-mg (n=764) or matched placebo (n=761). Overall, 27·8% of participants receiving baricitinib vs 30·5% receiving placebo progressed (primary endpoint, odds ratio 0·85, 95% CI 0·67-1·08; p=0·18). The 28-day all-cause mortality was 8·1% (n=62) for baricitinib and 13·1% (n=100) for placebo, corresponding to a 38·2% reduction in mortality (hazard ratio [HR] 0·57, 95% CI 0·41-0·78; nominal p=0·0018). The 60-day all-cause mortality was 10·3% (n=79) for baricitinib and 15·2% (n=116) for placebo (HR 0·62, 95% CI 0·47-0·83; p=0·0050). Frequency of serious adverse events (14·7% [n=110] vs 18·0% [n=135]), serious infections (8·5% [n=64] vs 9·8% [n=74]), and venous thromboembolic events (2·7% [n=20] vs 2·5% [n=19]) was similar between baricitinib and placebo, respectively.
Interpretation
While reduction of disease progression did not achieve statistical significance, treatment with baricitinib in addition to SOC (including dexamethasone) significantly reduced mortality, with a similar safety profile to SOC, in hospitalised COVID-19 participants.
Funding
Eli Lilly and Company.
Research in context
Evidence before this study
We searched PubMed using the terms “COVID-19”, “SARS-CoV-2”, “treatment”, “baricitinib” and “JAK inhibitor” for articles in English published up to April 31, 2020, regardless of article type. We considered previous and current clinical trials of investigational medications in COVID-19, as well as previous clinical trials of the Janus kinase (JAK)1 and JAK2 inhibitor, baricitinib, before undertaking this study. At the time the COV-BARRIER study was designed, there were no approved therapies for the treatment of COVID-19. Management of COVID-19 was supportive, and limited phase 3 randomised placebo-controlled studies had been completed. Limited phase 2 and 3 data on the antimalarial hydroxychloroquine and protease inhibitor lopinavir/ritonavir were available, and trials investigating the use of the antiviral remdesivir were ongoing. Baricitinib’s mechanism of action as a JAK1 and JAK2 inhibitor was identified as a potential intervention for the treatment of COVID-19 given its known anti-cytokine properties and potential for targeting host proteins for its antiviral mechanism. Additionally, early case series evaluating the efficacy and safety of baricitinib in the hospitalised patient population supported further evaluation of baricitinib as a potential treatment option for hospitalised patients with COVID-19. While COV-BARRIER was enrolling, ACTT-2, a phase 3 study evaluating baricitinib plus remdesivir was completed showing that baricitinib added to remdesivir improved time to recovery and other outcomes.
Added value of this study
This was the first phase 3 study to evaluate baricitinib in addition to the current standard of care (SOC) and included antivirals, anticoagulants, and corticosteroids. After the earliest publication of the RECOVERY study in June 2020, the treatment of hospitalised patients with COVID-19 changed with the adoption of dexamethasone as SOC. As a result of its design, COV-BARRIER became the first trial to evaluate the benefit/risk of baricitinib when added to the most current SOC (dexamethasone) in these patients. This was a randomised, double-blind, placebo-controlled trial conducted globally in regions with high COVID-19 hospitalisation rates. The reduction in the composite primary endpoint of progression to non-invasive ventilation, high flow oxygen, invasive mechanical ventilation, or death for baricitinib plus SOC (including dexamethasone) compared to placebo plus SOC did not reach statistical significance. However, in a pre-specified key secondary endpoint, treatment with baricitinib reduced 28-day all-cause mortality by 38·2% compared to placebo (HR 0·57, 95% CI 0·41-0·78; nominal p=0·0018); one additional death was prevented per 20 baricitinib-treated participants. The reduction of all-cause mortality with baricitinib was maintained by day 60 in an exploratory analysis. The frequency of serious adverse events, serious infections, and venous thromboembolic events was similar between baricitinib and placebo, respectively.
Implications of all the available evidence
In this phase 3 trial, baricitinib given in addition to SOC (which predominantly included dexamethasone) did not reduce a composite endpoint of disease progression, but showed a strong effect on reducing mortality by 28 days, an effect which was maintained by 60 days. In the ACTT-2 study, baricitinib further reduced time to recovery above the background use of remdesivir. Taken together, these findings suggest that baricitinib has synergistic effects to other SOC treatment modalities including remdesivir and dexamethasone. Based on all available evidence, baricitinib is a potentially effective oral treatment option to decrease mortality in hospitalised patients with COVID-19.
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SciScore for 10.1101/2021.04.30.21255934: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: All sites received approval from the authorized institutional review board.
Consent: All participants (or legally authorized representatives) provided informed consent.Sex as a biological variable not detected. Randomization Study Design and Oversight: This multi-center, randomized, double-blind, placebo-controlled, parallel-group, phase 3 trial included 101 centers from 12 countries in Asia, Europe, North and South America. Blinding An independent, blinded, clinical event committee adjudicated potential VTEs and deaths. Power Analysis not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are …
SciScore for 10.1101/2021.04.30.21255934: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: All sites received approval from the authorized institutional review board.
Consent: All participants (or legally authorized representatives) provided informed consent.Sex as a biological variable not detected. Randomization Study Design and Oversight: This multi-center, randomized, double-blind, placebo-controlled, parallel-group, phase 3 trial included 101 centers from 12 countries in Asia, Europe, North and South America. Blinding An independent, blinded, clinical event committee adjudicated potential VTEs and deaths. Power Analysis not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Limitations of this study may have included the choice of disease progression, as measured by clinical status including oxygen support levels, as the primary outcome. Measuring progression based on the NIAID-OS reflects treatment decisions and may be influenced by the heterogeneity of clinical practice across different geographies. Baricitinib showed a consistent reduction in progression versus placebo in the three components of the composite primary endpoint, however, the difference did not reach statistical significance. In contrast, mortality is an objective and definitive patient outcome that does not change across geographies. Baricitinib may prevent mortality without reaching significance on the primary endpoint because mortality as an outcome integrates the multi-organ effects of COVID-19, which include but are not limited to pulmonary effects. Baricitinib’s anti-inflammatory effects impact all organ systems, not only pulmonary function.18 Longer-term efficacy and safety data will be evaluated in the ongoing COV-BARRIER study.25 The COV-BARRIER trial did not demonstrate a reduction in COVID-19 progression versus SOC using a composite endpoint. However, the secondary endpoint of 28-day all-cause mortality was significantly improved in participants randomized to baricitinib plus SOC as demonstrated by its efficacy in preventing 1 additional death for every 20 participants treated when compared to placebo plus SOC. The 38.2% reduction in all-cause mortality was observed i...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04421027 Active, not recruiting A Study of Baricitinib (LY3009104) in Participants With COVI… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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