CME INDIA Presentation by Admin.
COV-BARRIER study is being cited as GREAT NEWS
In spite of treatment advances with Remdesivir, Dexamethasone, and Tocilizumab, a crucial unmet need exists in reducing mortality among hospitalised COVID-19 patients. Baricitinib, a selective affordable JK inhibitor has been studied in COV-BARRIER trial. Its findings have been hailed by the medical community as great news.
How Baricitinab came to light?
- Is a selective Janus kinase JAK)1/JAK2 inhibitor.
- It has known anti-inflammatory profile in patients with autoimmune diseases.
- It has been appraised in artificial intelligence and mechanistic laboratory studies and human clinical trials, with multiple mechanisms of action. In February 2020, baricitinib was identified by an artificial intelligence platform as a potential intervention for the treatment of COVID-19.
- It has been shown to have anti-cytokine effects.
- It also inhibits host cell viral propagation.
- The biochemical inhibitory effects of baricitinib on human Numb-associated kinases (AAK1, BIKE, and GAK) have been confirmed which are responsible for SARS-CoV-2 viral propagation.
- It has also shown to reduce multiple cytokines and biomarkers implicated in COVID-19 pathophysiology.
- Secondary infections and venous thrombosis are two very important adverse effects.
- In patients with rheumatoid arthritis which is the approved indication for baricitinib, such side effects are found to be negligible.
Why the COV-BARRIER study is being cited as GREAT NEWS, dated 01/09/2021
- Vincent Marconi and colleagues assessed the use of baricitinib in a randomised, placebo-controlled, double-blind trial (the COV-BARRIER study).
- It appeared in The Lancet Respiratory Medicine on September 01, 2021.
- The trial has been conducted in 101 centres across 12 countries, and enrolled 1525 patients.
- The composite primary endpoint:
- The proportion of participants who progressed to high-flow oxygen or non-invasive ventilation (NIAID-OS score 6),
- Invasive mechanical ventilation or extracorporeal membrane oxygenation (NIAID-OS score 7),
- Or death (NIAID-OS score 8) by day 28, in the baricitinib group compared with the placebo group.
- Secondary endpoint:
- All-cause mortality by day 28.
- Exploratory endpoint:
- All-cause mortality by day 60.
- The Great News
- Compared with placebo, patients who received baricitinib had a 38·2% relative reduction and 5 percentage points absolute reduction in 28-day all-cause mortality. (hazard ratio [HR] 0·57 [95% CI 0·41–0·78]; nominal p=0·0018).
- Number needed to treat (NNT) to prevent one additional death of 20.
- No other anti-COVID-19 therapy has shown such a profound reduction in mortality.
What other modalities shining?
- Only other two immunomodulatory treatments that were associated with a reduction in mortality
- Dexamethasone (which showed a 17% relative reduction and 2·8% absolute reduction in mortality and an NNT of 36)
- Tocilizumab (which showed a 15% relative reduction and 4% absolute reduction in mortality and an NNT of 25)
No significant effect on the composite primary disease progression
- COV-BARRIER trial did not show a statistically significant difference between groups for the composite primary disease progression outcome.
- Similar outcome was achieved in the Adaptive Covid Treatment Trial (ACTT)-2 study, which also compared baricitinib against placebo, but in combination with Remdesivir. ACTT-2 was not powered for mortality outcomes, still showed a consistently better survival and a significant reduction in 28-day mortality in patients who required supplemental or high-flow oxygen.
Independent of Steroids
- COV-BARRIER study showed the survival benefits provided by baricitinib independent of the presence or absence of concomitant use of steroids (mostly dexamethasone).
- So, there was an absence of treatment interaction.
- This finding is highly relevant in regard to tocilizumab as it showed benefits in an open-label trial only if concomitant steroids were given.
No more side effects than placebo
- Treatment with baricitinib was not associated with more side-effects than placebo).
- In more than 2500 patients, the safety of baricitinib was almost identical to that of placebo.
- In ACTT-2, the number of secondary infections was significantly lower in the baricitinib group than in the placebo group
- It suggests that the immunomodulation provided by baricitinib might be protective and not as immunosuppressive .
- Even with the addition of steroids baricitinib was not associated with more infections.
How administered?
- The baricitinib is given at a dose of 4 mg/day; however, 2 mg/day should be given if the patient had a baseline eGFR of 30 to less than 60 mL/min/1·73 m2.
- Baricitinib or placebo tablets should be administered orally (or crushed for nasogastric tube delivery) and given daily for up to 14 days or until discharge from hospital, whichever occurs first.
CME INDIA Learning Points
- Worth mentioning is that COV-BARRIER first phase 3 study evaluated baricitinib in addition to the current standard of care, and included patients receiving antivirals, anticoagulants, and corticosteroids.
- COV-BARRIER is the first international, multicentre, double-blind, randomised, placebo-controlled trial with Baricitinib.
- An important knowledge gap appears to be fulfilled by this study.
- In this study baricitinib plus standard of care (including dexamethasone) did not significantly reduced progression to increased oxygen support or death (the composite primary endpoint) when compared with placebo plus standard of care. But it does not dampen the very important findings in regard to Baricitinib treatment.
- In baricitinib group absolute risk reductions of 5 percentage points in all-cause mortality at 28 days and 4·9 percentage points in all-cause mortality at 60 days gives new wings to management as it resulted in number-needed-to-treat of 20.
- The study dataset provides clinically relevant safety information for the acute care of these patients with concomitant corticosteroids.
- In COV-BARRIER, baricitinib plus standard of care
“A 38·2% relative reduction in 28-day mortality compared with placebo plus standard of care even in those patients being treated with dexamethasone at baseline is something unique.”
Baricitinib might prevent death without a significant difference in the primary endpoint.
The significantly lower mortality by day 60 in the baricitinib group versus the placebo group confirms that the reduction in mortality with baricitinib persists.
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References
- Remdesivir for the treatment of COVID-19—final report. N Engl J Med. 2020; 383: 1813-1826
- Dexamethasone in hospitalized patients with COVID-19.N Engl J Med. 2021; 384: 693-704
- Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial.Lancet Respir Med. 2021; (published online Sept 1.)https://doi.org/10.1016/S2213-2600(21)00331-3
- Baricitinib plus remdesivir for hospitalized adults with COVID-19.N Engl J Med. 2021; 384: 795-807
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