Baricitinib improves recovery in sub-group of adults hospitalised COVID-19: results from ACTT-2 study

12 March 2021. Related: COVID-19: investigational drugs, COVID-19.

Simon Collins, HIV i-Base

On 4 March 2021, results from a large randomised controlled study reported faster recovery overall from using the oral anti-inflammatory drug baricitinib in adults hospitalised with COVID-19.

However, when categorised by baseline clinical score, only a subgroup of participants had a benefit and no effect was reported for those who were either least sick or most sick (based on a clinical ordinal score).  [1]

Baricitinib is a JAK inhibitor that inhibits the signaling pathway of cytokines elevated in severe Covid-19, including IL-2, IL-6, IL-10, IFN-gamma and gmCSF and improves lymphocyte counts in patients with Covid-19. Several early studies reported potential benefits. [2, 3, 4]

This large international study included 1033 participants who were randomised to add either baricitinib (oral 4 mg/day or by nasal drip for 14 days) or placebo to current standard of care that included remdesivir (10 days) for all participants. Results have just been published in the NEJM. Although most sites were in the US (55/67) other sites were in Singapore (4), South Korea (2), Mexico (2), Japan (1), Spain (1), the UK (1), and Denmark (1). Enrollment was during May and June 2020.

The primary outcome was median time to recovery with secondary endpoints that included clinical recovery at day 15 measured on an eight point ordinal scale.

Baseline characteristics included mean age 55 years, 63% male, race: 48% white, 15% Black, 10% Asian; 51% were Hispanic/Latino. Mean BMI was 32 and median time from symptom to randomization was 8 days (IQR: 5 to 10). Roughly two-thirds had moderate COVID-19 and one-third severe. Half were receiving supplementary oxygen score 5) with another 20% high flow (score 6) and 10% invasive (score 7).

In the study overall, median recovery with baricitinib vs placebo was 7 day (95%CI: 6 to 8) vs 8 days (95% CI: 7 to 9) with rate ratio: 1.16 (95% CI: 1.01 to 1.32), p=0.03). Baricitinib also improved clinical improvement by 30% at day 15 (OR: 1.3 (95%CI: 1.0 to 1.6).

However, recovery varied considerable depending on ordinal score and use of oxygen at baseline. Baricitinib made no difference for people not using oxygen (score 4), supplemental oxygen (score 5) or who were most ill (mechanical oxygen, score 7) – only showing a significant impact for the 20% of participants with score 6. In this group (with baseline use of high-flow oxygen or noninvasive ventilation) recovery was 10 vs 18 days, with RR: 1.51 (95% CI: 1.10 to 2.08).

Overall mortality at 28-days was 5.1% vs 7.8% which was not statistically significant (HR: 0.65; 95% CI: 0.39 to 1.09).

Serious adverse events were significantly less frequent with baricitinib (16% vs 21%; diff −5.0 percentage points; 95% CI, −9.8 to −0.3) p=0.03. New infections were also significantly reduced (5.9% vs 11.2%; diff −5.3 percentage points; 95% CI, −8.7 to −1.9) p=0.003.

comment

UK studies currently using include baricitinib include the TACTIC study and, more recently, the RECOVERY study. [5, 6]

References

1. Kalil AC et al. Baricitinib plus remdesivir for hospitalized adults with covid-19. N Engl J Med 2021; 384:795-807 DOI: 10.1056/NEJMoa2031994. (4 March 2021).
   https://www.nejm.org/doi/full/10.1056/NEJMoa2031994
2. Cantini et al. Retrospective, multicenter study on the impact of baricitinib in COVID-19 moderate pneumonia. J Infect. 2020 doi: 10.1016/j.jinf.2020.04.017.  (24 June 2020).
   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313480
3. Titanji BK et al. Use of baricitinib in patients with moderate and severe COVID-19. Clinical Infectious Diseases, ciaa879, DOI: 10.1093/cid/ciaa879. (29 June 2020).
   https://academic.oup.com/cid/article/doi/10.1093/cid/ciaa879/5864596
4. Stebbing J et al. Mechanism of baricitinib supports artificial intelligence‐predicted testing in COVID ‐19 patients. Embo Mol Med (2020), e12697. DOI: 10.15252/emmm.202012697. (24 June 2020).
   https://www.embopress.org/doi/full/10.15252/emmm.202012697
5. ClinicalTrials.gov. Multi-arm therapeutic study in pre-ICU patients admitted with COVID-19 – repurposed drugs (TACTIC-R) (TACTIC-R).
   https://clinicaltrials.gov/ct2/show/NCT04390464 (registry listing)
   https://cctu.org.uk/portfolio/COVID-19/TACTIC/TACTIC-R (website)
6. RECOVERY study. Baricitinib to be investigated as a possible treatment for COVID-19 in the RECOVERY trial. (2 February 2021).
   https://www.recoverytrial.net/news/baricitinib-to-be-investigated-as-a-possible-treatment-for-covid-19-in-the-recovery-trial

This report was first posted on 10 March 2021.