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Is the adding baricitinib to remdesivir better than remdesivir alone for Corona Virus Disease 2019 (COVID-19)?

Comment by InpharmD Researcher

The ACTT-2 randomized, controlled trial found that adding baricitinib to remdesivir can improve time to recovery by one (1) day compared to remdesivir alone. More data are needed to clarify the role of baricitinib in the management of COVID-19.

The National Institute of Health (NIH) COVID-19 Treatment Panel states that there are insufficient data to recommend either for or against the use of baricitinib in combination with remdesivir for the treatment of COVID-19 in hospitalized patients in cases where corticosteroids can be used instead. In the rare circumstances where corticosteroids cannot be used, the Panel recommends using baricitinib in combination with remdesivir for the treatment of COVID-19 in hospitalized, non-intubated patients who require oxygen supplementation. The Panel recommends against the use of baricitinib in the absence of remdesivir, except in a clinical trial setting. [1]

Baricitinib is a Janus kinase inhibitor that is hypothesized to be a therapeutic option for the early stages of SARS-CoV-2 by inhibiting clathrin-mediated endocytosis, thereby inhibiting viral infection of cells. It's anti-inflammatory properties may give it the potential to be used in late-stage COVID-19. Baricitinib lowers interleukin-6 (IL-6), regulates innate immunity blocking type-I interferon (IFN) signals, and down-regulates CD80/CD86 expression (except HLA-DR in human monocyte-derived dendritic cells, in a concentration-dependent manner). [2]

A systematic review assessing immune and antiviral therapy for COVID-19 stated that baricitinib can inhibit cytokine release and inhibit viral cell entry through its high affinity for AP2-associated protein kinase 1 (AAK1), which regulates endocytosis and can inhibit viral cell entry. In a retrospective study of baricitinib in mild-to-moderate COVID-19 pneumonia, 12 patients who received baricitinib with lopinavir/ritonavir were compared with 12 controls treated with lopinavir/ritonavir alone. At week 2, no serious adverse events were observed, and baricitinib had more discharges (7/12 [58%] vs 1/12 [8%]; P=0.027). However, the retrospective nature of this study combined with the small sample size means it is only hypothesis-generating. [3]

Another multicenter, retrospective trial conducted in seven Italian hospitals evaluated the efficacy of baricitinib in patients with moderate COVID-19 pneumonia. By week 2, mortality was lower with baricitinib 4 mg/day compared to controls (0/113 [0%] vs 5/78 [6.4%]; P=0.010). Baricitinib was well tolerated with no adverse effects, but the retrospective nature allowing for selection bias also means this study is only hypothesis-generating. [3]

A retrospective study of 20 patients receiving baricitinib combined with lopinavir/ritonavir also found a significant reduction of mortality in comparison with 56 controls treated with standard of care (5% vs 45%; P


[1] National Institutes of Health. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Available at Updated December 17, 2020. Accessed January 1, 2021.
[2] Magro G. COVID-19: Review on latest available drugs and therapies against SARS-CoV-2. Coagulation and inflammation cross-talking. Virus Res. 2020 Sep;286:198070. doi: 10.1016/j.virusres.2020.198070
[3] Cantini F, Goletti D, Petrone L, Najafi Fard S, Niccoli L, Foti R. Immune Therapy, or Antiviral Therapy, or Both for COVID-19: A Systematic Review. Drugs. 2020;80(18):1929-1946. doi:10.1007/s40265-020-01421-w

Relevant Prescribing Information

OLUMIANT® (baricitinib) is a Janus kinase (JAK) inhibitor indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies. The use of baricitinib with other JAK inhibitors, biological disease-modifying antirheumatic drugs (DMARDs), and potent immunosuppressants is not recommended. [4]

The recommended dose of baricitinib is 2 mg once daily and is provided in tablet form. Baricitinib may be used as monotherapy or in combination with methotrexate or other DMARDs, and can be taken with or without food. [4]

Baricitinib should be avoided in patients with hemoglobin less than 8 g/dL, an absolute lymphocyte count less than 500 cells/mm3, an an absolute neutrophil count less than 1000 cells/mm3, in patients with serious active infection, or with administration of live vaccines. Baricitinib is not recommended in patients with hepatic or renal impairment. Baricitinib should be used cautiously in patients with increased risk for thrombosis and gastrointestinal perforations. There is a U.S Boxed Warning for serious infections, malignancies, and thrombosis. The most common adverse event is infection (29%), with 16% being upper respiratory tract infection. [4]


[4] Olumiant [package insert]. Indianapolis, IN: Eli Lilly and Company; 2020.

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Is the adding baricitinib to remdesivir better than remdesivir alone for Corona Virus Disease 2019 (COVID-19)?

Please see Table 1 for your response.


Baricitinib plus Remdesivir for Hospitalized Adults with COVID-19 (ACTT-2)


Randomized, multicenter, adaptive, double-blind, placebo-controlled trial



To evaluate whether the combination of baricitinib plus remdesivir was superior to remdesivir alone

Study Groups

Baracitinib + remdesivir (n=515)

Placebo + remdesivir (n=518)

Inclusion Criteria

18 years of age or older; laboratory-confirmed SARS-CoV-2 infection (via polymerase chain reaction [PCR]) within 72 hours of randomization or >72 hours if unable to collect sample plus progressive disease suggestive of COVID-19; radiographic infiltrates by imaging, peripheral oxygen saturation (SpO2) ≤94% on room air, or requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO)

Exclusion Criteria

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 times the upper limit of the normal (ULN); impaired renal function (estimated glomerular filtration [eGFR] < 30 mL/min) or receiving hemodialysis or hemofiltration; allergy to study drugs; pregnancy or breast-feeding; anticipated discharge from the hospital or transfer within 72 hours of enrollment; neutropenia (<1,000/µL); lymphopenia (<200/µL); received similar or confounding medications (e.g. tyrosine kinase inhibitors, monoclonal antibodies targeting cytokines or B-cells, immunosuppressants) up to 4 weeks before screening; history of venous thromboembolism (VTE) in the past 12 weeks or any recurrent VTE


Participants were randomized 1:1 to receive either remdesivir and baricitinib or remdesivir and placebo. All patients also received standard supportive care at the trial site hospital.

All patients received remdesivir 200 mg on day 1, followed by 100 mg daily for 10 days or until hospital discharge or death. Baricitinib 4 mg daily (PO [two 2-mg tablets] or through a nasogastric tube) or placebo was given for 14 days or until hospital discharge. Patients with an eGFR < 60 mL/min received baricitinib at a dose of 2 mg once daily.


Enrollment: May 8 to July 1, 2020

Follow-up: 29 days

Outcome Measures

Primary: time to recovery through 28 days (defined as achieving category 1, 2, or 3 on the eight-category ordinal scale)

  • 1: Not hospitalized, no limitations on activities
  • 2: Not hospitalized, limitation on activities and/or requiring home oxygen
  • 3: Hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical care
  • 4: Hospitalized, not requiring supplemental oxygen – requiring ongoing medical care
  • 5: Hospitalized, requiring supplemental oxygen
  • 6: Hospitalized, on non-invasive ventilation or high flow oxygen devices
  • 7: Hospitalized, on mechanical ventilation or ECMO
  • 8: Death

Secondary: clinical status at day 15 (based on the eight-category ordinal scale), mortality, time to discharge, days receiving supplemental oxygen

Baseline Characteristics


Baracitinib + remdesivir (n=515)

Placebo + remdesivir (n=518)


Age, years

55.0±15.4 55.8±16.0    


319 (61.9%) 333 (64.3%)    
White  251 (48.7%) 245 (47.3%)    
Body mass index, kg/m2  32.2±8.2 32.3±8.4    
Time from symptom onset to randomization, days (interquartile range) 8 (5-10) 8 (5-11)    
Post-randomization corticosteroid use 56 (10.9%) 67 (12.9%)    

Clinical status (category) on 8-point ordinal scale

4: not requiring oxygen

5: requiring oxygen

6: requiring non-invasive ventilation

7: requiring mechanical ventilation


70 (13.6%)

288 (55.9%)

103 (20.0%)

54 (10.5%)


72 (13.9%)

276 (53.3%)

113 (21.8%)

57 (11.0%)


Patients presenting as category 6 or 7 were considered to have severe COVID-19 (30.5% vs 32.8%).

IQR=interquartile range



Baracitinib + remdesivir (n=515)

Placebo + remdesivir (n=518)

Rate ratio (95% CI)


Time to recovery, days (IQR)

Patients recovered (category of 1, 2, or 3)

7 (6-8)

433 (84.1%)

8 (7-9)

406 (78.4%)


1.16 (1.01 to 1.32)



By day 14

By day 28


8 (1.6%)

24 (4.7%)


15 (6.9%)

37 (7.1%)

Hazard ratio (95% CI)

0.54 (0.23 to 1.28)

0.65 (0.39 to 1.09)

Not significant
Time to one-category improvement, days (IQR) 6 (5-7) 8 (7-9) 1.21 (1.06 to 1.39) N/A 
Time to two-category improvement, days (IQR) 12 (12-13) 13 (not evaluable) 1.20 (1.05 to 1.38) N/A

Duration of hospitalization, days (IQR)

With imputation of data for those who died*

Among patients who did not die


10 (4 to 27)

9 (4 to 23)


12 (4 to 28)

10 (4 to 28)

Difference (95% CI)

−2.0 (−5.2 to 1.2)

−1.0 (−3.5 to 1.5)


A subgroup analysis showed no significant difference in time to recovery between the groups in patients with a baseline clinical status of 4, 5, or 7. Patients with a baseline status of 6 (on non-invasive ventilation or high flow oxygen) improved significantly when baricitinib was added (10 days vs 18 days; RR 1.51; 95% CI 1.10 to 2.08).

The odds of improvement in clinical status at day 15 were greater with baricitinib than with remdesivir alone (odds ratio [OR] 1.3; 95% CI 1.0 to 1.6). Patients with a baseline ordinal score of 6 who received baricitinib were most likely to have clinical improvement at day 15 (OR 2.2; 95% C, 1.4 to 3.6).

*The duration for patients who died was imputed as 28 days.

Adverse Events

Any grade 3 or 4 adverse events (40.7% vs 46.8%):

Hyperglycemia (4.9% vs 7.9%), anemia (4.9% vs 6.5%), decreased lymphocyte count (2.2% vs 4.7%), acute kidney injury (3.9% vs 7.1%)

Serious adverse events (16.0% vs 21.0%):

Acute respiratory failure (3.6% vs 2.6%), acute kidney injury (1.0% vs 2.2%), pulmonary embolism (1.0% vs 0.4%), respiratory failure (5.1% vs 7.3%)

Study Author Conclusions

Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status, notably among patients receiving high-flow oxygen or noninvasive mechanical ventilation. The combination was associated with fewer serious adverse events.

InpharmD Researcher Critique

Although the primary endpoint of this study was statistically significant, the clinical benefit of time to recovery by 1 day is debated. This significant result is exclusive to hospitalized patients on non-invasive ventilation or high flow oxygen devices, which made up 20% of patients. This suggests these results are merely hypothesis-generating.

The authors conclude that adding baricitinib is "superior" to remdesivir alone, but this study was not designed to detect statistical superiority between the treatments. Nor was this study powered to detect a difference in mortality. Additionally, the statistical analyses were not adjusted for multiple comparisons.

The mortality status by day 28 was unknown for 142 persons (13% with baricitinib; 14.5% with placebo); however, the authors estimate the incidence of death post-discharge is low.

While both groups received standard of care (per their hospital protocols), concomitant mediations/therapies given were not reported. This study concluded enrollment around 2 weeks after the results of the RECOVERY trial were released, which showed a mortality benefit with dexamethasone use. While the incidence of corticosteroid use after randomization was similar (no significant difference), the extent of their confounding or any comparison to baricitinib cannot be determined. 


Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus remdesivir for hospitalized adults with covid-19. N Engl J Med. Published online December 11, 2020:NEJMoa2031994.