What is the data behind using baricitinib for COVID-19? What patients should receive baricitinib?

Comment by InpharmD Researcher

As of August 18th, 2021, the U.S. Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) to permit the emergency use of baricitinib for treatment of coronavirus disease 2019 (COVID-19) in hospitalized adults and pediatric patients 2 years of age or older requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). Based on landmark trials, baricitinib likely provides a modest benefit when compared to standard of care. Examination of efficacy and safety outcomes for baricitinib under consistent conditions is warranted to establish its current role in COVID-19 therapy.

Background

The U.S. Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) to permit the emergency use of baricitinib for treatment of coronavirus disease 2019 (COVID-19) in hospitalized adults and pediatric patients 2 years of age or older requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). [1]

The National Institutes of Health (NIH) and Infectious Diseases Society of America (IDSA) Guidelines recommend baricitinib in recently hospitalized, COVID-19 positive patients requiring high-flow oxygen or noninvasive ventilation whose oxygen needs and inflammatory markers rapidly increase. Avoid concurrent use of baricitinib with tocilizumab due to the potential increased risk of infection and immunosuppression. [2], [3]

A 2020 review article analyzed the immunosuppressive and antiviral pharmacology, safety, and clinical experiences of baricitinib in COVID-19. A sudden clinical deterioration involving multiorgan failure and acute respiratory distress syndrome has been observed on days 7 - 10 during hospitalization. This phenomenon occurred alongside a decline in viral titers which may be due to an excessive immune response at the later course of therapy. [4]

The authors speculate baricitinib’s mechanism in relation to COVID-19 treatment. “Baricitinib is a reversible Janus‐associated kinase (JAK)‐inhibitor that interrupts the signaling of multiple cytokines implicated in COVID‐19 immunopathology. It may also have antiviral effects by targeting host factors that viruses rely for cell entry and by suppressing type I interferon driven angiotensin‐converting‐enzyme‐2 up regulation. However, baricitinib’s immunosuppressive effects may be detrimental during acute viral infections by delaying viral clearance and increasing vulnerability to secondary opportunistic infections.” [4]

Upon reviewing safety data from rheumatoid arthritis (RA) patients, the authors expressed concerns of increased risk of dose-related immuno-thromboembolic events, lymphopenia, and opportunistic infections. These safety concerns need to be further investigated in COVID-19, given its complex pathophysiology to guide the timing of baricitinib use. [4]

In one 2021 commentary, the authors raised concerns over the use of both dexamethasone and baricitinib plus remdesivir regimens together due to the potential of excessive immunosuppression. [5] While there is a significant difference in mortality between ACCT-2 (baricitinib and remdesivir compared to remdesivir alone; Table 2) and RECOVERY [6] (efficacy of dexamethasone only) trials of 7.8% and 25.7% respectively, it is problematic to compare the two trials. First, the overall critical care for COVID-19 management advanced between the two trial timeframes. Additionally, even though the ACTT-2 excluded patients receiving glucocorticoids for COVID-19 management, there were still 233 participants (~10%) who received various glucocorticoids for other medical conditions; whereas, no patients received baricitinib in the RECOVERY trial. The commentators do not currently support the empiric combination of dexamethasone with baricitinib and remdesivir. [5] This recommendation is not consistent with NIH clinical guidelines on the therapeutic management of hospitalized adults with COVID-19. [2]

One systematic review in 2020 reported results from three retrospective studies with a total of 145 patients treated with baricitinib prior to the publication of the ACTT-2 trial (Table 2). [7]

In the first trial, for patients with mild-to-moderate COVID-19 infections, baricitinib plus lopinavir/ritonavir (n = 12) was associated with a significantly higher rate of hospital discharge (7/12 [58%] vs. 1/12 [8%]; p = 0.027) as compared with lopinavir/ritonavir alone (n = 12). [7], [8]

In another multicenter retrospective study, baricitinib plus lopinavir/ritonavir (n = 113) was compared with hydroxychloroquine plus lopinavir/ritonavir (n = 78). At week 2, baricitinib was associated with significantly lower mortality rate (0% [0/113] vs. 6.4% [5/78]; p-value = 0.010; 95% CI, 0 to 0.46) and ICU admission (0.88% [1/113] vs. 17.9% [14/78]; p-value <0.0001; 95% CI, 0.0038 to 0.2624) and a higher discharge rate (77.8% [88/113] vs. 12.8% [10/78]; p <0.0001; 95% CI, 10.79 to 51.74) in moderate infection. [7], [8], [9]

A significant reduction in mortality was observed in the third study as well (5% in baricitinib plus lopinavir/ritonavir [n = 20] vs. 45% in the standard of care group [n = 26], p<0.001). [7], [8], [9], [10]

The authors highlighted that compared to other studied anti-JAKs, baricitinib exhibited a dual anti-viral functionality, inhibition of cytokine release, and viral entry. The comparable efficacy results from the three trials on ICU admissions and mortality rate. Overall, no serious adverse events were reported in the first two trials, and safety data were not available for the third study. In conclusion, the authors stated that a three-step combination therapy, including remdesivir in the early stage of the disease and combined dexamethasone plus baricitinib 4 mg/day, might be the best therapeutic strategy in COVID-19 management to target the aberrant immunoregulation. [7]

Relevant Prescribing Information

DOSING [11]

Adults with eGFR ≥ 60 mL/min/1.73 m2 and pediatric patients ≥ 9 years of age: 4 mg once daily for 14 days of total treatment or until hospital discharge, whichever is first.
Pediatric patients ≥ 2 years to <9 years of age: 2 mg once daily for 14 days of total treatment or until hospital discharge, whichever is first.

General Consideration for administration
Absolute lymphocyte count <200 cells/µL: Consider interruption until ALC is ≥ 200 cells/µL
Absolute neutrophil count <500 cells/µL: Consider interruption until ANC is ≥500 cells/µL

Renal impairment
eGFR 30 to <60 mL/min/1.73 m2: Adults and pediatric patients 9 years of age and older 2 mg once daily; Pediatric patients 2 years to less than 9 years of age 1 mg once daily
eGFR 15 to <30 mL/min/1.73 m2: Adults and pediatric patients 9 years of age and older 1 mg once daily; Pediatric patients 2 years to less than 9 years of age not recommended
Baricitinib is not recommended for patients who are on dialysis, have end-stage renal disease (ESRD, eGFR <15 mL/min/1.73 m2), have acute kidney injury, and patients with known active tuberculosis.

Hepatic impairment
Baricitinib has not been studied in patients with severe hepatic impairment. Baricitinib should only be used in patients with severe hepatic impairment if the potential benefit outweighs the potential risk. It is not known if dosage adjustment is needed in patients with severe hepatic impairment.

Pregnancy
Baricitinib should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus. Consistent with the mechanism of action, embryo-fetal toxicities including skeletal anomalies and reduced fertility have been observed in animals dosed in excess of the maximum human exposure. The limited human data on use of baricitinib in pregnant women are not sufficient to inform a drug-associated risk for major birth defects or miscarriage.

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the evidence regarding baricitinib for COVID-19? Which patients should receive baricitinib?

Level of evidence

B - One high-quality study or multiple studies with limitations Read more→

Please see Tables 1-2 for your response.

Efficacy and safety of baricitinib in patients with COVID-19 infection: Results from the randomized, double-blind, placebo-controlled, parallel-group COV-BARRIER Phase 3 trial
Design	Multi-center, randomized, double-blind, placebo-controlled, parallel-group, phase 3 trial N= 1,525
Objective	To evaluate the efficacy and safety of baricitinib in combination with standard of care (SOC) including dexamethasone, for the treatment of hospitalized adults with COVID-19
Study Groups	Baricitinib + SOC (n= 764) Placebo + SOC (n= 761)
Inclusion Criteria	Age ≥ 18 years old, hospitalized with laboratory-confirmed SARS-CoV-2 infection, had evidence of pneumonia or active, symptomatic COVID-19, and had ≥ 1 elevated inflammatory marker (C reactive protein, D-dimer, lactate dehydrogenase, ferritin)
Exclusion Criteria	Required invasive mechanical ventilation at study entry, received immunosuppressants (high dose corticosteroids, biologics, T cell or B cell targeted therapies, interferon, or JAK inhibitors), or treated with convalescent plasma or intravenous immunoglobulin for COVID-19
Methods	Hospitalized adults with COVID-19 receiving standard of care (systemic corticosteroids utilized in 79.3% of participants) were randomly assigned (1:1) to once daily baricitinib 4 mg or placebo orally for up to 14 days or until discharge whichever ocurred first. Participants with baseline eGFR ≥ 30 to < 60 mL/min/1.73 m² received a lower dose of baricitinib (2 mg). Venous thromboembolic events prophylaxis was required for all participants unless it was contradicted due to active bleeding events or history of heparin-induced thrombosis.
Duration	June 11, 2020 through January 15, 2021 Intervention: 14 days Follow up: 28 days
Outcome Measures	Composite primary endpoint: the proportion of patients who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28 Secondary endpoint: all-cause mortality by days 28 Exploratory endpoint: all-cause mortality by days 60
Baseline Characteristics		Placebo + SOC (n= 761)	Baricitinib + SOC (n= 764)	All (N= 1,525)
	Age, years	57.5 (13.8%)	57.8 (14.3%)	57.6 (14.1%)
	Female	288 (37.8%)	274 (35.9%)	562 (36.9%)
	Race White Black	440/741 (59.4%) 36/741 (4.9%)	480/752 (63.8%) 39/752 (5.2%)	920/1,493 (61.6%) 75/1,493 (5%)
	BMI (kg/m²)	30.6 ± 6.6	30.4 ± 6.4	30.5 ± 6.5
	Duration of symptoms prior to enrollment < 7 days ≥ 7 days	116/756 (15.3%) 640/756 (84.7%)	137/762 (18%) 625/762 (82%)	253/1,518 (16.7%) 1,265/1,518 (83.3%)
	Supplemental oxygen requirement No Yes	97/756 (12.8%) 472/756 (62.4%)	89/762 (11.7%) 490/762 (64.3%)	186/1,518 (12.3%) 962/1,518 (63.4%)
	Other treatments Remdesivir Dexamethasone	147/756 (19.4%) 592/756 (78.3%) 533/592 (90%)	140/762 (18.4%) 612/762 (80.3%) 566/612 (92.5%)	287/1,518 (18.9%) 1204/1518 (79.3%) 1,099/1,204 (91.3%)
	Pre-existing comorbid conditions Diabetes Chronic respiratory disease Hypertension	233 (30.6%) 36 (4.7%) 366 (48.1%)	224 (29.3%) 34 (4.5%) 365 (47.8%)	457 (30%) 70 (4.6%) 731 (47.9%)
Results	Endpoint	Placebo + SOC (n= 761)	Baricitinib + SOC (n= 764)	95 % CI	p-value
	Progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28 Population 1^* Population 2^**	30.5% 27.1%	27.8% 28.9%	0.85 (0.67 to 1. 08) 1.12 (0.58 to 2.16)	0.18 0.73
	All-cause mortality by days 28	100 (13.1%)	62 (8.1%)	0.57 (0.41 to 0.78)	0.0018
	All-cause mortality by days 60	116/761 (15.2%)	79/764 (10.3%)	0.62 (0.47 to 0.83)	0.0050
	Number of ventilator free days	23.7 ± 0.39	24.5 ± 0.39	0.75 (0.0 to 1.5 )	0.06
	Duration of hospitalization, days	13.7 ± 0.4	12.9 ± 0.4	-0.76 (-1.6 to 0.0)	0.06
	* Population 1: all randomized participants ** Population 2: participants who, at baseline, required oxygen supplementation and are not receiving dexamethasone or other systemic corticosteroids for the primary study condition
Adverse Events	Treatment emergent dverse events	Placebo + SOC (n=761)	Baricitinib + SOC (n=764)
	Death due to adverse event	31 (4.1%)	12 (1.6%)
	Discontinuation from study due to adverse event including death	70 (9.3%)	56 (7.5%)
	Treatment-emergent infection	123 (16.4%)	119 (15.9%)
	Venous thromboembolic event Deep vein thrombosis Pulmonary embolism	19 (2.5%) 2 (0.3%) 9 (1.2%)	20 (2.7%) 4 (0.5%) 13 (1.7%)
	Major cardiovascular event Cardiovascular death Myocardial infarction Stroke	9 (1.2%) 3 (0.4%) 4 (0.5%) 4 (0.5%)	8 (1.1%) 1 (0.1%) 4 (0.5%) 4 (0.5%)
Study Author Conclusions	While reduction of disease progression did not achieve statistical significance, treatment with baricitinib in addition to standard of care (including dexamethasone) significantly reduced mortality, with a similar safety profile to standard of care, in hospitalized COVID-19 participants.
InpharmD Researcher Critique	This study was the first randomized controlled trial that reported treatment outcomes after a 60 days follow up for hospitalized patients with COVID-19; however, the primary endpoint result may be impacted by heterogeneity of treatment decisions (certain oxygen delivery devices) in clinical practice across different geographics.

References:

Marconi VC, Ramanan AV, de Bono S, et al. 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. medRxiv 2021.04.30.21255934. doi:10.1101/2021.04.30.21255934

Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19

Design

Double-blind, multicenter, randomized, placebo-controlled trial

N= 1,033

Objective

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

Study Groups

Baricitinib + remdesivir (n= 515)

Placebo + remdesivir (n= 518)

Inclusion Criteria

Age ≥ 18 years, admitted with COVID-19 symptoms, laboratory-confirmed SARS-CoV-2 infection, current illness with one of the following indicators radiographic infiltrates by imaging, OR SpO2 ≤ 94% on room air, OR requiring supplemental oxygen, requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO)

Exclusion Criteria

Pregnancy and breastfeeding, alanine transaminase (ALT) or aspartate transaminase (AST) > 5 times the upper limit of normal (ULN), estimated glomerular filtration rate (eGFR) < 30 ml/min or on hemodialysis, neutropenia (absolute neutrophil count < 1000 cells/microliter), lymphopenia (absolute lymphocyte count <200 cells/microliter), received ≥ 3 doses of remdesivir, other immunosuppressants four weeks before study entry

Methods

Enrolled patients were randomized (1:1) to receive either remdesivir and baricitinib or remdesivir and placebo. Remdesivir was administered 200-mg intravenously on day 1, followed by 100-mg daily from day 2 to day 10 or until hospital discharge or death. Baricitinib was given 4-mg or 2-mg (eGFR < 60 ml/minute) daily either by mouth or through a nasogastric tube for 14 days or until the hospital discharge.

All COVIDd-19 patients received venous thromboembolism prophylaxis and stand supportive care based on hospital policies. However, no other experimental or off-label treatments for COVID-19 were not allowed, including glucocorticoids, unless for other clinically validated indications.

Duration

Enrollment: May 8, 2020, to July 1, 2020, from 67 sites in eight countries

Follow-up: daily during hospitalization day 1 through day 29 or until discharge or death

Outcome Measures

Primary outcome: time to recovery defined as the first day when a patient achieved category 1, 2, or 3 on the eight-category ordinal scale

Secondary outcomes: clinical status at day 15; time to improvement by one or two categories; time to discharge; the number of days of receipt of supplemental oxygen, noninvasive ventilation or high-flow oxygen, and invasive ventilation or ECMO up to day 29; the incidence and duration of new use of oxygen, new use of non-invasive ventilation or high-flow oxygen, and new use of invasive ventilation or ECMO; duration of hospitalization; mortality at 14 and 28 days after

Safety outcomes: grade 3 and 4 adverse events and serious adverse events, discontinuation or temporary suspension of trial-product administration, and changes in the laboratory values

Recovered	Ordinal scale	Definition
	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
Population Enrolled	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

Baseline Characteristics

Baricitinib + remdesivir

(n = 515)

Placebo + remdesivir

(n = 518)

Mean age, years

55 ± 15.4

55.8 ± 16

Female

196 (38.1%)

185 (35.7%)

Race/Ethnic group*

Asian

Black

White

Hispanic or Latino

49 (9.5%)

77 (15%)

251 (48.7%)

263 (51.1%)

52 (10%)

79 (15.3%)

245 (47.3%)

268 (51.7%)

Median time (IQR) from symptom onset to randomization — days

8 (5–10)

8 (5–11)

Disease severity

Moderate

Severe

358 (69.5%)

157 (30.5%)

348 (67.2%)

170 (32.8%)

Score on the ordinal scale

70 (13.6%)

288 (55.9%)

103 (20%)

54 (10.5%)

72 (13.9%)

276 (53.3%)

113 (21.8%)

57 (11%)

Plus-minus values are means ± SD. Percentages may not total 100 because of rounding. Covid-19 denotes coronavirus disease 2019, ECMO extracorporeal membrane oxygenation, IQR interquartile range.

*Race and ethnic group were reported by the patients. With respect to “other” races, the categories used when data on race were reported included American Indian or Alaska Native and Native Hawaiian or other Pacific Islander.

Results

Endpoint

Baricitinib + remdesivir

(n = 515)

Placebo + remdesivir

(n = 518)

Ordinal Score 6 at Baseline

Baricitinib

(n = 103)

Placebo

(n = 113)

Recovery

No. of recoveries

Median time to recovery (95% CI), days

Rate ratio (95% CI)†

433

7 (6 - 8)

1.16 (1.01–1.32 [P = 0.03])

406

8 (7 - 9)

10 (9 - 13)

1.51 (1.10–2.08)

18 (13 - 21)

Mortality over first 14 days‡

Hazard ratio (95% CI)

No. of deaths by day 14

0.54 (0.23–1.28)

0.21 (0.02 - 1.8)

Mortality over entire trial period‡

Hazard ratio (95% CI)

No. of deaths by day 28

0.65 (0.39–1.09)

0.55 (0.22 - 0.38)

Ordinal score at day 15 (±2 days)§

Odds ratio (95% CI)

177 (34.4)

8 (1.6)

1.3 (1.0–1.6)

165 (31.9)

163 (31.5)

3 (0.6)

27 (26.2)

30 (29.1)

2.2 (1.4–3.6)

17 (15.0)

24 (21.2)

Median time to improvement by one category on the ordinal scale

Rate ratio (95% CI)

1.21 (1.06 - 1.39)

Incidence of new use of oxygen

Difference (95% CI)

22.9%

- 17.4% (- 31.6 to -2.1)

40.3%

New use of mechanical ventilation of ECMO

Difference (95% CI)

10%

- 5.2% (- 9.5 to -0.5)

15.2%

Progression to death or noninvasive or invasive ventilation

Rate ratio (95% CI)

22.5%

0.77 (0.6 - 0.98)

28.4%

Progression to death or invasive ventilation

Rate ratio (95% CI)

12.2%

0.69 (0.5 - 0.95)

17.2%

Adverse Events

Treatment associated grade 3 or 4 adverse events: 25 vs. 28

Hyperglycemia (4.9% vs. 7.9%), anemia (5.9% vs. 5.9%), decreased lymphocyte count (4.5% vs. 6.9%), and acute kidney injury (3% vs. 5.3%)

Treatment associated serious adverse events: 6 vs. 5

New infection (5.9% vs. 11.2%), acute respiratory failure (3.6% vs. 2.6%), pulmonary embolism (1% vs. 0.4%)

Percentage that Discontinued due to Adverse Events: cause not reported, baricitinib plus remdesivir group (8.5%), remdesivir (13.1%)

Study Author 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 those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events.

InpharmD Researcher Critique

Based on the study results, the authors identified the specific patient population who would benefit the most from the combination therapy with baricitinib, those on high-flow or noninvasive ventilation.

Limitations of the study include a lack of power to find a significant difference in 28-day mortality between the two groups. At the study enrollment, patients were not allowed to receive glucocorticosteroids for COVID-19 treatment, which provided limited data on the combination therapy plus steroids. Of note, approximately 10% of patients eventually received a corticosteroid post-randomization (baricitinib plus remdesivir group [10.9%] versus remdesivir [12.9%]) but this subset of patients were not analyzed separately.

References:

Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. N Engl J Med. 2021;384(9):795-807. doi:10.1056/NEJMoa2031994