Baricitinib

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What are the treatment-emergent infections in the baricitinib COVID-19 clinical trials?

The incidence of treatment-emergent infections was similar between baricitinib (13%) and placebo (15%) groups in the COVID-19 clinical trials.

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Baricitinib Emergency Use Authorization for COVID-19

Baricitinib has not been approved, but has been authorized for emergency use by FDA for the treatment of COVID-19 in hospitalized adults and pediatric patients 2 years of age or older requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or ECMO.

Baricitinib is authorized for the treatment of COVID-19 in hospitalized adults and pediatric patients 2 years of age or older requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or ECMO only for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of the baricitinib under Section 564(b)(1) of the Act, 21 U.S.C. § 360bbb-3(b)(1), unless the declaration is terminated or authorization revoked sooner.

For information on the authorized use of baricitinib and mandatory requirements under the EUA, please review the FDA Letter of Authorization, Fact Sheet for Healthcare Providers, and Fact Sheet for Patients/Caregivers at baricitinibemergencyuse.com.

Baricitinib Fact Sheet for Healthcare Providers

Warnings Related to Serious Infections

There is limited information regarding use of baricitinib in patients with COVID-19 and concomitant active serious infections.

Serious infections have occurred in patients receiving BARI

  • Avoid the use of BARI with known active tuberculosis.
  • Consider if the potential benefits outweigh the potential risks of BARI treatment in patients with active serious infections other than COVID-19 or chronic / recurrent infections.1

Serious Side Effects

Serious venous thrombosis, including PE, and serious infections have been observed in COVID-19 patients treated with BARI and are known adverse drug reactions of BARI.1

See Warnings and Precautions in the FDA approved full prescribing information for additional information on risks associated with longer-term treatment with baricitinib.2

Baricitinib Available Clinical Data

Risk of Secondary Infection in Patients With COVID-19

In patients with COVID-19,

  • the reported incidence of secondary infections and coinfections has been variable, ranging from 7.0% to 14.3% as reported in several reviews and meta-analyses.3-6
  • although bacterial coinfections and secondary infections have been most commonly reported (91.8%), viral and fungal infections have also been noted in 31.5% and 23.3% of hospitalized patients, respectively.7
  • secondary infections often lead to worst outcomes and prolonged hospital/ICU stay as well as increased mortality.8

Additionally, corticosteroid therapy has been used in critically ill patients with COVID-19 and has been shown to increase the risk of secondary bacterial infections.9,10

Exclusion Criteria Related to Infections in the Baricitinib COVID-19 Clinical Trials

Tuberculosis

In the COV-BARRIER and ACTT-2 clinical trials, patients were excluded if they had a diagnosis of current active tuberculosis or, if known, latent tuberculosis treated for < 4 weeks with appropriate anti-tuberculosis therapy per local guidelines. Tuberculosis screening was not required but evaluated by patient history only.11,12

Additionally, the COV-BARRIER protocol noted that, if feasible, a complete physical examination was performed at the screening visit and should include an assessment of tuberculosis risk factors. 12

Other Infections

In the COV-BARRIER and ACTT-2 clinical trials, patients were excluded if they had a suspected serious, active bacterial, fungal, viral, or other infection (besides COVID-19) that in the opinion of the investigator could constitute a risk when taking investigational product.11,12

Additionally, the COV-BARRIER protocol noted, immunocompromised patients, patients with a chronic medical condition, or those taking a medication that cannot be discontinued at enrollment, who, in the judgment of the investigator, are at increased risk for serious infections or other safety concerns given the study products should be excluded.12

Summary of Baricitinib Exposure Across Clinical Trial Programs

The safety of BARI was assessed in 2 phase 3, randomized, double-blind, placebo-controlled clinical trials.

  • COV-BARRIER evaluated BARI 4 mg compared to placebo. Patients could remain on background therapy, as defined per local guidelines.
  • ACTT‑2 evaluated the combination of BARI 4 mg + RDV compared to placebo + RDV.1

Integrated Safety Dataset

In placebo-controlled COVID-19 clinical trials, ACTT-2 and COV-BARRIER, a total of

  • 1257 patients received at least one dose of BARI 4 mg once daily (8.0 days mean exposure, 1442 total patient-weeks of exposure), and
  • 1261 patients received placebo (8.1 days mean exposure, 1465 total patient-weeks of exposure).1,12

Patients received treatment for up to 14 days or hospital discharge, whichever occurred first. Safety data is through study day 29.1

COV-BARRIER Clinical Trial Exposure

In COV-BARRIER, a total of 1525 patients were randomized, of which 1502 received study drug with either

  • BARI 4 mg orally once daily + SOC (n=750, 8.1 days mean exposure, 866 total patient-weeks of exposure), or
  • placebo + SOC (n=752, 8.3 days mean exposure, 891 total patient-weeks of exposure).12

ACTT-2 Clinical Trial Exposure

In ACTT-2, a total of 1033 patients were randomized, of which 1016 received study drug with either

  • BARI 4 mg + RDV (n=507, 7.9 days mean exposure, 575 total patient-weeks of exposure), or
  • placebo + RDV (n=509, 7.9 days mean exposure, 574 total patient-weeks of exposure).11,12

Treatment-Emergent Infections in COVID-19 Clinical Trials

Integrated Safety Dataset

Through study day 29, there were no significant differences between the placebo and BARI groups in

Treatment-Emergent Infections in the COVID-19 Integrated Safety Dataseta1,12

Placebo
N=1261

BARI 4 mg
N=1257

Treatment-emergent infections, n (%)

183 (14.5)

159 (12.6)

Infections reported ≥2% in either treatment group, n(%)

Pneumonia

41 (3.3)

33 (2.6)

Septic shock

35 (2.8)

21 (1.7)

Infections of interest, %

Upper respiratory tract infectionsb

0.1

0.6

Herpes simplexc

0.3

0.1

Herpes zoster

0.3

0.1

Urinary tract infection

0.8

1.3

Serious infections, n (%)

94 (7.5)

76 (6.0)

Opportunistic infections,d n (%)

11 (0.9)

12 (1.0)

Infections leading to death,e n (%)

14 (1.1)

8 (0.6)

Abbreviations: BARI = baricitinib; COVID-19 = coronavirus disease 2019; MedDRA = Medical Dictionary for Regulatory Activities.

aIncludes all patients who were randomized and received study treatment in COV-BARRIER and ACTT-2 clinical trials.

bIncludes acute sinusitis, acute tonsillitis (placebo group only), chronic sinusitis, chronic tonsillitis, epiglottitis, laryngitis, nasopharyngitis, oropharyngeal pain, pharyngitis, pharyngotonsillitis, rhinitis, sinobronchitis, sinusitis, tonsillitis, tracheitis, and upper respiratory tract infection.

cIncludes eczema herpeticum, genital herpes, genital herpes simplex, herpes simplex, Kaposi’s varicelliform eruption, ophthalmic herpes simplex, and oral herpes.

dIncludes reported MedDRA preferred terms: systemic candida (n=1 placebo, n=2 BARI), candida infection (n=1 BARI), Aspergillus infection (n=1 placebo, n=1 BARI), bronchopulmonary aspergillosis (n=1 placebo, n=1 BARI), fungemia (n=1 BARI), fungal retinitis (n=1 BARI), herpes zoster (n=3 placebo, n=1 BARI), pulmonary tuberculosis (n=1 BARI), urinary tract infection fungal (n=1 BARI), candida sepsis (n=1 placebo), eye infection fungal (n=1 placebo), listeriosis (n=1 placebo), oropharyngeal candidiasis (n=1 placebo), and varicella zoster virus (n=1 placebo).

eIncludes reported MedDRA preferred terms: septic shock (n=8 placebo; n=7 BARI), pneumonia (n=2 placebo; n=1 BARI), COVID-19 pneumonia (n=1 placebo), sepsis (n=2 placebo), and severe acute respiratory syndrome (n=1 placebo).

Individual Clinical Trials

COV-BARRIER

Overall Infection

The proportion of participants with a TE infection was similar between the 2 groups:

  • 15.9% (n=119) in the BARI + SOC group, and
  • 16.4% (n=123) in the placebo + SOC group.12
Serious Infection

Frequency of serious infections was similar between BARI + SOC and placebo + SOC treatment groups (see Treatment-Emergent Serious Infections in COV-BARRIER).12

Treatment-Emergent Serious Infections in COV-BARRIER12

 

Placebo + SOC
N=752
n (%)

BARI + SOC
N=750
n (%)

Serious infections

74 (9.8)

64 (8.5)

Infections reported ≥2% in either treatment group, n(%)

COVID-19 pneumonia

20 (2.7)

21 (2.8)

Septic shock

24 (3.2)

13 (1.7)

Abbreviations: BARI = baricitinib; SOC = standard of care.

Infections Leading to Death

In the BARI + SOC group, the 6 treatment-emergent infections that led to death include

  • 5 events of septic shock, and
  • 1 event of pneumonia.12

In the placebo + SOC group, the 12  treatment-emergent infections that led to death include

  • 7 events of septic shock
  • 2 events of pneumonia
  • 1 event of COVID-19 pneumonia
  • 1 event of sepsis, and
  • 1 event of severe acute respiratory syndrome.12

ACTT-2

Overall Infection

The proportion of TE infection was significantly less in the BARI + RDV group than the placebo + RDV group

  • 5.9% (n=30) in the BARI + RDV group, and
  • 11.2% (n=57) in the placebo + RDV group (95% CI -8.7 to -1.9; p=.003).11
Serious Infection

Serious infections were reported less frequently in the BARI + RDV group compared with the placebo + RDV group. Infection-related SAEs are included in Infection-Related SAEs Occurring in 5 or More Patients in ACTT-2.12

Infection-Related SAEs Occurring in 5 or More Patients in ACTT-211

Preferred Term

PBO + RDV
N=509, n (%)

BARI + RDV
N=507, n (%)

Septic shock

8 (1.6)

4 (0.8)

Pneumonia

8 (1.6)

2 (0.4)

Sepsis

5 (1.0)

1 (0.2)

Abbreviations: ACTT-2 = Adaptive COVID-19 Treatment Trial 2; BARI = baricitinib; PBO = placebo; RDV = remdesivir; SAEs = serious adverse events. 

Infection-Related Adverse Events Resulting in Death

Septic shock leading to death was reported in

  • 2 patients in the BARI + RDV group (N=507), and
  • 1 patient in the placebo + RDV group (N=509).12

Infections With Concomitant Corticosteroid Use

In both COV-BARRIER and ACTT-2 trials, patients who received corticosteroids had a higher incidence of TE infections than those who did not. The incidence of TE infection was similar between BARI treatment groups and placebo groups in both clinical trials (see Treatment-Emergent Infections and Serious Infections by Concomitant Systemic Corticosteroid Use).11

Treatment-Emergent Infections and Serious Infections by Concomitant Systemic Corticosteroid Use12

 

Treatment-Emergent Overall Infections
n/N-obs (%)

Treatment-Emergent Serious Infections
n/N-obs (%)

Concomitant systemic corticosteroid use

Yes

No

Yes

No

COV-BARRIER

BARI + SOC

101/605 (16.7)

18/145 (12.4)

58/605 (9.6)

6/145 (4.1)

Placebo + SOC

100/590 (16.9)

23/162 (14.2)

63/590 (10.7)

11/162 (6.8)

ACTT-2

BARI + RDV

8/50 (16.0)

32/457 (7.0)

2/50 (4.0)

10/457 (2.2)

Placebo + RDV

10/51 (19.6)

50/458 (10.9)

2/51 (3.9)

18/458 (3.9)

Abbreviations: BARI= baricitinib; RDV = remdesivir; SOC = standard of care.

References

The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).

1U. S. Food and Drug Administration (FDA). Fact Sheet for Healthcare Providers. Emergency Use Authorization (EUA) of Baricitinib. 2021.

2Olumiant [package insert]. Indianapolis, IN: Eli Lilly and Company; 2020.

3Ripa M, Galli L, Poli A, et al. Secondary infections in patients hospitalized with COVID-19: incidence and predictive factors. Clin Microbiol Infect. 2021;27(3):451-457. https://doi.org/10.1016/j.cmi.2020.10.021

4Langford BJ, So M, Raybardhan S, et al. Bacterial co-infection and secondary infection in patients with COVID-19: a living rapid review and meta-analysis. Clin Microbiol Infect. 2020;26(12):1622-1629. https://doi.org/10.1016/j.cmi.2020.07.016

5Lansbury L, Lim B, Baskaran V, Lim WS. Co-infections in people with COVID-19: a systematic review and meta-analysis. J Infect. 2020;81(2):266-275. https://doi.org/10.1016/j.jinf.2020.05.046

6Rawson TM, Moore LSP, Zhu N, et al. Bacterial and fungal coinfection in individuals with coronavirus: a rapid review to support COVID-19 antimicrobial prescribing. Clin Infect Dis. 2020;71(9):2459-2468. https://doi.org/10.1093/cid/ciaa530

7Vaillancourt M, Jorth P. The unrecognized threat of secondary bacterial infections with COVID-19. mBio. 2020;11(4):e01806-20. https://doi.org/10.1128/mbio.01806-20

8Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062. https://doi.org/10.1016/s0140-6736(20)30566-3

9Singh AK, Majumdar S, Singh R, Misra A. Role of corticosteroid in the management of COVID-19: a systemic review and a clinician’s perspective. Diabetes Metab Syndr. 2020;14(5):971-978. https://doi.org/10.1016/j.dsx.2020.06.054

10IDSA Website. https://www.idsociety.org/covid-19-real-time-learning-network/therapeutics-and-interventions/corticosteroids/

11Kalil 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. https://doi.org/10.1056/NEJMoa2031994

12Data on file, Eli Lilly and Company and/or one of its subsidiaries.

Glossary

ACTT-2 = Adaptive COVID-19 Treatment Trial 2

AE = adverse event

BARI = baricitinib

COVID-19 = coronavirus disease 2019

ECMO = extracorporeal membrane oxygenation

EUA = Emergency Use Authorization

FDA = Food and Drug Administration

ICU = intensive care unit

MedDRA = Medical Dictionary for Regulatory Activities

RDV = remdesivir

SAE = serious adverse event

TE = treatment-emergent

Date of Last Review: June 02, 2021


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