Baricitinib

This information is provided in response to your request. Resources may contain information about doses, uses, formulations and populations different from product labeling. See Prescribing Information above, if applicable.

Did patients who received baricitinib for the treatment of COVID-19 have changes in lymphocyte or neutrophil counts?

The percentage of patients who had lymphocyte and neutrophil count abnormalities was similar between treatment groups with the exception of lymphopenia.

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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 Health Care Providers

Warnings Related to Lymphocyte and Neutrophil Levels

Evaluate baseline complete blood count to determine treatment suitability and dose, and thereafter according to local patient management practice. Monitor closely when treating patients with abnormal baseline and post-baseline laboratory values.

See Dosage Adjustments for Patients With Abnormal Laboratory Values for dosage adjustments for patients with abnormal hematological laboratory values. Manage patients according to routine clinical guidelines.1

Dosage Adjustments for Patients With Abnormal Laboratory Values1

Laboratory Analyte

Laboratory Analyte Value

Recommendation

ALC

≥200 cells/µL

  • Maintain dose

<200 cells/µL

  • Consider interruption until ALC is ≥200 cells/µL

ANC

≥500 cells/µL

  • Maintain dose

<500 cells/µL

  • Consider interruption until ANC is ≥500 cells/µL

Abbreviations: ALC = absolute lymphocyte count; ANC = absolute neutrophil count.

Notes: If a laboratory abnormality is likely due to the underlying disease state, consider the risks and benefits of continuing baricitinib at the same or a reduced dose.

Baricitinib Available Clinical Data

Risk of Lymphocyte and Neutrophil Count Abnormalities in Patients With COVID-19

In patients with COVID-19,

  • WBC abnormalities are common with the majority of patients developing lymphocytopenia2-4
  • disease severity appears to correlate with the amount of deviation from normal in WBC counts, with more severely ill patients experiencing more leukopenia and lymphocytopenia, and 2,4-6
  • an elevated NLR has been associated with more severe disease.2,7-9

Additionally, corticosteroid therapy has been used in critically ill patients with COVID-19 and has been shown to cause lymphocytopenia.2

Summary of Baricitinib Exposure Across Clinical Trial Program

Integrated Safety Dataset Exposure

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).1,10

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

Brief Study Design and Exposure From COV-BARRIER

COV-BARRIER is a phase 3, global, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of BARI in adult patients hospitalized due to COVID-19.11 

In COV-BARRIER, a total of 1502 patients were randomized and received treatment 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).10

Brief Study Design and Exposure From ACTT-2

Eli Lilly and Company entered into an agreement with the NIAID, part of the NIH, to study BARI as an arm in NIAID’s ACTT-2.12

This randomized, double-blind, placebo-controlled study investigated the efficacy and safety of BARI plus remdesivir in hospitalized adult patients with COVID-19. Study site locations were in North America as well as Europe and Asia.12

In ACTT-2, a total of 1016 were randomized and received treatment 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).10,12

Incidence of Lymphocyte and Neutrophil Abnormalities

Integrated Dataset

In the integrated dataset, the percentage of patients who experienced lymphocyte and neutrophil count abnormalities was similar between treatment groups with the exception of lymphopenia (Lymphocyte and Neutrophil Count Abnormalities by Treatment Arm in the Integrated Safety Analysis of COV-BARRIER and ACTT-2). A significantly larger proportion of patients who received placebo (2.2%) developed lymphopenia than did patients who received BARI (1.0%; p=.011).10

Lymphocyte and Neutrophil Count Abnormalities by Treatment Arm in the Integrated Safety Analysis of COV-BARRIER and ACTT-210

Preferred Term, n (%)

PBO (N=1261)

BARI (N=1257)

Lymphocyte count decreased

36 (2.9)

24 (1.9)

Lymphopenia

28 (2.2)

12 (1.0)a

Lymphocytosis

1 (0.1)

0

Neutrophil count decreased

0

1 (0.1)

Neutropenia

3 (0.2)

2 (0.2)

White blood cell count decreased

1 (0.1)

0

Leukopenia

3 (0.2)

4 (0.3)

Leukocytosis

11 (0.9)

11 (0.9)

Abbreviations: ACTT-2 = Adaptive COVID-19 Treatment Trial 2; BARI = baricitinib; PBO = placebo. 

ap=.011 vs PBO.

Shift Table

Shift Table of Lymphocyte and Neutrophil Count Abnormalities by Treatment Arm in the Integrated Safety Analysis of COV-BARRIER and ACTT-2 shows changes in CTCAE grades of lymphocytes and neutrophils for each treatment arm in the integrated safety analysis of COV-BARRIER and ACTT-2. 

Shift Table of Lymphocyte and Neutrophil Count Abnormalities by Treatment Arm in the Integrated Safety Analysis of COV-BARRIER and ACTT-210

Change in Analyte Count, n/NAR (%)

Leukocytes

Neutrophils

Lymphocytes

PBO (N=1261)

BARI (N=1257)

PBO (N=1261)

BARI (N=1257)

PBO (N=1261)

BARI (N=1257)

Any CTCAE grade increase

87/1193 (7.3)

107/1200 (8.9)

90/1169 (7.7)

143/1160 (12.3)a

335/1192 (28.1)

251/1192 (21.1)a

Increase to ≥ grade 1

76/1070 (7.1)

97/1099 (8.8)

82/1110 (7.4)

134/1127 (11.9)a

156/534 (29.2)

107/479 (22.3)b

Increase to ≥ grade 2

32/1162 (2.8)

35/1178 (3.0)

40/1152 (3.5)

65/1153 (5.6)b

182/806 (22.6)

136/772 (17.6)c

Increase to ≥ grade 3

14/1187 (1.2)

10/1197 (0.8)

22/1167 (1.9)

26/1158 (2.2)

128/1080 (11.9)

93/1072 (8.7)c

Increase to ≥ grade 4

7/1193 (0.6)

4/1200 (0.3)

7/1169 (0.6)

2/1160 (0.2)

35/1192 (2.9)

23/1192 (1.9)

Abbreviations: ACTT-2 = Adaptive COVID-19 Treatment Trial 2; BARI = baricitinib; CTCAE = Common Terminology Criteria for Adverse Events; NAR = number at risk; PBO = placebo.

Note: NAR is the number of patients at risk for the specified abnormality in each treatment group.

ap=.001 vs PBO.

bp=.013 vs PBO.

cp=.015 vs PBO.

COV-BARRIER

In COV-BARRIER, the percentage of patients who experienced lymphocyte and neutrophil count abnormalities was similar between treatment groups (Lymphocyte and Neutrophil Count Abnormalities by Treatment Arm in COV-BARRIER).10

Lymphocyte and Neutrophil Count Abnormalities by Treatment Arm in COV-BARRIER10

Preferred Term

PBO
(N=752), n (%)

BARI
(N=750), n (%)

Lymphocyte count decreased

1 (0.1)

0

Lymphopenia

4 (0.5)

1 (0.1)

Lymphocytosis

0

0

Neutrophil count decreased

0

0

Neutropenia

1 (0.1)

1 (0.1)

White blood cell count decreased

0

0

Leukopenia

2 (0.3)

3 (0.4)

Leukocytosis

11 (1.5)

9 (1.2)

 Abbreviations: BARI = baricitinib; PBO = placebo.  

ACTT-2

Incidence of Lymphocyte, Neutrophil, and Leukocyte Abnormalities

The number of patients who had treatment interrupted due to the stopping criteria for total white count, ANC <500, and ALC <200 was not specifically collected per protocol, and is not currently available. NIAID has indicated they will be able to provide reasons for treatment interruption when reported by the investigator.10

Leukocyte, lymphocyte, and neutrophil abnormalities that occurred in ACTT-2 are presented in Lymphocyte and Neutrophil Count Abnormalities by Treatment Arm in ACTT-2.

Lymphocyte and Neutrophil Count Abnormalities by Treatment Arm in ACTT-212

Preferred Terma

PBO + RDV
N=509, n (%)

BARI + RDV
N=508, n (%)

Lymphocyte count decreased

35 (6.9)b

24 (4.7)c

Lymphopenia

24 (4.7)d

11 (2.2)

Lymphocytosis

1 (0.2)

0

Neutrophil count decreased

0

1 (0.2)

Neutropenia

2 (0.4)d

1 (0.2)

White blood cell count decreased

1 (0.2)

0

Leukopenia

1 (0.2)

1 (0.2)

Leukocytosis

0

2 (0.4)

Abbreviations: ACTT-2 = Adaptive COVID-19 Treatment Trial 2; AE = adverse event; BARI = baricitinib; PBO = placebo; DAIDS = Division of AIDS; RDV = remdesivir.

aOnly grade 3 and grade 4 AEs based on DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events were captured during the study due to the severity of COVID-19 disease.

b5 of these events were reported as related to study treatment by the investigator.

c6 of these events were reported a related to study treatment by the investigator.

d1 of these events was reported as related to study treatment by the investigator.

Change in Lymphocyte and Neutrophil Count Values Among Evaluable Patients in ACTT-2

A summary of absolute baseline lymphocyte and neutrophil count values and change from baseline on day 29 lymphocyte and neutrophil count values are presented in  Absolute Baseline and Change from Baseline on Day 29 Lymphocyte and Neutrophil Count Values for the Treated Population in ACTT-2

 Absolute Baseline and Change from Baseline on Day 29 Lymphocyte and Neutrophil Count Values for the Treated Population in ACTT-210

Parameter

Baseline (absolute value)

Change from Baseline to Day 29

BARI + RDV

PBO + RDV

BARI + RDV

PBO + RDV

Na

Mean (SD)

Median (min-max)

Na

Mean (SD)

Median (min-max)

Na

Mean (SD)

Median (min-max)

Na

Mean (SD)

Median (min-max)

Basophils (109/L)

498

0.020 (0.058)

0.01
(0-1.00)

506

0.017 (0.032)

0.01
(0-0.30)

257

0.022 (0.045)

0.01
(-0.20-0.24)

250

0.036 (0.092)

0.02
(-0.20-1.00)

Eosinophils (109/L)

499

0.042 (0.157)

0
(0-3.00)

506

0.051 (0.182)

0
(0-3.20)

257

0.192 (0.171)

0.17 
(-0.30-0.95)

251

0.205 (0.267)

0.17
(-1.00-2.00)

Leukocytes (109/L)

503

7.698 (3.634)

6.80
(1.70-31.00)

508

7.455 (3.622)

6.72
(1.70-28.30)

260

-0.364 (4.532)

-0.06 (-24.20-28.00)

254

0.712 (4.176)

0.40 
(-15.30-19.40)

Lymphocytes (109/L)

499

1.316 (2.292)

1.00
(0.20-37.00)

508

1.310 (3.003)

1.03
(0-64.70)

257

0.653 (1.293)

0.70 (-13.00-2.72)

253

0.927 (1.996)

0.74
(-1.38-30.00)

Monocytes (109/L)

499

0.537 (0.898)

0.40
(0-13.40)

508

0.510 (0.686)

0.40
(0-10.70)

257

0.108 (0.434)

0.11
(-4.00-3.13)

253

0.212 (0.745)

0.14
(-3.20-9.00)

Neutrophils (109/L)

499

6.822 (8.354)

5.20
(1.10-94.60)

508

5.887 (5.019)

4.96
(1.00-86.00)

257

-1.708 (6.735)

-1.09 (-82.00-24.38)

253

-0.656 (4.205)

-0.50 (-37.00-14.40)

Abbreviations: ACTT-2 = Adaptive COVID-19 Treatment Trial 2; BARI = baricitinib; max = maximum; min = minimum; PBO = placebo; RDV = remdesivir; SD = standard deviation.

aNumber of subjects in the as treated population with laboratory data available for the parameter at the specified study visit.

Incidence of Lymphocyte and Neutrophil Count Abnormalities in Patients on Concomitant Corticosteroids in ACTT-2

In ACTT-2, systemic corticosteroid use was a non-randomized and non-standardized intervention utilized by approximately 20% of patients.13

Non-serious lymphocyte and neutrophil count abnormalities by treatment arm according to corticosteroid use are presented in Non-serious Lymphocyte and Neutrophil Count Abnormalities by Treatment Arm According to Corticosteroid Use in ACTT-2.

Non-serious Lymphocyte and Neutrophil Count Abnormalities by Treatment Arm According to Corticosteroid Use in ACTT-210

MedDRA Preferred Term

Corticosteroid Use After Enrollment 

No Corticosteroid Use After Enrollment 

BARI + RDV 
(N=105), n (%)

PBO + RDV
(N=118), n (%)

BARI + RDV
(N=402), n (%)

PBO + RDV
(N=391), n (%)

Lymphopenia

9 (8.6)

12 (10.2)

2 (0.5)

11 (2.8)

Neutropenia

0

0

1 (0.2)

2 (0.5)

Leukocytosis

1 (1.0)

0

1 (0.2)

0

Leukopenia

0

0

0

1 (0.3)

Lymphocytosis

0

0

0

1 (0.3)

Abbreviations: ACTT-2 = Adaptive COVID-19 Treatment Trial 2; BARI = baricitinib; MedDRA = Medical Dictionary for Regulatory Activities; PBO = placebo; RDV = remdesivir.

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.

2Slomka A, Kowalewski M, Zekanowska E. Coronavirus Disease 2019 (COVID-19): A short review on hematological manifestations. Pathogens. 2020;9(6):493. https://doi.org/10.3390/pathogens9060493

3Rawson 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

4Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. https://doi.org/10.1016/s0140-6736(20)30183-5

5Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708-1720. https://doi.org/10.1056/nejmoa2002032

6Liu K, Fang YY, Deng Y, et al. Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province. Chin Med J (Engl.). 2020;133:1025–1031. https://doi.org/10.1097/CM9.0000000000000744

7Liu J, Liu Y, Xiang P, et al. Neutrophil-to-lymphocyte ratio predicts critical illness patients with 2019 coronavirus disease in the early stage. J Transl Med. 2020;18(1):206. https://doi.org/10.1186/s12967-020-02374-0

8Yang AP, Liu JP, Tao WQ, Li HM. The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19 patients. Int Immunopharmacol. 2020;84:106504. https://doi.org/10.1016/j.intimp.2020.106504

9Lagunas-Rangel FA. Neutrophil-to-lymphocyte ratio and lymphocyte-to-C-reactive protein ratio in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis. J Med Virol. 2020;92:1733–1734. https://doi.org/10.1002/jmv.25819

10Data on file, Eli Lilly and Company and/or one of its subsidiaries.

11A study of baricitinib (LY3009104) in participants with COVID-19 (COV-BARRIER). ClinicalTrials.gov identifier: NCT04421027. Updated June 9, 2021. Accessed June 14, 2021. https://www.clinicaltrials.gov/ct2/show/NCT04421027

12Kalil 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

13Beigel J. Clinical trial update: JAK inhibitors in COVID-19. Abstract presented at: Therapeutics for COVID-19 Virtual Conference; October 8, 2020.

Glossary

ACTT-2 = Adaptive COVID-19 Treatment Trial 2

ALC = absolute lymphocyte count

ANC = absolute neutrophil count

BARI = baricitinib

COVID-19 = coronavirus disease 2019

CTCAE = Common Terminology Criteria for Adverse Events

ECMO = extracorporeal membrane oxygenation

EUA = Emergency Use Authorization

FDA = Food and Drug Administration

IV = intravenous

NIAID = National Institute of Allergy and Infectious Diseases

NIH = National Institutes of Health

NLR = neutrophil-to-lymphocyte ratio

RDV = remdesivir

SOC = standard of care

WBC = white blood cell

Date of Last Review: May 20, 2021


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