Olumiant ® (baricitinib)

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Olumiant® (Baricitinib): Incidence of Tuberculosis in Rheumatoid Arthritis

In all baricitinib treated patients with data up to 9.3 years of treatment and 14,744 patient-years of exposure, the EAIR of tuberculosis was 0.1 per 100 patient-years at risk and was reported in only patients receiving baricitinib 4 mg

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Tuberculosis in Rheumatoid Arthritis Clinical Trials

Analyses were conducted using the All-BARI-RA dataset, the largest dataset that included 3770 patients with rheumatoid arthritis (RA) who received any dose of baricitinib from 9 randomized studies and 1 long-term extension study.1

Incidence of Tuberculosis in Rheumatoid Arthritis Clinical Trials

Exposure-adjusted incidence rates (EAIRs) were calculated as the number of patients with an event per 100 patient-years of exposure (PYE) time, with exposure not censored at time of event.1

Safety Analysis Identification of Potential Tuberculosis Infections

Cases potentially representing TB infection were identified using a sponsor-defined list of Medical Dictionary for Regulatory Activities preferred terms from the Tuberculous Infections High Level Term and the Investigations System Organ Class.2

All BARI RA Dataset

The All BARI RA analysis set included 3770 patients with RA who received baricitinib at a variety of doses from 1 phase 1, 3 phase 2, and 5 phase 3 studies (RA-BEGIN, RA-BEAM, RA-BUILD, RA-BEACON, and RA-BALANCE). Data includes a long-term extension study (RA-BEYOND) with

  • 14,744 PYE to baricitinib
  • 15,114 PY overall observation including time on baricitinib and follow up
  • median exposure of 4.6 years, and
  • maximum exposure of 9.3 years.1

In the All BARI RA dataset, 19 (0.5%) patients treated with baricitinib 4 mg reported treatment-emergent TB with an EAIR of 0.1. All events of TB were reported in the Ever-on-4-mg group (see Tuberculosis in the Baricitinib 2 mg and Baricitinib 4 mg subsets of the All BARI RA Analysis Set ). 1,2

Tuberculosis in the Baricitinib 2 mg and Baricitinib 4 mg subsets of the All BARI RA Analysis Set2 

Ever on baricitinib 2 mg
N=1077
PYE=2678
n (%)
[EAIR]
[95% CI]

Ever on baricitinib 4 mg
N=3401
PYE=11872
n (%)
[EAIR]
[95% CI]

Tuberculosis

0

19 (0.6)
[0.16]
[0.10, 0.25]

Abbreviations: BARI = baricitinib; EAIR = exposure-adjusted incidence rate; RA = rheumatoid arthritis.

The IR for TB in the All BARI RA dataset did not increase with prolonged exposure. Reported TB events occurred almost exclusively in endemic countries, with 1 report in the United States (see Treatment-Emergent Tuberculosis in the All BARI RA Analysis Set and the Published Tuberculosis Incidence Rates in the General Population).1

Of the 19 cases of TB, 6 patients had negative TB results at screening and no patients received TB treatment at study entry. The 19 cases of TB included

  • 8 cases of TB or pulmonary TB
  • 5 cases of disseminated TB
  • 3 cases of bone TB 
  • 2 cases of lymph node TB, and
  • 1 case of extrapulmonary TB.2

Permanent discontinuation of study drug due to TB was reported in

  • 4 patients with TB or pulmonary TB
  • 5 patients with disseminated TB, and
  • 2 patients with bone TB.2

One death due to disseminated TB was reported. See Treatment-Emergent Tuberculosis in the All BARI RA Analysis Set and the Published Tuberculosis Incidence Rates in the General Population for further details on this patient.2

Treatment-Emergent Tuberculosis in the All BARI RA Analysis Set and the Published Tuberculosis Incidence Rates in the General Population2-4

Country

All BARI RA Number of Patients

Published TB IR in General Populationa per 100 People/Yearb

Taiwan

4

0.044c

India

4

0.193

South Africa

3d

0.615

Argentina

2

0.029

South Korea

1

0.059

China

1

0.058

Russia

1

0.050

Lithuania

1

0.042

Mexico

1

0.023

United States

1e

0.003

Abbreviations: IR = incidence rate per 100 patient years; RA = rheumatoid arthritis; TB = tuberculosis.

aGeneral population refers to the non-RA patient population; IR in the RA population was estimated at 4- to 10-fold higher than the general population.

bSource: WHO 2019. Data were converted from 100,000 to 100 people/year.

cSource: Centers for Disease Control, Republic of China (Taiwan) 2018 (estimates from 2016).

dOne case of death was reported in a 63 year old female patient due to disseminated TB. This patient was reported to have been vaccinated for TB and had a negative purified protein derivative test at screening.

eThe patient was a 71 year old female that had a serious adverse event of disseminated TB (miliary TB). The patient had received a TB vaccine prior to study entry, but did not receive preventive TB treatment.

Safety Analysis of Concomitant Isoniazid Treatment for Latent Tuberculosis in RA Clinical Trials

Description of Pooled Safety Analysis From RA-BEAM, RA-BUILD, and RA-BEACON

A post hoc analysis evaluated changes in alanine aminotransferase (ALT) in patients with latent TB who were treated with isoniazid for 4 weeks prior to randomization and during the clinical trials.5

A total of 2516 patients were pooled from 3 phase 3 studies and included

  • 891 in the baricitinib 4-mg group
  • 403 in the baricitinib 2-mg group
  • 330 in the adalimumab group, and
  • 892 in the placebo group.5,6

Changes in ALT levels were measured from baseline up to week 24 for all patients analyzed. The proportions of patients with ALT levels ≥1X, ≥3X, ≥5X, and ≥10X upper limit of normal (ULN) were calculated for each treatment group by concomitant isoniazid treatment or no isoniazid treatment.5

Alanine Aminotransferase Results in Isoniazid-Treated Patients

Of the 2516 patients analyzed, 246 were positive for latent TB, and 169 received isoniazid treatment. Isoniazid- treated patients with ALT levels ≥1X ULN included

  • 24/58 (41.4%) patients from the baricitinib 4-mg group
  • 9/27 (33.3%) patients from the baricitinib 2-mg group
  • 12/27 (44.4%) patients from the adalimumab group, and
  • 21/57 (36.8%) patients from the placebo group.5,6

Across all treatment groups, a higher number of isoniazid-treated patients had ALT levels ≥1X ULN than patients not taking isoniazid. However, there were no treatment interruptions or discontinuations due to abnormal hepatic laboratory results in patients taking concomitant isoniazid and baricitinib or adalimumab treatment.5,6

There were no reports of ALT levels ≥3X, ≥5X, and ≥10X ULN in patients treated with baricitinib 4 mg and isoniazid.5 Additional results on the proportion of patients with ALT levels ≥3X, ≥5X, ≥10X are provided in Alanine Transaminase Levels in Patients With and Without Isoniazid Treatment in RA Clinical Trials.

Alanine Transaminase Levels in Patients With and Without Isoniazid Treatment in RA Clinical Trialsa5,6

Changes from baseline to 24 weeks

n (%)

BARI 4 mgb
N=891

BARI 2 mgc
N=403

Adalimumabd
N=330

Placebob
N=892

INH
n=58

No INH
n=833

INH
n=27

No INH
n=376

INH
n=27

No INH
n=303

INH
n=57

No INH
n=835

ALT ≥1X ULN

24 (41.4)

260 (31.2)

9 (33.3)

82 (21.8)

12 (44.4)

91 (30.0)

21 (36.8)

183 (21.9)

ALT ≥3X ULN

0

13 (1.6)

2 (7.4)

6 (1.6)

2 (7.4)

9 (3.0)

2 (3.5)

13(1.6)

ALT ≥5X ULN

0

5 (0.6)

1 (3.7)

1 (0.3)

1 (3.7)

3 (1.0)

2 (3.5)

3 (0.4)

ALT ≥10X ULN

0

2 (0.2)

1 (3.7)

0

0

1 (0.3)

0

0

Abbreviations: ALT = alanine transaminase; BARI = baricitinib; INH = isoniazid; RA = rheumatoid arthritis; ULN = upper limit of normal.

aAll patients were on background conventional disease-modifying antirheumatic drugs, mainly methotrexate.

bPatient population from RA-BEAM, RA-BUILD, and RA-BEACON.

cPatient population from RA-BUILD and RA-BEACON.

dPatient population from RA-BEAM.

Rheumatoid Arthritis Clinical Trial Exclusion Criteria Related to Tuberculosis

Patients were excluded from participation in phase 3 RA studies if they had evidence of

  • active TB, documented by
    • a positive skin test or in vitro immunoassay
    • medical history
    • clinical symptoms, and
    • abnormal chest x-ray at screening, or
  • latent TB, documented by
    • a positive skin test or in vitro immunoassay
    • no clinical symptoms, and
    • a normal chest x-ray at screening.2,5

Patients could participate in the studies if they had

  • latent TB with at least 4 weeks of appropriate treatment completed prior to randomization, and agreed to complete the remainder of treatment while in the study, or
  • a history of active or latent TB with documented evidence of completed appropriate treatment.5

Across the RA phase 3 studies,

  • 0.6 to 0.9% of screened patients were excluded from randomization due to active TB
  • 1.1 to 4.5% of screened patients were excluded from randomization due to latent TB
  • 7 to 12% of randomized patients had evidence of latent TB, and
  • 2 to 13% of patients were receiving isoniazid as treatment during enrollment.2,5

Information From the Label

Patients should be screened for tuberculosis (TB) before starting therapy.7

  • Baricitinib should not be given to patients with active TB.7
  • Anti-TB therapy should be considered prior to initiation of treatment in patients with previously untreated latent TB.7

References

1Taylor PC, Takeuchi T, Burmester GR, et al. Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treatment: final results from long-term extension study and integrated database. Ann Rheum Dis. 2022;81(3):335-343. https://doi.org/10.1136/annrheumdis-2021-221276

2Data on file, Eli Lilly and Company and/or one of its subsidiaries.

3Brassard P, Lowe AM, Bernatsky S, et al. Rheumatoid arthritis, its treatments, and the risk of tuberculosis in Quebex, Canada. Arthritis Rheum. 2009;61(3):300-304. https://dx.doi.org/10.1002/art.24476

4Winthrop KL, Baxter R, Liu L, et al. Mycobacterial diseases and antitumor necrosis factor therapy in USA. Ann Rheum Dis. 2013;72(1):37-42. https://dx.doi.org/10.1136/annrheumdis-2011-200690

5Winthrop KL, Harigai M, Genovese MC, et al. Infections in baricitinib clinical trials for patients with active rheumatoid arthritis. Ann Rheum Dis. 2020;79:1290-1297. http://dx.doi.org/10.1136/annrheumdis-2019-216852

6Hsieh TY, Huang WN, Tony HP, et al. Hepatic safety in patients with rheumatoid arthritis who received isoniazid for latent tuberculosis: post-hoc analysis from phase 3 baricitinib studies [abstract]. Ann Rheum Dis. 2018;77(suppl 2):098. https://ard.bmj.com/content/77/Suppl_2/593.1.abstract

7Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

Date of Last Review: 27 June 2022


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