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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
UK_cFAQ_BAR125A_TUBERCULOSIS_RA
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Content Overview
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
Ever on baricitinib 2 mg |
Ever on baricitinib 4 mg |
|
Tuberculosis |
0 |
19 (0.6) |
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
Country |
All BARI RA Number of Patients |
|
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
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
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.
Changes from baseline to 24 weeks n (%) |
BARI 4 mgb |
BARI 2 mgc |
Adalimumabd |
Placebob |
||||
INH |
No INH |
INH |
No INH |
INH |
No INH |
INH |
No INH |
|
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
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
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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