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Olumiant ® (baricitinib)
This information is intended for UK registered healthcare professionals only as a scientific exchange in response to your search for information. For current prescribing information for all Lilly products, including Summaries of Product Characteristics, Patient Information Leaflets and Instructions for Use, please visit: www.medicines.org.uk (England, Scotland, Wales) or www.emcmedicines.com/en-GB/northernireland/ (Northern Ireland).
What is the clinical trial long-term safety of Olumiant® (baricitinib) in the treatment of rheumatoid arthritis?
Data up to 9.3 years, accounting for 14,744 patient-years of exposure, show that the incidence of DVT/PE, MACE, malignancy, and deaths in patients who received baricitinib for the treatment of rheumatoid arthritis remained stable over time.
Content overview
Overview of phase 3 clinical trials
Each of the 4 phase 3 studies in the baricitinib clinical program evaluated a distinct treatment population of patients with moderate-to-severe rheumatoid arthritis.
- RA-BEGIN compared baricitinib 4 mg monotherapy, baricitinib 4 mg plus methotrexate, and methotrexate monotherapy in patients who had limited or no prior treatment with methotrexate and were naïve to other disease-modifying antirheumatic drugs (DMARDs).1
- RA-BEAM compared baricitinib 4 mg vs placebo or adalimumab, with background methotrexate, in patients with inadequate response to methotrexate.2
- RA-BUILD compared baricitinib 2 mg and 4 mg vs placebo, with background conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy, in patients with inadequate response to csDMARDs.3
- RA-BEACON compared baricitinib 2 mg and 4 mg vs placebo, with background csDMARD therapy, in patients with an inadequate response to at least one tissue necrosis factor (TNF) inhibitor, who may also have had an inadequate response to one or more non-TNF inhibitor biologic DMARDs.4
Patients completing the phase 3 clinical trial program were eligible to enter an ongoing extension study, also known as RA-BEYOND.5
Please refer to Study Design Features and Baseline Patient Characteristics for a summary of study design features and baseline patient characteristics in each trial.1-4
See Proportion of Patients Reporting Treatment-Emergent Adverse Events or Serious Adverse Events in Phase 3 Studies for an overview of the proportion of patients in each treatment arm of the 4 phase 3 trials who reported a treatment-emergent adverse event or a serious adverse event.
Study and Treatment |
TEAEs |
SAEs |
RA-BEGIN (through 52 weeks) |
||
MTX Monotherapy |
72% |
10% |
BARI Monotherapy |
71% |
8% |
BARI Plus MTX |
78% |
8% |
RA-BEAM (through 24 weeks) |
||
Placebo |
60% |
5% |
Adalimumab |
68% |
2% |
BARI |
71% |
5% |
RA-BUILD (through 24 weeks) |
||
Placebo |
71% |
5% |
BARI 2 mg |
67% |
3% |
BARI 4 mg |
71% |
5% |
RA-BEACON (through 24 weeks) |
||
Placebo |
64% |
7% |
BARI 2 mg |
71% |
4% |
BARI 4 mg |
77% |
10% |
Abbreviations: BARI = baricitinib; MTX = methotrexate; SAE = serious adverse event; TEAE = treatment-emergent adverse event.
Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 9.3 years
An integrated analysis of data from 1 phase 1 study, 3 phase 2 studies, 5 phase 3 studies, and the long-term extension study have summarized the safety profile of baricitinib for the treatment of rheumatoid arthritis in 3770 patients with a maximum exposure of 9.3 years (median exposure, 4.6 years) with data including 14,744 patient-years of exposure.6
In this analysis,
- rates of safety events of special interest, including deaths, malignancies, major adverse cardiovascular events, and deep vein thrombosis and/or pulmonary embolism remained stable through exposures up to 9.3 years and were generally similar between the baricitinib 2-mg and 4-mg groups, and
- the results showed a safety profile of baricitinib consistent with previous reports.6
See Safety Summary of Baricitinib for the Treatment of Rheumatoid Arthritis With Data Through 9.3 Years for a summary of safety data from this integrated analysis.
Event |
All-BARI-RA (N=3770; 14,744 PYE) |
Treatment-emergent adverse events, n (EAIR) |
|
Any treatment-emergent adverse event |
3421 (22.6) |
Serious adverse event |
1117 (7.4) |
Temporary study drug interruption due to adverse event |
1282 (8.5)a |
Permanent discontinuation of the study drug due to adverse event |
704 (4.7) |
Death, n (IR) |
85 (0.56) |
Malignancy, n (IR) |
|
Malignancy excluding nonmelanoma skin cancer |
139 (0.9) |
Lymphoma |
9 (0.06) |
Nonmelanoma skin cancer |
50 (0.3) |
Infection, n (IR) |
|
Treatment-emergent infectionsb |
2590 (17.1) |
Serious infection |
372 (2.6) |
Herpes zoster |
422 (3.0) |
Tuberculosisb |
19 (0.1) |
Opportunistic infection excluding tuberculosis |
69 (0.5) |
Major adverse cardiovascular event, n (IR)c |
73 (0.5) |
Myocardial infarction |
24 (0.2) |
Cardiovascular death |
20 (0.1) |
Stroke |
38 (0.3) |
Deep vein thrombosis/pulmonary embolism |
73 (0.5) |
Deep vein thrombosisd |
52 (0.4) |
Pulmonary embolism |
39 (0.3) |
Gastrointestinal perforations, n (IR) |
9 (0.06) |
Abbreviations: BARI = baricitinib; EAIR = exposure-adjusted incidence rates per 100 patient-years (exposure time not censored at event); IR = incidence rates per 100 patient-years (exposure time censored at event); PYE = patient-years of exposure; RA = rheumatoid arthritis.
aSome studies did not collect temporary interruption of study drug.
bUsed EAIR per 100 PY (patient exposure not censored at the event).
cPotential cardiovascular adverse events from the phase III and long-term extension trials, identified by investigators or according to a predefined list of event terms, were adjudicated by an independent, external Clinical Endpoint Committee that remained blinded to treatment assignments.
dDeep vein thrombosis includes distal events below the knee.
Adverse Events of Special Interest in the 2-mg and 4-mg Subsets of Baricitinib for the Treatment of Rheumatoid Arthritis With Data Through 9.3 Years shows the exposure-adjusted incidence rates (EAIRs) of adverse events of special interest for the 2-mg and 4-mg subsets.
EAIRa (95% CI) |
Ever Received BARI 2 mg (N=1077) |
Ever Received BARI 4 mg (N=3401) |
All BARI-RA (N=3770) |
Death |
0.56 (0.31-0.92) |
0.57 (0.44-0.73) |
0.56 (0.45-0.70) |
Serious infections |
2.13 (1.61-2.76) |
2.62 (2.34-2.93) |
2.58 (2.33-2.86) |
Thromboembolic events |
|||
Deep vein thrombosis and/or pulmonary embolism |
0.49 (0.26-0.83) |
0.51 (0.39-0.66) |
0.49 (0.38-0.61) |
Deep vein thrombosis |
0.41 (0.21-0.73) |
0.35 (0.25-0.48) |
0.35 (0.26-0.45) |
Pulmonary embolism |
0.26 (0.11-0.54) |
0.27 (0.18-0.38) |
0.26 (0.18-0.35) |
Major adverse cardiovascular eventb |
0.42 (0.21-0.74) |
0.54 (0.41-0.69) |
0.51 (0.40-0.64) |
Abbreviations: BARI = baricitinib; EAIR = exposure-adjusted incidence rate; PYE = patient-years of exposure; RA = rheumatoid arthritis.
aExposure-adjusted incidence rates per 100 patient-years were calculated as the number of patients with an event per 100 patient-years of overall exposure time.
bPositively adjudicated events of myocardial infarction, stroke, and cardiovascular deaths.
Additional details by individual safety topics are available upon request.
Postmarketing required Studies
RA-BRIDGE and RA-BRANCH
Two randomized, controlled, open-label, phase 3b/4 studies, RA-BRIDGE (NCT03915964) and RA-BRANCH (NCT04086745), are evaluating the safety of high- and low-dose baricitinib compared to adalimumab or etanercept in patients with rheumatoid arthritis who had an inadequate response or intolerance to at least one DMARD. The outcome measures are the time from first dose of study treatment to the first
In RA-BRIDGE and RA-BRANCH, patients had at least 1 of the following baseline characteristics:
RA-BRIDGE includes an estimated enrollment of 2600 participants from sites in the United States and outside the United States. The estimated primary completion date is April 2025.8
RA-BRANCH is currently recruiting patients in the United States. The estimated enrollment will be 1300 patients and the estimated primary completion date is December 2024.7
References
1Fleischmann R, Schiff M, van der Heijde D, et al. Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Rheumatol. 2017;69(3):506-517. http://dx.doi.org/10.1002/art.39953
2Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2017;376(7):652-662. http://dx.doi.org/10.1056/NEJMoa1608345
3Dougados M, van der Heijde D, Chen YC, et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis. 2017;76(9):1634. http://dx.doi.org/10.1136/annrheumdis-2016-210094corr1
4Genovese MC, Kremer J, Zamani O, et al. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med. 2016;374(13):1243-1252. http://dx.doi.org/10.1056/NEJMoa1507247
5An extension study in participants with moderate to severe rheumatoid arthritis (RA-BEYOND). ClinicalTrials.gov identifier: NCT01885078. Updated February 1,2022. Accessed February 28, 2022. http://clinicaltrials.gov/ct2/show/NCT01885078.
6Taylor 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. Published online October 27, 2021. https://doi.org/10.1136/annrheumdis-2021-221276
7A study of baricitinib in participants with rheumatoid arthritis (RA-BRANCH). ClinicalTrials.gov identifier: NCT04086745. Updated April 19, 2022. Accessed March 14, 2022. https://clinicaltrials.gov/ct2/show/NCT04086745
8A study of baricitinib (LY3009104) in participants with rheumatoid arthritis (RA-BRIDGE). ClinicalTrials.gov identifier: NCT03915964. Updated June 10, 2021. Accessed March 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03915964
9Data on file, Eli Lilly and Company and/or one of its subsidiaries.
Appendix
STUDY DESIGN |
RA-BEGIN |
RA-BEAM |
RA-BUILD |
RA-BEACON |
Patient Type |
DMARD-naïve |
MTX-IR |
csDMARD-IR |
TNFi-IR |
Background DMARDs |
None |
MTX |
csDMARD(s) allowed but |
csDMARD(s) |
TJC and SJC Entry Criteria |
≥6 TJC |
≥6 TJC |
≥6 TJC |
≥6 TJC |
hsCRP Entry Criteria |
≥3.6 mg/L |
≥6.0 mg/L |
≥3.6 mg/L |
≥3 mg/L |
Joint erosion/RF/ACPA entry criteria |
Joint erosion (none); Either RF or ACPA+ |
≥3 erosions or |
None |
None |
Primary Endpoint |
ACR20 Week 24 |
ACR20 Week 12 |
ACR20 Week 12 |
ACR20 Week 12 |
Study Duration |
52 Weeks |
52 Weeks |
24 Weeks |
24 Weeks |
First opportunity for rescue therapy (as needed) |
Week 24 |
Week 16 |
Week 16 |
Week 16 |
BASELINE |
RA-BEGIN |
RA-BEAM |
RA-BUILD |
RA-BEACON |
Age (y), mean (SD) |
49.9 (13) |
53.3 (12) |
51.8 (12) |
55.7 (11) |
Female, n (%) |
425 (73) |
1008 (77) |
560 (82) |
431 (82) |
RA duration from symptom onset (y), mean (SD) |
2.6 (5) |
10.1 (9) |
7.5 (8) |
14.0 (9) |
ACPA + (>10 U/ml), n (%) RF + (>14 IU/ml), n (%) |
527 (90) 562 (96) |
1146 (88) 1191 (91) |
504 (74) 521 (76) |
368 (70) 386 (73) |
≥ 1 joint erosion, n (%) |
380 (65) |
NRa |
502 (74) |
NR |
Prior cDMARD, n (%) |
||||
None |
533 (91) |
NA |
NA |
NA |
One |
51 (9)b |
600 (46) |
298 (44) |
212 (40) |
Two |
0 |
412 (32) |
210 (31) |
153 (29) |
≥ Three |
0 |
292 (22) |
171 (25) |
161 (31) |
Corticosteroid use, n (%) |
206 (35) |
766 (59) |
346 (51) |
304 (58) |
HAQ-DI (0-3), mean (SD) |
1.6 (0.7) |
1.6 (0.7) |
1.5 (0.6) |
1.7 (0.6) |
TJC (68), mean (SD) SJC (66), mean (SD) |
27 (15) 16 (10) |
23 (13) 15 (9) |
24 (14) 13 (8) |
29 (16) 17 (11) |
ESR (mm/h), mean (SD) hsCRP (mg/L), mean (SD) |
52 (27) 24 (26) |
49 (26) 21 (22) |
43 (24) 17 (19) |
47 (25) 20 (24) |
DAS28-ESR, mean (SD) DAS28-hsCRP, mean (SD) |
6.6 (1.0) 5.9 (1.0) |
6.4 (1.0) 5.7 (0.9) |
6.2 (1.0) 5.6 (0.9) |
6.6 (1.0) 5.9 (1.0) |
Abbreviations: ACPA = anti-citrullinated peptide antibody; ACR20 = American College of Rheumatology 20% improvement criteria; csDMARD = conventional synthetic disease-modifying antirheumatic drug; DAS28-ESR = 28-joint Disease Activity Score based on erythrocyte sedimentation rate; DAS28-hsCRP = 28-joint Disease Activity Score based on high-sensitivity C-reactive protein; DMARD = disease-modifying antirheumatic drug; ESR = erythrocyte sedimentation rate; HAQ-DI = Health Assessment Questionnaire Disability Index; hsCRP = high-sensitivity C-reactive protein; IR = inadequate responder; MTX = methotrexate; NA = not applicable; NR = not reported; RA = rheumatoid arthritis; RF = rheumatoid factor; SJC = swollen joint count; TJC = tender joint count; TNFi = tumor-necrosis factor inhibitors.
Note: Data in table are based on a modified intent-to-treat population.
aPer study inclusion criteria, all patients had either 1 to 2 joint erosions and seropositivity or 3+ joint erosions at baseline.
b Per protocol, patients could have had up to 3 doses of MTX prior to enrollment.
Date of Last Review: 05 October 2021