Description
of Baricitinib Rheumatoid Arthritis Phase 3 Clinical Trials
Each
of the 4 phase 3 studies in the clinical program evaluated a distinct
treatment population of patients with moderate-to-severe RA.
RA-BUILD
compared BARI 2 mg and 4 mg vs PBO, with background csDMARD therapy,
in patients with inadequate response to csDMARDs.1
RA-BEACON
compared BARI 2 mg and 4 mg vs PBO, with background csDMARD therapy,
in patients with inadequate response to TNF inhibitors, other
biologic DMARDs, or both.2
RA-BEAM
compared BARI 4 mg vs PBO or adalimumab, with background MTX, in
patients with inadequate response to MTX.3
RA-BEGIN
compared BARI 4 mg monotherapy, MTX monotherapy, and BARI 4 mg plus
MTX in patients who had limited or no prior treatment with MTX and
were naïve to other DMARDs.4
The
study population of DMARD-naïve patients from the RA-BEGIN study
is not included in the approved label. However, the RA-BEGIN study is
supportive for the target population of patients with an inadequate
response to, or intolerance to, other DMARDs.5
Clinical
Trial Program Criteria
Concomitant
use of anticoagulant treatments was not prohibited in the phase 3
clinical studies.6
Concomitant use of anticoagulant treatments are not included in the
drug-drug interaction information specific to BARI, and drug-drug
interaction studies were not performed specifically for BARI and any
anticoagulant therapies.7
Patients
were excluded from the phase 3 trials if they had
history
or presence of cardiovascular, respiratory, or hematological
disorders or any other serious or unstable illness that, in the
opinion of the investigator, could constitute a risk when taking
investigational product or could interfere with the interpretation
of data, and
any
major surgery within 8 weeks prior to study entry or would require
major surgery during the study that, in the opinion of the
investigator in consultation with Lilly or its designee, would pose
an unacceptable risk to the patient.6
Drug-Drug
Interactions
Antithrombotic
Treatments
Concomitant
use of antithrombotic treatments are not included in the drug-drug
interaction information specific to BARI, and drug-drug interaction
studies were not performed specifically for BARI and any
anticoagulant or antiplatelet agents.7
Drug-Drug
Interaction Pharmacology Studies
Based
on clinical pharmacology studies, no clinically relevant effects on
BARI pharmacokinetics occurred with the co-administration of BARI and
Co-administration
of BARI with either a CYP3A substrate or a Pgp substrate resulted in
no clinically relevant effects on the pharmacokinetics of these
drugs.7
Thrombosis
Risk
Baseline
Use of Antithrombotics and Antiplatelets and Association of VTE
Patient
baseline use of antithrombotics, but not dose amount, was captured in
the clinical trials as part of concomitant medications.
Antithrombotics include aspirin and other antiplatelet agents.
Aspirin accounted for the majority of antiplatelet agents used at
baseline.6
For
data on patients receiving concomitant aspirin in the BARI RA phase 3
trials, please see Table 1.
For
data on patients receiving concomitant antithrombotics, please see
VTE
Risk Factor Analysis
Through
13 February 2018, 49 patients reported VTE events with an
IR of 0.5 per 100 PY of observation time.
Factors
from the multi-variable analysis associated with an increased risk
for VTE in the ALL BARI RA dataset included
These
are among reported conventional risk factors for VTE for the general
population.10,11
In
data collected through April 1, 2017,
concomitant
use of BARI and antithrombotic agents was observed in
3
(7.1%) of the 42 patients with VTE, and
300
(8.7%) of the 3450 patients without VTE, and
concomitant
use of BARI and antiplatelet agents was observed in
0
of the 42 patients with VTE, and
272
(7.9%) of the 3450 patients without VTE.6
No
association has been observed between baseline use of antithrombotic
or antiplatelet medications and VTE incidence.6
Information
from the label
Events
of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been
reported in patients receiving baricitinib. Baricitinib should be
used with caution in patients with risk factors for DVT/PE, such as
older age, obesity, a medical history of DVT/PE, or patients
undergoing surgery and immobilisation. If clinical features of DVT/PE
occur, baricitinib treatment should be discontinued and patients
should be evaluated promptly, followed by appropriate treatment.5
DVT
and PE are listed as uncommon in the table of adverse reactions in
the summary of product characteristics. 5
Management
of Patients Reporting a VTE
Of
the 42 BARI-treated patients reporting a VTE through 1 April 2017, 28
patients had exposure to BARI after the event, duration ranging from
7 days to 30 months; 22 patients had at least 6 months of exposure to
BARI after the event.12
Of
the 28 patients exposed to BARI after the VTE event,
25
were put on continuous anti-coagulation therapy and 3 were not, and
2
reported an additional event, 1 and 2 years later with new risk
factors, which included surgery and discontinuation of warfarin.12
For
12 patients, the VTE was reported after they had already discontinued
BARI. Five patients reporting a VTE permanently discontinued BARI
treatment (IR=0.06).13
Appendix
Table
1. Concomitant Aspirin Use in Baricitinib Rheumatoid Arthritis Phase
3 Clinical Trials6
|
|
|
|
|
|
Concomitant
ASA Use by ATCa, n
(%)
|
Study
|
n
|
Antithrombotic
|
Analgesic
|
RA-BEACONb2(N=527)
|
BARI
2 mg
|
174
|
20
(11.5)
|
0
|
BARI
4 mg
|
177
|
24
(13.6)
|
1
(0.6)
|
PBO
|
176
|
21
(11.9)
|
0
|
RA-BUILDc1 (N=684)
|
BARI
2 mg
|
229
|
19
(8.3)
|
1
(0.4)
|
BARI
4 mg
|
227
|
20
(8.8)
|
1
(0.4)
|
PBO
|
228
|
16
(7.0)
|
1
(0.4)
|
RA-BEAMd3
(N=1305)
|
BARI
4 mg
|
487
|
34
(7.0)
|
0
|
Adalimumab
|
330
|
19
(5.8)
|
1
(0.3)
|
PBO
|
488
|
22
(4.5)
|
1
(0.2)
|
RA-BEGINe14
(N=584)
|
BARI
4 mg
|
159
|
13
(8.2)
|
1
(0.6)
|
BARI
4 mg + MTX
|
215
|
11
(5.1)
|
0
|
MTX
|
210
|
10
(4.8)
|
0
|
Abbreviations:
ASA = acetylsalicylic acid; ATC = Anatomical Therapeutic Chemical
classification system; BARI = baricitinib; MTX = methotrexate; PBO =
placebo; RA = rheumatoid arthritis.
a
Dose or dose range was not collected.
b
RA-BEACON compared BARI 2 mg and 4 mg vs PBO, with background
csDMARD therapy, in patients with inadequate response to TNF
inhibitors, other biologic DMARDs, or both.
c
RA-BUILD compared BARI 2 mg and 4 mg vs PBO, with background
csDMARD therapy, in patients with inadequate response to cDMARDs.
d
RA-BEAM compared BARI 4 mg vs PBO or adalimumab, with
background MTX, in patients with inadequate response to MTX.
e
RA-BEGIN compared BARI 4 mg monotherapy, MTX monotherapy, and
BARI 4 mg plus MTX in patients who had limited or no prior treatment
with MTX and were naïve to other DMARDs.
Table
2. Concomitant Antithrombotic Therapies Other Than Aspirin
Administered for Rheumatoid Arthritis in Study RA-BUILD6
ATC
Level 2 Term (Preferred Name)
|
Placebo
(N=228)
n (%)
|
BARI
2 mg (N=229)
n (%)
|
BARI
4 mg (N=227)
n (%)
|
Antithrombotic
Agents
|
23
(10.1)
|
25
(10.9)
|
26
(11.5)
|
Cilostazol
|
0
|
0
|
1
(0.4)
|
Clopidogrel
|
2
(0.9)
|
1
(0.4)
|
1
(0.4)
|
Enoxaparin
|
5
(2.2)
|
0
|
1
(0.4)
|
Heparinoid
|
0
|
0
|
1
(0.4)
|
Mesoglycan
|
0
|
0
|
1
(0.4)
|
Rivaroxaban
|
0
|
0
|
1
(0.4)
|
Warfarin
|
0
|
2
(0.9)
|
1
(0.4)
|
Acenocoumarol
|
1
(0.4)
|
0
|
0
|
Fondaparinux
|
0
|
1
(0.4)
|
0
|
Magnyl
|
0
|
2
(0.9)
|
0
|
Phenprocoumon
|
1
(0.4)
|
0
|
0
|
Ticagrelor
|
1
(0.4)
|
0
|
0
|
Abbreviations:
ATC = Anatomical Therapeutic Chemical classification system; BARI =
baricitinib.
Table
3. Concomitant Antithrombotic Therapies Other Than Aspirin
Administered for Rheumatoid Arthritis in Study RA-BEACON6
ATC
Level 2 Term (Preferred Name)
|
Placebo
(N=176)
n (%)
|
BARI
2 mg (N=174)
n (%)
|
BARI
4 mg (N=177)
n (%)
|
Antithrombotic
Agents
|
30
(17.0)
|
25
(14.4)
|
33
(18.6)
|
Clopidogrel
|
6
(3.4)
|
2
(1.1)
|
6
(3.4)
|
Warfarin
|
5
(2.8)
|
2
(1.1)
|
5
(2.8)
|
Phenprocoumon
|
0
|
1
(0.6)
|
2
(1.1)
|
Enoxaparin
|
1
(0.6)
|
2
(1.1)
|
1
(0.6)
|
Fondaparinux
|
0
|
0
|
1
(0.6)
|
Heparin
|
1
(0.6)
|
0
|
1
(0.6)
|
Acenocoumarol
|
0
|
1
(0.6)
|
0
|
Certoparin
Sodium
|
0
|
1
(0.6)
|
0
|
Dabigatran
|
2
(1.1)
|
1
(0.6)
|
0
|
Dalteparin
|
0
|
1
(0.6)
|
0
|
Prasugrel
|
1
(0.6)
|
0
|
0
|
Abbreviation:
ATC = Anatomical Therapeutic Chemical classification system; BARI =
baricitinib.
Table
4. Concomitant Antithrombotic Therapies Other Than Aspirin
Administered for Rheumatoid Arthritis in Study RA BEAM6
ATC
Level 2 Term (Preferred Name)
|
Placebo
(N=488)
n (%)
|
BARI
4 mg (N=487)
n (%)
|
ADA
(N=330)
n (%)
|
Antithrombotic
Agents
|
35
(7.2)
|
47
(9.7)
|
28
(8.5)
|
Warfarin
|
4
(0.8)
|
6
(1.2)
|
0
|
Enoxaparin
|
4
(0.8)
|
4
(0.8)
|
2
(0.6)
|
Clopidogrel
|
3
(0.6)
|
3
(0.6)
|
3
(0.9)
|
Nadroparin
|
0
|
2
(0.4)
|
0
|
Rivaroxaban
|
0
|
2
(0.4)
|
0
|
Acenocoumarol
|
1
(0.2)
|
1
(0.2)
|
2
(0.6)
|
Dipyridamole
|
0
|
1
(0.2)
|
0
|
Heparin
|
2
(0.4)
|
1
(0.2)
|
0
|
Prasugrel
|
0
|
1
(0.2)
|
0
|
Sulodexide
|
0
|
1
(0.2)
|
1
(0.3)
|
Ticagrelor
|
0
|
1
(0.2)
|
0
|
Tinzaparin
|
0
|
1
(0.2)
|
0
|
Cilostazol
|
1
(0.2)
|
0
|
0
|
Dalteparin
|
0
|
0
|
1
(0.3)
|
Heparinoid
|
0
|
0
|
1
(0.3)
|
Magnyl
|
0
|
0
|
1
(0.3)
|
Paynocil
|
0
|
0
|
1
(0.3)
|
Streptokinase
|
0
|
0
|
1
(0.3)
|
Ticlopidine
|
0
|
0
|
1
(0.3)
|
Abbreviations:
ADA = adalimumab; ATC = Anatomical Therapeutic Chemical
classification system; BARI = baricitinib.
Table
5. Concomitant Antithrombotic Therapies Other Than Aspirin
Administered for Rheumatoid Arthritis in Study RA BEGIN6
ATC
Level 2 Term (Preferred Name)
|
MTX
(N=210)
n (%)
|
BARI
4 mg (N=159)
n (%)
|
BARI
4 mg + MTX (N=215)
n (%)
|
Antithrombotic
Agents
|
15
(7.1)
|
15
(9.4)
|
14
(6.5)
|
Enoxaparin
|
1
(0.5)
|
0
|
3
(1.4)
|
Rivaroxaban
|
0
|
0
|
2
(0.9)
|
Acenocoumarol
|
0
|
0
|
1
(0.5)
|
Alteplase
|
0
|
0
|
1
(0.5)
|
Clopidogrel
|
1
(0.5)
|
2
(1.3)
|
1
(0.5)
|
Heparin
|
2
(1.0)
|
1
(0.6)
|
1
(0.5)
|
Warfarin
|
0
|
0
|
1
(0.5
|
Magnyl
|
0
|
1
(0.6)
|
0
|
Phenprocoumon
|
1
(0.5)
|
0
|
0
|
Ticagrelor
|
0
|
1
(0.6)
|
0
|
Abbreviations:
ATC = Anatomical Therapeutic Chemical classification system; BARI =
baricitinib; MTX = methotrexate.
References
1.
Dougados 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 [published
correction appears in Ann Rheum Dis. 2017;76(9):1634.
http://dx.doi.org/10.1136/annrheumdis-2016-210094corr1
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http://dx.doi.org/10.1136/annrheumdis-2016-210094
2.
Genovese MC, Kremer J, Zamani O, et al. Baricitinib in patients with
refractory rheumatoid arthritis. N Engl J Med.
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3.
Taylor 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
4.
Fleischmann 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
5.
Olumiant [summary of product characteristics]. Eli Lilly Nederland
B.V., The Netherlands.
6.
Data on file, Eli Lilly and Company and/or one of its subsidiaries.
7.
Payne C, Zhang X, Shahri N, et al. Evaluation of Potential Drug-Drug
Interactions With Baricitinib. Poster presented at: the Annual
Meeting of the American Association of Pharmaceutical Scientists
(AAPS); October 25-29, 2015; Orlando, FL.
8.
Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of
baricitinib for the treatment of rheumatoid arthritis up to 7 years:
an updated integrated safety analysis. Ann Rheum Dis.
2019;78(2):308-309.
http://dx.doi.org/10.1136/annrheumdis-2019-eular.691
9.
Weinblatt M, Taylor PC, Burmester GR, et al. Cardiovascular Safety –
Update from up to 6 Years of Treatment with Baricitinib in Rheumatoid
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https://acrabstracts.org/abstract/cardiovascular-safety-update-from-up-to-6-years-of-treatment-with-baricitinib-in-rheumatoid-arthritis-clinical-trials/
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12.
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Accessed April 19, 2018.
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DO NOT USE - Fleischmann 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 anti-rheumatic
drug treatment. Arthritis Rheumatol. 2017;69(3):506-517.
http://dx.doi.org/10.1002/art.39953
▼ This
medicinal product is subject to additional monitoring. This will
allow quick identification of new safety information. Healthcare
professionals are asked to report any suspected adverse reactions.
Glossary
BARI
= baricitinib
BMI
= body mass index
COX-2
= cyclooxygenase-2
CYP
= cytochrome P450
csDMARD
= conventional synthetic disease-modifying antirheumatic drug
DMARD
= disease-modifying antirheumatic drug
DVT
= deep vein thrombosis
Lilly
= Eli Lilly and Company
MTX
= methotrexate
PBO
= placebo
PE =
pulmonary embolism
Pgp
= P-glycoprotein
RA =
rheumatoid arthritis
VTE
= venous thromboembolism