Olumiant ® ▼ (baricitinib)

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Olumiant®▼ (baricitinib): Incidence and Risk of Venous Thromboembolic Events in the Atopic Dermatitis Clinical Development Program

The incidence rate for VTE was 0.13 in baricitinib treated patients in the AD clinical trials. In a US claims analysis, the incidence rate for VTE was 0.31 in patients with moderate to severe AD vs 0.25 in non-AD patients.

Warnings and Precautions Related to Venous Thromboembolism

Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving baricitinib.1

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.1

If clinical features of DVT/PE occur, baricitinib treatment should be discontinued and patients should be evaluated promptly, followed by appropriate treatment.1

Clinical Trial Protocol Information Related to Venous Thromboembolism

Exclusion Criteria

Clinical Trials Outside the United States

In the AD clinical trials outside the US (BREEZE AD1, AD2, AD4, and AD7), patients were excluded from study enrollment if they

  • had a VTE within 12 weeks of screening

  • had a history of recurrent (≥2) VTE, or

  • were considered as high risk for VTE by the investigator.2,3

Clinical Trial in the United States

In the US-based clinical trial, BREEZE-AD5, patients were excluded from study enrollment if they

  • had a history of VTE

  • were considered as high risk for VTE by the investigator, or

  • had 2 or more of the following risk factors for VTE

    • aged >65 years

    • BMI>35 kg/m2, and

    • oral contraceptive use AND current smoker.2,3

Venous Thromboembolic Events During Clinical Trials

Clinical Trials Outside the United States

In the AD clinical trials, if patients had clinical features of a VTE, study treatment was interrupted and patients were promptly evaluated. Study treatment was

  • resumed if VTE was ruled out or appropriately treated, or

  • permanently discontinued if this was a second VTE or the investigator deemed the patient was at significant risk.3

Temporary interruption of study drug was not required at times of increased risk of VTE such as

  • surgery

  • significant air travel, or

  • prolonged immobilization.3

However, following appropriate VTE prophylaxis guidelines to mitigate risk was recommended in the clinical trials.3

Clinical Trial in the United States

In the US-based clinical trial, BREEZE-AD5, if patients had signs and symptoms of a VTE, appropriate local laboratory tests and imaging were performed. If a diagnosis of VTE was confirmed, study drug was permanently discontinued.3

Incidence of Venous Thromboembolism in Atopic Dermatitis Clinical Trials

Venous thromboembolic events were identified by the investigative site or through medical review and were sent to a blinded external Clinical Event Committee for adjudication.2

The integrated safety datasets used to evaluate VTE are described in more detail in Table 4.

Placebo-Controlled Period

Through 16 weeks, there was 1 VTE in the BARI 4 mg treatment group. There were no VTEs in the BARI 2 mg or placebo groups (see Table 1).2

All Baricitinib-Treated Patients With Extended Data

In patients treated with all BARI doses in the All BARI AD dataset, there were 3 positively adjudicated VTE events (IR=0.13), including DVT, PE, and other peripheral venous thrombosis (see Table 1).3 Details of the 3 events are presented in Table 2.

Table 1. Incidence of Venous Thromboembolic Events in the Atopic Dermatitis Safety Datasets2,3












BARI 2 mg Placebo-Controlleda
n (adj %)
b

BARI 4 mg Placebo-Controlleda
n (adj %)
b

BARI 2 mg vs 4 mga
n (adj %)
b

BARI 2 mg vs 4 mg Ext
n (adj %)
b [adj IR]

All BARI AD
n (%) [IR]


Placebo
n=840

BARI 2 mg
n=684

Placebo
n=694

BARI 4 mg
n=451

BARI 2 mg
n=539

BARI 4 mg
n=451

BARI 2 mg
n=539

BARI 4 mg
n=451

All Doses
N=2456

VTEc

0

0

0

1 (0.1)

0

1 (0.1)

1 (0.2) [0.28]

2 (0.3) [0.40]

3 (0.1) [0.13]

DVT

0

0

0

0

0

0

0

0

0

PE

0

0

0

1 (0.1)

0

1 (0.1)

0

2 (0.3) [0.40]

2 (0.1) [0.09]

Other peripheral venous thrombosis

0

0

0

0

0

0

1 (0.2) [0.28]

0

1 (0.0) [0.04]

Abbreviations: AD = atopic dermatitis; adj = adjusted; AEs = adverse events; BARI = baricitinib; DVT = deep vein thrombosis; Ext = extended; IR = incidence rate; PE = pulmonary embolism; VTE = venous thromboembolic event.

a Data through 16-week placebo-controlled period.

b For the integrated controlled analysis sets where the randomized ratio of patients receiving BARI to placebo or BARI to active control is not the same across all the integrated studies (eg, 2:1:1:1 vs 1:1:1:1), the study-size adjusted percentages were calculated for the AEs to provide appropriate direct comparisons between treatment groups.

c Patients with ≥1 positively adjudicated VTE event, including DVT, PE, and other peripheral venous thrombosis.

Table 2. Details of Each Individual Venous Thromboembolic Case in the Atopic Dermatitis Clinical Trials2,3

Patient

Age/Gender

Event

Serious

BARI Dose/Time From Start of BARI Treatment to Event

Relevant Medical History

Elevated Plateletsa

BARI Treatment
Status

AC Treatment

Outcome

1

51/F

PE

Yes

BARI 4 mg/10 weeks

Ex-smoker, concomitant oral contraceptives

No

Perm D/C

Yes

Recovered

2

61/M

PE

Yes

BARI 4 mg/19 weeks

10-hr plane trip 10 weeks prior

No

Perm D/C

Yes

Recovering

3

34/F

Other peripheral venous thrombosisb

No

BARI 2 mg/40 weeks

Factor V  Leiden mutation, contraceptive vaginal ring

No

Perm D/C

Yes

Recovering

Abbreviations: AC = anticoagulant; BARI = baricitinib; F = female; M = male; PE = pulmonary embolism; Perm D/C = permanently discontinued.

a ≥400x109/L.

b Defined as such per external adjudication committee as clot was located below the knee.

Risk of Venous Thromboembolism in the Atopic Dermatitis Population

Based on publicly available literature, background risk of VTE in the AD population has not been established. Therefore, a retrospective cohort study was conducted to understand the risk of VTE in patients with AD compared to a matched general population without AD.3,4

Study Design

Data were pulled from MarketScan, an administrative US claims database, to include patients

  • with diagnosed AD (overall AD cohort)

  • with moderate-to-severe AD (sub-cohort), and

  • without AD (non-AD controls matched for age, gender, and calendar time).

Both crude and adjusted HRs of VTE were calculated to compare the 2 cohorts to non-AD controls.4

Results

The incidence rates for VTE were

  • 0.24 in the overall AD cohort (n=198,685)

  • 0.31 in the moderate-to-severe AD sub-cohort (n=113,927), and

  • 0.25 in the non-AD controls (n=198,685) (see Figure 1).4

Figure 1. Venous Thromboembolism Incidence Rates in AD and Non-AD Populations4

Abbreviation: AD = atopic dermatitis.

There was no greater risk of VTE in the overall AD cohort compared to non-AD controls based on both crude and adjusted hazard ratio values. Overall, the moderate-to-severe AD cohort had a higher VTE risk than the non-AD controls. However, after adjusting for VTE risk factors there was no difference (see Table 3).4

Table 3. Risk of Venous Thromboembolism in AD Compared to Non-AD Populations4








Number of Events

Crude HR vs Non-AD Controls

Adjusted HRa vs Non-AD Controls


HR (95% CI)

P Value

HR (95% CI)

P Value

Overall AD cohort (n=198,685)

VTE

2137

0.98 (0.90, 1.06)

.61

0.69 (0.63, 0.77)

<.0001

PE

719

0.86 (0.74, 1.00)

.05

0.62 (0.52, 0.73)

<.0001

DVT

1660

1.02 (0.94, 1.12)

.70

0.73 (0.65, 0.81)

<.0001

Moderate-to-severe AD cohortb (n=113,927)

VTE

1859

1.30 (1.18, 1.42)

<.0001

0.97 (0.87, 1.08)

.60

PE

629

1.17 (1.00, 1.37)

.05

0.87 (0.72, 1.05)

.15

DVT

1438

1.34 (1.20, 1.48)

<.0001

1.01 (0.90, 1.15)

.84

Abbreviations: AD = atopic dermatitis; DVT = deep vein thrombosis; HR = hazard ratio; PE = pulmonary embolism; VTE = venous thromboembolism.

a Adjusted for age, gender, healthcare utilization, medications (hormone therapy, systemic corticosteroids, methotrexate, statins, antipsychotics, and COX-2 inhibitors), and comorbidities.

b Patients were selected as moderate-to-severe AD based on use of medications such as high or ultrahigh potency topical corticosteroids, systemic corticosteroids, phototherapies, or systemic immunosuppressants.

Postmarketing Spontaneous Reports

The postmarketing information provided below is based on cases reported prior to an approved indication of BARI for the treatment of atopic dermatitis.

Based on postmarketing spontaneous reports from February 2017, after the first global approval for rheumatoid arthritis, through August 2020

  • PE was rarely reported (≥0.01% and <0.1%), and

  • DVT was rarely reported (≥0.01% and <0.1%).3

Postmarketing cases of VTE were reported for both BARI 2 mg and BARI 4 mg doses and from many countries. The reporting rates were similar between BARI 2 mg and BARI 4 mg doses for VTE, DVT, and PE.3

Based on available information supplied at time of report and any follow-up, reported postmarketing cases were associated with one or more risk factors including

  • older age

  • previous history of VTE

  • post-surgical

  • lack of mobility

  • obesity

  • presence of malignancy, and/or

  • concomitant use of

    • corticosteroids

    • COX-2 inhibitor, and/or

    • estrogen.3

Postmarketing data do not necessarily represent the rate of occurrence of an AE in a treated population, but they represent a reporting rate of a particular AE to the company. Spontaneous reporting of AEs can be highly variable and is not appropriately controlled clinical information on which to base an assessment of whether a particular drug product is the causal agent of an event.5

Spontaneous reporting has limited use due to

  • lack of control population

  • under-reporting or reporting bias, and

  • missing or incomplete information regarding medical history or concomitant medications.5

Integrated Safety Datasets Table

Table 4. Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials2,3

Analysis Set

Description

BARI 2 mg Placebo-Controlled

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE- AD4, BREEZE- AD5, and BREEZE-AD7

Compares BARI 2 mg vs placebo

Includes patients with AD from 1 phase 2 and 5 phase 3 studies who were randomized to

  • BARI 2 mg (n=721, PYE=210.6), or

  • placebo (n=889, PYE=252.7).

Treatment period was 0 to 16 weeks.

BARI 4 mg Placebo-Controlled

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE- AD4, and BREEZE-AD7

Compares BARI 4 mg vs placebo

Includes patients with AD from 1 phase 2 and 4 phase 3 studies who were randomized to

  • BARI 4 mg (n=489, PYE=147.1), or

  • placebo (n=743, PYE=211.8).

Treatment period was 0 to 16 weeks.

BARI 2 mg vs 4 mg

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, and BREEZE-AD7

Compares BARI 2 mg vs BARI 4 mg through 16 weeks

Includes patients with AD from 1 phase 2 and 4 phase 3 studies who were randomized to

  • BARI 2 mg (n=576, PYE=169.1), or

  • BARI 4 mg (n=489, PYE=147.1).

Treated for 0 to 16 weeks during the placebo-controlled period.

BARI 2 mg vs 4 mg Extended

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD7, and extension study BREEZE-AD3

Compares BARI 2 mg vs BARI 4 mg including extended evaluations

Includes patients with AD from 1 phase 2 and 4 phase 3 studies and any further exposure for those patients in the phase 3 extension study, BREEZE-AD3, who were randomized to

  • BARI 2 mg (n=576, PYE=425.5), or

  • BARI 4 mg (n=489, PYE=459.3).

Data censored at dose or treatment change (rescue, dose switch, or re-randomization to a different BARI dose or placebo) for BREEZE-AD4 and BREEZE-AD3.

All BARI AD

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD5, BREEZE-AD7, and extension studies BREEZE-AD3, BREEZE-AD6

No between-group comparisons

Includes 2531 (total PYE=2247.4) patients with AD from 1 phase 2, 5 phase 3, and 2 phase 3 extension studies who received BARI at a variety of doses, including

  • BARI 2 mg (n=1580, PYE=1129.5), and

  • BARI 4 mg (n=914, PYE=872.8).

Includes all patients who were exposed to any BARI dose at any time during the studies, either from randomization or from switch or rescue from placebo.

 No censoring of data at dose change.

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; PYE = patient-years of exposure.

References

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

2. Bieber T, Thyssen JP, Reich K, et al. Pooled safety analysis of baricitinib in adult patients with atopic dermatitis from 8 randomized clinical trials. J Eur Acad Dermatol Venereol. 2021;35(2):476-485. https://doi.org/10.1111/jdv.16948

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

4. Meyers K, Goodloe R, Pierce E, et al. Risk of venous thromboembolism among patients with atopic dermatitis: a cohort study in a US administrative claims database [abstract]. European Academy of Dermatology 29th Congress; October 28 - November 1, 2020; Vienna, Austria.

5. Goldman SA. Limitations and strengths of spontaneous reports data. Clin Ther. 1998;20(suppl 3):C40-C44. http://dx.doi.org/10.1016/S0149-2918(98)80007-6

Glossary

AD = atopic dermatitis

AE = adverse event

BARI = baricitinib

BMI = body mass index

COX-2 = cyclooxygenase-2

DVT = deep vein thrombosis

IR = incidence rate

PE = pulmonary embolism

US = United States

VTE = venous thromboembolism

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.

Date of Last Review: February 21, 2021


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