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Olumiant® ▼ (baricitinib): Behandlingsavbrott i reumatoid artrit

De vanligaste orsakerna till tillfälliga behandlingsavbrott i kliniska studier med reumatoid artrit var biverkningar.

Interruption of Treatment in the Rheumatoid Arthritis Clinical Trial Program

Short Answer Summary

  • Baricitinib is a potent, selective, and reversible inhibitor of the JAK family of protein tyrosine kinases, specifically JAK1 and JAK21, with a half-life of approximately 13 hours in patients with RA.2

  • The most common reasons for temporary interruption in the clinical trial program were AEs; other reasons included

    • abnormal laboratory results

    • investigator decisions, and

    • suspected pregnancies.3

  • Post hoc analysis from phase 3 studies evaluated changes in efficacy response in patients with and without interruptions in treatment.4

    • The group of patients who experienced interruptions had similar overall disease control responses compared with the group of patients without interruptions.4

    • Compared with the last pre-interruption values, modest patient reported symptom increases were observed in

      • morning joint stiffness severity

      • worst tiredness, and

      • worst joint pain.4

    • Symptoms improved following resumption of treatment and often returned to pre-interruption levels.4

  • The short half-life of BARI makes it feasible to temporarily interrupt treatment prior to surgery; and temporary interruption of treatment may also facilitate the management of AEs or laboratory abnormalities in patients with RA.3

Temporary Treatment Interruptions During RA Clinical Studies

Temporary Treatment Interruptions from Integrated Datasets

Pooled integrated datasets from the RA clinical trial program were used to evaluate safety, including temporary treatment interruptions. For a description of the datasets, including treatment arms, number of patients, patient-years of exposure, median and maximum exposure, and data cut-off dates, see Table 3.

Reasons for Temporary Interruptions

The most common reasons for temporary interruption in the clinical trial program were AEs. Other reasons for temporary interruptions were

  • abnormal laboratory results

  • investigator decisions, and

  • suspected pregnancies ( ).3

Patients were allowed to remain in their respective studies and resume study treatment when laboratory or AE outcome data met criteria for resumption of treatment.3

Table 1. Overview of Temporary Interruption of Treatment From Integrated Analysis Datasets3


7-Study Placebo Controlled, 0-16 weeks

7-Study Placebo Controlled, 0-16 weeks

7-Study Placebo Controlled, 0-16 weeks

4-Study Extended Dataseta

4-Study Extended Datasetb

All BARI RAa

Placebo
N=1215

BARI 2 mg
N=479

BARI 4 mg
N=1142

BARI 2 mg
N=479

BARI 4 mg
N=479

N=3717c

Patients with ≥1 interruption, n (%)

92 (7.6)

50 (10.4)

110 (9.6)

127 (26.5)

138 (28.8)

1385 (37.3)

Interruptions per interrupted patient, mean number (SD)

0.1 (0.3)

0.1 (0.4)

0.1 (0.3)

0.5 (1.1)

0.5 (1.1)

0.8 (1.6)

Reasons for interruption, n (% of N)

Adverse event

71 (5.8)

31 (5.6)

87 (7.6)

110d (23.0)

123d(25.7)

1259 (33.9)

Abnormal lab result

14 (1.2)

7 (1.3)

13 (1.1)

14 (2.9)

12 (2.5)

155 (4.2)

Investigator decision

6 (0.5)

3 (0.6)

7 (0.6)

8 (1.7)

7 (1.5)

77 (2.1)

Suspected pregnancy

0

0

0

0

0

1 (0.0)

Individual interruption duratione

Mean (SD), days

11.5 (11.4)

11.4 (12.8)

10.2 (8.9)

19.1 (24.0)

18.0 (19.0)

24.2 (32.5)

Median, days

7.0

8.0

7.0

12.5

11.0

14.0

Abbreviations: BARI = baricitinib; RA = rheumatoid arthritis.

a Data through 01 September 2019.

b Data through 01 September 2019.

c N includes eligible studies that collected treatment interruption data.

d Some events were not included in the analysis due to timing of AE, study drug interruption, and study drug resumption.

e Data represent the mean and median durations for all temporary interruptions by treatment assignment among patients who had interruptions; patients may have had more than one temporary treatment interruption.

Treatment Interruption Duration

The median duration for treatment interruptions was ≤ 2 weeks across the pooled safety datasets. For additional details see  .3

Temporary Interruptions Attributed to Adverse Events

Adverse events from the infections and infestations MedDRA System Organ Class were the most common reported AEs leading to temporary interruption. More details and other AE's leading to temporary interruption are presented in  .

Table 2. Adverse Events Leading to Temporary Interruption of Treatment by System Organ Class3

 

7-Study Placebo-Controlled Dataset (Week 24)

7-Study Placebo-Controlled Dataset (Week 24)

7-Study Placebo-Controlled Dataset (Week 24)

4-Study Extended Dataset

4-Study Extended Dataset

All BARI RA Dataset

n (EAIR)

Placebo
N=1215
PYE=450.8

BARI 2 mg
N=479
PYE=185.8

BARI 4 mg
N=1142
PYE=471.8

BARI 2 mg
N=479
PYE=774.9

BARI 4 mg
N=479
PYE=781.1

N=3647
PYE=13,101.5

Patients with ≥ treatment interruption due to AE

98 (21.7)

50 (26.9)

117 (24.8)

115 (14.8)

126 (16.1)

1241 (9.5)

Infections and infestations

54 (12.0)

34 (18.3)

69 (14.6)

71 (9.2)

75 (9.6)

805 (6.1)

Gastrointestinal disorders

8 (1.8)

4 (2.2)

12 (2.5)

10 (1.3)

13 (1.7)

121 (0.9)

Surgical and medical procedures

2 (0.4)

0

4 (0.8)

7 (0.9)

10 (1.3)

117 (0.9)

Investigations

8 (1.8)

3 (1.6)

4 (0.8)

6 (0.8)

8 (1.0)

101 (0.8)

Musculoskeletal and connective tissue disorders

6 (1.3)

0

2 (0.4)

6 (0.8)

10 (1.3)

92 (0.7)

Blood and lymphatic disorders

6 (1.3)

1 (0.5)

8 (1.7)

3 (0.4)

4 (0.5)

86 (0.7)

Injury, poisoning, and procedural complications

1 (0.2)

2 (1.1)

1 (0.2)

4 (0.5)

8 (1.0)

79 (0.6)

Respiratory, thoracic and mediastinal disorders

2 (0.4)

2 (1.1)

5 (1.1)

9 (1.2)

7 (0.9)

73 (0.6)

Skin and subcutaneous tissue disorders

2 (0.4)

1 (0.5)

7 (1.5)

3 (0.4)

7 (0.9)

36 (0.3)

Cardiac disorders

1 (0.2)

1 (0.5)

2 (0.4)

4 (0.5)

4 (0.5)

39 (0.3)

Hepatobiliary disorders

2 (0.4)

1 (0.5)

1 (0.2)

3 (0.4)

2 (0.3)

38 (0.3)

Nervous system disorders

3 (0.7)

1 (0.5)

1 (0.2)

2 (0.3)

2 (0.3)

34 (0.3)

Renal and urinary disorders

2 (0.4)

1 (0.5)

3 (0.6)

4 (0.5)

2 (0.3)

31 (0.2)

Neoplasms benign, malignant, and unspecified

1 (0.2)

0

1 (0.2)

1 (0.1)

3 (0.4)

28 (0.2)

General disorders and administration site conditions

2 (0.4)

1 (0.5)

3 (0.6)

2 (0.3)

4 (0.5)

27 (0.2)

Reproductive system and breast disorders

0

1 (0.5)

1 (0.2)

3 (0.4)

3 (0.4)

28 (0.2)

Vascular disorders

0

2 (1.1)

3 (0.6)

5 (0.6)

2 (0.3)

20 (0.2)

Eye disorders

3 (0.7)

0

0

2 (0.3)

2 (0.3)

12 (0.1)

Metabolism and nutrition disorders

0

0

0

0

2 (0.3)

9 (0.1)

Psychiatric disorders

2 (0.4)

0

0

1 (0.1)

1 (0.1)

6 (0.0)

Ear and labyrinth disorders

1 (0.2)

0

0

0

0

5 (0.0)

Endocrine disorders

1 (0.2)

0

0

1 (0.1)

0

6 (0.0)

Product issues

0

0

0

0

2 (0.3)

5 (0.0)

Immune system disorders

0

0

1 (0.2)

0

1 (0.1)

1 (0.0)

Congenital, familial, and genetic disorders

0

0

0

0

1 (0.1)

2 (0.0)

Abbreviations: BARI = baricitinib; EAIR = exposure adjusted incidence rate; PBO = placebo; PYE = patient-years of exposure.
Notes: The 4 Study Extended dataset and the All BARI RA dataset include data through 13 February 2018. Adverse events were anchored according to the EAIRs (≥0.2) of patients treated with BARI 4 mg in the 6 Study Dataset. Exposure adjusted incidence rates represent the number of unique patients with an event per 100 PYE.

7-Study Placebo-Controlled Dataset

The proportion of patients with temporary interruption attributed to an AE through 24 weeks was

  • 10.2% in the BARI 4-mg group

  • 10.4% in the BARI 2-mg group, and

  • 8.1% in the placebo group.3

4-Study Extended Dataset

The proportion of patients with temporary interruption attributed to an AE was

  • 25.7% in BARI 4-mg group, and

  • 23.0% in the BARI 2-mg group.3

All BARI RA

The proportion of patients with temporary interruption attributed to an AE was 33.9%.3

Temporary Interruptions in Individual Phase 3 RA 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-BEGIN compared BARI 4 mg monotherapy, BARI 4 mg plus MTX, and MTX monotherapy in patients who had limited or no prior treatment with MTX and were naïve to other DMARDs.5

  • RA-BEAM compared BARI 4 mg vs placebo or adalimumab, with background MTX, in patients with inadequate response to MTX.6 

  • RA-BUILD compared BARI 2 mg and 4 mg vs placebo, with background csDMARD therapy, in patients with inadequate response to csDMARDs.7

  • RA-BEACON compared BARI 2 mg and 4 mg vs placebo, with background csDMARD therapy, in patients with an inadequate response to at least one TNF inhibitor, who may also have had an inadequate response to one or more non-TNF inhibitor biologic DMARDs.8

Across the phase 3 studies, most treatment interruptions were due to AEs. Infections were the most common AEs leading to temporary interruptions with the majority being non-serious, mild, or moderate respiratory infections.4

A smaller proportion of treatment interruptions were due to abnormal laboratory results, with the most common being hepatic related.4


The duration of treatment interruption for each study and treatment group is provided in Figure 1.

Figure 1. Duration of Interruptions in the Rheumatoid Arthritis Phase 3 Trials4

Abbreviations: MTX = methotrexate; RA = rheumatoid arthritis.

Phase 3 clinical trials: A - RA-BEGIN, B - RA-BEAM, C - RA-BEACON, D - RA-BUILD
Notes:
Interruptions are based on daily tablet baricitinib study drug, including in non-baricitinib groups, which represent interruptions of the matching placebo for baricitinib.
Temporary interruption is defined as a temporary withholding of study drug that is followed by resumption of study drug during the study.

Study RA-BEGIN

RA-BEGIN included patients with limited or no prior treatment with DMARDs.5

Through 52 weeks of assigned treatment, the number of AEs leading to temporary interruption was

  • 36 in the MTX monotherapy group (N=210)

  • 14 in the BARI 4-mg monotherapy group (N=159), and

  • 53 in the BARI 4-mg plus MTX group (N=215).4

Study RA-BEAM

RA-BEAM included patients with an inadequate response to MTX.6

Through 24 weeks of assigned treatment, the number of AEs leading to temporary interruption was

  • 53 in the placebo group (N=488)

  • 28 in the adalimumab group (N=330), and

  • 57 in the BARI 4-mg group (N=487).4

Study RA-BUILD

RA-BUILD included patients with an inadequate response to conventional DMARDs.7

Through 24 weeks of assigned treatment, the number of AEs leading to temporary interruption was

  • 26 in the placebo group (N=228)

  • 19 in the BARI 2-mg group (N=229), and

  • 32 in the BARI 4-mg group (N=227).4

Study RA-BEACON

RA-BEACON included patients with an inadequate response to tumor necrosis factor inhibitors.8

Through 24 weeks of treatment assignment, the number of AEs leading to temporary interruption was

  • 15 in the placebo group (N=176)

  • 36 in the BARI 2-mg group (N=174), and

  • 38 in the BARI 4-mg group (N=177).4

Tolerability After Reinitiation of Treatment

Data was pooled from the 4 phase 3 clinical studies to assess whether initial tolerability effects persisted upon reinitiation of BARI treatment. A smaller proportion of patients reported adverse events during the first 4 weeks after resuming BARI treatment (25.2%) than during the first 4 weeks after initiating BARI treatment (50.3%).4

Treatment Response in Patients With and Without Treatment Interruption

Post hoc analysis were conducted using data from phase 3 studies RA-BEAM and RA-BUILD to evaluate changes in efficacy response in patients with and without interruptions in treatment.4

Changes in Measures of Disease Activity and Control

Measures of disease activity and control included

  • ACR20 and ACR50 response criteria, and

  • DAS28-hsCRP.4

The group of patients who experienced interruptions had similar overall responses by these measures compared with the group of patients without interruptions (Figure 2).4

Figure 2. Proportions of Patients Achieving Treatment Response With and Without Interruption of Treatment4

Abbreviations: ACR = American College of Rheumatology; ACR20 = ACR 20% response criteria; ACR50 = ACR 50% response criteria; DAS28-hsCRP = 28-joint Disease Activity Score based on high-sensitivity C-reactive protein.

Note: Based on an analysis of pooled data from RA-BEAM and RA-BUILD through 24 weeks with data up to rescue. DAS28-hsCRP ≤3.2 is a criterion of low diseases activity.

Changes in Patient Reported Rheumatoid Arthritis Symptoms

Patients evaluated for changes in RA symptoms

  • were randomized to assigned treatment at least 7 days prior to temporary interruption

  • had a treatment interruption of at least 3 days, and

  • were subsequently retreated.4

Patient reported RA symptoms collected daily over 12 weeks were

  • duration of morning joint stiffness

  • severity of morning joint stiffness

  • worst tiredness, and

  • worst joint pain.4

Modest patient reported symptom increases were observed both in the BARI and placebo groups compared with the last pre-interruption values. Symptoms improved following resumption of treatment and often returned to pre-interruption levels or better (Figure 3).4

Figure 3. Patient Reported Electronic Daily Diary Scores Before, During, and After Treatment Interruption 4

Abbreviations: NRS = numeric rating scale

Notes: Time profile of daily diary scores among csDMARD/MTX-IR patients who were retreated following interruptions.a Data presented are combined from RA-BEAM and RA-BUILD for duration of  A - morning joint stiffness, B - morning joint stiffness severity, C - worst joint pain, D - worst tiredness.
a
Excludes interruptions without at least 3 diary entries during interruption.
b
Average of values obtained within the first 3 days following randomization.
c
Average of up to 3 most recent values obtained in the 7 days prior to interruption.
d
Average of 3 most recent values in the last 7 days of the interruption.
e
Average of last 3 available values obtained following interruption and prior to any subsequent interruption or week 12 study visit.

Baricitinib Label Information Related to Treatment Interruption

Recommendations Regarding Baricitinib Treatment Interruption

If an infection develops, the patient should be monitored carefully and baricitinib therapy should be temporarily interrupted if the patient is not responding to standard therapy. Baricitinib treatment should not be resumed until the infection resolves.9

If a patient develops herpes zoster, baricitinib treatment should be temporarily interrupted until the episode resolves.9

Treatment should not be initiated, or should be temporarily interrupted, in patients with an

  • absolute neutrophil count (ANC) < 1 x 109 cells/L,

  • absolute lymphocyte count (ALC) < 0.5 x 109 cells/L or

  • haemoglobin < 8 g/dL

observed during routine patient management.9

If increases in ALT or AST are observed during routine patient management and drug-induced liver injury is suspected, baricitinib should be temporarily interrupted until this diagnosis is excluded.9

If clinical features of DVT/PE occur, baricitinib treatment should be discontinued and patients should be evaluated promptly, followed by appropriate treatment.9

Individuals of Reproductive Potential

The JAK/STAT pathway has been shown to be involved in cell adhesion and cell polarity which can affect early embryonic development.9

  • There are no adequate data from the use of baricitinib in pregnant women.

  • Studies in animals have shown reproductive toxicity.

  • Baricitinib was teratogenic in rats and rabbits.

  • Animal studies indicate that baricitinib may have an adverse effect on bone development in utero at higher dosages.9

Baricitinib is contraindicated during pregnancy. Women of childbearing potential have to use effective contraception during and for at least 1 week after treatment.9

If a patient becomes pregnant while taking baricitinib the parents should be informed of the potential risk to the foetus.9

Integrated Safety Analysis Dataset 

Table 3. Integrated Analysis Datasets Used to Evaluate Safety in Rheumatoid Arthritis Clinical Trials3,10,11

Analysis Set

Descriptiona

7-Study Placebo-Controlled Dataset

Studies: JADC, JADA, JADN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BALANCE

Compares BARI 4 mg vs placebo

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

  • BARI 4 mg (N=1142, [exposure through 24 weeks: PYE=471.8, median exposure=169 days, maximum exposure=211 days]), or

  • placebo (N=1215, [exposure through 24 weeks: PYE=450.8, median exposure=166 days, maximum exposure=235 days]).

Patients in the placebo group could have been taking

  • background MTX, or

  • in some studies, other conventional DMARD therapy.

Evaluation time periods included

  • through the 12-week placebo-controlled period in phase 2 studies

  • through 16 weeks of assigned treatment before any opportunity for rescue therapy in phase 3 studies, and

  • through 24 weeks of assigned treatment or until rescue in phase 3 studies.

BARI 2 mg Analysis Set

BARI 2 mg data is derived from 4 studies in which both BARI 2 mg (N=479, [exposure through 24 weeks: PYE=185.8, median exposure=168 days, maximum exposure=197 days]) and BARI 4 mg were options during randomization (JADA, JADN, RA-BUILD, RA-BEACON).

4-Study Extended Dataset

Studies: JADA, JADN, RA-BUILD, RA-BEACON, RA-BEYOND (extension)

Compares BARI 4 mg vs BARI 2 mg including extended evaluations

Includes patients with RA from 2 phase 2 and 2 phase 3 studies and any further exposure for those patients in the phase 3 extension study, RA-BEYOND, who were randomized to

  • BARI 4 mg (N=479, PYE=781.1, median exposure=342 days, maximum exposure=3085 days), or

  • BARI 2 mg (N=479, PYE=774.9, median exposure=257 days, maximum exposure=2370 days).

Evaluation time period included randomization through last available observation incorporating extension data through 01 September 2019 unless otherwise specified.

All BARI RA Dataset

Studies: JADB, JADC, JADA, JADN, RA-BEGIN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BALANCE, RA-BEYOND (extension)

No between-group comparisons

Includes patients with RA (N=3770, PYE=13,148, median exposure=4.2 yrs, maximum exposure=8.4 yrs) from 1 phase 1, 3 phase 2, 5 phase 3 studies, and 1 phase 3 extension study who received BARI at a variety of doses, including

  • BARI 4 mg (n=3400)

  • BARI 2 mg (n=1077), and

  • BARI 1 mg, 7 mg, 8 mg, and 10 mg QD doses not evaluated in confirmatory studies.

Patients had to have received at least 1 dose of BARI and could have received different doses throughout the trials.

Evaluation time period is all exposure time points including after rescue or changes in study drug through 01 September 2019 unless otherwise specified.

Abbreviations: BARI = baricitinib; DMARD = disease-modifying antirheumatic drug; MTX = methotrexate; PYE = patient-years of exposure; QD = once daily; RA = rheumatoid arthritis.

a Patients with renal function impairment who were randomized to BARI 4 mg, but treated with the 2-mg dose were analyzed in the BARI 4-mg group.

References

1. Fridman JS, Scherle PA, Collins R, et al. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. J Immunol. 2010;184(9):5298-5307. http://dx.doi.org/10.4049/jimmunol.0902819

2. Emery P, Tanaka Y, Cardillo TE, et al. Temporary interruptions of study drug during the baricitinib phase 3 rheumatoid arthritis program. Abstract presented at: European League Against Rheumatism (EULAR) Annual Meeting; June 14-17, 2017; Madrid, Spain. https://b-com.mci-group.com/Abstract/Statistics/AbstractStatisticsViewPage.aspx?AbstractID=349216

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

4. Emery P, Tanaka Y, Cardillo T, et al. Temporary interruption of baricitinib: characterization of interruptions and effect on clinical outcomes in patients with rheumatoid arthritis. Arthritis Res Ther. 2020;22(1):115. https://doi.org/10.1186/s13075-020-02199-8

5. 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

6. 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

7. 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 ]. Ann Rheum Dis. 2017;76(1):88-95. http://dx.doi.org/10.1136/annrheumdis-2016-210094

8. Genovese 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

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

10. Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 8.4 years: an updated integrated safety analysis [abstract]. Ann Rheum Dis. 2020;79(suppl 1):638. https://ard.bmj.com/content/79/Suppl_1/642.1

11. Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis over a median of 3 years of treatment: an updated integrated safety analysis. Lancet Rheumatol. 2020;2(6):E347-E357. https://doi.org/10.1016/S2665-9913(20)30032-1

Glossary

ACR20 = 20% improvement in American College of Rheumatology criteria

ACR50 = 50% improvement in American College of Rheumatology criteria

AE = adverse event

BARI = baricitinib

csDMARD = conventional synthetic disease-modifying antirheumatic drug

DAS28-hsCRP = Disease Activity Score based on high-sensitivity C-reactive protein

DMARD = disease-modifying antirheumatic drug

JAK = Janus kinase

MedDRA = Medical Dictionary for Regulatory Activities

MTX = methotrexate

RA = rheumatoid arthritis

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.

Datum fӧr senaste ӧversyn 2020 M06 17


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