Olumiant ® (baricitinib) tabletter

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Olumiant® ▼ (baricitinib): Patientrapporterade effekter på fysisk funktion

I Fas 3-studier av baricitinib bedömdes fysisk funktion med hjälp av Health Assessment Questionnaire-Disability Index (HAQ-DI).

Summary

  • Each of the 4 phase 3 studies of BARI assessed physical function using the HAQ-DI.

  • In the phase 3 studies, improvements in physical function as compared with placebo (MTX for RA-BEGIN) were

    • as early as 1 week for BARI 4 mg in RA-BEAM, RA-BUILD, RA-BEGIN, and RA-BEACON

    • as early as week 1 for BARI 2 mg in RA-BEACON

    • as early as week 8 for BARI 2 mg in RA-BUILD, and

    • at the primary endpoint in the BARI treatment groups (week 12 for RA-BEAM, RA-BUILD, and RA-BEACON; week 24 for RA-BEGIN).1-4

  • Post hoc descriptive analysis from RA-BEGIN and RA-BEAM evaluated the impact of disease control on normalization of physical functioning.5

  • Post hoc analysis from RA-BEAM and RA-BUILD evaluated if RA csDMARD-IR patients with MDA at baseline benefit from improved physical function with BARI treatment to the same extent as patients with HDA at baseline.6

  • Using MAIC methods, pain improvements were compared in patients treated with BARI, adalimumab, tocilizumab, and tofacitinib monotherapy from randomized, MTX-controlled trials in csDMARD or bDMARD-naïve RA patients.7

Physical Functioning Assessments in the Baricitinib Phase 3 Rheumatoid Arthritis Program

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.2

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

  • RA-BUILD compared BARI 2 mg and 4 mg vs placebo, with background csDMARD therapy, in patients with inadequate response to csDMARDs.1

  • 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.3

Each of the 4 phase 3 studies of BARI assessed physical function using the HAQ-DI.

The HAQ-DI consisted of 24 items under 8 domains including

  • dressing and grooming

  • arising

  • eating

  • walking

  • hygiene

  • reaching

  • grip, and

  • activities.8-10

Domain scores were averaged to calculate an index score ranging from 0 to 3, with lower scores reflecting better physical function. The HAQ-DI score changes were also assessed in the context of a MCID of 0.22.11-14

Early Improvements in Patient Reported Physical Function Maintained Over Time

In the phase 3 studies, improvements in physical function as compared with placebo (MTX for RA-BEGIN) were

  • as early as 1 week for BARI 4 mg in RA-BEAM, RA-BUILD, RA-BEGIN, and RA-BEACON

  • as early as week 1 for BARI 2 mg in RA-BEACON

  • as early as week 8 for BARI 2 mg in RA-BUILD, and

  • at the primary endpoint in the BARI treatment groups (week 12 for RA-BEAM, RA-BUILD, and RA-BEACON; week 24 for RA-BEGIN).1-4

These improvements were maintained throughout the duration of each of the studies Figure 1.

In RA-BEAM, compared with adalimumab, patients in the BARI 4-mg group had statistically significant improvements in HAQ-DI

  • as early as week 4

  • at the primary endpoint week 12, and

  • through the end of the 52-week study (panel B of Figure 1).14

Figure 1. Changes in HAQ-DI Over Time1-4

Abbreviations: HAQ-DI = Health Assessment Questionnaire-Disability Index; LS = least squares; MTX = methotrexate; RA = rheumatoid arthritis.

P value vs placebo (or MTX in RA-BEGIN):

* p≤.05.

** p≤.01.

*** p≤.001.

P value vs adalimumab:

+ p≤.05.

++ p≤.01.

+++ p≤.001.

Proportion of Patients Achieving Minimum Clinically Important Difference in Assessments of Physical Function

Compared to placebo (or MTX monotherapy in RA-BEGIN) significantly more patients in the BARI treatment groups (both doses BARI 4 mg and 2 mg in RA-BUILD and RA-BEACON) achieved an MCID of 0.22 in the HAQ-DI assessment

  • at the primary endpoint week 12 in RA-BEAM, RA-BUILD, and RA-BEACON

  • at the primary endpoint week 24 in RA-BEGIN, and through the end of the 24-week controlled study period for RA-BEAM, RA-BUILD, and RA-BEACON, and

  • through the end of the 52-week study in RA-BEGIN and RA-BEAM.1-4

Compared to adalimumab significantly more patients treated with BARI 4 mg achieved an MCID of 0.22 in the HAQ-DI assessment at week 24 and 52.4

See Figure 2 for HAQ-DI MCID details through week 52 for RA-BEAM and RA-BEGIN and through week 24 for RA-BUILD and RA-BEACON.

Figure 2. HAQ-DI Minimum Clinically Important Difference: Percentage of Patients Achieving Improvement of ≥0.221-4

Abbreviations: BARI = baricitinib; HAQ-DI = Health Assessment Questionnaire-Disability Index; MCID = minimum clinically important difference; MTX = methotrexate; RA = rheumatoid arthritis.
P value vs placebo (or MTX in RA-BEGIN):

* p≤.05.

** p≤.01.

*** p≤.001.

P value vs adalimumab:

+ p≤.05.

++ p≤.01.

Number Needed to Treat for a Clinically Meaningful Difference in Physical Function

Post hoc analysis of RA-BEAM and RA-BEACON were conducted to determine the NNT to report improvements greater than or equal to the MCIDs in multiple PROs.15 

The percentages of patients reporting improvements ≥MCID for HAQ-DI were determined at week 12 and the NNTs were calculated as 1/difference in response (MCID) rates between BARI 4 mg or BARI 2 mg and placebo at week 12. Number needed to treat ≤10 vs placebo are considered clinically meaningful.15

In RA-BEAM and RA-BEACON patients there were clinically meaningful improvements in PROs, such as HAQ-DI, after treatment with BARI

  • The clinically meaningful definition of physical function improvement as measured by HAQ-DI was MCID ≥0.22 points.

  • These analyses indicate that <10 patients need to be treated with BARI 4 mg or BARI 2 mg to have clinically meaningful benefits.

  • The NNT for physical funcation (HAQ-DI) in

    • RA-BEAM was 6.0 (95% CI of 4.5 - 9.3) for BARI 4 mg, and

    • RA-BEACON was 6.2 (95% CI of 3.8 - 17.6) and 4.2 (95% CI of 2.9-7.2) for BARI 2 mg and 4 mg respectively.15

Control of Disease Activity May Impact Normalization of Physical Functioning

Post hoc descriptive analysis from RA-BEGIN and RA-BEAM evaluated the impact of disease control on normalization of physical functioning.5

Evaluation Parameters

The 1228 patients evaluated from RA-BEAM included groups were administered

  • placebo plus MTX (n=448)

  • adalimumab plus MTX (n=309), and

  • BARI 4 mg plus MTX (n=471).5

The 543 patients evaluated from RA-BEGIN included groups were administered

  • MTX monotherapy (n=190)

  • BARI 4 mg monotherapy (n=156), and

  • BARI 4 mg plus MTX (n=197).5

Clinical disease activity index scores categorized disease control as

  • remission, defined as CDAI ≤2.8

  • low disease activity or CDAI >2.8 to ≤10

  • moderate disease activity or CDAI >10 to ≤22, and

  • high disease activity or CDAI >22.5

Normalization of physical function was defined as a HAQ-DI score of <0.5.5

Last observation carried forward was used to impute missing HAQ-DI values.5

RA-BEAM Analyses

Among patients who were administered adalimumab plus MTX and then achieved remission, normal physical function was reported in

  • 73% (16/22) at week 12, and

  • 69% (27/39) at week 24.5

Among patients who were administered BARI 4 mg plus MTX and then achieved remission, normal physical function was reported in

  • 65% (26/40) at week 12, and

  • 73% (55/75) at week 24.5

RA-BEGIN Analyses

Among patients who were administered MTX monotherapy and then achieved remission, normal physical function was reported in

  • 79% (11/14) at week 12, and

  • 82% (18/22) at week 24.5

Among patients who were administered BARI 4 mg monotherapy and then achieved remission, normal physical function was reported in

  • 91% (20/22) at week 12, and

  • 82% (28/34) at week 24.5

Among patients who were administered BARI 4 mg plus MTX and then achieved remission, normal physical function was reported in

  • 77% (30/39) at week 12, and

  • 91% (42/46) at week 24.5

Improvement in Physical Function in csDMARD-IR Patients With Moderate Disease Activity at Baseline

Post hoc analysis from RA-BEAM and RA-BUILD evaluated if RA csDMARD-IR patients with MDA at baseline benefit from improved physical function with BARI treatment to the same extent as patients with HDA at baseline.6

Evaluation Parameters

The patients evaluated from RA-BEAM included groups were administered

  • placebo plus MTX (n=390)

  • adalimumab plus MTX (n=270), and

  • BARI 4 mg plus MTX (n=396).6

The patients evaluated from RA-BUILD included groups were administered

  • placebo (n=185)

  • BARI 2 mg (n=186), and

  • BARI 4 mg (n=189).6

Patient analyses were from the modified intention-to-treat populations from RA-BEAM and RA-BUILD with

  • moderate to severe disability (HAQ-DI score ≥1)

  • non-missing SDAI data at baseline, and

  • all patients fulfilled ACR criteria for RA.6

Patient analyses were from the modified intention-to-treat populations from RA-BEAM and RA-BUILD with either

  • MDA (baseline SDAI score 11.1-26.0), or

  • HDA (baseline SDAI score >26.0).6

Baseline Mean Adjusted Health Assessment Questionnaire-Disability Index Scores

At baseline, mean adjusted HAQ-DI scores were greater in patients with HDA than in those with MDA; see Figure 3.6

Figure 3. Baseline Mean Adjusted HAQ-DI Scores in Patients From RA-BEAM and RA-BUILD With MDA or HDA6

Abbreviations: HAQ-DI = Health Assessment Questionnaire-Disability Index; HDA = high disease activity; MDA = moderate disease activity; MLR = multivariable linear regression; RA = rheumatoid arthritis.

Data presented for patients with HAQ-DI ≥1 and non-missing data after MLR. Patient numbers do not match those presented in text due to some missing data for the baseline covariates used in the MLR.

RA-BEAM

Physical function was improved at week 24 with BARI 4 mg treatment compared to placebo in patients with either MDA (p=.001) or HDA (p<.001) at baseline Figure 4.6

Figure 4. Mean Adjusted HAQ-DI at Week 24 in Patients From RA-BEAM With MDA and HDA at Baseline6

Abbreviations: HAQ-DI = Health Assessment Questionnaire-Disability Index; HDA = high disease activity; MDA = moderate disease activity; MLR = multivariable linear regression; RA = rheumatoid arthritis; Δ = difference in HAQ-DI score.

Data presented for patients with HAQ-DI ≥1 and non-missing data after MLR. Patient numbers do not match those presented in text due to some missing data for the baseline covariates used in the MLR.

RA-BUILD

The adjusted mean difference in HAQ-DI score between placebo and BARI 4 mg (.263) was not statistically significant (p=.109) in patients with MDA at baseline. Physical function was improved (.443 points) at week 24 with BARI 4 mg treatment compared to placebo in patients with HDA (p<.001) at baseline in RA-BUILD.

Figure 5. Mean Adjusted HAQ-DI at Week 24 in Patients From RA-BUILD With Either MDA or HDA at Baseline6

Abbreviations: HAQ-DI = Health Assessment Questionnaire-Disability Index; HDA = high disease activity; MDA = moderate disease activity; MLR = multivariable linear regression; RA = rheumatoid arthritis; Δ = difference in HAQ-DI score.

Data presented for patients with HAQ-DI ≥1 and non-missing data after MLR. Patient numbers do not match those presented in text due to some missing data for the baseline covariates used in the MLR.

Comparative Effectiveness of Baricitinib Monotherapy, Adalimumab, Tocilizumab, and Tofacitinib on Pain and Physical Function

Using MAIC methods, pain improvements were compared in patients treated with BARI, adalimumab, tocilizumab, and tofacitinib monotherapy from randomized, MTX-controlled trials in csDMARD or bDMARD-naïve RA patients.7

There was improved physical function (HAQ-DI) for BARI monotherapy compared with tocilizumab (p≤.01) and adalimumab (p≤.001) monotherapy at 6 months (see Figure 6). No statistically significant differences in improved physical function were observed between BARI and tofacitinib with the MAIC analyses (see Figure 6).7

Figure 6. Indirect Comparisons of BARI Monotherapy (RA-BEGIN), Adalimumab, Tocilizumab and Tofacitinib on Physical Function (HAQ-DI) With Matching by Treatment, Study, and Without Matching7

Abbreviations: BARI = baricitinib; ESS = effective sample size; HAQ-DI=Health Assessment Questionnaire-Disability Index; MTX=methotrexate; RA = rheumatoid arthritis; VAS=visual analogue scale.

N is the sum of both active arm and MTX arm.

Effective sample size (HAQ-DI) after re-weighing of total N=369 (BARI, n=159 MTX, n=210)

* p≤.05 vs placebo.
** p≤.01 vs placebo.
*** p≤.001 vs placebo.

Information from the label

Treatment with baricitinib 4 mg, alone or in combination with cDMARDs, resulted in significant improvements in all individual ACR components, including tender and swollen joint counts, patient and physician global assessments, HAQ-DI, pain assessment and CRP, compared to placebo or MTX monotherapy. In RA-BEAM, treatment with baricitinib resulted in significant improvement in patient and physician global assessments, HAQ-DI, pain assessment and CRP at Weeks 12, 24 and 52 compared to adalimumab.16

Treatment with baricitinib 4 mg, alone or in combination with cDMARDs, resulted in a significant improvement in physical function compared to all comparators (placebo, MTX, adalimumab), as measured by HAQ-DI, at 12, 24 and 52 weeks. The proportion of patients achieving a clinically significant improvement (HAQ-DI ≥ 0.30) was also higher with baricitinib compared to placebo or MTX at week 12. Improvements were seen as early as Week 1 and, in studies RA-BEGIN and RA-BEAM, this was maintained for up to 52 weeks.16

Treatment with baricitinib 4 mg, alone or in combination with cDMARDs, resulted in a significant improvement in pain compared to all comparators (placebo, MTX, adalimumab), as measured on a 0-100 visual analogue scale, at 12 weeks. Statistically significant pain reduction was seen as early as Week 1 and in studies RA-BEGIN and RA-BEAM this was maintained for up to 52 weeks.16

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

2. 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

3. 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

4. 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

5. de Vlam K, Fautrel B, van de Laar M, et al. Impact of controlling disease activity on regaining normal physical function, and achieving no or limited pain in patients with rheumatoid arthritis treated with baricitinib. Poster presented at: European League Against Rheumatism (EULAR) Annual Meeting; June 13-16, 2018; Amsterdam, Netherlands. http://scientific.sparx-ip.net/archiveeular/index.cfm?searchfor=baricitinib&c=a&view=1&item=2018AB0258

6. Kirkham B, Nikiphorou E, López-Romero P, et al. Effect of baricitinib on functional impairment in RA patients with moderate disease activity and an inadequate response to conventional DMARDs [abstract]. Arthritis Rheumatol. 2019;71(suppl 10). https://acrabstracts.org/abstract/effect-of-baricitinib-on-functional-impairment-in-ra-patients-with-moderate-disease-activity-and-an-inadequate-response-to-conventional-dmards/

7. Fautrel B, Zhu B, Taylor PC, et al. Comparative effectiveness of improvement in pain and physical function for baricitinib versus adalimumab, tocilizumab and tofacitinib monotherapies in rheumatoid arthritis patients who are naïve to treatment with biologic or conventional synthetic disease-modifying antirheumatic drugs: a matching-adjusted indirect comparison. RMD Open. 2020;6(1). http://dx.doi.org/10.1136/rmdopen-2019-001131

8. Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis Rheumatol. 1980;23(2):137-145. http://dx.doi.org/10.1002/art.1780230202

9. Ramey DR, Fries JF, Singh G. The Health Assessment Questionnaire 1995: status and review. In: Spiker B, editor. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd ed. Philadelphia, Pa: Lippincott-Raven; 1996:227-237. https://www.niehs.nih.gov/research/resources/assets/docs/haq_instructions_508.pdf

10. Bruce B, Fries JF. The Health Assessment Questionnaire (HAQ). Clin Exp Rheumatol. 2005;23(suppl 39):14-18. http://www.clinexprheumatol.org/article.asp?a=2681

11. Emery P, Blanco R, Maldonado Cocco J, et al. Patient-reported outcomes from a phase III study of baricitinib in patients with conventional synthetic DMARD-refractory rheumatoid arthritis. RMD Open. 2017;3(1):e000410. http://dx.doi.org/10.1136/rmdopen-2016-000410

12. Schiff M, Takeuchi T, Fleischmann R, et al. Patient-reported outcomes of baricitinib in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Res Ther. 2017;19(1):208. https://doi.org/10.1186/s13075-017-1410-1

13. Smolen JS, Kremer JM, Gaich CL, et al. Patient-reported outcomes from a randomised phase III study of baricitinib in patients with rheumatoid arthritis and an inadequate response to biological agents (RA-BEACON). Ann Rheum Dis. 2017;76(4):694-700. http://dx.doi.org/10.1136/annrheumdis-2016-209821

14. Keystone EC, Taylor PC, Tanaka Y, et al. Patient-reported outcomes from a phase 3 study of baricitinib versus placebo or adalimumab in rheumatoid arthritis: Secondary analyses from the RA-BEAM study. Ann Rheum Dis. 2017;76(11):1853-1861. http://dx.doi.org/10.1136/annrheumdis-2017-211259

15. Strand V, Sun L, Ross Terres J et al. Number needed to treat to achieve minimum clinically significant differences in patient-reported outcomes in patients treated with baricitinib [abstract]. Ann Rheum Dis. 2020;79(suppl 1):595. http://scientific.sparx-ip.net/archiveeular/?searchfor=baricitinib&c=a&view=1&item=2020FRI0048

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

Glossary

ACR = American College of Rheumatology

BARI = baricitinib

CDAI = Clinical Disease Activity Index

csDMARD = conventional synthetic disease-modifying antirheumatic drug

csDMARD-IR = inadequate response or intolerant to csDMARD treatment

DMARD = disease-modifying antirheumatic drug

HAQ-DI = Health Assessment Questionnaire-Disability Index

HDA = high disease activity

MAIC = matching-adjusted indirect comparison

MCID = minimum clinically important difference

MDA = Moderate Disease Activity

MTX = methotrexate

NNT = number needed to treat

PRO(s) = patient-reported outcome(s)

RA = rheumatoid arthritis

SDAI = Simplified Disease Activity Index

TNF = tumor necrosis factor

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 M05 13


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