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).

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.1

Health Assessment Questionnaire-Disability Index

Phase 3 studies of baricitinib assessed physical function using the HAQ-DI.

Please refer to Table 1 for a summary of study design features and baseline patient characteristics in each phase 3 study.

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

  • dressing and grooming

  • arising

  • eating

  • walking

  • hygiene

  • reaching

  • grip, and

  • activities.2-4

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 0.22.5-8

Early Improvements in Patient-Reported Physical Function Maintained Over Time

Study RA-BEGIN

Study RA-BEGIN evaluated patients who

  • had limited or no prior treatment with MTX, and

  • were naïve to other DMARDs.9

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.1

Health Assessment Questionnaire-Disability Index

Compared with MTX monotherapy, patients in the BARI 4-mg monotherapy and the BARI 4 mg plus MTX groups had statistically significant improvements in HAQ-DI

  • as early as week 1

  • at the primary endpoint week 24, and

  • through the end of the 52-week study period (panel A of Figure 1).7

At the primary endpoint week 24, the proportion of patients achieving an MCID of 0.22 was

  • 70% for MTX monotherapy

  • 81% for BARI monotherapy (p≤.05 vs MTX), and

  • 79% for BARI plus MTX (p≤.05 vs MTX).9

See panel A of Figure 2for HAQ-DI MCID details through week 52.

Study RA-BEAM

Study RA-BEAM evaluated patients with inadequate response to MTX. The majority of patients had previously received at least 2 csDMARDs. Patients received stable background MTX during the study.10

Health Assessment Questionnaire-Disability Index

Compared with placebo, patients in the BARI 4-mg group had statistically significant improvements in HAQ-DI

  • as early as week 1

  • at the primary endpoint week 12, and

  • through the end of the 24-week controlled study period (panel B of Figure 1).6

Compared with ADA, 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).6

At the primary endpoint week 12, the proportion of patients achieving an MCID of 0.22 was

  • 58% for placebo

  • 75% for BARI 4 mg (p≤.001 vs placebo; not significant vs ADA), and

  • 71% for ADA (p≤.001 vs placebo).10

See panel B of Figure 2for HAQ-DI MCID details through week 52.

Study RA-BUILD

Study RA-BUILD evaluated patients with inadequate response to csDMARDs. Of the patients randomized to BARI or placebo,

  • 49% received stable background MTX alone

  • 23% received combination with an additional csDMARD

  • 16% received a single concomitant non-MTX csDMARD, and

  • 7% received no concomitant csDMARD.11

Health Assessment Questionnaire-Disability Index

Compared with placebo, patients in the BARI 4-mg and 2-mg groups had statistically significant improvements in HAQ-DI

  • as early as week 1 for BARI 4 mg

  • as early as week 8 for BARI 2 mg

  • at the primary endpoint week 12 for both doses, and

  • through the end of the 24-week study for both doses (panel C of Figure 1).5

At the primary endpoint week 12, the proportion of patients achieving an MCID of 0.22 was

  • 54% for placebo

  • 69% for BARI 2 mg (p≤.001 vs placebo), and

  • 64% for BARI 4 mg (p≤.05 vs placebo).11

See panel C  of Figure 2for HAQ-DI MCID details through week 24.

Study RA-BEACON

Study RA-BEACON evaluated patients

  • with treatment refractory RA, and

  • an inadequate response to 1 or more TNF inhibitors.12

These patients were previously treated with 1 (42%), 2 (30%), or ≥3 (27%) bDMARDs; 38% had also received at least 1 bDMARD that was not a TNF inhibitor. Concomitant administration of background csDMARDs was required during the study.12

Health Assessment Questionnaire-Disability Index

Compared with placebo, patients in the BARI 4-mg and 2-mg groups had statistically significant improvements in HAQ-DI

  • as early as week 1 for both doses

  • at the primary endpoint week 12 for both doses, and

  • through the end of the 24-week study for both doses (panel D of Figure 1).8

At the primary endpoint week 12, the proportion of patients achieving an MCID of 0.22 was

  • 43% for placebo

  • 59% for BARI 2 mg (p≤.01 vs placebo), and

  • 67% for BARI 4 mg (p≤.001 vs placebo).12

See panel D of Figure 2for HAQ-DI MCID details through week 24.

Control of Disease Activity May Impact Normalization of Physical Functioning

Post hoc descriptive analyses from RA-BEAM and RA-BEGIN evaluated the impact of disease control on normalization of physical functioning.13

Evaluation Parameters

The 1228 patients evaluated from RA-BEAM included groups administered

  • placebo plus MTX (n=448)

  • ADA plus MTX (n=309), and

  • BARI 4 mg plus MTX (n=471).13

The 543 patients evaluated from RA-BEGIN included groups administered

  • MTX monotherapy (n=190)

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

  • BARI 4 mg plus MTX (n=197).13

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 >22.13

Normalization of physical function was defined as a HAQ-DI score of <0.5.13

Last observation carried forward was used to impute missing HAQ-DI values.13

RA-BEAM Analyses

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

  • 73% (16/22) at week 12, and

  • 69% (27/39) at week 24.13

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 24.13

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 24.13

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 24.13

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 24.13

Table 1. Study Design Features and Baseline Patient Characteristics9-12,14

STUDY DESIGN

RA-BEGIN
(N=584)

RA-BEAM
(N=1305)

RA-BUILD
(N=684)

RA-BEACON
(N=527)

Patient Type

DMARD naïve

MTX IR

csDMARD IR

TNFi IR

Background DMARDs

None

MTX

cDMARD(s) allowed but not required

cDMARD(s)

TJC and SJC Entry Criteria

6 TJC, ≥6 SJC

hsCRP Entry Criteria

3.6 mg/L

6.0 mg/L

3.6 mg/L

3.0 mg/L

Joint Erosion/RF/ACPA Entry Criteria

Either RF or ACPA+

3 erosions or 1-2 erosions if RF/ACPA+

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, mean (SD) years

49.9 (13)

53.3 (12)

51.8 (12)

55.7 (11)

Female, n (%)

425 (73)

1008 (77)

560 (82)

431 (82)

RA Duration Since Symptom Onset, mean (SD) years

2.6 (5)

10.1 (9)

7.5 (8)

14.0 (9)

ACPA + (>10 U/ml), n (%)

527 (90)

1146 (88)

504 (74)

368 (70)

RF + (>14 IU/ml), n (%)

562 (96)

1191 (91)

521 (76)

386 (73)

1 joint erosion, n (%)

380 (65)

NRa

502 (74)

NR

Prior csDMARD, 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)

27 (15)

23 (13)

24 (14)

29 (16)

SJC (66), mean (SD)

16 (10)

15 (9)

13 (8)

17 (11)

ESR (mm/h), mean (SD)

52 (27)

49 (26)

43 (24)

47 (25)

hsCRP (mg/L), mean (SD)

24 (26)

21 (22)

17 (19)

20 (24)

DAS28-ESR, mean (SD)

6.6 (1.0)

6.4 (1.0)

6.2 (1.0)

6.6 (1.0)

DAS28-hsCRP, mean (SD)

5.9 (1.0)

5.7 (0.9)

5.6 (0.9)

5.9 (1.0)

Abbreviations: ACPA = anti-citrullinated peptide antibody; ACR20 = ACR 20% response criteria; csDMARD = conventional 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.

a Per 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.

Figure 1. Changes in HAQ-DI Over Time9-12

Abbreviations: HAQ-DI = Health Assessment Questionnaire-Disability Index; LS = least squares; MTX = methotrexate.
P value vs placebo (or MTX in RA-BEGIN): *** p≤.001, ** p≤.01, * p≤.05.
P value vs adalimumab: +++ p≤.001, ++ p≤.01, + p≤.05.

Figure 2. HAQ-DI Minimum Clinically Important Difference: Percentage of Patients Achieving Improvement of ≥0.229-12

Abbreviations: BARI = baricitinib; HAQ-DI = Health Assessment Questionnaire-Disability Index; MCID = minimum clinically important difference; MTX = methotrexate.
P value vs placebo (or MTX in RA-BEGIN): *** p≤.001, ** p≤.01, * p≤.05.
P value vs adalimumab: ++ p≤.01, + p≤.05.

References

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

2. 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

3. 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

4. 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

5. 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

6. 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; [epub ahead of print]. http://dx.doi.org/10.1136/annrheumdis-2017-211259

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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. Abstract 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

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

Glossary

ADA = adalimumab

BARI = baricitinib

bDMARD = biologic disease-modifying antirheumatic drug

CDAI = Clinical Disease Activity Index

csDMARD = conventional synthetic disease-modifying antirheumatic drug

DMARD = disease-modifying antirheumatic drug

HAQ-DI = Health Assessment Questionnaire-Disability Index

MCID = minimum clinically important difference

MTX = methotrexate

RA = rheumatoid arthritis

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 2018 M02 23


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