RA-BEAM
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Estudio primario

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A Study in Moderate to Severe Rheumatoid Arthritis

Registro de estudios clinicaltrials.gov
Año 2012
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The purpose of this study is to determine whether baricitinib is superior to placebo in the treatment of participants with moderately to severely active Rheumatoid Arthritis (RA) who have had an inadequate response to methotrexate (MTX) treatment.

Estudio primario

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A Phase 3 Study in Moderate to Severe Rheumatoid Arthritis

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Registro de estudios EU Clinical Trials Register
Año 2012
Enlaces EUCTR - HU EUCTR - GR EUCTR - BE EUCTR - LV EUCTR - GB EUCTR - DE EUCTR - PT EUCTR - CZ EUCTR - NL EUCTR - LT EUCTR - SK EUCTR - ES EUCTR - SI
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INTERVENTION: Product Name: baricitinib Product Code: LY3009104 Pharmaceutical Form: Tablet Current Sponsor code: LY3009104 Other descriptive name: baricitinib Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 4‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use Product Name: baricitinib Product Code: LY3009104 Pharmaceutical Form: Tablet Current Sponsor code: LY3009104 Other descriptive name: baricitinib Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 2‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use Trade Name: Humira Pharmaceutical Form: Solution for injection INN or Proposed INN: ADALIMUMAB CAS Number: 331731‐18‐1 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 40/0.8‐ Pharmaceutical form of the placebo: Solution for injection Route of administration of the placebo: Subcutaneous use CONDITION: Moderately to severely active rheumatoid arthritis ; MedDRA version: 14.1 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 ‐ Musculoskeletal and connective tissue disorders Therapeutic area: Diseases [C] ‐ Musculoskeletal Diseases [C05] PRIMARY OUTCOME: Main Objective: Determine whether baricitinib is superior to placebo in the treatment of patients with moderately to severely active RA despite MTX treatment (i.e., MTX IR), as assessed by the proportion of patients achieving ACR20 at Week 12. Primary end point(s): Proportion of patients achieving ACR20 response compared to placebo . Secondary Objective: • change from baseline to Week 24 in structural joint damage as measured by modified Total Sharp Score (mTSS [van der Heijde method]) compared to placebo; • change from baseline to Week 12 in Health Assessment Questionnaire‐Disability Index (HAQ‐DI) score compared to placebo; • change from baseline to Week 12 in DAS28‐high‐sensitivity C‐reactive protein (hsCRP) compared to placebo; • proportion of patients achieving an SDAI score =3.3 at week 12; • proportion of patients achieving ACR20 response at Week 12 compared to adalimumab ; • proportion of patients achieving DAS28‐hsCRP =3.2 and DAS28‐hsCRP <2.6 at Week 12, Week 24, and Week 52; • change from baseline to Week 16 and Week 52 in structural joint damage as measured by mTSS; • proportion of patients achieving DAS28‐ESR =3.2 and DAS28‐ESR <2.6 at Week 12, Week 24, and Week 52; Timepoint(s) of evaluation of this end point: Change from baseline to Week 12. SECONDARY OUTCOME: Secondary end point(s): ‐ Modified Total Sharp Score (mTSS [van der Heijde method]) ; ‐ Health Assessment Questionnaire Disability Index (HAQ‐DI) ; ‐ DAS28‐high‐sensitivity C‐reactive protein (hsCRP) ; ‐ Proportion of patients achieving ACR50 and ACR70 response ; ‐ proportion of patients achieving DAS28‐hsCRP =3.2; proportion of patients achieving DAS28‐ hsCRP <2.6 ; ‐ proportion of patients achieving ACR20 response compared to adalimumab ; ‐ proportion of patients achieving DAS28‐ESR =3.2; proportion of patients achieving DAS28‐ESR <2.6 Timepoint(s) of evaluation of this end point: ‐ Modified Total Sharp Score (mTSS [van der Heijde method]): Change from baseline to Week 24 and 52 ; ‐ Health Assessment Questionnaire Disability Index (HAQ‐DI): Change from baseline to Week 12 ; ‐ DAS28‐high‐sensitivity C‐reactive protein (hsCRP): Change from baseline to Week 12 ; ‐ Proportion of patients achieving ACR50 and ACR70 response: Change from baseline to Week 12, 24 and 52 ; ‐ proportion of patients achieving DAS28‐hsCRP =3.2; proportion of patients achieving DAS28‐ hsCRP <2.6: Weeks 12, 24 and 52 ; ‐ proportion of patients achieving ACR20 response compared to adalimumab: Weeks 12 ; ‐ proportion of patients achieving DAS28‐ESR =3.2; proportion of patients achieving DAS28‐ESR <2.6: Weeks 12, 24 and 52 INCLUSION CRITERIA: • are at least 18 years of age • have a diagnosis of adult‐onset RA as defined by the ACR/EULAR 2010 Criteria for the Classification of RA • have moderately to severely active RA defined as the presence of at least 6/68 tender joints and at least 6/66 swollen joints • have a C‐reactive protein (CRP) (or hsCRP) measurement =6 mg/L • have had regular use of MTX for at least the 12 weeks prior to study entry at a dose that is considered acceptable to adequately assess clinical response. • have at least 1 joint erosion in hand, wrist, or foot joints based on radiographic interpretation by the central reader and be rheumatoid factor or anticyclic citrullinated peptide (anti‐CCP) antibody positive; or have at least 3 joint erosions in hand, wrist, or foot joints based on radiographic interpretation by the central reader regardless of rheumatoid factor or anti‐CCP antibody status Are the trial subjects under 18? no Number of subjects

Estudio primario

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Effects of baricitinib on multibiomarker disease activity scores and their components in a phase 2b study in moderate-to-severe rheumatoid arthritis patients

Revista Annals of the Rheumatic Diseases
Año 2015
Enlaces DOI www.cochranelibrary.com
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Background: Baricitinib, an oral inhibitor of JAK1 and JAK2 signaling, improved the signs and symptoms in patients with active rheumatoid arthritis (RA) who were methotrexate inadequate responders (MTX-IR) in a double-blind, placebo (PBO) controlled study1. Objectives: To investigate how a quantitative, multibiomarker disease activity score (MBDA) and its individual components are affected by treatment with baricitinib 4 mg (n=50) once daily compared to PBO (n=79) during a 12 week treatment period in moderate-to-severe RA patients. Methods: Serum samples collected at baseline andWeeks 4 and 12 from patients in the study1 were shipped frozen to Crescendo Biosciences for analysis2. MBDA scores and changes in individual MBDA components were subjected to post-hoc statistical analyses. Results: At baseline, the proportion of patients with low, moderate, and high MBDA scores were similar in the 2 groups, as were median MBDA scores (PBO=44 vs. baricitinib 4 mg=47). Unlike PBO-treated patients, baricitinib 4 mg patients had decreased MBDA scores at 4 and 12 weeks compared to baseline (baricitinib 4 mg =35.5 and 37.0 (p<0.001) vs. PBO=46.0 and 45.0, respectively). At both 4 and 12 weeks of treatment and compared to PBO, baricitinib-treated patients had significant decreases in MBDA components including C-Reactive Protein (CRP), Matrix metalloproteinase (MMP)-3, serum amyloid A (SAA), soluble TNF receptor (TNF-RI), VCAM-1, and YKL-40 (human cartilage glycoprotein 39). Compared to PBO, there were no significant (p>0.05) changes for baricitinib-treated patients at either timepoint for epidermal growth factor (EGF), MMP-1, or vascular endothelial growth factor-A (VEGF-A). For baricitinib-treated patients versus PBO, at 4 but not 12 weeks, Interleukin-6 (IL-6) and resistin were significantly decreased and at 12 but not 4 weeks, leptin was significantly increased. Conclusions: Consistent with other indices of disease activity1, the treatment of MTX-IR patients with baricitinib 4 mg once daily resulted in a reduction in the MBDA scores, apparent by 4 weeks. Decreases in MBDA scores and the components were present at both 4 and 12 weeks. Reduction in the levels of inflammatory markers beyond those associated with an acute phase response is apparent in these patients.

Estudio primario

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Baricitinib versus placebo or adalimumab in patients with active rheumatoid arthritis (RA) and an Appendix B – details of included studies 27 inadequate response to background methotrexate therapy: Results of a phase 3 study.

Revista Arthritis and Rheumatology Conference: American College of Rheumatology/Association of Rheumatology Health Professionals Annual Scientific Meeting, ACR/ARHP
Año 2015
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Estudio primario

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Baricitinib Versus Placebo or Adalimumab in Patients with Active Rheumatoid Arthritis (RA) and an Inadequate Response to Background Methotrexate Therapy: Results of a Phase 3 Study

Conferencia Arthritis & Rheumatology
Año 2015
Enlaces acrabstracts.org
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BACKGROUND/PURPOSE: In phase 3 studies, baricitinib (bari) improved disease activity in patients (pts) with active RA and an inadequate response (IR) to conventional synthetic DMARDs1 or biologic DMARDs2. This abstract reports the 24-wk results from a 52-wk, global, phase 3, double-blind, placebo (PBO) and active-controlled study of bari in MTX-IR RA pts. METHODS: Pts with active RA (TJC≥6 & SJC≥6 & hsCRP≥6 mg/L) despite stable background MTX were randomized 3:3:2 to PBO, bari 4 mg once daily (QD), or adalimumab (ADA) 40 mg biweekly (Q2W), stratified by region and baseline joint erosion status. Non-responders were rescued from Wk 16. At Wk 24, pts on PBO switched to bari 4 mg QD. The primary endpoint was ACR20 response at Wk 12 for bari vs. PBO. Major secondary endpoints included comparisons of bari vs. ADA for ACR20 and change in DAS28-CRP at Wk 12. RESULTS: Of 1305 randomized pts, 89%, 94% and 93% completed Wk 24 in PBO, bari and ADA groups, respectively. Rescue rates were 26%, 7% and 12% for PBO, bari and ADA, respectively. ACR20 response at Wk 12 was higher for bari vs. PBO (70% vs. 40%, p≤.001 – Table 1). At Wks 12 and 24, statistically significant improvements in ACR 20/50/70 & HAQ-DI response rates, and DAS28, CDAI, and SDAI low disease activity and remission rates were seen for bari vs. PBO, many as early as Wk 1. Compared to ADA, bari was superior with respect to measures including ACR20 response and improvement in DAS28-CRP at Wk 12. Compared to PBO, daily diary measures of morning joint stiffness (MJS) duration and severity, worst tiredness, and worst joint pain were significantly improved in pts receiving bari, from as early as Wk 1. Rates of treatment-emergent adverse events (TEAEs), including infections, were higher for bari and ADA compared to PBO (Table 2). Compared to PBO, serious adverse events (SAE) rates were similar for bari and lower for ADA; serious infection rates were similar across groups. Two deaths occurred (bari), 1 pneumonia and 1 duodenal ulcer haemorrhage. Five malignancies were reported, 2 bari and 3 PBO. Three potential opportunistic infections occurred, 2 bari and 1 PBO; none were SAEs. One case of tuberculosis occurred (ADA). There were no GI perforations. Lab abnormalities were consistent with other phase 3 studies1,2; few led to discontinuation. CONCLUSION: In pts with active RA despite background MTX, once-daily oral bari was associated with significant clinical improvements compared to PBO and to ADA, with an acceptable safety and tolerability profile.

Estudio primario

No clasificado

Characterisation of changes in lymphocyte subsets in baricitinib-treated patients with rheumatoid arthritis in two phase 3 studies

Revista Annals of the Rheumatic Diseases
Año 2016
Enlaces DOI www.cochranelibrary.com
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Background and objectives Baricitinib is an oral, reversible inhibitor of Janus kinase (JAK)1/JAK2 being developed as treatment for patients with RA. Previous studies have shown transient increases in total lymphocyte count within hours of dosing and return to baseline prior to the next dose. We examined changes over time in lymphocyte subsets in RA patients treated with baricitinib or placebo in the phase 3 RA-BUILD and RA-BEACON studies. Materials and methods Patients had active RA with insufficient response (IR) to conventional synthetic DMARDs (csDMARDs) (RA-BUILD; N=684) or TNF inhibitors (TNFi) (RA-BEACON; N=527). Patients were randomised 1:1:1 to placebo or 2 or 4mg baricitinib QD for 24 weeks. Lymphocyte subsets and natural killer (NK) cells were quantified by flow cytometry at baseline and Week (wk) 4, wk12, and wk24. Total lymphocyte count was measured at each visit. Results Significant improvements in disease activity were seen for baricitinib versus placebo in both studies. Total lymphocyte increases at wk4 for baricitinib were generally within normal ranges. Change in total lymphocyte count was similar at wk12 and wk24 for baricitinib versus placebo. In RA-BUILD/RA-BEACON, increased T-cells/μL (158.3/22.6 and 124.1/170.7 for 2mg and 4mg, p ≤ 0.05), B-cells/μL (66.7/36.8 and 82.9/74.3 for 2mg and 4mg,p ≤ 0.001), and NK-cells/μL (59.5/36.8 and 46.2/77.0 for 2mg and 4mg,p ≤ 0.01) versus placebo were seen at wk4. Decreased T-cells/μL (wk12= -20.9/0.7 and -87.6/-33.1 for 2mg and 4mg; wk24 = -117.2/-128.1 and -83.4/-53.8 for 2mg and 4mg,p ≤ 0.05) and NK-cells/μL (wk12 = -36.7/-22.0 and -57.0/- 22.7 for 2mg and 4mg,p ≤ 0.001 in RA-BEACON; wk24 = - 41.2/-45.0 and -53.4/-40.9 for 2mg and 4mg, p ≤ 0.05 in RABEACON) and increased B-cells/μL (wk12 = 65.0/49.3 and 75.1/70.2 for 2mg and 4mg, p ≤ 0.001; wk24= 24.3/22.6 and 55.2/65.0 for 2mg and 4mg,p ≤ 0.001 for 4mg) were seen later for baricitinib groups. Changes in other T- and B-cell populations were variable, but generally reflected these patterns. Decreased NK-cell count did not appear to be associated with an increased incidence of infection. Conclusions Baricitinib produced significant clinical improvements in disease activity in csDMARD-IR and TNFi-IR RA patients. Improvements were accompanied by a variety of changes in lymphocyte counts, predominantly within normal ranges. Similar lymphocyte subset assessments will be available in a long-term extension study.

Estudio primario

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Patient-reported outcomes from a phase 3 study of baricitinib versus placebo or adalimumab in patients with active rheumatoid arthritis and an inadequate response to background methotrexate therapy

Revista Annals of the Rheumatic Diseases
Año 2016
Enlaces DOI www.cochranelibrary.com
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Background: Baricitinib (bari), an oral JAK1 and JAK2 inhibitor, was efficacious in a Ph 3 study (RA-BEAM) in RA patients (pts) with active disease and an inadequate response (IR) to MTX.1 Objectives: To evaluate patient-reported outcomes (PROs) from RA-BEAM. Methods: Pts on stable background MTX were randomized to placebo (PBO), bari 4 mg QD, or adalimumab (ADA) 40 mg Q2W. PROs listed in the table and the Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA) were collected on electronic tablets during study visits. Bari vs. PBO and bari vs. ADA were assessed with ANCOVA and logistic regression models. Results: 1305 pts were randomized. Functional disability at baseline (mean HAQ-DI) was: 1.55, 1.57, 1.59 for PBO, bari, and ADA, respectively. Compared to PBO, bari was superior in physical function, Pt's Global Assessment of Disease Activity (PtGDA), pain, fatigue and quality of life (physical component score [PCS]), at Wk 12 and 24. Compared to ADA, bari was superior in physical function, PtGDA, and pain at Wks 12, 24 and 52. Compared to PBO, a similar proportion of bari and ADA pts were employed throughout the study. Statistically significant improvements in all components of the WPAI-RA (absenteeism, presenteeism, work productivity loss and activity impairment) were seen in the bari pts compared to PBO at Wk 12; statistically significant improvements were seen for work loss and activity impairment for bari pts compared to ADA at Wk 12. Conclusions: In this Ph 3 study of RA patients with an IR to MTX, treatment with bari resulted in significant improvement in most PROs compared with PBO or ADA, including functional disability, pain, and fatigue.

Estudio primario

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Response to baricitinib at 4 weeks predicts response at 12 and 24 weeks in patients with rheumatoid arthritis: Results from two phase 3 studies

Revista Annals of the Rheumatic Diseases
Año 2016
Enlaces DOI www.cochranelibrary.com
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Background: Baricitinib (bari), a JAK1 and JAK2 inhibitor, showed significant improvements across multiple measures of disease activity as early as week (wk) 1 that were maintained through wk 52 in ph 3 studies of patients (pts) with active RA.1,2 Objectives: To determine if, in bari-treated pts, early changes in disease activity predicted later achievement of low disease activity (LDA) or remission. Methods: 1305 pts with inadequate response to methotrexate (MTX) were randomized in RA-BEAM (3:3:2, oral PBO/4 mg bari QD/SC injection adalimumab [ADA] Q2W, 52 wks); 584 MTX-naïve pts were randomized in RA-BEGIN (4:3:4, oral MTX QW/4 mg bari QD/4 mg bari QD+MTX QW, 52 wks). Improvement from baseline (BL) to wk 4 was used to predict LDA or remission defined by Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) at wks 12/24 (bari 4 mg arm, both studies). Early responder and early nonresponder were predefined as Clinical Disease Activity Index (CDAI) improvement ≥6 and <6, respectively, at wk 4. Results: Compared to PBO or ADA (RA-BEAM) or MTX (RA-BEGIN), treatment with bari was associated with rapid decrease in DAS28 and CDAI from wk 1.1,2 By wk 4, 86% (RA-BEAM) and 85% (RA-BEGIN) of bari pts had a CDAI decrease ≥6. In both studies, LDA/remission rates at wks 12/24 were higher in pts with CDAI improvement ≥6 compared to pts with CDAI improvement <6 from BL to wk 4 (Table). Negative predictive values (NPV) for remission at wks 12/24 associated with CDAI improvement <6 from BL to wk 4 exceeded 90%, indicating that pts with CDAI improvement <6 were highly unlikely to achieve remission; NPV for LDA exceeded 80%. Conclusions: In RA-BEAM/RA-BEGIN, lack of early clinical response to bari 4 mg (failure to achieve CDAI improvement ≥6 at 4 wks) was associated with low rates of LDA/remission at wks 12/24. These results are consistent with similar analyses from previous ph 3 studies of bari.3 The majority of bari pts had improvement in CDAI ≥6 at wk 4; these decreases were associated with improved clinical responses at wks 12/24. Early identification of pts (4 wks) who are not likely to achieve LDA/remission may be useful in tailoring therapy to individual pts. (Table Presented).

Estudio primario

No clasificado

Effects of baricitinib on multibiomarker disease activity scores and their components in a phase 2B study in moderate-to-severe rheumatoid arthritis patients

Revista Annals of the Rheumatic Diseases
Año 2016
Enlaces DOI www.cochranelibrary.com
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Background and objectives Baricitinib, an oral inhibitor of JAK1 and JAK2 signalling, improved signs and symptoms in patients with active rheumatoid arthritis (RA) who were methotrexate inadequate responders (MTX-IR) in a double-blind, placebo (PBO) controlled study. We investigated how a quantitative, multibiomarker disease activity score (MBDA) and its components are affected by treatment with baricitinib 4mg (n = 50) once daily compared to PBO (n = 79) during 12 weeks' treatment in moderate-to-severe RA patients. Materials and methods Serum samples were collected at baseline and Weeks 4 and 12. MBDA scores and changes in individual MBDA components were subjected to post-hoc statistical analyses. Results At baseline, the proportion of patients with low, moderate, and high MBDA scores were similar in the 2 groups, as were median MBDA scores (PBO=44 vs. baricitinib=47). Unlike PBO-treated patients, baricitinib patients had decreased MBDA scores at 4 and 12 weeks compared to baseline (baricitinib=35.5 and 37.0 (p < 0.001) vs. PBO=46.0 and 45.0, respectively). Baricitinib- treated patients had significant (p < 0.05) median % decreases in MBDA components vs. PBO including C-Reactive Protein (- 66.9 vs. 6.6/-56.1 vs. 8.2 at 4/12 weeks), Matrix metalloproteinase (MMP)-3 (-12.3 vs. 4.5/-14.5 vs. 6.3 at 4/12 weeks), serum amyloid A (-56.4 vs. 9.9/-37.6 vs. 9.2 at 4/12 weeks), soluble TNF receptor (-12.1 vs. -0.1/-12.0 vs. 1.2 at 4/12 weeks), VCAM-1 (- 15.9 vs. 1.4/-12.1 vs. 1.0 at 4/12 weeks), and human cartilage glycoprotein 39; -26.2 vs. -0.5/-9.9 vs. -1.6 at 4/12 weeks). Compared to PBO, there were no significant changes for baricitinib-treated patients at either time-point for epidermal growth factor (EGF), MMP-1, or vascular endothelial growth factor-A. For baricitinib- treated patients versus PBO, at 4 but not 12 weeks, Interleukin-6 and resistin were significantly decreased and at 12 but not 4 weeks, leptin was significantly increased. Conclusions Consistent with other indices of disease activity, the treatment of MTX-IR patients with baricitinib 4mg once daily resulted in a reduction in MBDA scores, by 4 weeks. Decreases in MBDA scores and the components were present at both 4 and 12 weeks. Reduction in the levels of inflammatory markers beyond those associated with an acute phase response is apparent in these patients.

Estudio primario

No clasificado

Characterization of changes in lymphocyte subsets in baricitinib-treated patients with rheumatoid arthritis in a phase 3 study (RA-beam)

Revista Annals of the Rheumatic Diseases
Año 2016
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Background: Baricitinib (bari; an oral JAK 1/JAK 2 inhibitor) is in development for patients (pts) with active RA. In healthy subjects, absolute lymphocyte counts (ALC) increased after bari administration, returning to baseline (BL) by 24 hrs.1 Objectives: To examine changes in ALC and lymphocyte (LYM) subsets in pts with active RA treated with bari (4 mg QD), placebo (PBO), or adalimumab (ADA, 40 mg Q2W). Methods: 1305 pts with active RA despite MTX treatment were randomized 3:3:2 to PBO, bari, or ADA. ALC, T, and B cell subsets (T: Th1, Th17, CD4, CD8, T reg, CD3+CD4+CD127-/loCD25+; B: switched/nonswitched memory, mature naive, immature transitional), and natural killer (NK) cells were quantified by flow cytometry at BL and wks 4, 12, and 24. Wk 4 phlebotomy was postdose bari or PBO; wks 12 and 24 were predose. Results: ALC and T cells/subsets increased with bari and ADA at wk 4 (generally within normal ranges), returning to near BL at wks 12 and 24 in bari but remaining elevated in ADA (Table). B cells/subsets increased at wks 4 in bari and ADA and remained elevated through wk 24. NK cells were increased at wk 4 in bari and were below BL but within the normal range at wks 12 and 24; NK cells were increased at wks 12 and 24 in ADA. The percentages of pts with ≥1 low NK cell count were 20.5%, 32.6%, and 20.6% in PBO, bari, and ADA, respectively; percentage of pts with ALC CTCAE grade ≥2 were 14.1%, 9.9%, and 10.0%. Through wk 24, serious infection rates were 1.4%, 1.0%, and 0.6% for PBO, bari, and ADA; rates were 1.0%, 1.3%, and 0%, respectively, in pts with ≥1 low NK cell count and 2.9%, 4.2%, and 0% in pts with ≥1 ALC CTCAE Grade ≥2 value. Rates of herpes zoster (HZ) were 0.4%, 1.4%, and 1.2% for PBO, bari, and ADA; rates were 0%, 0.6%, and 0%, respectively, in pts with ≥1 low NK cell count and 1.4%, 2.1%, and 0% in pts with ≥1 ALC CTCAE Grade ≥2 value (no statistically significant differences between treatment groups). Conclusions: Changes in ALC and subpopulations with bari in RA-BEAM were largely within normal ranges and are consistent with previous data.2 Sustained increases in B cells were observed in bari and ADA. Sustained increases in ALC/T cells were only seen in ADA. A modest reduction in NK cells at wks 12 and 24 with bari was not associated with serious infection or HZ. (Table Presented) .

Estudio primario

No clasificado

Baricitinib versus adalimumab in patients with active rheumatoid arthritis: Analysis of patients achieving a moderate eular response at week 4

Revista Annals of the Rheumatic Diseases
Año 2017
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Background: Baricitinib (BARI) is a selective inhibitor of Janus kinase,1 improves disease activity in patients (pts) with rheumatoid arthritis (RA), and is associated with inhibition of structural joint damage.2-4 Response to BARI observed at week (wk) 4 may be useful to predict future response.5 Objectives: To characterise pts with RA who achieved moderate EULAR responses (MERs)6 at wk 4 and to describe the outcomes through wk 52 while continuing the assigned treatment. Methods: Pts enrolled in the RA-BEAM study with active RA who had an inadequate response to methotrexate (MTX) were randomised 3:3:2 to placebo (PBO), BARI 4 mg once daily, or adalimumab (ADA) 40 mg biweekly.1 Pts who showed good or no EULAR responses at wk 4 were excluded. For the MER cohort, the cumulative incidence for first transition to good EULAR response and to no EULAR response from wk 4 through wk 52 was estimated in the presence of competing risks events, which either hinder observation of the events of interest or modify the chance that these events occur.7 Pts who transitioned from MER to no EULAR response or pts who were rescued or discontinued because of an adverse event or lack of efficacy were counted as no EULAR response; pts who discontinued the study for other reasons (eg, lost to follow-up, death) were censored at the time of discontinuation. No formal statistical tests were performed for these post hoc analyses. Results: Of 1305 pts who received at least 1 dose of study drug, 683 experienced MERs at wk 4, including 37.3% (182/488), 62.0% (302/487), and 60.3% (199/330) of pts on PBO, BARI, and ADA, respectively. Pts who achieved MERs at wk 4 on BARI and ADA had similar baseline disease activity characteristics (Table 1). The mean age of the MER subgroup was 53 years, and the mean disease duration was 8.7 years. The mean MTX dosage was 15 mg/wk, and 59% of pts were taking concomitant oral glucocorticoids. At wk 4, 27% (131/487) and 11% (54/487) of pts on BARI vs 29% (95/330) and 11% (36/330) of pts on ADA experienced no response or good response, respectively. The cumulative incidence for the first transitions to good EULAR response at wks 12, 24, and 52 was higher in pts who reached MERs at wk 4 on BARI than those on ADA. The cumulative incidence for the first transitions to subsequent no EULAR response was higher in pts who achieved MER at wk 4 on ADA (Figures 1A and 1B, Table 2) than those on BARI. Conclusions: Among pts achieving early MER on BARI and ADA, subsequent loss of response was less common for pts on BARI than for those on ADA. Transitions to good EULAR response were more common for pts who achieved MERs on BARI than for those on ADA. Mechanistic explanations warrant future study.

Estudio primario

No clasificado

Patient-reported outcomes from a phase 3 study of baricitinib versus placebo or adalimumab in rheumatoid arthritis: secondary analyses from the RA-BEAM study.

Revista Annals of the rheumatic diseases
Año 2017
Enlaces Pubmed DOI PubMed Central
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BACKGROUND: To assess the effect of baricitinib on patient-reported outcomes (PROs) in patients with active rheumatoid arthritis and an inadequate response to methotrexate (MTX). METHODS: In this double-blind phase 3 study, patients were randomised 3:3:2 to placebo (n=488), baricitinib 4 mg once daily (n=487), or adalimumab 40 mg biweekly (n=330) with background MTX. PROs included the SF-36, EuroQol 5-D (EQ-5D) index scores and visual analogue scale, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient's Global Assessment of Disease Activity (PtGA), patient's assessment of pain and Work Productivity and Activity Impairment Questionnaire-Rheumatoid Arthritis (WPAI-RA), and measures collected in electronic patient daily diaries: duration and severity of morning joint stiffness (MJS), Worst Ttiredness and Worst Joint Pain. The primary study endpoint was at week 12. Treatment comparisons were assessed with logistic regression for categorical measures or analysis of covariance for continuous variables. RESULTS: Compared with placebo and adalimumab, baricitinib showed statistically significant improvements (p≤0.05) in HAQ-DI, PtGA, pain, FACIT-F, SF-36 physical component score, EQ-5D index scores and WPAI-RA daily activity at week 12. Improvements were maintained for measures assessed to week 52. Statistically significant improvement in patient diary measures (MJS duration and severity), worst tiredness and worst joint pain were observed for baricitinib versus placebo and adalimumab at week 12 (p≤0.05). CONCLUSIONS: Baricitinib provided significantly greater improvement in most PROs compared with placebo and adalimumab, including physical function MJS, pain, fatigue and quality of life. Improvement was maintained to the end of the study (week 52). TRIAL REGISTRATION: NCT01710358.

Estudio primario

No clasificado

Pain reduction is associated with improved work productivity in patients with rheumatoid arthritis

Revista Annals of the Rheumatic Diseases
Año 2017
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Background: Patients with rheumatoid arthritis (RA) indicate pain is an important aspect of disease burden and may persist despite control of disease. In a randomized, double-blind phase 3 clinical trial of baricitinib (RA-BEAM),1 baricitinib provided significant improvement in pain reduction. It is not clear, however, how much reductions in pain impacted other aspects of life, such as work productivity. Objectives: To assess the relationship between pain reduction and improvements, regardless of treatment, in daily activity and work productivity in patients with RA. Methods: In this post-hoc analysis of RA-BEAM1, pain for the intention-to-treat patients was assessed using the patient's assessment of pain (0-100 mm visual analogue scale). The Work Productivity and Activity Impairment Questionnaire- RA (WPAI-RA) instrument was used to evaluate the percentage of activity impairment due to RA (impairment in regular daily activities, N=1302), percentage of work-time missed due to RA (absenteeism, N=521), percentage of impairment while working due to RA (presenteeism, N=490), and percentage of overall work impairment due to RA (impairment in work productivity, N=490). Pain was divided into pain reduction groups (<30%, 30% - <50%, ≥50% at Weeks 12 and 24; ≥30% [Y/N] and ≥50% [Y/N] at Weeks 1 and 2). Pairwise comparisons on improvement in WPAI-RA scores between pain reduction groups at Weeks 12 and 24 were assessed by ANCOVA adjusting for region, baseline joint erosion status, and baseline values of outcome variables. Missing values were imputed using the modified last-observation carried forward method. Results: At baseline across treatment groups, the mean values ranged from 56- 58 for daily activity impairment, 12-13 for absenteeism, 42-46 for presenteeism, and 45-49 for work productivity impairment. A ≥30% reduction in pain as early as Week 1 was associated with significantly greater (p<0.001) improvement than <30% pain reduction in regular daily activity (-22.8 vs -16.0), presenteeism (-17.5 vs. -12.1), and work productivity (-16.8 vs. -11.6) at Week 12. Greater improvement was observed in most WPAI-RA scores in patients who had more pain reduction at Weeks 12 and 24; with a reduction of ≥50% in pain from baseline, the WPAI-RA scores were substantially improved at Weeks 12 or 24 for daily activity, presenteeism, and work productivity (Table). Conclusions: Regardless of treatment, pain reduction was associated with improved regular daily activity and work productivity in patients with RA, with larger levels of reduction related to more improvement.

No clasificado

Effects of baricitinib on haemoglobin and related laboratory parameters in rheumatoid arthritis patients

Revista Annals of the Rheumatic Diseases
Año 2017
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Background: Baricitinib (bari), a selective, transient and reversible inhibitor of Janus kinase (JAK)1 and JAK2, improved signs and symptoms of active rheumatoid arthritis (RA) in multiple phase 3 studies. Since erythropoietin (EPO) stimulates erythrocyte production via the JAK2 signaling pathway, haemoglobin (Hgb) and other haematologic parameters were thoroughly evaluated in the bari RA clinical development program. Objectives: To evaluate baseline and subsequent changes in Hgb and related laboratory parameters in RA patients (pts) treated with bari (2 or 4 mg once daily), placebo (PBO), or active comparator (methotrexate [MTX] or adalimumab [ADA]). Methods: Blood samples were analyzed at baseline and at each study visit for complete blood count, with more extensive phlebotomy at baseline (Wk 0) and Wks 12, 24, and 52 (Figure 1). Data were aggregated from completed Phase 2 and 3 RA studies and one ongoing long-term extension study. EPO and reticulocyte (RET) data were collected from a Phase 2 RA study in Japan. Results: Hgb levels below the gender-adjusted lower limit of normal (LLN) were often observed at baseline (25%). Small declines in Hgb were observed at Wk 2 and again at Wk 14 in bari (2 and 4 mg) and PBO-treated RA pts consistent with the volume and frequency of phlebotomy (Figure 1). Initial decreases in Hgb were accompanied by declines in RET counts in bari-treated RA pts. Subsequent increases in Hgb were associated with increases in RET after Wk 8 and statistically significant dose-dependent increases vs. PBO in total iron (Fe), total iron binding capacity (TIBC) and EPO. Treatment-emergent (TE) shifts in Hgb from normal to <LLN were very common in all groups without differences across groups except for ADA, which was associated with a lower incidence of TE low Hgb. TE Common Terminology Criteria for Adverse Events (CTCAE) shifts in Hgb from <grade 3 to ≥grade 3 (<4.9 and ≥4.0 mmol/L; <8.0g/dL and ≥6.5g/dL) were uncommon and occurred in similar proportions of RA pts across groups (Table 1). Permanent discontinuation of study drug due to CTCAE ≥grade 3 Hgb shifts was uncommon (0.2%). Conclusions: The proportions of RA pts with TE abnormally low Hgb did not differ significantly between bari and PBO. Reductions in Hgb, including to ≥grade 3, were generally not associated with adverse outcomes. Despite concerns about the impact of JAK2 inhibition on EPO signaling, following initial declines incident to phlebotomy, dose-dependent increases in EPO, Fe, and TIBC with return to baseline in RET and Hgb were observed with bari. This suggests that homeostatic mechanisms counterbalance the pharmacologic effect of JAK inhibition on EPO signaling and that bari treatment enhances iron utilisation markers associated with anaemia of chronic disease.

Estudio primario

No clasificado

Baricitinib showed rapid and greater reduction in pain compared to adalimumab or placebo in patients with rheumatoid arthritis

Revista Annals of the Rheumatic Diseases
Año 2017
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Background: A rapid and meaningful reduction in pain is important to quality of life in patients (pts) with rheumatoid arthritis (RA). Baricitinib (bari) is a selective inhibitor of Janus kinase (JAK)1/JAK 2 in development for pts with active RA.1 Objectives: To evaluate the effect of bari treatment on pain reduction compared to adalimumab (ADA) or placebo (PBO) in pts with inadequate response to methotrexate (MTX) or biologic disease-modifying antirheumatic drugs (bDMARDs). Methods: In RA-BEAM (NCT01710358), 1305 patients with inadequate response to MTX were randomised 3:3:2 to PBO QD, bari 4 mg once daily (QD), or ADA 40 mg biweekly.2 In RA-BEACON (NCT01721044), 527 pts with inadequate response or intolerance to bDMARDs were randomised 1:1:1 to PBO or bari (2 or 4 mg) QD.3 This post-hoc analysis reports the pts' assessment of pain using a visual analogue scale (VAS, range: 0 to 100 mm). The proportion of pts who achieved pain improvement of ≥30%, ≥50%, and ≥70% of their baseline pain at 1, 2, 4, 8, 12, 16, 20, and 24 weeks of treatment were compared between treatment groups using logistic models adjusted for geographic region, baseline pain score, baseline joint erosion status (RA-BEAM only), and history of bDMARD at screening (RA-BEACON only). Missing data were imputed using modified last observation carried forward. Results: Mean baseline pain scores were 60, 62, and 61 for PBO, bari 4 mg, and ADA, respectively, in RA-BEAM and 65, 62, and 66 for PBO, bari 2 mg, and bari 4 mg, respectively, in RA-BEACON. A significantly greater proportion of pts treated with bari 4 mg achieved ≥30% and ≥50% pain improvement as early as week 1 compared to PBO (both studies) and as early as week 4 compared to ADA (RA-BEAM) (Table). A significant pain improvement of ≥70% was achieved at week 12 for pts treated with bari 4 mg compared to PBO (both studies) and ADA (RA-BEAM). Pain improvement of ≥30%, ≥50%, and ≥70% with bari 2 mg was significant compared to PBO by week 12 (RA-BEACON). Significant improvements in pain for bari vs PBO and bari vs ADA were sustained through week 24. Conclusions: Bari-treated pts reported significantly greater and more rapid reductions in pain severity as measured by the pain VAS compared to PBO or ADA; improvements were sustained through 24 weeks. The results were similar regardless of the pt population. (Table Presented).

Estudio primario

No clasificado

Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis.

Revista The New England journal of medicine
Año 2017
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BACKGROUND: Baricitinib is an oral, reversible inhibitor of the Janus kinases JAK1 and JAK2 that may have therapeutic value in patients with rheumatoid arthritis. METHODS: We conducted a 52-week, phase 3, double-blind, placebo- and active-controlled trial in which 1307 patients with active rheumatoid arthritis who were receiving background therapy with methotrexate were randomly assigned to one of three regimens in a 3:3:2 ratio: placebo (switched to baricitinib after 24 weeks), 4 mg of baricitinib once daily, or 40 mg of adalimumab (an anti-tumor necrosis factor α monoclonal antibody) every other week. End-point measures evaluated after adjustment for multiplicity included 20% improvement according to the criteria of the American College of Rheumatology (ACR20 response) (the primary end point), the Disease Activity Score for 28 joints (DAS28), the Health Assessment Questionnaire-Disability Index, and the Simplified Disease Activity Index at week 12, as well as radiographic progression of joint damage as measured by the van der Heijde modification of the total Sharp score (mTSS) (range, 0 to 448, with higher scores indicating greater structural joint damage) at week 24. RESULTS: More patients had an ACR20 response at week 12 with baricitinib than with placebo (primary end point, 70% vs. 40%, P<0.001). All major secondary objectives were met, including inhibition of radiographic progression of joint damage, according to the mTSS at week 24 with baricitinib versus placebo (mean change from baseline, 0.41 vs. 0.90; P<0.001) and an increased ACR20 response rate at week 12 with baricitinib versus adalimumab (70% vs. 61%, P=0.014). Adverse events, including infections, were more frequent through week 24 with baricitinib and adalimumab than with placebo. Cancers were reported in five patients (two who received baricitinib and three who received placebo). Baricitinib was associated with reductions in neutrophil counts and increases in levels of creatinine and low-density lipoprotein cholesterol. CONCLUSIONS: In patients with rheumatoid arthritis who had had an inadequate response to methotrexate, baricitinib was associated with significant clinical improvements as compared with placebo and adalimumab. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01710358 .).

Estudio primario

No clasificado

Concomitant use of conventional synthetic DMARDs and response to baricitinib

Revista Annals of the Rheumatic Diseases
Año 2017
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Background: Baricitinib (BARI), an oral JAK1/JAK2 inhibitor, is in development for patients (pts) with moderate to severe rheumatoid arthritis (RA).1,2 Objectives: This post-hoc analysis of two phase 3 studies assessed whether concomitant use of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) altered the response or safety outcomes to BARI in RA pts and evaluated the effect of concomitant corticosteroid use on the efficacy of BARI. Methods: Pts with ≥6 swollen and tender joints and no prior biologic DMARD use were enrolled. In RA-BEAM (NCT01710358), methotrexate (MTX)-inadequate responder (IR) pts were randomised to PBO once daily (QD), BARI 4 mg QD, or adalimumab 40 mg biweekly.1 In RA-BUILD (NCT01710358), csDMARD-IR pts were randomised to placebo (PBO) or BARI (2 or 4 mg) QD.2 Pts continued background csDMARD (including MTX) therapy. This post-hoc analysis included the PBO (N=716) and BARI 4 mg (N=714) pts and assessed the number and type of concomitant csDMARDS and concurrent corticosteroid use. Results: 71%, 21%, and 6% of PBO pts were taking MTX alone, MTX + ≥1 other csDMARD, and non-MTX csDMARDs, respectively; in BARI 4 mg pts, the rates were 74%, 18%, and 6%, respectively. Oral corticosteroids were used in 56% of PBO and 55% of BARI pts at baseline; pts continued use throughout the studies. The differences in clinical efficacy between BARI 4 mg and PBO at 12 weeks was similar regardless of the number or type of csDMARDs concomitantly used (Table) or the concomitant use of corticosteroids (data not shown). The rates of serious adverse events and discontinuation due to adverse events were comparable regardless of the number or type of csDMARDs used (Table) or corticosteroid use. ACR20/50/70=20%, 50%, and 70% improvement in American College of Rheumatology criteria; csDMARDs=conventional synthetic disease-modifying antirheumatic drugs; DAS28-ESR=Disease Activity Score 28-erythrocyte sedimentation rate; MTX=methotrexate; SDAI=Simple Disease Activity Index. Conclusions: BARI has demonstrated clinical safety and efficacy in a wide range of pts, regardless of the number of concomitant csDMARDs or concomitant use of corticosteroids.

Estudio primario

No clasificado

A RAPID3-like index documents superior efficacy of baricitinib to adalimumab and placebo, similar to DAS28 and cdai in the ra-beam clinical trial in patients with rheumatoid arthritis

Revista Annals of the Rheumatic Diseases
Año 2017
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Background: RAPID3 (Routine Assessment of Patient Index Data) indicates differences in efficacy of active versus control treatments at levels similar to DAS28-ESR (Disease Activity Score 28-Erythrocyte Sedimentation Rate) and CDAI (Clinical Disease Activity Index) in clinical trials of adalimumab, abatacept, certolizumab. Objectives: To compare improvement according to RAPID3, DAS 28-ESR, and CDAI in the RA-BEAM trial of baricitinib vs adalimumab and placebo. Methods: Post-hoc analyses were performed of the RA-BEAM trial, in which patients with moderately to severely active rheumatoid arthritis and an inadequate response to methotrexate (MTX) were randomized to baricitinib, adalimumab, or placebo. All patients were to continue stable background MTX and other DMARDs, as well as stable low-dose prednisone and/or NSAIDs, if indicated. A RAPID3-like index was computed from 3 measures: physical function (FN), pain (PN), and patient global assessment (PATGL). FN on a HAQ (Health Assessment Questionnaire) of 20 items [rather than MDHAQ (multidimensional HAQ) of 10 items] was recalculated from 0-3 to 0-10; PN and PATGL (visual analog scales) were recalculated from 0-100 to 0-10, for a 0-30 total score, hence “RAPID3-like”. Mean values at baseline and Week 24 for RAPID3-like, DAS28-ESR, and CDAI, and percent change from baseline were computed in the 3 treatment groups. The proportion of patients with high/moderate activity/severity at Week 24 versus low activity/severity/remission, as well as correlations of the 3 indices at Week 24, were calculated. Statistical significance for percent change was analyzed using Wilcoxon tests, after imputation of missing values using modified last observation carried forward (mLOCF); low activity/severity/remission was compared between groups using a logistic model, adjusting for region and baseline joint erosion status after imputation of missing values using non-responder imputation. Results: Improvement from baseline to Week 24 ranged from 19.2% to 37.0% in placebo patients, 40.0% to 65.9% in baricitinib-treated patients, and 37.6% to 60.9% in adalimumab-treated patients (Table), least in DAS28-ESR, intermediate in RAPID3-like, and highest in CDAI. Changes according to RAPID3-like, DAS28- ESR and CDAI were similar in the 3 treatment groups; baricitinib and adalimumab were superior to placebo according to all indices, and baricitinib was superior to adalimumab according to RAPID3-like and CDAI (Table). Correlations of RAPID3- like with DAS28-ESR and CDAI ranged from r=0.61 to 0.75 and for DAS28-ESR with CDAI from r=0.86 to 0.91 (all p<0.001). The proportion of patients with low activity/severity/remission at Week 24 ranged from 9.6% to 19.7% in placebo patients, 31.6% to 49.9% in baricitinib-treated patients, and 33.6% to 47.6% in adalimumab-treated patients. RAPID3-like results were intermediate between DAS28-ESR and CDAI. Conclusions: RAPID3-like documented greater efficacy of baricitinib versus adalimumab and placebo in the RA-BEAM trial, with results in similar ranges to DAS28-ESR and CDAI. RAPID3 is feasible to provide quantitative, standard medical history data; almost of the time and effort is by the patient rather than a health professional, assuring quantitative data in the infrastructure of usual clinical care.

Estudio primario

No clasificado

Differences in patient-reported outcomes between baricitinib and comparators among patients with rheumatoid arthritis who achieved low disease activity or remission

Revista Annals of the Rheumatic Diseases
Año 2017
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Background: Achieving remission is the ideal goal in treating rheumatoid arthritis (RA). In a randomised phase 3 trial, high remission and low disease activity (LDA) rates were achieved with baricitinib (BARI). However, little is known about the differences in patient reported outcomes (PROs) among patients (pts) who have already achieved these targets. Objectives: To compare PROs between BARI, adalimumab (ADA), and placebo (PBO) in pts with RA who achieved LDA or remission in the Phase 3 RA-BEAM study. Methods: 1305 pts with RA and background treatment with methotrexate were randomised to receive PBO (n=488), ADA (n=330), or BARI 4 mg (n=487) for 52 wks (24 wks for PBO). In each treatment group, pts in remission (DAS28- ESR<2.6) and with LDA (DAS28-ESR≤3.2) at wk 24 were assessed from baseline for the following PROs: Pain VAS, HAQ-DI, WPAI, Morning Joint Stiffness (MJS), and FACIT-F. Sensitivity analyses were conducted for pts in remission or LDA by DAS28-CRP, SDAI, or CDAI. The assessment of response at wk 24 was determined by using the observed data, and the missing values for PRO measures were imputed by using mLOCF. Results: Among pts in LDA, significantly greater improvements in Pain VAS and HAQ-DI scores were observed with BARI than ADA and PBO, and significantly greater improvements in MJS were observed with BARI and ADA than PBO. Significantly greater residual pain and HAQ-DI scores were observed with PBO. Among pts in remission, significantly greater improvements in pain and HAQ-DI scores were also observed with BARI than PBO. Patients in remission or LDA showed greater numerical improvement and less residual impairment in other PROs with BARI and ADA than PBO (Table 1). Consistent results were observed using other composite measures to define LDA and remission. Conclusions: The preliminary findings from this study suggest that BARI showed greater improvements in pain and HAQ-DI compared to ADA for pts in LDA, and greater improvements in pain and HAQ-DI scores as well as less physical impairment compared to PBO for pts in LDA and remission.

Estudio primario

No clasificado

Patient-re ported outcomes from phase 3 baricitinib ra-beam study: latin American subgroup analysis

Revista
Año 2017
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Objectives: To evaluate effect of baricitinib (BARI) on patient‐reported outcomes (PROs) in Latin American (LA)∗ patients with moderately to severely active rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX). ∗LA countries: Argentina and Mexico. Methods: In the double‐blind RA‐BEAM study, 1305 patients with active RA on established methotrexate treatment were randomized in 3:3:2 to receive 4 mg BARI orally once daily, 40 mg adalimumab (ADA) subcutaneously once every 2 weeks, or matching placebo (PBO) for up to 52 weeks; the latter were switched to BARI at Week 24. Rescue treatment was provided to all nonresponders from Week 16. PROs were measured using Health Assessment Questionnaire‐Disability Index (HAQ‐DI), pain visual analog scale (VAS), Functional Assessment of Chronic Illness Therapy‐Fatigue (FACIT‐F), and Short Form‐36 for 380 LA patients from baseline to Week 24 and were compared between treatments using ANCOVA for continuous variables and logistic models for categorical variables. Missing values were imputed using modified last observation‐carried forward (mLOCF) for continuous variables and nonresponder imputation (NRI) for categorical variables. Results: A total of 143 LA patients received BARI, 96 ADA, and 141 PBO. Baseline characteristics of These patients were comparable among the treatment groups with mean duration of RA of 9.9 years. Patients receiving BARI showed significantly (p< 0.01) greater improvement compared to PBO in pain and HAQ‐DI as early as Week 1. By Week 24, patients receiving BARI had statistically significant improvement (p< 0.01) in pain, HAQ‐DI, SF‐36 physical component score (PCS), and FACIT‐F compared to PBO. The percentage of patients who met/exceeded the MCID for the HAQ‐DI (≥ 0.22), PCS ≥ 5, and MCS ≥ 5 was significantly (p< 0.05) higher for BARI vs. PBO at Week 24. ConClusions: Significant improvement in PROs including physical function, pain, and fatigue was noted in patients treated with BARI versus PBO and numeric improvements were observed versus ADA.

Estudio primario

No clasificado

Efficacy and safety of baricitinib versus placebo and adalimumab in patients with moderately to severely active rheumatoid arthritis and inadequate response to methotrexate: summary results from the 52-week phase 3 RA-BEAM study

Autores [No se listan los autores]
Revista
Año 2017
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Background: Baricitinib, an oral JAK1/JAK2 inhibitor, has shown promising results in patients with active rheumatoid arthritis (RA). We present efficacy and safety results from the phase 3 RA‐BEAM study in patients with active RA and inadequate response (IR) to methotrexate (MTX). Methods: Patients with moderate to severe RA and MTX‐IR were randomized 3:3:2 to placebo, baricitinib 4 mg QD or adalimumab 40 mg biweekly. All patients continued stable background MTX therapy. Non‐responders were rescued at week 16. At week 24, patients receiving placebo switched to baricitinib 4 mg QD. The study compared baricitinib, placebo and adalimumab using multiple endpoints, including non‐inferiority and superiority testing; the primary endpoint was baricitinib versus placebo ACR20 response at week 12. Results: Of 1305 randomized patients, 83%, 88% and 87% completed week 52 in the placebo, baricitinib and adalimumab groups, respectively; rescue rates were 27%, 9% and 15%, respectively. ACR20 response at week 12 was higher for baricitinib versus placebo (p<=.001; Table 1). At weeks 12 and 24, significant improvements were seen for baricitinib versus placebo in ACR20/50/ 70 and DAS28, CDAI and SDAI low disease activity and remission rates, many by week one. Baricitinib was superior to adalimumab in ACR20 response rates at weeks 12, 24 and 52, and in DAS28‐ CRP<=3.2 at weeks 12 and 52. Change in mTSS at weeks 24 and 52 was significantly lower for baricitinib versus placebo (Table). At week 24, more baricitinib patients had improved physical function and reduced fatigue and pain versus placebo and adalimumab (Table). During weeks 0‐24, more treatment‐emergent AEs occurred with baricitinib and adalimumab versus placebo (71%, 67%, 60%); serious AE rates were 5%, 2% and 4%, respectively. By week 52, treatmentemergent AE rates for baricitinib versus adalimumab were 79% versus 77% and serious AE rates were 8% versus 4%; serious infection rates were similar across groups; three major cardiovascular events (2 baricitinib, 1 adalimumab), three deaths (2 baricitinib, 1 adalimumab), one tuberculosis case (adalimumab), and five malignancies (2 baricitinib, 3 placebo) were reported. Conclusion: In patients with moderate to severe RA and MTX‐IR receiving background MTX, addition of baricitinib was associated with significant clinical improvements versus placebo and adalimumab, with an acceptable safety profile. (Table presented).

Estudio primario

No clasificado

A high level of clinical response based on composite indices is associated with improved health-related quality of life: Analyses from a phase 3 clinical trial in patients with rheumatoid arthritis

Revista Annals of the Rheumatic Diseases
Año 2017
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Background: Rheumatoid arthritis (RA) is a chronic disease associated with inflammatory activity and joint damage that result in disability, pain, and other impairments. The current recommendation is to assess disease activity based on composite indices with objective signs of inflammation (e.g. synovitis, acute phase reactants) and patient's assessment of disease activity. The patient's perception of disease impact and its treatment also facilitate shared decision-making about treatment. Objectives: To compare patient-reported outcomes (PROs) for RA patients who achieved low disease activity (LDA) or remission based upon the DAS28-ESR compared to those with moderate and high disease activity (MDA and HDA) in this post-hoc analysis of a randomized, double-blind phase 3 clinical trial, RA-BEAM1. Methods: 1305 patients were randomized to placebo (N=488), adalimumab (N=330) or baricitinib 4 mg (N=487). Patients with observed DAS28-ESR values at Week 24 (N=1,010) were divided into 4 disease activity groups: HDA (DAS28-ESR>5.1), MDA (3.2<DAS28-ESR≤5.1), LDA (2.6≤DAS28-ESR≤3.2), or remission (DAS28-ESR<2.6). Change from baseline to Week 24 were assessed for the pain visual analogue scale (VAS, 0-100 mm), Health Assessment Questionnaire-Disability Index (HAQ-DI) and SF-36 physical and mental component score (PCS and MCS) for the intent-to-treat (ITT) patients. Results: Patients with HDA and MDA at Week 24 had greater baseline pain and HAQ-DI scores and lower PCS and MCS scores than patients achieving LDA or remission at Week 24. Lower disease activity at Week 24 was associated with improvement in pain, HAQ-DI, SF-36 PCS and MCS at Week 24. Among patients who achieved remission, residual pain was observed, with close to 40% still experiencing some level of pain and 20% of patients in remission at Week 24 had a residual pain score>20. Sensitivity analyses using other clinical measures (DAS28-CRP, SDAI, CDAI) to define disease activity confirmed the findings. Conclusions: Improving patient disease activity is associated with improved health-related quality of life. Patients who achieved remission had greater improvement in PROs but residual pain remained. Further research is needed to understand the treatment differences in the association between disease activity and PROs among different therapies.

Estudio primario

No clasificado

Converting patient-reported physical function outcomes scores to promis metric scores in phase 3 trials of baricitinib in rheumatoid arthritis

Revista Annals of the Rheumatic Diseases
Año 2018
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Background: In patients (pts) with RA, physical function (PF) can be measured with the Health Assessment Questionnaire-Disability Index (HAQ-DI). Patient- Reported Outcomes Measurement Information System (PROMIS) was developed by the National Institutes of Health using a population-calibrated T-score metric (Mean 50, SD 10). Crosswalk tables that link legacy instruments to PROMIS instruments, including PF, have been developed. Comparisons to the general population can also be made from PROMIS scores.1-2 Objectives: To convert HAQ-DI scores to PROMIS PF scores to determine how the PROMIS metric performs in 2 phase 3 baricitinib (bari) clinical trials in pts with RA. Methods: In RA-BEAM, pts with inadequate response (IR) to methotrexate were randomised 3:3:2 to placebo (PBO) once daily (QD), bari 4 mg QD, or adalimumab (ADA) 40 mg biweekly.3 In RA-BEACON, pts with IR to bDMARDs were randomised 1:1:1 to receive PBO or bari 2 mg or 4 mg QD.4 In both studies, PF was assessed using HAQ-DI. Patient-level HAQ-DI scores were converted to PROMIS PF scores using a validated crosswalk table.1 Analysis of covariance was conducted on the PROMIS PF score conversions to compare bari to all treatment arms in both studies. Missing data were imputed using modified last observation carried forward. Results: Pts had considerable PF impairment at baseline; mean scores exceeded 2 SD (20 points on the T-score metric) from population means (table 1). Treatment with bari was associated with clinically relevant improvements approaching or exceeding 0.5 SD (5 points on the T-score metric) by week 24 (minimally important difference for PROMIS PF: 0.2 SD or 2 points5) vs PBO in HAQ-DI converted to PROMIS PF scores (table 1). Using the converted PROMIS scores, bari remained associated with significant improvements in PF vs PBO through 24 weeks in both studies and vs ADA through 52 weeks in RA-BEAM (figure 1). Conclusions: While RA-BEAM and RA-BEACON did not use the PROMIS instrument directly, these results indicate PROMIS PF has the potential to show responsiveness and differentiate between active treatments in clinical trials.

Estudio primario

No clasificado

Efficacy and safety of baricitinib in Japanese patients with rheumatoid arthritis: Subgroup analyses of four multinational phase 3 randomized trials.

Revista Modern rheumatology
Año 2018
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OBJECTIVES: To evaluate efficacy/safety of baricitinib for rheumatoid arthritis (RA) in Japanese subpopulations from four phase 3 studies, and assess whether results in these subpopulations are consistent with the overall study populations. METHODS: Subgroup analyses (394 patients) of four phase 3 randomized controlled trials: RA-BEGIN [no or limited treatment with disease-modifying antirheumatic drugs (DMARDs)], RA-BEAM [inadequate response (IR) to methotrexate], RA-BUILD [IR to conventional synthetic DMARDs (csDMARDs)], and RA-BEACON (IR to tumor necrosis factor inhibitors receiving csDMARDs). RESULTS: For American College of Rheumatology 20% improvement (ACR20) response rate, Japanese patients receiving baricitinib 4-mg showed similar improvement compared to methotrexate at Week 24 (72 versus 69%; RA-BEGIN), and greater improvement compared with placebo at Week 12 (67 versus 34%; RA-BEAM). Japanese patients receiving baricitinib 4-mg also showed greater improvement compared with placebo at Week 12 in RA-BUILD and RA-BEACON. Across all studies, baricitinib was well-tolerated, with no deaths and one malignancy. In RA-BEGIN and RA-BEAM, herpes zoster rates were higher for Japanese patients than for overall populations; all events were mild/moderate. CONCLUSION: Data for baricitinib, with/without methotrexate, in Japanese subpopulations across all stages of the RA treatment continuum accord with the efficacy/safety profile in overall study populations. Baricitinib appears to be similarly effective in Japanese patients.

Estudio primario

No clasificado

Converting patient-reported outcome measures of fatigue and pain to promis scores: Data from phase 3 baricitinib rheumatoid arthritis trials

Revista Annals of the Rheumatic Diseases
Año 2018
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Background: Fatigue and pain in patients (pts) with RA are often measured with the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and the Medical Outcomes Study Short-Form-36 (SF-36). Patient-Reported Outcomes Measurement Information System (PROMIS) was developed using a populationcalibrated T-score metric (Mean 50, SD 10). Crosswalk tables were developed linking legacy instruments to PROMIS instruments, including Fatigue and Pain Interference (PI). Comparisons to the general population can be made from PROMIS scores.1-2 Objectives: To convert FACIT-F and SF-36 Bodily Pain (BP) scores to PROMIS Fatigue and PI scores to determine how PROMIS performs in 2 phase 3 baricitinib (bari) RA trials. Methods: In RA-BEAM, pts with inadequate response (IR) to MTX were randomised 3:3:2 to placebo (PBO) once daily (QD), bari-4 mg QD, or adalimumab (ADA) 40 mg biweekly.3 In RA-BEACON, pts with IR to bDMARDs were randomised 1:1:1 to receive PBO or bari 2 mg or 4 mg QD.4 FACIT-F assessed fatigue and SF-36 BP, pain. Pt-level PROMIS scores were converted from FACIT-F/SF- 36 BP using validated crosswalk tables.1-2 Analysis of covariance was conducted on PROMIS score conversions to compare bari to all treatment arms. Results: Pts had considerable baseline fatigue/pain; mean scores approached or exceeded 1 SD (10 points on the metric) from population norms. Bari was associated with clinically relevant improvements (exceeding 0.5 SD/5 points on the Tscore metric) vs PBO for PROMIS fatigue/PI scores (table 1). PROMIS fatigue/PI scores in RA-BEAM reached population norms (<55) by week 12 for bari and ADA (table 1). Bari remained associated with significant improvements in PROMIS fatigue/PI vs PBO through 24 weeks in both studies and vs ADA for PI in RABEAM (figure 1). (Figure Presented) Conclusions: While PROMIS was not used in the studies directly, pt-level crosswalk tables provide an estimate of effect that may be demonstrated when using PROMIS in clinical trials. These results provide preliminary evidence of the ability of PROMIS to demonstrate treatment benefit.

Estudio primario

No clasificado

Microarray pathway analysis comparing baricitinib and adalimumab in moderate to severe rheumatoid arthritis from a phase 3 study

Revista Annals of the Rheumatic Diseases
Año 2018
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Introduction In RA-BEAM (NCT01710358), baricitinib (BARI), an oral selective inhibitor of Janus kinase (JAK) 1 and JAK 2, showed significant improvements in patients (pts) with active RA who had an inadequate response to methotrexate compared to placebo (PBO) or adalimumab (ADA). Objectives To analyse pathways modulated by BARI compared with ADA (both relative to PBO) through 12 wks of treatment. Methods Pts (n=1307) were randomised 3:3:2 to PBO, BARI 4 mg QD, ADA 40 mg q 2 wks. Total RNA extracted from whole blood drawn at baseline (BL), wk4, and wk12 was analysed using the GeneChip Human Transcriptome Array 2.0 (Affymetrix). Data were analysed using a mixed effects model on a log2 transformed response. Results There was little overlap of the immune pathways modulated by both BARI and ADA at wk4 with no significant overlap by wk12. BARI downregulated JAK/Signal Transducer and Activator of Transcription (STAT) signalling pathways, like those induced by IFNs, IL-6, GM-CSF, IL-5, and IL-3. Expression of interferon responsive genes (IRGs) was downregulated by BARI and upregulated by ADA. BARI reduced IRGs by 75% at wk4 in pts that had high IFN gene expression at BL. ADA modulated complement pathways. Of interest, STAT transcripts were reduced at wk4 by BARI (STAT1, 2, 3, 5A, 5B, 6); by wk12 several STATs (STAT 1, 2, 5A) did not differ from PBO. Additional differences were noted in the number of genes modulated by each treatment. BARI modulated more genes than ADA at wks 4 and 12; BARI resulted in more gene modulation at wk12 than at wk4, whereas ADA gene modulation was similar at wks 4 and 12. Both the numbers and types of genes modulated by BARI diverged further from ADA at wk12 than at wk4. Conclusions Gene expression profiling showed significant differences between BARI and ADA treatments. BARI and ADA modulated JAK/STAT or complement pathways, respectively, and the drugs had opposite effects on interferons, indicating different and possibly complementary mechanisms of action of each targeted therapy.

Estudio primario

No clasificado

Summary of baricitinib effect on patientreported outcomes (PROS) in methotrexateinadequate responder patient population

Revista Rheumatology (United Kingdom)
Año 2018
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Background: In addition to assessment by physical examination, laboratory tests and imaging, Patient-Reported Outcomes (PROs) have become increasingly important in the evaluation of rheumatoid arthritis (RA) patients (pts). The objective is to summarise the effect of baricitinib (BARI) treatment on PROs compared to adalimumab (ADA) or placebo (PBO) in patients with inadequate response to methotrexate (MTX). Methods: In RA-BEAM (NCT01710358), 1305 patients with inadequate response to MTX were randomised 3:3:2 to PBO QD, BARI 4mg QD, or ADA 40mg EOW. Post-hoc analyses of RA-BEAM focused on different aspects of the impact of BARI on PRO measures for physical function, fatigue, and pain such as the visual analogue scale (VAS), Health Assessment Questionnaire-Disability Index (HAQ-DI); Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), duration of morning joint stiffness (MJS): the proportion of patients (Table Presented) who, at different time points, achieved pain improvement of≤50% of their baseline (BL) pain (VAS: 0-100mm) in each treatment arm; differences in PROs, at week (Wk) 24, among patients with DAS28-ESR defined low disease activity (LDA) and remission in each treatment group. Results: A significantly greater proportion of patients treated with BARI 4mg achieved ≤50% pain improvement as early as Wk1 compared to PBO (26% vs 13%; p≥0.001) and as early as Wk4 compared to ADA (48% vs 37%; p≥0.01); improvements were sustained through Wk24 (BARI 61% vs ADA 52%; p≥0.05). Patients in LDA at Wk24 who were treated with BARI 4mg reported significantly greater improvements in pain and HAQ-DI than those with ADA and PBO (Table). Among patients in remission at Wk24, significantly greater improvements in HAQ-DI scores were reported with BARI than with PBO; among patients with LDA, significantly greater improvements in morning joint stiffness duration were also observed with BARI and ADA than with PBO (Table 1). Conclusion: BARI demonstrated rapid and sustained improvements in pain. Attainment of remission or LDA is associated with improvements in pain, physical functioning and health-related quality of life (QOL) for patients treated with BARI, ADA or PBO but with most marked improvements on BARI and ADA.

Estudio primario

No clasificado

Baricitinib in Patients with Rheumatoid Arthritis and an Inadequate Response to Conventional Disease-Modifying Antirheumatic Drugs in United States and Rest of World: A Subset Analysis

Revista Rheumatology and therapy
Año 2018
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Introduction: This article evaluates the efficacy and safety of baricitinib 4 mg versus placebo in United States including Puerto Rico (US) and rest of the world (ROW) subpopulations using data pooled from RA-BEAM and RA-BUILD, which enrolled patients with moderate-to-severe adult-onset rheumatoid arthritis (RA). Methods: In RA-BEAM, patients with an inadequate response (IR) to methotrexate, at least one X-ray erosion, and high sensitivity C-reactive protein (hsCRP) ≥ 6 mg/L were randomized to placebo or orally administered baricitinib 4 mg daily or subcutaneously administered adalimumab 40 mg every other week. In RA-BUILD, patients with an IR to at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD) and with hsCRP ≥ 3.6 mg/L were randomized to placebo or baricitinib 2 or 4 mg daily. Patients in both trials were biologic naive. In this post hoc analysis, data from both studies were pooled (714 baricitinib 4 mg-treated, 716 placebo-treated patients). Results: Overall, 188 US and 1242 ROW patients were included. Subgroups differed in baseline characteristics including race, weight, age, time since RA diagnosis, current corticosteroid use, and previous csDMARD use. At weeks 12 and 24, baricitinib-treated patients had larger responses compared to placebo-treated patients for multiple efficacy outcomes: American College of Rheumatology 20/50/70 response, low disease activity, remission, Disease Activity Score 28-C-reactive protein, and Health Assessment Questionnaire-Disability Index. Overall, similar efficacy was observed in US and ROW subgroups with no notable safety differences between subgroups at weeks 12 or 24. Conclusion: Baricitinib 4 mg was efficacious compared to placebo in US and ROW subpopulations. Safety was similar between subgroups. Funding: Eli Lilly & Company and Incyte Corporation. Trial Registration: ClinicalTrials.gov identifiers, NCT01721057; NCT01710358.

Estudio primario

No clasificado

Response to baricitinib therapy in patients with rheumatoid arthritis with inadequate response to csDMARDs as a function of baseline characteristics

Revista RMD open
Año 2018
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Objective: We analysed the effects of baseline characteristics on the safety and efficacy of baricitinib in patients with rheumatoid arthritis (ra) with inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMarDs) from two phase iii trials. Methods: In ra-BeaM (nct01710358), patients with inadequate response to methotrexate were randomised to placebo, baricitinib 4 mg or adalimumab 40 mg. ra-BUilD (nct01721057) patients had inadequate response to ≥1 csDMarDs and were randomised to either placebo or once-daily baricitinib (2 or 4 mg). Both study populations were naïve to biologic DMarDs (bDMarDs). Primary end point for both studies was American college of rheumatology 20% improvement (acr20) response at week 12. Pooled data from the two trials were analysed post hoc based on select subgroups defined by age, previous csDMarD use, baseline ra disease activity, etc, with assessment of clinical and safety outcomes at week 12 and radiographic outcomes at week 24 for the baricitinib 4 mg and placebo-treated patients. Results: efficacy was observed with baricitinib 4 mg treatment irrespective of patient demographics and baseline disease characteristics. Ors primarily favoured baricitinib over placebo in the acr20 response. in other outcomes such as Disease activity Score for 28 joints based on high-sensitivity c reactive protein levels, Simplified Disease activity index score ≤11 and radiographic progression, baricitinib 4 mg showed better responses than placebo regardless of baseline characteristics. Safety events were more common in patients over 65 years, but similar between baricitinib 4 mg and placebo patients. Conclusion: Baseline characteristics did not substantially affect clinical response to baricitinib 4 mg in patients with ra with inadequate response to csDMarDs.

No clasificado

Linking FACIT fatigue data to PROMIS® fatigue scores to enhance interpretability: data from phase 3 baricitinib rheumatoid arthritis trials

Revista
Año 2018
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Aims: Fatigue in patients with rheumatoid arthritis (RA) is common and debilitating. In clinical trials, fatigue is often measured with the 13‐item Functional Assessment of Chronic Illness Therapy‐Fatigue instrument (FACIT‐F). The Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue item bank was developed using aUS general population‐calibrated T‐score metric (mean 50, SD 10). PROMIS Fatigue includes the FACIT‐F items within it, and scores on the two scales are thereby interchangeable. Content debriefing of the FACIT‐F identified 10 items relevant to patients with RA. We assessed performance of these 10 items and the 13‐item FACIT‐F instrument using both crosswalk tables and a PROMIS scoring algorithm using data from 2 phase 3 baricitinib RA trials. Methods: In RA‐BEAM, patients with inadequate response to methotrexate were randomized 3:3:2 to placebo once daily (QD), baricitinib 4mg QD, or adalimumab 40mgbiweekly.1 In RA‐BEACON, patients with inadequate response to bDMARDs were randomized 1:1:1 to receive placebo or baricitinib 2 mg or 4 mg QD.2 Patient‐level FACIT‐F scores were linked to PROMIS Fatigue scores using validated crosswalk tables (http://www.prosettastone.org) and the scoring algorithm (http://www.healthmeasures.net/exploremeasurement‐ systems/promis). Analysis of covariance was conducted on PROMIS score conversions to compare responses across treatment arms. Results: At baseline, average PROMIS fatigue scores reflected moderate‐to‐high levels of fatigue relative to population means (e.g., approaching or exceeding 1 SDabove), ranging across treatment groups and scoring methods from 57.4 to 59.7 in RA‐BEAM and 60.1 to 63.7 in RA‐BEACON (Table). Fatigue scores decreased in RA‐BEAM to within normal ranges (<55) by week 4 for baricitinib and adalimumab (data not shown). Statistically and clinically meaningful reductions in mean fatigue scores (exceeding 0.5 SD/5 points) were associated with treatment through 24 weeks in both studies. Conclusions: These results support the FACIT‐F to PROMIS Fatigue crosswalk and scoring algorithm approaches, including the use of a subset of 10 FACIT‐F items deemed most relevant to RA. This enables comparisons across studies that use FACIT‐F or PROMIS Fatigue item subsets and their interpretation in relation to US general population norms. (Table Presented).

Estudio primario

No clasificado

Hepatic safety in patients with rheumatoid arthritis treated with baricitinib: post-hoc analysis from clinical studies

Autores [No se listan los autores]
Revista
Año 2019
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Background: Latent tuberculosis infection (LTBI) and hepatitis B virus (HBV) reactivation are important issues in the management of rheumatoid arthritis patients. Isoniazid (INH) plays a vital role in controlling TB but it may result in hepatic abnormalities. We present hepatic safety and HBV reactivation in patients with RA treated with baricitinib (BARI). Methods: Hepatic safety with INH treatment was analyzed in data from 3 placebo (PBO)‐controlled Phase 3 studies, and HBV analyses included additional Phase 3 and a long‐term extension studies. Respectively, changes in alanine aminotransferase (ALT) levels (≥1X/≥3X/≥5X/≥10X ULN) from baseline up to 24 weeks; and HBV surface antigen, core antibody (HBcAb), surface antibody (HBsAb), and HBV DNA at baseline or post‐baseline, were analyzed. Results: (1). INH: Total, 2516 patients were treated with BARI 4‐mg/BARI 2‐mg/adalimumab (ADA)/PBO. Background csDMARDs were continued. Overall, 246 patients reported LTBI across all treatment groups. of these, 175 with confirmed lab data received INH. Table 1 represents changes in ALT. Percentage of patients with ALT ≥ 1XULN was higher in INH‐treated patients across all treatment groups. No BARI/ADA patients using INH had study treatment interruption due to abnormal hepatic tests. (2). HBV: of 2890 patients, 269 had baseline serology suggestive of prior infection (HBcAb+/HBsAb+, n = 255; HBcAb+/HBsAb‐, n = 14; Figure 1). of these, 32 BARI‐treated patients (32/269; 11.9%) later (post‐baseline) tested with HBV DNA+. Out of 32 patients, 8 patients had results above the lower limit of quantitation (LLQ); subsequent tests were either not detectable or below LLQ. No patients developed clinical evidence of hepatitis; ALT tests were within normal range. Conclusion: Data do not suggest an increased hepatic safety risk in patients treated with BARI and concomitant INH. Although some BARI‐treated patients had post‐baseline detectable HBV DNA, none developed clinical evidence of hepatitis. (Table Presented).

Estudio primario

No clasificado

Association between baseline haemoglobin levels and radiographic joint damage progression in patients with rheumatoid arthritis treated with baricitinib or standard of care

Revista Annals of the Rheumatic Diseases
Año 2019
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Background: In patients with active rheumatoid arthritis (RA), haemoglobin (Hb) levels have been inversely associated with radiographic progression of structural joint damage.1-3. In two randomized 52-week (wk) studies, baricitinib (BARI), a selective JAK1/JAK2 inhibitor, reduced radiographic progression in patients with moderate to severe active RA who had received no/minimal prior methotrexate (MTX; RA-BEGIN)4 or had inadequate response to MTX (RA-BEAM).5 Objectives: To assess the association between baseline Hb levels and structural damage progression and to study the effect of BARI 4-mg once daily on structural damage progression at 52 wks based on baseine Hb levels. Methods: Data from the modified intention-to-treat (mITT) populations of RA-BEGIN (MTX=210; BARI 4-mg=159; BARI 4-mg + MTX=215 patients) and RA-BEAM (placebo [PBO]=488, adalimumab [ADA]=328, BARI 4-mg=487 patients) were included for analysis. Structural damage progression was defined as change from baseline (CFB) greater than the smallest detectable change (SDC) in the modified total Sharp score (mTSS) at wk 52. In RA-BEGIN SDC was 1.4 and in RA-BEAM SDC was 1.5. Missing mTSS data at wk 52 were imputed using linear extrapolation based on baseline data and the most recent radiographic data prior to the missed radiograph. Observed proportions of patients with CFB in mTSS >SDC at wk 52 were calculated for low (males:<13.0g/dL, females:<12.0g/dL) or normal baseline Hb for each treatment arm from both studies. Multivariate logistic regression (MLR) was used to study the association of baseline Hb with structural joint damage at 52 wks. The MLR included treatment, baseline Hb (g/dL), baseline hsCRP (Normal <3mg/L; Elevated >3mg/L), baseline CDAI, baseline HAQ-DI, BMI, smokng status (Yes/No), geographical area and joint erosion status at baseine (Yes/No in RA-BEGIN; >3/1 or 2 + seropositivity in RA-BEAM). Thirty-nine patients from RA-BEGIN (MTX=18; BARI 4-mg=5; BARI 4-mg + MTX=16) and 68 patients from RA-BEAM (PBO=36; ADA=18; BARI 4-mg=14) with missing baseline/post-baseline radiographic data were excluded from MLR analyses; in addition, 7 and 19 patients from RA-BEGIN and RA-BEAM with missing data for the covariates of the MLR were excluded. All analyses were post-hoc. Results: Overall, RA-BEGIN and RA-BEAM patients with higher baseline Hb were less likely to show CFB in mTSS >SDC (RA-BEGIN: adjusted odds ratio [OR]=0.72, p=0.001; RA-BEAM: adjusted OR=0.76, p<0.001) at 52 wks, independent of other factors included in the MLR model. In RA-BEGIN (Figure A), CFB in mTSS >SDC was less frequent in patients with low baseline Hb who received BARI alone or BARI + MTX versus those on MTX alone; in patients with normal baseline Hb, the difference between treatments was less pronounced. In RA-BEAM (Figure B), CFB in mTSS >SDC was less frequent in patients with both low or normal baseline Hb for patients receiving BARI or ADA versus PBO Conclusion: In patients with RA, lower baseline Hb levels were associated with increased structural damage progression. Treatment with BARI 4-mg reduced structural progression, irrespective of patient baseline Hb status; structural progression at 52 wks was more pronounced in patients with low baseline Hb receiving MTX alone (RA-BEGIN) or PBO and background MTX (RA-BEAM).

Estudio primario

No clasificado

Achieving pain control in rheumatoid arthritis with baricitinib or adalimumab plus methotrexate: Results from the RA-BEAM trial

Revista Journal of clinical medicine
Año 2019
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The purpose of the study was to assess the proportion of patients who achieve pain relief thresholds, the time needed to reach the thresholds, and the relationship between pain and inflammation among patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate in RA-BEAM (NCT0170358). A randomized, double-blind trial was conducted, comparing baricitinib (N = 487), adalimumab (N = 330), and placebo (N = 488) plus methotrexate. Pain was evaluated by patient’s assessment on a 0–100 mm visual analog scale (VAS). The following were assessed through a 24-week placebo-controlled period: the proportion of patients who achieved ≥30%, ≥50%, and ≥70% pain relief, the time to achieve these pain relief thresholds, remaining pain (VAS ≤ 10 mm, ≤20 mm, or ≤40 mm), and the relationship between inflammation markers and pain relief. Baricitinib-treated patients were more likely (p < 0.05) to achieve ≥30%, ≥50%, and ≥70% pain relief than placebo-and adalimumab-treated patients, as early as Week 1 vs. placebo and at Week 4 vs. adalimumab. A greater proportion of baricitinib-treated patients achieved ≤20 mm or ≤40 mm remaining pain vs. placebo-and adalimumab-treated patients. Baricitinib-treated patients tended to demonstrate consistent pain relief independent of levels of inflammation control. In RA patients with an inadequate response to methotrexate, baricitinib provided greater and more rapid pain relief than adalimumab and placebo. Analyses suggest the relationship between inflammation and pain may be different for baricitinib and adalimumab treatments.

Estudio primario

No clasificado

Assessment of pain improvement in rheumatoid arthritis patients treated with baricitinib, who were inadequate responders to methotrexate and tumor necrosis factor inhibitors

Revista Rheumatology (United Kingdom)
Año 2019
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Background: During the development programme, baricitinib (BARI) demonstrated greater and faster pain relief relative to placebo (PBO) and active comparator in different RA populations. Here, we summarise the findings from two recent post hoc analyses focused on the effect of BARI on pain in two clinically relevant patient populations: methotrexate-inadequate responders (MTX-IR; RA-BEAM) and tumor necrosis factor inhibitor-inadequate responders (TNFi-IR; RABEACON). Methods: In both clinical trials (RA-BEAM and RA-BEACON), pain was assessed with a visual analog scale (VAS, 0-100mm) at each study visit. In RA-BEAM, 1,305 patients on stable background MTX were randomized 3:3:2 to PBO, BARI 4-mg, or adalimumab (ADA) 40-mg. The likelihood of achieving ≥30%, ≥50%, and ≥70% pain VAS improvement through Week 24 and the median time when 50% of patients achieved these pain improvement thresholds was assessed with Cox proportional hazard models and the cumulative incidence estimate. Analyses were not adjusted for multiplicity. In RA-BEACON, 527 patients were randomised to placebo (n=176), BARI 2-mg (n=174), or 4-mg (n=177) once daily for 24 weeks. Approximately 40% of patients had received >1 TNF inhibitor and a quarter of patients had received 53 bDMARDs, representing patients with highly refractory disease. The proportion of patients achieving ≥30%, ≥50%, and ≥70% pain relief at Week-12 was compared between BARI 2-mg or 4-mg and PBO using logistic models. Missing pain values were imputed using modified last observation-carried-forward. Results: In the MTX-IR population, BARI-treated patients were more likely to achieve at least 30%, 50%, and 70% pain improvement than PBO and ADA with HR of 1.7, 1.9 and 2.5, respectively (p<0.001) compared to PBO, and 1.1 (p=0.145), 1.2 (p=0.032) and 1.3 (p=0.003) compared to ADA. The median time for 50% of patients to achieve at least 30%, 50%, and 70% pain improvement, respectively, was 1.9, 4.0 and 12.4 weeks for BARI, 2.0, 7.9 and 20.0 weeks for ADA, and 4.6, 14.0 and >24 weeks for PBO. In the TNFi-IR population, at Week-12, significantly more patients achieved ≥30%, ≥50%, and ≥70% pain relief with BARI 2-mg or 4-mg vs PBO (p<0.05, for all comparisons). Consistent improvements were observed regardless of baseline pain. Regardless of treatment history, patients receiving BARI 2-mg or 4-mg were more likely to reach all pain relief thresholds than placebo. Conclusion: In both MTX-IR and TNFi-IR populations, BARI demonstrated greater pain improvement than comparators at Weeks 24 and 12, respectively.

Estudio primario

No clasificado

Effect of baricitinib and adalimumab in reducing pain and improving function in patients with rheumatoid arthritis in low disease activity: Exploratory analyses from RA-BEAM

Revista Journal of clinical medicine
Año 2019
Enlaces Pubmed DOI PubMed Central www.cochranelibrary.com
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Patients with rheumatoid arthritis (RA) may experience residual pain and functional impairment despite good control of disease activity. This study compared improvements in pain and physical function in patients with well-controlled RA after 24 weeks’ treatment with baricitinib, adalimumab or placebo in the 52-week RA-BEAM phase III study. Adults with active RA and inadequate response to methotrexate received baricitinib 4 mg once daily, adalimumab 40 mg every two weeks or placebo, with background methotrexate. Patients (N = 1010) were categorised as in remission, in remission or low disease activity, or not in remission or low disease activity at week 24. For patients in remission or low disease activity (n = 310), improvements in mean pain and physical function scores at week 24 were significantly greater with baricitinib than placebo (p < 0.001 and p < 0.01, respectively) and adalimumab (p < 0.05 for both). For both outcomes, differences between adalimumab and placebo were not significant. The proportions of patients in remission or low disease activity with minimal or no pain and with normalised physical function were numerically greater with baricitinib than placebo. Baricitinib 4 mg once daily provided enhanced improvement in pain and physical function in patients with well-controlled RA, suggesting it may produce effects beyond immunomodulation.

Estudio primario

No clasificado

Temporary interruption of baricitinib: characterization of interruptions and effect on clinical outcomes in patients with rheumatoid arthritis

Revista Arthritis research & therapy
Año 2020
Enlaces Pubmed DOI PubMed Central
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BACKGROUND: In clinical practice, temporary interruption of rheumatoid arthritis (RA) therapy is common for various reasons including side effects, non‐compliance, or necessity for surgery. To characterize temporary interruptions of baricitinib and placebo‐matched tablets in phase 3 studies of patients with moderate‐to‐severe rheumatoid arthritis (RA) and describe their impact on efficacy and safety. METHODS: During 4 baricitinib phase 3 studies, investigators documented timing, reason, and duration of investigator‐initiated temporary interruptions of study drug. In 2 studies, patients recorded RA symptoms in daily diaries for 12 weeks. Post hoc analyses investigated changes in symptom scores during interruptions and resumption of treatment. Interruptions were evaluated for reoccurrence of adverse events or laboratory abnormalities after retreatment. RESULTS: Across the placebo‐controlled studies, interruptions occurred in larger proportions of baricitinib‐ (2 mg, 18%; 4 mg, 18%) vs placebo‐treated (9%) patients in only one study (bDMARD‐inadequate responder patients, RA‐BEACON). In the active comparator‐controlled studies, the lowest rates of interruption were in the baricitinib monotherapy arm (9%) of RA‐BEGIN (vs methotrexate monotherapy or combination therapy), and proportions were similar for baricitinib (10%) and adalimumab (9%) in RA‐BEAM. Adverse events were the most common reason for interruption, but their reoccurrence after drug restart was infrequent. Most interruptions lasted ≤ 2 weeks. Daily diaries indicated modest symptom increases during interruption with return to pre‐interruption levels or better after resumption. Interruptions had no impact on long‐term efficacy outcomes. CONCLUSIONS: Consistent with its pharmacologic properties, brief interruptions of baricitinib during phase 3 studies were associated with minor increases in RA symptoms that resolved following retreatment. This analysis provides useful information for clinicians, as temporary interruption of antirheumatic therapy is common in the care of patients with RA. TRIAL REGISTRATION: ClinicalTrials.gov; NCT01710358, NCT01711359, NCT01721057, NCT01721044.

No clasificado

Number needed to treat to achieve minimum clinically significant differences in patientreported outcomes in patients treated with baricitinib

Revista Annals of the Rheumatic Diseases
Año 2020
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Background: Baricitinib (BARI) provided rapid and sustained improvements in patient-reported outcomes (PROs) in randomized, controlled trials (RCTs) in patients (pts) with active rheumatoid arthritis (RA) and inadequate responses (IR) to methotrexate (MTX) (RA-BEAM; NCT01710358)1,2 and biologic DMARDs (bDMARD-IR; RA-BEACON; NCT01721044)3,4. Objectives: To determine the number needed to treat (NNT) to report improvements ≥minimum clinically important differences (MCIDs) in multiple PROs at Week (Wk) 12 after treatment with BARI 4-mg in RA-BEAM and BARI 2-mg or BARI 4-mg in RA-BEACON. NNTs ≤10 vs placebo (PBO) are considered clinically meaningful. Methods: Evaluated PROs with respective MCID definitions included Patient Global Assessment of Disease Activity (PtGA, 0-100 mm visual analog scale [VAS], MCID ≥10 mm), pain (0-100 mm VAS, MCID ≥10 mm), physical function (Health Assessment Questionnaire-Disability Index, MCID ≥0.22 points), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F], MCID≥4.0), and health-related quality of life (SF-36 physical component summary [PCS: MCID ≥2.5] and domain scores: physical function [PF], role physical [RP], bodily pain [BP], general health [GH], vitality [VT], social functioning [SF], role emotional [RE], mental health [MH], MCID ≥5.0).5 The percentages of pts reporting improvements ≥MCID were determined at Wk 12. NNTs were calculated as 1/difference in response rates between BARI 2-mg or 4-mg and PBO. Results: At Wk 12, percentages of pts reporting clinically meaningful improvements were greater and statistically different from PBO (p<0.01) with BARI 2-mg and 4-mg across most PROs in both RCTs. Most NNTs were ≤10. (Figure) Conclusion: Across different populations, MTX-IR and bDMARD-IR pts with active RA reported clinically meaningful improvements in PROs after BARI treatment. The NNTs in these analyses indicate that <10 pts need to be treated with BARI 2-or 4-mg to report a clinically meaningful benefit.

Estudio primario

No clasificado

Conversion of Functional Assessment of Chronic Illness Therapy?Fatigue to Patient-Reported Outcomes Measurement Information System Fatigue Scores in Two Phase III Baricitinib Rheumatoid Arthritis Trials

Revista Arthritis care & research
Año 2021
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Objective: The Functional Assessment of Chronic Illness Therapy?Fatigue (FACIT‐F) is validated for measuring fatigue in rheumatoid arthritis (RA). However, 10 of 13 FACIT‐F items are identified as relevant to patients with RA. The Patient‐Reported Outcomes Measurement Information System (PROMIS) uses an item response theory?calibrated T score metric. The PROMIS Fatigue item bank includes the FACIT‐F items, enabling score conversion. The performance of converted PROMIS Fatigue scores has not been evaluated in RA populations or clinical trials. Our objective was to assess the performance of converted PROMIS Fatigue scores in 2 RA clinical trials of baricitinib. Methods: Crosswalk tables and pattern‐scoring methods converted FACIT‐F scores to PROMIS Fatigue for both the 13‐item FACIT‐F and the 10‐item RA‐optimized FACIT‐F instrument, in 2 RA clinical trials evaluating baricitinib, RA‐BEAM, and RA‐BEACON. RA‐BEAM patients had an inadequate response to methotrexate. RA‐BEACON patients had an inadequate response or intolerance to ?1 tumor necrosis factor inhibitor. Baricitinib was compared to all treatment arms via analysis of covariance on PROMIS Fatigue score conversions. Results: Baseline FACIT‐F?derived PROMIS Fatigue scores reflected severe fatigue across treatment groups and were similar using different scoring methods. At week 24 in both studies, baricitinib was associated with clinically meaningful improvements in PROMIS Fatigue scores. PROMIS Fatigue scores were consistent for conversion methods and for the 13‐item or 10‐item FACIT‐F. Conclusion: All 4 conversion methods showed differentiation of active treatment compared with placebo from week 12, supporting the use of the PROMIS Fatigue and converting the 10‐item FACIT‐F to assess fatigue and demonstrate treatment benefit in RA clinical trials on a standardized metric.

Estudio primario

No clasificado

Rapid and concurrent improvements in patient-reported outcomes of rheumatoid arthritis with baricitinib in ra-beam

Revista Annals of the Rheumatic Diseases
Año 2021
Enlaces DOI www.cochranelibrary.com
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Background: The efficacy and safety of baricitinib (BARI), an oral selective Janus kinase (JAK)1/JAK2 inhibitor, were evaluated in the randomized, controlled trial, RA-BEAM (NCT01710358), in patients (pts) with active rheumatoid arthritis (RA) and inadequate responses (IR) to methotrexate (MTX).1,2,3 Objectives: To compare the time to onset and magnitude of improvement across different patient-reported outcomes (PROs) of BARI, adalimumab (ADA) and placebo (PBO) during the first 12 weeks of treatment in RA-BEAM. Methods: 1,305 patients on stable background MTX were randomized 3:3:2 to PBO, BARI 4 mg, or ADA 40 mg. In this intent-to-treat analysis, least-squares mean changes and percentage changes from baseline were assessed up to Week 12 for pain (0-100 mm visual analog scale [VAS]), SF-36 physical component summary (PCS, 0-100), morning joint stiffness (MJS) severity (0-10), Health Assessment Questionnaire-Disability Index (HAQ-DI, 0-3), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F, 0-52), and Patient Global Assessment of disease activity (PtGA, 0-100 mm VAS) scores. PROs were compared between treatments with ANCOVA; the model included change from baseline as the response variable, baseline of interest, regional baseline, joint erosion status, and treatment as explanatory variables. Last-observation-carried-forward was applied to impute missing data. Speed of onset and magnitude of PRO improvement are presented in spydergrams. Results: Statistically significant improvements (P<0.05) with BARI and ADA vs. PBO were reported as early as Week 1 for pain, MJS severity, HAQ-DI, and PtGA and at Week 4 for FACIT-F and SF-36 PCS scores. Statistically significantly larger improvements (P<0.05) with BARI vs. ADA were observed as early as Week 2 for pain, PtGA, Week 3 for MJS severity, and Week 4 for HAQ-DI and SF-36 PCS scores. These improvements were maintained to Week 12. Conclusion: Among MTX-IR pts, BARI and ADA treatment resulted in improvements across all PROs by Week 4, and as early as Week 1, for all but FACIT-F and SF-36 PCS scores. Statistically significant larger improvements for BARI compared with ADA were reported for all PROs, except FACIT-F, by Week 12.

Estudio primario

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Pain Reduction in Rheumatoid Arthritis Patients Who Use Opioids: A Post Hoc Analysis of Phase 3 Trials of Baricitinib

Revista ACR open rheumatology
Año 2022
Enlaces Pubmed DOI PubMed Central www.cochranelibrary.com
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OBJECTIVE: Pain reduction with baricitinib was assessed in patients with rheumatoid arthritis (RA) who either used opioids or did not use opioids during three randomized, double-blind phase 3 trials. METHODS: Analysis populations were as follows: i) baricitinib 4 mg once daily versus placebo groups integrated from RA-BEAM (NCT01710358) for patients with inadequate response (IR) to methotrexate, RA-BUILD (NCT01721057) with IR to conventional disease-modifying antirheumatic drugs, and RA-BEACON (NCT01721044) with IR to at least one tumor necrosis factor inhibitors; ii) baricitinib 2 mg versus placebo from RA-BUILD and RA-BEACON; and iii) adalimumab 40 mg every other week versus placebo from RA-BEAM. Pain was measured by the Patient Assessment of Pain Visual Analog Scale. Analysis of covariance modeling assessed differences in pain reduction between treatments at each time point through Week 24, with an interaction term to test heterogeneous treatment effects across opioid users and nonusers. RESULTS: Baricitinib 4 mg had greater pain reduction versus placebo in opioid users and nonusers (P < 0.05) at all time points starting from Week 1; the pain reduction was similar between opioid users and nonusers. Baricitinib 2 mg had greater pain reduction versus placebo in opioid users and nonusers starting at Week 4. A significant difference in pain reduction was not observed for adalimumab versus placebo in the opioid users but was observed in nonusers at all time points. CONCLUSION: Pain reduction was observed and was similar between opioid users and nonusers with baricitinib 2 mg and 4 mg but not adalimumab in this post hoc analysis.

Estudio primario

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Baricitinib further enhances disease-modifying effects by uncoupling the link between disease activity and joint structural progression in patients with rheumatoid arthritis.

Revista Annals of the rheumatic diseases
Año 2022
Enlaces Pubmed DOI PubMed Central
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OBJECTIVES: To evaluate if baricitinib, a Janus kinase inhibitor, further enhances disease-modifying effects by uncoupling the link between disease activity and structural damage progression in patients with rheumatoid arthritis (RA) using two phase III randomised, double-blinded trials. METHODS: In RA-BEAM, patients with established RA and inadequate response to methotrexate (MTX-IR) received placebo (PBO), baricitinib 4 mg or adalimumab 40 mg on background MTX. In RA-BEGIN, conventional synthetic disease-modifying antirheumatic drug (csDMARD)-naïve patients received MTX, baricitinib 4 mg or baricitinib 4 mg plus MTX. Using linear regression analyses, joint damage progression (assessed by change from baseline in van der Heijde modification of the Total Sharp Score) was compared between treatment groups for patients achieving certain disease activity states by the Clinical Disease Activity Index. Time-averaged postbaseline responses were used to week 24 (RA-BEAM) and week 52 (RA-BEGIN). RESULTS: For MTX-IR patients, structural damage progression was reduced regardless of disease activity states in baricitinib-treated patients (p=0.6), whereas in PBO patients there was a clear dependence on disease activity states, being significantly lower in those who achieved remission/low disease activity (REM/LDA) compared with moderate/high disease activity (MDA/HDA) (p=0.02). Furthermore, the baricitinib MDA/HDA group had less damage progression than the PBO MDA/HDA group (p<0.001). For csDMARD-naïve patients, progression was lower in REM/LDA versus MDA/HDA within the MTX group (p<0.001). However, for baricitinib+MTX (p=0.5) or baricitinib monotherapy (p=0.07), progression was similar regardless of disease activity. In MDA/HDA groups, progression was lower with baricitinib+MTX (p<0.001) and numerically lower with baricitinib monotherapy (p=0.07) versus MTX. C reactive protein (≤5 mg/L and >5 mg/L) sensitivity analyses supported the primary findings. CONCLUSIONS: Baricitinib reduces structural damage progression versus PBO with background MTX and/or MTX, even in patients with MDA/HDA, showing a disease-modifying effect across all disease activity states.