RA-BUILD
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Estudio primario

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A Study in Moderate to Severe Rheumatoid Arthritis Participants

Registro de estudios ClinicalTrials.gov
Año 2012
Enlaces Registro de estudios

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The purpose of this study is to determine whether baricitinib 4 milligram (mg) once daily (QD) is superior to placebo in the treatment of participants with moderately to severely active Rheumatoid Arthritis (RA) who have had inadequate response to or are intolerant to at least 1 conventional disease-modifying antirheumatic drug (cDMARD)(cDMARD-IR \[inadequate response\] participants) and who have not received a biologic disease-modifying antirheumatic drug (DMARD).

Estudio primario

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Patient-Reported Outcomes from a Phase 3 Study of Baricitinib in Patients with Rheumatoid Arthritis with Inadequate Response to Conventional Synthetic Disease-Modifying Antirheumatic Drugs

Autores Emery P , Gaich CL , DeLozier AM
Revista Arthritis Rheumatol
Año 2015

Este artículo está incluido en 1 Revisión sistemática Revisiones sistemáticas (1 referencia)

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Estudio primario

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Baricitinib, an oral janus kinase (jak)1/jak2 inhibitor, in patients with active rheumatoid arthritis (RA) and an inadequate response to cDMARD therapy: Results of the phase 3 Ra-build study

Revista Annals of the Rheumatic Diseases
Año 2015
Enlaces DOI www.cochranelibrary.com

Este artículo está incluido en 1 Revisión sistemática Revisiones sistemáticas (1 referencia)

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Background: In ph 2 studies, baricitinib (bari) improved disease activity with an acceptable safety profile in patients (pts) with active RA and inadequate response (IR) to conventional DMARDs (cDMARDs). Objectives: To report results from a 24-week (Wk) global ph 3 study of bari in pts with active RA and an IR or intolerance to ≥1 cDMARD. Methods: Pts with active RA (TJC & SJC≥6 & hsCRP≥3.6 mg/L) with stable background treatment were randomized 1:1:1 to placebo (PBO) or bari (2 or 4 mg) QD, stratified by region and baseline joint erosion status, with rescue from Wk 16 for nonresponders. Primary endpoint was ACR20 response at Wk 12 for bari 4 mg vs. PBO. Results: Of 684 randomized pts, 81% were seropositive with mean baseline DAS28 of 5.55 (-hsCRP) and 6.22 (-ESR). Rescue rates were 9%, 7%, and 24% for bari 2 mg, 4 mg, PBO, respectively. ACR20 response at Wk 12 was 62% with bari 4 mg vs. 40% with PBO (p≤0.001). Improvements in ACR50, ACR70, DAS28, CDAI, SDAI, and HAQ-DI were seen (Table), many as early as Wk 1. Change in mTSS at Wk 24 was lower with bari 2 or 4 mg vs. PBO (p≤0.05, p≤0.01, respectively). TEAE and SAE rates, including serious infections, were similar among pts receiving bari 2 or 4 mg or PBO (SAEs: 3%, 5%, 5%, respectively). There were no GI perforations or opportunistic infections. In the bari 4 mg group, 1 TB case and 1 NMSC case occurred. In the PBO group, 2 deaths and 2 MACE occurred. Lab findings were similar to ph 2; few abnormalities led to discontinuation. (Table Presented) Conclusions: Once daily oral bari was associated with rapid and sustained clinical improvement and inhibition of radiographic joint damage, with an acceptable safety and tolerability profile. The most robust benefit across measures was seen with the 4 mg dose.

Estudio primario

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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.

No clasificado

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

Revista Annals of the Rheumatic Diseases
Año 2017
Enlaces DOI www.cochranelibrary.com
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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 in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study.

Revista Annals of the rheumatic diseases
Año 2017
Enlaces Pubmed DOI PubMed Central

Este artículo está incluido en 17 Revisiones sistemáticas Revisiones sistemáticas (17 referencias)

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BACKGROUND: Baricitinib is an oral, reversible, selective Janus kinase 1 and 2 inhibitor. METHODS: In this phase III, double-blind 24-week study, 684 biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with rheumatoid arthritis and inadequate response or intolerance to ≥1 conventional synthetic DMARDs were randomly assigned 1:1:1 to placebo or baricitinib (2 or 4 mg) once daily, stratified by region and the presence of joint erosions. Endpoint measures included American College of Rheumatology 20% response (ACR20, primary endpoint), Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) score ≤3.3. RESULTS: More patients achieved ACR20 response at week 12 with baricitinib 4 mg than with placebo (62% vs 39%, p≤0.001). Compared with placebo, statistically significant improvements in DAS28, SDAI remission, Health Assessment Questionnaire-Disability Index, morning joint stiffness, worst joint pain and worst tiredness were observed. In a supportive analysis, radiographic progression of structural joint damage at week 24 was reduced with baricitinib versus placebo. Rates of adverse events during the treatment period and serious adverse events (SAEs), including serious infections, were similar among groups (SAEs: 5% for baricitinib 4 mg and placebo). One patient had an adverse event of tuberculosis (baricitinib 4 mg); one patient had an adverse event of non-melanoma skin cancer (baricitinib 4 mg). Two deaths and three major adverse cardiovascular events occurred (placebo). Baricitinib was associated with a decrease in neutrophils and increases in low-density and high-density lipoprotein. CONCLUSIONS: In patients with rheumatoid arthritis and an inadequate response or intolerance to conventional synthetic DMARDs, baricitinib was associated with clinical improvement and inhibition of progression of radiographic joint damage. TRIAL REGISTRATION NUMBER: NCT01721057; Results.

Estudio primario

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Concomitant use of conventional synthetic DMARDs and response to baricitinib

Revista Annals of the Rheumatic Diseases
Año 2017
Enlaces DOI www.cochranelibrary.com

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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

Patient-reported outcomes from a phase III study of baricitinib in patients with conventional synthetic DMARD-refractory rheumatoid arthritis

Revista RMD open
Año 2017
Enlaces Pubmed DOI PubMed Central www.cochranelibrary.com

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Objectives To evaluate the effect of baricitinib on patient-reported outcomes (PROs) in patients with active rheumatoid arthritis (RA) and an inadequate response or intolerance to conventional synthetic disease-modifying antirheumatic drugs. Methods In this phase III study, patients were randomised 1:1:1 to placebo (N=228), baricitinib 2 mg once daily (QD, N=229) or baricitinib 4 mg QD (N=227). PROs included the Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient's Global Assessment of Disease Activity (PtGA), patient's assessment of pain, measures from patient electronic daily diaries (duration and severity of morning joint stiffness (MJS), Worst Tiredness, Worst Joint Pain), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), SF-36, EuroQol 5-D index scores and visual analogue scales (VAS) and the Work Productivity and Activity Impairment Questionnaire-RA. The primary time point for the study was week 12. Treatment comparisons were assessed with logistic regression for categorical measures and analysis of covariance for continuous variables. Results Statistically significant improvements were observed for both baricitinib groups versus placebo in HAQ-DI, PtGA, pain, daily diary measures, EuroQoL index scores and SF-36 physical component score at week 12 and for those measures when assessed at week 24. Baricitinib 2 mg and baricitinib 4 mg were statistically significantly improved versus placebo for the EuroQoL VAS and FACIT-F, respectively, at week 24. Conclusions Baricitinib 2 or 4 mg provided significant improvement versus placebo in PROs across different domains of RA, including physical function, MJS, fatigue, pain and quality of life. Trial registration number NCT01721057; Results.

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.

No clasificado

Efficacy of baricitinib in patients with rheumatoid arthritis who failed 2 or more DMARDs

Revista Annals of the Rheumatic Diseases
Año 2018
Enlaces DOI www.cochranelibrary.com
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Background: Baricitinib (Bari) is an oral Janus Kinase (JAK)1/JAK2 inhibitor in development for patients with active rheumatoid arthritis (RA). In Phase 3 studies, Bari has demonstrated clinical efficacy and has a favorable safety profile. Objectives: To evaluate Bari 2-and 4-mg in patients who have failed multiple DMARDs, across several studies. Methods: Data from the subgroup of patients who had failed ≥2 DMARDs, including approx. one-half of patients in RA-BUILD (csDMARD-IR) and RA-BEAM (MTX-IR) and all patients from RA-BEACON (bDMARD-IR) were assessed, post hoc, for comparison of Bari 2-mg and 4-mg to placebo across time points using the following measures: ACR20, ACR50, ACR70, SDAI, CDAI, DAS28-CRP, HAQ-DI, and radiographic assessment of structural damage (mTSS), as well as safety. For patients who had failed ≥2 DMARDs from RA-BEAM, a comparison was also made between Bari 4-mg and adalimumab. Results: In the ≥2 DMARD-IR populations from RA-BEACON, RA-BUILD, and RA-BEAM, >95% had failed MTX as one of the DMARDs. Compared to PBO in this population, Bari resulted in statistically significantly greater improvement in efficacy measures at Week 24, including physical function (Table). In the ≥2 DMARD-IR population from RA-BEAM (all patients received background MTX), Bari 4-mg was associated with greater improvements compared to adalimumab (table 1 and figure 1). Compared to PBO, Bari 4-mg statistically significantly inhibited structural progression at Week 24 in the ≥2 DMARD-IR subsets of RA-BEAM and RA-BUILD. The overall safety profile of Bari 4-mg in the ≥2 DMARD-IR population was consistent with findings from the overall baricitinib-treated population. ¥Data are the proportion (%) of pts who achieved the response at Week 24 (nonresponder imputation), unless otherwise indicated. Approximately 56% of patients in RA-BUILD and 54% of patients in RA-BEAM failed ≥2 DMARDs. D=least squares mean change from baseline (modified last observation carried forward). mTSS data are as randomized using last observation carried forward. (Table Presented) Conclusions: These data demonstrate that a dose response is present between Bari 2-mg and Bari 4-mg, with both doses providing benefit in the patients who failed multiple DMARDs in the phase 3 program by improving signs and symptoms, physical function, and structure.

Estudio primario

No clasificado

Effects of baricitinib on radiographic progression of structural joint damage at 1 year in patients with rheumatoid arthritis and an inadequate response to conventional synthetic Disease-Modifying antirheumatic drugs

Revista RMD open
Año 2018
Enlaces Pubmed DOI PubMed Central www.cochranelibrary.com
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Background Baricitinib was efficacious in a 24-week phase III study in patients with rheumatoid arthritis (RA) and an inadequate response to conventional synthetic disease-modifying anti rheumatic drugs (DMARDs) (csDMARDs) (RA-BUILD). Objectives To evaluate radiographic progression of structural joint damage in RA-BUILD patients over 48 weeks of baricitinib treatment in the long-term extension study, RA-BEYOND. Methods In RA-BUILD, patients were randomised to placebo, baricitinib 2 mg or 4 mg once daily, with rescue possible from week 16. Patients completing RA-BUILD and entering RA-BEYOND continued to receive the baricitinib dose received at the end of RA-BUILD. Patients receiving placebo were switched to baricitinib 4 mg in RA-BEYOND. Joint damage was measured using the van der Heijde modified total Sharp score. To account for missing scores and scores obtained after rescue, switch or discontinuation of study drug, data were analysed using (1) linear extrapolation (LE) and (2) observed/last observation carried forward (LOCF). The observed/LOCF method used all available observed data, including after rescue or switch, with patients analysed according to original treatment assignment. Results Using LE, radiographic progression at 24 and 48 weeks was statistically significantly lower for both baricitinib 2 or 4 mg compared with placebo. Only baricitinib 4 mg demonstrated statistically significant inhibition of progressive radiographic joint damage compared with patients initially randomised to placebo using observed/LOCF at week 48. Conclusions Once daily oral baricitinib inhibited radiographic progression of structural joint damage in patients with an inadequate response or intolerance to csDMARDs over 48 weeks. The most robust benefit was seen for the 4 mg dose.

Estudio primario

No clasificado

Safety and Efficacy of Baricitinib in Patients Receiving Conventional Synthetic Disease-Modifying Antirheumatic Drugs or Corticosteroids

Revista Rheumatology and therapy
Año 2018
Enlaces Pubmed DOI PubMed Central www.cochranelibrary.com
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Introduction: This study assessed if concomitant use of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or corticosteroids altered the response or safety outcomes to baricitinib in rheumatoid arthritis (RA) patients. Methods: Patients with ≥ 6 swollen/tender joints and no prior biologic DMARD were eligible for study inclusion. In RA-BUILD, csDMARD-inadequate responder (IR) patients were randomized to placebo or baricitinib (2 or 4 mg) once daily (QD). In RA-BEAM, methotrexate (MTX)-IR patients were randomized to placebo QD, baricitinib 4-mg QD, or adalimumab 40-mg biweekly. Patients continued background csDMARD (including MTX) therapy. This post hoc analysis of placebo and baricitinib 4-mg patients assessed the number and type of concomitant csDMARDS and concurrent corticosteroid use. Results: From 716 placebo patients, 71, 21, and 6% were taking MTX alone, MTX + ≥ 1 csDMARD, and non-MTX csDMARDs, respectively; from 714 baricitinib patients, the rates were 74, 18, and 6%; 56% of placebo and 55% of baricitinib patients used corticosteroids at baseline (mean dose, 6.0 mg/day for both groups); patients continued use throughout the studies. The odds ratios for achieving American College of Rheumatology response at the 20% improvement level (ACR20) and Clinical Disease Activity Index (CDAI) ≤ 10 at week 12 favored baricitinib for most subgroups; no significant interactions were observed. Rates of adverse events were similar regardless of csDMARD group or corticosteroid use. There were numerically more serious adverse events in placebo patients taking corticosteroids (4.2 vs. 1.6%) and a higher rate of discontinuations in baricitinib patients taking corticosteroids (4.1 vs. 1.2%). Conclusions: Baricitinib was efficacious regardless of concomitant use of csDMARDs or corticosteroids; the incidence of adverse events was similar across all groups of patients. Funding: Eli Lilly and Company and Incyte Corporation.

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
Enlaces Pubmed DOI PubMed Central www.cochranelibrary.com
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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
Enlaces Pubmed DOI PubMed Central www.cochranelibrary.com
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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.

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

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

Revista Arthritis research & therapy
Año 2020
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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.

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Erratum: temporary interruption of baricitinib: characterization of interruptions and effect on clinical outcomes in patients with rheumatoid arthritis (Arthritis Research & Therapy (2020) 22 (115) DOI: 10.1186/s13075-020-02199-8)

Revista
Año 2020
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Following publication of the original article [1], the authors identified errors in Fig. 1. The legends in Fig. 1c and d refer to placebo, baricitinib 4‐mg and adalimumab treatment groups; the legends should refer to placebo, baricitinib 2‐mg, and baricitinib 4‐mg and the reference to these two studies in the figure caption are reversed. Additionally, the total number of interruptions for baricitinib 4‐mg in RA‐BEAM (Fig. 1b) has been corrected from 82 to 62 and the title for RA‐BEAM has been corrected from 0‐52 weeks to 0‐24 weeks; labels have been corrected for MTX (8–14 days) in RA‐BEGIN from 28 to 29 and for placebo (15–21 days) in RA‐BUILD from 17 to 16. The corrected Fig. 1 is given below. (Figure Presented).

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The Janus kinase 1/2 inhibitor baricitinib reduces biomarkers of joint destruction in moderate to severe rheumatoid arthritis

Revista Arthritis research & therapy
Año 2020
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Background: Tissue released blood‐based biomarkers can provide insight into drug mode of action and response. To understand the changes in extracellular matrix turnover, we analyzed biomarkers associated with joint tissue turnover from a phase 3, randomized, placebo‐controlled study of baricitinib in patients with active rheumatoid arthritis (RA). Methods: Serum biomarkers associated with synovial inflammation (C1M, C3M, and C4M), cartilage degradation (C2M), bone resorption (CTX‐I), and bone formation (osteocalcin) were analyzed at baseline, and weeks 4 and 12, from a subgroup of patients (n = 240) randomized to placebo or 2‐mg or 4‐mg baricitinib (RA‐BUILD, NCT01721057). Mixed‐model repeated measure was used to identify biomarkers altered by baricitinib. The relationship between changes in biomarkers and clinical measures was evaluated using correlation analysis. Results: Treatment arms were well balanced for baseline biomarkers, demographics, and disease activity. At week 4, baricitinib 4‐mg significantly reduced C1M from baseline by 21% compared to placebo (p < 0.01); suppression was sustained at week 12 (27%, p < 0.001). Baricitinib 4‐mg reduced C3M and C4M at week 4 by 14% and 12% compared to placebo, respectively (p < 0.001); they remained reduced by 16% and 11% at week 12 (p < 0.001). In a pooled analysis including all treatment arms, patients with the largest reduction (upper 25% quartile) in C1M, C3M, and C4M by week 12 had significantly greater clinical improvement in the Simplified Disease Activity Index at week 12 compared to patients with the smallest reduction (lowest 25% quartile). Conclusion: Baricitinib treatment resulted in reduced circulating biomarkers associated with joint tissue destruction as well as concomitant RA clinical improvement. Trial registration: ClinicalTrials.gov NCT01721057; date of registration: November 1, 2012.

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Efficacy of Long-Term Treatment with Once-Daily Baricitinib 2 mg in Patients with Active Rheumatoid Arthritis: Post Hoc Analysis of Two 24-Week, Phase III, Randomized, Controlled Studies and One Long-Term Extension Study

Revista Rheumatology and therapy
Año 2021
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Introduction: To evaluate long-term efficacy of once-daily baricitinib 2 mg in patients with active rheumatoid arthritis who had an inadequate response (IR) to conventional synthetic disease-modifying antirheumatic drugs (csDMARD) or biologic DMARDs (bDMARD). Methods: Data from patients treated with baricitinib 2 mg daily in two 24-week, phase III studies, RA-BUILD (csDMARD-IR; NCT01721057) and RA-BEACON (bDMARD-IR; NCT01721044), and one long-term extension study (RA-BEYOND; NCT01885078), were analyzed (120 weeks). The main outcomes were achievement of low-disease activity (LDA; Simple Disease Activity Index [SDAI] ≤ 11), clinical remission (SDAI ≤ 3.3), Health Assessment Questionnaire Disability Index (HAQ-DI) ≤ 0.5 and improvement from baseline of ≥ 0.22, and safety. Analysis populations included (1) all patients and (2) never-rescued patients. Completer and non-responder imputation (NRI) analyses were conducted on each population. Results: In RA-BUILD, 684 were randomized (229 to baricitinib 2 mg, 180 of whom completed RA-BUILD and entered RA-BEYOND). In RA-BEACON, 527 were randomized (174 to baricitinib 2 mg, 117 of whom completed RA-BEACON and entered RA-BEYOND). In RA-BUILD-BEYOND, 85.1% (63/74, completer) and 27.5% (63/229, NRI) of csDMARD-IR patients treated with baricitinib 2 mg achieved SDAI LDA; 40.5% (30/74, completer) and 13.1% (30/229, NRI) were in SDAI remission; 62.2% (46/74, completer) and 20.1% (46/229, NRI) had HAQ-DI ≤ 0.5 and 81.1% (60/74, completer); and 26.2% (60/229, NRI) achieved ≥ 0.22 change from baseline at week 120. In RA-BEACON-BEYOND, 86.5% (32/37, completer) and 18.4% (32/174, NRI) of bDMARD-IR patients treated with baricitinib 2 mg achieved SDAI LDA; 24.3% (9/37, completer) and 5.2% (9/174, NRI) were in SDAI remission; 50.0% (19/38, completer) and 10.9% (19/174, NRI) had HAQ-DI ≤ 0.5; and 73.7% (28/38, completer) and 16.1% (28/174, NRI) achieved ≥ 0.22 change from baseline at week 120. Rates of adverse events of special interest were consistent with previous reports. Conclusions: Long-term treatment with baricitinib 2 mg demonstrated efficacy for up to 120 weeks and was well tolerated. Trial registration: ClinicalTrials.gov identifier, NCT01721057, NCT01721044, and NCT01885078.

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Maintenance of Patient-Reported Outcomes in Baricitinib-Treated Patients with Moderate-to-Severe Active Rheumatoid Arthritis: Post Hoc Analyses from Two Phase 3 Trials

Revista Rheumatology and therapy
Año 2022
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INTRODUCTION: Baricitinib has been shown to improve patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) who are inadequate responders (IR) to conventional synthetic and biologic disease-modifying antirheumatic drugs (csDMARDs and bDMARDs, respectively). We assessed the ability of baricitinib 2-mg to maintain minimal clinically important differences (MCIDs) in PROs until week 24 among week 4 and 12 responders. METHODS: Data were from two phase 3 trials, RA-BUILD (NCT01721057; csDMARD-IR patients) and RA-BEACON (NCT01721044; bDMARD-IR patients). PROs included Pain Visual Analogue Scale, Health Assessment Questionnaire-Disability Index, Functional Assessment of Chronic Illness Therapy-Fatigue, Short-Form 36 Physical Component Score, and Patient's Global Assessment of Disease Activity. Outcomes were evaluated by proportions of patients achieving MCID improvements, number needed to treat (NNT) at weeks 4, 12, and 24, proportions of patients maintaining MCID responses at week 24 among week 4 or 12 responders, and median time to achieve substantial response with baricitinib 2-mg versus placebo. RESULTS: A higher proportion of baricitinib-treated patients achieved MCID improvements, with NNTs ranging from 5 to 8 for baricitinib 2-mg versus placebo at week 24. Generally, early MCID responses in PROs at weeks 4 or 12 were better maintained through week 24 in RA patients treated with baricitinib 2-mg versus placebo. Patients treated with baricitinib 2-mg also achieved substantial PRO responses or normative values more quickly than placebo. CONCLUSIONS: These results suggest baricitinib-treated patients with RA achieving MCID improvement in PROs at weeks 4 and 12 maintained those improvements over time and that substantial PRO responses were achieved quickly.

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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
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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.