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: Methotrexat HEXAL® 2,5 mg Tabletten Pharmaceutical Form: Capsule INN or Proposed INN: METHOTREXATE CAS Number: 59‐05‐2 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 2.5‐ Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use Trade Name: Methotrexate 2.5mg Tablets Pharmaceutical Form: Capsule INN or Proposed INN: METHOTREXATE CAS Number: 59‐05‐2 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 2.5‐ Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use Trade Name: Methotrexate 2.5 mg tablets Pharmaceutical Form: Capsule INN or Proposed INN: METHOTREXATE CAS Number: 59‐05‐2 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 2.5‐ Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use Trade Name: Methotrexat HEXAL® 2,5 mg Tabletten Pharmaceutical Form: Capsule INN or Proposed INN: METHOTREXATE CAS Number: 59‐05‐2 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 5‐ Trade Name: Methotrexate 2.5mg Tablets Pharmaceutical Form: Capsule INN or Proposed INN: METHOTREXATE CAS Number: 59‐05‐2 Concentration unit: mg milligram(s) Concentration type: equal Concentration numbe CONDITION: Moderately to severely active rheumatoid arthritis ; MedDRA version: 17.1 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 ‐ Musculoskeletal and connective tissue disorders Therapeutic area: Diseases [C] ‐ Musculoskeletal Diseases [C05] SECONDARY OUTCOME: Secondary end point(s): Endpoint 2 ‐ Proportion of patients achieving ACR20 (baricitinib plus MTX compared to MTX monotherapy) ; Endpoint 3 ‐ Change from baseline in Health Assessment Questionnaire Disability Index (HAQ‐DI) ; Endpoint 4 ‐ Change from baseline in DAS28‐high‐sensitivity C‐reactive protein (hsCRP) ; Endpoint 5 ‐ Change from baseline in Modified Total Sharp Score (mTSS [van der Heijde method]) ; Endpoint 6 ‐ AUC of HAQ‐DI (baricitinib monotherapy compared to MTX monotherapy) ; Endpoint 7 ‐ AUC of DAS28‐hsCRP (baricitinib monotherapy compared to MTX monotherapy) ; Endpoint 8 ‐Proportion of patients achieving ACR20 ; Endpoint 9 ‐ Proportion of patients achieving ACR50 ; Endpoint 10 ‐ Proportion of patients achieving ACR70 ; Endpoint 11 ‐ Proportion of patients achieving DAS28‐hsCRP =3.2 ; Endpoint 12 ‐ Proportion of patients achieving DAS28‐ hsCRP <2.6 ; Endpoint 13 ‐ Proportion of patients achieving DAS28‐ESR =3.2 ; Endpoint 14 ‐ Proportion of patients achieving DAS28‐ESR <2.6 ; ; ; Timepoint(s) of evaluation of this end point: Enpoints 2 to 7: Week 24 ; Enpoint 8: Weeks 12 and 52 ; Enpoints 9 to 14: Weeks 12, 24 and 52 INCLUSION CRITERIA: • are at least 18 years of age • have a diagnosis of adult‐onset RA as defined by ACR/EULAR 2010 Criteria for the Classification of RA • have documented history of positive rheumatoid factor and/or cyclic citrullinated peptide (CCP) antibody test PRIMARY OUTCOME: Main Objective: Determine whether baricitinib monotherapy is noninferior to MTX monotherapy in the treatment of patients with moderate to severe active RA who have had limited or no treatment with MTX and are naive to other conventional or biologic DMARDs, as assessed by the proportion of patients achieving a 20% improvement in American College of Rheumatology criteria (ACR20) at Week 24. Primary end point(s): Endpoint 1: Proportion of patients achieving ACR20 (noninferiority of baricitinib monotherapy to MTX monotherapy); Secondary Objective: • proportion of patients achieving ACR20 at Week 24 for baricitinib plus MTX versus MTX monotherapy; • change from baseline to Week 24 in Health Assessment Questionnaire‐Disability Index (HAQ‐DI) score ; • change from baseline to Week 24 in DAS28–high‐sensitivity C reactive protein (hsCRP) ; • change from baseline to Week 24 in structural joint damage as measured by modified Total Sharp Score (mTSS [van der Heijde method]) for baricitinib plus MTX versus MTX monotherapy; • change from baseline up to Week 24 in HAQ‐DI score for baricitinib monotherapy versus MTX monotherapy; • change from baseline up to Week 24 in DAS28‐hsCRP score for baricitinib monotherapy versus MTX monotherapy; • proportion of patients achieving an SDAI score =3.3 at week 12 Timepoint(s) of evaluation of this end point: Enpoint 1: Week 24; • 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 (or hsCRP) measurement =1.2 times the upper limit of normal (ULN) • have had limited or no treatment with MTX Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range
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 CONDITION: Moderately to severely active rheumatoid arthritis ; MedDRA version: 14.1 Level: SOC Classification code 10028395 Term: Musculoskeletal and connective tissue disorders System Organ Class: 10028395 ‐ Musculoskeletal and connective tissue disorders ; 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 4 mg QD is superior to placebo in the treatment of patients with moderately to severely active RA who have had inadequate response to or are intolerant to at least 1 cDMARD (cDMARD‐IR [inadequate response] patients) and who have not received a biologic DMARD, as assessed by the portion of patients achieving ACR20 at Week 12 ECG Addendum ‐ Approved: 22‐Aug‐2012 Primary objective is to compare the change from baseline in QTcF interval at approximately 90 minutes following first dose of investigational product (Week 0) and at week 1, Week 4, and week 12 between Baricitinib 4 mg QD and placebo. Primary end point(s): Proportion of patients achieving ACR20 response (baricitinib 4mg compared to placebo) Secondary Objective: ‐ change from baseline to Week 12 in Health Assessment Questionnaire‐Disability Index (HAQ‐DI) score ‐ change from baseline to week 12 in DAS28‐high‐sensitivity C‐reactive protein (hsCRP) ‐ proportion of patients achieving ACR20 at Week 12 (Baricitinib 2 mg compared to placebo) Timepoint(s) of evaluation of this end point: Week 12 SECONDARY OUTCOME: Secondary end point(s): DAS28‐high‐sensitivity C‐reactive protein (hsCRP): ‐ Proportion of patients achieving ACR20 response (baricitinib 2mg compared to placebo) Timepoint(s) of evaluation of this end point: DAS28‐high‐sensitivity C‐reactive protein (hsCRP): Change from baseline to Weeks 12 and 24 ‐ Proportion of patients achieving ACR20 response (baricitinib 2mg compared to placebo) : Week 12 INCLUSION CRITERIA: ‐almeno 18 anni di età ‐diagnosi di Artrite Reumatoide iniziata in età adulta come definito dai criteri per la classificazione di AR ACR/EULAR 2010 ‐ AR da moderata a severa definita come almeno 6/68 articolazioni lasse e 6/66 tumefazioni delle articolazioni ‐ Valore della Proteina reattiva C > o uguale ad 1.2 ULN Risposta insufficiente o intolleranza ai cDMARDs o entrambe: uso regolare di un cDMARD per almeno 12 settimane prima di entrare in studio con un una dose continua e stabile per almeno le precedenti 8 settimane; Pe i pazienti che non in trattamento con cDMARD al momento dell'entrata in studio, l'investigatore dovrà documentare in cartella che il paziente ha fallito, non era in grado di tollerare o aveva qualche cntroindicazone per il trattamento con cDMARDs Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 600 F.1.3 Elderly (>=65 y
The purpose of this study is to determine whether baricitinib therapy alone is noninferior to methotrexate (MTX) therapy alone in the treatment of moderate to severe active rheumatoid arthritis (RA) in those who have had limited or no treatment with MTX and are naive to other conventional or biologic disease-modifying antirheumatic drugs (DMARDs).
Background: Baricitinib (bari), an oral JAK1 and JAK2 inhibitor, was efficacious in a Ph 3 study (RA-BEGIN) in RA patients (pts) who had limited or no exposure to methotrexate (MTX) and who were naïve to other csDMARDs and bDMARDs.1 Objectives: To evaluate patient-reported outcomes (PROs) from RA-BEGIN. Methods: Pts were randomized to MTX QW, bari 4 mg QD, or bari 4 mg QD+MTX QW. PROs listed in the table and the Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA) questionnaire were collected on electronic tablets during study visits. Bari vs. MTX and bari+MTX vs. MTX were assessed with ANCOVA and logistic regression models. Results: 584 pts were randomized. Mean baseline PROs for MTX, bari, and bari+MTX, respectively, were HAQ-DI:1.67, 1.64, 1.58; Pt's Global Assessment of Disease Activity (PtGDA):65.6, 65.0, 63.1; pt assessment of pain:65.2, 64.1, 62.6. Compared to MTX, bari and bari+MTX were superior in physical function, PtGDA, pain, and fatigue at Wks 24 and 52. Statistically significant improvements in all components of the WPAI-RA (absenteeism, presenteeism, work productivity loss and activity impairment) were seen in the bari and bari+MTX pts vs. MTX at Wk 24; statistically significant improvements were seen for work loss for bari+MTX vs. MTX at Wk 52 and for activity impairment for bari and bari+MTX vs MTX at Wk 52. Conclusions: In this Ph 3 study of pts with early active RA, bari alone or with MTX was associated with significant improvements at 24 and 52 wks compared to MTX in most PROs.
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).
OBJECTIVE: We undertook this phase III study to evaluate baricitinib, an orally administered JAK-1/JAK-2 inhibitor, as monotherapy or combined with methotrexate (MTX) compared to MTX monotherapy in patients with active rheumatoid arthritis (RA) who had received no or minimal conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and who were naive to biologic DMARDs.
METHODS: A total of 588 patients were randomized 4:3:4 to receive MTX monotherapy (once weekly), baricitinib monotherapy (4 mg once daily), or the combination of baricitinib and MTX for 52 weeks. The primary end point assessment was a noninferiority comparison of baricitinib monotherapy to MTX monotherapy based on the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 24.
RESULTS: The study met its primary objective. Moreover, baricitinib monotherapy was found to be superior to MTX monotherapy at week 24, with a higher ACR20 response rate (77% versus 62%; P ≤ 0.01). Similar results were observed for combination therapy. Compared to MTX monotherapy, significant improvements in disease activity and physical function were observed for both baricitinib groups as early as week 1. Radiographic progression was reduced in both baricitinib groups compared to MTX monotherapy; the difference was statistically significant for baricitinib plus MTX. The rates of serious adverse events (AEs) were similar across treatment groups, while rates of some treatment-emergent AEs, including infections, were increased with baricitinib plus MTX. Three deaths were reported, all occurring in the MTX monotherapy group. Malignancies, including nonmelanoma skin cancer, were reported in 1 patient receiving MTX monotherapy, 1 receiving baricitinib monotherapy, and 4 receiving baricitinib plus MTX.
CONCLUSION: Baricitinib alone or in combination with MTX demonstrated superior efficacy with acceptable safety compared to MTX monotherapy as initial therapy for patients with active RA.
Background: Baricitinib (BARI), an oral inhibitor of Janus kinase (JAK) 1 and JAK 2, is being developed for the treatment of rheumatoid arthritis (RA). RA-BEGIN was a phase 3 double-blind, three-arm multicentre study of BARI administered as monotherapy or in combination with methotrexate (MTX) to patients (pts) with early active RA who had no or limited treatment with DMARDs. Methotrexate (MTX) monotherapy was the active comparator. Objectives: To evaluate the proportion of pts with structural damage progression, defined as change from baseline (CFB) greater than the smallest detectable change (SDC) in mTSS at week (wk) 52, depending on their disease state as measured by DAS28-CRP. Methods: Pts were classified into two groups based on DAS28-CRP. Group A included pts who achieved sustained DAS28-CRP ≤3.2 at weeks 16, 20 and 24. Pts who did not achieve DAS28-CRP ≤3.2 consecutively at weeks 16, 20 and 24 and pts with missing DAS28-CRP at any of those 3 visits were included in Group B. The proportion of pts with CFB mTSS > SDC at wk 52 was estimated for each treatment arm for the two defined groups of response. The SDC in mTSS in the RA-BEGIN population at wk 52 was 1.4. Missing mTSS at wk 52 were imputed using linear extrapolation based on baseline data and the most recent radiographic data prior to the missed radiograph. No formal statistical tests were performed and comparisons are merely descriptive. All analyses were post-hoc. Results: Out of the 584 pts of the modified-ITT population (all randomised pts who received at least 1 dose of study drug) in the RA-BEGIN study, 212 were classified in Group A: 21.4% (45/210), 42.1% (67/159), and 46.5% (100/215) for MTX, BARI and BARI+MTX, respectively. The odds ratios for sustained DAS28-CRP ≤3.2 response (weeks 16, 20 and 24) to BARI and BARI+MTX vs. MTX, were respectively 2.8 (95% CI 1.7-4.4) and 3.3 (95% CI 2.1-5.1). Pts classified in Group A maintained an adequate level of response up to wk 52. Further, pts in Group A (sustained DAS28-CRP ≤3.2) on either BARI + MTX or BARI, were less likely to show structural progression than patients who achieved sustained DAS28-CRP ≤3.2 on MTX. Pts in Group B on MTX or BARI monotherapy were more likely to show structural progression than patients who did not achieve a sustained DAS28-CRP ≤3.2 response on BARI + MTX (Figure 1). Footnote: Group A: Patients who achieved sustained DAS28-CRP ≤3.2 (NRI) at weeks 16, 20 and 24 (N=212); Group B: Complement group Conclusions: In patients who achieved sustained low DAS28-CRP scores, progression rates compared to MTX were reduced to a similar degree with BARI as monotherapy or in combination with MTX. Compared to MTX in patients who did not achieve sustained low DAS28-CRP scores, progression rates were reduced most markedly with combination therapy.
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.
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 limited or no disease-modifying antirheumatic drug (DMARD) and naïve to biologic DMARDs. ∗LA countries: Argentina, Brazil, and Mexico. Methods: In the global 52-week, double-blind RA-BEGIN study, 584 patients were randomized to receive orally methotrexate (MTX) once weekly, 4 mg BARI daily, and 4 mg BARI plus MTX. Physical function, pain, fatigue, and quality of life (HRQOL) (Health Assessment Questionnaire-Disability Index [HAQ-DI], pain visual analog scale, Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F], and Short Form-36 [SF-36], respectively) for 169 LA patients from baseline to Week 24 were compared between treatments using ANCOVA. Missing values were imputed using modified last observation-carried forward (mLOCF). Results: Significantly greater improvement (p< 0.05) in HAQ-DI for patients treated with BARI monotherapy (mono) or combination therapy (combo) vs. patients treated with MTX mono was observed as early as Week 1 and at Week 24. Patients treated with BARI mono or combo also showed significantly greater (p< 0.05) improvements in pain and FACIT-F as early as Week 1. This result was maintained at Week 24 (p< 0.05) for the combination therapy in comparison with MTX monotherapy. Greater improvement in the mental and physical component scores of the SF-36 was observed in the BARI combo patients versus MTX mono (p< 0.05) at Week 24. No differences in any PROs were observed between BARI mono and combo at Week 24. ConClusions: This post hoc analysis of LA patients from RA-BEGIN shows improvement in PROs with BARI mono and significant improvement with BARI combo in comparison to MTX mono. The results from this subgroup of LA patients are similar with those observed in the global RA-BEGIN study.
BACKGROUND: This study evaluates patient-reported outcomes (PROs) in a double-blind, phase III study of baricitinib as monotherapy or combined with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) with no or minimal prior conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and naïve to biological DMARDs.
METHODS: Patients were randomized 4:3:4 to MTX administered once weekly (N = 210), baricitinib monotherapy (4 mg once daily (QD), N = 159), or combination of baricitinib (4 mg QD) and MTX (baricitinib + MTX, N = 215). PROs included the Patient's Global Assessment of Disease Activity (PtGA), patient's assessment of pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), duration of morning joint stiffness (MJS), worst joint pain, worst tiredness, Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA), Short Form 36 version 2, Acute (SF-36); and EuroQol 5-Dimensions (EQ-5D) Health State Profile. Comparisons were assessed with analysis of covariance (ANCOVA) and logistic regression models.
RESULTS: Compared to MTX, patients in both baricitinib groups reported greater improvement (p ≤ 0.01) in HAQ-DI, PtGA, pain, fatigue, worst join pain, SF-36 physical component score, and EQ-5D at weeks 24 and 52. For the SF-36 mental component score, patients in both baricitinib groups reported statistically significant improvements (p ≤ 0.01) at week 52 compared to MTX-treated patients. Statistically significant improvements (p ≤ 0.05) were observed with the WPAI-RA for the baricitinib groups vs. MTX at week 24 and for the WPAI-RA daily activity and work productivity measures for baricitinib + MTX at week 52.
CONCLUSIONS: In this study, baricitinib alone or in combination with MTX, when used as initial therapy, resulted in significant improvement compared to MTX in the majority of the pre-specified PRO measures.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT01711359 . Registered on 18 October 2012.
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.
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).
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.
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).
OBJECTIVES: This post hoc analysis assessed speed, magnitude and maintenance of pain improvement in patients with early rheumatoid arthritis (RA) receiving baricitinib, baricitinib and methotrexate (MTX), or MTX over 1 year. Cumulative pain and quality of life benefits were also assessed.
METHODS: Randomised, double-blind, phase 3 study RA-BEGIN (NCT01711359) compared baricitinib 4 mg (N=159), baricitinib 4 mg +MTX (N=215) and MTX (N=210) in patients with RA who had no or limited prior disease-modifying antirheumatic drug treatment. Pain was assessed on a 0-100 mm Visual Analogue Scale (VAS). Proportion of patients with ≥30%, ≥50% and ≥70% pain improvement from baseline; ≤20 mm and ≤10 mm on the pain VAS; and time to achieve pain improvement thresholds were assessed over 52 weeks, as were Patient Global Assessment (PtGA) and 36-Item Short Form Health Survey Physical Component Score (SF-36 PCS) outcomes.
RESULTS: Baricitinib monotherapy or combination with MTX provides greater (least square mean changes (LSM) from baseline -40 mm and -43 mm, respectively) and more rapid (median 12 and 8 weeks to ≥70% improvement, respectively) pain relief than MTX alone (LSM -31 mm, median 20 weeks to ≥70% improvement) over 52 weeks. Baricitinib, alone or combination, provides 9-10 additional weeks of limited to no pain, similar gain in achievable wellness measured through PtGA, and 5-7 additional weeks with change in SF-36 PCS ≥5 vs MTX over 1 year.
CONCLUSIONS: Patients treated with baricitinib reported significantly greater and more rapid pain relief, more weeks with limited to no pain, and clinically meaningful improvements in physical health than patients treated with MTX alone over 1 year.
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.
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: Methotrexat HEXAL® 2,5 mg Tabletten Pharmaceutical Form: Capsule INN or Proposed
INN:
METHOTREXATE CAS Number: 59‐05‐2 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 2.5‐ Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use Trade Name: Methotrexate 2.5mg Tablets Pharmaceutical Form: Capsule INN or Proposed
INN:
METHOTREXATE CAS Number: 59‐05‐2 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 2.5‐ Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use Trade Name: Methotrexate 2.5 mg tablets Pharmaceutical Form: Capsule INN or Proposed
INN:
METHOTREXATE CAS Number: 59‐05‐2 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 2.5‐ Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use Trade Name: Methotrexat HEXAL® 2,5 mg Tabletten Pharmaceutical Form: Capsule INN or Proposed
INN:
METHOTREXATE CAS Number: 59‐05‐2 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 5‐ Trade Name: Methotrexate 2.5mg Tablets Pharmaceutical Form: Capsule INN or Proposed
Moderately to severely active rheumatoid arthritis ; MedDRA version: 17.1 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 ‐ Musculoskeletal and connective tissue disorders Therapeutic area: Diseases [C] ‐ Musculoskeletal Diseases [C05]
SECONDARY OUTCOME:
Secondary end point(s): Endpoint 2 ‐ Proportion of patients achieving ACR20 (baricitinib plus MTX compared to MTX monotherapy) ; Endpoint 3 ‐ Change from baseline in Health Assessment Questionnaire Disability Index (HAQ‐DI) ; Endpoint 4 ‐ Change from baseline in DAS28‐high‐sensitivity C‐reactive protein (hsCRP) ; Endpoint 5 ‐ Change from baseline in Modified Total Sharp Score (mTSS [van der Heijde method]) ; Endpoint 6 ‐ AUC of HAQ‐DI (baricitinib monotherapy compared to MTX monotherapy) ; Endpoint 7 ‐ AUC of DAS28‐hsCRP (baricitinib monotherapy compared to MTX monotherapy) ; Endpoint 8 ‐Proportion of patients achieving ACR20 ; Endpoint 9 ‐ Proportion of patients achieving ACR50 ; Endpoint 10 ‐ Proportion of patients achieving ACR70 ; Endpoint 11 ‐ Proportion of patients achieving DAS28‐hsCRP =3.2 ; Endpoint 12 ‐ Proportion of patients achieving DAS28‐ hsCRP <2.6 ; Endpoint 13 ‐ Proportion of patients achieving DAS28‐ESR =3.2 ; Endpoint 14 ‐ Proportion of patients achieving DAS28‐ESR <2.6 ; ; ; Timepoint(s) of evaluation of this end point: Enpoints 2 to 7: Week 24 ; Enpoint 8: Weeks 12 and 52 ; Enpoints 9 to 14: Weeks 12, 24 and 52
INCLUSION CRITERIA:
• are at least 18 years of age • have a diagnosis of adult‐onset RA as defined by ACR/EULAR 2010 Criteria for the Classification of RA • have documented history of positive rheumatoid factor and/or cyclic citrullinated peptide (CCP) antibody test
PRIMARY OUTCOME:
Main Objective: Determine whether baricitinib monotherapy is noninferior to MTX monotherapy in the treatment of patients with moderate to severe active RA who have had limited or no treatment with MTX and are naive to other conventional or biologic DMARDs, as assessed by the proportion of patients achieving a 20% improvement in American College of Rheumatology criteria (ACR20) at Week 24. Primary end point(s): Endpoint 1: Proportion of patients achieving ACR20 (noninferiority of baricitinib monotherapy to MTX monotherapy); Secondary Objective: • proportion of patients achieving ACR20 at Week 24 for baricitinib plus MTX versus MTX monotherapy; • change from baseline to Week 24 in Health Assessment Questionnaire‐Disability Index (HAQ‐DI) score ; • change from baseline to Week 24 in DAS28–high‐sensitivity C reactive protein (hsCRP) ; • change from baseline to Week 24 in structural joint damage as measured by modified Total Sharp Score (mTSS [van der Heijde method]) for baricitinib plus MTX versus MTX monotherapy; • change from baseline up to Week 24 in HAQ‐DI score for baricitinib monotherapy versus MTX monotherapy; • change from baseline up to Week 24 in DAS28‐hsCRP score for baricitinib monotherapy versus MTX monotherapy; • proportion of patients achieving an SDAI score =3.3 at week 12 Timepoint(s) of evaluation of this end point: Enpoint 1: Week 24; • 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 (or hsCRP) measurement =1.2 times the upper limit of normal (ULN) • have had limited or no treatment with MTX Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range
