INTERVENTION: Trade Name: Olumiant Product Name: Olumiant Product Code: LY3009104 Pharmaceutical Form: Tablet INN or Proposed INN: baricitinib Current Sponsor code: LY3009104 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 Trade Name: Olumiant Product Name: Olumiant Product Code: LY3009104 Pharmaceutical Form: Tablet INN or Proposed INN: baricitinib Current Sponsor code: LY3009104 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: Rheumatoid arthritis ; MedDRA version: 20.0 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: The primary objective of the study is to evaluate the long‐term safety and tolerability of baricitinib.; Primary end point(s): a) Proportion of patients experiencing Treatment emergent adverse events (TEAEs), adverse events of special interest, and serious adverse; events (SAEs) over long term follow‐up.; b) Temporary study drug interruptions and/or permanent study drug discontinuations over the long term follow‐up; c) Vital signs and laboratory evaluations (including chemistry and hematology) Secondary Objective: To evaluate in patients initially randomized to receive baricitinib in the originating study, the effect of long‐term administration of baricitinib on the progression of structural joint damage, joint space narrowing and bone erosion. score, duration of morning stiffness, and changes in the European Quality of Life‐5 Dimensions‐5 Level (EQ‐5D‐5L) scores and in healthcare resource utilization.; Timepoint(s) of evaluation of this end point: a) All study visits.; b) All study visits except Visits 1, 2, 5 and 801.; c) All study visits. SECONDARY OUTCOME: Secondary end point(s): a) Proportion of patients who maintain an improvement of 20, 50, or 70 percent, respectively, in the American College of Rheumatology criteria ; (ACR20, ACR50 and ACR70) ; b) Proportion of patients who maintain a ; • Disease Activity Score modified to include the 28 diathrodial joint count (DAS28)‐high sensitivity C‐reactive protein (hsCRP)/DAS28 erythrocyte sedimentation rate (ESR)=3.2, DAS28‐hsCRP <2.6, and DAS28‐ESR <2.6 ; • Clinical Disease Activity Index (CDAI) =10, and CDAI =2.8; ; • Simplified Disease Activity Index (SDAI) =11 and SDAI =3.3 ; • ACR/EULAR remission according to the Boolean‐based definition ; • Health Assessment Questionnaire Disability Index (HAQ‐DI) improvement =0.22 and =0.3 ; c)Structural joint damage as measured by modified Total Sharp Score (mTSS) [van der Heijde method]) ; d) Proportion of patients with mTSS change =0 ; e) Joint space narrowing and bone erosion score ; f) Duration of morning stiffness ; g) European Quality of Life‐5 Dimensions‐5 Level (EQ‐5D‐5L) scores and healthcare resource utilization ; b) same as a) ; c) Change from baseline of originating study through each 12 months of treatment ; d) same as c) ; e) same as c) ; f) Change from baseline in duration of morning stiffness through each 12 months of treatment ; g) Change from baseline through each 12 months of treatment ; h) All study visits ; I) All study visits INCLUSION CRITERIA: Have completed the final active treatment study visit in Study I4V‐MC‐JADV, I4V‐MC‐JADZ, I4V‐MC‐JADX, JADW, or I4V‐MC‐JADA, or I4V‐MC‐JAGS. ; h) Proportion of patients who maintain a CDAI score of =10 from Studies JADV, JADW, and JADX after 3 months of treatment with baricitinib 2 mg QD and with patients continuing treatment with the 4‐mg QD dose ; I) Time to relapse (CDAI score >10 from Studies JADV, JADW, and JADX) after randomization to the baricitinib 2‐mg and 4‐mg QD doses Timepoint(s) of evaluation of this end point: a) Change from Month 6 (of the originating study) through each 12 months of treatment 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 3000 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 350
Background: Ph3 studies demonstrated clinical efficacy of 2 different once-daily (QD) doses of baricitinib (bari) (2mg and 4mg) in patients (pts) with active rheumatoid arthritis (RA) and an inadequate response (IR) to conventional synthetic DMARDs1 or biologic DMARDs2. In general, larger, more rapid and more consistent treatment effects were observed for the 4mg dose across measures. Objectives: To investigate the effects of bari dose step-down in patients who had achieved sustained low disease activity (LDA) or remission with bari 4mg QD. Methods: Pts who completed a bari Ph3 Study (RA-BEGIN, RA-BEAM, RABUILD, or RA-BEACON) could enter a long-term extension study, RA-BEYOND. In RA-BEYOND, pts who had received bari 4mg for at least 15 months and who had achieved sustained LDA or remission (defined by CDAI score at 2 consecutive visits at least 3 months apart) were re-randomized in a double blind manner to continue receiving bari 4mg or to step down to a 2mg QD dose. Disease activity was assessed at a 12 week (wk) landmark following re-randomization. Results: Among pts who achieved satisfactory and sustained disease control with bari 4mg QD, randomized, double blind dose reduction to 2mg QD was associated with modest, statistically significant increases in disease activity across measures at a subsequent 12 wk landmark assessment (Table). However, a large majority of pts (in both the continued 4mg and reduced to 2mg groups) retained the state of LDA or remission that led to their re-randomization. Conclusions: Consistent with completed studies, these data indicate that 4mg QD was the most efficacious dose of bari for pts with RA in clinical studies. Most pts who had achieved sustained disease control with bari 4mg sustained LDA or remission 12 wks after randomized, blinded dose taper to 2mg QD.
Background: Baricitinib (bari), a JAK1 and JAK2 inhibitor, was efficacious in a 24-week (wk) Ph 3 study in patients (pts) with active RA and an inadequate response (IR) to conventional synthetic DMARDs (csDMARDs) (RA-BUILD)1. Objectives: To evaluate radiographic progression of structural joint damage in RA-BUILD pts with IR or intolerance to ≥1 csDMARD over 48 wks of bari treatment in the long-term extension study, RA-BEYOND. Methods: In the 24-wk RA-BUILD study, pts were randomized to placebo (PBO; N=228), bari 2mg (N=229) or bari 4mg (N=227) once daily (QD), with rescue possible from Wk16. Pts completing RA-BUILD and entering RA-BEYOND continued to receive the bari dose received at the end of RA-BUILD. Pts receiving PBO at the end of RA-BUILD were switched to bari 4mg in RA-BEYOND. Pt and investigator blinding was maintained in RA-BEYOND. Joint damage was measured using the van der Heijde modified total Sharp score (mTSS). To account for missing scores and scores obtained after rescue or discontinuation of study drug, data were analyzed using 1) linear extrapolation (LE), and 2) last observation carried forward (LOCF). The observed/LOCF method used all available observed data, including after rescue or switch, with pts analyzed according to original treatment assignment. Results: Using LE, progression of mTSS, bone erosion, and joint space narrowing (JSN) at 24 and 48 wks was statistically significantly lower for both bari 2 or 4mg compared to PBO (Table). Only bari 4mg demonstrated statistically significant inhibition of progressive radiographic joint damage compared to PBO using observed/LOCF at Wk 48 or based on categorical measures. Conclusions: Once daily oral bari inhibited radiographic progression of structural joint damage in pts with an IR or intolerance to csDMARDs over 48 wks of treatment. The most robust benefit across measures of radiographic progression was seen for the 4mg dose. (Table Presented).
Background: Patients (pts) with rheumatoid arthritis (RA) often experience comorbidities that may affect efficacy and safety when treated with different drugs.1 Baricitinib (BARI) is a selective inhibitor of Janus kinase2,3 1 and 2 that improves disease activity in pts with RA with an acceptable safety profile.4-6 Objectives: To investigate the effect of selected comorbidities on safety and efficacy outcomes in pts treated with BARI. Methods: Pts were selected for this post hoc analysis on the basis of historical or ongoing conditions defined by Medical Dictionary for Regulatory Activities and divided by the following comorbidity subgroups: depression, osteoporosis, hepatic disorders, and previous cardiovascular events. Efficacy outcomes included 20% and 50% improvement in American College of Rheumatology 20 Response (ACR20) and American College of Rheumatology 50 Response (ACR50) criteria, respectively; the proportion of pts who achieved a Disease Activity Score for 28- joint count using high-sensitivity C-reactive protein (DAS28-hsCRP) score ≤3.2; and change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at week 12. Pts who had an inadequate response (IR) to conventional disease-modifying antirheumatic drugs (cDMARDS) from 5 studies with BARI 4 mg and placebo (PBO) were included in efficacy analyses (N=1684) and safety analyses (N=1683). The interaction of comorbidity by treatment was analysed using logistic regression or analysis of variance modelling. Interaction tests were performed within each comorbidity subgroup, and the effect size in pts with and without the comorbidity was analysed. Results: Pts in the efficacy set had similar baseline demographic and diseaseactivity characteristics across treatments within each comorbidity subgroup. The presence of a comorbid condition did not affect the incidence of treatmentemergent adverse events (TEAEs), serious adverse events (AE), discontinuations, or deaths caused by AEs for BARI 4 mg vs PBO (Table 1). The most common TEAEs across the subgroups for BARI and PBO were nasopharyngitis and upper respiratory tract infection. For cDMARD-IR pts, change from baseline for each comorbidity subgroup for ACR20, ACR50, DAS28-hsCRP ≤3.2 response, and HAQ-DI was higher for BARI 4 mg compared with PBO. Within each comorbidity subgroup, BARI responses compared with PBO were similar (interaction P >0.1) (Table 2). Conclusions: Treatment with BARI 4 mg showed similar effect in selected comorbidity subgroups with depression, osteoporosis, cardiovascular events, and hepatic impairment for efficacy and safety. No trends were noted for pts in each comorbidity subgroup for increased risk of events after treatment with BARI 4 mg compared with PBO.
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.
Background: In ph3 studies, baricitinib (bari) inhibited progression of radiographic joint damage for up to 1 year in patients (pts) with active rheumatoid arthritis (RA) who were DMARD-naïve or who had an inadequate response to conventional synthetic DMARDs (csDMARD-IR). Objectives: To evaluate radiographic progression of structural joint damage in pts with RA over 2 years of treatment. Methods: Upon completion of a bari ph 3 study, pts could enter a long-term extension (LTE) study, in which they continued to receive the same bari dose as in the original ph3 study. At 52 wks, DMARD-naïve pts receiving methotrexate (MTX) or combination therapy (bari 4mg + MTX) were switched to bari 4mg monotherapy; MTX-IR pts receiving adalimumab (ADA) were switched to bari 4mg on background MTX. At 24 wks, csDMARD-IR pts receiving placebo (PBO) were switched to 4mg on background csDMARD. Radiographs at baseline, year 1 and year 2 were scored using the van der Heijde modified total sharp score (mTSS). Data are least squares mean change from baseline using mixed model repeated measures on observed data. Results: Of all pts randomised, 82.5% entered the LTE, and 87.6% of those could be entered in this analysis. At year 2, progression was significantly lower with initial bari (including monotherapy) vs. initial MTX in DMARD-naïve pts. In MTX/csDMARD-IR pts, progression with initial bari was significantly lower than initial PBO, and similar to initial ADA. Conclusions: Treatment with once-daily oral bari resulted in low rates of radiographic progression for up to 2 years. Pts starting with bari showed progression that was significantly less than those starting with PBO or MTX, and comparable to those starting with ADA. The most robust benefit was seen with the 4mg dose.
Background: In patients (pts) with active rheumatoid arthritis (RA) and inadequate response (IR) to DMARDs, ph3 studies demonstrated efficacy of baricitinib (bari) (2mg and 4mg). Larger, more rapid treatment effects were observed for bari 4mg. Objectives: To investigate the effects of bari dose step-down in pts who achieved sustained disease control with bari 4mg. Methods: Pts with RA who completed a bari ph3 study could enter a long-term extension (LTE) study. In the LTE, pts who received bari 4mg for ≥15 months and who achieved sustained low disease activity ([LDA]-CDAI score ≤10) or remission (CDAI ≤2.8) at 2 consecutive visits ≥3 months apart were re-randomised in a blinded manner to continue bari 4mg or step down to 2mg. Patients could rescue (to bari 4mg) if CDAI >10. Efficacy and safety were assessed through 48 weeks (wks) following re-randomisation. Results: Among pts who achieved sustained disease control with bari 4mg, dose reduction to 2mg resulted in significant increases in disease activity at 12, 24, and 48 wks; however, the majority of pts in both groups maintained the state of LDA or remission. Rescue rates were 7.3% for bari 4mg, 17.1% for bari 2mg. Most rescued patients could regain LDA or remission. Dose reduction was associated with a lower rate of non-serious infections; rates of SAEs and AEs leading to discontinuation were similar across groups. Conclusions: These data indicate that 4mg once daily was the most efficacious dose of bari for pts with RA; increases in disease activity were consistently seen with dose reduction from 4mg to 2mg in well-controlled pts. However, after step-down most pts could maintain LDA or remission, or recapture control with return to 4mg if needed. Attempted dose taper may be a reasonable consideration for some pts following induction of sustained disease control with bari 4mg.
Background: In patients with rheumatoid arthritis (RA) and inadequate response (IR) to DMARDs, ph3 studies demonstrated efficacy of baricitinib (Bari) (2-mg and 4-mg). Objectives: To investigate the effects of Bari dose step-down in patients who achieved sustained disease control with Bari 4-mg. Methods: Patients with RA participating in the Bari ph3 long-term extension study who received Bari 4-mg for ≥15 months and who achieved sustained low disease activity ([LDA] -CDAI score ≤10) or remission ([REM] -CDAI ≤2.8) ≥3 months apart were re-randomised in a blinded manner to continue Bari 4-mg or step down to 2-mg. Patients could rescue to Bari 4-mg. Efficacy and safety were assessed through 48 weeks (wks) following re-randomisation. (Table Presented) Efficacy and safety data are n/N (%), and n [EAIR], respectively. RABEAM= MTX-IR patients; RA-BUILD=csDMARD-IR patients; RA-BEACON=bDMARD-IR patients; EAIR=exposure-adjusted incidence rate; NRI=nonresponder imputation; SDEAE=step-down emergent adverse event; ∗ p≤0.05, ∗∗ p≤0.01, ∗∗∗ p≤0.001 vs. continued Bari 4-mg Results: The majority of patients in both groups maintained the state of LDA or REM over the 48 wks. However, dose reduction to 2-mg resulted in significant increases in disease activity at 12, 24, and 48 wks (Table). Dose reduction also resulted in a shorter time to relapse (defined as loss of step-down eligibility criteria); significantly more patients relapsed over 48 wks compared to the 4-mg group (figure 1). Rescue rates were 8.3% for Bari 4-mg, 16.6% for Bari 2-mg. Most rescued patients could regain LDA or REM. Dose reduction was associated with a lower rate of infections; rates of SAEs and AEs leading to discontinuation were similar across groups. Conclusions: These data indicate that disease control was better maintained with Bari 4-mg than 2-mg. However, most stepped-down patients could maintain LDA or REM, or recapture control with re-introduction of the 4-mg dose. Stepping down to a dose of 2-mg daily may be a viable option for many patients who have achieved sustained LDA or REM on the 4-mg dose.
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.
OBJECTIVES: This study investigated the effects of dose step-down in patients with rheumatoid arthritis (RA) who achieved sustained disease control with baricitinib 4 mg once a day.
METHODS: Patients who completed a baricitinib phase 3 study could enter a long-term extension (LTE). In the LTE, patients who received baricitinib 4 mg for ≥15 months and maintained CDAI low disease activity (LDA) or remission (REM) were blindly randomised to continue 4 mg or taper to 2 mg. Patients could rescue (to 4 mg) if needed. Efficacy and safety were assessed through 48 weeks.
RESULTS: Patients in both groups maintained LDA (80% 4 mg; 67% 2 mg) or REM (40% 4 mg; 33% 2 mg) over 48 weeks. However, dose reduction resulted in small, statistically significant increases in disease activity at 12, 24 and 48 weeks. Dose reduction also produced earlier and more frequent relapse (loss of step-down criteria) over 48 weeks compared with 4 mg maintenance (23% 4 mg vs 37% 2 mg, p=0.001). Rescue rates were 10% for baricitinib 4 mg and 18% for baricitinib 2 mg. Dose reduction was associated with a numerically lower rate of non-serious infections (30.6 for baricitinib 4 mg vs 24.9 for 2 mg). Rates of serious adverse events and adverse events leading to discontinuation were similar across groups.
CONCLUSIONS: In a large randomised, blinded phase 3 study, maintenance of RA control following induction of sustained LDA/REM with baricitinib 4 mg was greater with continued 4 mg than after taper to 2 mg. Nonetheless, most patients tapered to 2 mg could maintain LDA/REM or recapture with return to 4 mg if needed.
Objectives To evaluate radiographic progression of structural joint damage over 2 years in patients with rheumatoid arthritis from baricitinib clinical trials who were disease-modifying antirheumatic drug (DMARD)-naïve or had an inadequate response to conventional synthetic DMARDs (csDMARD-IR). Methods Patients had completed one of three phase III studies and entered a long-term extension (LTE) study, continuing on the same baricitinib dose as at originating study completion. At 52 weeks, DMARD-naïve patients receiving methotrexate (MTX) or combination therapy (baricitinib 4 mg+MTX) were switched to baricitinib 4 mg monotherapy (±MTX per investigator opinion); MTX-IR patients receiving adalimumab were switched to baricitinib 4 mg on background MTX. At 24 weeks, csDMARD-IR patients receiving placebo were switched to baricitinib 4 mg on background csDMARD. Radiographs at baseline, year 1 and year 2 were scored using the van der Heijde modified Total Sharp Score. Linear extrapolation was used for missing data. Results Of 2573 randomised patients, 2125 (82.6%) entered the LTE, of whom 1893 (89.1%) entered this analysis. At year 2, progression was significantly lower with initial baricitinib (monotherapy or combination therapy) versus initial MTX in DMARD-naïve patients (proportion with non-progression defined by ≤smallest detectable change (SDC): 87.3% baricitinib 4 mg+MTX; 70.6% MTX; p≤ 0.001). In MTX-IR patients, progression with initial baricitinib was significantly lower than with initial placebo and similar to initial adalimumab (≤SDC: 82.7% baricitinib 4 mg; 83.5% adalimumab; 70.6% placebo; p≤0.001). In csDMARD-IR patients, significant benefit was seen with baricitinib 4 mg (≤SDC: 87.2% vs 73.2% placebo; p≤0.01). Conclusions Treatment with once-daily baricitinib resulted in low rates of radiographic progression for up to 2 years.
1. In panels A (mTSS) and B (ES) for the RA-BEGIN graphs, the symbol (‡) indicating the significance level for the comparison between the baricitinib 4-mg and baricitinib 4-mg plus MTX treatment groups (denoting p≤0.05) should be over the 1 year time point, not the 2 year time point in both graphs. 2. In panel A (mTSS) for RA-BEAM, for the adalimumab versus placebo comparison at 2 years, the significance should have been shown as ++ (p≤0.01) and not +++ (p≤0.001). 3. In the Results text, p.8, line 12 (relating to Figure 3, panel A) '⋯baricitinib treatment groups (0.21±0.01⋯' should read: '⋯baricitinib treatment groups (0.21±0.10⋯' (Figure Presented).
Objective To evaluate the long-term efficacy of once-daily baricitinib 4 mg in patients with active RA who were either naïve to DMARDs or who had inadequate response (IR) to MTX. Methods Analyses of data from two completed 52-week, phase III studies, RA-BEGIN (DMARD-naïve) and RA-BEAM (MTX-IR), and one ongoing long-term extension (LTE) study (RA-BEYOND) were performed (148 total weeks). At week 52, DMARD-naïve patients treated with MTX monotherapy or baricitinib 4 mg+MTX in RA-BEGIN were switched to open-label baricitinib 4 mg monotherapy; MTX-IR patients treated with adalimumab (+MTX) in RA-BEAM were switched to open-label baricitinib 4 mg (+MTX) in the LTE. Patients who received placebo (+MTX) were switched to baricitinib 4 mg (+MTX) at week 24. Low disease activity (LDA) [Simple Disease Activity Index (SDAI) ≤11], clinical remission (SDAI ≤ 3.3), and physical functioning [Health Assessment Questionnaire Disability Index (HAQ-DI) ≤ 0.5] were assessed. Data were assessed using a non-responder imputation. Results At week 148, SDAI LDA was achieved in up to 61% of DMARD-naïve patients and 59% of MTX-IR patients initially treated with baricitinib, and SDAI remission was achieved in up to 34% of DMARD-naïve patients and 24% of MTX-IR patients; HAQ-DI ≤ 0.5 was reached in up to 48% of DMARD-naïve patients and 38% of MTX-IR patients initially treated with baricitinib. Over 148 weeks, 3.6% and 10.7% of MTX-IR patients discontinued across treatment groups due to lack of efficacy or due to adverse events, respectively; discontinuation rates were similar in the DMARD-naïve population. Conclusion Treatment with baricitinib 4 mg demonstrated efficacy for up to 3 years and was well tolerated.
Aim: Baricitinib (BARI) is an oral, selective, reversible Janus kinase 1/2 inhibitor approved for treatment of adults with active rheumatoid arthritis (RA). Evaluation of long‐term efficacy of once‐daily BARI4mg in methotrexate (MTX)‐na�ve/inadequately responding (IR) patients with active RA. Methods: Analyses were performed on data from RA‐BEGIN (MTXna�ve) and RA‐BEAM (MTX‐IR) for 52weeks, and from the long‐term extension (LTE) study (RA‐BEYOND) for an additional 96weeks (148weeks total). At week52, MTX‐na�ve patients initially treated with MTX, BARI4mg, or BARI4mg+MTX (RA‐BEGIN) switched to open‐label BARI4mg monotherapy in the LTE. At week52, MTX‐IR patients initially treated with BARI4mg or adalimumab (ADA)+MTX in RA‐BEAM were switched to open‐label BARI4mg (+MTX) treatment in the LTE. Placebo (+MTX)‐treated patients switched to openlabel BARI4mg (+MTX) at week24. The analyses of efficacy (SDAI) and physical function (HAQ‐DI) were conducted on all patients randomized into RA‐BEGIN and RA‐BEAM receiving?1 dose of study drug (mITT population). The proportion of patients reaching low disease activity (LDA), measured by SDAI?11, was evaluated, along with change from baseline in HAQ‐DI. The non‐responder imputation (NRI) was used for the categorical analysis. Results: By week24 in RA‐BEGIN (N = 584), 62%of BARI4mg or BARI4mg+MTX‐treated patients achieved SDAI LDA compared to 40%of MTX group; response rates for BARI groups were maintained through week148. By week24 in RA‐BEAM (N = 1305), 52%of BARI4mg (+MTX)‐treated, and 50% of ADA (+MTX)‐treated patients achieved SDAI LDA compared to 26%of PBO (+MTX)‐treated patients. BARI4mg and ADA week24 response rates were maintained through week148 even after ADA‐to‐BARI4mg switch at week52. Improvement and maintenance of physical function measured by HAQ‐DI were demonstrated. The overall discontinuation rate (DR) across treatment groups from RA‐BEGIN (19.5%) and RA‐BEAM (14.2%) have been published. In LTE, BARI‐treated DR was13.7%for RA‐BEGIN (1.1%due to lack of efficacy, 6.4%due to safety) and 12.6%for RABEAM (1.8%due to lack of efficacy, 5.9%due to safety). Conclusions: Long‐term BARI4mg treatment demonstrated the maintenance of clinically‐relevant outcomes for up to 3years. Low discontinuation rates during the LTE indicate that BARI4mg treatment was well‐tolerated.
<b>OBJECTIVE: </b>To evaluate the effect of baricitinib on inhibiting radiographic progression of structural joint damage over 5 years in patients with active rheumatoid arthritis (RA).<b>METHODS: </b>Patients completed 1 of 3 phase III baricitinib trials (ClinicalTrials.gov: NCT01711359, NCT01710358, or NCT01721057) and entered the long-term extension RA-BEYOND (NCT01885078), in which patients received once-daily 4 mg or 2 mg baricitinib. Across these trials, patients initially receiving methotrexate (MTX) or adalimumab (ADA) switched to baricitinib 4 mg at Week 52. Patients initially receiving placebo (PBO) switched to baricitinib 4 mg at Week 24. Radiographs were scored at baseline and Years 2, 3, 4, and 5. Change from baseline in van der Heijde modified total Sharp score (ΔmTSS) was computed.<b>RESULTS: </b>Overall, 2125 of 2573 (82.6%) randomized patients entered RA-BEYOND; 1837 of 2125 (86.4%) entered this analysis. From Years 3 to 5, higher proportions of disease-modifying antirheumatic drug (DMARD)-naïve patients on initial baricitinib (monotherapy or with MTX) had no progression vs initial MTX (ΔmTSS ≤ 0 at Year 5: 59.6% baricitinib 4 mg; 66.2% baricitinib 4 mg + MTX; 40.7% MTX). Higher proportions of patients with inadequate response (IR) to MTX on initial baricitinib or ADA vs PBO had no progression (ΔmTSS ≤ 0 at Year 5: 54.8% baricitinib 4 mg; 55.0% ADA; 50.3% PBO). Higher proportions of patients with conventional synthetic DMARD-IR on initial baricitinib 4 mg had less progression vs initial PBO or baricitinib 2 mg (ΔmTSS ≤ 0 at Year 5: 66.7% baricitinib 4 mg; 58.2% baricitinib 2 mg; 60.0% PBO).<b>CONCLUSION: </b>Oral baricitinib maintained lower levels of radiographic progression than initial conventional synthetic DMARD or PBO through 5 years in patients with active RA.
OBJECTIVE: This study examines the impact of dose step-down in patients with rheumatoid arthritis (RA) who achieved sustained disease control with baricitinib 4-mg once-daily up to 96-weeks.
METHODS: Patients who completed a baricitinib phase 3 study could enter a long-term extension (LTE). In the LTE, patients who received baricitinib 4-mg for ≥15 months and maintained clinical disease activity index (CDAI) low disease activity (LDA) or remission (REM) were blindly randomized to continue 4-mg or taper to 2-mg. If needed, 2-mg treated patients could be rescued to 4-mg, and 4-mg treated patients could be rescued by adding or increasing conventional synthetic disease-modifying antirheumatic drugs. Efficacy and safety were assessed through 96-weeks. Non-responder imputation, considering rescued or discontinued patients as non-responders, was used for CDAI response analyses.
RESULTS: At 96-weeks, most patients maintained LDA in both 2-mg and 4-mg arms, with a lower maintenance rate in 2-mg than 4-mg (NRI 59.9% and 70.2%, respectively). Patients maintained REM in 2-mg and 4-mg arms, 30.8% and 36.6% respectively. Rescue rates were 14.7% for baricitinib 4-mg and 22.5% for 2-mg. Of 112 patients who lost LDA in the 2-mg arm and rescued to 4-mg, 76.2% and 75.6% achieved LDA again at 12- and 24-weeks post-rescue.
CONCLUSION: In a randomized, blinded, phase 3 LTE study, maintenance of RA control following induction of sustained LDA/REM with baricitinib 4-mg was greater with continued 4-mg than after taper to 2-mg. Nonetheless, 76% of patients tapered to 2-mg could maintain LDA/REM or recapture with return to 4-mg if needed.
Trade Name: Olumiant Product Name: Olumiant Product Code: LY3009104 Pharmaceutical Form: Tablet INN or Proposed
INN:
baricitinib Current Sponsor code: LY3009104 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 Trade Name: Olumiant Product Name: Olumiant Product Code: LY3009104 Pharmaceutical Form: Tablet INN or Proposed
INN:
baricitinib Current Sponsor code: LY3009104 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
Main Objective: The primary objective of the study is to evaluate the long‐term safety and tolerability of baricitinib.; Primary end point(s): a) Proportion of patients experiencing Treatment emergent adverse events (TEAEs), adverse events of special interest, and serious adverse; events (SAEs) over long term follow‐up.; b) Temporary study drug interruptions and/or permanent study drug discontinuations over the long term follow‐up; c) Vital signs and laboratory evaluations (including chemistry and hematology) Secondary Objective: To evaluate in patients initially randomized to receive baricitinib in the originating study, the effect of long‐term administration of baricitinib on the progression of structural joint damage, joint space narrowing and bone erosion. score, duration of morning stiffness, and changes in the European Quality of Life‐5 Dimensions‐5 Level (EQ‐5D‐5L) scores and in healthcare resource utilization.; Timepoint(s) of evaluation of this end point: a) All study visits.; b) All study visits except Visits 1, 2, 5 and 801.; c) All study visits.
SECONDARY OUTCOME:
Secondary end point(s): a) Proportion of patients who maintain an improvement of 20, 50, or 70 percent, respectively, in the American College of Rheumatology criteria ; (ACR20, ACR50 and ACR70) ; b) Proportion of patients who maintain a ; • Disease Activity Score modified to include the 28 diathrodial joint count (DAS28)‐high sensitivity C‐reactive protein (hsCRP)/DAS28 erythrocyte sedimentation rate (ESR)=3.2, DAS28‐hsCRP <2.6, and DAS28‐ESR <2.6 ; • Clinical Disease Activity Index (CDAI) =10, and CDAI =2.8; ; • Simplified Disease Activity Index (SDAI) =11 and SDAI =3.3 ; • ACR/EULAR remission according to the Boolean‐based definition ; • Health Assessment Questionnaire Disability Index (HAQ‐DI) improvement =0.22 and =0.3 ; c)Structural joint damage as measured by modified Total Sharp Score (mTSS) [van der Heijde method]) ; d) Proportion of patients with mTSS change =0 ; e) Joint space narrowing and bone erosion score ; f) Duration of morning stiffness ; g) European Quality of Life‐5 Dimensions‐5 Level (EQ‐5D‐5L) scores and healthcare resource utilization ; b) same as a) ; c) Change from baseline of originating study through each 12 months of treatment ; d) same as c) ; e) same as c) ; f) Change from baseline in duration of morning stiffness through each 12 months of treatment ; g) Change from baseline through each 12 months of treatment ; h) All study visits ; I) All study visits
INCLUSION CRITERIA:
Have completed the final active treatment study visit in Study I4V‐MC‐JADV, I4V‐MC‐JADZ, I4V‐MC‐JADX, JADW, or I4V‐MC‐JADA, or I4V‐MC‐JAGS. ; h) Proportion of patients who maintain a CDAI score of =10 from Studies JADV, JADW, and JADX after 3 months of treatment with baricitinib 2 mg QD and with patients continuing treatment with the 4‐mg QD dose ; I) Time to relapse (CDAI score >10 from Studies JADV, JADW, and JADX) after randomization to the baricitinib 2‐mg and 4‐mg QD doses Timepoint(s) of evaluation of this end point: a) Change from Month 6 (of the originating study) through each 12 months of treatment 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 3000 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 350
