The purpose of this study is to determine whether baricitinib 4 milligram (mg) once daily is superior to placebo in the treatment of participants with moderately to severely active Rheumatoid Arthritis (RA) who have had an inadequate response to a tumor necrosis factor (TNF) inhibitor, despite ongoing treatment with conventional disease-modifying antirheumatic drugs (cDMARDs).
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: 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 an inadequate response to a TNF inhibitor, despite ongoing treatment with cDMARDs, as assessed by the proportion of patients achieving ACR20 at Week 12. 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 (baricitinib 4mg compared to placebo); ‐ change from baseline to Week 12 in DAS28‐high‐sensitivity C‐reactive protein (hsCRP) (baricitinib 4mg compared to placebo); ‐ proportion of patients achieving ACR20 at Week 12 (baricitinib 2mg compared to placebo); ‐ change from baseline to Week 12 in HAQ‐DI score (baricitinib 2mg compared to placebo); ‐ change from baseline to Week 12 in DAS28‐hsCRP (baricitinib 2mg compared to placebo); Timepoint(s) of evaluation of this end point: Week 12 SECONDARY OUTCOME: Secondary end point(s): ‐ Health Assessment Questionnaire‐Disability Index (HAQ‐DI) score ; ‐ DAS28‐high‐sensitivity C‐reactive protein (hsCRP) ; ‐ Proportion of patients achieving ACR20 response (baricitinib 2mg compared to placebo) ; ‐ Proportion of patients achieving ACR20 response ; ‐ Proportion of patients achieving ACR50 and ACR70 response ; ‐ proportion of patients achieving DAS28‐hsCRP =3.2; proportion of patients achieving DAS28‐ hsCRP <2.6 ; ‐ proportion of patients achieving DAS28‐ESR =3.2; proportion of patients achieving DAS28‐ ESR <2.6 ; Timepoint(s) of evaluation of this end point: ‐ Health Assessment Questionnaire‐Disability Index (HAQ‐DI) score: Change from baseline to Weeks 12 and 24 ; ‐ 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 ; ‐ Proportion of patients achieving ACR20 response: Week 24 ; ‐ Proportion of patients achieving ACR50 and ACR70 response: Weeks 12 and 24 ; ‐ proportion of patients achieving DAS28‐hsCRP =3.2; proportion of patients achieving DAS28‐ hsCRP <2.6: Weeks 12 and 24 ; ‐ proportion of patients achieving DAS28‐ESR =3.2; proportion of patients achieving DAS28‐ ESR <2.6: Weeks 12 and 24 ; INCLUSION CRITERIA: • are at least 18 years of age • have a diagnosis of adult‐onset RA as defined by the ACR/EULAR 2010 Criteria for the Classification of RA • have moderately to severely active RA defined as the presence of at least 6/68 tender joints and at least 6/66 swollen joints • have a C‐reactive protein (or hsCRP) measurement =1 times the upper limit of normal (ULN) • have been treated at approved doses with at least 1 biologic TNF‐ a inhibitor and either: ‐ experienced insufficient efficacy or loss of efficacy ‐ experienced intolerance of such treatment • have had regular use of at least 1 cDMARD for at least the 12 weeks prior to study entry with a continuous, nonchanging dose for at least 8 weeks prior to study entry 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 N
Background: In ph 2 studies, baricitinib (bari) improved disease activity with an acceptable safety profile in pts with active RA naïve to biologic DMARDs (bDMARDs).1,2 Objectives: To report patient-reported outcomes (PRO) from a ph 3 study of bari in pts with active RA on 1 or 2 conventional DMARDs (cDMARDs) and an inadequate response or intolerance to ≥1 TNF inhibitors. Methods: Pts were randomized 1:1:1 to placebo (PBO) or bari (2 or 4 mg) QD for 24 wks. PROs are listed in the table. Analyses included ANCOVA, logistic regression, and nonparametric methods and compared bari 2 or 4 mg vs. PBO. Results: 527 pts were randomized. Assessment of PROs at baseline revealed severe impairment of physical function (HAQ-DI: 1.7-1.8) and QoL. Bari 2 and 4 mg resulted in statistically significant improvements from baseline vs. PBO in most PROs at 24 wks (Table). Conclusions: In this ph 3 study of pts with active RA on cDMARDs and an inadequate response to bDMARDs, bari was associated with significant improvement in most PROs through 24 wks compared to PBO. (Table Presented).
Background: In ph 2 studies, baricitinib (bari) improved disease activity with an acceptable safety profile in patients (pts) with active RA naïve to biologic DMARDs (bDMARDs).1,2 Objectives: To report results from a ph 3 study of bari in pts with active RA and an inadequate response or intolerance to ≥1 TNF inhibitor (TNFi). Methods: Pts with active RA (TJC & SJC ≥6, hsCRP ≥3mg/L) on conventional DMARDs (cDMARDs) were randomized 1:1:1 to placebo (PBO) or bari (2 or 4 mg) QD for 24 wks. All bDMARDs were discontinued ≥28d prior to treatment. Primary endpoint was ACR20 response at Wk 12 for bari 4 mg vs. PBO. Results: Of 527 randomized pts, 57% had received ≥2 bDMARDs and 38% had received ≥1 non-TNFi bDMARD. Fewer pts discontinued treatment prior to Wk 24 on bari 2 or 4 mg vs. PBO (10%, 11%, 18%, respectively). ACR20 response at Wk 12 was higher with bari 4 mg vs. PBO (55% vs. 27%, p≤0.001). Improvements in ACR20, ACR50, ACR70, DAS28, CDAI, SDAI, and HAQ-DI were seen (Table), many as early as Wk 1. Treatment benefit was sustained through Wk 24 for the 4 mg dose. More TEAEs occurred in pts receiving bari 2 or 4 mg compared to PBO (71%, 77%, 64%, respectively) including infections (44%, 40%, 31%, respectively). SAE rates through 24 wks were similar among pts receiving bari 2 or 4 mg or PBO (4%, 10%, and 7%, respectively) including serious infections (2%, 3%, and 3%, respectively). There were no opportunistic infections, TB, or GI perforations. Two non-melanoma skin cancers and 2 major adverse cardiovascular events, including 1 death (stroke), were seen with bari 4 mg. Lab findings were consistent with ph 2 studies. Abnormalities leading to discontinuation were infrequent. Conclusions: In pts with active RA on cDMARDs and an inadequate response to bDMARDs, once daily oral bari was associated with rapid and sustained clinical improvements through 24 wks, with an acceptable safety and tolerability profile. The largest benefit was seen with the 4 mg dose. Additional ph 3 studies in bDMARD-naive pts are ongoing.
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.
<b>BACKGROUND: </b>In phase 2 studies, baricitinib, an oral Janus kinase 1 and 2 inhibitor, reduced disease activity in patients with rheumatoid arthritis who had not previously received treatment with biologic disease-modifying antirheumatic drugs (DMARDs).<b>METHODS: </b>In this phase 3 study involving 527 patients with an inadequate response to or unacceptable side effects associated with one or more tumor necrosis factor inhibitors, other biologic DMARDs, or both, we randomly assigned the patients in a 1:1:1 ratio to baricitinib at a dose of 2 or 4 mg daily or placebo for 24 weeks. End points, tested hierarchically at week 12 to control type 1 error, were the American College of Rheumatology 20% (ACR20) response (primary end point), the Health Assessment Questionnaire-Disability Index (HAQ-DI) score, the 28-joint Disease Activity Score based on C-reactive protein level (DAS28-CRP), and a Simplified Disease Activity Index (SDAI) score of 3.3 or less (on a scale of 0.1 to 86.0, with a score of 3.3 or less indicating remission). Comparisons with placebo were made first with the 4-mg dose of baricitinib and then with the 2-mg dose.<b>RESULTS: </b>Significantly more patients receiving baricitinib at the 4-mg dose than those receiving placebo had an ACR20 response at week 12 (55% vs. 27%, P<0.001). Differences between the higher-dose baricitinib group and the placebo group were also significant for the HAQ-DI score and the DAS28-CRP but not for an SDAI score of 3.3 or less. Adverse-event rates through 24 weeks were higher for patients receiving the 2-mg dose of baricitinib and those receiving the 4-mg dose than for patients receiving placebo (71% and 77%, respectively, vs. 64%), including infections (44% and 40%, vs. 31%). The rates of serious adverse events were 4%, 10%, and 7% in the three groups, respectively. Two nonmelanoma skin cancers and two major adverse cardiovascular events, including a fatal stroke, occurred in the higher-dose group. Baricitinib was associated with a small reduction in neutrophil levels and increases in serum creatinine and low-density lipoprotein cholesterol levels.<b>CONCLUSIONS: </b>In patients with rheumatoid arthritis and an inadequate response to biologic DMARDs, baricitinib at a daily dose of 4 mg was associated with clinical improvement at 12 weeks. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01721044.).
<b>OBJECTIVES: </b>To assess baricitinib on patient-reported outcomes (PROs) in patients with moderately to severely active rheumatoid arthritis, who had insufficient response or intolerance to ≥1 tumour necrosis factor inhibitors (TNFis) or other biological disease-modifying antirheumatic drugs (bDMARDs).<b>METHODS: </b>In this double-blind phase III study, patients were randomised to once-daily placebo or baricitinib 2 or 4 mg for 24 weeks. PROs included the Short Form-36, EuroQol 5-D, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient's Global Assessment of Disease Activity (PtGA), patient's assessment of pain, duration of morning joint stiffness (MJS) and Work Productivity and Activity Impairment Questionnaire-Rheumatoid Arthritis. Treatment comparisons were performed with logistic regression for categorical measures or analysis of covariance for continuous variables.<b>RESULTS: </b>527 patients were randomised (placebo, 176; baricitinib 2 mg, 174; baricitinib 4 mg, 177). Both baricitinib-treated groups showed statistically significant improvements versus placebo in most PROs. Improvements were generally more rapid and of greater magnitude for patients receiving baricitinib 4 mg than 2 mg and were maintained to week 24. At week 24, more baricitinib-treated patients versus placebo-treated patients reported normal physical functioning (HAQ-DI <0.5; p≤0.001), reductions in fatigue (FACIT-F ≥3.56; p≤0.05), improvements in PtGA (p≤0.001) and pain (p≤0.001) and reductions in duration of MJS (p<0.01).<b>CONCLUSIONS: </b>Baricitinib improved most PROs through 24 weeks compared with placebo in this study of treatment-refractory patients with previously inadequate responses to bDMARDs, including at least one TNFi. PRO results aligned with clinical efficacy data for baricitinib.<b>Trial Registration Number: </b>NCT01721044; Results.
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: A rapid and meaningful reduction in pain is important to quality of life in patients (pts) with rheumatoid arthritis (RA). Baricitinib (bari) is a selective inhibitor of Janus kinase (JAK)1/JAK 2 in development for pts with active RA.1 Objectives: To evaluate the effect of bari treatment on pain reduction compared to adalimumab (ADA) or placebo (PBO) in pts with inadequate response to methotrexate (MTX) or biologic disease-modifying antirheumatic drugs (bDMARDs). Methods: In RA-BEAM (NCT01710358), 1305 patients with inadequate response to MTX were randomised 3:3:2 to PBO QD, bari 4 mg once daily (QD), or ADA 40 mg biweekly.2 In RA-BEACON (NCT01721044), 527 pts with inadequate response or intolerance to bDMARDs were randomised 1:1:1 to PBO or bari (2 or 4 mg) QD.3 This post-hoc analysis reports the pts' assessment of pain using a visual analogue scale (VAS, range: 0 to 100 mm). The proportion of pts who achieved pain improvement of ≥30%, ≥50%, and ≥70% of their baseline pain at 1, 2, 4, 8, 12, 16, 20, and 24 weeks of treatment were compared between treatment groups using logistic models adjusted for geographic region, baseline pain score, baseline joint erosion status (RA-BEAM only), and history of bDMARD at screening (RA-BEACON only). Missing data were imputed using modified last observation carried forward. Results: Mean baseline pain scores were 60, 62, and 61 for PBO, bari 4 mg, and ADA, respectively, in RA-BEAM and 65, 62, and 66 for PBO, bari 2 mg, and bari 4 mg, respectively, in RA-BEACON. A significantly greater proportion of pts treated with bari 4 mg achieved ≥30% and ≥50% pain improvement as early as week 1 compared to PBO (both studies) and as early as week 4 compared to ADA (RA-BEAM) (Table). A significant pain improvement of ≥70% was achieved at week 12 for pts treated with bari 4 mg compared to PBO (both studies) and ADA (RA-BEAM). Pain improvement of ≥30%, ≥50%, and ≥70% with bari 2 mg was significant compared to PBO by week 12 (RA-BEACON). Significant improvements in pain for bari vs PBO and bari vs ADA were sustained through week 24. Conclusions: Bari-treated pts reported significantly greater and more rapid reductions in pain severity as measured by the pain VAS compared to PBO or ADA; improvements were sustained through 24 weeks. The results were similar regardless of the pt population. (Table Presented).
Background: In patients (pts) with RA, physical function (PF) can be measured with the Health Assessment Questionnaire-Disability Index (HAQ-DI). Patient- Reported Outcomes Measurement Information System (PROMIS) was developed by the National Institutes of Health using a population-calibrated T-score metric (Mean 50, SD 10). Crosswalk tables that link legacy instruments to PROMIS instruments, including PF, have been developed. Comparisons to the general population can also be made from PROMIS scores.1-2 Objectives: To convert HAQ-DI scores to PROMIS PF scores to determine how the PROMIS metric performs in 2 phase 3 baricitinib (bari) clinical trials in pts with RA. Methods: In RA-BEAM, pts with inadequate response (IR) to methotrexate were randomised 3:3:2 to placebo (PBO) once daily (QD), bari 4 mg QD, or adalimumab (ADA) 40 mg biweekly.3 In RA-BEACON, pts with IR to bDMARDs were randomised 1:1:1 to receive PBO or bari 2 mg or 4 mg QD.4 In both studies, PF was assessed using HAQ-DI. Patient-level HAQ-DI scores were converted to PROMIS PF scores using a validated crosswalk table.1 Analysis of covariance was conducted on the PROMIS PF score conversions to compare bari to all treatment arms in both studies. Missing data were imputed using modified last observation carried forward. Results: Pts had considerable PF impairment at baseline; mean scores exceeded 2 SD (20 points on the T-score metric) from population means (table 1). Treatment with bari was associated with clinically relevant improvements approaching or exceeding 0.5 SD (5 points on the T-score metric) by week 24 (minimally important difference for PROMIS PF: 0.2 SD or 2 points5) vs PBO in HAQ-DI converted to PROMIS PF scores (table 1). Using the converted PROMIS scores, bari remained associated with significant improvements in PF vs PBO through 24 weeks in both studies and vs ADA through 52 weeks in RA-BEAM (figure 1). Conclusions: While RA-BEAM and RA-BEACON did not use the PROMIS instrument directly, these results indicate PROMIS PF has the potential to show responsiveness and differentiate between active treatments in clinical trials.
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: Fatigue and pain in patients (pts) with RA are often measured with the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and the Medical Outcomes Study Short-Form-36 (SF-36). Patient-Reported Outcomes Measurement Information System (PROMIS) was developed using a populationcalibrated T-score metric (Mean 50, SD 10). Crosswalk tables were developed linking legacy instruments to PROMIS instruments, including Fatigue and Pain Interference (PI). Comparisons to the general population can be made from PROMIS scores.1-2 Objectives: To convert FACIT-F and SF-36 Bodily Pain (BP) scores to PROMIS Fatigue and PI scores to determine how PROMIS performs in 2 phase 3 baricitinib (bari) RA trials. Methods: In RA-BEAM, pts with inadequate response (IR) to MTX were randomised 3:3:2 to placebo (PBO) once daily (QD), bari-4 mg QD, or adalimumab (ADA) 40 mg biweekly.3 In RA-BEACON, pts with IR to bDMARDs were randomised 1:1:1 to receive PBO or bari 2 mg or 4 mg QD.4 FACIT-F assessed fatigue and SF-36 BP, pain. Pt-level PROMIS scores were converted from FACIT-F/SF- 36 BP using validated crosswalk tables.1-2 Analysis of covariance was conducted on PROMIS score conversions to compare bari to all treatment arms. Results: Pts had considerable baseline fatigue/pain; mean scores approached or exceeded 1 SD (10 points on the metric) from population norms. Bari was associated with clinically relevant improvements (exceeding 0.5 SD/5 points on the Tscore metric) vs PBO for PROMIS fatigue/PI scores (table 1). PROMIS fatigue/PI scores in RA-BEAM reached population norms (<55) by week 12 for bari and ADA (table 1). Bari remained associated with significant improvements in PROMIS fatigue/PI vs PBO through 24 weeks in both studies and vs ADA for PI in RABEAM (figure 1). (Figure Presented) Conclusions: While PROMIS was not used in the studies directly, pt-level crosswalk tables provide an estimate of effect that may be demonstrated when using PROMIS in clinical trials. These results provide preliminary evidence of the ability of PROMIS to demonstrate treatment benefit.
Aims: Fatigue in patients with rheumatoid arthritis (RA) is common and debilitating. In clinical trials, fatigue is often measured with the 13‐item Functional Assessment of Chronic Illness Therapy‐Fatigue instrument (FACIT‐F). The Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue item bank was developed using aUS general population‐calibrated T‐score metric (mean 50, SD 10). PROMIS Fatigue includes the FACIT‐F items within it, and scores on the two scales are thereby interchangeable. Content debriefing of the FACIT‐F identified 10 items relevant to patients with RA. We assessed performance of these 10 items and the 13‐item FACIT‐F instrument using both crosswalk tables and a PROMIS scoring algorithm using data from 2 phase 3 baricitinib RA trials. Methods: In RA‐BEAM, patients with inadequate response to methotrexate were randomized 3:3:2 to placebo once daily (QD), baricitinib 4mg QD, or adalimumab 40mgbiweekly.1 In RA‐BEACON, patients with inadequate response to bDMARDs were randomized 1:1:1 to receive placebo or baricitinib 2 mg or 4 mg QD.2 Patient‐level FACIT‐F scores were linked to PROMIS Fatigue scores using validated crosswalk tables (http://www.prosettastone.org) and the scoring algorithm (http://www.healthmeasures.net/exploremeasurement‐ systems/promis). Analysis of covariance was conducted on PROMIS score conversions to compare responses across treatment arms. Results: At baseline, average PROMIS fatigue scores reflected moderate‐to‐high levels of fatigue relative to population means (e.g., approaching or exceeding 1 SDabove), ranging across treatment groups and scoring methods from 57.4 to 59.7 in RA‐BEAM and 60.1 to 63.7 in RA‐BEACON (Table). Fatigue scores decreased in RA‐BEAM to within normal ranges (<55) by week 4 for baricitinib and adalimumab (data not shown). Statistically and clinically meaningful reductions in mean fatigue scores (exceeding 0.5 SD/5 points) were associated with treatment through 24 weeks in both studies. Conclusions: These results support the FACIT‐F to PROMIS Fatigue crosswalk and scoring algorithm approaches, including the use of a subset of 10 FACIT‐F items deemed most relevant to RA. This enables comparisons across studies that use FACIT‐F or PROMIS Fatigue item subsets and their interpretation in relation to US general population norms. (Table Presented).
OBJECTIVE: RA patients who have failed biologic DMARDs (bDMARDs) represent an unmet medical need. We evaluated the effects of baseline characteristics, including prior bDMARD exposure, on baricitinib efficacy and safety.
METHODS: RA-BEACON patients (previously reported) had moderate to severe RA with insufficient response to one or more TNF inhibitor and were randomized 1:1:1 to once-daily placebo or 2 or 4 mg baricitinib. Prior bDMARD use was allowed. The primary endpoint was a 20% improvement in ACR criteria (ACR20) at week 12 for 4 mg vs placebo. An exploratory, primarily post hoc, subgroup analysis evaluated efficacy at weeks 12 and 24 by ACR20 and Clinical Disease Activity Index (CDAI) ⩽10. An interaction P-value ⩽0.10 was considered significant, with significance at both weeks 12 and 24 given more weight.
RESULTS: The odds ratios predominantly favored baricitinib over placebo and were generally similar to those in the overall study (3.4, 2.4 for ACR20 weeks 12 and 24, respectively). Significant quantitative interactions were observed for baricitinib 4 mg vs placebo at weeks 12 and 24: ACR20 by region (larger effect Europe) and CDAI ⩽10 by disease duration (larger effect ⩾10 years). No significant interactions were consistently observed for ACR20 by age; weight; disease duration; seropositivity; corticosteroid use; number of prior bDMARDs, TNF inhibitors or non-TNF inhibitors; or a specific prior TNF inhibitor. Treatment-emergent adverse event rates, including infections, appeared somewhat higher across groups with greater prior bDMARD use.
CONCLUSION: Baricitinib demonstrated a consistent, beneficial treatment effect in bDMARD-refractory patients across subgroups based on baseline characteristics and prior bDMARD use.
TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov/), NCT01721044.
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).
Background: During the development programme, baricitinib (BARI) demonstrated greater and faster pain relief relative to placebo (PBO) and active comparator in different RA populations. Here, we summarise the findings from two recent post hoc analyses focused on the effect of BARI on pain in two clinically relevant patient populations: methotrexate-inadequate responders (MTX-IR; RA-BEAM) and tumor necrosis factor inhibitor-inadequate responders (TNFi-IR; RABEACON). Methods: In both clinical trials (RA-BEAM and RA-BEACON), pain was assessed with a visual analog scale (VAS, 0-100mm) at each study visit. In RA-BEAM, 1,305 patients on stable background MTX were randomized 3:3:2 to PBO, BARI 4-mg, or adalimumab (ADA) 40-mg. The likelihood of achieving ≥30%, ≥50%, and ≥70% pain VAS improvement through Week 24 and the median time when 50% of patients achieved these pain improvement thresholds was assessed with Cox proportional hazard models and the cumulative incidence estimate. Analyses were not adjusted for multiplicity. In RA-BEACON, 527 patients were randomised to placebo (n=176), BARI 2-mg (n=174), or 4-mg (n=177) once daily for 24 weeks. Approximately 40% of patients had received >1 TNF inhibitor and a quarter of patients had received 53 bDMARDs, representing patients with highly refractory disease. The proportion of patients achieving ≥30%, ≥50%, and ≥70% pain relief at Week-12 was compared between BARI 2-mg or 4-mg and PBO using logistic models. Missing pain values were imputed using modified last observation-carried-forward. Results: In the MTX-IR population, BARI-treated patients were more likely to achieve at least 30%, 50%, and 70% pain improvement than PBO and ADA with HR of 1.7, 1.9 and 2.5, respectively (p<0.001) compared to PBO, and 1.1 (p=0.145), 1.2 (p=0.032) and 1.3 (p=0.003) compared to ADA. The median time for 50% of patients to achieve at least 30%, 50%, and 70% pain improvement, respectively, was 1.9, 4.0 and 12.4 weeks for BARI, 2.0, 7.9 and 20.0 weeks for ADA, and 4.6, 14.0 and >24 weeks for PBO. In the TNFi-IR population, at Week-12, significantly more patients achieved ≥30%, ≥50%, and ≥70% pain relief with BARI 2-mg or 4-mg vs PBO (p<0.05, for all comparisons). Consistent improvements were observed regardless of baseline pain. Regardless of treatment history, patients receiving BARI 2-mg or 4-mg were more likely to reach all pain relief thresholds than placebo. Conclusion: In both MTX-IR and TNFi-IR populations, BARI demonstrated greater pain improvement than comparators at Weeks 24 and 12, respectively.
Background: Baricitinib (BARI) provided rapid and sustained improvements in patient-reported outcomes (PROs) in randomized, controlled trials (RCTs) in patients (pts) with active rheumatoid arthritis (RA) and inadequate responses (IR) to methotrexate (MTX) (RA-BEAM; NCT01710358)1,2 and biologic DMARDs (bDMARD-IR; RA-BEACON; NCT01721044)3,4. Objectives: To determine the number needed to treat (NNT) to report improvements ≥minimum clinically important differences (MCIDs) in multiple PROs at Week (Wk) 12 after treatment with BARI 4-mg in RA-BEAM and BARI 2-mg or BARI 4-mg in RA-BEACON. NNTs ≤10 vs placebo (PBO) are considered clinically meaningful. Methods: Evaluated PROs with respective MCID definitions included Patient Global Assessment of Disease Activity (PtGA, 0-100 mm visual analog scale [VAS], MCID ≥10 mm), pain (0-100 mm VAS, MCID ≥10 mm), physical function (Health Assessment Questionnaire-Disability Index, MCID ≥0.22 points), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F], MCID≥4.0), and health-related quality of life (SF-36 physical component summary [PCS: MCID ≥2.5] and domain scores: physical function [PF], role physical [RP], bodily pain [BP], general health [GH], vitality [VT], social functioning [SF], role emotional [RE], mental health [MH], MCID ≥5.0).5 The percentages of pts reporting improvements ≥MCID were determined at Wk 12. NNTs were calculated as 1/difference in response rates between BARI 2-mg or 4-mg and PBO. Results: At Wk 12, percentages of pts reporting clinically meaningful improvements were greater and statistically different from PBO (p<0.01) with BARI 2-mg and 4-mg across most PROs in both RCTs. Most NNTs were ≤10. (Figure) Conclusion: Across different populations, MTX-IR and bDMARD-IR pts with active RA reported clinically meaningful improvements in PROs after BARI treatment. The NNTs in these analyses indicate that <10 pts need to be treated with BARI 2-or 4-mg to report a clinically meaningful benefit.
Objective: The Functional Assessment of Chronic Illness Therapy?Fatigue (FACIT‐F) is validated for measuring fatigue in rheumatoid arthritis (RA). However, 10 of 13 FACIT‐F items are identified as relevant to patients with RA. The Patient‐Reported Outcomes Measurement Information System (PROMIS) uses an item response theory?calibrated T score metric. The PROMIS Fatigue item bank includes the FACIT‐F items, enabling score conversion. The performance of converted PROMIS Fatigue scores has not been evaluated in RA populations or clinical trials. Our objective was to assess the performance of converted PROMIS Fatigue scores in 2 RA clinical trials of baricitinib. Methods: Crosswalk tables and pattern‐scoring methods converted FACIT‐F scores to PROMIS Fatigue for both the 13‐item FACIT‐F and the 10‐item RA‐optimized FACIT‐F instrument, in 2 RA clinical trials evaluating baricitinib, RA‐BEAM, and RA‐BEACON. RA‐BEAM patients had an inadequate response to methotrexate. RA‐BEACON patients had an inadequate response or intolerance to ?1 tumor necrosis factor inhibitor. Baricitinib was compared to all treatment arms via analysis of covariance on PROMIS Fatigue score conversions. Results: Baseline FACIT‐F?derived PROMIS Fatigue scores reflected severe fatigue across treatment groups and were similar using different scoring methods. At week 24 in both studies, baricitinib was associated with clinically meaningful improvements in PROMIS Fatigue scores. PROMIS Fatigue scores were consistent for conversion methods and for the 13‐item or 10‐item FACIT‐F. Conclusion: All 4 conversion methods showed differentiation of active treatment compared with placebo from week 12, supporting the use of the PROMIS Fatigue and converting the 10‐item FACIT‐F to assess fatigue and demonstrate treatment benefit in RA clinical trials on a standardized metric.
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.
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.
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.
The purpose of this study is to determine whether baricitinib 4 milligram (mg) once daily is superior to placebo in the treatment of participants with moderately to severely active Rheumatoid Arthritis (RA) who have had an inadequate response to a tumor necrosis factor (TNF) inhibitor, despite ongoing treatment with conventional disease-modifying antirheumatic drugs (cDMARDs).
