B Zhu

Determinants of Patient’s Global Assessment of Disease Activity and Physician’s Global Assessment of Disease Activity in patients with rheumatoid arthritis: A post hoc analysis of overall and Japanese results from phase 3 clinical trials

Abstract Objectives: To assess the determinants of Patient’s Global Assessment of Disease Activity (PtGA) and Physician’s Global Assessment of Disease Activity (PhGA) in overall and Japanese patients with rheumatoid arthritis (RA) from two large randomized controlled trials. Methods: Post hoc analysis of overall and Japanese RA patients who had previous inadequate responses to methotrexate or who had no/minimal previous disease-modifying antirheumatic drug treatment. We examined correlations between PtGA/PhGA and tender joint count in 28 joints (TJC28), swollen joint count in 28 joints (SJC28), inflammatory markers, pain visual analog scale (VAS), and other patient-reported outcomes at baseline, Week 12, and Week 24. Determinants of PtGA/PhGA were identified. Results: In overall populations, pain VAS was the main determinant of PtGA, whereas TJC28 was the main determinant of PhGA in both studies. In Japanese populations, consistent with overall populations, pain VAS was the main determinant of PtGA in both studies; in contrast to overall populations, pain VAS and SJC28/TJC28 played an important role in PhGA. Conclusion: Pain was the most important determinant of PtGA, whereas determinants of PhGA varied between populations/studies and were mostly explained by pain/joint counts. Physicians should be aware of patients’ perceptions of disease activity when performing assessments/prescribing treatments.

Relationship between disease activity and patient-reported outcomes in rheumatoid arthritis: Post hoc analyses of overall and Japanese results from two phase 3 clinical trials

Abstract Objective: To examine patient-reported outcomes (PROs) in patients with different rheumatoid arthritis (RA) disease activity levels and identify residual symptoms. Methods: Post hoc analyses of overall and Japanese data from two randomized controlled trials including RA patients with previous inadequate responses to methotrexate (NCT01710358) or no/minimal previous disease-modifying antirheumatic drug treatment (NCT01711359) (sponsor: Eli Lilly and Company). Week 24 assessments were disease activity (Simplified Disease Activity Index, Disease Activity Score/Disease Activity Score 28 joints-erythrocyte sedimentation rate) and PROs (pain visual analog scale [VAS], morning joint stiffness [MJS], Health Assessment Questionnaire-Disability Index, Functional Assessment of Chronic Illness Therapy-Fatigue, and Medical Outcomes Study Short Form 36 Health Survey Physical and Mental Component Scores). Results: Patients achieving remission/low disease activity (LDA) at Week 24 had larger/significant improvements from baseline in pain, MJS, disability, fatigue, and physical and emotional quality of life versus patients with high/moderate disease activity. Some patients achieving remission and LDA, reported residual pain (pain VAS >10u2009mm): 20.8–39.3% and 48.7–70.0% (overall study populations), 16.0–34.5% and 47.1–62.0% (Japanese patients). Residual MJS and fatigue were also reported. Conclusion: Remission/LDA were associated with improvements in PROs in overall and Japanese patient populations; however, some patients achieving remission had residual symptoms, including pain.

DIFFERENCES IN PATIENT-REPORTED OUTCOMES BETWEEN BARICITINIB AND COMPARATORS AMONG PATIENTS WITH RHEUMATOID ARTHRITIS WHO ACHIEVED LOW DISEASE ACTIVITY OR REMISSION

Background Achieving remission is the ideal goal in treating rheumatoid arthritis (RA). In a randomised phase 3 trial, high remission and low disease activity (LDA) rates were achieved with baricitinib (BARI). However, little is known about the differences in patient reported outcomes (PROs) among patients (pts) who have already achieved these targets. Objectives To compare PROs between BARI, adalimumab (ADA), and placebo (PBO) in pts with RA who achieved LDA or remission in the Phase 3 RA-BEAM study. Methods 1305 pts with RA and background treatment with methotrexate were randomised to receive PBO (n=488), ADA (n=330), or BARI 4 mg (n=487) for 52 wks (24 wks for PBO). In each treatment group, pts in remission (DAS28-ESR<2.6) and with LDA (DAS28-ESR≤3.2) at wk 24 were assessed from baseline for the following PROs: Pain VAS, HAQ-DI, WPAI, Morning Joint Stiffness (MJS), and FACIT-F. Sensitivity analyses were conducted for pts in remission or LDA by DAS28-CRP, SDAI, or CDAI. The assessment of response at wk 24 was determined by using the observed data, and the missing values for PRO measures were imputed by using mLOCF. Results Among pts in LDA, significantly greater improvements in Pain VAS and HAQ-DI scores were observed with BARI than ADA and PBO, and significantly greater improvements in MJS were observed with BARI and ADA than PBO. Significantly greater residual pain and HAQ-DI scores were observed with PBO. Among pts in remission, significantly greater improvements in pain and HAQ-DI scores were also observed with BARI than PBO. Patients in remission or LDA showed greater numerical improvement and less residual impairment in other PROs with BARI and ADA than PBO (Table 1). Consistent results were observed using other composite measures to define LDA and remission. Conclusions The preliminary findings from this study suggest that BARI showed greater improvements in pain and HAQ-DI compared to ADA for pts in LDA, and greater improvements in pain and HAQ-DI scores as well as less physical impairment compared to PBO for pts in LDA and remission. Acknowledgements The authors acknowledge the contribution of Inmaculada de la Torre MD, PhD, Senior Medical Advisor. Disclosure of Interest B. Fautrel: None declared, M. van de Laar: None declared, B. Kirkham: None declared, R. Alten Consultant for: Eli Lilly and Company, R. Cseuz Consultant for: Eli Lilly and Company, S. Van der Geest Employee of: Eli Lilly and Company, B. Zhu Employee of: Eli Lilly and Company, F. De Leonardis Employee of: Eli Lilly and Company, P. Taylor Consultant for: Eli Lilly and Company; Abvie

SAT0055 Baricitinib showed rapid and greater reduction in pain compared to adalimumab or placebo in patients with rheumatoid arthritis

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.Table 1. Percent Pain Improvement in RA-BEAM and RA-BEACON RA-BEAM RA-BEACON PBO Bari 4 mg ADA PBO Bari 2 mg Bari 4 mg (N=488) (N=487) (N=330) (N=176) (N=174) (N=177) Pain Improvement ≥30% u2003Week 1 27 48*** 47*** 20 25 32** u2003Week 4 37 67***† 60*** 29 38 50*** u2003Week 12 47 73***† 64*** 31 43* 58*** u2003Week 24 49 74*** 69*** 34 44* 57*** Pain Improvement ≥50% u2003Week 1 13 26*** 28*** 6 9 17** u2003Week 4 22 48***‡ 37*** 15 25* 30*** u2003Week 12 31 57***† 49*** 17 31** 35*** u2003Week 24 32 61***† 52*** 20 32** 45*** Pain Improvement ≥70% u2003Week 1 4 12*** 11*** 2 3 6 u2003Week 4 8 26*** 21*** 6 11 14* u2003Week 12 14 37***‡ 28*** 7 19*** 18** u2003Week 24 16 41***‡ 32*** 9 22*** 29*** *p≤0.05 vs PBO; **p≤0.01 vs PBO; ***p≤0.001 vs PBO; †p≤0.05 vs ADA; ‡p≤0.01 vs ADA; p-values based on logistic regression model. ADA = adalimumab; Bari = baricitinib; PBO = placebo. 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. References Fridman JS, et al. J Immunol 2010;184:5298–307. Taylor PC, et al. Arthritis Rheumatol 2015;67 (suppl 10):abstr 2L. Genovese MC, et al. N Engl J Med 2016;374:1243–52. Disclosure of Interest P. Taylor Grant/research support from: AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos, GlaxoSmithKline, Merck, Pfizer, UCB, Biogen, Sandoz and Janssen., Consultant for: AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos, GlaxoSmithKline, Merck, Pfizer, UCB, Biogen, Sandoz and Janssen., B. Zhu Employee of: Eli Lilly and Company, C. Gaich Employee of: Eli Lilly and Company, X. Zhang Employee of: Eli Lilly and Company, A. DeLozier Employee of: Eli Lilly and Company, D. Schlichting Employee of: Eli Lilly and Company, H. Patel: None declared, F. Durand: None declared, B. Fautrel Consultant for: AbbVIe, Biogen, BMS, Celgene, Hospira, Janssen, Lilly, Novartis, Pfizer, Roche, SOBI pharma, UCB

SAT0225 Comparative effectiveness in pain and haq-di improvement for baricitinib versus adalimumab, tocilizumab, and tofacitinib monotherapies in csdmard-naÏve rheumatoid arthritis patients: a matching-adjusted indirect comparison (MAIC)

Background: In Phase 3 trial, RA-BEGIN, baricitinib (BARI) monotherapy demonstrated superiority to MTX in pain reduction and HAQ-DI improvement in treatment of csDMARD-naïve active RA patients.1 No prospective head-to-head (H2H) trial data are available comparing BARI monotherapy vs. bDMARD monotherapy in csDMARD-naïve RA patients. Objectives: To assess pain and HAQ-DI for BARI monotherapy from a randomized, MTX-controlled trial vs adalimumab (ADA), tocilizumab (TCZ), and tofacitinib (TOFA) monotherapy from similar randomized, MTX-controlled trials in csDMARD/bDMARD naïve RA patients using matching-adjusted indirect comparison (MAIC). Methods: Individual patient data from the RA-BEGIN BARI 4 mg arm were weighted to match baseline characteristics of the ADA arm from PREMIER,2 TOFA 5 mg arm from ORAL-START,3 and TCZ 8 mg/kg arm from combination of AMBITION and FUNCTION,4,5 respectively; MTX arms were also matched between trials. Method of moments was used to determine weights for age, gender, baseline disease scores, and baseline values of the outcome variable. Mean change on pain VAS and HAQ-DI at Week 24 for BARI were adjusted for the above baseline characteristics with the weighted linear model, and then indirectly compared vs. respective published results for Week 24 TCZ and TOFA and for Week 26 ADA data. Statistical significance of the weighted treatment effect was assessed with the bootstrap method. Sensitivity analyses included MAIC with study level matching6, Bucher’s method without matching adjustment7, and inclusion of disease duration as an additional matching variable. Results: Across trials, the mean baseline pain VAS ranged from 58.7 to 65.2 with a 6-month mean change in pain of -28.3 to -33.5 for the MTX arm, indicating comparability between trials. Similar HAQ-DI and changes in HAQ-DI for the MTX arm were observed. At Week 24, BARI showed numerically greater improvement over MTX in pain than that for TCZ, ADA, and TOFA; statistically significant pain improvement were observed for BARI vs ADA and TCZ with all 3 matching methods but only with the Bucher method for TOFA (figure 1). BARI-treated patients showed significantly greater improvement in HAQ-DI at Week 24 than TCZ and ADA but not TOFA (figure 1). Sensitivity analyses showed consistent results. Conclusions: This indirect comparison of different studies in cs/bDMARD-naïve RA patients, after adjusting for differences in baseline characteristics, suggest a greater pain reduction and improved physical function for BARI monotherapy vs. TCZ and ADA monotherapy. There is suggestion of greater pain reduction for BARI monotherapy vs. TOFA monotherapy, but no differences in improved physical function between the JAK inhibitors. A H2H clinical trial would be needed to confirm these results. References 1Fleischmann, et al. Arthritis Rheumatol2017. 2Breedveld, et al. Arthritis Rheumatol2006. 3Lee, et al. N Engl J Med2014. 4Jones, et al. Ann Rheum Dis2010. 5Burmester, et al. Ann Rheum Dis2016. 6Signorovitch, et al. Pharmacoeconomics2010. 7Bucher, et al. J Clin Epi1997. Disclosure of Interest: B. Fautrel Grant/research support from: AbbVie, MSD, Pfizer, Consultant for: AbbVie, Biogen, BMS, Celgene, Janssen, Lilly, Medac, MSD, NORDIC Pharma, Novartis, Pfizer, Roche, Sanofi-Aventis, SOBI, UCB, B. Zhu Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, P. Taylor Grant/research support from: Celgene, Eli Lilly and Company, Galapagos, UCB, Abide Therapeutics, Consultant for: AbbVie, Eli Lilly and Company, Galapagos, GlaxoSmithKline, Pfizer, UCB, Biogen, Sandoz, Novartis, and Janssen, M. van de Laar Grant/research support from: Abbvie; BMS; Grunenthal; Pfizer; Janssen; MSD, Lilly, Consultant for: Abbvie, Grunenthal; Pfizer, Janssen, MSD, Lilly, Speakers bureau: Pfizer; Janssen, Eli Lilly, P. Emery Consultant for: Pfizer, MSD, Abbvie, BMS, UCB, Roche, Novartis, Samsung, Sandoz, Eli Lilly and Company, F. De Leonardis Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, C. Gaich Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, C. Nicolay Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Z. Kadziola Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, I. De La Torre Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, R. Fleischmann Grant/research support from: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Genetech, GlaxoSmithKline, Janssen, Eli Lilly and Company, Merck, Pfizer, Regeneron, Roche, Sanofi, Aventis, UCB, Consultant for: AbbVie, Akros, Amgen, Bristol-Myers Squibb, Celgene, Genentech, GSK, Janssen, Eli Lilly and Company, Pfizer, Sanofi-Aventis, UCB

SAT0069 A RAPID3-like index documents superior efficacy of BARICITINIB to ADALIMUMAB and placebo, similar to DAS28 and CDAI in the RA-BEAM clinical trial in patients with rheumatoid arthritis

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

FRI0099 Pain reduction is associated with improved work productivity in patients with rheumatoid arthritis

Background Patients with rheumatoid arthritis (RA) indicate pain is an important aspect of disease burden and may persist despite control of disease. In a randomized, double-blind phase 3 clinical trial of baricitinib (RA-BEAM),1 baricitinib provided significant improvement in pain reduction. It is not clear, however, how much reductions in pain impacted other aspects of life, such as work productivity. Objectives To assess the relationship between pain reduction and improvements, regardless of treatment, in daily activity and work productivity in patients with RA. Methods In this post-hoc analysis of RA-BEAM1, pain for the intention-to-treat patients was assessed using the patients assessment of pain (0–100 mm visual analogue scale). The Work Productivity and Activity Impairment Questionnaire-RA (WPAI-RA) instrument was used to evaluate the percentage of activity impairment due to RA (impairment in regular daily activities, N=1302), percentage of work-time missed due to RA (absenteeism, N=521), percentage of impairment while working due to RA (presenteeism, N=490), and percentage of overall work impairment due to RA (impairment in work productivity, N=490). Pain was divided into pain reduction groups (<30%, 30%

FRI0116 A high level of clinical response based on composite indices is associated with improved health-related quality of life: analyses from a phase 3 clinical trial in patients with rheumatoid arthritis

-<

226 Summary of baricitinib effect on patient-reported outcomes (PROs) in methotrexate-inadequate responder patient population

50%, ≥50% at Weeks 12 and 24; ≥30% [Y/N] and ≥50% [Y/N] at Weeks 1 and 2). Pairwise comparisons on improvement in WPAI-RA scores between pain reduction groups at Weeks 12 and 24 were assessed by ANCOVA adjusting for region, baseline joint erosion status, and baseline values of outcome variables. Missing values were imputed using the modified last-observation carried forward method. Results At baseline across treatment groups, the mean values ranged from 56–58 for daily activity impairment, 12–13 for absenteeism, 42–46 for presenteeism, and 45–49 for work productivity impairment. A ≥30% reduction in pain as early as Week 1 was associated with significantly greater (p<0.001) improvement than <30% pain reduction in regular daily activity (-22.8 vs -16.0), presenteeism (-17.5 vs. -12.1), and work productivity (-16.8 vs. -11.6) at Week 12. Greater improvement was observed in most WPAI-RA scores in patients who had more pain reduction at Weeks 12 and 24; with a reduction of ≥50% in pain from baseline, the WPAI-RA scores were substantially improved at Weeks 12 or 24 for daily activity, presenteeism, and work productivity (Table). Conclusions Regardless of treatment, pain reduction was associated with improved regular daily activity and work productivity in patients with RA, with larger levels of reduction related to more improvement. References Taylor PC, Keystone E, van der Heijde D, et al. Baricitinib Versus Placebo or Adalimumab in Patients with Active Rheumatoid Arthritis (RA) and an Inadequate Response to Background Methotrexate Therapy: Results of a Phase 3 Study. Arthritis Rheum 2015;67(Suppl 10):3928. Disclosure of Interest K. Michaud Grant/research support from: Pfizer, B. Zhu Employee of: Eli Lilly and Company, C. Gaich Employee of: Eli Lilly and Company, A. DeLozier Employee of: Eli Lilly and Company, V. Arora Employee of: Eli Lilly and Company, C. Dickson Employee of: Eli Lilly and Company, J. Smolen Grant/research support from: Abbvie, Janssen, Lilly, MSD, Pfizer, Roche and has provided expert advice to and/or had speaking engagements for Abbvie, Amgen, Astra-Zeneca, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, Glaxo, ILTOO, Janssen, Lilly, Medimmune, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB