A.M. DeLozier

Patient-reported outcomes from a randomised phase III study of baricitinib in patients with rheumatoid arthritis and an inadequate response to biological agents (RA-BEACON)

Objectives 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). Methods 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), Patients Global Assessment of Disease Activity (PtGA), patients 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. Results 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). Conclusions 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. Trial registration number NCT01721044; Results.

Patient-reported outcomes from a phase 3 study of baricitinib versus placebo or adalimumab in rheumatoid arthritis: secondary analyses from the RA-BEAM study

Background To assess the effect of baricitinib on patient-reported outcomes (PROs) in patients with active rheumatoid arthritis and an inadequate response to methotrexate (MTX). Methods In this double-blind phase 3 study, patients were randomised 3:3:2 to placebo (n=488), baricitinib 4 mg once daily (n=487), or adalimumab 40 mg biweekly (n=330) with background MTX. PROs included the SF-36, EuroQol 5-D (EQ-5D) index scores and visual analogue scale, 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 and Work Productivity and Activity Impairment Questionnaire-Rheumatoid Arthritis (WPAI-RA), and measures collected in electronic patient daily diaries: duration and severity of morning joint stiffness (MJS), Worst Ttiredness and Worst Joint Pain. The primary study endpoint was at week 12. Treatment comparisons were assessed with logistic regression for categorical measures or analysis of covariance for continuous variables. Results Compared with placebo and adalimumab, baricitinib showed statistically significant improvements (p≤0.05) in HAQ-DI, PtGA, pain, FACIT-F, SF-36 physical component score, EQ-5D index scores and WPAI-RA daily activity at week 12. Improvements were maintained for measures assessed to week 52. Statistically significant improvement in patient diary measures (MJS duration and severity), worst tiredness and worst joint pain were observed for baricitinib versus placebo and adalimumab at week 12 (p≤0.05). Conclusions Baricitinib provided significantly greater improvement in most PROs compared with placebo and adalimumab, including physical function MJS, pain, fatigue and quality of life. Improvement was maintained to the end of the study (week 52). Trial registration NCT01710358.

Baricitinib in adult patients with moderate-to-severe atopic dermatitis: a phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study

Background: Baricitinib, an oral selective inhibitor of Janus kinase 1 and Janus kinase 2, modulates proinflammatory cytokine signaling. Objectives: The efficacy and safety of baricitinib were evaluated in patients with moderate‐to‐severe atopic dermatitis (AD). Methods: In this phase 2, randomized, double‐blind, placebo‐controlled study, 124 patients with moderate‐to‐severe AD applied topical corticosteroids (TCSs) for 4 weeks before randomization to once‐daily placebo, 2 mg of baricitinib, or 4 mg of baricitinib for 16 weeks. Use of TCSs was permitted during the study. The primary outcome was the proportion of patients achieving at least a 50% reduction in the Eczema Area and Severity Index (EASI‐50) compared with placebo. Results: Significantly more patients who received baricitinib, 4 mg, achieved EASI‐50 than did patients receiving placebo (61% vs 37% [P = .027]) at 16 weeks. The difference between the proportion of patients receiving baricitinib, 2 or 4 mg, who achieved EASI‐50 and the proportion of patients receiving placebo and achieving EASI‐50 was significant as early as week 4. Baricitinib also improved pruritus and sleep loss. Treatment‐emergent adverse events were reported in 24 of the patients receiving placebo (49%), 17 of those receiving 2 mg of baricitinib (46%), and 27 of those receiving 4 mg of baricitinib (71%). Limitations: A TCS standardization period before randomization reduced disease severity, limiting the ability to compare results with those of baricitinib monotherapy. Longer studies are required to confirm baricitinibs efficacy and safety in patients with AD. Conclusions: Baricitinib used with TCSs reduced inflammation and pruritus in patients with moderate‐to‐severe AD.

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

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

Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial

BACKGROUND Patients with systemic lupus erythematosus have substantial unmet medical need. Baricitinib is an oral selective Janus kinase (JAK)1 and JAK2 inhibitor that we hypothesised might have therapeutic benefit in patients with systemic lupus erythematosus. METHODS In this double-blind, multicentre, randomised, placebo-controlled, 24-week phase 2 study, patients were recruited from 78 centres in 11 countries. Eligible patients were aged 18 years or older, had a diagnosis of systemic lupus erythematosus, and had active disease involving skin or joints. We randomly assigned patients (1:1:1) to receive once-daily baricitinib 2 mg, baricitinib 4 mg, or placebo for 24 weeks. The primary endpoint was the proportion of patients achieving resolution of arthritis or rash at week 24, as defined by Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K). Efficacy and safety analyses included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02708095. FINDINGS Between March 24, 2016, and April 27, 2017, 314 patients were randomly assigned to receive placebo (n=105), baricitinib 2 mg (n=105), or baricitinib 4 mg (n=104). At week 24, resolution of SLEDAI-2K arthritis or rash was achieved by 70 (67%) of 104 patients receiving baricitinib 4 mg (odds ratio [OR] vs placebo 1·8, 95% CI 1·0-3·3; p=0·0414) and 61 (58%) of 105 patients receiving baricitinib 2 mg (OR 1·3, 0·7-2·3; p=0·39). Adverse events were reported in 68 (65%) patients in the placebo group, 75 (71%) patients in the baricitinib 2 mg group, and 76 (73%) patients in the baricitinib 4 mg group. Serious adverse events were reported in ten (10%) patients receiving baricitinib 4 mg, 11 (10%) receiving baricitinib 2 mg, and five (5%) receiving placebo; no deaths were reported. Serious infections were reported in six (6%) patients with baricitinib 4 mg, two (2%) with baricitinib 2 mg, and one (1%) with placebo. INTERPRETATION The baricitinib 4 mg dose, but not the 2 mg dose, significantly improved the signs and symptoms of active systemic lupus erythematosus in patients who were not adequately controlled despite standard of care therapy, with a safety profile consistent with previous studies of baricitinib. This study provides the foundation for future phase 3 trials of JAK1/2 inhibition with baricitinib as a new potential oral therapy for systemic lupus erythematosus. FUNDING Eli Lilly and Company.

SAT0349 Patient-Reported Outcomes from a Phase 3 Study of Baricitinib in Patients with Rheumatoid Arthritis (RA) and an Inadequate Response to Tumor Necrosis Factor Inhibitors

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).Table 1 PRO, LSM change from baseline (unless noted) Wk 24 PBO (N=176) 2 mg QD (N=174) 4 mg QD (N=177) Physical function (HAQ-DI) (% Achieving MCID [≥0.22]/% Achieving MCID [≥0.3]) −0.15 [30/24] −0.37***[50***/41***] −0.42*** [53***/44***] Patient global assessment of disease activity −8.8 −20.3*** −24.8*** Patient Assessment of Pain −8.8 −18.8*** −24.0*** QoL: SF-36 PCS (% Achieving MCID [≥5])/MCS (% Achieving MCID [≥5]) 1.9 [21]/1.9 [22] 6.2*** [39***]/2.8 [26] 7.1*** [45***]/2.7 [29] EQ-5D Health State Index Score US algorithm/UK algorithm/VAS 0.025/0.038/1.9 0.074**/0.111**/7.9* 0.107***/0.159***/11.3*** Fatigue (FACIT-F) (% Achieving MCID [≥3.56]) 5.7 [38] 8.1*[50*] 9.2** [53**] Median duration of morning joint stiffness (minutes), change from baseline −8.0 −25.5** −27** WPAI-RA: Employment both at baseline & at 24 weeks, N (%) 22 (82) 38 (86) 42 (89) Absenteeism (% of work-time missed) 8.0 5.7 6.0 Presenteeism (% of work-time impaired) −3.2 −7.6 −11.7 Work productivity loss (% of overall work impairment) −0.6 −6.3 −8.4 Activity impairment (% regular activity impairment) −15.2 −22.2* −26.3*** LSM, least squares mean; MCID, minimum clinically important difference; MCS, mental component score; PCS, physical component score; QoL, quality of life.* p≤0.05,** p≤0.01,*** p≤0.001 vs. PBO; p-values not adjusted for multiple comparisons. 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. References Keystone et al. Ann Rheum Dis 2015;74:333-340. Tanaka et al. Arthritis Rheum 2013;65(S10):S765. Disclosure of Interest J. Smolen Grant/research support from: Abbvie, Janssen, MSD, Pfizer, Roche, UCB, Consultant for: Abbvie, Amgen, Astra-Zeneca, Astro, Celgene, Glaxo, Janssen, Lilly, Medimmune, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB, J. Kremer Grant/research support from: Abbvie, Amgen, BMS, Genentech, Lilly, Pfizer and UCB, Employee of: Part time employment with Corrona, C. Gaich Employee of: Eli Lilly and Company, A. DeLozier Employee of: Eli Lilly and Company, D. Schlichting Employee of: Eli Lilly and Company, L. Xie Employee of: Eli Lilly and Company, M. Genovese Grant/research support from: Abbvie, Astellas, Eli Lilly and Company, Galapagos, Pfizer, and Vertex

Basal insulin initiation use and experience among people with type 2 diabetes mellitus with different patterns of persistence: results from a multi-national survey

Abstract Background and objective: People with type 2 diabetes mellitus (T2DM) often interrupt basal insulin treatment soon after initiation. This study aimed to describe the experiences during and after basal insulin initiation among people with T2DM with different persistence patterns. Methods: Adults with T2DM from France, Germany, Spain, UK, US, Brazil, and Japan were identified from consumer panels for an online survey. Respondents who initiated basal insulin 3–24 months prior to survey date were categorized as continuers (no gaps of ≥7 days in insulin treatment); interrupters (first gap ≥7 days within 6 months of initiation and restarted insulin); and discontinuers (stopped insulin for ≥7 days within 6 months of initiation without restarting). Results: Among 942 participants, continuers were older than interrupters and discontinuers (46, 37, and 38 years, respectively, p < .01). Continuers reported having fewer concerns before and after insulin initiation than interrupters and discontinuers, while interrupters had the most concerns. Continuers also reported fewer challenges during the first week of insulin use. Continuers were more likely to respond that insulin use had a positive impact on specific aspects of life than interrupters and discontinuers, for example on glycemic control (73.0%, 63.0%, and 61.8%, respectively; p < .01 vs. continuers). Conclusion: Among people with T2DM with different persistence patterns after basal insulin initiation there were significant differences in patient characteristics and experience during and after insulin initiation. Interrupters and discontinuers more frequently reported having concerns and challenges during the initiation process, negative impacts after initiation, and less improvement in glycemic control than continuers.

Study protocol: systematic review and meta-analysis of randomized controlled trials in first-line treatment of squamous non-small cell lung cancer

BackgroundThere is a high unmet need for effective treatments for patients with squamous non-small cell lung cancer (NSCLC). Eli Lilly and Company is conducting a phase III, randomized, multicenter, open-label study of gemcitabine plus cisplatin plus necitumumab (GC + N) versus gemcitabine plus cisplatin (GC) for the first-line treatment of patients with stage IV squamous NSCLC. Given GC is not the only treatment commonly used for the treatment of squamous NSCLC, this study was designed to compare the survival, toxicity, and quality of life outcomes of current treatment strategies for squamous NSCLC in the first-line setting.Methods/DesignA systematic review and meta-analysis (including indirect comparisons) of treatments used in squamous NSCLC will be conducted to assess the clinical efficacy (overall and progression-free survival), health-related quality of life (HRQoL), and safety (grade 3–4 toxicity) of GC + N compared to other treatments used in squamous NSCLC. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines will be followed for all aspects of this study. A systematic literature review will be conducted to identify randomized controlled trials evaluating chemotherapy treatment in first-line NSCLC. Eligible articles will be restricted to randomized controlled trials (RCTs) among chemotherapy-naïve advanced NSCLC cancer patients that report outcome data (survival, toxicity, or quality of life) for patients with squamous histology. Following data extraction and validation, data consistency and study heterogeneity will be assessed. A network meta-analysis will be conducted based on the available hazard ratios for overall and progression-free survival, odds ratios for published toxicity data, and mean difference of HRQoL scales. Sensitivity analyses will be conducted.DiscussionThis is a presentation of the study protocol only. Results and conclusions are pending completion of this study.Systematic review registrationPROSPEROCRD42014008968

Psychometric properties of the single-item measure, severity of worst tiredness, in patients with moderately to severely active rheumatoid arthritis

BackgroundTo assess the reliability, validity, and responsiveness to treatment change of the single-item measure, Severity of Worst Tiredness, in patients with rheumatoid arthritis (RA).MethodsData from two Phase 3, randomized, placebo-controlled (RA-BUILD; and active-controlled [RA-BEAM]), clinical studies of the efficacy of baricitinib in adults with moderately to severely active RA were used. The psychometric properties of the single-item measure, Severity of Worst Tiredness, were assessed, including test-retest reliability, convergent and discriminant validity, known-groups validity, and responsiveness, using other patient- and clinician-reported outcomes frequently assessed in RA patients.ResultsTest-retest reliability of the Severity of Worst Tiredness was supported through large intraclass correlation coefficients (0.89 ≤ ICC ≤ 0.91). Moderate-to-large correlations were observed between this patient-reported outcome (PRO) and other related patient- and clinician-reported assessments of RA symptoms and patient functioning, supporting construct validity of the measure (│r│ ≥ 0.41). The instrument also displayed known-groups validity through statistically significant differences between mean values of the Severity of Worst Tiredness defined using other indicators of RA severity. Finally, responsiveness was supported by large and statistically significant differences in change scores from Day 1 to Week 12 for patients comparing responders and nonresponders using the American College of Rheumatology 20 (ACR20) criteria.ConclusionThe Severity of Worst Tiredness PRO demonstrated adequate reliability, validity, and responsiveness in clinical trials of adults with moderately to severely active RA and is fit for purpose in this patient population.

Psychometric properties of morning joint stiffness duration and severity measures in patients with moderately to severely active rheumatoid arthritis

BackgroundTo assess the measurement properties of two single-item patient-reported outcome (PRO) measures that assessed the length of time (in minutes) and severity of morning joint stiffness (MJS) experienced each day.MethodsData from two Phase 3, randomized placebo-controlled (and active-controlled [RA-BEAM]), clinical studies assessing the safety and efficacy of baricitinib in adults with moderately to severely active rheumatoid arthritis (RA) were used to evaluate the psychometric properties of the Duration of MJS and Severity of MJS PROs.ResultsTest-retest reliability of Duration of MJS and Severity of MJS was supported through large intraclass correlation coefficients among stable patients (coefficient range for both studies: 0.88 to 0.93). In support of construct validity, moderate correlations were evidenced between Duration of MJS and other related patient- and clinician-reported assessments of RA symptoms and patient functioning, whereas moderate-to-strong correlations were evidenced between these same patient- and clinician-reported assessments and Severity of MJS. Statistically significant differences between the median and mean values of Duration of MJS and Severity of MJS for differing categories of RA disease severity supported known-groups validity. Finally, large and statistically significant differences in change scores from Day 1 to Week 12 for patients defined as responders versus non-responders using the American College of Rheumatology 20 criteria supported the responsiveness of both PROs.ConclusionDuration of MJS and Severity of MJS PROs demonstrated reliability, validity, and responsiveness in adults with moderately to severely active RA, supporting the measurement of these key symptoms in clinical trials.