Baricitinib, Methotrexate, or Combination in Patients With Rheumatoid Arthritis and No or Limited Prior Disease-Modifying Antirheumatic Drug Treatment.
ABSTRACT: We undertook this phase III study to evaluate baricitinib, an orally administered JAK-1/JAK-2 inhibitor, as monotherapy or combined with methotrexate (MTX) compared to MTX monotherapy in patients with active rheumatoid arthritis (RA) who had received no or minimal conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and who were naive to biologic DMARDs.A total of 588 patients were randomized 4:3:4 to receive MTX monotherapy (once weekly), baricitinib monotherapy (4 mg once daily), or the combination of baricitinib and MTX for 52 weeks. The primary end point assessment was a noninferiority comparison of baricitinib monotherapy to MTX monotherapy based on the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 24.The study met its primary objective. Moreover, baricitinib monotherapy was found to be superior to MTX monotherapy at week 24, with a higher ACR20 response rate (77% versus 62%; P ≤ 0.01). Similar results were observed for combination therapy. Compared to MTX monotherapy, significant improvements in disease activity and physical function were observed for both baricitinib groups as early as week 1. Radiographic progression was reduced in both baricitinib groups compared to MTX monotherapy; the difference was statistically significant for baricitinib plus MTX. The rates of serious adverse events (AEs) were similar across treatment groups, while rates of some treatment-emergent AEs, including infections, were increased with baricitinib plus MTX. Three deaths were reported, all occurring in the MTX monotherapy group. Malignancies, including nonmelanoma skin cancer, were reported in 1 patient receiving MTX monotherapy, 1 receiving baricitinib monotherapy, and 4 receiving baricitinib plus MTX.Baricitinib alone or in combination with MTX demonstrated superior efficacy with acceptable safety compared to MTX monotherapy as initial therapy for patients with active RA.
Project description:The objective of this study was to evaluate structural damage progression based on clinical response in rheumatoid arthritis patients with no or limited prior disease-modifying anti-rheumatic drug treatment receiving the Janus kinase (JAK)1/JAK2 inhibitor baricitinib 4 mg, methotrexate (MTX), or the combination. Data from the phase 3 RA-BEGIN study were analysed post hoc. Proportions of patients with structural damage progression (change from baseline greater than the smallest detectable change in modified total Sharp score) at week 52 were evaluated based on sustained Disease Activity Score for 28-joint count with serum high-sensitivity C-reactive protein (DAS28-hsCRP) ??3.2 or Simplified Disease Activity Index (SDAI) score ??11; no formal statistical comparisons between treatments were performed to test these proportions. Baseline factors associated with risk of structural damage progression, including Clinical Disease Activity Index (CDAI) score, were identified using multivariate analysis. Patients achieving versus not achieving sustained DAS28-hsCRP ??3.2 or SDAI score ??11 were less likely to experience structural damage progression at week 52. In patients achieving these responses, structural damage progression was less likely with baricitinib monotherapy or plus MTX than with MTX monotherapy. In patients not achieving these sustained clinical thresholds, structural damage progression was less likely with baricitinib plus MTX than with either monotherapy. Independent of treatment, baseline factors significantly associated with increased risk of structural damage progression included higher hsCRP and CDAI score, smoking, female sex, and lower body mass index. In conclusion, patients achieving versus not achieving sustained DAS28-hsCRP ??3.2 or SDAI score ??11 were less likely to show structural damage progression, irrespective of treatment.
Project description:We investigated the clinical efficacy and safety of tocilizumab (a humanized anti-IL-6 receptor antibody) monotherapy in active rheumatoid arthritis (RA) patients with an inadequate response to low dose methotrexate (MTX). In a multicenter, double-blind, randomized, controlled trial, 125 patients were allocated to receive either tocilizumab 8 mg/kg every 4 weeks plus MTX placebo (tocilizumab group) or tocilizumab placebo plus MTX 8 mg/week (control group) for 24 weeks. The clinical responses were measured using the American College of Rheumatology (ACR) criteria and the Disease Activity Score in 28 joints. Serum vascular endothelial growth factor (VEGF) levels were also monitored. At week 24, 25.0% in the control group and 80.3% in the tocilizumab group achieved ACR20 response. The tocilizumab group showed superior ACR response criteria over control at all time points. Additionally, serum VEGF levels were significantly decreased by tocilizumab treatment. The overall incidences of adverse events (AEs) were 72 and 92% (serious AEs: 4.7 and 6.6%; serious infections: 1.6 and 3.3%) in the control and the tocilizumab groups, respectively. All serious adverse events improved by adequate treatment. Tocilizumab monotherapy was well tolerated and provided an excellent clinical benefit in active RA patients with an inadequate response to low dose MTX.
Project description:The safety and efficacy of certolizumab pegol (CZP) 400 mg every 4 weeks (Q4W) monotherapy (FAST4WARD/NCT00548834) and in combination with methotrexate (MTX) (014/NCT00544154) in active rheumatoid arthritis (RA) has been published previously. This report outlines final long-term outcomes from the open-label extension (OLE) study (015/NCT00160693), which enrolled patients from these randomized controlled trials (RCTs).Patients who withdrew from or completed the 24-week 014/FAST4WARD RCTs were enrolled and received CZP 400 mg Q4W with/without MTX. Exposure-adjusted event rates (ER) per 100 patient-years (PYs) of adverse events (AEs) and serious AEs (SAEs) were reported for all patients receiving ≥1 dose of CZP in RCTs or OLE (N = 427) between first CZP dose and up to 24 weeks after last CZP dose or study withdrawal. Efficacy assessments included clinical (ACR20/50/70 response rates, TJC, SJC) and patient-reported outcomes (HAQ-DI, PtGADA, pain, fatigue) to week 304 (5.8 years) in the CZP intent-to-treat population. SDAI and CDAI outcomes were analyzed post hoc. Outcomes for CZP monotherapy and CZP+MTX combination-therapy were compared.Globally, ERs of AEs and SAEs were 408.1 and 25.2 per 100 PY, respectively. Eleven patients had AEs leading to death (ER 0.6). Improvements in clinical and patient-reported outcomes during the 24-week RCTs were maintained to week 304, and were similar between all subpopulations.The longest exposure duration to date with CZP 400 mg Q4W treatment confirmed the safety profile observed in previous studies. Initial improvements in signs and symptoms of RA, including PROs, were maintained in both CZP monotherapy and CZP + MTX combination-therapy patients.ClinicalTrials.gov identifier, NCT00160693.UCB Pharma.
Project description:INTRODUCTION:Janus kinase (JAK) inhibitors are a class of targeted therapies for rheumatoid arthritis (RA) with established clinical efficacy. However, little is known about their efficacy compared with each other. This network meta-analysis (NMA) estimated the comparative efficacy of JAK inhibitors currently approved for RA. METHODS:A targeted literature review was conducted for phase III randomized controlled trials (RCTs) evaluating the efficacy of three approved JAK inhibitors (tofacitinib, baricitinib, and upadacitinib) as monotherapy or combination therapy among patients with moderate-to-severe RA who had inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARD-IR). Using Bayesian NMA, American College of Rheumatology (ACR) 20/50/70 responses and clinical remission (defined as DAS28-CRP?<?2.6) were evaluated separately at 12 and 24 weeks. RESULTS:Eleven RCTs were identified and included in the NMA. All JAK inhibitors demonstrated significantly better efficacy than csDMARD. Among combination therapies, upadacitinib 15 mg had the highest 12-week ACR50 responses (median [95% credible interval]: 43.4% [33.4%, 54.5%]), followed by tofacitinib 5 mg (38.7% [28.6%, 49.8%]), baricitinib 2 mg (37.1% [25.0%, 50.6%]), and baricitinib 4 mg (36.7%, [27.2%, 47.0%]). Similar results were observed for ACR20/70 and at week 24. Upadacitinib 15 mg?+?csDMARD was also found to have the highest clinical remission rates at week 12 (29.8% [16.9%, 47.0%]), followed by tofacitinib 5 mg (24.3%, [12.7%, 40.2%]), baricitinib 4 mg (22.8%, [11.8%, 37.5%]), and baricitinib 2 mg (20.1%, [8.6%, 37.4%]). Similar results were seen at week 24. Among monotherapies, upadacitinib had a higher ACR50 response (38.5% [25.3%, 53.2%]) than tofacitinib (30.4% [18.3%, 45.5%]). The differences in efficacy measures were not statistically significant between the JAK inhibitors. CONCLUSIONS:The NMA found that upadacitinib 15 mg once daily had numerically higher efficacy in terms of ACR response and clinical remission among approved JAK combination therapies and monotherapies for csDMARD-IR patients with RA.
Project description:OBJECTIVE:To compare the efficacy and safety of ABT-494, a novel selective JAK-1 inhibitor, with placebo in patients with moderate-to-severe rheumatoid arthritis (RA) and an inadequate response or intolerance to at least 1 anti-tumor necrosis factor (anti-TNF) agent. METHODS:In this 12-week, double-blind, placebo-controlled, dose-ranging study, 276 RA patients receiving a stable dose of methotrexate (MTX) who had previously received treatment with at least 1 anti-TNF agent were randomized equally to receive immediate-release ABT-494 at 3, 6, 12, or 18 mg twice daily or matching placebo twice daily. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 12. RESULTS:At week 12, significantly more patients receiving ABT-494 (53-71%) than those receiving placebo (34%) achieved an ACR20 response (by nonresponder imputation analysis) (P < 0.05), with a dose-response relationship among all ABT-494 doses (P < 0.001). ACR50 and ACR70 response rates were significantly higher in those receiving ABT-494 (36-42% and 22-26%, respectively) than in those receiving placebo (16% and 4%, respectively). Changes from baseline in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) were significantly greater for all doses of ABT-494 than for placebo (P ≤ 0.01). Onset of action of ABT-494 was rapid, with significant differences from placebo at week 2 both in ACR20 response rate (for 12 and 18 mg) and in change in the DAS28-CRP (P < 0.001 for 6-18 mg). The most frequent adverse events (AEs) were headache, nausea, upper respiratory tract infection, and urinary tract infection. Infection rates were higher at higher doses of ABT-494, but no infections were serious. No deaths were reported among those receiving ABT-494. CONCLUSION:In patients with an inadequate response or intolerance to anti-TNF agents, ABT-494 added to MTX showed rapid, dose-dependent improvements in RA signs and symptoms, with safety and tolerability similar to those of other drugs of this class. No new AEs were identified.
Project description:This study evaluates patient-reported outcomes (PROs) in a double-blind, phase III study of baricitinib as monotherapy or combined with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) with no or minimal prior conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and naïve to biological DMARDs.Patients were randomized 4:3:4 to MTX administered once weekly (N?=?210), baricitinib monotherapy (4 mg once daily (QD), N?=?159), or combination of baricitinib (4 mg QD) and MTX (baricitinib?+?MTX, N?=?215). PROs included the Patient's Global Assessment of Disease Activity (PtGA), patient's assessment of pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), duration of morning joint stiffness (MJS), worst joint pain, worst tiredness, Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA), Short Form 36 version 2, Acute (SF-36); and EuroQol 5-Dimensions (EQ-5D) Health State Profile. Comparisons were assessed with analysis of covariance (ANCOVA) and logistic regression models.Compared to MTX, patients in both baricitinib groups reported greater improvement (p???0.01) in HAQ-DI, PtGA, pain, fatigue, worst join pain, SF-36 physical component score, and EQ-5D at weeks 24 and 52. For the SF-36 mental component score, patients in both baricitinib groups reported statistically significant improvements (p???0.01) at week 52 compared to MTX-treated patients. Statistically significant improvements (p???0.05) were observed with the WPAI-RA for the baricitinib groups vs. MTX at week 24 and for the WPAI-RA daily activity and work productivity measures for baricitinib?+?MTX at week 52.In this study, baricitinib alone or in combination with MTX, when used as initial therapy, resulted in significant improvement compared to MTX in the majority of the pre-specified PRO measures.ClinicalTrials.gov, NCT01711359 . Registered on 18 October 2012.
Project description:Evaluate golimumab in patients with active rheumatoid arthritis (RA) and previous tumour necrosis factor-α (TNF) inhibitor use.Patients (n=461) previously receiving ≥1 TNF inhibitor were randomised to subcutaneous injections of placebo, golimumab 50 mg or golimumab 100 mg q4 weeks. Primary endpoint (≥20% improvement in American College of Rheumatology (ACR20) criteria at week 14) findings have been reported for all patients in the trial. Reported herein are further assessments of efficacy/safety among patients receiving golimumab+methotrexate (MTX).Among efficacy-evaluable patients who received MTX at baseline, more receiving golimumab+MTX (n=201) than placebo+MTX (n=103) achieved ACR20 (40.8% vs 14.6%), ACR50 (20.9% vs 3.9%), and ACR70 (11.4% vs 2.9%) responses at week 24. Among the 137 patients who had received only one prior TNF inhibitor (adalimumab, n=33; etanercept, n=47; and infliximab, n=57), week 24 ACR20 rates were 30.3%, 46.8% and 50.9%, respectively, and thus lowest among those who previously used adalimumab. ACR20 response rates were 44.5% (61/137), 36.2% (17/47) and 23.5% (4/17) among patients who had received one, two or three TNF inhibitors, respectively. Adverse event (AE) rates were comparable across type/number of prior anti-TNF agents, but appeared somewhat higher among patients who discontinued previous TNF inhibitor(s) due to intolerance (37/49, 75.5%) versus lack of efficacy (LOE, 113/191, 59.2%).Patients with active RA previously treated with ≥1 TNF inhibitor had clinically relevant improvement with golimumab+MTX, which appeared somewhat enhanced among those who received only etanercept or infliximab as their prior TNF inhibitor. Golimumab+MTX safety appeared similar across patients, regardless of TNF inhibitor(s) previously used, with fewer AEs occurring among patients who discontinued prior therapy for LOE.
Project description:BACKGROUND:Clinical guidelines recommend pneumococcal and tetanus vaccinations in patients with rheumatoid arthritis (RA). Baricitinib is an oral, selective Janus kinase (JAK) 1/JAK 2 inhibitor and is approved for the treatment of moderately to severely active RA in adults in over 50 countries including European countries, the USA, and Japan. This substudy evaluated pneumococcal conjugate and tetanus toxoid vaccine (TTV) responses in patients with RA receiving baricitinib. These vaccines elucidate predominantly T cell-dependent humoral antibody response. METHODS:Eligible RA patients receiving baricitinib 2 mg or 4 mg with or without concomitant methotrexate (MTX) were enrolled in a phase 3 long-term extension trial (RA-BEYOND; ClinicalTrials.gov, NCT01885078) in USA/Puerto Rico. Patients were vaccinated with 13-serotype pneumococcal conjugate vaccine (PCV-13) and TTV. Primary endpoints were the proportion of patients achieving a satisfactory humoral response for PCV-13 (≥ 2-fold increase in anti-pneumococcal antibody concentrations in ≥ 6 serotypes) and TTV (≥ 4-fold increase in anti-tetanus concentrations) at 5 weeks post-vaccination. Secondary endpoints included humoral responses at 12 weeks and functional responses of serotypes 4, 6B, 14, and 23F (twofold and fourfold increases in opsonic indexes at 5 and 12 weeks). RESULTS:Of 106 patients with a mean duration of RA of approximately 12 years, 80% were female, 30% were taking corticosteroids, and 89% (N = 94) were taking baricitinib plus MTX; most patients (97% PCV-13/96% TTV) completed the evaluations. Overall, 68% (95% CI 58.4, 76.2) of patients achieved a satisfactory response to PCV-13, 43% (34.0, 52.8) achieved a ≥ 4-fold increase in anti-tetanus concentrations, and 74% (64.2, 81.1) achieved a ≥ 2-fold increase. PCV-13 response was similar for patients taking corticosteroids (71%; 53.4, 83.9) vs those not (67%; 55.2, 76.5). The percentage of sera with a ≥ 2-fold increase in post-vaccination opsonic indexes at week 5 ranged from 47% (serotype 14) to 76% (serotype 6B). Through 12 weeks post-vaccination, seven patients (6.6%) reported injection-site events. There were no deaths during the substudy, and three patients experienced a serious adverse event. CONCLUSIONS:Approximately two thirds of patients on long-term baricitinib achieved satisfactory humoral and functional responses to PCV-13 vaccination, while TTV responses were less robust. PCV-13 response was not diminished in those taking concomitant corticosteroids. TRIAL REGISTRATION:ClinicalTrials.gov, NCT01885078 . Registered on 24 June 2013.
Project description:INTRODUCTION:This study assessed if concomitant use of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or corticosteroids altered the response or safety outcomes to baricitinib in rheumatoid arthritis (RA) patients. METHODS:Patients with???6 swollen/tender joints and no prior biologic DMARD were eligible for study inclusion. In RA-BUILD, csDMARD-inadequate responder (IR) patients were randomized to placebo or baricitinib (2 or 4 mg) once daily (QD). In RA-BEAM, methotrexate (MTX)-IR patients were randomized to placebo QD, baricitinib 4-mg QD, or adalimumab 40-mg biweekly. Patients continued background csDMARD (including MTX) therapy. This post hoc analysis of placebo and baricitinib 4-mg patients assessed the number and type of concomitant csDMARDS and concurrent corticosteroid use. RESULTS:From 716 placebo patients, 71, 21, and 6% were taking MTX alone, MTX?+???1 csDMARD, and non-MTX csDMARDs, respectively; from 714 baricitinib patients, the rates were 74, 18, and 6%; 56% of placebo and 55% of baricitinib patients used corticosteroids at baseline (mean dose, 6.0 mg/day for both groups); patients continued use throughout the studies. The odds ratios for achieving American College of Rheumatology response at the 20% improvement level (ACR20) and Clinical Disease Activity Index (CDAI)???10 at week 12 favored baricitinib for most subgroups; no significant interactions were observed. Rates of adverse events were similar regardless of csDMARD group or corticosteroid use. There were numerically more serious adverse events in placebo patients taking corticosteroids (4.2 vs. 1.6%) and a higher rate of discontinuations in baricitinib patients taking corticosteroids (4.1 vs. 1.2%). CONCLUSIONS:Baricitinib was efficacious regardless of concomitant use of csDMARDs or corticosteroids; the incidence of adverse events was similar across all groups of patients. FUNDING:Eli Lilly and Company and Incyte Corporation.
Project description:OBJECTIVE: To compare the efficacy and toxicity of cyclosporin A (CsA) monotherapy with CsA plus methotrexate (MTX) combination therapy in patients with early rheumatoid arthritis (RA). PATIENTS AND METHODS: 120 patients with active RA, rheumatoid factor positive and/or erosive, were randomly allocated to receive CsA with MTX (n=60) or CsA with placebo (n=60). Treatment with CsA was started in all patients at 2.5 mg/kg/day and increased to a maximum of 5 mg/kg/day in 16 weeks. MTX was started at 7.5 mg/week and increased to a maximal dose of 15 mg/week at week 16. Primary outcomes were clinical remission (Pinals criteria) and radiological damage (Larsen score), at week 48. RESULTS: Treatment was discontinued prematurely in 27 patients in the monotherapy group (21 because of inefficacy, and six because of toxicity) and in 26 patients in the combination therapy group (14 and 12, respectively). At week 48, clinical remission was achieved in four patients in the monotherapy group and in six patients in the combination therapy group (p=0.5). The median Larsen score increased to 10 (25th, 75th centiles: 3.5; 13.3) points in the monotherapy group and to 4 (1.0; 10.5) points in the combination therapy group (p=0.004). 28/60 (47%) of patients in the monotherapy group v 34/60 (57%) of patients in the combination therapy group had reached an American college of Rheumatology 20% (ACR20) response (p=0.36) at week 48; 15/60 (25%) v 29/60 (48%) of patients had reached an ACR50 response (p=0.013); and 7 (12%) v 12 (20%) of patients had reached an ACR70 response (p=0.11). Their was a tendency towards more toxicity in the combination therapy group. CONCLUSIONS: In patients with early RA, neither CsA plus MTX combination therapy nor CsA monotherapy is very effective in inducing clinical remission. Combination therapy is probably better at improving clinical disease activity, and definitely better at slowing radiological progression. Combination therapy should still be compared with methotrexate monotherapy.