Baricitinib as rescue therapy in a patient with COVID-19 with no complete response to sarilumab.
ABSTRACT: A patient with COVID-19-related severe respiratory failure, with insufficient response to an antiretroviral therapy, hydroxychloroquine and Interleukin-6 (IL-6) antagonist therapy, presented a prompt resolution of the respiratory function and improvement in the radiological picture after baricitinib at an oral dose of 4 mg per day for 2 weeks.
Project description:INTRODUCTION:The objective of this study was to evaluate treatment patterns in patients with rheumatoid arthritis (RA), with a focus on the utilization of baricitinib, an oral highly selective Janus kinase 1 and 2 inhibitor, in an Italian real-world setting. METHODS:This observational retrospective analysis was based on data collected in selected Italian administrative databases. Patients aged ??18 years with a diagnosis of RA defined by hospitalization discharge diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification code 714.0) or by disease exemption code 006 for RA in 2018 were included. The index date (ID) was defined as the date of first prescription for a drug indicated for RA during the inclusion period. Patients without a prescription for biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) before the ID were considered to be b/tsDMARD naïve. A further analysis was performed on patients only receiving baricitinib. RESULTS:A total of 41,290 RA patients were enrolled, of whom 55.6% were not treated with conventional synthetic DMARDs (csDMARDs) or b/tsDMARDs, 39.4% were receiving therapy with csDMARDs, and 5.0% were using b/tsDMARDs. In the latter group, 2.7% (n?=?56) were receiving therapy with baricitinib. In 2018, 13.2% of csDMARD-treated patients switched to b/tsDMARDs, of whom 4.3% (n?=?93) of these switched to baricitinib. In total, 149 patients (mean age?± standard deviation 57.6?±?12.1; 12.8% male) had a baricitinib prescription, of whom 51% were b/tsDMARD naïve. At baseline, 61.7% of baricitinib users were receiving combination therapy with csDMARDs plus corticosteroids, 26.2% were receiving combination therapy with corticosteroids, and 8.1% were receiving combination therapy with csDMARDs; 4% were receiving baricitinib monotherapy. During follow-up, the proportion of patients receiving baricitinib monotherapy increased to 38.9%, while 26.9, 18.8, and 15.4% of baricitinib users received combination therapy with corticosteroids, csDMARDs plus corticosteroids, and csDMARDs, respectively. CONCLUSION:This study provides a current view of the treatment patterns in Italian patients with RA in a real-world setting of daily clinical practice, with a focus on baricitinib utilization.
Project description:Importance:Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced disease severity in moderate to severe atopic dermatitis (AD) in 2 phase 3 monotherapy studies. Objective:To assess the efficacy and safety of 4 mg and 2 mg of baricitinib in combination with background topical corticosteroid (TCS) therapy in adults with moderate to severe AD who previously had an inadequate response to TCS therapy. Design, Setting, and Participants:This double-blind, placebo-controlled, phase 3 randomized clinical trial, BREEZE-AD7 (Study of Baricitinib [LY3009104] in Combination With Topical Corticosteroids in Adults With Moderate to Severe Atopic Dermatitis) was conducted from November 16, 2018, to August 22, 2019, at 68 centers across 10 countries in Asia, Australia, Europe, and South America. Patients 18 years or older with moderate to severe AD and an inadequate response to TCSs were included. After completing the study, patients were followed up for up to 4 weeks or enrolled in a long-term extension study. Interventions:Patients were randomly assigned (1:1:1) to receive 2 mg of baricitinib once daily (n?=?109), 4 mg of baricitinib once daily (n?=?111), or placebo (n?=?109) for 16 weeks. The use of low-to-moderate potency TCSs was allowed. Main Outcomes and Measures:The primary end point was the proportion of patients achieving a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of 0 (clear) or 1 (almost clear), with a 2-point or greater improvement from baseline at week 16. Results:Among 329 patients (mean [SD] age, 33.8 [12.4] years; 216 [66%] male), at week 16, a vIGA-AD score of 0 (clear) or 1 (almost clear) was achieved by 34 patients (31%) receiving 4 mg of baricitinib and 26 (24%) receiving 2 mg of baricitinib compared with 16 (15%) receiving placebo (odds ratio vs placebo, 2.8 [95% CI, 1.4-5.6]; P?=?.004 for the 4-mg group; 1.9 [95% CI, 0.9-3.9]; P?=?.08 for the 2-mg group). Treatment-emergent adverse events were reported in 64 of 111 patients (58%) in the 4-mg group, 61 of 109 patients (56%) in the 2-mg group, and 41 of 108 patients (38%) in the placebo group. Serious adverse events were reported in 4 patients (4%) in the 4-mg group, 2 (2%) in the 2-mg group, and 4 (4%) in the placebo group. The most common adverse events were nasopharyngitis, upper respiratory tract infections, and folliculitis. Conclusions and Relevance:A dose of 4 mg of baricitinib in combination with background TCS therapy significantly improved the signs and symptoms of moderate to severe AD, with a safety profile consistent with previous studies of baricitinib in AD. Trial Registration:ClinicalTrials.gov Identifier: NCT03733301.
Project description: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:BACKGROUND:In clinical practice, temporary interruption of rheumatoid arthritis (RA) therapy is common for various reasons including side effects, non-compliance, or necessity for surgery. To characterize temporary interruptions of baricitinib and placebo-matched tablets in phase 3 studies of patients with moderate-to-severe rheumatoid arthritis (RA) and describe their impact on efficacy and safety. METHODS:During 4 baricitinib phase 3 studies, investigators documented timing, reason, and duration of investigator-initiated temporary interruptions of study drug. In 2 studies, patients recorded RA symptoms in daily diaries for 12?weeks. Post hoc analyses investigated changes in symptom scores during interruptions and resumption of treatment. Interruptions were evaluated for reoccurrence of adverse events or laboratory abnormalities after retreatment. RESULTS:Across the placebo-controlled studies, interruptions occurred in larger proportions of baricitinib- (2 mg, 18%; 4 mg, 18%) vs placebo-treated (9%) patients in only one study (bDMARD-inadequate responder patients, RA-BEACON). In the active comparator-controlled studies, the lowest rates of interruption were in the baricitinib monotherapy arm (9%) of RA-BEGIN (vs methotrexate monotherapy or combination therapy), and proportions were similar for baricitinib (10%) and adalimumab (9%) in RA-BEAM. Adverse events were the most common reason for interruption, but their reoccurrence after drug restart was infrequent. Most interruptions lasted ??2?weeks. Daily diaries indicated modest symptom increases during interruption with return to pre-interruption levels or better after resumption. Interruptions had no impact on long-term efficacy outcomes. CONCLUSIONS:Consistent with its pharmacologic properties, brief interruptions of baricitinib during phase 3 studies were associated with minor increases in RA symptoms that resolved following retreatment. This analysis provides useful information for clinicians, as temporary interruption of antirheumatic therapy is common in the care of patients with RA. TRIAL REGISTRATION:ClinicalTrials.gov; NCT01710358, NCT01711359, NCT01721057, NCT01721044.
Project description:BACKGROUND:Reactivation of hepatitis B virus (HBV) replication is a well-recognised complication in patients receiving disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA). Limited data exist on HBV reactivation among patients with RA treated with janus kinase (JAK) inhibitors. The objective of the current study was to assess HBV reactivation in clinical trials of baricitinib, an oral selective JAK1 and JAK2 inhibitor in RA. METHODS:Data were integrated from four completed Phase 3 trials and one ongoing long-term extension (data up to 1 April 2017) in patients naïve to DMARDs or who had inadequate response (IR) to DMARDs including methotrexate (MTX)-IR and/or other conventional synthetic DMARD (csDMARD)-IR, or tumour necrosis factor inhibitors-IR. Within the clinical programme, baricitinib-treated patients may have received concomitant csDMARDs including MTX, or previous treatment with active comparators including MTX or adalimumab + MTX. At screening, all patients were tested for HBV surface antigen (HBsAg), core antibody (HBcAb) and surface antibody (HBsAb). Patients were excluded if they had (1) HBsAg+, (2) HBcAb+/HBsAb- (in Japan, could enrol if HBV DNA-) or (3) HBsAb+ and?HBV DNA+. HBV DNA monitoring, following randomisation in the originating Phase 3 studies, was performed in Japan for patients with HBcAb+ and/or HBsAb+ at screening, and was later instituted globally for HBcAb+ patients in accordance with evolving guidance for HBV monitoring and management with immunomodulatory therapy. RESULTS:In total, 2890 patients received at least one dose of baricitinib in Phase 3 (6993 patient-years exposure). Of 215 patients with baseline serology suggestive of prior HBV infection (HbcAb+) who received a post-baseline DNA test, 32 (14.9%) were HBV DNA+ at?some point following treatment initiation; 8 of 215 patients (3.7%) had a single quantifiable result (?29?IU/mL). Of these eight patients, four met the definition of reactivation of HBV (HBV DNA level ?100?IU/mL); baricitinib was permanently discontinued in four patients, and temporarily interrupted in two patients. No patient developed clinical evidence of hepatitis and in five of eight patients, antiviral therapy was not used. CONCLUSION:HBV reactivation can occur among RA patients treated with DMARDs, including baricitinib, with prior HBV exposure. Our data suggest that such patients should be monitored for HBV DNA during treatment and might be treated safely with the use of antiviral therapy as needed. The risk of HBV reactivation in patients with HBsAg treated with baricitinib is unknown.
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: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 assess the frequency of cardiovascular and venous thromboembolic events in clinical studies of baricitinib, an oral, selective JAK1 and JAK2 inhibitor approved in more than 50 countries for the treatment of moderately-to-severely active rheumatoid arthritis (RA). METHODS:Data were pooled from 9 RA studies. Placebo comparison up to 24 weeks included data from 6 studies. Randomized dose comparison between baricitinib doses of 2 mg and 4 mg used data from 4 studies and from the associated long-term extension study. The data analysis set designated "All-bari-RA" included all baricitinib exposures at any dose. RESULTS:Overall, 3,492 RA patients received baricitinib (7,860 patient-years of exposure). No imbalance compared to the placebo group was seen in the incidence of major adverse cardiovascular events (MACE) (incidence rates [IRs] of 0.5 per 100 patient-years for placebo and 0.8 per 100 patient-years for 4 mg baricitinib), arterial thrombotic events (ATE) (IRs of 0.5 per 100 patient-years for placebo and 0.5 per 100 patient-years for 4 mg baricitinib), or congestive heart failure (CHF) broad term (IRs of 4.3 per 100 patient-years for placebo and 2.4 per 100 patient-years for 4 mg baricitinib). Deep vein thrombosis (DVT)/pulmonary embolism (PE) were reported in 0 of 1,070 patients treated with placebo and 6 of 997 patients treated with 4 mg baricitinib during the placebo-controlled period; these events were serious in 2 of 6 patients, while all 6 had risk factors and 1 patient developed DVT/PE after discontinuation of the study drug. In the 2 mg-4 mg-extended data analysis set, IRs of DVT/PE were comparable between the doses across event types (IRs of 0.5 per 100 patient-years in those receiving 2 mg baricitinib and 0.6 per 100 patient-years in those receiving 4 mg baricitinib). In the All-bari-RA data analysis set, the rates were stable over time, with an IR of DVT/PE of 0.5 per 100 patient-years. CONCLUSION:In RA clinical trials, no association was found between baricitinib treatment and the incidence of MACE, ATE, or CHF. With regard to incidence of DVT/PE, 6 events occurred in patients treated with 4 mg baricitinib, but no cases of DVT/PE were reported in the placebo group. During longer-term evaluation, the incidence of DVT/PE was similar between the baricitinib dose groups, with consistent IR values over time, and this was similar to the rates previously reported in patients with RA.
Project description:Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, undergoes active renal tubular secretion. Baricitinib was not predicted to inhibit hepatic and renal uptake and efflux drug transporters, based on the ratio of the unbound maximum eliminating-organ inlet concentration and the in vitro half-maximal inhibitory concentrations (IC50 ). In vitro, baricitinib was a substrate for organic anion transporter (OAT)3, multidrug and toxin extrusion protein (MATE)2-K, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Probenecid, a strong OAT3 inhibitor, increased the area under the concentration-time curve from time zero to infinity (AUC[0-∞] ) of baricitinib by twofold and decreased renal clearance to 69% of control in healthy subjects. Physiologically based pharmacokinetic (PBPK) modeling reproduced the renal clearance of baricitinib and the inhibitory effect of probenecid using the in vitro IC50 value of 4.4 μM. Using ibuprofen and diclofenac in vitro IC50 values of 4.4 and 3.8 μM toward OAT3, 1.2 and 1.0 AUC(0-∞) ratios of baricitinib were predicted. These predictions suggest clinically relevant drug-drug interactions (DDIs) with ibuprofen and diclofenac are unlikely.
Project description:Background: Baricitinib is an oral janus kinase inhibitor for the treatment of rheumatoid arthritis (RA) and is approved in Europe for use in adults with moderately-to-severely active RA and an inadequate response or intolerance to conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy. To date, no economic evaluations have assessed the cost-effectiveness of baricitinib in the Spanish setting. Objectives: To evaluate the cost-effectiveness of baricitinib versus adalimumab for the treatment of moderately-to-severely active RA in the Spanish setting. Methods: A discrete event simulation model was developed in Microsoft Excel. Costs and outcomes were estimated over a lifetime horizon using the Spanish national payer perspective. The model compared baricitinib 4 mg once daily in combination with methotrexate with adalimumab 40 mg every other week in combination with methotrexate. Effectiveness and physical function were captured using the American College of Rheumatology criteria and the Health Assessment Questionnaire-Disability Index, input values of which were derived from a phase 3, double-blind, placebo- and active-controlled trial (RA-BEAM; funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01710358). Costs are presented in Euros, 2018 values. Results: In the base case analysis, baricitinib was associated with a quality-adjusted life year gain of 0.09 years over a lifetime horizon, at an incremental cost of -€558 versus adalimumab. Results of various scenario analyses and probabilistic sensitivity analysis generally were consistent with the base case analysis. Conclusion: This analysis suggests that baricitinib is a cost-effective treatment option compared to adalimumab for Spanish patients with moderately-to-severely active RA and a previous inadequate response or intolerance to csDMARD therapy.