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Effects of concomitant glucocorticoids in TOZURA, a common-framework study programme of subcutaneous tocilizumab in rheumatoid arthritis.

ABSTRACT: OBJECTIVES:This post hoc analysis of the TOZURA study programme evaluated the efficacy and safety of subcutaneous tocilizumab (TCZ-SC) as monotherapy or with concomitant conventional synthetic DMARDs (csDMARDs) in patients with RA categorized by baseline glucocorticoid (GC) use. METHODS:TOZURA was a multinational, open-label, single-arm, common-framework study programme (11 protocols, 22 countries) in patients with moderate to severe RA in whom csDMARDs or biologic therapies had failed or who were MTX naïve. Patients received once-weekly TCZ-SC 162 mg for ?24 weeks as monotherapy or in combination with csDMARDs and/or oral GC use (?10 mg/day prednisone or equivalent), which was to be continued unchanged for 24 weeks. Treatment subgroups were defined by baseline GC use and analysed for efficacy and safety. RESULTS:Of 1804 patients who received TCZ-SC, 145 received monotherapy + GC, 208 received monotherapy without GC, 730 received combination therapy + GC and 721 received combination therapy without GC. The median GC dose in both GC subgroups was 5 mg/day. The proportion of patients who achieved clinical remission, defined as DAS in 28 joints using ESR <2.6, increased similarly from baseline to week 24 in all subgroups. Improvements in patient-reported outcomes were similar in all subgroups. Overall adverse event profiles were generally similar between subgroups, with some slight numerical differences between GC and non-GC subgroups. CONCLUSION:The incremental efficacy benefits of TCZ-SC as monotherapy and in combination with csDMARDs were similar between patients with and without previous and continued oral GC treatment, with generally similar safety profiles. TRIAL REGISTRATION:ClinicalTrials.gov, http://www.clinicaltrials.gov, NCT01941940, NCT01941095, NCT01951170, NCT01987479, NCT01988012, NCT01995201, NCT02001987, NCT02011334, NCT02031471, NCT02046603, NCT02046616.

SUBMITTER: Choy E

PROVIDER: S-EPMC6532446 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Effects of concomitant glucocorticoids in TOZURA, a common-framework study programme of subcutaneous tocilizumab in rheumatoid arthritis.

Choy Ernest E Caporali Roberto R Xavier Ricardo R Fautrel Bruno B Sanmarti Raimon R Bao Min M Devenport Jenny J Pethö-Schramm Attila A

Rheumatology (Oxford, England) 20190601 6

<h4>Objectives</h4>This post hoc analysis of the TOZURA study programme evaluated the efficacy and safety of subcutaneous tocilizumab (TCZ-SC) as monotherapy or with concomitant conventional synthetic DMARDs (csDMARDs) in patients with RA categorized by baseline glucocorticoid (GC) use.<h4>Methods</h4>TOZURA was a multinational, open-label, single-arm, common-framework study programme (11 protocols, 22 countries) in patients with moderate to severe RA in whom csDMARDs or biologic therapies had f ...[more]

PMID: 30649524

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Project description:Rheumatoid arthritis (RA) is a chronic systemic autoimmune condition which affects approximately 1% of the adult population worldwide and is characterized by joint inflammation, with extra-articular features being common. Interleukin 6 (IL-6) is one of the chief pro-inflammatory cytokines found in the joints and sera of patients with RA. Increased levels of IL-6 correlate with inflammation, disease activity, and radiological damage. RA treatment should focus on minimizing the signs and symptoms of disease (pain, stiffness, and swelling of the joints) and on preventing or minimizing joint damage to preserve functionality and quality of life. The benefits of early, intensive intervention are now acknowledged, with all patients with newly diagnosed, active RA being started on methotrexate (MTX) monotherapy or combination therapy. Lack of efficacy, intolerance, and/or toxicity can lead to discontinuation of this drug, and there is a need for exploring further treatment options. In the UK, patients with persistently high disease activity who have failed at least two conventional disease-modifying agents (DMARDs) including MTX may qualify for biologic therapy. Numerous trials have shown intravenous (IV) tocilizumab (TCZ), a biologic drug targeting and inhibiting IL-6, to be effective for controlling inflammation in RA, with an acceptable safety profile. Its superiority in monotherapy when compared with other biologic agents makes it the drug of choice for patients who are intolerant or have contraindications to traditional DMARDs. However, one of the drawbacks of IV TCZ is the requirement for monthly infusions, which is inherently inconvenient for the patient and associated with increased cost. Subcutaneous (SC) TCZ has now been approved following two clinical trials which showed similar efficacy and safety compared to IV TCZ, and better efficacy compared to placebo (SUMMACTA and BREVACTA trials, respectively). Respiratory infections are the most common side effects in patients receiving SC TCZ. Advantages of SC formulations include convenience and reduced cost compared with IV therapies. Overall, patients tend to have a preference for SC over IV administration of medications. Close monitoring of patients should be undertaken in all cases, paying particular attention to the full blood count, liver enzymes, and cholesterol levels.

Project description:BackgroundThe treatment of rheumatoid arthritis is based on the use of disease-modifying antirheumatic drugs (DMARDs). Tocilizumab can be used as monotherapy or in combination with conventional synthetic DMARDs for the treatment of moderate-to-severe active rheumatoid arthritis. Subcutaneous (SC) and intravenous forms of the drug are available, but the SC form is more widely used.ObjectiveTo understand the real-world dose modification patterns of SC tocilizumab in the treatment of patients with rheumatoid arthritis in the United States.MethodsData were obtained from the Truven (now IBM) MarketScan and Optum Clinformatics databases. Patients were included if they had ≥1 pharmacy claims for SC tocilizumab and met other inclusion criteria. The mean, standard deviation, and median values were reported for the continuous variables, and frequency was reported for the categorical variables. Kaplan-Meier analysis was used to analyze the time to first dose modification. Logistic regression modeling was used to identify predictors of the likelihood of dose modification.ResultsThe study included 1266 patients in the Truven database and 512 patients in the Optum database who had commercial or Medicare Advantage or supplemental insurance. Of the patients who started treatment with biweekly SC tocilizumab (48% each in the Truven and Optum databases), 37% in Truven and 40% in Optum had dose escalation to a weekly dose. Of those who started weekly SC tocilizumab (43% in the Truven and 49% in the Optum databases), 3% (Truven) and 4% (Optum) had dose reduction. The remaining patients started alternative SC tocilizumab doses. Overall, 60% and 68% of patients in the Truven and Optum cohorts, respectively, initiated or escalated to the higher weekly dose of tocilizumab; the mean time to dose escalation was 126 days and 112 days, respectively. In the Truven cohort, corticosteroid use, age, and anemia were the main predictors for dose escalation. In the Optum cohort, female patients had increased odds of dose escalation compared with male patients.ConclusionThe dosing trends observed in this study show that physicians have taken advantage of the option to increase SC tocilizumab dosing, but only a few providers chose to reduce the dose. This trend in dose modification may increase the costs related to SC tocilizumab therapy.

Project description:IntroductionPatients with rheumatoid arthritis (RA) have decreased survival because of increased cardiovascular risk compared with the general population, and treatment with tocilizumab (TCZ) has been shown to increase lipid levels; however, the relationship between lipids and cardiovascular risk is unknown. This post hoc analysis expanded on previously reported 24-week results by characterizing statin use and subsequent changes in lipid parameters in patients with RA treated with intravenous or subcutaneous TCZ (TCZ-IV or TCZ-SC) over 2 years of treatment.MethodsData were collected from patients with moderate to severe active RA who received ≥1 dose of the study drug in seven international, randomized, double-blind, controlled phase 3 and 4 clinical trials of TCZ-IV or TCZ-SC. Lipid levels and safety events were assessed over 2 years of treatment. Data were summarized for all pooled treatment groups of the intention-to-treat populations in the TCZ-IV and TCZ-SC studies, and results were stratified by concomitant statin use.ResultsData from this descriptive, retrospective, pooled analysis indicated that statins can stabilize lipid levels without a clinically significant increase in adverse events. Approximately 30% of patients in the TCZ treatment arms who never received a statin demonstrated a shift in low-density-lipoprotein cholesterol (LDL-C) from <130 mg/dl at baseline to ≥130 mg/dl at 2 years. However, despite the increased potential cardiovascular risk, <15% of patients with LDL-C ≥100 mg/dl and <35% of patients with a total cholesterol:high-density-lipoprotein cholesterol ratio >5 at 2 years were receiving concomitant statins.ConclusionConcomitant statin use attenuated TCZ-mediated lipid increases; however, a large proportion of TCZ-treated patients potentially at risk of cardiovascular disease were untreated. These findings highlight the need for better understanding of potential risk associated with TCZ-mediated lipid elevations as well as implementation of RA-specific guidelines on the recognition and management of elevated risk of cardiovascular events in patients with RA.FundingF. Hoffmann-La Roche, Ltd.

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Effects of concomitant glucocorticoids in TOZURA, a common-framework study programme of subcutaneous tocilizumab in rheumatoid arthritis.

Publications

Effects of concomitant glucocorticoids in TOZURA, a common-framework study programme of subcutaneous tocilizumab in rheumatoid arthritis.

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