Modified- versus immediate-release tofacitinib in Japanese rheumatoid arthritis patients: a randomized, phase III, non-inferiority study

Abstract

ObjectiveTofacitinib is an oral Janus kinase inhibitor for treatment of RA. We compared tofacitinib modified-release (MR) 11 mg once daily (QD) with tofacitinib immediate-release (IR) 5 mg twice daily (BID) in Japanese patients with RA and inadequate response to MTX.MethodsPhase III, randomized, double-blind, double-dummy, 12-week study. Patients were randomized to tofacitinib MR 11 mg QD (n = 104) or IR 5 mg BID (n = 105), with stable MTX. Compliance was based on returned pill counts. The primary objective was to demonstrate non-inferiority of MR 11 mg QD to IR 5 mg BID. Non-inferiority was declared if the upper bound of the two-sided 95% CI for the difference in change from baseline in DAS28-4(CRP) at week 12 was <0.6.ResultsAt week 12, with tofacitinib MR 11 mg QD and IR 5 mg BID, respectively, the change from baseline in least squares mean DAS28-4(CRP) was −2.43 and −2.85; the mean difference was 0.43 (95% CI 0.17, 0.69). Non-inferiority of MR 11 mg QD to IR 5 mg BID was not met. Improvement of DAS28-4(CRP) ⩾1.2 was observed in 89 and 85% of patients, respectively, corresponding to a clinically important, significant change in both groups. The frequency of adverse events (52.9 and 51.4%, respectively) and serious adverse events (4.8 and 3.8%, respectively) was generally similar between treatments. No deaths were reported.ConclusionNon-inferiority of MR 11 mg QD to IR 5 mg BID was not met in this study. However, clinically meaningful improvements in RA were observed with both tofacitinib formulations in Japanese patients. The safety profile was similar with both formulations.Trial registrationClinicalTrials.gov, http://clinicaltrials.gov, NCT02281552.

Safety of synthetic and biological DMARDs: a systematic literature review informing the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis

“…In total, 21 studies evaluating bsDMARDs,52–72 18 studies evaluating boDMARDs73–90 and 21 studies evaluating tsDMARDs91–111 were included (online supplementary table S104). Overall, the incidence of major adverse events was low in all RCTs with mostly no differences between the active treatment and placebo or active comparator.…”

“…History of diverticulitis was an exclusion criteria in only one study,73 and no association with other known risk factors, for example, treatment with glucocorticoids or NSAIDs, has been reported in any study. The risk of LIP was assessed in nine RCTs/LTEs in patients on tsDMARDs and all report no cases 91 92 94 97 98 102 108 110 111…”

Janus kinase inhibitors in immuno-inflammatory rheumatic diseases: new opportunities and prospects

“…пациентов) [16] и в целом сходны с таковыми ГИБП [37]. В настоящее время создана новая лекарственная форма ТОФА, основанная на использовании осмотической системы, которая позволяет назначать ТОФА (11 мг) 1 раз в день, однако ее эффективность, по сравнению со стандартной терапией ТОФА, требует дальнейшего подтверждения [38].…”

Real-World Evidence to Contextualize Clinical Trial Results and Inform Regulatory Decisions: Tofacitinib Modified-Release Once-Daily vs Immediate-Release Twice-Daily for Rheumatoid Arthritis

“…Clinically meaningful improvements in RA were demonstrated with tofacitinib MR 11 mg QD in a global phase 3b/4 randomized controlled trial (RCT) [ 18 ] and a Japanese phase 3 double-blind RCT [ 19 ]. The latter is the only double-blind RCT that assessed noninferiority of tofacitinib MR 11 mg QD vs IR 5 mg BID.…”

“…The latter is the only double-blind RCT that assessed noninferiority of tofacitinib MR 11 mg QD vs IR 5 mg BID. Noninferiority was not demonstrated per change from baseline (∆) in Disease Activity Score in 28 joints, C-reactive protein (DAS28-4[CRP]) at week 12 [ 19 ]. However, this analysis used a narrower noninferiority margin than would commonly be used, as a result of Japanese Pharmaceutical and Medical Devices Agency requests [ 19 ].…”