Objective. To compare the efficacy, safety, and tolerability of 4 doses of oral tofacitinib (CP-690,550) with placebo in Japanese patients with active rheumatoid arthritis (RA) receiving stable background methotrexate (MTX) who had an inadequate response to MTX alone. Methods. A total of 140 patients were randomized to receive tofacitinib 1, 3, 5, and 10 mg twice a day or placebo in this 12-week, phase II, double-blind study. All patients remained on background MTX. Efficacy and safety were assessed at weeks 1, 2, 4, 8, and 12. The primary efficacy end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12.Results. ACR20 response rates at week 12 were significant (P < 0.0001) for all tofacitinib treatment groups: 1 mg twice a day, 64.3%; 3 mg twice a day, 77.8%; 5 mg twice a day, 96.3%; and 10 mg twice a day, 80.8% versus placebo, 14.3%. A significant dose-response relationship for the ACR20 was observed (P < 0.0001). Low disease activity was achieved by 72.7% of patients with high baseline disease activity for tofacitinib 10 mg twice a day at week 12 (P < 0.0001). Significant improvements in the ACR50, ACR70, Health Assessment Questionnaire Disability Index, and Disease Activity Score 28-3 (C-reactive protein) were also reported. The most commonly reported adverse events (AEs) were nasopharyngitis (n ‫؍‬ 13) and increased alanine aminotransferase (n ‫؍‬ 12) and aspartate aminotransferase (n ‫؍‬ 9) levels. These AEs were mild or moderate in severity. Serious AEs were reported by 5 patients. No deaths occurred. Conclusion. In Japanese patients with active RA with an inadequate response to MTX, tofacitinib in combination with MTX over 12 weeks was efficacious and had a manageable safety profile.

BackgroundTofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Here, tofacitinib safety and efficacy data from a long-term extension study in Japanese patients are presented.MethodsStudy A3921041 was a multi-centre, open-label, long-term extension study that included Japanese patients who had participated in a prior Phase 2 or Phase 3 study of tofacitinib as monotherapy or with background methotrexate. Patients received tofacitinib 5 mg twice daily (BID) or tofacitinib 10 mg BID. Dose adjustment of tofacitinib during treatment period, and concomitant usage of disease-modifying antirheumatic drugs including methotrexate after week 12 were permitted. Primary endpoints were adverse events, laboratory parameters and vital signs. Secondary efficacy endpoints included American College of Rheumatology (ACR)20/50/70 response rates, Disease Activity Score (DAS)28-4(erythrocyte sedimentation rate (ESR))<2.6 response rate (DAS-defined remission) and Health Assessment Questionnaire-Disability Index (HAQ-DI) score. Safety and efficacy data were assessed throughout the study.ResultsA total of 486 patients were recruited and treated (1439.9 patient-years of exposure). 308 patients completed the study. Median (range) duration of treatment in this extension study was 1185 (5–2016) days. 476 patients (97.9 %) experienced adverse events; the majority of which (97.8 %) were of mild or moderate severity. The two most common treatment-emergent adverse events were nasopharyngitis (n = 293, 60.3 %) and herpes zoster (n = 94, 19.3 %). For all tofacitinib-treated patients, the incidence rate (patients with events per 100 patient-years) was 10.7 for serious adverse events, 3.3 for serious infections, 7.4 for herpes zoster (serious and non-serious) and 1.2 for malignancies (excluding non-melanoma skin cancer). Mean changes from baseline (start of the index study) in laboratory parameters were consistent with those seen in previously reported studies of tofacitinib. ACR20/50/70 response rates, DAS-defined remission rates and HAQ-DI scores were sustained through to study completion.ConclusionsTofacitinib (with or without background methotrexate) demonstrated a stable safety profile and sustained efficacy in Japanese patients with active rheumatoid arthritis. The risk of herpes zoster appears to be higher in Japanese patients treated with tofacitinib than in the global population.Trial registrationClinicaltrials.gov NCT00661661. Registered 7 February 2008.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-0932-2) contains supplementary material, which is available to authorized users.

Objectives. To evaluate oral tofacitinib versus placebo for treatment of active rheumatoid arthritis in Japanese patients with inadequate response to disease-modifying antirheumatic drugs. Methods. In this double-blind, placebo-controlled, randomized, parallel-group, 12-week, phase 2 study (clinicaltrials.gov NCT00687193), 317 patients received tofacitinib: 1, 3, 5, 10, or 15 mg as monotherapy or placebo twice daily (BID). Primary endpoint: response rate by American College of Rheumatology (ACR) ≥ 20% improvement criteria (ACR20) at week 12. Results. ACR20 response rates: 37.7% (20/53), 67.9% (36/53), 73.1% (38/52), 84.9% (45/53), and 90.7% (49/54) with tofacitinib: 1, 3, 5, 10, and 15 mg BID, respectively, versus 15.4% (8/52) with placebo (p < 0.01; all doses). Dose-dependent ACR20 responses with tofacitinib versus placebo occurred from week 2 onward (p < 0.05). Changes from baseline in 28-joint disease activity score using erythrocyte sedimentation rate improved with tofacitinib versus placebo from week 4 (p < 0.01; all doses). Six tofacitinib patients experienced treatment-related serious adverse events (AEs). Most common treatment-emergent AEs: nasopharyngitis (10% vs 12%) and hyperlipidemia (5% vs 0%). Serum creatinine, hemoglobin, and total-, low-, and high-density lipoprotein-cholesterol levels increased with tofacitinib. Conclusions. Tofacitinib produced dose-dependent ACR20 responses and reduced disease activity. The safety profile was consistent with that reported from global monotherapy trials.

Tofacitinib is an oral Janus kinase inhibitor that is being investigated for psoriasis and psoriatic arthritis. Japanese patients aged 20 years or more with moderate to severe plaque psoriasis and/or psoriatic arthritis were double‐blindly randomized 1:1 to tofacitinib 5 or 10 mg b.i.d. for 16 weeks, open‐label 10 mg b.i.d. for 4 weeks, then variable 5 or 10 mg b.i.d. to Week 52. Primary end‐points at Week 16 were the proportion of patients achieving at least a 75% reduction in Psoriasis Area and Severity Index (PASI75) and Physician's Global Assessment of “clear” or “almost clear” (PGA response) for psoriasis, and 20% or more improvement in American College of Rheumatology criteria (ACR20) for patients with psoriatic arthritis. Safety was assessed throughout. Eighty‐seven patients met eligibility criteria for moderate to severe plaque psoriasis (5 mg b.i.d., n = 43; 10 mg b.i.d., n = 44), 12 met eligibility criteria for psoriatic arthritis (5 mg b.i.d., n = 4; 10 mg b.i.d., n = 8) including five who met both criteria (10 mg b.i.d.). At Week 16, 62.8% and 72.7% of patients achieved PASI75 with tofacitinib 5 and 10 mg b.i.d., respectively; 67.4% and 68.2% achieved PGA responses; all patients with psoriatic arthritis achieved ACR20. Responses were maintained through Week 52. Adverse events occurred in 83% of patients through Week 52, including four (4.3%) serious adverse events and three (3.2%) serious infections (all herpes zoster). No malignancies, cardiovascular events or deaths occurred. Tofacitinib (both doses) demonstrated efficacy in patients with moderate to severe plaque psoriasis and/or psoriatic arthritis through 52 weeks; safety findings were generally consistent with prior studies.

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.