Efficacy and safety of upadacitinib in Japanese patients with rheumatoid arthritis (SELECT-SUNRISE): a placebo-controlled phase IIb/III study.
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SUBMITTER: Kameda H
PROVIDER: S-EPMC7590414 | biostudies-literature | 2020 Nov
REPOSITORIES: biostudies-literature
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Efficacy and safety of upadacitinib in Japanese patients with rheumatoid arthritis (SELECT-SUNRISE): a placebo-controlled phase IIb/III study.
Kameda Hideto H Takeuchi Tsutomu T Yamaoka Kunihiro K Oribe Motohiro M Kawano Mitsuhiro M Zhou Yijie Y Othman Ahmed A AA Pangan Aileen L AL Kitamura Susumu S Meerwein Sebastian S Tanaka Yoshiya Y
Rheumatology (Oxford, England) 20201101 11
<h4>Objective</h4>To evaluate upadacitinib efficacy and safety dose response in Japanese patients with active RA and an inadequate response to conventional synthetic DMARDs (csDMARDs).<h4>Methods</h4>This was a multicentre, phase IIb/III, dose-ranging study conducted in Japan, in which patients on previously stable csDMARDs were randomized to receive upadacitinib 7.5, 15 or 30 mg once daily or matching placebo for a 12-week double-blind period. The primary endpoint was a 20% improvement in ACR c ...[more]
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Project description:BackgroundThe objective of the study was to evaluate the efficacy and safety of upadacitinib over 84 weeks in Japanese patients with active rheumatoid arthritis (RA) and an inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs.MethodsAll patients completing a 12-week, randomized, double-blind treatment period entered a blinded extension and continued upadacitinib 7.5, 15, or 30 mg once daily (QD), or were switched from placebo to upadacitinib 7.5, 15, or 30 mg QD. Efficacy and safety were assessed over 84 weeks.ResultsOf 197 randomized patients, 187 (94.9%) completed the 12-week period and entered the blinded extension; 152 (77.2%) patients were ongoing at week 84. At week 84, the proportions of patients achieving a 20% improvement in American College of Rheumatology criteria (ACR20) were 85.7%, 77.6%, and 58.0% with continued upadacitinib 7.5, 15, and 30 mg, respectively (nonresponder imputation), and were similar in patients who had switched from placebo. Favorable response rates were also observed for more stringent measures of response (ACR50/70) and remission (defined by the Disease Activity Score of 28 joints with C-reactive protein, Clinical Disease Activity Index, or Simplified Disease Activity Index). The 15 mg and 30 mg doses of upadacitinib were associated with more rapid and numerically higher initial responses for some measures of disease activity and remission compared with the 7.5 mg dose. Rates of adverse events, infection, opportunistic infection, serious infection, and herpes zoster were lower with upadacitinib 7.5 and 15 mg versus 30 mg.ConclusionsUpadacitinib demonstrated sustained efficacy and was well tolerated over 84 weeks in Japanese patients with RA, with upadacitinib 15 mg offering the most favorable benefit-risk profile.Trial registrationClinicalTrials.gov NCT02720523 . Registered on March 22, 2016.
| S-EPMC7789301 | biostudies-literature
Project description:ObjectivesThis integrated analysis presents the safety profile of upadacitinib, a Janus kinase inhibitor, at 15 mg and 30 mg once daily in patients with moderately to severely active rheumatoid arthritis (RA).MethodsTreatment-emergent adverse events (TEAEs) and laboratory data from five randomised, placebo- or active-controlled phase III trials of upadacitinib for patients with RA were analysed and summarised. Exposure-adjusted event rates are shown for placebo (three trials; 12/14 weeks), methotrexate (two trials; mean exposure: 36 weeks), adalimumab (one trial; mean exposure: 42 weeks), upadacitinib 15 mg (five trials; mean exposure: 53 weeks) and upadacitinib 30 mg (four trials; mean exposure: 59 weeks).Results3834 patients received one or more doses of upadacitinib 15 mg (n=2630) or 30 mg (n=1204), for a total of 4020.1 patient-years of exposure. Upper respiratory tract infection, nasopharyngitis and urinary tract infection were the most commonly reported TEAEs with upadacitinib. Rates of serious infection were similar between upadacitinib 15 mg and adalimumab but higher compared with methotrexate. Rates of herpes zoster and creatine phosphokinase (CPK) elevations were higher in both upadacitinib groups versus methotrexate and adalimumab, and rates of gastrointestinal perforations were higher with upadacitinib 30 mg. Rates of deaths, malignancies, adjudicated major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs) were similar across treatment groups.ConclusionIn the phase III clinical programme for RA, patients receiving upadacitinib had an increased risk of herpes zoster and CPK elevation versus adalimumab. Rates of malignancies, MACEs and VTEs were similar among patients receiving upadacitinib, methotrexate or adalimumab.Trial registration numbersSELECT-EARLY: NCT02706873; SELECT-NEXT: NCT02675426; SELECT-COMPARE: NCT02629159; SELECT-MONOTHERAPY: NCT02706951; SELECT-BEYOND: NCT02706847.
| S-EPMC7892382 | biostudies-literature
Project description:ObjectiveTo evaluate the impact of upadacitinib vs placebo and adalimumab treatment, on patient-reported outcomes (PROs) in SELECT-COMPARE in an active RA population with inadequate responses to MTX (MTX-IR).MethodsPROs in patients receiving upadacitinib (15 mg QD), placebo, or adalimumab (40 mg EOW) while on background MTX were evaluated over 48 weeks. PROs included Patient Global Assessment of Disease Activity (PtGA) and pain by visual analogue scale (VAS), the HAQ Disability Index (HAQ-DI), the 36-Item Short Form Survey (SF-36), morning (AM) stiffness duration and severity, the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and work instability. Least squares mean (LSM) changes and proportions of patients reporting improvements ≥ minimal clinically important differences (MCIDs) and scores ≥ normative values were evaluated.ResultsUpadacitinib and adalimumab resulted in greater LSM changes from baseline vs placebo across all PROs (P < 0.05) at week 12, and pain and AM stiffness severity (P < 0.05) at week 2. More upadacitinib- vs placebo-treated (P < 0.05) and similar percentages of upadacitinib- vs adalimumab-treated patients reported improvements ≥ MCID across all PROs at week 12. Upadacitinib vs adalimumab resulted in greater LSM changes from baseline in PtGA, pain, HAQ-DI, stiffness severity, FACIT-F, and the SF-36 Physical Component Summary (PCS) (all P < 0.05) at week 12. More upadacitinib- vs adalimumab-treated patients reported scores ≥ normative values in HAQ-DI and SF-36 PCS (P < 0.05) at week 12. More upadacitinib- vs adalimumab-treated patients maintained clinically meaningful improvements in PtGA, pain, HAQ-DI, FACIT-F, and AM stiffness through 48 weeks.ConclusionIn MTX-IR patients with RA, treatment with upadacitinib resulted in statistically significant and clinically meaningful improvements in PROs equivalent to or greater than with adalimumab.Trial registrationClinicalTrials.gov, http://clinicaltrials.gov, NCT02629159.
| S-EPMC8645276 | biostudies-literature
Project description:ObjectiveIncreased risk of serious adverse events (AEs) was reported for tofacitinib relative to tumour necrosis factor inhibitor therapy in patients with rheumatoid arthritis (RA) aged ≥50 years enriched for cardiovascular (CV) risk (ORAL Surveillance). We assessed post hoc the potential risk of upadacitinib in a similar RA population.MethodsPooled safety data from six phase III trials were evaluated post hoc for AEs in patients receiving upadacitinib 15 mg once a day (with or without conventional synthetic disease-modifying antirheumatic drugs), adalimumab 40 mg every other week with concomitant methotrexate (MTX), or MTX monotherapy in the overall trial population and in a subset of patients with higher CV risk (aged ≥50 years, ≥1 CV risk factor). Higher-risk patients from a head-to-head study of upadacitinib 15 mg versus adalimumab (SELECT-COMPARE) were assessed in parallel. Exposure-adjusted incidence rates for treatment-emergent AEs were summarised based on exposure to upadacitinib or comparators.ResultsA total of 3209 patients received upadacitinib 15 mg, 579 received adalimumab and 314 received MTX monotherapy; ~54% of the patients were included in the overall and SELECT-COMPARE higher-risk populations. Major adverse cardiovascular events (MACE), malignancy (excluding non-melanoma skin cancer (NMSC)) and venous thromboembolism (VTE) were more frequent in the higher-risk cohorts versus the overall population but were generally similar across treatment groups. Rates of serious infections in higher-risk populations and herpes zoster (HZ) and NMSC in all populations were higher with upadacitinib 15 mg than comparators.ConclusionsAn increased risk of MACE, malignancy (excluding NMSC) and VTE was observed in higher-risk populations with RA, yet risk was comparable between upadacitinib-treated and adalimumab-treated patients. Higher rates of NMSC and HZ were observed with upadacitinib versus comparators across all populations, and increased rates of serious infections were detected in upadacitinib-treated patients at higher CV risk.Trial registration numbersNCT02706873, NCT02675426, NCT02629159, NCT02706951, NCT02706847 and NCT03086343.
| S-EPMC10423494 | biostudies-literature
Project description:ObjectiveTo evaluate the effect of upadacitinib (UPA) monotherapy vs MTX on patient-reported outcomes (PROs) in patients with RA who were MTX-naïve or who had an inadequate response to MTX (MTX-IR).MethodsPROs from the SELECT-EARLY and SELECT-MONOTHERAPY randomized controlled trials were evaluated at Weeks 2 and 12/14. Patients were ≥18 years of age with RA symptoms for ≥6 weeks (SELECT-EARLY, MTX-naïve) or diagnosed RA for ≥3 months (SELECT-MONOTHERAPY, MTX-IR) and received UPA monotherapy (15 or 30 mg) or MTX. PROs included Patient Global Assessment of Disease Activity (PtGA), pain visual analogue scale, HAQ Disability Index (HAQ-DI), morning stiffness duration/severity, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (SELECT-EARLY), health-related quality of life (HRQOL) by the 36-iem Short Form Health Survey and Work Productivity and Activity Impairment (WPAI; SELECT-EARLY). Least square mean (LSM) changes and proportions of patients reporting improvements greater than or equal to the minimum clinically important differences and normative values were determined.ResultsIn 945 MTX-naïve and 648 MTX-IR patients, UPA monotherapy (15 mg, 30 mg) vs MTX resulted in greater reported LSM changes from baseline at Weeks 12/14 in PtGA, pain, HAQ-DI, morning stiffness duration/severity, FACIT-F (SELECT-EARLY), HRQOL and WPAI (SELECT-EARLY). These changes were statistically significant with both doses of UPA vs MTX at Weeks 12/14 in both RCTs. Improvements were reported as early as week 2. Compared with MTX, more UPA-treated MTX-naïve and MTX-IR patients reported improvements greater than or equal to the minimum clinically important differences and scores greater than or equal to normative values.ConclusionAmong MTX-naïve and MTX-IR patients with active RA, UPA monotherapy at 15 or 30 mg for 12/14 weeks resulted in statistically significant and clinically meaningful improvements in pain, physical function, morning stiffness, HRQOL and WPAI compared with MTX alone.Clinical trial registration numberSELECT-EARLY (NCT02706873) and SELECT-MONOTHERAPY (NCT02706951) are registered with ClinicalTrials.gov.
| S-EPMC8516509 | biostudies-literature
Project description:Introduction/objectivesRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by ongoing inflammation and degradation of synovial joints. The oral JAK inhibitor, upadacitinib, is approved for RA. We conducted an integrated safety analysis of upadacitinib 15 mg once daily (QD) in patients from Latin America (LATAM) versus the rest of the world (RoW).MethodsTreatment-emergent adverse events (AEs) and laboratory data from six phase 3, randomized controlled trials, adjusted for upadacitinib 15 mg QD use in RA, were analyzed.ResultsOverall, 3209 patients received upadacitinib 15 mg QD for 7024 patient-years (PY). LATAM patients (n = 725) had a mean upadacitinib exposure of 1518 PY. Baseline characteristics were generally similar between LATAM and RoW populations. AE rates (including serious/opportunistic infections, tuberculosis, and herpes zoster) and deaths were comparable between populations. LATAM patients had lower serious AE rates per 100 PY (9.4 vs 14.0 E/100 PY) and discontinuation-related AEs (3.9 vs 6.0 E/100 PY) versus RoW. Rates of cardiovascular events were low (≤ 0.5 E/100 PY) and similar between populations. Malignancies, excluding non-melanoma skin cancer, were less common in the LATAM population versus RoW (0.2 vs 1.0 E/100 PY). Laboratory abnormalities were similar between populations, with decreases in hemoglobin, lymphocyte, and neutrophil counts, and elevations in liver enzymes and creatine phosphokinase. Mean change from baseline in low- and high-density lipoprotein cholesterol was generally comparable between LATAM and RoW populations.ConclusionUpadacitinib 15 mg QD demonstrated a consistent safety profile across LATAM and RoW patient populations, with no new safety risks observed.Trial registration numbersSELECT-EARLY, NCT02706873; SELECT-NEXT, NCT02675426; SELECT-COMPARE, NCT02629159; SELECT-MONOTHERAPY, NCT02706951; SELECT-BEYOND, NCT02706847; SELECT-CHOICE, NCT03086343.
| S-EPMC9886207 | biostudies-literature
Project description:IntroductionUpadacitinib is a Janus kinase inhibitor with demonstrated efficacy in patients with rheumatoid arthritis (RA).ObjectiveThe aim of this study was to assess the long-term safety of upadacitinib in patients with active RA from Japan compared with global clinical trial populations.MethodsPooled data in patients enrolled from Japan (the 'Japanese population'; SELECT-SUNRISE, SELECT-EARLY, and SELECT-MONOTHERAPY) were compared with that from global (Japan and ex-Japan) upadacitinib clinical trial populations and summarized descriptively.ResultsThe Japanese population (mean age 57.0 years; mean RA duration 6.1 years) received upadacitinib 7.5 mg (n = 121), 15 mg (n = 126), and 30 mg (n = 124) once daily, while the global population (mean age 54.8 years; mean RA duration 9.1 years) received upadacitinib 6 mg twice daily/15 mg once daily (n = 2883) and 12 mg twice daily/30 mg once daily (n = 1375). Most patients were female (79.3%). The exposure-adjusted incidence rates (EAIRs) of serious adverse events in the Japanese population were 11.5, 12.2, and 21.2 per 100 patient-years (PY) with upadacitinib 7.5, 15, and 30 mg, respectively. Herpes zoster rates were higher in the Japanese population (7.8, 12.4, and 16.7 per 100 PY with 7.5, 15, and 30 mg, respectively) versus global populations (3.7 and 7.0 per 100 PY with 15 and 30 mg, respectively). Prior herpes zoster was a significant risk factor for herpes zoster.ConclusionsThe safety profile of upadacitinib was generally similar between Japanese and global RA populations, except for higher EAIRs for serious adverse events and infections, including herpes zoster, in the Japanese population.Trial registration numbersSELECT-EARLY: NCT02706873; SELECT-NEXT: NCT02675426; SELECT-COMPARE: NCT02629159; SELECT-MONOTHERAPY: NCT02706951; SELECT-BEYOND: NCT02706847; SELECT-SUNRISE: NCT02720523; BALANCE I: NCT01960855; BALANCE II: NCT02066389.
| S-EPMC8184701 | biostudies-literature
Project description:Treating to a target of clinical remission or low disease activity is an important principle for managing rheumatoid arthritis (RA). Despite the availability of biologic disease-modifying antirheumatic drugs (bDMARDs), a substantial proportion of patients with RA do not achieve these treatment targets. Upadacitinib is a once-daily, oral Janus kinase (JAK) inhibitor with increased selectivity for JAK1 over JAK2, JAK3, and tyrosine kinase 2. The SELECT phase III upadacitinib clinical program comprised five pivotal trials of approximately 4400 patients with RA, including inadequate responders (IR) to conventional synthetic (cs)DMARDs or bDMARDs. This review aims to provide insights into the benefit-risk profile of upadacitinib in patients with RA. Upadacitinib 15 mg once daily, in combination with csDMARDs or as monotherapy, achieved all primary and ranked secondary endpoints in the five pivotal trials across csDMARD-naïve, csDMARD-IR, and bDMARD-IR populations. Upadacitinib 15 mg also demonstrated significantly higher rates of remission and low disease activity in all five pivotal trials, compared with placebo, methotrexate, or adalimumab. Labeled warnings of JAK inhibitors include serious infections, herpes zoster, malignancies, major cardiovascular events, and venous thromboembolic events. Short- and long-term integrated analyses showed that upadacitinib 15 mg was associated with increased risk of herpes zoster and creatine phosphokinase elevations compared with methotrexate and adalimumab but otherwise had comparable safety with these active comparators. This review suggests that upadacitinib 15 mg had a favorable benefit-risk profile. The safety of upadacitinib will continue to be monitored in long-term extensions and post-marketing studies.
| S-EPMC8053169 | biostudies-literature
Project description:BackgroundUpadacitinib is a Janus kinase inhibitor under evaluation for the treatment of psoriatic arthritis (PsA). We evaluated upadacitinib in patients with PsA and prior inadequate response or intolerance to at least one biologic disease-modifying antirheumatic drug (DMARD).MethodsIn this 24-week randomised, placebo-controlled, double-blind, phase 3 trial, 642 patients were randomised (2:2:1:1) to once per day upadacitinib 15 mg or 30 mg, placebo followed by upadacitinib 15 mg or placebo followed by upadacitinib 30 mg at week 24. The primary endpoint was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at week 12. Achievement of minimal disease activity (MDA) was assessed at week 24. Treatment-emergent adverse events are reported for all patients who received at least one dose of trial drug.ResultsAt week 12, significantly more patients receiving upadacitinib 15 mg and 30 mg versus placebo achieved ACR20 (56.9% and 63.8% vs 24.1%; p<0.001 for both comparisons). At week 24, MDA was achieved by more upadacitinib 15 mg-treated (25.1%) and 30 mg-treated patients (28.9%) versus placebo (2.8%; p<0.001 for both comparisons). Generally, the rates of treatment-emergent adverse events were similar with placebo and upadacitinib 15 mg and higher with upadacitinib 30 mg at week 24. Rates of serious infections were 0.5%, 0.5% and 2.8% with placebo, upadacitinib 15 mg and upadacitinib 30 mg, respectively.ConclusionIn this trial of patients with active PsA who had inadequate response or intolerance to at least one biologic DMARD, upadacitinib 15 mg and 30 mg was more effective than placebo over 24 weeks in improving signs and symptoms of PsA.Clinical trial registration numberNCT03104374.
| S-EPMC7892371 | biostudies-literature
Project description:Exposure-response analyses of upadacitinib (UPA) key efficacy and safety end points (3,685 and 4,577 subjects for efficacy and safety, respectively) using data from phase II and phase III rheumatoid arthritis (RA) studies were conducted to support benefit-risk assessment. Percentage of subjects achieving American College of Rheumatology (ACR)20/50/70, disease activity score 28 (C-reactive protein) (DAS28-CRP) ? 3.2, and DAS28-CRP < 2.6 increased with increasing UPA plasma exposures. With the small number of observed safety events, no clear trends for exposure-response relationships were identified for pneumonia, herpes zoster infection, changes in platelet count, lymphopenia (Grade ? 4), or neutropenia (Grade ? 3) up to Week 26. Shallow exposure-response relationships were observed for > 2 g/dL decrease in hemoglobin, lymphopenia Grade ? 3 at Week 12/14, and serious infections at Week 24/26. Exposure-efficacy analyses demonstrate that UPA 15 mg q.d. (once daily) dose provided the optimal benefit-risk in RA through maximizing efficacy with only small incremental benefit with 30 mg q.d.; and with consistency across RA subpopulations and with UPA monotherapy or combination with conventional synthetic disease-modifying antirheumatic drugs.
| S-EPMC7158206 | biostudies-literature