In patients with rheumatoid arthritis (RA), persistent inflammation and increasing disease activity are associated with increased risk of adverse events (AEs).To assess relationships between RA disease activity and AEs of interest in patients treated with tofacitinib or tumor necrosis factor inhibitors (TNFi).This was a post hoc analysis of a long-term, postauthorization safety endpoint trial of tofacitinib versus TNFi.In ORAL Surveillance, 4362 patients aged ⩾50 years with active RA despite methotrexate, and ⩾1 additional cardiovascular (CV) risk factor, were randomized 1:1:1 to tofacitinib 5 or 10 mg twice daily or TNFi for up to 72 months. Post hoc time-dependent multivariable Cox analysis evaluated the relationships between disease activity [Clinical Disease Activity Index (CDAI)], inflammation [C-reactive protein (CRP)], and AEs of interest. The AEs included major adverse CV events (MACE), malignancies excluding nonmelanoma skin cancer (NMSC), venous thromboembolism (VTE), serious infections, herpes zoster (HZ), nonserious infections excluding HZ (NSI), and death.Across treatments, risk for NSI was higher when patients had CDAI-defined active disease versus remission; MACE and VTE risks trended higher, but did not reach significance. Hazard ratios for MACE, malignancies excluding NMSC, VTE, infections, and death rose by 2-9% for each 5-mg/L increment in serum CRP. The interaction terms evaluating the impact of treatment assignment on the relationship between disease activity and AEs were all p > 0.05.In ORAL Surveillance, higher NSI risk was observed in the presence of active RA versus remission. The risk of MACE and VTE directionally increased in active disease versus remission, although statistical power was limited due to small event numbers in these categories. The relationship between active disease and AEs was not impacted by treatment with tofacitinib versus TNFi.NCT02092467.The link between disease activity and adverse medical events in people with rheumatoid arthritis taking tofacitinib or tumor necrosis factor inhibitors. Why was the study done? • People with rheumatoid arthritis (RA) who have uncontrolled symptoms (high disease activity) have a higher chance of having adverse medical events (medical problems that occur during treatment with a medication) than people who have mild symptoms (low disease activity). • We looked at the link between levels of disease activity and the risk of having adverse medical events in people with RA who took tofacitinib or a tumor necrosis factor inhibitor (TNFi) medication. What did the researchers do? • We used the results of ORAL Surveillance, a long-term safety trial in people with RA. ○ In this study, people with RA were 50 years or older and at high risk of a major cardiovascular event such as heart attack or stroke. • For up to 6 years, people took tofacitinib 5 or 10mg tablets two times a day or TNFi injections. • We used statistical tests to examine the link between different levels of RA disease activity or inflammation and different adverse medical events, such as: ○ major cardiovascular events (such as heart attack, stroke, or death due to heart failure) ○ cancers ○ blood clots ○ infections ○ deaths. What did the researchers find? • In people who took tofacitinib or TNFi: ○ People with active disease (those with RA symptoms) had a higher risk of infections that did not lead to hospitalization (nonserious infections) than people in remission (those with very mild symptoms or no symptoms at all). ○ People with active disease also had a slightly higher risk of major cardiovascular events and blood clots than those in remission. ○ Higher levels of inflammation led to increased risk of major cardiovascular events, cancers, blood clots, infections, and deaths. What do the findings mean? • Active RA disease leads to higher risk of adverse medical events. • The medication used (tofacitinib or TNFi) did not affect the link between levels of RA disease activity and adverse medical events. • This study was limited by the low number of adverse medical events recorded.
This article presents the results of a pivotal Phase 3 study that assesses a new treatment for the management of chronic low back pain: a transdermal patch containing the opioid buprenorphine. In this randomized, placebo-controlled study with an enriched enrollment design, the buprenorphine transdermal system (BTDS) was found to be efficacious and generally well tolerated.This enriched, multicenter, randomized, double-blind study evaluated the efficacy, tolerability, and safety of BTDS in opioid-naïve patients who had moderate to severe chronic low back pain.Patients who tolerated and responded to BTDS (10 or 20 mcg/hour) during an open-label run-in period were randomized to continue BTDS 10 or 20 mcg/hour or receive matching placebo. The primary outcome was "average pain over the last 24 hours" at the end of the 12-week double-blind phase, collected on an 11-point scale (0=no pain, 10=pain as bad as you can imagine). Sleep disturbance (Medical Outcomes Study subscale) and total number of supplemental analgesic tablets used were secondary efficacy variables.Fifty-three percent of patients receiving open-label BTDS (541 of 1024) were randomized to receive BTDS (n=257) or placebo (n=284). Patients receiving BTDS reported statistically significantly lower pain scores at Week 12 compared with placebo (least square mean treatment difference: -0.58, P=0.010). Sensitivity analyses of the primary efficacy variable and results of the analysis of secondary efficacy variables supported the efficacy of BTDS relative to placebo. During the double-blind phase, the incidence of treatment-emergent adverse events was 55% for the BTDS treatment group and 52% for the placebo treatment group. Laboratory, vital sign, and electrocardiogram evaluations did not reveal unanticipated safety findings.BTDS was efficacious in the treatment of opioid-naïve patients with moderate to severe chronic low back pain. Most treatment-emergent adverse events observed were consistent with those associated with the use of opioid agonists and transdermal patches.
Abstract Background In patients with ulcerative colitis (UC), risks of infection and malignancies increase with age. Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of UC. This analysis assessed age as a risk factor for adverse events of special interest (AESI) in the tofacitinib UC clinical program. Methods Data were from phase 2 and 3 induction studies, a phase 3 maintenance study, and an open-label, long-term extension study. Efficacy and/or safety outcomes were analyzed in the Induction, Maintenance, and Overall Cohorts (patients who received ≥ 1 dose of tofacitinib), stratified by age. The effects of baseline demographic and disease-related factors on AESI incidence were assessed by Cox proportional-hazards regression analysis. Results In the Overall Cohort (1157 patients with ≤ 6.8 years’ tofacitinib treatment), age was a statistically significant predictor of herpes zoster (HZ), malignancies excluding nonmelanoma skin cancer (NMSC), and NMSC. Other statistically significant predictors included prior tumor necrosis factor inhibitor failure for HZ, NMSC, and opportunistic infection events, and prior duration of UC for malignancies excluding NMSC. In the Induction and Maintenance Cohorts, a higher proportion of tofacitinib-treated than placebo-treated patients (numerical difference) achieved the efficacy endpoints (endoscopic improvement, clinical remission, clinical response) across all age groups. Conclusions Older individuals receiving tofacitinib as induction and maintenance therapy to treat UC may have an increased risk of HZ, malignancies (excluding NMSC), and NMSC versus similarly treated younger patients, consistent with findings from the general population. Across all age groups, tofacitinib demonstrated greater efficacy than placebo as an induction and maintenance therapy. ClinicalTrials.gov Registration Numbers NCT00787202; NCT01465763; NCT01458951; NCT01458574; NCT01470612.
The objective of this analysis was to assess disease activity metrics using a variety of disease outcome measures following methotrexate (MTX) withdrawal in ORAL Shift, a phase 3b/4 study of tofacitinib with/without MTX, in patients with rheumatoid arthritis (RA) achieving Clinical Disease Activity Index (CDAI)-defined low disease activity (LDA). Patients aged ≥ 18 years with active RA and an inadequate response to MTX received open-label tofacitinib modified-release 11 mg once daily plus MTX for 24 weeks. In the double-blind MTX withdrawal phase, those who had achieved CDAI LDA (≤ 10) at week 24 were randomised 1:1 to receive tofacitinib monotherapy or continued tofacitinib plus MTX. Efficacy analyses were performed in subgroups defined by whether remission and/or LDA had been achieved at week 24 with: Disease Activity Score in 28 joints, erythrocyte sedimentation rate [DAS28-4(ESR)], Routine Assessment of Patient Index Data 3 (RAPID3), CDAI and Simplified Disease Activity Index (SDAI); or DAS28-4[C-reactive protein(CRP)] < 2.4/ < 2.6/ < 2.9/ ≤ 3.2. Five hundred and thirty patients received treatment in the double-blind MTX withdrawal phase. Proportions of patients achieving each disease activity criterion at week 24 varied by metric. Across disease activity metrics [excluding DAS28-4(ESR) remission], 58–89% of patients per group, and numerically more patients receiving tofacitinib plus MTX, achieved the same criterion at week 48 as at week 24. Differences between groups in least squares mean change from baseline (Δ) DAS28-4(ESR) from week 24–48 favoured tofacitinib plus MTX (nominal p values < 0.05). RAPID3 and DAS28-4(CRP) estimated a higher proportion of patients with acceptable disease state versus DAS28-4(ESR), CDAI remission and SDAI remission. Response rates at the beginning of the double-blind phase varied across metrics. A consistent trend towards higher response rates with tofacitinib plus MTX was observed across metrics after randomisation, with nominal differences in DAS28-4(ESR) responses. Compared with continued combination therapy, MTX withdrawal did not lead to a clinically meaningful reduction in the response to tofacitinib. DAS28-4(CRP) and RAPID3 were the least stringent metrics. ClinicalTrials.gov identifier: NCT02831855.
Background Uncontrolled rheumatoid arthritis (RA) activity and acute disease flares are associated with higher risk of adverse outcomes such as cardiovascular (CV) disease, venous thromboembolism (VTE), malignancy and infection. 1-4 Objectives To evaluate associations of acute and cumulative Clinical Disease Activity Index (CDAI) measurements with major CV, malignancy, or infectious adverse events (AEs) of special interest in ORAL Surveillance. Methods ORAL Surveillance ( NCT02092467 ) was a post-authorisation safety study of tofacitinib vs TNF inhibitors (TNFi) in patients (pts) aged ≥50 yrs with active RA despite methotrexate (MTX), and ≥1 additional CV risk factor. Pts were randomised 1:1:1 to tofacitinib 5 or 10 mg twice daily (BID) or subcutaneous TNFi. Two post hoc analyses were performed: (1) a time-varying multivariate Cox model examined risks of major AEs when pts were in CDAI-defined low (>2.8–≤10; LDA), moderate (>10–≤22; MDA) or high (>22; HDA) disease activity vs remission (≤2.8). The Cox model also included pt demographics, medical history, RA characteristics, prior treatments, baseline (BL) medications and treatment arm, pre-selected using backward selection; (2) area under the curve (AUC) per yr for CDAI prior to event or to study end (pts without event) was calculated and compared using an analysis of variance model with treatment arm, event status and interaction (supportive). Nominal p values <0.10 were considered evidence of associations. Results 4362 pts were included. Mean RA duration at BL was approximately 10 yrs. All pts were on MTX at BL, and 28% had previously been on one other synthetic disease-modifying antirheumatic drug (DMARD). Overall, 10% of pts had been on one biologic DMARD. Hazard ratios suggested that when pts had LDA, MDA or HDA vs remission, they were potentially at higher risk of developing major adverse CV events (MACE), VTE and non-serious infections (NSIs) excluding herpes zoster (HZ), but not malignancies, serious infections or HZ (Figure 1). Similarly, mean CDAI AUC trended higher for MACE, VTE and NSIs (Table 1). Table 1. Cumulative CDAI (from BL to event) for pts with vs without events (AUC/yr) Major AE Pts with events Pts without events LS mean difference in pts with vs without events p value Treatment n LS mean AUC/yr n LS mean AUC/yr MACE Tofacitinib 5 mg BID 42 6275.4 1336 4607.3 1668.1 0.0018 * Tofacitinib 10 mg BID 50 5237.4 1306 4482.6 754.8 0.1253 TNFi 36 5234.5 1312 4851.5 383.0 0.5069 VTE Tofacitinib 5 mg BID 15 6546.7 1363 4614.4 1932.3 0.0293 * Tofacitinib 10 mg BID 31 6688.2 1323 4458.5 2229.7 0.0003 * TNFi 8 6423.6 1339 4839.4 1584.1 0.1907 Malignancy excl. NMSC Tofacitinib 5 mg BID 59 5249.3 1319 4618.9 630.4 0.1655 Tofacitinib 10 mg BID 55 4793.7 1301 4482.2 311.5 0.5077 TNFi 39 5561.4 1308 4826.3 735.1 0.1854 Serious infections Tofacitinib 5 mg BID 127 5710.2 1242 4577.5 1132.7 0.0004 * Tofacitinib 10 mg BID 150 5425.2 1197 4476.4 948.8 0.0013 * TNFi 105 6058.4 1240 4807.7 1250.7 0.0003 * HZ Tofacitinib 5 mg BID 175 5184.5 1199 4738.1 446.4 0.1101 Tofacitinib 10 mg BID 163 5549.1 1186 4481.3 1067.8 0.0002 * TNFi 56 5667.2 1291 4875.5 791.8 0.0930 * NSIs excl. HZ Tofacitinib 5 mg BID 760 6608.3 463 5122.5 1485.8 <0.0001 * Tofacitinib 10 mg BID 750 6587.8 426 5009.6 1578.2 <0.0001 * TNFi 722 6737.6 521 5217.5 1520.1 <0.0001 * * p<0.10. Data collected after pts who were randomised to tofacitinib 10 mg BID had their dose reduced to 5 mg BID were included in the tofacitinib 10 mg BID group LS, least squares; n, number of pts in analysis of variance model Conclusion In ORAL Surveillance, the risk of MACE, VTE and NSIs excluding HZ appeared higher when pts had active disease than when in remission. Greater cumulative RA disease activity was seen in pts who suffered these AEs vs those who did not. Our findings support treat-to-target recommendations for RA. References [1]Molander et al. Ann Rheum Dis 2021; 80: 169-175. [2]Maradit-Kremers et al. Arthritis Rheum 2005; 52: 722-732. [3]Au et al. Ann Rheum Dis 2011; 70: 785-791. [4]Baecklund et al. Arthritis Rheum 2006; 54: 692-701. Acknowledgements Study sponsored by Pfizer Inc. Medical writing support was provided by Karen Thompson, PhD, CMC Connect, and funded by Pfizer Inc. Disclosure of Interests George Karpouzas Speakers bureau: Sanofi-Genzyme-Regeneron, Consultant of: Janssen and Sanofi-Genzyme-Regeneron, Grant/research support from: Pfizer Inc, Zoltán Szekanecz Speakers bureau: AbbVie, Eli Lilly, Novartis, Pfizer Inc, Roche and Sanofi, Paid instructor for: AbbVie, Eli Lilly, Gedeon Richter, Novartis, Pfizer Inc and Roche, Consultant of: AbbVie, Eli Lilly, Novartis, Pfizer Inc, Roche and Sanofi, Eva Baecklund: None declared, Ted Mikuls Paid instructor for: Pfizer Inc, Consultant of: Gilead Sciences, Horizon and Sanofi, Grant/research support from: Bristol-Myers Squibb and Horizon, Deepak L Bhatt Grant/research support from: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Eli Lilly, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Lexicon, Medtronic, MyoKardia, Novo Nordisk, Owkin, Pfizer Inc, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic and The Medicines Company, Harry Shi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Cunshan Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Gosford Sawyerr Consultant of: Pfizer Inc, Employee of: Syneos Health Inc, Yan Chen Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Sujatha Menon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Carol A. Connell Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Steven R. Ytterberg Consultant of: Corbus Pharmaceuticals, Kezar Life Sciences and Pfizer Inc, Mahta Mortezavi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc.
Background: The Phase 3b/4 study ORAL Shift demonstrated sustained efficacy and safety of tofacitinib modified-release (MR) 11 mg once daily (QD) following methotrexate (MTX) withdrawal that was non-inferior to continued tofacitinib + MTX use (per DAS28-4[ESR]), in patients (pts) with rheumatoid arthritis (RA) who achieved CDAI-defined low disease activity (LDA) with tofacitinib + MTX at Week (W)24. 1 Objectives: To assess the performance of alternative disease activity measures at W24 (randomisation) and W48 (study endpoint) in ORAL Shift. Methods: ORAL Shift ( NCT02831855 ) enrolled pts aged ≥18 years with moderate to severe RA and an inadequate response to MTX. Pts received open-label tofacitinib MR 11 mg QD + MTX for 24 weeks. Achievement of CDAI LDA (≤10) at W24 was set as the criteria for entry to the 24-week double-blind MTX withdrawal phase, with pts randomised 1:1 to receive tofacitinib MR 11 mg QD + placebo (PBO) (ie blinded MTX withdrawal) or continue tofacitinib + MTX. In this post hoc analysis, efficacy analyses were performed in 8 subgroups defined by achievement of various disease activity criteria at W24: DAS28-4(ESR) remission (<2.6) or LDA (≤3.2); DAS28-4(CRP) <2.6 or ≤3.2; RAPID3 remission (≤3) or LDA (≤6); CDAI remission (≤2.8); and SDAI remission (≤3.3). For each subgroup, the proportion of pts who achieved the corresponding disease activity criterion at W48 was calculated, with a 95% confidence interval (CI) estimated using the normal approximation to the binomial distribution. The change (Δ) from W24 to W48 in least squares (LS) mean DAS28-4(ESR) and DAS28-4(CRP) was also calculated in each subgroup, with a 95% CI for the difference between treatment groups estimated using a mixed model with repeated measures. Nominal p values were calculated and are presented with no formal statistical hypothesis testing formulated. Results: Overall, 694 pts entered the open-label phase of ORAL Shift, and 530 were randomised and received treatment in the double-blind phase; 264 and 266 pts received tofacitinib + PBO and tofacitinib + MTX, respectively (Figure 1a). Considering those pts who were randomised and treated, the proportion of pts achieving each disease activity criterion at W24 varied, but was similar between treatments within each subgroup (Figure 1a). Among pts who met each disease activity criterion at W24, generally the majority of pts in both treatment groups also met the same criterion at W48 (Figure 1b). Numerically more pts receiving tofacitinib + MTX vs tofacitinib + PBO continued to meet the corresponding criterion at W48. Regardless of the disease activity criterion met at W24, differences between treatment groups in LS mean ΔDAS28-4(ESR) (Figure 1c) and ΔDAS28-4(CRP) (data not shown) from W24 to W48 favoured tofacitinib + MTX vs tofacitinib + PBO. Conclusion: This post hoc analysis of data from pts randomised and treated in ORAL Shift demonstrated that, regardless of the disease activity state criterion met at W24, generally a majority of pts receiving tofacitinib maintained achievement of the corresponding disease activity criterion at W48, with or without continued MTX. Differences between treatment groups in LS mean ΔDAS28-4(ESR) from W24 to W48, as defined by achievement of LDA or remission with a variety of disease activity measures, were less than a change of 1.2, which is considered to be the threshold for a minimal clinically important improvement. 2 References: [1]Cohen et al. Lancet Rheumatol 2019; 1: E23-34. [2]Ward et al. Ann Rheum Dis 2015; 74: 1691-1696. Acknowledgements: Study sponsored by Pfizer Inc. Medical writing support was provided by Gemma Turner, CMC Connect, and funded by Pfizer Inc. Disclosure of Interests: Roy Fleischmann Speakers bureau: Pfizer Inc, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celltrion, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, UCB, Grant/research support from: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celltrion, Eli Lilly, Genentech, GlaxoSmithKline, Janssen, Novartis, Pfizer Inc, Samumed, Sanofi-Aventis, UCB, VORSO, Boulos Haraoui Speakers bureau: Amgen, Pfizer Inc, UCB, Consultant of: AbbVie, Amgen, Eli Lilly, Merck, Pfizer Inc, UCB, Grant/research support from: AbbVie, Maya H Buch Speakers bureau: AbbVie, Consultant of: AbbVie, Eli Lilly, Gilead, MSD, Pfizer Inc, Roche, Sanofi, Grant/research support from: Pfizer Inc, Roche, UCB, David Gold Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Gosford Sawyerr Consultant of: Pfizer Inc, Employee of: Syneos Health Inc, Harry Shi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Annette Diehl Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Kristen Lee Shareholder of: Pfizer Inc, Employee of: Pfizer Inc.
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