Background Final data are presented for the ORAL Sequel long-term extension (LTE) study evaluating the safety and efficacy of tofacitinib 5 mg and 10 mg twice daily (BID) for up to 9.5 years in patients with rheumatoid arthritis (RA). Methods Eligible patients had previously completed a phase 1, 2, or 3 qualifying index study of tofacitinib and received open-label tofacitinib 5 mg or 10 mg BID. Stable background therapy, including csDMARDs, was continued; adjustments to tofacitinib or background therapy were permitted at investigators’ discretion. Assignment to dose groups (5 mg or 10 mg BID) was based on patients’ average total daily dose. The primary objective was to determine the long-term safety and tolerability of tofacitinib 5 mg and 10 mg BID; the key secondary objective was to evaluate the long-term persistence of efficacy. Results Between February 5, 2007, and November 30, 2016, 4481 patients were enrolled. Total tofacitinib exposure was 16,291 patient-years. Safety data are reported up to month 114 for all tofacitinib; efficacy data are reported up to month 96 for tofacitinib 5 mg BID and month 72 for 10 mg BID (with low patient numbers limiting interpretation beyond these time points). Overall, 52% of patients discontinued (24% due to adverse events [AEs] and 4% due to insufficient clinical response); the safety profile remained consistent with that observed in prior phase 1, 2, 3, or LTE studies. The incidence rate (IR; number of patients with events per 100 patient-years) for AEs leading to discontinuation was 6.8. For all-cause AEs of special interest, IRs were 3.4 for herpes zoster, 2.4 for serious infections, 0.8 for malignancies excluding non-melanoma skin cancer, 0.4 for major adverse cardiovascular events, and 0.3 for all-cause mortality. Clinically meaningful improvements in the signs and symptoms of RA and physical functioning, which were observed in the index studies, were maintained. Conclusions Tofacitinib 5 mg and 10 mg BID demonstrated a consistent safety profile (as monotherapy or combination therapy) and sustained efficacy in this open-label LTE study of patients with RA. Safety data are reported up to 9.5 years, and efficacy data up to 8 years, based on adequate patient numbers to support conclusions. Trial registration NCT00413699 , funded by Pfizer Inc (date of trial registration: December 20, 2006) Electronic supplementary material The online version of this article (10.1186/s13075-019-1866-2) contains supplementary material, which is available to authorized users.

Objective Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). Altered lymphocyte cell counts and a potential association with increased infection rates have been reported in RA patients treated with JAK inhibitors. This analysis was undertaken to evaluate the short‐, mid‐, and long‐term effects of tofacitinib on lymphocytes and infection rates in patients with RA. Methods In this post hoc analysis, absolute lymphocyte counts (ALCs) were obtained from phase III studies (12–24 months; n = 717–958) and phase I/II/III/long‐term extension studies of tofacitinib (≤117 months) (All RA population; n = 7,061); lymphocyte subset counts (LSCs) were from phase II studies (1.5–6 months’ exposure; n = 236–486), an ORAL Sequel vaccine substudy (~22 months; n = 198), and an ORAL Sequel lymphocyte substudy (~50 months; n = 55–1,035) of tofacitinib. The reversibility of ALC/LSC changes was evaluated. The relationship of ALC and LSC to infections was analyzed in the All RA population. The value of monitoring ALC alone was assessed by examining correlations between ALCs and LSCs. Results Tofacitinib treatment resulted in an initial increase in ALC versus pretreatment baseline, which gradually declined to steady state by ~48 months. CD4+ and CD8+ T cell counts decreased over long‐term treatment, and ALC and LSC changes were reversible upon treatment cessation. Patients with ALCs of <500 cells/mm3 had an increased risk of serious infections. There was no strong association between CD4+ T cell, CD8+ T cell, B cell, or natural killer cell counts and serious infection incidence rates. ALC and CD4+ or CD8+ T cell counts correlated well (R = 0.65–0.86). Conclusion Our findings indicate that monitoring of ALC alone appears to be adequate to assess infection risk in tofacitinib‐treated patients with RA.

Background:Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA).Objectives:To report tofacitinib safety and tolerability up to 114 months and clinical efficacy up to 96 months in long-term extension (LTE) studies.Methods:Data were pooled from 2 open-label studies (NCT00413699 [database locked as of March 2017]; and NCT00661661) of patients with RA who had participated in qualifying Phase 1/2/3 studies of tofacitinib. Patients received tofacitinib 5 or 10 mg twice daily (BID) as monotherapy or with background conventional synthetic (cs)DMARDs. As patients in the LTE studies were allowed to switch doses, they were assigned to the 5 mg BID group if the total daily dose (TDD) was <15 mg/day, and to the 10 mg BID group if TDD was ≥15 mg/day. Primary endpoints were adverse events (AEs) and confirmed laboratory safety data. Other endpoints included clinical efficacy measures (ACR20/50/70 response rates, mean DAS28–4[ESR] score, mean HAQ-DI score and mean change from baseline in Clinical Disease Activity Index score). Safety data were included up to Month 114 and completer-analyzed efficacy data up to Month 96 (n≤100 post-Month 96).Table 1Safety data (Month 114) and clinical efficacy outcomes (up to Month 96; as observed) in LTE studies of tofacitinib in patients with RAResults:Overall, 4967 patients were treated (mean [max] duration: 3.5 [9.4] years). Total tofacitinib exposure was 17,738.5 patient-years (py); 76.4% of patients maintained their initial dose. In total, 2518 patients (50.7%) discontinued (AEs: 1189 [23.9%]; insufficient clinical response: 179 [3.6%]). The most common classes of AE were infections and infestations (69.6%; exposure adjusted event rate [EAER; events per 100 py], 19.71) and musculoskeletal/connective tissue disorders (40.3%; EAER, 11.40). The most common AEs were nasopharyngitis (19.1%; EAER, 5.41), upper respiratory tract infection (17.9%; EAER, 5.07), bronchitis (12.6%; EAER, 3.58) and urinary tract infection (12.5%; EAER, 3.55). Serious AEs occurred in 29.4% of patients and serious infections (SIEs) in 8.9% of patients. Malignancies, excluding non-melanoma skin cancer, were reported in 3.0% of patients. Incidence rates (IR; patients with events per 100 py) for AEs of interest, with 95% confidence intervals, are provided in the table 1. IRs for SAEs, SIEs and malignancies through Month 114 did not increase vs reported data through Month 105.1 Confirmed laboratory data are provided in the table 1. No new safety risks were identified. Clinical responses were sustained from Month 1 to Month 96 (table 1).Conclusions:In patients with RA who remained in the LTE studies, tofacitinib (5 or 10 mg BID), with or without background csDMARDs, was associated with consistent safety through Month 114 and sustained clinical efficacy through Month 96.Reference[1]Wollenhaupt J, et al. Arthritis Rheumatol2016;68(suppl 10): Abstract 1647.Acknowledgements:Study sponsored by Pfizer Inc. Medical writing support was provided by A McCluskey of CMC and funded by Pfizer Inc.Discl...

BackgroundThe detection of statistically significant reductions in radiographic progression during clinical studies in patients with rheumatoid arthritis (RA) has become increasingly difficult over the past decade due to early-escape study designs and declining rates of progression in control-group patients. We investigated the impact of extremes of radiographic data (outliers) and baseline prognostic factors on detection of treatment effects, to provide guidance on future analysis of joint structural data in RA clinical trials.MethodsData were from two, phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib in adult patients with moderate to severe RA: ORAL Scan (NCT00847613) and ORAL Start (NCT01039688). These studies detected significant reductions in radiographic progression with tofacitinib 10 mg twice daily (BID) plus background methotrexate (ORAL Scan), and with tofacitinib 5 or 10 mg BID as monotherapy (ORAL Start). We evaluated mean changes from baseline in van der Heijde modified total Sharp score (mTSS) at month 6 and month 12, using analysis of covariance (ANCOVA). A trimmed analysis was used to deal with extremes of data. The impact of baseline prognostic factors on radiographic progression was evaluated using ANCOVA to analyze the mean change from baseline in mTSS for each factor in turn.ResultsThe analysis included data from 720 patients from ORAL Scan and 880 patients from ORAL Start. Trimmed analyses were unbiased for the true mean estimate and enabled us to remove the effect of influential extreme observations in the data set. Almost all patients had at least one poor prognostic factor at baseline (e.g., high level of disease activity, or positive for rheumatoid factor). The strongest predictor of treatment effect was the severity of radiographic damage at baseline.ConclusionsA trimmed analysis can establish whether any significant inhibition of structural damage is being driven by extremes of data, and should be one of the sensitivity analyses of choice for structural data in RA clinical trials. Furthermore, analysis of radiographic data based on baseline prognostic factors may reveal increased treatment effects. Application of these methods to analysis of radiographic data from clinical trials in patients with RA, allows a more complete interpretation of data.Trial registrationClinicaltrials.gov NCT00847613 (registered 17 February 2009) and NCT01039688 (registered 23 December 2009)Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1106-y) contains supplementary material, which is available to authorized users.

Background/Objective Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Interstitial lung disease (ILD) is an extra-articular manifestation of RA. We investigated incidence rates of ILD in patients with RA, receiving tofacitinib 5 or 10 mg twice daily, and identified potential risk factors for ILD. Methods This post hoc analysis comprised a pooled analysis of patients receiving tofacitinib 5 or 10 mg twice daily or placebo from 2 phase (P)1, 10 P2, 6 P3, 1 P3b/4, and 2 long-term extension studies. Interstitial lung disease events were adjudicated as “probable” (supportive clinical evidence) or “possible” (no supportive clinical evidence) compatible adverse events. Incidence rates (patients with events per 100 patient-years) were calculated for ILD events. Results Of 7061 patients (patient-years of exposure = 23,393.7), 42 (0.6%) had an ILD event; median time to ILD event was 1144 days. Incidence rates for ILD with both tofacitinib doses were 0.18 per 100 patient-years. Incidence rates generally remained stable over time. There were 17 of 42 serious adverse events (40.5%) of ILD; for all ILD events (serious and nonserious), 35 of 42 events (83.3%) were mild to moderate in severity. A multivariable Cox regression analysis identified age 65 years or older (hazard ratio 2.43 [95% confidence interval, 1.13–5.21]), current smokers (2.89 [1.33–6.26]), and Disease Activity Score in 28 joints–erythrocyte sedimentation rate score (1.30 [1.04–1.61]) as significant risk factors for ILD events. Conclusions Across P1/2/3/4/long-term extension studies, incidence rates for ILD events were 0.18 following tofacitinib treatment, and ILD events were associated with known risk factors for ILD in RA.

ObjectiveTo describe the outcomes of MTX and biologic DMARD (bDMARD) treatment in patients with RA and assess unmet needs in patients who fail treatment, using real-world data from the Norwegian DMARD (NOR-DMARD) registry.MethodsData included RA treatment courses from January 2007 until July 2016. Patients received MTX monotherapy (in MTX-naïve patients), bDMARD monotherapy, bDMARDs + MTX, or bDMARDs + other conventional synthetic DMARDs (csDMARDs). DAS28-4(ESR) was used to measure remission (<2.6) and inadequate response (>3.2) across all groups at Months 6 and 12. Estimated ACR20/50/70 and EULAR good and good/moderate response rates (based on DAS28-4[ESR] score) for bDMARDs were modelled at Months 6 and 12 using logistic mixed regression. DAS28-4(ESR) scores and changes from baseline, and rates and reasons for discontinuation, were evaluated for all groups over 24 months.ResultsThe 2778 treatment courses in this analysis included 714 MTX monotherapy, 396 bDMARD monotherapy, 1460 bDMARDs + MTX and 208 bDMARDs + other csDMARDs. Of patients with DAS28-4(ESR) data at Months 6 and 12 (25.0–34.1%), 33.9–47.2% did not switch treatment and were inadequate-responders at Month 12. There were no significant differences in efficacy between bDMARD groups (bDMARD monotherapy, or bDMARDs + MTX or other csDMARDs). Lack of efficacy was the most common reason for stopping treatment across all groups (13.7–22.1% over 24 months).ConclusionAn unmet treatment need exists for patients still experiencing inadequate response to MTX monotherapy and bDMARDs as monotherapy or in combination with MTX/other csDMARDs after 12 months.Trial registrationClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01581294.

BackgroundTofacitinib is an oral JAK inhibitor for the treatment (tx) of rheumatoid arthritis (RA). Studies have shown diminishing response to tx in RA patients (pts) when cycling through TNF inhibitors. Prior analyses assessed tofacitinib in csDMARD-inadequate response (IR) pts vs overall bDMARD-IR pts.ObjectivesTo compare tofacitinib safety and efficacy in RA pts who have previously failed tx (lack of efficacy and/or safety reasons) with csDMARDs, with pts who failed tx with either 1 or ≥2 prior bDMARDs.MethodsData from pts who received ≥1 dose of tofacitinib in 19 RA studies up to 96 months (2 Phase [P] 1; 9 P2; 6 P3; 2 LTE studies [1 LTE ongoing; data as of March 2015]) were used in this analysis. Data were pooled across all 19 studies for safety assessments in the All RA population: csDMARD-IR, n=4377; bDMARD-IR, n=838 (1 bDMARD-IR, n=533; ≥2 bDMARD-IR n=305). Safety was also assessed up to 24 months in pts randomised to tofacitinib 5 or 10 mg BID or placebo (PBO) in a pooled P2/P3 randomised controlled trial (RCT) population (8 P2, 6 P3 studies; csDMARD-IR, n=3328; bDMARD-IR, n=782). Incidence rates (pts with events/100 pt-years) were calculated for serious AEs (SAEs), serious infections (SIs) and herpes zoster (HZ). Efficacy was assessed by pts achieving ACR20 response and DAS28-4(ESR) ≤3.2 at Month 3 in a pooled P3 RCT population (csDMARD-IR, n=2375; bDMARD-IR, n=664).ResultsPrior to tofacitinib tx, bDMARD-IR pts had longer RA duration, greater disease burden and more corticosteroid use vs csDMARD-IR pts. SAEs were more common among bDMARD-IR vs csDMARD-IR pts in both the P2/P3 RCT and the All RA populations; SAE rates were not higher in pts failing ≥2 bDMARDs vs 1 bDMARD (Table). Incidence rates for SIs were generally greater in pts with IR to bDMARDs vs csDMARDs in the All RA population, but generally lower in pts with IR to 1 or ≥2 bDMARDs vs csDMARDs in the P2/P3 RCT population; incidence with 5 mg BID was lower for 1 vs ≥2 bDMARDs in the P2/P3 RCT population. Incidence rates for HZ were similar between pts with IR to csDMARDs or 1 bDMARD, but appeared numerically greater in pts with IR to ≥2 bDMARDs in both the P2/P3 RCT and the All RA populations. A similar pattern was observed across tofacitinib and PBO groups. Efficacy at Month 3 in the P3 RCT population was greater with both tofacitinib doses vs PBO. Although absolute response was smaller in pts with IR to bDMARDs vs csDMARDs, generally similar efficacy was observed in pts with IR to 1 or ≥2 bDMARDs (Table).ConclusionsSAEs and SIEs were more common in tofacitinib- and PBO-treated pts with IR to bDMARDs vs csDMARDs; increased risk was generally not observed with increasing number of prior bDMARDs. HZ risk appeared greater with ≥2 bDMARDs vs 1 bDMARD. Efficacy was greater with tofacitinib vs PBO for csDMARD-IR and bDMARD-IR pts, with similar response observed in pts with IR to ≥2 or 1 bDMARD. These data support the use of tofacitinib in different lines of therapy, although the analysis is limited by smaller sample size in some groups.Acknowledgement...

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To characterise the relative safety profile of tofacitinib to biologic disease-modifying antirheumatic drugs (bDMARDs), the accrued patient-years (pt-yrs) of exposure needed in an RA clinical trial programme to detect a potential increase in risk of specific adverse events (AEs) was determined. This case study/framework was constructed on the pt-yrs’ accrual within pooled phase (P)1, P2 and P3, as well as long-term extension, studies of tofacitinib in RA (March 2015 data-cut) and published AE incidence rates for bDMARDs. Sample size calculations were based on a Poisson distribution to estimate pt-yrs’ exposure required for 90 % probability that the lower bound of the 95 % confidence interval for tofacitinib/bDMARD would be >1, assuming that tofacitinib rates were 1.2×/1.5×/2.0× greater than comparator rates. AE rates for bDMARDs were derived from sources intended to optimise similarity with the tofacitinib database in terms of baseline characteristics, study duration and follow-up. Based on the tofacitinib exposure accrued (19,406 pt-yrs), data were sufficient (90 % probability) to detect potential differences over external bDMARD comparator rates in serious infections (≥1.2×), malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC, major adverse cardiovascular events (MACE) and lymphoma (each ≥1.5×), as well as opportunistic infections and gastrointestinal perforations (≥2×), should they exist. This risk characterisation approach can support the comparative safety of new RA medications. To date, tofacitinib safety appears similar to approved published data from bDMARDs with respect to serious infections, malignancies (excluding NMSC), NMSC, MACE, lymphoma, opportunistic infections and gastrointestinal perforations.Electronic supplementary materialThe online version of this article (doi:10.1007/s10067-016-3359-x) contains supplementary material, which is available to authorized users.