Carol A. Connell

Placebo-Controlled Trial of Tofacitinib Monotherapy in Rheumatoid Arthritis

BACKGROUND Tofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis. METHODS In this phase 3, double-blind, placebo-controlled, parallel-group, 6-month study, 611 patients were randomly assigned, in a 4:4:1:1 ratio, to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, placebo for 3 months followed by 5 mg of tofacitinib twice daily, or placebo for 3 months followed by 10 mg of tofacitinib twice daily. The primary end points, assessed at month 3, were the percentage of patients with at least a 20% improvement in the American College of Rheumatology scale (ACR 20), the change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores (which range from 0 to 3, with higher scores indicating greater disability), and the percentage of patients with a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating more disease activity). RESULTS At month 3, a higher percentage of patients in the tofacitinib groups than in the placebo groups met the criteria for an ACR 20 response (59.8% in the 5-mg tofacitinib group and 65.7% in the 10-mg tofacitinib group vs. 26.7% in the combined placebo groups, P<0.001 for both comparisons). The reductions from baseline in HAQ-DI scores were greater in the 5-mg and 10-mg tofacitinib groups than in the placebo groups (-0.50 and -0.57 points, respectively, vs. -0.19 points; P<0.001). The percentage of patients with a DAS28-4(ESR) of less than 2.6 was not significantly higher with tofacitinib than with placebo (5.6% and 8.7% in the 5-mg and 10-mg tofacitinib groups, respectively, and 4.4% with placebo; P=0.62 and P=0.10 for the two comparisons). Serious infections developed in six patients who were receiving tofacitinib. Common adverse events were headache and upper respiratory tract infection. Tofacitinib treatment was associated with elevations in low-density lipoprotein cholesterol levels and reductions in neutrophil counts. CONCLUSIONS In patients with active rheumatoid arthritis, tofacitinib monotherapy was associated with reductions in signs and symptoms of rheumatoid arthritis and improvement in physical function. (Funded by Pfizer; ORAL Solo ClinicalTrials.gov number, NCT00814307.).

Tofacitinib (CP‐690,550) in patients with rheumatoid arthritis receiving methotrexate: Twelve‐month data from a twenty‐four–month phase III randomized radiographic study

OBJECTIVE The purpose of this 24-month phase III study was to examine structural preservation with tofacitinib in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX). Data from a planned 12-month interim analysis are reported. METHODS In this double-blind, parallel-group, placebo-controlled study, patients receiving background MTX were randomized 4:4:1:1 to tofacitinib at 5 mg twice daily, tofacitinib at 10 mg twice daily, placebo to tofacitinib at 5 mg twice daily, and placebo to tofacitinib at 10 mg twice daily. At month 3, nonresponder placebo-treated patients were advanced in a blinded manner to receive tofacitinib as indicated above; remaining placebo-treated patients were advanced at 6 months. Four primary efficacy end points were all analyzed in a step-down procedure. RESULTS At month 6, response rates according to the American College of Rheumatology 20% improvement criteria for tofacitinib at 5 mg and 10 mg twice daily were higher than those for placebo (51.5% and 61.8%, respectively, versus 25.3%; both P < 0.0001). At month 6, least squares mean (LSM) changes in total modified Sharp/van der Heijde score for tofacitinib at 5 mg and 10 mg twice daily were 0.12 and 0.06, respectively, versus 0.47 for placebo (P = 0.0792 and P ≤ 0.05, respectively). At month 3, LSM changes in the Health Assessment Questionnaire disability index score for tofacitinib at 5 mg and 10 mg twice daily were -0.40 (significance not declared due to step-down procedure) and -0.54 (P < 0.0001), respectively, versus -0.15 for placebo. At month 6, rates of remission (defined as a value <2.6 for the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate) for tofacitinib at 5 mg and 10 mg twice daily were 7.2% (significance not declared due to step-down procedure) and 16.0% (P < 0.0001), respectively, versus 1.6% for placebo. The safety profile was consistent with findings in previous studies. CONCLUSION Data from this 12-month interim analysis demonstrate that tofacitinib inhibits progression of structural damage and improves disease activity in patients with RA who are receiving MTX.

Phase IIb dose‐ranging study of the oral JAK inhibitor tofacitinib (CP‐690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease‐modifying antirheumatic drugs

OBJECTIVE To compare the efficacy, safety, and tolerability of 5 doses of oral tofacitinib (CP-690,550) or adalimumab monotherapy with placebo for the treatment of active rheumatoid arthritis (RA) in patients with an inadequate response to disease-modifying antirheumatic drugs. METHODS In this 24-week, double-blind, phase IIb study, patients with RA (n = 384) were randomized to receive placebo, tofacitinib at 1, 3, 5, 10, or 15 mg administered orally twice a day, or adalimumab at 40 mg injected subcutaneously every 2 weeks (total of 6 injections) followed by oral tofacitinib at 5 mg twice a day for 12 weeks. The primary end point was the responder rate according to the American College of Rheumatology 20% improvement criteria (ACR20) at week 12. RESULTS Treatment with tofacitinib at a dose of ≥3 mg twice a day resulted in a rapid response with significant efficacy when compared to placebo, as indicated by the primary end point (ACR20 response at week 12), achieved in 39.2% (3 mg; P ≤ 0.05), 59.2% (5 mg; P < 0.0001), 70.5% (10 mg; P < 0.0001), and 71.9% (15 mg; P < 0.0001) in the tofacitinib group and 35.9% of patients in the adalimumab group (P = 0.105), compared with 22.0% of patients receiving placebo. Improvements were sustained at week 24, according to the ACR20, ACR50, and ACR70 response rates as well as classifications of remission according to the 3-variable Disease Activity Score in 28 joints (DAS28) using C-reactive protein and the 4-variable DAS28 using the erythrocyte sedimentation rate. The most common treatment-emergent adverse events (AEs) in patients across all tofacitinib treatment arms (n = 272) were urinary tract infection (7.7%), diarrhea (4.8%), headache (4.8%), and bronchitis (4.8%). CONCLUSION Tofacitinib monotherapy at ≥3 mg twice a day was efficacious in the treatment of patients with active RA over 24 weeks and demonstrated a manageable safety profile.

A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone.

OBJECTIVE To compare the efficacy, safety, and tolerability of 6 dosages of oral tofacitinib (CP-690,550) with placebo for the treatment of active rheumatoid arthritis (RA) in patients receiving a stable background regimen of methotrexate (MTX) who have an inadequate response to MTX monotherapy. METHODS In this 24-week, double-blind, phase IIb study, patients with active RA (n = 507) were randomized to receive placebo or tofacitinib (20 mg/day, 1 mg twice daily, 3 mg twice daily, 5 mg twice daily, 10 mg twice daily, or 15 mg twice daily). All patients continued to receive a stable dosage of MTX. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. RESULTS At week 12, ACR20 response rates for patients receiving all tofacitinib dosages ≥3 mg twice daily (52.9% for 3 mg twice daily, 50.7% for 5 mg twice daily, 58.1% for 10 mg twice daily, 56.0% for 15 mg twice daily, and 53.8% for 20 mg/day) were significantly (P ≤ 0.05) greater than those for placebo (33.3%). Improvements were sustained at week 24 for the ACR20, ACR50, and ACR70 responses, scores for the Health Assessment Questionnaire disability index, the 3-variable Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP), and a 3-variable DAS28-CRP of <2.6. The most common treatment-emergent adverse events occurring in >10% of patients in any tofacitinib group were diarrhea, upper respiratory tract infection, and headache; 21 patients (4.1%) experienced serious adverse events. Sporadic increases in transaminase levels, increases in cholesterol and serum creatinine levels, and decreases in neutrophil and hemoglobin levels were observed. CONCLUSION In patients with active RA in whom the response to MTX has been inadequate, the addition of tofacitinib at a dosage ≥3 mg twice daily showed sustained efficacy and a manageable safety profile over 24 weeks.

THU0185 Tofacitinib, An Oral JAK Inhibitor, in The Treatment of Rheumatoid Arthritis: Safety and Clinical and Radiographic Efficacy in Open-Label, Long-Term Extension Studies over 7 Years

Background Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). Objectives To report tofacitinib safety, tolerability and clinical response over 84 months (mo), and radiographic data over 12 mo, in long-term extension (LTE) studies. Methods Data were from two open-label studies (NCT00413699 [ongoing; database unlocked at March 2015 data-cut] and NCT00661661]) of patients (pts) with RA who completed randomised Phase (P)1/2/3 tofacitinib studies. Pts received tofacitinib 5 or 10 mg BID as monotherapy or with background DMARDs; data were pooled. Primary endpoints: AEs and lab safety. Confirmed data are reported for decreased Hgb, neutrophil and lymphocyte counts, and increases >50% from BL in creatinine. Secondary endpoints: DAS28-4(ESR), HAQ-DI and mTSS. Safety data were included up to 96 mo and efficacy up to Mo 84 (n≤30 post-Mo 84). Results 4867 pts were treated (mean [max] duration: 1107 [2895] days). BL data were from P1/P2/P3 index studies for 90.9% of pts. Total tofacitinib exposure was 14926 pt-years (py); 79.2% of pts maintained initial dose. In total, 2132 pts (43.8%) discontinued (AEs: 1051 [21.6%]; insufficient clinical response: 153 [3.1%]). Most common AE classes: infections and infestations (67.6%) and musculoskeletal/connective tissue disorders (37.3%). Most common AEs: nasopharyngitis (18.1%), upper respiratory tract infection (16.2%) and bronchitis (11.7%). SAEs occurred in 26.8% of pts (incidence rate [IR] 9.7/100 py [95% CI 9.2, 10.2]), and serious infection events (SIEs) in 8.4% of pts (IR 2.8/100 py [95% CI 2.5, 3.0]). Malignancies excluding NMSC were reported in 3.0% of pts (IR 1.0/100 py [95% CI 0.8, 1.1]). IRs for SIEs and malignancies through Mo 96 did not increase vs reported data through Mo 84.1 Decreased Hgb (>30% decrease from BL/Hgb <8 g/dL) occurred in <1.0% of pts. Increased aminotransferases (>3×ULN) occurred in 5.4% (ALT) and 3.1% (AST) of pts. Moderate to severe neutropenia (absolute neutrophil count [ANC] 0.5–1.5×103/mm3) was noted in 1.5% of pts; there were no confirmed cases of ANC <0.5×103/mm3. Confirmed absolute lymphocyte counts <0.5×103/mm3 occurred in 1.3% of pts. Increases >50% from BL in creatinine were seen in 2.4% of pts. Mean DAS28-4(ESR) was 6.29 at BL, 3.74 at Mo 1 and 3.20 at Mo 84. Mean HAQ-DI score was 1.42 at BL, 0.81 at Mo 1 and 0.78 at Mo 84. Radiographic data were available for 1099 pts. Mean mTSS was 24.0 at BL (last P1/P2/P3 index value), 25.1 at Mo 6 and 24.3 at Mo 12. Mean change from BL in mTSS was 0.3 at Mo 6 and 0.2 at Mo 12. Conclusions Consistent safety and sustained efficacy over 84 mo was seen in pts with RA receiving tofacitinib 5 or 10 mg BID in LTE studies. Changes in mTSS were minimal at Mo 12 in LTE studies. References Wollenhaupt J et al. Arthritis Rheumatol 2014; 66: S375. Acknowledgement Previously presented (Wollenhaupt J et al. Arthritis Rheumatol 2015; 67 (S10): 1645) and reproduced with permission. This study was funded by Pfizer Inc. Editorial support was provided by S. Johnson of Complete Medical Communications and funded by Pfizer Inc. Disclosure of Interest J. Wollenhaupt Consultant for: Pfizer Inc, Speakers bureau: Pfizer Inc, J. Silverfield Grant/research support from: Pfizer Inc, Speakers bureau: Pfizer Inc, E. B. Lee Consultant for: Pfizer Inc, K. K. Terry Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Kwok Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, I. Lazariciu Consultant for: Pfizer Inc, Employee of: Quintiles Inc, C. Nduaka Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. A. Connell Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. DeMasi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Effect of Glucocorticoids on the Clinical and Radiographic Efficacy of Tofacitinib in Patients with Rheumatoid Arthritis: A Posthoc Analysis of Data from 6 Phase III Studies

Objective. Tofacitinib has been investigated for the treatment of rheumatoid arthritis (RA) in phase III studies in which concomitant glucocorticoids (GC) were allowed. We analyzed the effect of GC use on efficacy outcomes in patients with RA receiving tofacitinib and/or methotrexate (MTX) or conventional synthetic disease-modifying antirheumatic drugs (csDMARD) in these studies. Methods. Our posthoc analysis included data from 6 phase III studies (NCT01039688; NCT00814307; NCT00847613; NCT00853385; NCT00856544; NCT00960440). MTX-naive patients or patients with inadequate response to csDMARD or biological DMARD received tofacitinib 5 or 10 mg twice daily alone or with csDMARD, with or without concomitant GC. Patients receiving GC (≤ 10 mg/day prednisone or equivalent) before enrollment maintained a stable dose throughout. Endpoints included the American College of Rheumatology (ACR) 20/50/70 response rates, rates of Clinical Disease Activity Index (CDAI)-defined low disease activity (LDA; CDAI ≤ 10) and remission (CDAI ≤ 2.8), and changes from baseline in CDAI, 28-joint count Disease Activity Score (DAS28-4)–erythrocyte sedimentation rate (ESR), Health Assessment Questionnaire–Disability Index (HAQ-DI), pain visual analog scale (VAS), and modified total Sharp score. Results. Of 3200 tofacitinib-treated patients, 1258 (39.3%) received tofacitinib monotherapy and 1942 (60.7%) received tofacitinib plus csDMARD; 1767 (55.2%) received concomitant GC. ACR20/50/70 response rates, rates of CDAI LDA and remission, and improvements in CDAI, DAS28-4-ESR, HAQ-DI, and pain VAS with tofacitinib were generally similar with or without GC in monotherapy and combination therapy studies. GC use did not appear to affect radiographic progression in tofacitinib-treated MTX-naive patients. MTX plus GC appeared to inhibit radiographic progression to a numerically greater degree than MTX alone. Conclusion. Concomitant use of GC with tofacitinib did not appear to affect clinical or radiographic efficacy. MTX plus GC showed a trend to inhibit radiographic progression to a greater degree than MTX alone.

SAT0220 Radiographic Progression in Modern RA Trials is Still a Robust Outcome: Results of Comprehensive Sensitivity Analysis in Two Phase 3 Trials with Tofacitinib

Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. In Phase 3 ORAL Scan (NCT00847613; MTX-inadequate responders) and ORAL Start (NCT01039688; MTX-naïve) 24-month studies, progression in radiographic scores of the protocol-specified primary analysis at the 12-month interim was measured by mean change from baseline (BL) in van der Heijde modified Sharp scores (mTSS) at Month 6. This co-primary endpoint was analysed using Analysis of Covariance (ANCOVA). In ORAL Scan, tofacitinib 10 mg but not 5 mg twice daily (BID) demonstrated statistically significant inhibition of progression in mTSS vs placebo (PBO). In ORAL Start, tofacitinib 5 and 10 mg BID doses showed statistically significant inhibition of progression in mTSS vs MTX. Mean change from BL in mTSS at Month 6 was 0.47 with PBO in ORAL Scan and 0.84 with MTX 20 mg/week in ORAL Start. Objectives To better understand the degree to which radiographic progression was inhibited by tofacitinib in two different patient populations. The goals of these analyses were to demonstrate: 1) the magnitude of tofacitinib efficacy in the presence of predictors of higher risk of structural progression, and 2) whether the results were driven by outliers. The latter was approached by use of a trimmed analysis, whereby extreme values are systematically removed. Methods A literature review was performed for factors predicting higher risk of structural progression. BL data were used to subset the patients by these high-risk factors, tailored to the tofacitinib program, regardless of treatment group assignment. ANCOVA was then applied to each high-risk subset. For trimmed analyses, data were trimmed in 1% increments up to 10% (2% trimming deletes observations >1st and <99th percentile) and ANCOVA was applied to each trimmed data set. Results High-risk factors for radiographic progression within the tofacitinib program included: anti-CCP+; BL DAS28-4(ESR) >5.1; CRP+ (>7 mg/L); both seropositive (RF+ or anti-CCP+) and BL erosion score ≥3; and, >median BL mTSS. For mTSS, high-risk subsets generally showed greater differentiation, although the degree of differentiation varied by BL risk (Figure). With regard to trimmed analyses, in ORAL Scan, statistical significance (p≤0.05; not corrected for multiple comparisons) was achieved for both tofacitinib doses at 1% trimming, and the significance was maintained with further trimming, with mean values stable at 3%. The trimmed analyses in ORAL Start showed that statistical significance in both doses was maintained, and the upper limit of the confidence intervals remained stable for tofacitinib 5 and 10 mg BID. Conclusions In ORAL Scan and ORAL Start, both tofacitinib 5 and 10 mg BID demonstrated inhibition of structural damage progression vs comparator in high-risk patients, and the trimmed analyses demonstrate that significant inhibition of structural damage was not driven by outliers. These results show that the degree of inhibition of radiographic progression is consistent across the two patient populations. Acknowledgements Study sponsored by Pfizer Inc. Editorial support was provided, under the guidance of the authors, by A Smith, PhD, of CMC, and funded by Pfizer Inc. Disclosure of Interest D. Van der Heijde Consultant for: AbbVie, Amgen, AstraZeneca, Augurex, BMS, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GSK, Janssen Biologics, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer Inc, Roche, Sanofi-Aventis, UCB, Vertex, Employee of: Imaging Rheumatology, C. Connell Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Bradley Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, D. Gruben Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Strengholt Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Landewé Grant/research support from: Pfizer Inc, Abbott, Janssen, Merck, Consultant for: Abbott, Amgen, Astra, Bristol-Myers Squibb, Centocor, GlaxoSmithKline, Janssen, Pfizer Inc, UCB, Vertex

A pooled analysis of the safety of tofacitinib as monotherapy or in combination with background conventional synthetic disease-modifying antirheumatic drugs in a Phase 3 rheumatoid arthritis population

OBJECTIVE This post-hoc, pooled analysis of Phase 3 studies of tofacitinib examined the safety of tofacitinib 5 and 10 mg twice daily (BID) when used as monotherapy versus combination therapy with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with rheumatoid arthritis (RA). METHODS Pooled data from six double-blind, randomized controlled Phase 3 studies of tofacitinib 5 and 10 mg BID in patients with RA were analyzed for safety and stratified by administration as monotherapy (ORAL Solo: NCT00814307 and ORAL Start: NCT01039688) or in combination with csDMARDs (ORAL Sync: NCT00856544, ORAL Standard: NCT00853385, ORAL Scan: NCT00847613, and ORAL Step: NCT00960440), and by glucocorticoid use at baseline. Safety assessments included incidence rates (IRs) for serious adverse events (SAEs), discontinuations due to AEs, serious infection events, and herpes zoster (HZ), and were evaluated throughout the duration of the Phase 3 studies. RESULTS In total, 3881 patients were included in the safety analysis (monotherapy studies: n = 1380; combination therapy studies: n = 2501). IRs for selected AEs of interest were generally numerically lower in patients who received tofacitinib 5 and 10 mg BID as monotherapy than as combination therapy (SAEs: IR [range] 6.21-6.72 versus IR 10.17-13.46; discontinuations due to AEs: IR 5.53-6.18 versus IR 10.80-11.01; serious infections: IR 1.57-1.66 versus IR 3.39-3.56; HZ: IR 1.95-2.93 versus IR 4.37-4.99, respectively), irrespective of tofacitinib dose or glucocorticoid use. There were too few patients and events within the placebo group to fully evaluate effect between combination therapy and monotherapy. CONCLUSIONS Safety profiles were generally similar between patients receiving monotherapy and combination therapy; however, selected safety events of interest, including HZ and serious infections, showed lower IRs with non-overlapping 95% confidence intervals for tofacitinib all monotherapy versus combination therapy. Tofacitinib monotherapy may, therefore, have fewer safety events compared with combination therapy, and have a favorable risk-benefit profile in patients with active RA who are intolerant to csDMARDs.

THU0186 Magnitude and duration of early response with tofacitinib: post-hoc analysis of two phase 3, placebo-controlled studies

Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. ORAL Solo (NCT00814307) and ORAL Sync (NCT00856544) were two Phase 3 index studies that demonstrated the efficacy of tofacitinib in adult patients (pts) with RA who were DMARD inadequate responders (DMARD-IR). Early onset of effect is a clinically meaningful endpoint. Objectives This post hoc analysis examined the magnitude and durability of early response to tofacitinib in ORAL Solo and ORAL Sync. Methods ORAL Solo and ORAL Sync were double-blind, placebo (PBO)-controlled, parallel-group studies in pts with active RA and an inadequate response to ≥1 conventional synthetic (cs) or biologic (b) DMARDs. Pts were randomised to tofacitinib 5 mg BID, tofacitinib 10 mg BID, PBO advanced to tofacitinib 5 mg BID, or PBO advanced to tofacitinib 10 mg BID, either as monotherapy in ORAL Solo or with background csDMARDs in ORAL Sync. In ORAL Solo, pts randomised to PBO were advanced to tofacitinib at Month (M) 3; in ORAL Sync, pts randomised to PBO were advanced to tofacitinib at M3 (non-responders) or M6 (all other pts). In this post hoc analysis, the following clinical efficacy data for pts on tofacitinib or PBO (prior to advancement to tofacitinib) ± csDMARDs, were evaluated at Week 2, M3 and M6 (ORAL Sync only; no M6 PBO comparison in ORAL Solo): change from baseline (CFB) in Clinical Disease Activity Index (CDAI) >12,1 HAQ-DI CFB ≥0.22, CDAI ≥50% improvement from baseline, CDAI ≥70% improvement from baseline, CDAI ≥85% improvement from baseline, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score improvement from baseline ≥4, Pain visual analogue scale (VAS) score CFB ≥10. This analysis was post hoc and multiplicity adjustment was done. Results Clinical efficacy endpoint data are summarised in the Table. At Week 2, more patients receiving tofacitinib 5 or 10 mg BID ± csDMARDs (compared with PBO ± csDMARDs) achieved a CDAI CFB >12, HAQ-DI CFB ≥0.22, CDAI ≥50% improvement from baseline and pain VAS CFB ≥10. By M3, more pts receiving tofacitinib 5 or 10 mg BID ± csDMARDs (compared with PBO ± csDMARDs) achieved the efficacy outcomes measured including improvements from baseline in FACIT-F scores ≥4, CDAI ≥50%, CDAI ≥70% and CDAI ≥85%. Responses attained at M3 were maintained or increased at M6. Conclusions DMARD-IR pts with active RA receiving tofacitinib ± csDMARDs appeared to show greater improvements compared with PBO in clinical disease activity, HAQ-DI, and pain as early as Week 2 (first post-baseline assessment), and improvements in fatigue by M3. Responses were maintained or improved through M3 (monotherapy) or M6 (with background csDMARDs). References Curtis JR et al. Arthritis Care Res (Hoboken) 2015; 67:1345–1353. Acknowledgements Previously presented at ACR 2016 and reproduced with permission. This study was sponsored by Pfizer Inc. Editorial support was provided by AG McCluskey of CMC and was funded by Pfizer Inc. Disclosure of Interest D. Aletaha Consultant for: AbbVie, BMS, Eli Lilly, Janssen, MSD, Pfizer Inc, Roche, and UCB, Speakers bureau: AbbVie, BMS, Eli Lilly, Janssen, MSD, Pfizer Inc, Roche, and UCB, A. Kivitz Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Genentech, Pfizer Inc, Consultant for: AbbVie, Amgen, Bristol Myers Squibb, Genentech, Pfizer Inc, Speakers bureau: AbbVie, Amgen, Bristol Myers Squibb, Genentech, Pfizer Inc, G. Valenzuela Speakers bureau: AbbVie, Janssen, Eli-Lilly, Merck, Novartis and Pfizer Inc, J. Tesser Grant/research support from: Pfizer Inc, Consultant for: Pfizer Inc, Speakers bureau: Pfizer Inc, S. Hays Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, H. Li Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. A. Connell Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, E. Bananis Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, A. Soonasra Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. S. Smolen Grant/research support from: AbbVie, Janssen, Lilly, MSD, Pfizer Inc, and Roche, Consultant for: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Glaxo, ILTOO, Janssen, Lilly, MedImmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, and UCB, Speakers bureau: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Glaxo, ILTOO, Janssen, Lilly, MedImmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, and UCB

THU0200 Effect of Methotrexate Dose on The Efficacy of Tofacitinib: Treatment Outcomes from A Phase 3 Clinical Trial of Patients with Rheumatoid Arthritis

Background Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). ORAL Scan was a 2-year, randomised, Phase 3, clinical trial that evaluated tofacitinib therapy with background methotrexate (MTX) in patients (pts) with RA and an inadequate response (IR) to MTX.1 Objectives To study the effect of MTX dose on tofacitinib efficacy in pts from the ORAL Scan study. Methods In ORAL Scan, MTX-IR pts with RA were randomised 4:4:1:1 to tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID, or placebo with advancement to 5 mg BID or to 10 mg BID at Month (Mo) 3 or Mo 6, in combination with background MTX. MTX dose was stable throughout the study and was categorised as Low (≤12.5 mg/week), Medium (>12.5 to <17.5 mg/week), or High (≥17.5 mg/week). Endpoints evaluated at Mo 6 included ACR response rates, proportion of pts achieving low disease activity measured by Clinical Disease Activity Index (CDAI ≤10), CDAI defined remission rate (CDAI ≤2.8), proportion of pts achieving an improvement ≥0.5 in Health Assessment Questionnaire-Disability Index (HAQ-DI), and least squares mean change from baseline in HAQ-DI, Disease Activity Score (DAS28-4[ESR]) and CDAI. Binary variables were evaluated with non-responder imputation, and continuous variables were analysed using a longitudinal model. Regression analyses were conducted to evaluate efficacy responses by MTX dose group and other covariates. Results 797 pts were randomised and treated (tofacitinib 5 mg BID, n=321; tofacitinib 10 mg BID, n=316; placebo, n=160). In total, 242 pts were included in the Low MTX (9 mg mean) dose group, 333 in the Medium MTX (15 mg mean) dose group, and 222 in the High MTX (21 mg mean) dose group. Baseline demographics and disease characteristics were generally similar across MTX dose groups, though weight, BMI, glucocorticoid (GC) use and CDAI were higher in the High MTX dose group. At Mo 6, greater efficacy was seen with tofacitinib compared with placebo for all endpoints across the 3 MTX dose groups (Table). Efficacy for placebo-treated pts was generally numerically greater in the Medium and High MTX dose groups than in the Low MTX dose group. Efficacy with tofacitinib appeared similar regardless of MTX dose group. Regression analyses demonstrated a lack of effect of BMI, GC use and MTX dose groups on efficacy assessments. Conclusions In this post-hoc analysis, clinical efficacy of tofacitinib at Mo 6 was greater than placebo, and appeared similar regardless of MTX dose, as in these pts, tofacitinib was added to patients that had an inadequate response to MTX. Higher MTX doses did not appear to result in additional efficacy to tofacitinib than lower doses. A randomised clinical trial is needed in which different doses of MTX are added to tofacitinib in MTX-naïve pts in order to examine the effect of MTX dose on tofacitinib efficacy. References van der Heijde D et al. Arthritis Rheumatol 2013; 65: 559–570. Acknowledgement Previously presented (Fleischmann R et al. Arthritis Rheumatol 2015; 67 (S10): Abstr 1640) and reproduced with permission from Arthritis Rheumatol. This study was funded by Pfizer Inc. Editorial support was provided by S Johnson of CMC, and funded by Pfizer Inc. Disclosure of Interest R. Fleischmann Grant/research support from: Pfizer Inc, AbbVie, Consultant for: Pfizer Inc, AbbVie, P. Mease Grant/research support from: Pfizer Inc, Speakers bureau: Pfizer Inc, S. Schwartzman Consultant for: Pfizer Inc, L.-J. Hwang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Soma Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Connell Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Takiya Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, E. Bananis: None declared