Session Information
Date: Monday, November 9, 2015
Title: Rheumatoid Arthritis - Small Molecules, Biologics and Gene Therapy Poster II
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). ORAL Scan was a 2-year, randomized, 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 In this analysis, the effect of MTX dose on tofacitinib efficacy in pts from ORAL Scan was studied.
Methods: In ORAL Scan, MTX-IR pts with RA were randomized 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 3 or Month 6, in combination with background MTX. MTX dose was stable throughout the study and was categorized as Low (≤12.5 mg/week), Medium (>12.5 to <17.5 mg/week), or High (≥17.5 mg/week). Endpoints evaluated at Month 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 analyzed using a longitudinal model. Regression analyses were conducted to evaluate efficacy responses by MTX dose group and other covariates.
Results: 797 pts were randomized and treated (tofacitinib 5 mg BID, n=321; tofacitinib 10 mg BID, n=316; placebo, n=160). 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 similar across MTX dose groups, though weight, BMI, glucocorticoid (GC) use, and CDAI were higher in the High MTX dose group. At Month 6, greater efficacy was seen with tofacitinib compared to 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.
Conclusion: In this post-hoc analysis, clinical efficacy of tofacitinib at Month 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 randomized 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.
Reference: 1. van der Heijde D et al. Arthritis Rheum 2013; 65: 559-570.
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Table: Efficacy responses at Month 6 by MTX dose group and treatment group for patients in ORAL Scan |
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Low MTX (≤12.5 mg/week; category mean = 9 mg/week) N=242 |
Medium MTX (>12.5 to <17.5 mg/week; category mean = 15 mg/week) N=333 |
High MTX (≥17.5 mg/week; category mean = 21 mg/week) N=222 |
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Placebo N=47 |
Tofacitinib 5 mg BID N=102 |
Tofacitinib 10 mg BID N=93 |
Placebo N=73 |
Tofacitinib 5 mg BID N=131 |
Tofacitinib 10 mg BID N=129 |
Placebo N=40 |
Tofacitinib 5 mg BID N=88 |
Tofacitinib 10 mg BID N=94 |
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ACR20, % |
22.2 |
54.0* |
62.2* |
27.5 |
48.0* |
62.4* |
25.0 |
53.6* |
60.6* |
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ACR50, % |
6.7 |
35.0* |
44.4* |
7.3 |
31.2* |
42.4* |
12.5 |
31.0* |
44.7* |
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ACR70, % |
0.0 |
17.0* |
24.4* |
2.9 |
15.2* |
21.6* |
0.0 |
10.7* |
21.3* |
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CDAI ≤10, % |
8.9 |
42.0* |
52.2* |
13.0 |
32.0* |
41.1* |
12.5 |
35.7* |
39.4* |
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CDAI ≤2.8, % |
2.2 |
9.0 |
13.3* |
1.5 |
8.8* |
13.7* |
0.0 |
9.5* |
16.0* |
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HAQ-DI change ≥0.5, % |
8.9 |
32.0* |
45.6* |
14.5 |
36.0* |
47.6* |
7.5 |
36.1* |
50.0* |
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LS mean CFB in HAQ-DI |
-0.01 |
-0.46* |
-0.57* |
-0.25 |
-0.56* |
-0.62* |
-0.28 |
-0.45 |
-0.68* |
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LS mean CFB in DAS28-4 (ESR) |
-1.00 |
-2.15* |
-2.48* |
-1.33 |
-2.28* |
-2.39* |
-2.07 |
-2.14 |
-2.67* |
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LS mean CFB in CDAI |
-13.0 |
-21.4* |
-22.7* |
-16.3 |
-22.6* |
-23.3* |
-20.12 |
-23.3 |
-25.8* |
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*p<0.05 vs placebo Data for binary endpoints are full analysis set with non-responder imputation; data for continuous endpoints are full analysis set, longitudinal model. Non-responder imputation was applied to patients who discontinued, and to patients who, at Month 3, had not achieved a 20% improvement in tender and swollen joint counts regardless of treatment assignment. ACR, American College of Rheumatology response; BID, twice daily; CDAI, Clinical Disease Activity Index; CFB, change from baseline; DAS28, Disease Activity Score; ESR, erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire-Disability Index; LS, least squares; MTX, methotrexate
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To cite this abstract in AMA style:
Fleischmann R, Mease PJ, Schwartzman S, Hwang LJ, Patel A, Soma K, Connell CA, Takiya L, Bananis E. Effect of Methotrexate Dose on the Efficacy of Tofacitinib: Treatment Outcomes from a Phase 3 Clinical Trial of Patients with Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/effect-of-methotrexate-dose-on-the-efficacy-of-tofacitinib-treatment-outcomes-from-a-phase-3-clinical-trial-of-patients-with-rheumatoid-arthritis/. Accessed .« Back to 2015 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/effect-of-methotrexate-dose-on-the-efficacy-of-tofacitinib-treatment-outcomes-from-a-phase-3-clinical-trial-of-patients-with-rheumatoid-arthritis/