Patient-reported outcomes for tofacitinib with and without methotrexate, or adalimumab with methotrexate, in rheumatoid arthritis: a phase IIIB/IV trial

Vibeke Strand, Eduardo Mysler, Robert J Moots, Gene V Wallenstein, Ryan DeMasi, David Gruben, Koshika Soma, Noriko Iikuni, Josef S Smolen, Roy Fleischmann, Vibeke Strand, Eduardo Mysler, Robert J Moots, Gene V Wallenstein, Ryan DeMasi, David Gruben, Koshika Soma, Noriko Iikuni, Josef S Smolen, Roy Fleischmann

Abstract

Objective: To provide the first direct comparison of patient-reported outcomes (PROs) following treatment with tofacitinib monotherapy versus tofacitinib or adalimumab (ADA) in combination with methotrexate (MTX) in patients with rheumatoid arthritis (RA) with inadequate response to MTX (MTX-IR).

Methods: ORAL Strategy (NCT02187055), a phase IIIB/IV, head-to-head, randomised controlled trial, assessed non-inferiority between tofacitinib 5 mg two times per day monotherapy, tofacitinib 5 mg two times per day+MTX and ADA 40 mg every other week+MTX. PROs assessed included the following: Patient Global Assessment of disease activity (PtGA), Pain, Health Assessment Questionnaire-Disability Index, Functional Assessment of Chronic Illness Therapy-Fatigue and 36-Item Short-Form Health Survey (SF-36) summary and domain scores.

Results: Substantial improvements from baseline were reported across all PROs in all treatment arms, which, in the majority, met or exceeded minimum clinically important differences. Compared with tofacitinib monotherapy, tofacitinib+MTX combination treatment conferred significantly greater improvements in PtGA, Pain and SF-36 physical component summary scores at month 6. Statistically or numerically greater improvements were often, but not uniformly, reported for combination treatments compared with tofacitinib monotherapy at other time points.

Conclusion: Treatment with tofacitinib+MTX, ADA+MTX and tofacitinib monotherapy resulted in clinically meaningful improvements in PROs in MTX-IR patients with RA. These were comparatively greater with combination treatments versus tofacitinib monotherapy, although differences between treatment arms were small, limiting our ability to confer clinical meaning.

Trial registration number: NCT02187055.

Keywords: DMARDs (biologic); DMARDs (synthetic); outcomes research; rheumatoid arthritis.

Conflict of interest statement

Competing interests: VS has received consulting fees from AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Corrona, Eli Lilly, Genentech/Roche, GSK, Janssen, Merck, Novartis, Pfizer Inc, Regeneron, Samsung, Sandoz, Sanofi and UCB. EM has received research grants, consulting fees or other remuneration from, and is a member of the speakers’ bureau for, AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, MedImmune, Pfizer Inc and Roche. RJM has received research grants and consulting fees from, or is a member of the speakers’ bureau for, AbbVie, AKL Pharma, Biogen, Bristol-Myers Squibb, Chugai, Eli Lilly, Novartis, Pfizer Inc, Roche, Sandoz, Sanofi and UCB. DG, KS and NI are employees and shareholders of Pfizer Inc. GVW and RD were employees and shareholders of Pfizer Inc at the time of the analysis. JSS has received consulting fees, speaking fees and honoraria from AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celltrion, Eli Lilly, GSK, ILTOO, Janssen, MedImmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi and UCB Pharma; and has received institutional grants from AbbVie, Eli Lilly, Janssen, MSD, Pfizer Inc and Roche. RF has received research grants or consulting fees from AbbVie, ACEA, Amgen, AstraZeneca, Bristol-Myers Squibb, Celltrion, Eli Lilly, Genentech, GSK, Janssen, Novartis, Pfizer Inc, Samsung, Sanofi-Aventis, Tahio and UCB.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
PRO scores over time for (A) PtGA, (B) Pain, (C) HAQ-DI, (D) FACIT-F, (E) SF-36 PCS and (F) SF-36 MCS (FAS). PtGA and Pain were assessed using 0–100 mm VAS. N numbers evaluable for each outcome may be ≤ those reported for the FAS. *p†p<0.05 ADA+MTX versus tofacitinib monotherapy; ††p<0.01 ADA+MTX versus tofacitinib monotherapy; ‡p<0.05 tofacitinib+MTX versus ADA+MTX. ADA, adalimumab; BID, two times per day; FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; FAS, full analysis set; HAQ-DI, Health Assessment Questionnaire-Disability Index; LSM, least squares mean; MCID, minimum clinically important difference; MCS, mental component summary; MTX, methotrexate; Pain, arthritis pain; PCS, physical component summary; PtGA, Patient Global Assessment of Disease Activity; PRO, patient-reported outcome; SE, standard error; SF-36, 36-Item Short-Form Health Survey; VAS, visual analogue scale.
Figure 2
Figure 2
Proportion of patients reporting improvements ≥MCID in (A) PtGA, (B) Pain, (C) HAQ-DI, (D) FACIT-F, (E) SF-36 PCS and (F) SF-36 MCS (FAS). MCID: ≥10 mm decrease from baseline in PtGA and Pain; ≥0.22-point decrease from baseline in HAQ-DI score; ≥2.5-point increase from baseline in SF-36 PCS and MCS scores; ≥4-point increase from baseline in FACIT-F score. *p†p<0.05 ADA+MTX versus tofacitinib monotherapy; ‡p<0.05 tofacitinib+MTX versus ADA+MTX; ‡‡p<0.01 tofacitinib+MTX versus ADA+MTX. ADA, adalimumab; BID, two times per day; FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; FAS full analysis set; HAQ-DI, Health Assessment Questionnaire-Disability Index; MCID, minimum clinically important difference; MCS, mental component summary; MTX, methotrexate; Pain, arthritis pain; PCS, physical component summary; PtGA, Patient Global Assessment of Disease Activity; SF-36, 36-Item Short-Form Health Survey.
Figure 3
Figure 3
The proportion of patients reporting (A) Pain scores †p<0.05 ADA+MTX versus tofacitinib monotherapy; ††p<0.01 ADA+MTX versus tofacitinib monotherapy. ADA, adalimumab; BID, two times per day; FAS, full analysis set; MTX, methotrexate; Pain, arthritis pain.
Figure 4
Figure 4
Spydergrams representing mean SF-36 domain scores over time for (A) tofacitinib 5 mg two times per day, (B) tofacitinib 5 mg two times per day+MTX and (C) ADA+MTX. The sample sizes indicated represent the number of patients who took the SF-36 at that visit. Some domains may have had one to two patients fail to respond. ADA, adalimumab; AG norms, age-matched and gender-matched norms; BID, two times per day; BP, Bodily Pain; GH, General Health; MH, Mental Health; MTX, methotrexate; PF, Physical Functioning; RE, Role Emotional; RP, Role Physical; SF, Social Functioning; SF-36, 36-Item Short-Form Health Survey; VT, Vitality.

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