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Abstract Number: 428

Significant Pain Reduction with Oral Methotrexate in Knee Osteoarthritis; Results from a Randomised Controlled Phase III Trial of Treatment Effectiveness

Sarah R. Kingsbury1, Puvan Tharmanathan2, Ada Keding2, Belen Corbacho2, Fiona E Watt3, David L Scott4, Edward Roddy5, Fraser Birrell6, Nigel K Arden7, Catherine Arundel2, Sarah Ronaldson2, Lema Vernon8, Catherine Hewitt2, Michael Doherty9, David Torgerson2 and Philip G. Conaghan1, 1Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and National Institute for Health Research (NIHR) Leeds Biomedical Research Centre, Leeds, United Kingdom, Leeds, United Kingdom, 2York Trials Unit, University of York, York, United Kingdom, 3Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom, 4Department of Rheumatology, King's College London, London, United Kingdom, 5Staffordshire and Stoke on Trent Partnership NHS Foundation Trust, Newcastle Under Lyme, United Kingdom, 6Northumbria Healthcare NHS Foundation Trust, North Shields, United Kingdom, 7Arthritis Research UK Centre for Sports, Exercise and Osteoarthritis, University of Oxford, Oxford, United Kingdom, 8Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom, 9The University of Nottingham, Nottingham, United Kingdom

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Knee, methotrexate (MTX), Osteoarthritis, randomized trials and therapy

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Session Information

Date: Sunday, October 21, 2018

Title: Osteoarthritis – Clinical Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Current treatments for osteoarthritis (OA) are severely limited. Synovitis is prevalent in OA and is associated with pain. The slow-acting anti-rheumatic drug methotrexate (MTX) is the gold-standard treatment for synovitis in inflammatory arthritides. The primary aim of the PROMOTE trial was to determine the effectiveness of MTX versus placebo as an analgesic treatment for knee OA. 

Methods: PROMOTE was a multi-centre, randomised, placebo-controlled trial with 12 months follow-up. Participants with symptomatic (visual analogue scale (VAS) pain ≥4/10) and radiographic tibiofemoral knee OA, fulfilling clinical ACR criteria, were recruited across UK primary and secondary care. Participants were randomized on a 1:1 basis to MTX or placebo, in addition to ongoing usual care, with dose escalation from 10mg to 25mg over 8 weeks and maintenance at 25mg (or the highest tolerated dose) for the remainder of the study. The primary endpoint was average knee pain during the previous week (numerical rating scale [0-10], NRS) at 6-months. Secondary endpoints included WOMAC, quality-of-life and adverse events. Linear mixed models compared outcomes between groups on an intention-to-treat (ITT) basis. In a sub-study, contrast-enhanced MRI of the index knee was performed at baseline and 6 months.

Results: Of 207 patients screened, 155 participants (64% women, mean age 60.9 years, 50% K-L Grade 3-4) were randomized. Primary endpoint data at 6 months were available for 134 patients (86%); only ITT data are presented. At 6 months, average knee pain (as measured by NRS) was 6.2 in the placebo group and 5.1 in the MTX group, with a baseline adjusted treatment difference of -0.83 points (95% CI -1.55 to -0.10; p=0.025), equivalent to a standard effect size of 0.36. Statistically significant differences at 6 months were seen for WOMAC stiffness and physical function, but not pain. Treatment benefits were reduced by 12 months. 94 patients had analysable MRI data at baseline and 80 at 6 months; no change in synovial volume was found. Four serious adverse events were reported (MTX: 2 [not defined as possibly related], placebo: 2).

Conclusion: MTX added to usual care demonstrated significant reduction in knee OA pain at 6 months, and suggests improvements in WOMAC stiffness and function. Despite a moderate standard effect size, the treatment effect was smaller than thresholds considered clinically meaningful. Further analyses will explore predictors of response to understand if subsets with enhanced response can be identified.

We acknowledge Arthritis Research UK for funding support.

 

 

Table 1: Selected PROMOTE outcomes at baseline and 6 months follow-up (primary endpoint)

    MTX Placebo Adjusted Difference at   6 months (95% CI) p-value
Month N Mean (SD) N Mean (SD)
Average Knee Pain NRS (0-10) M0 77 6.4 (1.78) 78 6.8 (1.62) -0.83 (-1.55 to -0.10) 0.025
M6 66 5.1 (2.32) 68 6.2 (2.30)
WOMAC Pain M0 77 10.5 (3.49) 78 11.7 (3.77) -0.95 (-2.17 to 0.27) 0.126
M6 66 8.1 (4.56) 68 9.9 (4.38)
WOMAC Stiffness M0 77 4.6 (1.57) 78 4.9 (1.97) -0.60 (-1.18 to -0.01) 0.045
M6 66 3.6 (1.80) 68 4.4 (2.05)
WOMAC Physical Function M0 76 35.4 (10.98) 78 37.0 (13.54) -5.01 (-8.74 to -1.29) 0.008
M6 66 26.4 (14.73) 68 32.5 (15.32)
EQ-5D Utility M0 77 0.57 (0.19) 78 0.48 (0.25) 0.0227 (-0.040 to 0.085) 0.476
M6 66 0.63 (0.21) 68 0.53 (0.27)
Height adjusted synovial volume M0 47 130 (106.8) 47 127 (115.8) 14.89 (-18.19 to 47.96) 0.373
M6 42 132 (115.8) 38 116 (108.8)

 


Disclosure: S. R. Kingsbury, None; P. Tharmanathan, None; A. Keding, None; B. Corbacho, None; F. E. Watt, None; D. L. Scott, None; E. Roddy, None; F. Birrell, None; N. K. Arden, Freshfields Bruckhaus Deringer, 5,Bioiberica; Merck, 2,Bioventus; Flexion; Regeneron, 9; C. Arundel, None; S. Ronaldson, None; L. Vernon, None; C. Hewitt, None; M. Doherty, None; D. Torgerson, None; P. G. Conaghan, Novartis, 5, 8,Pfizer, 5, 8,Centrexion; Flexion; Galapagos; GlaxoSmithKline; Medivir, 5.

To cite this abstract in AMA style:

Kingsbury SR, Tharmanathan P, Keding A, Corbacho B, Watt FE, Scott DL, Roddy E, Birrell F, Arden NK, Arundel C, Ronaldson S, Vernon L, Hewitt C, Doherty M, Torgerson D, Conaghan PG. Significant Pain Reduction with Oral Methotrexate in Knee Osteoarthritis; Results from a Randomised Controlled Phase III Trial of Treatment Effectiveness [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/significant-pain-reduction-with-oral-methotrexate-in-knee-osteoarthritis-results-from-a-randomised-controlled-phase-iii-trial-of-treatment-effectiveness/. Accessed .
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