Pain reduction with oral methotrexate in knee osteoarthritis, a pragmatic phase iii trial of treatment effectiveness (PROMOTE): study protocol for a randomized controlled trial.

Sarah R Kingsbury ,Michael Green,Terence W O’Neill,Catherine Hewitt,Fraser Birrell,Rod Hughes,Michael Doherty,Toby Garrood,Edward Roddy,Puvan Tharmanathan,Kim Cocks,Andrew J Grainger ,Robert J Moots ,David Scott ,David Torgerson ,M Batley ,N K Arden ,C Edwards ,Fiona E Watt ,Philip G Conaghan

doi:10.1186/s13063-015-0602-8

Abstract

BackgroundOsteoarthritis (OA) is the fastest growing cause of disability worldwide. Current treatments for OA are severely limited and a large proportion of people with OA live in constant, debilitating pain. There is therefore an urgent need for novel treatments to reduce pain. Synovitis is highly prevalent in OA and is associated with pain. In inflammatory arthritides such as rheumatoid arthritis, methotrexate (MTX) is the gold standard treatment for synovitis and has a well-known, acceptable toxicity profile. We propose that using MTX to treat patients with symptomatic knee OA will be a practical and safe treatment to reduce synovitis and, consequently, pain.Methods/DesignPain Reduction with Oral Methotrexate in knee Osteoarthritis, a pragmatic phase III trial of Treatment Effectiveness (PROMOTE) is an investigator-initiated, multi-centre, randomized, double-blind, pragmatic placebo-controlled trial. A total of 160 participants with symptomatic knee OA will be recruited across primary and secondary care sites in the United Kingdom and randomized on a 1:1 basis to active treatment or placebo, in addition to usual care, for 12 months. As is usual practice for MTX, dosing will be escalated over six weeks to 25 mg (or maximum tolerated dose) weekly for the remainder of the study. The primary endpoint is change in average knee pain during the past week (measured on an 11-point numerical rating scale) between baseline and six months. Secondary endpoints include other self-reported pain, function and quality-of-life measures. A health economics analysis will also be performed. A magnetic resonance imaging substudy will be conducted to provide an explanatory mechanism for associated symptom change by examining whether MTX reduces synovitis and whether this is related to symptom change. Linear and logistic regression will be used to compare changes between groups using univariable and multivariable modelling analyses. All analyses will be conducted on an intention-to-treat basis.DiscussionThe PROMOTE trial is designed to examine whether MTX is an effective analgesic treatment for OA. The MRI substudy will address the relationship between synovitis and symptom change. This will potentially provide a much needed new treatment for knee OA.Trial registrationCurrent Controlled Trials identifier: ISRCTN77854383 (registered: 25 October 2013).

Highlights

Osteoarthritis (OA) is the fastest growing cause of disability worldwide
Current treatments are aimed at providing symptomatic relief, recent studies suggest that the large majority of people with OA live in constant pain despite use of available therapies [10]
Because the typical OA patient is of advanced age with multiple comorbidities, many have contraindications to the use of traditional OA medications

Summary

Introduction

Osteoarthritis (OA) is the fastest growing cause of disability worldwide. We propose that using MTX to treat patients with symptomatic knee OA will be a practical and safe treatment to reduce synovitis and, pain. With a rapidly ageing population, osteoarthritis (OA) has become the fastest growing cause of disability worldwide [1,2]. Current treatments are aimed at providing symptomatic relief, recent studies suggest that the large majority of people with OA live in constant pain despite use of available therapies [10]. These therapies are associated with significant toxicities. There is a pressing need to identify alternative therapies for OA in order to tackle this increasing problem [11,12]

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