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

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).

The effect of pregabalin or duloxetine on arthritis pain: a clinical and mechanistic study in people with hand osteoarthritis

“…Since this was a proof-of-concept analgesic endpoint study, we did not collect structural outcome data including joint damage progression changes by plain radiograph and synovitis by ultrasound, as described in other studies, 31 – 34 , 37 which could be addressed in future work. We also recognize that our study has been conducted in hand arthritis pain, whereas several large previous datasets have focused on knee OA, 35 – 37 and there may be some differences in pain characteristics including loading effects due to structural joint differences between the hand and knee.…”

Current research on pharmacologic and regenerative therapies for osteoarthritis

“…A pragmatic phase 3 RCT with anticipated 160 participants was also conducted by this group from 2014 to 2015. 86 , 87 Although the study was completed, the actual efficacy has not yet been determined, as no published data were provided from this study. 87 Another Egyptian group performed a randomized placebo-controlled trial with 144 patients to assess the efficacy of methotrexate in the treatment of symptomatic knee OA.…”

Use of disease-modifying anti-rheumatic drugs in the therapy of osteoarthritis

“…Kingsbury и соавт. [30] заявили о начале крупного многоцентрового рандомизированного плацебо-контролируемого одногодичного исследования PROMOTE. В него включали пациентов с ОА коленных суставов, подтвержденным рентгенологически, и недостаточным ответом на терапию или непереносимостью парацетамола, НПВП или опиоидов (n=160).…”