Accessibility statement

PROMOTE – Placebo-controlled trial of methotrexate to treat painful knee osteoarthritis

We proposed that using methotrexate to treat patients with symptomatic knee osteoarthritis (OA) could be a practical and safe treatment to reduce synovitis and, consequently, pain. Despite a moderate standard effect size, the analgesic effect was of borderline clinical meaningfulness.

Why did we do this research?

Current treatments for OA are severely limited so there is an urgent need for novel treatments to reduce pain. Synovitis is highly prevalent in OA and is associated with pain. Methotrexate is the gold standard treatment for synovitis in other forms of arthritis. We proposed that using methotrexate to treat patients with symptomatic knee OA could be a practical and safe treatment to reduce synovitis and, consequently, pain.

What did we do?

We undertook a pragmatic randomised, double-blind trial of oral methotrexate compared to placebo for the reduction of pain in participants with knee OA. Participants were randomised on a 1:1 basis to methotrexate or placebo, in addition to ongoing usual care, with dose escalation over 8 weeks and a maintenance dose for the remainder of the study. The primary endpoint was average knee pain during the previous week at 6-months. Secondary endpoints included pain, quality-of-life and adverse events. 

Who was involved?

Participants with symptomatic (visual analogue scale pain 4/10) and radiographic tibiofemoral knee OA, fulfilling clinical radiology criteria, were recruited across UK primary and secondary care. 

What did we find?

Methotrexate added to usual care demonstrated significant reduction in knee OA pain at six months, and significant improvements in pain, stiffness and function. Despite a moderate standard effect size, the analgesic effect was of borderline clinical meaningfulness.

Outputs

  • Publications

Kingsbury SR, Tharmanathan P, Arden NK, et al. Pain reduction with oral methotrexate in knee osteoarthritis, a pragmatic phase iii trial of treatment effectiveness (PROMOTE): study protocol for a randomized controlled trial. Trials. 2015 Mar 4;16:77. https://doi.org/10.1186/s13063-015-0602-8  PMID: 25872649

  • Presentations

Kingsbury SR, Tharmanathan P, Keding A, et al. Significant pain reduction with oral methotrexate in knee osteoarthritis; results from the promote randomised controlled phase iii trial of treatment effectiveness. 2019 Osteoarthritis Research Society International (OARSI) World Congress in Toronto, Canada. Abstract. Volume 27, Supp 1, S84-S85, https://www.oarsijournal.com/issue/S1063-4584(19)X0004-7

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Team

Department of Health Sciences, University of York, York

 

  • Sarah R Kingsbury
  • Philip G Conaghan
  • Andrew J Grainger

Division of Rheumatic and Musculoskeletal Disease and National Institute of Health Research (NIHR) Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Leeds

 

  • Nigel K Arden

NIHR Musculoskeletal Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Nuffield Orthopaedic Centre, University of Oxford, Oxford

 

  • Michael Batley

Department of Rheumatology, Maidstone and Tunbridge Wells NHS Trust, Pembury, Tunbridge Wells, Kent

 

  • Fraser Birrell

Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle, UK

  • Michael Doherty

Academic Rheumatology, University of Nottingham, Nottingham

 

  • Chris J Edwards

Department of Rheumatology and NIHR Wellcome Trust Clinical Research Facility, University Hospital Southampton NHS Foundation Trust, Southampton

 

  • Toby Garrood

Guy’s and St Thomas’ Hospitals Foundation NHS Trust, London, 

 

  • Michael Green

York Hospitals NHS Foundation Trust, Wigginton Road, York, 

 

  • Rod Hughes

Rheumatology Department, St Peters Hospital, Guildford Road, Chertsey, Surrey, 

 

  • Robert Moots

Institute of Integrative Biology, University of Liverpool and Institute of Ageing and Chronic Disease, University Hospital Aintree, Liverpool

 

  • Terence W O’Neill

Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester

 

  • Edward Roddy

Research Institute for Primary Care and Health Sciences, Keele University, Keele

 

  • David L Scott

Department of Rheumatology, King’s College London School of Medicine, King’s College London and Department of Rheumatology, King’s College Hospital, London

 

  • Fiona E Watt 

Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, and Imperial College London, London

Funding

The research was funded by an Arthritis Research UK Clinical Studies Grant (reference number: 20186).  The project was started in October 2012 and completed in September 2016.

Study Registration

ISRCTN77854383 (registered: 25 October 2013).

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