title: 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: BACKGROUND
  Osteoarthritis (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
  Pain 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.
  
  
  CONCLUSIONS
  The 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.
  
  
  BACKGROUND
  Current Controlled Trials identifier: ISRCTN77854383 (registered: 25 October 2013).
authors: Leeds Institute of Rheumatic and Musculoskeletal Medicine and National Institute of Health Research (NIHR) Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Chapeltown Road, Leeds, LS7 4SA, UK. s.r.kingsbury@leeds.ac.uk.
authors: Sarah R
authors: SR
authors: Kingsbury
authors: York Trials Unit, Department of Health Sciences, Faculty of Science, Seebohm Rowntree Building, University of York, Heslington, York, YO10 5DD, UK. puvan.nathan@york.ac.uk.
authors: Puvan
authors: P
authors: Tharmanathan
authors: NIHR Musculoskeletal Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Nuffield Orthopaedic Centre, University of Oxford, Windmill Road, Headington, Oxford, OX3 7LD, UK. nigel.arden@ndorms.ox.ac.uk.
authors: Nigel K
authors: NK
authors: Arden
authors: Department of Rheumatology, Maidstone and Tunbridge Wells NHS Trust, Pembury, Tunbridge Wells, Kent, TN2 4QJ, UK. mbatley@nhs.net.
authors: Michael
authors: M
authors: Batley
authors: Musculoskeletal Research Group, Institute for Cellular Medicine, Newcastle University, Musculoskeletal Research Group, 4th Floor Catherine Cookson Building, The Medical School, Framlington Place, Newcastle University, Newcastle, NE2 4HH, UK. Fraser.Birrell@newcastle.ac.uk.
authors: Fraser
authors: F
authors: Birrell
authors: York Trials Unit, Department of Health Sciences, Faculty of Science, Seebohm Rowntree Building, University of York, Heslington, York, YO10 5DD, UK. kim.cocks@york.ac.uk.
authors: Kim
authors: K
authors: Cocks
authors: Academic Rheumatology, Clinical Sciences Building, University of Nottingham, Nottingham City Hospital, Hucknall Road, Nottingham, NG5 1 PB, UK. Michael.doherty@nottingham.ac.uk.
authors: Michael
authors: M
authors: Doherty
authors: Department of Rheumatology and NIHR Wellcome Trust Clinical Research Facility, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK. cedwards@soton.ac.uk.
authors: Chris J
authors: CJ
authors: Edwards
authors: Guy's and St Thomas' Hospitals Foundation NHS Trust, Great Maze Pond, London, SE1 9RT, UK. toby.garrood@gstt.nhs.uk.
authors: Toby
authors: T
authors: Garrood
authors: Leeds Institute of Rheumatic and Musculoskeletal Medicine and National Institute of Health Research (NIHR) Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Chapeltown Road, Leeds, LS7 4SA, UK. andrewgrainger@nhs.net.
authors: Andrew J
authors: AJ
authors: Grainger
authors: The York Hospital, York Hospitals NHS Foundation Trust, Wigginton Road, York, YO31 8HE, UK. Michael.Green@york.nhs.uk.
authors: Michael
authors: M
authors: Green
authors: York Trials Unit, Department of Health Sciences, Faculty of Science, Seebohm Rowntree Building, University of York, Heslington, York, YO10 5DD, UK. catherine.hewitt@york.ac.uk.
authors: Catherine
authors: C
authors: Hewitt
authors: Rheumatology Department, St Peters Hospital, Guildford Road, Chertsey, Surrey, KT16 0PZ, UK. Rod.Hughes@asph.nhs.uk.
authors: Rod
authors: R
authors: Hughes
authors: Institute of Integrative Biology, University of Liverpool and Institute of Ageing and Chronic Disease, University Hospital Aintree, Longmoor Lane, Fazakerley, Liverpool, Merseyside, L9 7AL, UK. R.J.Moots@liverpool.ac.uk.
authors: Robert
authors: R
authors: Moots
authors: Arthritis Research UK Centre for Epidemiology, The University of Manchester, 2nd floor, Stopford Building, Oxford Road, Manchester, M13 9PT, UK. terence.oneill@manchester.ac.uk.
authors: Terence W
authors: TW
authors: O'Neill
authors: Research Institute for Primary Care and Health Sciences, Keele University, Keele, Staffordshire, ST5 5BG, UK. e.roddy@keele.ac.uk.
authors: Edward
authors: E
authors: Roddy
authors: Department of Rheumatology, King's College London School of Medicine, King's College London and Department of Rheumatology, King's College Hospital, 10 Cutcombe Road, London SE5 9RJ, London, UK. d.scott1@nhs.net.
authors: David L
authors: DL
authors: Scott
authors: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Windmill Road, Oxford, OX3 7HE, UK and Imperial College London, South Kensington Campus, London, SW7 2AZ, UK. fiona.watt@kennedy.ox.ac.uk.
authors: Fiona E
authors: FE
authors: Watt
authors: York Trials Unit, Department of Health Sciences, Faculty of Science, Seebohm Rowntree Building, University of York, Heslington, York, YO10 5DD, UK. david.torgerson@york.ac.uk.
authors: David J
authors: DJ
authors: Torgerson
authors: Leeds Institute of Rheumatic and Musculoskeletal Medicine and National Institute of Health Research (NIHR) Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Chapeltown Road, Leeds, LS7 4SA, UK. p.conaghan@leeds.ac.uk.
authors: Philip G
authors: PG
authors: Conaghan
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage* / Q000009:adverse effects; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000009:adverse effects; D018771:Arthralgia / Q000175:diagnosis / Q000188:drug therapy*; D002985:Clinical Protocols; D004311:Double-Blind Method; D006801:Humans; D057194:Intention to Treat Analysis; D016014:Linear Models; D016015:Logistic Models; D008279:Magnetic Resonance Imaging; D008727:Methotrexate / Q000008:administration & dosage* / Q000009:adverse effects; D015999:Multivariate Analysis; D020370:Osteoarthritis, Knee / Q000175:diagnosis / Q000188:drug therapy*; D010147:Pain Measurement; D012107:Research Design; D013585:Synovitis / Q000175:diagnosis / Q000188:drug therapy*; D013997:Time Factors; D016896:Treatment Outcome; D006113:United Kingdom
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D008727:Methotrexate