title: Does flare trial design affect the effect size of non-steroidal anti-inflammatory drugs in symptomatic osteoarthritis? A systematic review and meta-analysis.
abstract: OBJECTIVE
  It is thought that the clinical trial benefits of oral non-steroidal anti-inflammatory drugs (NSAIDs) may relate to flare designs. The aim of this study was to examine the difference in NSAID (including cyclooxygenase-2 (COX-2) inhibitors) response in osteoarthritis (OA) trials based on different designs.
  
  
  METHODS
  Systematic review was undertaken of the databases MEDLINE, EMBASE, AMED, CINAHL and the Cochrane library till February 2015. Randomised controlled trials assessing pain, function and/or stiffness following commencement of NSAIDs in flare and non-flare designs were eligible. Trials were assessed using the Cochrane Risk of Bias tool. Meta-analyses were conducted to assess the effect sizes (ES) of NSAIDs for OA with flare versus non-flare trial designs.
  
  
  RESULTS
  Fifty-seven studies including 33 263 participants assessing 26 NSAIDs were included. Twenty-two (39%) were flare design, 24 (42%) were non-flare designs, 11 (19%) were possible flare designs. On meta-analysis, there was no statistically significant difference in ES of NSAIDs versus placebo between flare and non-flare trial designs for absolute pain and function or stiffness at immediate-term (1 week), short-term (2-4 week) or longer-term (12-13 week) follow-up periods (p>0.05). However there was a lower ES for mean change in pain in flare and possible flare trials compared with non-flare trials at short-term follow-up (0.36 vs 0.69; p=0.05).
  
  
  CONCLUSIONS
  Contrary to previous understanding, flare trial designs do not result in an increased treatment effect for NSAIDs in people with OA compared with non-flare design. Whether flare design influences other outcomes such as joint effusion remains unknown.
authors.affiliation: Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, UK.
authors.forename: Toby O
authors.initials: TO
authors.lastname: Smith
authors.affiliation: Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Affiliated Hospital of University of Electronic Science and Technology, Sichuan, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Zou
authors.affiliation: Division of Rheumatology, Orthopaedics and Dermatology, University of Nottingham, Nottingham, UK.
authors.forename: Natasya
authors.initials: N
authors.lastname: Abdullah
authors.affiliation: Division of Rheumatology, Orthopaedics and Dermatology, University of Nottingham, Nottingham, UK.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds & NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds, UK.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Kingsbury
authors.affiliation: Division of Rheumatology, Orthopaedics and Dermatology, University of Nottingham, Nottingham, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Doherty
authors.affiliation: Faculty of Medicine & Health Sciences, University of Nottingham, Nottingham, UK.
authors.forename: Weiya
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds & NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds, UK.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Conaghan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000188:drug therapy*; D012107:Research Design; D016896:Treatment Outcome
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal
keywords: Health services research; NSAIDs; Osteoarthritis