title: Systematic Review and Meta-analysis: Placebo Rates in Induction and Maintenance Trials of Ulcerative Colitis.
abstract: OBJECTIVE
  Minimisation of the placebo responses in randomised controlled trials [RCTs] is essential for efficient evaluation of new interventions. Placebo rates have been high in ulcerative colitis [UC] clinical trials, and factors influencing this are poorly understood. We quantify placebo response and remission rates in UC RCTs and identify trial design factors influencing them.
  
  
  METHODS
  MEDLINE, EMBASE, and the Cochrane Library were searched from inception through April 2014 for placebo-controlled trials in adult patients with UC of a biological agent, corticosteroid, immunosuppressant, or aminosalicylate. Data were independently doubly extracted. Quality was assessed using the Cochrane risk of bias tool.
  
  
  RESULTS
  In all, 51 trials [48 induction and 10 maintenance phases] were identified. Placebo response and remission rates were pooled according to random-effects models, and mixed-effects meta-regression models were used to evaluate effects of study-level characteristics on these rates. Pooled estimates of placebo remission and response rates for induction trials were 10% (95% confidence interval [CI] 7-13%) and 33% [95% CI 29-37%], respectively. Corresponding values for maintenance trials were 19% [95% CI 11-30%] and 22% [95% CI 17-28%]. Trials enrolling patients with more active disease confirmed by endoscopy [endoscopy subscore ≥ 2] were associated with lower placebo rates. Conversely, placebo rates increased with increasing trial duration and number of study visits.
  
  
  CONCLUSIONS
  Objective assessment of greater disease activity at trial entry by endoscopy lowered placebo rates, whereas increasing trial duration and more interactions with healthcare providers increased placebo rates. These findings have important implications for design and conduct of clinical trials.
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, UK Robarts Research Institute, University of Western Ontario, London, ON, Canada Department of Medicine, University of Western Ontario, London, ON, Canada vipul.jairath@robartsinc.com.
authors.forename: Vipul
authors.initials: V
authors.lastname: Jairath
authors.affiliation: Robarts Research Institute, University of Western Ontario, London, ON, Canada Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada.
authors.forename: Guangyong
authors.initials: G
authors.lastname: Zou
authors.affiliation: Robarts Research Institute, University of Western Ontario, London, ON, Canada Department of Medicine, University of Western Ontario, London, ON, Canada.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Parker
authors.affiliation: Robarts Research Institute, University of Western Ontario, London, ON, Canada Department of Medicine, University of Western Ontario, London, ON, Canada.
authors.forename: John K
authors.initials: JK
authors.lastname: Macdonald
authors.affiliation: Robarts Research Institute, University of Western Ontario, London, ON, Canada Department of Medicine, University of Western Ontario, London, ON, Canada Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Mahmoud H
authors.initials: MH
authors.lastname: Mosli
authors.affiliation: Robarts Research Institute, University of Western Ontario, London, ON, Canada Department of Medicine, University of Western Ontario, London, ON, Canada.
authors.forename: Reena
authors.initials: R
authors.lastname: Khanna
authors.affiliation: Robarts Research Institute, University of Western Ontario, London, ON, Canada.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Shackelton
authors.affiliation: Robarts Research Institute, University of Western Ontario, London, ON, Canada.
authors.forename: Margaret K
authors.initials: MK
authors.lastname: Vandervoort
authors.affiliation: Department of Medicine, King Fahad Specialist Hospital-Dammam, Dammam, Saudi Arabia.
authors.forename: Turki
authors.initials: T
authors.lastname: AlAmeel
authors.affiliation: Department of Medicine, King Fahad Specialist Hospital-Dammam, Dammam, Saudi Arabia.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Al Beshir
authors.affiliation: Division of Gastroenterology, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Majid
authors.initials: M
authors.lastname: AlMadi
authors.affiliation: Haya Al-Habeeb Gastroenterology Center, Mubarak Al-Kabeer Hospital, Jabriya, Kuwait.
authors.forename: Talal
authors.initials: T
authors.lastname: Al-Taweel
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, UK.
authors.forename: Nathan S S
authors.initials: NS
authors.lastname: Atkinson
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, UK.
authors.forename: Sujata
authors.initials: S
authors.lastname: Biswas
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, UK.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Chapman
authors.affiliation: Robarts Research Institute, University of Western Ontario, London, ON, Canada Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA.
authors.forename: Parambir S
authors.initials: PS
authors.lastname: Dulai
authors.affiliation: Division of Medical Sciences, University of Oxford, Oxford, UK.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Glaire
authors.affiliation: Department of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hoekman
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, UK.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koutsoumpas
authors.affiliation: Department of Geratology, Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Minas
authors.affiliation: Department of Gastroenterology, Guy's and St Thomas' Hospital NHS Trust, London, UK.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Samaan
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Travis
authors.affiliation: Robarts Research Institute, University of Western Ontario, London, ON, Canada Department of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Geert
authors.initials: G
authors.lastname: D'Haens
authors.affiliation: Robarts Research Institute, University of Western Ontario, London, ON, Canada Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA.
authors.forename: Barrett G
authors.initials: BG
authors.lastname: Levesque
authors.affiliation: Robarts Research Institute, University of Western Ontario, London, ON, Canada Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Sandborn
authors.affiliation: Robarts Research Institute, University of Western Ontario, London, ON, Canada Department of Medicine, University of Western Ontario, London, ON, Canada Department of Medicine, University of Western Ontario, London, ON, Canada.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Feagan
mesh_terms: D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D003093:Colitis, Ulcerative / Q000188:drug therapy*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D060828:Induction Chemotherapy; D060046:Maintenance Chemotherapy; D015233:Models, Statistical; D015990:Placebo Effect; D016032:Randomized Controlled Trials as Topic; D012107:Research Design; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents
keywords: DAI; Disease Activity Index; MCS; Mayo Clinic Score; RCT; UC; randomised controlled trial; ulcerative colitis