Systematic Review and Meta-analysis: Placebo Rates in Induction and Maintenance Trials of Ulcerative Colitis

Vipul Jairath; Guangyong Zou; Claire E Parker; John K Macdonald; Mahmoud H Mosli; Reena Khanna; Lisa M Shackelton; Margaret K Vandervoort; Turki AlAmeel; Mohammad Al Beshir; Majid AlMadi; Talal Al-Taweel; Nathan S S Atkinson; Sujata Biswas; Thomas P Chapman; Parambir S Dulai; Mark A Glaire; Daniel Hoekman; Andreas Koutsoumpas; Elizabeth Minas; Mark A Samaan; Simon Travis; Geert D'Haens; Barrett G Levesque; William J Sandborn; Brian G Feagan

doi:10.1093/ecco-jcc/jjw004

Systematic Review and Meta-analysis: Placebo Rates in Induction and Maintenance Trials of Ulcerative Colitis

J Crohns Colitis. 2016 May;10(5):607-18. doi: 10.1093/ecco-jcc/jjw004. Epub 2016 Jan 7.

Authors

Vipul Jairath¹, Guangyong Zou², Claire E Parker³, John K Macdonald³, Mahmoud H Mosli⁴, Reena Khanna³, Lisa M Shackelton⁵, Margaret K Vandervoort⁵, Turki AlAmeel⁶, Mohammad Al Beshir⁶, Majid AlMadi⁷, Talal Al-Taweel⁸, Nathan S S Atkinson⁹, Sujata Biswas⁹, Thomas P Chapman⁹, Parambir S Dulai¹⁰, Mark A Glaire¹¹, Daniel Hoekman¹², Andreas Koutsoumpas⁹, Elizabeth Minas¹³, Mark A Samaan¹⁴, Simon Travis⁹, Geert D'Haens¹⁵, Barrett G Levesque¹⁰, William J Sandborn¹⁰, Brian G Feagan¹⁶

Affiliations

¹ 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.
² Robarts Research Institute, University of Western Ontario, London, ON, Canada Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada.
³ Robarts Research Institute, University of Western Ontario, London, ON, Canada Department of Medicine, University of Western Ontario, London, ON, Canada.
⁴ 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.
⁵ Robarts Research Institute, University of Western Ontario, London, ON, Canada.
⁶ Department of Medicine, King Fahad Specialist Hospital-Dammam, Dammam, Saudi Arabia.
⁷ Division of Gastroenterology, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia.
⁸ Haya Al-Habeeb Gastroenterology Center, Mubarak Al-Kabeer Hospital, Jabriya, Kuwait.
⁹ Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, UK.
¹⁰ Robarts Research Institute, University of Western Ontario, London, ON, Canada Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA.
¹¹ Division of Medical Sciences, University of Oxford, Oxford, UK.
¹² Department of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands.
¹³ Department of Geratology, Oxford University Hospitals NHS Trust, Oxford, UK.
¹⁴ Department of Gastroenterology, Guy's and St Thomas' Hospital NHS Trust, London, UK.
¹⁵ Robarts Research Institute, University of Western Ontario, London, ON, Canada Department of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands.
¹⁶ 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.

Abstract

Background and aims: 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.

Keywords: DAI; Disease Activity Index; MCS; Mayo Clinic Score; RCT; UC; randomised controlled trial; ulcerative colitis.

Publication types

Meta-Analysis
Review
Systematic Review

MeSH terms

Anti-Inflammatory Agents / therapeutic use*
Colitis, Ulcerative / drug therapy*
Humans
Immunosuppressive Agents / therapeutic use*
Induction Chemotherapy*
Maintenance Chemotherapy*
Models, Statistical
Placebo Effect*
Randomized Controlled Trials as Topic
Research Design
Treatment Outcome

Substances

Anti-Inflammatory Agents
Immunosuppressive Agents

Grants and funding

T32 DK007202/DK/NIDDK NIH HHS/United States