C Ma1,2, L Guizzetti2, R Panaccione1, R N Fedorak3, R K Pai2,4, C E Parker2, T M Nguyen2, R Khanna2,5, N Vande Casteele2,6, G D'Haens2,7, W J Sandborn2,6, B G Feagan2,5,8, V Jairath2,5,8. 1. Division of Gastroenterology and Hepatology, University of Calgary, Calgary, AB, Canada. 2. Robarts Clinical Trials, Western University, London, ON, Canada. 3. Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada. 4. Department of Pathology and Laboratory Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA. 5. Department of Medicine, Western University, London, ON, Canada. 6. Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. 7. Inflammatory Bowel Disease Centre, Academic Medical Centre, Amsterdam, The Netherlands. 8. Department of Epidemiology and Biostatistics, Western University, London, ON, Canada.
Abstract
BACKGROUND: Regulatory requirements for claims of mucosal healing in ulcerative colitis (UC) will require demonstration of both endoscopic and histologic healing. Quantifying these rates is essential for future drug development. AIMS: To meta-analyse endoscopic and histologic placebo response and remission rates in UC randomised controlled trials (RCTs) and identify factors influencing these rates. METHODS: MEDLINE, EMBASE and the Cochrane Library were searched from inception to March 2017 for placebo-controlled trials of pharmacological interventions for UC. Endoscopic and histologic placebo rates were pooled by random effects. Mixed effects univariable and multivariable meta-regression was used to evaluate the influence of patient, intervention and trial-related study-level covariates on these rates. RESULTS: Fifty-six induction (placebo n = 4171) and 8 maintenance trials (placebo n = 1011) were included. Pooled placebo endoscopic remission and response rates for induction trials were 23% [95 confidence interval (CI) 19-28%] and 35% [95% CI 27-42%] respectively, and 20% [95% CI 16-24%] for maintenance of remission. The pooled histologic placebo remission rate was 14% [95% CI 8-22%] for induction trials. High heterogeneity was observed for all outcomes (I2 56.2%-88.3%). On multivariable meta-regression, central endoscopy reading was associated with significantly lower endoscopic placebo remission rates (16% vs 25%; OR = 0.52, [95% CI 0.29-0.92], P = 0.03). On univariable meta-regression, higher histologic placebo remission was associated with concomitant corticosteroids (OR = 1.17 [95% CI 1.08-1.26], P < 0.0001, per 10% increase in corticosteroid use). CONCLUSIONS: Placebo endoscopic and histologic rates range from 14% to 35% in UC RCTs but are highly heterogeneous. Outcome standardisation may reduce heterogeneity and is needed in this field.
BACKGROUND: Regulatory requirements for claims of mucosal healing in ulcerative colitis (UC) will require demonstration of both endoscopic and histologic healing. Quantifying these rates is essential for future drug development. AIMS: To meta-analyse endoscopic and histologic placebo response and remission rates in UC randomised controlled trials (RCTs) and identify factors influencing these rates. METHODS: MEDLINE, EMBASE and the Cochrane Library were searched from inception to March 2017 for placebo-controlled trials of pharmacological interventions for UC. Endoscopic and histologic placebo rates were pooled by random effects. Mixed effects univariable and multivariable meta-regression was used to evaluate the influence of patient, intervention and trial-related study-level covariates on these rates. RESULTS: Fifty-six induction (placebo n = 4171) and 8 maintenance trials (placebo n = 1011) were included. Pooled placebo endoscopic remission and response rates for induction trials were 23% [95 confidence interval (CI) 19-28%] and 35% [95% CI 27-42%] respectively, and 20% [95% CI 16-24%] for maintenance of remission. The pooled histologic placebo remission rate was 14% [95% CI 8-22%] for induction trials. High heterogeneity was observed for all outcomes (I2 56.2%-88.3%). On multivariable meta-regression, central endoscopy reading was associated with significantly lower endoscopic placebo remission rates (16% vs 25%; OR = 0.52, [95% CI 0.29-0.92], P = 0.03). On univariable meta-regression, higher histologic placebo remission was associated with concomitant corticosteroids (OR = 1.17 [95% CI 1.08-1.26], P < 0.0001, per 10% increase in corticosteroid use). CONCLUSIONS: Placebo endoscopic and histologic rates range from 14% to 35% in UC RCTs but are highly heterogeneous. Outcome standardisation may reduce heterogeneity and is needed in this field.
Authors: Kelly C Cushing; William Tan; David H Alpers; Vikram Deshpande; Ashwin N Ananthakrishnan Journal: Aliment Pharmacol Ther Date: 2019-11-07 Impact factor: 8.171
Authors: Robert Battat; Parambir S Dulai; Christopher Ma; Vipul Jairath; Brian G Feagan; William J Sandborn; Reena Khanna Journal: Curr Treat Options Gastroenterol Date: 2020-01-04
Authors: Christopher Ma; Rocio Sedano; Ahmed Almradi; Niels Vande Casteele; Claire E Parker; Leonardo Guizzetti; David F Schaeffer; Robert H Riddell; Reetesh K Pai; Robert Battat; Bruce E Sands; Christophe Rosty; Marla C Dubinsky; Florian Rieder; Noam Harpaz; Maria T Abreu; Robert V Bryant; Gregory Y Lauwers; Richard Kirsch; Mark A Valasek; Eileen Crowley; William J Sandborn; Brian G Feagan; Rish K Pai; Vipul Jairath Journal: Gastroenterology Date: 2021-02-19 Impact factor: 22.682
Authors: HoUng Kim; Rieke Alten; Luisa Avedano; Axel Dignass; Fernando Gomollón; Kay Greveson; Jonas Halfvarson; Peter M Irving; Jørgen Jahnsen; Péter L Lakatos; JongHyuk Lee; Souzi Makri; Ben Parker; Laurent Peyrin-Biroulet; Stefan Schreiber; Steven Simoens; Rene Westhovens; Silvio Danese; Ji Hoon Jeong Journal: Drugs Date: 2020-02 Impact factor: 9.546