P492 A comparison of treatment effects for clinical, endoscopic and histological remission in ulcerative colitis clinical trials
Sedano, R.(1);Hogan, M.(2);Zou, G.(3);Narula, N.(4);Singh, S.(5);Ma, C.(6);Jairath, V.(7);
(1)Division of Gastroenterology- Department of Medicine- Western University- London- Ontario- Canada/Alimentiv Inc.- London- Ontario- Canada, Department of Medicine- Western University- London- Ontario- Canada, London, Canada;(2)Alimentiv Inc, n/a, London, Canada;(3)Alimentiv Inc., na, London, Canada;(4)Division of Gastroenterology- Department of Medicine Farncombe Family Digestive Health Research Institute- McMaster University- Hamilton- ON- Canada, Division of Gastroenterology- Department of Medicine, Hamilton, Canada;(5)Division of Gastroenterology- University of California San Diego- La Jolla- California- USA, Division of Gastroenterology, San Diego, United States;(6)Division of Gastroenterology & Hepatology- Departments of Medicine and Community Health Sciences- University of Calgary- Calgary- Alberta- Canada, Division of Gastroenterology & Hepatology- Departments of Medicine and Community Health Sciences-, Calgary, Canada;(7)Western University / Alimentiv Inc, Division of Gastroenterology- Department of Medicine- Department of Epidemiology and Biostatistics, London, Canada;
Background
Clinical remission, defined by the Mayo Clinic Score (MCS) or modified MCS, is the accepted regulatory endpoint in drug development for ulcerative colitis (UC). Whilst histologic remission is a more stringent outcome, recent trials have reported numerically higher rates compared to endoscopic or clinical remission rates at the same timepoint, suggesting that histologic remission may be a more sensitive endpoint for detecting treatment response
Methods
A systematic review was performed from inception to December 2020, including all placebo-controlled drug trials for adults with UC. Clinical, endoscopic, and histologic induction remission rates for active treatment and placebo arms were pooled on the logit scale using a random-effects model to account for both between- and within-study variability. Risk ratios (RR) and risk differences comparing the rate of remission in active treatment arms to the rate of remission in placebo arms were also pooled using a random-effects model.
Results
For induction trials, 15/84 reported clinical, endoscopic, and histologic remission rates at the same timepoint. Clinical remission was mostly defined as a MCS≤2 with no individual subscore>1 (10/15;66.6%), and endoscopic remission as MES=0 (6/15; 40%) or MES≤1 (9/15; 60%). Histologic remission was defined using Geboes score in 10/15(66.7%) trials, with a score≤1.0 in 4/10(40%), score=0 in 3/10(30%), and score<3.0 in 3/10(30%) trials. For placebo/active treatment arms, the pooled clinical, endoscopic, and histologic remission rates were 11.3%(95% CI 7.4–16.9%) /17.8%(95% CI 13.7–22.8%), 13.4%(95% CI 8.5–20.5%) /18.7% (95% CI 12.2–27.5%), and 18.2%(95% CI 13.8–23.6%) /27%(95% CI 20.6–34.7%), respectively(Figure 1). The differences in pooled clinical, endoscopic, and histologic remission rates between active treatment and placebo were 7.2%(95% CI 4.3%–10.1%), 6.6% (95% CI 2.5%–10.7%), and 8.4% (95% CI 4.3%–12.4%), respectively(Figure 2A), and the pooled RR comparing clinical, endoscopic, and histologic remission rates in the active treatment and placebo arms were 1.59 (95%CI 1.19–2.13), 1.49 (95%CI 1.16–1.90), and 1.47 (95%CI 1.20–1.81), respectively(Figure 2B)
Conclusion
Histologic remission has been proposed as a treatment target for patients with UC, given an association between this outcome and lower rates of clinical relapse.1 Although we found numerically higher pooled histologic remission rates for active treatment and placebo arms, compared to pooled clinical and endoscopic remission rates, we found no difference in the pooled RR for clinical, endoscopic, and histologic remission rates in the active treatment and placebo arms. Whilst histology has the potential to serve as a more efficient endpoint for drug development, more studies are needed.