Comparison of adequate relief with symptom, global, and responder endpoints in linaclotide phase 3 trials in IBS-C

Abstract

Background: Optimal clinical trial endpoints for irritable bowel syndrome with constipation (IBS-C) are uncertain.

Objective: The objective of this article is to compare adequate relief (AR) to abdominal/bowel symptoms, global endpoints, and FDA and EMA responder criteria; and to use AR as an anchor to assess clinically meaningful change (CMC) in IBS-C symptoms.

Methods: Using pooled 12-week data from two phase 3 linaclotide clinical trials, daily abdominal/bowel symptoms and weekly global assessments were correlated with AR. Symptom CMC thresholds were estimated using AR as an anchor. Agreement between AR and FDA/EMA responder criteria was assessed.

Results: Correlations of AR with percentage change in abdominal symptoms, bowel symptoms, and global endpoints ranged from 0.48-0.54, 0.32-0.39, and 0.61-0.71, respectively. Using AR as an anchor, CMC thresholds were 29% improvement in abdominal pain, 29% improvement in abdominal discomfort, and 0.7/week increase in CSBMs, similar to thresholds for IBS-C responder endpoints recommended by the FDA and EMA. There was considerable agreement of weekly responder rates between AR and the FDA and EMA endpoints (on average, 70%-76% and 71%-82% of weeks with agreement, respectively).

Conclusions: AR bridges IBS-C clinical trials, putting into perspective the disparate primary endpoints recommended by professional societies and regulatory authorities, and allowing researchers, practitioners, and regulators to compare trial results.

Keywords: GC-C; IBS-C; Linaclotide; adequate relief; clinically meaningful change; responder endpoints.

Figures

Figure 1.

Within-patient agreement between weekly adequate relief and weekly FDA responder criteria. Pooled phase 3 IBS-C ITT population, Weeks 1–12. ****p < 0.0001 for linaclotide vs placebo; p values were obtained from an ANOVA model with treatment group, geographic region, and trial as factors. Agreement (average % of weeks with AR and FDA weekly responder + no AR and not FDA weekly responder) = 70.2% for linaclotide and 76.4% for placebo; average % of weeks with AR and not FDA weekly responder = 24.0% for linaclotide and 18.2% for placebo; average % of weeks no AR and FDA weekly responder = 5.7% for linaclotide and 5.5% for placebo. FDA: Food and Drug Administration; IBS-C: irritable bowel syndrome with constipation; ITT: intent to treat; ANOVA: analysis of variance; AR: adequate relief.

Figure 2.

Within-patient agreement between weekly adequate relief and weekly EMA responder criteria. (a) Weekly abdominal pain/abdominal discomfort responder. Pooled phase 3 IBS-C ITT population, Weeks 1–12. ****p < 0.0001 for linaclotide vs placebo; p values were obtained from an ANOVA model with treatment group, geographic region, and trial as factors. Agreement (average % of weeks with AR and abdominal pain/discomfort weekly responder + no AR and not abdominal pain/discomfort weekly responder) = 71.8% for linaclotide and 71.2% for placebo; average % of weeks with AR and not abdominal pain/discomfort weekly responder = 13.9% for linaclotide and 10.0% for placebo; average % of weeks no AR and abdominal pain/discomfort weekly responder = 14.3% for linaclotide and 18.7% for placebo. (b) Weekly IBS degree of relief responder. Pooled phase 3 IBS-C ITT population, Weeks 1–12. ****p < 0.0001 for linaclotide vs placebo; p values were obtained from an ANOVA model with treatment group, geographic region, and trial as factors. Agreement (average % of weeks with AR and IBS degree of relief weekly responder + no AR and not IBS degree of relief weekly responder) = 79.8% for linaclotide and 81.5% for placebo; average % of weeks with AR and not IBS degree of relief weekly responder = 17.5% for linaclotide and 16.0% for placebo; average % of weeks no AR and IBS degree of relief weekly responder = 2.7% for linaclotide and 2.4% for placebo. EMA: European Medicines Agency; IBS-C: irritable bowel syndrome with constipation; ITT: intent to treat; ANOVA: analysis of variance; AR: adequate relief.