S1215 Linaclotide’s Time to Response for Chronic Idiopathic Constipation Symptom Relief: A Post Hoc Analysis of Randomized Controlled Studies

Introduction: Linaclotide (LIN) is United States Food and Drug Administration-approved to treat chronic idiopathic constipation (CIC) in adults. The efficacy of LIN for relieving bowel and abdominal CIC symptoms is established, but data on the timing of symptom relief are limited. This post hoc analysis examined the time to response for key symptoms of CIC in patients receiving LIN. Methods: Data were pooled from four Phase 3 randomized studies (NCT00730015, NCT00765882, NCT01642914, NCT02291679) of adults with CIC who received LIN 72 µg, LIN 145 µg or placebo (PBO). All studies enrolled patients meeting modified Rome II/III criteria for CIC. Kaplan–Meier analyses assessed time to event (symptom relief) over 12 weeks. Bowel symptom relief was measured by complete spontaneous bowel movement (CSBM) response, defined as achieving ≥3 CSBMs/week, and first spontaneous bowel movement (SBM) after the initial treatment dose. Abdominal symptom relief was defined as a ≥30% improvement from baseline in weekly average score. Results: Overall, 2400 patients were included: LIN 72 µg, n = 411, mean age: 45.8 years, female: 75.9%; LIN 145 µg, n = 994, 47.5 years, 84.3%; PBO, n = 995, 46.7 years, 85.4%. Median (95% CI) time to achieving ≥3 CSBMs/week was 11 (8, 12) and 5 (4, 6) weeks for patients treated with LIN 72 µg and 145 µg, respectively (not reached [NR] for PBO). Median time to first SBM after initial dose of LIN (72 µg or 145 µg) was 2 days vs 3 days with PBO. For abdominal symptoms, median time to response with LIN 72 µg and 145 µg, respectively, was NR and 8 weeks (pain), and 12 and 7 weeks (discomfort and bloating); all responses were NR for PBO. Based on median response times for each dose, patients were classified as ‘early’ (≤median), ‘late’ (>median) and ‘non’ (NR by 12 weeks) responders. CSBM and abdominal symptom responders were cross tabulated to explore response patterns. Patients were most often both early CSBM responders and early abdominal symptom responders. A lack of improvement in one symptom did not rule out a response for the other. Conclusion: Compared with PBO, LIN reduced the median time to bowel symptom relief in adults with CIC; for the LIN 145 µg dose, most patients had CSBM improvements within 5 weeks. Further, time to relief of abdominal bloating and discomfort, common CIC symptoms, were improved with both LIN doses. These results reinforce the therapeutic value of LIN in addressing multifaceted symptom burden of CIC. Future research could explore the characteristics of early, late and nonresponders.