A237 IMPROVEMENT IN ABDOMINAL SYMPTOMS WITH LINACLOTIDE IN PATIENTS WITH IRRITABLE BOWEL SYNDROME WITH CONSTIPATION: RESULTS FROM A PHASE 3B TRIAL

Background Linaclotide (LIN) is a guanylate cyclase-C agonist approved to treat irritable bowel syndrome with constipation (IBS-C) in adults. Abdominal symptoms are important to patients with IBS-C. In a recent Phase 3b study, LIN significantly improved a composite score of abdominal bloating, pain, and discomfort (Abdominal Score), which was used as the primary endpoint in the study. Aims To evaluate the efficacy of LIN for improving additional efficacy abdominal symptom endpoints in a randomized, double-blind, placebo (PBO)-controlled Phase 3 study of LIN in patients with IBS-C. Methods Adults with IBS-C were randomized to PBO (N=308) or LIN 290 μg (N=306) once daily for 12 weeks. Patients recorded their daily abdominal symptoms, including the individual items of bloating, pain, and discomfort, using an 11-point scale (0–10; 0=none, 10=worst possible). The primary endpoint was the Abdominal Score. Additional efficacy endpoints included 6/12-week abdominal pain and constipation (APC)+1 responder, 6/12-week abdominal bloating responder, 6/12-week abdominal pain responder, and 6/12-week abdominal discomfort responder. For individual symptoms, a responder was a patient who had an improvement from baseline of ≥2 points in the respective endpoint for ≥6 of the 12 weeks. Changes from baseline (CFB) over 12 weeks in abdominal bloating, pain, and discomfort were evaluated using a mixed model with repeated measures framework. Proportions of responders were compared between groups for each responder endpoint using a Cochran-Mantel-Haenszel test. Results 614 patients (mean age, 46.7 years; 81% female; similar baseline abdominal symptoms) were randomized. LIN-treated patients had greater least-squares mean (LSM) CFB in abdominal bloating (LSM difference [95% CI]: –0.889 [–1.249, –0.530], p<0.001), pain (–0.881 [–1.238, –0.524], p<0.001), and discomfort (–0.837 [–1.196, –0.478], p<0.001) compared to PBO-treated patients. There was a greater proportion of LIN-treated vs. PBO-treated patients who were 6/12-week APC+1 (29% vs. 17%; p=0.0003), bloating (40% vs. 24%; p<0.001), pain (42% vs. 25%; p<0.001), and discomfort (42% vs. 26%; p<0.001) responders (Figure). Diarrhea was the most common treatment-emergent adverse event (LIN: 4.6%; PBO: 1.6%). Conclusions LIN significantly improved multiple abdominal symptom and secondary responder endpoints in patients with IBS-C. These results support the effectiveness of LIN for improving a spectrum of abdominal symptoms in IBS-C. Funding Agencies This study was sponsored by Allergan plc, Dublin, Ireland (prior to acquisition by AbbVie Inc.). Writing and editorial assistance were provided to the authors by Brittany Y. Jarrett, PhD, Jane Beck, MA, and Rebecca Fletcher, BA(Hons) of Complete HealthVizion, Inc., Chicago, IL, USA and funded by Allergan plc (prior to acquisition by AbbVie Inc.).

Timeliness of Presentation and Referral Among Cancer Patients Who Presented With Abdominal Symptoms: Evidence to Inform Symptom Awareness Campaigns

Background: Abdominal symptoms at presentation are common among patients subsequently diagnosed with cancer. While public health education campaigns in England and other countries have traditionally focused on 'red flag' symptoms associated with a single common cancer (e.g., 'blood in poo' and colorectal cancer), there is increasing interest in raising awareness of symptoms grouped by body area or system (eg 'abdominal symptoms'). Evidence regarding the frequency and nature of abdominal symptoms at presentation among a representative cancer patient cohort could inform the design and evaluation of community based cancer symptom awareness campaigns. Aim: To describe the frequency of abdominal symptoms at presentation among an incident cohort of cancer patients, examine variation in diagnostic timeliness and subsequently diagnosed cancer sites by abdominal symptom. Methods: The presenting symptom(s) of 15,956 cancer patients from a national audit of primary care records in England was coded into symptom categories. Eight abdominal symptoms with a range of predictive values and specificity for cancer were studied: abdominal pain, change in bowel habit, bloating/distension, dyspepsia, rectal bleeding, dysphagia, reflux, and nausea/vomiting. We investigated the prevalence of abdominal symptoms among the cancer patient population, examined variation in the length of the patient interval (time from symptom onset to presentation to primary care) and primary care interval (time from presentation to specialist referral) by symptom, and described the associated spectrum of diagnosed cancer sites for each individual symptom. Results: Almost a quarter (23%) of the incident cancer patient population had abdominal symptom(s) at presentation (n=3,661/15,956). The relative lengths of the patient and primary care intervals varied greatly by abdominal symptom. One in two cancer patients who had dysphagia before diagnosis presented 30 days after symptom onset (median (IQR) patient interval: 30 (10-61) days), but were referred immediately (median (IQR) primary care interval: 0 (0-14) days). In comparison, cancer patients who presented with abdominal pain had longer intervals postpresentation (median (IQR) patient interval: 7 (0-28) days, median (IQR) primary care interval: 16 (2-43) days). The majority (88.6%) of cancer patients who presented with an abdominal symptom were diagnosed with an abdominal or adjacent cancer, including colorectal, esophageal, ovarian, and pancreatic cancers. However, the remainder of patients were diagnosed with solid tumors of nonabdominal organ origin (7.6%) or a hematologic cancer (3.8%). Conclusion: Cancer symptom awareness campaigns focusing on abdominal symptoms could contribute to the earlier diagnosis of numerous common and rarer cancers. Evidence regarding the relative lengths of the patient and primary care intervals could be used as a measure of relative need for raising awareness.