Linaclotide Reduced Response Time for Irritable Bowel Syndrome With Constipation Symptoms: Analysis of 4 Randomized Controlled Trials.

INTRODUCTION: These post hoc analyses provide clinically relevant data concerning time to response for individual irritable bowel syndrome with constipation (IBS-C) symptoms after linaclotide use. METHODS: Time-to-response data were pooled from 4 randomized controlled trials. Response time for abdominal symptoms (pain, discomfort, and bloating) and complete spontaneous bowel movements (CSBMs) were analyzed using the Kaplan-Meier method; patients were categorized as early responders (≤4 weeks), late responders (>4-12 weeks), or nonresponders. RESULTS: Among 2,350 patients (1,172 placebo and 1,178 linaclotide 290 µg), >50% of patients with IBS-C who initiated linaclotide treatment experienced a decrease of ≥30% in abdominal pain, discomfort, or bloating within 3-4 weeks (median). The median time to achieving ≥3 CSBMs was 4 weeks. Although not all linaclotide-treated patients responded within 12 weeks, a late response occurred between 4 and 12 weeks in 1 in 6 patients for abdominal pain and in approximately 1 in 10 patients for CSBM frequency. Comparisons of early responders, late responders, and nonresponders for both response definitions indicated that women, Whites, and patients with less severe baseline abdominal symptoms were more likely to respond early. DISCUSSION: Although treatment responses with linaclotide occurred in >50% of patients with IBS-C within 4 weeks of treatment initiation, benefits for individual abdominal symptoms and/or CSBM frequency can still occur between 4 and 12 weeks. A lack of improvement in one symptom does not negate the possibility of response for others, highlighting the importance of discussing all symptoms with patients and not assuming treatment futility at 4 weeks.

The spectrum of constipation-predominant irritable bowel syndrome and chronic idiopathic constipation: US survey assessing symptoms, care seeking, and disease burden.

INTRODUCTION: The irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) are associated with substantial symptom and disease burden. Although typically classified as distinct diseases, symptoms frequently overlap. AIM: The objective of this study was to characterize symptom and disease burden in IBS-C and CIC sufferers and examine a subset of CIC sufferers with abdominal symptoms. METHODS: In a US population-based survey, respondents meeting the Rome III criteria for IBS-C or CIC rated symptom frequency and bothersomeness, missed work and disrupted productivity, and degree of obtaining and satisfaction with physician care. CIC respondents were analyzed in two subgroups: those with abdominal symptoms ≥once weekly (CIC-A) and those without (CIC-NA). RESULTS: Of the 10,030 respondents, 328 met the criteria for IBS-C and 552 for CIC (363 CIC-A; 189 CIC-NA). All symptoms were significantly more frequent in IBS-C vs. CIC respondents (P<0.0001). Constipation was extremely/very bothersome in 72% of IBS-C respondents, 62% of CIC-A, and 40% of CIC-NA (P<0.01 all pairs). All 11 other measured symptoms were significantly more bothersome in IBS-C and CIC-A vs. CIC-NA respondents. In IBS-C vs. CIC-A, abdominal discomfort, bloating, straining, and pellet-like stools were also significantly more bothersome, with other remaining symptoms similar. Gastrointestinal symptoms disrupted productivity a mean of 4.9 days per month in IBS-C respondents, 3.2 in CIC-A, and 1.2 in CIC-NA (P<0.001 all pairs); missed days were similar in IBS-C and CIC-A respondents. CONCLUSION: CIC respondents with abdominal symptoms experience greater disease burden compared with CIC respondents without frequent abdominal symptoms and have a disease burden profile that is similar to IBS-C respondents.

Analysis of hereditary angioedema attacks requiring a second dose of ecallantide.

BACKGROUND: Effective treatment of acute attacks is critical in managing hereditary angioedema (HAE). Ecallantide, a plasma kallikrein inhibitor, is approved for the treatment of HAE attacks. Occasionally, a second dose is needed when treating attacks of HAE. OBJECTIVE: To evaluate the characteristics of HAE attacks requiring a second dose (dose B) of ecallantide. METHODS: Data from all ecallantide clinical trials (EDEMA2, EDEMA4, and DX-88/19) that allowed an open-label dose B were included in this analysis. Patient and attack characteristics potentially predictive of dose B after ecallantide were analyzed by logistic regression. A multivariate model was built using a backward selection process, incorporating variables from the univariate model with P < .20 and removing factors with the highest P value until only significant (P < .05) factors remained. RESULTS: The analysis included 732 ecallantide-treated HAE attacks in 179 patients. Dose B was required in 88 attacks (12.0%), most (80.5%) for incomplete response. By attack location, 31 of 325 abdominal attacks (9.5%), 17 of 158 laryngeal attacks (10.8%), and 40 of 242 peripheral attacks (16.5%) required dose B. On the basis of the univariate analysis, baseline severity (odds ratio = 1.33, P = .15) and peripheral attack (odds ratio = 1.80, P = .01) were identified as potential predictive factors; abdominal attacks had an inverse correlation (odds ratio = 0.64, P = .055). However, the multivariate analysis identified only peripheral attacks as statistically significantly correlated (P < .05) with dose B requirement. CONCLUSION: A single, 30-mg dose of ecallantide was effective for most HAE attacks (88.0%). Patients with peripheral attacks of HAE were more likely to require a second dose of ecallantide after 4 hours. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: not applicable for EDEMA2 (trial was conducted before registration requirements were implemented), NCT00457015 for EDEMA4, and NCT00456508 for DX-88/19.

Lessons learned: Chronic idiopathic constipation patient experiences with over-the-counter medications.

INTRODUCTION: Chronic idiopathic constipation (CIC) is a prevalent functional gastrointestinal disorder diagnosed based on patient-reported symptoms and the absence of structural gastrointestinal abnormalities. Individuals with CIC typically institute dietary changes and use stool softeners or over-the-counter (OTC) laxatives, possibly at the direction of a healthcare provider, before prescription medications for CIC are initiated. Although highly prevalent, there is limited information regarding CIC patient experiences with OTC medications. METHODS: This post-hoc analysis used patient-reported data from a questionnaire administered during patient screening for a prospective linaclotide Phase 3b clinical trial in patients with CIC (N = 1482 screened). The questionnaire asked patients to report their experiences with OTC CIC medications over the preceding 6 months. RESULTS: Among patients with screening responses (N = 1423), most were female (85%) and white (66%), with a mean age of 48.9 years. A high proportion of patients had used one or more OTC medications (70% had ≥1 OTC; 19% had ≥3 OTCs), with the majority being bisacodyl (33%) and polyethylene glycol (30%). The most commonly cited reason for stopping an OTC medication was insufficient symptom relief (17-40%). The majority of patients taking OTC medications reported no or little satisfaction with the medication's effect on their constipation (62%) and CIC-specific abdominal symptoms (78%). Many patients had little to no confidence in bowel movement (BM) frequency after taking OTC medications and their confidence in their ability to predict BM timing was also low (49-81% not at all confident). CONCLUSIONS: Treatment effects on individual CIC symptoms, predictability of bowel habits, and satisfaction with treatment are all important factors for healthcare providers and patients to consider when establishing an effective treatment regimen for CIC. TRIAL REGISTRATION NUMBER: NCT01642914.

Safety and tolerability of linaclotide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation: pooled Phase 3 analysis.

BACKGROUND: Linaclotide is approved for treating irritable bowel syndrome with constipation (IBS-C; 290 µg QD) and chronic idiopathic constipation (CIC; 145 µg or 72 µg QD). These analyses aimed to assess linaclotide safety in a large, pooled Phase 3 population. METHODS: In six randomized controlled trials (RCTs), patients received linaclotide (72 µg, 145 µg, 290 µg) or placebo daily for 12-26 weeks; in two long-term safety (LTS) studies, patients received open-label linaclotide for ≤78 additional weeks. Laboratory values, vital signs, and treatment-emergent adverse events (TEAEs) were assessed. RESULTS: Overall, 3853 patients received ≥1 dose of linaclotide. The most common TEAE was diarrhea (majority [90.5% in RCTs] mild/moderate). Linaclotide patients experienced 1.1 diarrhea TEAE per patient-year in the RCTs (0.2 in placebo), and 0.3 in the LTS studies. In RCTs, 6.9% linaclotide and 3.0% placebo patients discontinued due to any adverse event (AE); 4.0% linaclotide and 0.3% placebo patients discontinued due to diarrhea. In LTS studies, 9.4% patients discontinued due to any AE, and 3.8% due to diarrhea. Serious AEs (SAEs) were rare and similar across treatment groups; there were no SAEs of diarrhea. CONCLUSION: These pooled analyses of patients treated for ≤104 weeks confirm linaclotide's overall safety.

Symptom burden and consulting behavior in patients with overlapping functional disorders in the US population.

BACKGROUND: Regulatory and treatment guidelines focus on individual conditions, yet clinicians often see patients with overlapping conditions. OBJECTIVE: This cross-sectional survey study assesses the impact of overlapping functional dyspepsia (FD), gastroesophageal reflux disease (GERD), irritable bowel syndrome with constipation (IBS-C), and chronic idiopathic constipation (CIC) on symptom burden and consulting behavior. METHODS: Survey participants met Rome III criteria for FD, IBS-C, and/or CIC, and/or reported GERD; participants answered questions about symptom frequency and bothersomeness, work and productivity, and consulting behavior. RESULTS: Of 2641 respondents, 1592 (60.3%) had one condition; 832 (31.5%) had two; and 217 (8.2%) had three; 57.3% of 1690 FD, 54.6% of 1337 GERD, 82.6% of 328 IBS-C, and 62.5% of 552 CIC respondents had condition overlap. Overall GI symptoms were very/extremely bothersome in 28.6% of single-condition respondents, 50.7% of two-condition, and 69.6% of three-condition respondents (p < 0.001, chi square). Symptom frequency and productivity losses both increased with condition overlap. Over 12 months, 43.7% of single-condition, 49.9% of two-condition, and 66.5% of three-condition respondents consulted a physician about GI symptoms (p < 0.001, chi square). CONCLUSION: Functional GI disorders frequently overlap with each other and with GERD. Condition overlap is associated with greater symptom burden and increased physician consultations.

Economic costs associated with acute attacks and long-term management of hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by recurrent acute attacks of swelling of the larynx, abdomen, and periphery. OBJECTIVE: To assess the economic burden associated with acute attacks and long-term management of HAE. METHODS: Burden was assessed via a Web-based survey of HAE patients (> or = 18 years old) that solicited information on attack characterization, short-term treatment, long-term disease management, impact on work, and patient costs. A standardized instrument, the Work Productivity and Activity Impairment questionnaire, was included to assess impact on work productivity. Standard medical costs and US average wage costs were assigned to survey items to assess direct medical and indirect costs, respectively. RESULTS: Total annual per-patient costs are estimated at $42,000 for the average HAE patient, with costs totaling $14,000 for patients with mild attacks, $27,000 for patients with moderate attacks, and $96,000 for patients with severe attacks. Hospital costs account for 67% of direct medical costs. Respondents reported high rates of missed work, lost productivity, and lost income, contributing to indirect costs totaling $16,000 annually for the average patient. Almost all costs increase with disease severity, although the distribution varies with severity: indirect costs account for 75% of costs for patients with mild attacks, whereas emergency department and hospital costs account for 68% of costs for patients with severe attacks. CONCLUSIONS: HAE results in considerable economic burden to patients, payers, and society in terms of direct medical and indirect costs and compounds the substantial humanistic burdens, which will be reported separately.