Efficacy, safety, and tolerability of plecanatide in patients with irritable bowel syndrome with constipation: results of two phase 3 randomized clinical trials.

OBJECTIVES: Two identical, phase 3, randomized, double-blind, placebo-controlled trials evaluated the efficacy and safety of plecanatide in patients with irritable bowel syndrome with constipation (IBS-C). METHODS: Adults meeting Rome III criteria for IBS-C were randomized (1:1:1) to placebo or plecanatide (3 or 6 mg) for 12 weeks. The primary efficacy end point was the percentage of overall responders (patients reporting ≥30% reduction from baseline in worst abdominal pain plus an increase of ≥1 complete spontaneous bowel movement (CSBM)/week from baseline in the same week for ≥6 of 12 treatment weeks). Safety was assessed by adverse events (AEs). RESULTS: Overall, 2189 individuals were randomized across the two studies and 1879 completed the studies. Demographic and baseline characteristics were similar across treatment groups and between studies. The percentage of overall responders in Study 1 was 30.2% and 29.5% for plecanatide 3 and 6 mg, respectively, vs. 17.8% placebo (P < 0.001 for each dose vs. placebo), and in Study 2 was 21.5% (P = 0.009) and 24.0% (P < 0.001) for plecanatide 3 and 6 mg, respectively, compared to 14.2% for placebo. The percentage of sustained efficacy responders (overall responders plus weekly responders for ≥2 of last 4 weeks of the 12-week treatment period) was significantly greater for both doses of plecanatide vs. placebo across both studies. All secondary end points (stool frequency/consistency, straining, abdominal symptoms) showed statistically significant improvements compared with placebo. The most common AE was diarrhea (3 mg, 4.3%; 6 mg, 4.0%; placebo, 1.0%). Discontinuation due to diarrhea was infrequent (3 mg, 1.2%; 6 mg, 1.4%; placebo, 0). CONCLUSIONS: Plecanatide significantly improved both abdominal pain and constipation symptoms of IBS-C with minimal associated side effects and high levels of tolerability.

The Better Understanding and Recognition of the Disconnects, Experiences, and Needs of Patients with Chronic Idiopathic Constipation (BURDEN-CIC) Study: Results of an Online Questionnaire.

INTRODUCTION: There is limited literature comparing the experiences and attitudes of patients with chronic idiopathic constipation (CIC) to those of healthcare professionals (HCPs) treating CIC patients. The BURDEN-CIC study was conducted to better understand the experiences and ongoing needs of CIC patients and to assess their alignment versus disconnection with the perceptions and needs of HCPs who treat CIC patients. METHODS: The BURDEN-CIC study was an author-developed, online questionnaire that used KnowledgePanel® to survey individuals with CIC (n = 1223). HCPs who treat CIC patients were recruited separately and participated in a complementary online questionnaire (n = 331). RESULTS: Most patients had used (58%) or were using (51%) over-the-counter treatments for their CIC, with only 16% currently on prescription therapy. More than half (59%) of current CIC prescription users were not satisfied/completely satisfied with their current chronic treatment. Many patients (42%) felt frustrated regarding their CIC, and a similar percentage (40%) expressed acceptance that CIC was part of their daily life. The majority of HCPs agreed that CIC patients were frustrated (72%), stressed (50%), or fed up (43%) with current treatment options but were relatively unaware (21%) that patients were accepting of their CIC. HCPs reported the greatest challenges in treating CIC patients as response rates to current therapies (55%), treatment adherence (55%), management of treatment-related diarrhea (34%), and lack of treatment options (34%). CONCLUSION: BURDEN-CIC identified that many patients and HCPs are frustrated and not satisfied with current CIC treatments due to lack of efficacy and side effects, such as diarrhea. The survey identified that many patients are "accepting" of their disease, potentially compromising treatment outcomes. More dialogue is needed between HCPs and CIC patients, especially regarding management of treatment expectations and side effects. Further, additional treatment options would be useful for both patients and HCPs. FUNDING: Synergy Pharmaceuticals Inc.

A Randomized Phase III Clinical Trial of Plecanatide, a Uroguanylin Analog, in Patients With Chronic Idiopathic Constipation.

OBJECTIVES: This study assessed the efficacy and safety of plecanatide, a guanylate cyclase-C (GC-C) agonist and the first uroguanylin analog approved for the treatment of chronic idiopathic constipation (CIC). METHODS: This phase III, multicenter, double-blind, placebo-controlled study randomized 1,394 patients with CIC. Patients received either plecanatide (3 or 6 mg) or placebo, orally, once daily, for 12 weeks. The primary efficacy endpoint was the percentage of patients who were durable overall complete spontaneous bowel movement (CSBM) responders over the 12-week treatment period. Patients were instructed to record their daily bowel movements, stool consistency scores, and abdominal symptoms in an electronic diary. Treatment-emergent adverse events (AEs) were collected. RESULTS: Each dose of plecanatide resulted in a significantly greater percentage of durable overall CSBM responders (21.0%, 3 mg; 19.5%, 6 mg) as compared with placebo (10.2%; P<0.001 for both). Plecanatide (3 and 6 mg) also significantly increased mean weekly CSBM frequency from baseline (increase of 2.5 and 2.2/week, respectively) vs. placebo (1.2/week; P<0.001 for both) and mean weekly spontaneous bowel movement frequency (increase of 3.2 and 3.1/week, respectively) vs. placebo (1.3/week; P<0.001, for both) over the 12-week treatment period. Both plecanatide doses significantly improved all secondary and additional efficacy endpoints. The most common AE, diarrhea, occurred in 1.3% (placebo), 5.9% (3 mg) and 5.7% (6 mg) of patients. CONCLUSIONS: Plecanatide significantly improved constipation and its related symptoms with a low rate of adverse events. These results suggest that plecanatide will be a useful treatment option in the management of CIC. ClinicalTrials.gov: NCT01982240.

Vulvar and vaginal atrophy in postmenopausal women: findings from the REVIVE (REal Women's VIews of Treatment Options for Menopausal Vaginal ChangEs) survey.

INTRODUCTION: Vulvar and vaginal atrophy (VVA) is a chronic medical condition experienced by many postmenopausal women. Symptoms include dyspareunia (pain with intercourse), vaginal dryness, and irritation and may affect sexual activities, relationships, and activities of daily life. AIM: The aim of this study is to characterize postmenopausal women's experience with and perception of VVA symptoms, interactions with healthcare professionals (HCPs), and available treatment options. METHODS: An online survey was conducted in the United States in women from KnowledgePanel(®) , a 56,000-member probability-selected Internet panel projectable to the overall US population. Altogether, 3,046 postmenopausal women with VVA symptoms (the largest US cohort of recent surveys) responded to questions about their knowledge of VVA, impact of symptoms on their activities, communication with HCPs, and use of available treatments. MAIN OUTCOME MEASURES: Percent is calculated as the ratio of response over total responding for each question for all and stratified participants. RESULTS: The most common VVA symptoms were dryness (55% of participants), dyspareunia (44%), and irritation (37%). VVA symptoms affected enjoyment of sex in 59% of participants. Additionally, interference with sleep, general enjoyment of life, and temperament were reported by 24%, 23%, and 23% of participants, respectively. Few women attributed symptoms to menopause (24%) or hormonal changes (12%). Of all participants, 56% had ever discussed VVA symptoms with an HCP and 40% currently used VVA-specific topical treatments (vaginal over-the-counter [OTC] products [29%] and vaginal prescription therapies [11%]). Of those who had discussed symptoms with an HCP, 62% used OTC products. Insufficient symptom relief and inconvenience were cited as major limitations of OTC products and concerns about side effects and cancer risk limited use of topical vaginal prescription therapies. CONCLUSIONS: VVA symptoms are common in postmenopausal women. Significant barriers to treatment include lack of knowledge about VVA, reluctance to discuss symptoms with HCPs, safety concerns, inconvenience, and inadequate symptom relief from available treatments.

Levetiracetam does not alter body weight: analysis of randomized, controlled clinical trials.

INTRODUCTION: Increases in body weight gain are important, and clinically significant adverse effects of several antiepileptic drugs (AED) including valproate and gabapentin. Weight gain may contribute to medication non-compliance, discontinuation, and importantly, may have secondary medical implications as well. Levetiracetam (LEV) is indicated for adjunctive treatment of partial seizures. The objective of the present evaluation was to examine the effects of LEV treatment on body weight in adult patients. METHODS: We analyzed data derived from four prospective, placebo-controlled randomized, clinical trials conducted in both in the US and Europe. Patients included in the present analysis were both men and women, greater than 16 years old, and who had LEV exposure for at least 1 month. Body weight was measured at baseline and at the final LEV study visit. Data are analyzed for all patients, by gender, body mass index (BMI), duration of LEV exposure and by concomitant AED treatment. Wilcoxan Signed Rank, or Rank Sum test used where appropriate, with significance assigned at P<0.05. Data are presented as mean values+/-1 S.D. RESULTS: Nine-hundred and seventy patients (age=37.5 years, 54% men/46% women) were evaluated. There were no significant differences in baseline demographics between LEV (n=631) or placebo (n=339) treated patient groups. Mean LEV dose and duration of treatment were 2053 mg/day (maximum dose of 4000 mg/day) and 125 days (maximum=181 days), respectively. Concomitant AED therapy included CBZ, PHT, VPA, PB, GBP, LTG, and VGB. For LEV-treated patients, no significant changes in body weight were noted. Mean body weight at baseline versus final study visit for LEV was 74.3+/-16.6 kg and 74.3+/-16.6 kg, respectively. For placebo-treated patients, baseline versus end of treatment weight was 72.4+/-15.4 kg and 72.7+/-15.9 kg, respectively, representing a slight, yet clinically trivial increase. Clinically significant weight change as defined as >7% change from baseline weight, occurred in 9% of LEV-treated patients (4.5% had increase in weight/4.5% decrease) versus 9.4% (5.9% had increase/3.5% decrease) in placebo-treated patients. Weight changes were not significantly different between groups. Neither baseline BMI, gender, or background AEDs, appeared to predispose to significant weight change for LEV-treated patients. CONCLUSIONS: We conclude that treatment with LEV at clinically relevant dosages is not associated with significant weight change. LEV would, therefore, appear to be a weight neutral AED.