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.

Plecanatide, an oral guanylate cyclase C agonist acting locally in the gastrointestinal tract, is safe and well-tolerated in single doses.

PURPOSE: Plecanatide, an analogue of uroguanylin, activates the guanylate cyclase C (GC-C) receptor found on the GI mucosal epithelial cells, leading to secretion of fluid, facilitating bowel movements. Plecanatide is being investigated as a potential treatment for constipating GI disorders. The aim of this investigation was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single doses of plecanatide in healthy volunteers. METHODS: A total of 72 healthy volunteers at a single site were randomized in 9 cohorts to receive oral plecanatide or placebo from 0.1 to 48.6 mg. Plasma PK samples were collected pre-dose and post-dose. PD assessments included time to first stool, stool frequency, and stool consistency using the Bristol Stool Form Scale. All adverse events were documented. RESULTS: Plecanatide was safe and well-tolerated at all dose levels. A total of 17 of 71 subjects (23.9%) reported 25 treatment-emergent adverse events (TEAEs) during the study. The number of TEAEs reported by subjects who received plecanatide or placebo was comparable (24.5 vs. 22.2%, respectively). There were no dose-related increases in TEAEs or any SAEs reported. No measurable systemic absorption of oral plecanatide was observed at any of the oral doses studied, utilizing an assay sensitive down to 1 ng/mL. CONCLUSIONS: Plecanatide, an oral GC-C agonist, acting locally within the GI tract without measurable systemic exposure, was safe and well-tolerated in single doses up to 48.6 mg. The study was not powered for statistical analyses, but trends in PD parameters supported continued clinical development.

Randomized clinical trial: efficacy and safety of plecanatide in the treatment of chronic idiopathic constipation.

BACKGROUND: Plecanatide, with the exception of a single amino acid replacement, is identical to human uroguanylin and is approved in the United States for adults with chronic idiopathic constipation (CIC). This double-blind, placebo-controlled, phase III study evaluated the efficacy and safety of plecanatide versus placebo in CIC. METHODS: Adults meeting modified Rome III CIC criteria were randomized to plecanatide 3 mg (n = 443), 6 mg (n = 449), or placebo (n = 445). Patients recorded bowel movement (BM) characteristics [including spontaneous BMs (SBMs) and complete SBMs (CSBMs)] and rated CIC symptoms in daily electronic diaries. The primary endpoint was the percentage of durable overall CSBM responders (weekly responders for ⩾9 of 12 treatment weeks, including ⩾3 of the last 4 weeks). Weekly responders had ⩾3 CSBMs/week and an increase of ⩾1 CSBM from baseline for the same week. RESULTS: A significantly greater percentage of durable overall CSBM responders resulted with each plecanatide dose compared with placebo (3 mg = 20.1%; 6 mg = 20.0%; placebo = 12.8%; p = 0.004 each dose). Over the 12 weeks, plecanatide significantly improved stool consistency and stool frequency. Significant increases in mean weekly SBMs and CSBMs began in week 1 and were maintained through week 12 in plecanatide-treated patients. Adverse events were mostly mild/moderate, with diarrhea being the most common (3 mg = 3.2%; 6 mg = 4.5%; placebo = 1.3%). CONCLUSIONS: Plecanatide resulted in a significantly greater percentage of durable overall CSBM responders and improved stool frequency and secondary endpoints. Plecanatide was well tolerated; the most common AE, diarrhea, occurred in a small number of patients.[ClinicalTrials.gov identifier: NCT02122471].

Mortality related to gender, age, sepsis, and ethnicity in severely burned children.

Several studies have noted gender differences in adult mortality related to thermal injury, however, little is published on gender-related outcomes of burn patients 17 years of age or less. The aim of this study was to evaluate the relationships between mortality, gender, prepubertal and during puberty, ethnic origin, and age, with or without identified sepsis in severely burned children. Seven hundred forty-seven children admitted to our burn hospital from March 1985 to January 2005 with burns greater than 40% total body surface area were studied. Mortality associated with identified sepsis, gender, age, and ethnic origin were outcomes of interest. Two hundred sixty (35%) of the patients studied were girls and 487 (65%) were boys. No significant difference could be shown between girls and boys for the number of operations, time from burn to hospital admission, or the presence of identifiable inhalation injury. Nearly 60% of the male nonsurvivors and 48% of the female nonsurvivors in this study had identifiable sepsis at postmortem. The mortality rate was higher in infants and toddlers, age 0 to 2.9 years, compared with children and adolescents, age 3 to 17 years; however, there was no significant difference in rate of mortality between genders, prepuberty versus puberty, those with septic episodes, or ethnic origin. Burn mortality among infants and toddlers, children, and adolescents with greater than 40% total body surface area burns with or without identified sepsis could not be shown to be gender or ethnic origin dependent.

Identification of factors contributing to hepatomegaly in severely burned children.

Hepatomegaly is a common postmortem observation in severely burned children, with the liver often tripling in size when compared with normal livers for age, weight, and sex. Lesions identified at autopsy include deposition of large and small fat droplets in the hepatocyte, congestion, centrilobular necrosis, and cholestasis. The present study was designed to identify the primary causes of hepatomegaly in severely burned children postmortem. For this purpose, 41 autopsies were reviewed and, when available, blood and tissue samples were studied. Histopathologic findings showed that large intrahepatocytic fat droplets within hepatocytes and cholestasis were important contributors to hepatomegaly. Liver density and wet/dry weight ratios significantly decreased with increasing liver size. Hepatocyte volume increased with increasing liver size (P < 0.001) as did total fat content (P < 0.001). The liver enzymes, alanine aminotransferase and aspartate aminotransferase, remained normal except within 5 to 10 days of injury and 5 to 10 days of death. Triglycerides made up 4% to 70% of the total fat, with the percentage of triglycerides increasing with the severity of hepatomegaly. Saturated fatty acids represented about 85% of the total fatty acids in normal-sized livers, whereas in the largest livers (400% of predicted), only 25% of the fatty acids were saturated. This study provides evidence that 85% to 90% of the hepatomegaly observed in severely burned children postmortem is associated with hepatocyte enlargement, which includes up to 19% intracellular fat. Increases in extracellular protein, intracellular glycogen, and fluid accumulation may make a minor contribution to postburn hepatomegaly.

Influence of demographics and inhalation injury on burn mortality in children.

BACKGROUND: Pulmonary failure has emerged as one of the leading causes of mortality in burned children due, in part, to the success in reducing the incidence of sepsis, early surgery and fluid resuscitation, and new advances in nutritional support. To evaluate the effect of pulmonary injury, age, gender, race, and burn size on mortality, the records of 3179 burned children admitted to our burn center from 1985 to 2001 were reviewed. In this population, 1246 were admitted within 14 days of injury with burns greater than 20% of their total body surface area (TBSA). METHODS: Lethal burn areas (LAs) for a thermal injury only or burn plus inhalation injury were estimated from best fit probit curve within 95% confidence limits. Data analysis was by chi(2)-test, t-test, or Fisher's exact test where appropriate. RESULTS: The lethal burn area for a 10% mortality rate with and without concomitant inhalation injury was a 50 and 73% TBSA burn, respectively. Children up to the age of 3 with >/=20% TBSA burns had a higher rate of mortality (9.9%) compared to those 3-12 years of age (4.9%) and 13-18 years of age (4.2%). Children with 21-80% TBSA burns showed a significant difference in mortality (P<0.05) between those with burn plus inhalation injury (13.9%) and burn only (2.9%), while those with 81-100% TBSA burns showed no significant difference between burn only and burn plus inhalation injury. CONCLUSION: Inhalation injury remains one of the primary contributors to burn mortality. Children under the age of 3 years, however, are at a higher risk both with and without inhalation injury.

The use of beta-adrenergic blockade in preventing trauma-induced hepatomegaly.

OBJECTIVE: The objective of this study was to test the hypothesis that hepatomegaly in burned children can be attenuated or reversed by blocking lipolysis and reducing free fatty acids delivered to the liver. SUMMARY BACKGROUND DATA: Accelerated lipolysis in severely burned children has been shown to play an important role in the accumulation of hepatic TGs. Severely burned children who survive 10 days or more after injury commonly have enlarged livers often twice or more normal size for their sex, age, and weight. METHODS: Ninety-eight children, 2 to 18 years of age, with burns covering more than 40% of their body surface and who received either propranolol (beta-adrenergic blockade) or placebo were studied. Liver weights were measured by ultrasonic scanning. Body composition changes were identified by dual-image x-ray absorptiometry and validated by whole-body potassium-40 scintillation counting. Discarded abdominal cutaneous adipose tissue was collected before and after propranolol or placebo for microarray analysis. RESULTS: In 80% of severely burned children studied not receiving propranolol, liver sizes increased by 100% or more while 86% of burned children receiving propranolol showed a decrease or no change in liver size over the same period of time after injury. Gene expression patterns of adipose tissue after propranolol treatment showed that all of the identified genes related to lipid metabolism were down-regulated. CONCLUSIONS: Data reported here support the hypothesis that beta-adrenergic blockade can reduce delivery of fatty acids to the liver and hepatic congestion commonly found in severely burned children by inhibiting lipolysis and reducing hepatic blood flow.