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).
...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.
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.
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.
Acceptability and tolerance of bowel preparation is critical to overcome patient hesitancy in undergoing colon cancer screening and surveillance colonoscopy. To improve patient experience, a new ...sports drink-flavored bowel preparation containing polyethylene glycol (PEG) and sulfate salts (FPSS) was developed to provide a similar experience to a commonly used but not United States Food and Drug Administration (FDA) approved PEG and sports drink bowel preparation (PEG-SD), while also achieving improved cleansing efficacy.
This FPSS preparation, approved by the FDA in June 2023, was evaluated in a non-randomized Phase 2 study in which 40 patients requiring colonoscopy were prepared with FPSS and 20 with PEG-SD.
Overall cleansing success was high with FPSS based on unblinded local endoscopist assessment (93%) and blinded central reading (97%), exceeding PEG-SD which achieved success rates of 84% (local read), 74% and 68% (blinded central reads). Similar differences favoring FPSS were seen for excellent preparations and cleansing success by colon segment as rated by local endoscopists. Both preparations were well-tolerated, with 93% of FPSS patients rating their preparation as Tolerable to Very Easy to consume, compared to 100% of PEG-SD. Patients who had previously taken a preparation for colonoscopy found FPSS and PEG-SD better than their prior preparation (73% and 70%, respectively) and nearly all would request their assigned study preparation again in the future. About two thirds of FPSS patients agreed that the preparation tasted similar to a sports drink.
The new sports drink-like flavored preparation compares favorably to PEG-SD for bowel cleansing efficacy while achieving similar patient satisfaction. The study was registered at www.
gov (NCT03328507) on 01/11/2017.
Diabetic gastroparesis may be associated with impaired nitric oxide metabolism and reduced tetrahydrobiopterin (BH4) synthesis. Oral treatment with CNSA-001 (sepiapterin, currently known as PTC923) ...increased BH4 levels in humans in a previous study. This Phase 2 study evaluated CNSA-001 in women with diabetic gastroparesis.
Non-pregnant diabetic women with moderate/severe symptomatic gastroparesis, delayed gastric emptying, and impaired gastric accommodation (nutrient satiety testing) were randomized to 10mg/kg BID CNSA-001 or matching placebo for 14days. The primary endpoint was change in gastric accommodation (maximal tolerated liquid meal volume) at 14- and 28-days' follow-up.
Gastric accommodation improved in CNSA-001-treated vs. placebo-treated subjects at 28days (least squares mean LSM difference: 98 95% CI 36 to 161, p=0.0042). Subjects' ratings of bloating, fullness, nausea, and pain were lower vs. baseline in the CNSA-001 group at 14 and 28days, though these improvements were not observed consistently in placebo-treated subjects. There were no significant group differences in upper gastrointestinal symptom scores, and in gastric emptying breath test parameters. CNSA-001 was well tolerated, with no withdrawals for adverse events.
CNSA-001 improved gastric accommodation in women with diabetic gastroparesis. Further evaluation of CNSA-001 in gastroparesis is warranted; ClinicalTrials.gov number, NCT03712124.
•Effects of CNSA-001 (sepiapterin, currently known as PTC923) in women with diabetic gastroparesis were studied.•CNSA-001 improved gastric accommodation measured by nutrient satiety (maximal tolerated liquid meal volume) versus placebo.•Restoring nitrergic signalling with CNSA-001 is a novel approach to correct underlying etiology of diabetic gastroparesis.
Summary The association between gastroesophageal reflux disease (GERD) and extraesophageal symptoms is poorly understood and difficult to document. pH monitoring in this group of patients has ...resulted in conflicting data due to lack of diagnostic sensitivity. Recently, a new sensitive pH device for detection of liquid and aerosolized droplets in the oropharynx (The Dx–pH Measurement System Dx–pH) has become available. Our hypothesis is that we will be able to improve our ability to identify and understand this group of patients with this device. The aim of this preliminary observation study was to compare the results of this new device to the standard esophageal and pharyngeal pH probes in a small group of patients with extraesophageal symptoms. Patients with suspected extraesophageal GER symptoms underwent traditional 24-hour esophago-pharyngeal pH monitoring (24pH) simultaneous with Dx–pH monitoring in the oropharynx. Tracings were reviewed for comparison and correlation between the two probes, with an event in the Dx–pH Probe being defined as a rapid drop >3 standard deviation from baseline. Fifteen patients (10 females, 5 males) with mean age of 57.5 years (range, 25–75) were studied. The predominant chief complaint included 12/15 chronic cough, 2/15 asthma; and 1/15 throat clearing. All Dx–pH events were preceded and associated with distal esophageal pH drops in a progressive ante grade manner. Ten patients had 1–13 abnormal oropharyngeal pH events as measured by Dx–pH monitoring with a total of 48 events. The median pH of reflux events had a statistically significant increase from 3.1 at the distal esophageal probe to 5.2 at the pharynx and 5.6 at the oropharynx, the latter being 80% higher than the distal esophageal probe ( P < 0.001). The percentage of acid events decreased in a cephalad manner from 66.7% at distal esophagus to 25% at the pharynx and only 6.25% at the oropharyngeal Dx–pH Probe, with the remaining events being weakly acidic. Dx–pH Probe is a new sensitive oropharyngeal pH device whose values correlate well with the gold-standard 24-hour pH device, and appears to accurately detect pH events that begin at the distal esophagus and travel upward to the oropharynx. This device suggests that supraesophageal events manifest themselves as rapid pH drops (>10%), which are likely not to be identified using the standard criteria of pH <4 due to the gradient of increasing pH from the lower esophagus to the oropharynx.
Background Prehospital resuscitation with crystalloid exacerbates fibrinolysis, which is associated with high mortality. We hypothesized that plasma compared with crystalloid resuscitation prevents ...hyperfibrinolysis in a tissue plasminogen activator (tPA)-rich environment via preservation of proteins essential for regulation of fibrinolysis. Study Design Healthy individuals donated blood, which was assayed using a native (nonactivated) thrombelastography (TEG). Whole-blood was mixed with normal saline (NS) or platelet poor plasma (PPP) at progressive dilutions. Tissue plasminogen activator was added to promote a fibrinolytic environment. In a separate experiment, PPP was run through a 100 kDa filter and liquid remaining on top of the filter (TFP) and below the filter (BFP) was obtained. Whole blood was diluted by 50% with TFP, BFP, and NS and assayed with a tPA TEG challenge. The TFP and BFP were assayed for protein concentration and protein composition. Results Normal saline and PPP dilution of whole blood without tPA did not affect clot lysis at 30 minutes (LY30) (NS Spearman's rho 0.300, p = 0.186 and PPP 0.294, p = 0.288). When tPA was added, NS dilution of whole blood increased LY30 in a percentage-dependent manner (0.844, p < 0.001), but did not significantly increase with PPP dilution (0.270, p = 0.202). The difference in LY30 from whole blood to diluted whole blood with PPP (mean change, −1.05, 95% CI, −9.42 to 7.33) was similar with TFP (1.23, 95% CI, −5.20 to 7.66, p = 0.992). However, both BFP (37.65, 95% CI 24.47 to 50.82, p = 0.001) and NS (47.36, 95% CI 34.3 to 60.45, p < 0.001) showed large increases in fibrinolysis compared with PPP. Conclusions Crystalloid and plasma dilution of whole blood does not increase fibrinolysis. However, NS dilution of whole blood increases susceptibility to tPA-mediated fibrinolysis. Plasma resuscitation, simulated by plasma dilution of whole blood, attenuates increased susceptibility to tPA-mediated fibrinolysis. The benefits of plasma resuscitation are mediated through preservation of plasma proteins.
Abstract Background Metabolites are underappreciated for their effect on coagulation. Taurocholic acid (TUCA), a bile acid, has been shown to regulate cellular activity and promote fibrin sealant ...degradation. We hypothesize that TUCA impairs whole blood clot formation and promotes fibrinolysis. Methods TUCA was exogenously added to whole blood obtained from volunteers. A titration from 250 μM–750 μM was used due to biologic relevance. Whole blood mixtures were assayed using thrombelastography for clot strength (maximum amplitude MA) and fibrinolysis (LY30) quantification. Tranexamic acid was used to block plasmin-mediated fibrinolysis. Platelet microfluidics were performed. A proteomic analysis was completed on citrated plasma obtained from a shock and resuscitation rat model. Results Fibrinolysis increased when 750-μM TUCA was added to whole blood (median LY30 0.08–5.7, P = 0.010) and clot strength decreased (median MA of 53.3–43.8, P = 0.010). The addition of tranexamic acid, to a 750-μM TUCA titration, partially reversed the induced fibrinolysis (LY30: without 7.7 versus with 2.7) and the decrease in clot strength (MA: without 48.2 versus with 53.2), but did not reverse the effects to whole blood levels. Platelet function reduced by 50% in the presence of 100-μM TUCA. Rats had a median 52-fold increase in TUCA, after a shock state that stayed elevated after resuscitation. Conclusions TUCA reduces clot strength and promotes fibrinolysis. The clot strength reduction is attributable to platelet inhibition. This metabolic effect on coagulation warrants further investigation, as localized areas of the body, with high levels of bile acid, may be at risk for postoperative bleeding.
Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological ...features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH.
In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6.
Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 8% patients in the placebo group, 35 11% in the obeticholic acid 10 mg group p=0·18, and 36 12% in the obeticholic acid 25 mg group p=0·13). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 19% in the placebo group, 183 28% in the obeticholic acid 10 mg group, and 336 51% in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 11% patients in the placebo group, 72 11% in the obeticholic acid 10 mg group, and 93 14% in the obeticholic acid 25 mg group).
Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes.
Intercept Pharmaceuticals.
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