Arndt, Kayla

SummaryBackgroundGastroparesis is defined by delayed gastric emptying with associated symptoms in the absence of mechanical obstruction.AimTo evaluate pharmacokinetics and pharmacodynamics of felcisetrag, a highly selective 5‐HT4 receptor agonist, on total gut transit in patients with documented delayed gastric emptying of solids.MethodsSingle‐centre, placebo‐controlled study of 36 participants receiving placebo, 0.1mg, 0.3mg or 1.0mg of felcisetrag I.V. infusion, daily, for 3 days. At baseline, each participant completed a 4h, 99mTc‐egg meal (300 kcal, 30% fat) gastric emptying test. Following infusion (Day 2), gastric, small bowel and colonic transit of solids were measured over 48h (same meal plus 111In‐charcoal delivered in methacrylate‐coated capsule). Samples were collected for pharmacokinetics. The primary endpoint was gastric emptying T1/2. Statistical analysis used baseline parameters as covariates (ANCOVA).ResultsPatients (22 idiopathic, 14 diabetic gastroparesis) were randomised to felcisetrag (0.1 mg, n = 10; 0.3 mg, n = 9; 1.0 mg, n = 7) or placebo (n = 10). Compared to placebo, felcisetrag significantly accelerated gastric emptying T1/2, colonic filling at 6h, and 10% small bowel transit time (overall P < 0.01; all three doses individually Bonferroni corrected P < 0.05) for all three measurements. Ascending colon emptying (T1/2) was significantly accelerated (all doses), and colonic transit at 48 hours was accelerated with 0.1 mg and 0.3 mg felcisetrag compared to placebo. Pharmacokinetic results were dose proportional. Felcisetrag was well tolerated with no clinically significant findings from clinical laboratory, vital signs or ECG.ConclusionI.V. felcisetrag significantly accelerated gastric, small bowel and colonic transit in patients with gastroparesis, and should be further evaluated for short‐term treatment of gastric and intestinal motility disorders.ClinicalTrials.gov #NCT03281577

Abnormal gastric accommodation (GA) and gastric emptying contribute to pathophysiology in functional dyspepsia (FD). Secretin is a key regulator of GA in animal studies. Our aim was to study the effects of secretin on gastric motility, satiation, postprandial symptoms, and key hormones. We performed two double-blind, randomized, saline-controlled crossover trials in 10 healthy volunteers and 10 patients with FD by Rome IV criteria. We used measured GA (by validated SPECT method) after a 111In radiolabeled Ensure 300-mL meal and quantified gastric emptying for 30 min by scintigraphy. Satiation was measured by volume to fullness (VTF) and maximum tolerated volume (MTV) on an Ensure nutrient drink test and postprandial symptoms 30 min post-MTV. Fasting and postprandial GLP-1, GIP, and HPP were measured. The ages and sex distribution of healthy controls and patients with FD were similar. Compared with placebo, secretin delayed gastric emptying at 30 min in both health [−11% (−16, −4), P = 0.004]; and FD [−8% (−9, 0), P = 0.03]. Satiation (VTF and MTV), GA, and plasma levels of GLP-1, GIP, and HPP did not differ between treatment arms in health or FD. On ANCOVA analysis (adjusting for age and sex), secretin did not consistently increase postprandial symptoms in health or FD. Secretin delayed gastric emptying in both health and FD without significantly altering GA, VTF, or MTV or selected hormones. Thus, secretin receptor activation may provide a novel therapeutic mechanism for patients with FD and rapid gastric emptying. NEW & NOTEWORTHY The naturally occurring hormone secretin retards gastric emptying of solids without deleteriously affecting gastric accommodation, satiation, other upper gastrointestinal hormones, or postprandial symptoms. Given these findings, a subset of patients with rapid gastric emptying (e.g., the estimated 20% of patients with functional dyspepsia) could be candidates for treatments that stimulate a secretin receptor such as sacubitril, which inhibits neprilysin, an enzyme that degrades secretin.

INTRODUCTION: Reduced gastric accommodation (GA) or accelerated or delayed gastric emptying (GE) contributes to pathophysiology in functional dyspepsia (FD). Secretin is an endogenous hormone secreted postprandially from the duodenal mucosa. Our objective was to determine the effects of secretin in human gastric motor functions and satiation in health and FD. METHODS: We conducted a double-blind, randomized, placebo-controlled, cross-over trial in 10 healthy participants and 10 patients with FD by Rome IV criteria. Subjects were randomized to IV secretin or normal saline with a 1-4 week washout period. We measured GA using validated 99m Tc-single photon emission computed tomography with a standardized 300 mL meal of 111 In radiolabeled Ensure®. We measured GE using scintigraphy of the same meal and symptoms 30 minutes post meal based on 100 mm visualized analog scale (VAS). To measure volume to fullness (VTF) and maximum tolerated volume (MTV), we performed Ensure® nutrient drink test (NDT) and recorded symptoms 30 min post-MTV. Wilcoxon Signed-Rank Test was used for comparison within healthy and FD groups and ANCOVA modeling was used for intention to treat comparison between groups, adjusting for age, sex, and treatment arm (secretin vs. placebo). Study drug was provided by ChiroClin, Inc. RESULTS: The median age for healthy volunteers (HV) was 45.0 years [IQR: 38.0, 49.0 (80% female)] and for FD was 50.5 years [42.0, 55.0 (70% female)]. There was no statistical difference in either group for secretin vs. placebo for GA. Secretin delayed GE in both HV and FD (Table 1). There was decrease in GE for secretin vs. placebo in HV at 20 minutes [-10% (-13, -7), P = 0.008] and 30 minutes [-11% (-16, -4), P = 0.004]. This finding was also seen in the FD group for GE at 25 minutes [-5% (-9, 0), P = 0.047] and 30 minutes [-8% (-9, 0), P = 0.03]. There were no statistically significant differences between treatment arms for VTF or MTV in either HV or FD. On ANCOVA analysis, there were statistically significant increases in nausea at 30 minutes ( P = 0.0016) and fullness at 30 minutes ( P = 0.0002) for secretin vs. placebo in FD compared to HV. CONCLUSION: Secretin delayed GE in both healthy volunteers and FD without significantly altering GA, VTF, or MTV. Secretin receptor stimulation deserves further study in FD patients with accelerated GE.