Randomised study: effects of the 5-HT4 receptor agonist felcisetrag vs placebo on gut transit in patients with gastroparesis

Victor Chedid, Justin Brandler, Kayla Arndt, Priya Vijayvargiya, Xiao Jing Wang, Duane Burton, W Scott Harmsen, Jenifer Siegelman, Chunlin Chen, Yinzhong Chen, Cristina Almansa, George Dukes, Michael Camilleri, Victor Chedid, Justin Brandler, Kayla Arndt, Priya Vijayvargiya, Xiao Jing Wang, Duane Burton, W Scott Harmsen, Jenifer Siegelman, Chunlin Chen, Yinzhong Chen, Cristina Almansa, George Dukes, Michael Camilleri

Abstract

Background: Gastroparesis is defined by delayed gastric emptying with associated symptoms in the absence of mechanical obstruction.

Aim: To 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.

Methods: Single-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, 99m Tc-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 111 In-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).

Results: Patients (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.

Conclusion: I.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.

© 2021 Mayo Foundation for Medical and Research. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
Study design
FIGURE 2
FIGURE 2
CONSORT flow diagram
FIGURE 3
FIGURE 3
Effects of felcisetrag (0.1 mg, 0.3 mg, 1.0 mg) and placebo on GE T1/2 at baseline and Day 2, and percent change in GE T1/2 from baseline GE T1/2 = gastric half‐emptying time
FIGURE 4
FIGURE 4
Gastric emptying of solids (% emptied) over time in patients with diabetic or idiopathic gastroparesis based on treatment group on Day 2 of placebo or increasing doses of felcisetrag; data show mean at each time point
FIGURE 5
FIGURE 5
Small bowel transit time 10% in patients with diabetic or idiopathic gastroparesis based on treatment group on Day 2 of placebo or increasing doses of felcisetrag; data show median, IQR, time point
FIGURE 6
FIGURE 6
Progression of colonic geometric centre over time in patients with diabetic or idiopathic gastroparesis based on treatment group after 48 hours of placebo or increasing doses of felcisetrag; data show mean at each time point for the different treatment groups

References

    1. Camilleri M, Chedid V, Ford AC, et al. Gastroparesis. Nature Reviews Disease Primers. 2018;4:41.
    1. Camilleri M, Parkman HP, Shafi MA, et al. Clinical guideline: management of gastroparesis. Am J Gastroenterol. 2013;108:18–37.
    1. Revicki DA, Camilleri M, Kuo B, et al. Development and content validity of a gastroparesis cardinal symptom index daily diary. Aliment Pharmacol Ther. 2009;30:670–680.
    1. Park S‐Y, Acosta A, Camilleri M, et al. Gastric motor dysfunction in patients with functional gastroduodenal symptoms. Am J Gastroenterol. 2017;112:1689–1699.
    1. Chedid V, Brandler J, Vijayvargiya P, et al. Characterization of upper gastrointestinal symptoms, gastric motor functions, and associations in patients with diabetes at a referral center. Am J Gastroenterol. 2019;114:143–154.
    1. Shahsavari D, Zhao H, Ehrlich AC, et al. Factors associated with hospital admissions and readmissions in patients with gastroparesis using the Nationwide Readmission Database. J Clin Gastroenterol. 2020;54:801–805.
    1. Thielemans L, Depoortere I, Perret J, et al. Desensitization of the human motilin receptor by motilides. J Pharmacol Exp Ther. 2005;313:1397–1405.
    1. Manabe N, Wong BS, Camilleri M. New‐generation 5‐HT4 receptor agonists: potential for treatment of gastrointestinal motility disorders. Expert Opin Investig Drugs. 2010;19:765–775.
    1. De Maeyer JH, Lefebvre RA, Schuurkes JA. 5‐HT4 receptor agonists: similar but not the same. Neurogastroenterol Motil. 2008;20:99–112.
    1. Shin A, Camilleri M, Kolar G, et al. Systematic review with meta‐analysis: highly selective 5‐HT4 agonists (prucalopride, velusetrag or naronapride) in chronic constipation. Aliment Pharmacol Ther. 2014;39:239–253.
    1. Beattie DT, Higgins DL, Ero MP, et al. An in vitro investigation of the cardiovascular effects of the 5‐HT(4) receptor selective agonists, velusetrag and TD‐8954. Vascul Pharmacol. 2013;58:150–156.
    1. Bouras EP, Camilleri M, Burton DD, et al. Prucalopride accelerates gastrointestinal and colonic transit in patients with constipation without a rectal evacuation disorder. Gastroenterology. 2001;120:354–360.
    1. Carbone F, Van den Houte K, Clevers E, et al. Prucalopride in gastroparesis: a randomized placebo‐controlled crossover study. Am J Gastroenterol. 2019;114:1265–1274.
    1. Beattie DT, Armstrong SR, Vickery RG, et al. The pharmacology of TD‐8954, a potent and selective 5‐HT(4) receptor agonist with gastrointestinal prokinetic properties. Front Pharmacol. 2011;2:25.
    1. McKinnell RM, Armstrong SR, Beattie DT, et al. Discovery of TD‐8954, a clinical stage 5‐HT(4) receptor agonist with gastrointestinal prokinetic properties. Bioorg Med Chem Lett. 2013;23:4210–4215.
    1. Chapman MJ, Jones KL, Almansa C, et al. Blinded, double‐dummy, parallel‐group, phase 2a randomized clinical trial to evaluate the efficacy and safety of a highly selective 5‐hydroxytryptamine type 4 receptor agonist in critically ill patients with enteral feeding intolerance. J Parenter Enteral Nutr 2020. Jan 28. 10.1002/jpen.1732. Online ahead of print
    1. Wang YR, Fisher RS, Parkman HP. Gastroparesis‐related hospitalizations in the United States: trends, characteristics, and outcomes, 1995–2004. Am J Gastroenterol. 2008;103:313–322.
    1. Bharucha AE, Low P, Camilleri M, et al. A randomised controlled study of the effect of cholinesterase inhibition on colon function in patients with diabetes mellitus and constipation. Gut. 2013;62:708–715.
    1. Revicki DA, Camilleri M, Kuo B, et al. Evaluating symptom outcomes in gastroparesis clinical trials: validity and responsiveness of the Gastroparesis Cardinal Symptom Index‐Daily Diary (GCSI‐DD). Neurogastroenterol Motil. 2012;24:456–463.
    1. Zinsmeister AR, Burton D, Camilleri M. Pharmacodynamic and clinical endpoints for functional colonic disorders: statistical considerations. Dig Dis Sci. 2013;58:509–518.
    1. Vijayvargiya P, Camilleri M, Chedid V, et al. Effects of promotility agents on gastric emptying and symptoms: a systematic review and meta‐analysis. Gastroenterology. 2019;156:1650–1660.
    1. Camilleri M, Colemont LJ, Phillips SF, et al. Human gastric emptying and colonic filling of solids characterized by a new method. Am J Physiol. 1989;257:G284–G290.
    1. Greydanus MP, Camilleri M, Colemont LJ, et al. Ileocolonic transfer of solid chyme in small intestinal neuropathies and myopathies. Gastroenterology. 1990;99:158–164.
    1. Ohe MRVD, Camilleri M, Kvols LK, et al. Motor dysfunction of the small bowel and colon in patients with the carcinoid syndrome and diarrhea. N Engl J Med. 1993;329:1073–1078.
    1. von der Ohe MR, Camilleri M, Thomforde GM, et al. Differential regional effects of octreotide on human gastrointestinal motor function. Gut. 1995;36:743–748.
    1. Saslow SB, Scolapio JS, Camilleri M, et al. Medium‐term effects of a new 5HT3 antagonist, alosetron, in patients with carcinoid diarrhoea. Gut. 1998;42:628–634.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren