Proof of Principle Study for an Efficacy Trial of Linaclotide for Cystic Fibrosis

Summary

Linaclotide is a medicine used to treat constipation and irritable bowel syndrome with constipation (IBS-C). It works by acting on the surface of the gut lining, where it increases the movement of salt and water into the bowel. This softens stools, makes them easier to pass, and can also reduce gut pain One advantage of linaclotide is that, unlike some natural substances in the gut, it is stable and can act throughout the intestine. Studies in animals show that it has the strongest effect in the upper small intestine, but it may act in other parts of the bowel as well. In people, however, it is not yet clear whether linaclotide mainly works in the small intestine or in the large intestine (colon). Knowing this is important, because it could help the investigators understand whether linaclotide might also be useful in other conditions, such as cystic fibrosis, where the gut does not handle fluid properly. Linaclotide is taken as a capsule, but less than 1% is absorbed into the bloodstream. Instead, it stays in the gut, where it is broken down into smaller active parts. This means both the small intestine and colon may be exposed to its effects. Until now, it has been hard to study this because traditional methods only measure one part of the gut at a time. A team at the University of Nottingham has developed MRI scanning methods that can safely and non-invasively measure water content in the small intestine and colon. The aim of this pilot study is to use MRI in healthy volunteers to see exactly where linaclotide acts. This knowledge will help optimise future studies in conditions such as cystic fibrosis.

Timeline

Start

2026-03-09

Primary completion

2026-08

Completion

2026-10

Publications

• Background Wilkinson-Smith, V., Hoad, C., Atkinson, D., Marciani, L., Corsetti, M., Scott, S. M., Taylor, S., Gowland, P., & Spiller, R. (2021). O59 MRI methods to define colonic function in health and constipation. Gut, 70(Suppl 1), A32-A33. https://doi.org/10.1136/GUTJNL-2020-BSGCAMPUS.59
• Background Stefano MA, Sandy NS, Zagoya C, Duckstein F, Ribeiro AF, Mainz JG, Lomazi EA. Diagnosing constipation in patients with cystic fibrosis applying ESPGHAN criteria. J Cyst Fibros. 2022 May;21(3):497-501. doi: 10.1016/j.jcf.2021.08.021. Epub 2021 Sep 9. No abstract available.
• Background Stefano MA, Poderoso RE, Mainz JG, Ribeiro JD, Ribeiro AF, Lomazi EA. Prevalence of constipation in cystic fibrosis patients: a systematic review of observational studies. J Pediatr (Rio J). 2020 Nov-Dec;96(6):686-692. doi: 10.1016/j.jped.2020.03.004. Epub 2020 May 8.
• Background Rubinstein S, Moss R, Lewiston N. Constipation and meconium ileus equivalent in patients with cystic fibrosis. Pediatrics. 1986 Sep;78(3):473-9.
• Background McHugh DR, Cotton CU, Moss FJ, Vitko M, Valerio DM, Kelley TJ, Hao S, Jafri A, Drumm ML, Boron WF, Stern RC, McBennett K, Hodges CA. Linaclotide improves gastrointestinal transit in cystic fibrosis mice by inhibiting sodium/hydrogen exchanger 3. Am J Physiol Gastrointest Liver Physiol. 2018 Nov 1;315(5):G868-G878. doi: 10.1152/ajpgi.00261.2017. Epub 2018 Aug 17.
• Background Marciani L, Wright J, Foley S, Hoad CL, Totman JJ, Bush D, Hartley C, Armstrong A, Manby P, Blackshaw E, Perkins AC, Gowland PA, Spiller RC. Effects of a 5-HT(3) antagonist, ondansetron, on fasting and postprandial small bowel water content assessed by magnetic resonance imaging. Aliment Pharmacol Ther. 2010 Sep;32(5):655-63. doi: 10.1111/j.1365-2036.2010.04395.x.
• Background Marciani L, Garsed KC, Hoad CL, Fields A, Fordham I, Pritchard SE, Placidi E, Murray K, Chaddock G, Costigan C, Lam C, Jalanka-Tuovinen J, De Vos WM, Gowland PA, Spiller RC. Stimulation of colonic motility by oral PEG electrolyte bowel preparation assessed by MRI: comparison of split vs single dose. Neurogastroenterol Motil. 2014 Oct;26(10):1426-36. doi: 10.1111/nmo.12403. Epub 2014 Jul 24.
• Background Luo M, Liu Y, Nikolovska K, Riederer B, Patrucco E, Hofmann F, Seidler U. cGMP-dependent kinase 2, Na+/H+ exchanger NHE3, and PDZ-adaptor NHERF2 co-assemble in apical membrane microdomains. Acta Physiol (Oxf). 2024 Apr;240(4):e14125. doi: 10.1111/apha.14125. Epub 2024 Mar 27.
• Background Hayee B, Watson KL, Campbell S, Simpson A, Farrell E, Hutchings P, Macedo P, Perrin F, Whelan K, Elston C. A high prevalence of chronic gastrointestinal symptoms in adults with cystic fibrosis is detected using tools already validated in other GI disorders. United European Gastroenterol J. 2019 Aug;7(7):881-888. doi: 10.1177/2050640619841545.
• Background Hannig G, Tchernychev B, Kurtz CB, Bryant AP, Currie MG, Silos-Santiago I. Guanylate cyclase-C/cGMP: an emerging pathway in the regulation of visceral pain. Front Mol Neurosci. 2014 Apr 16;7:31. doi: 10.3389/fnmol.2014.00031. eCollection 2014.
• Background Ford AC, Suares NC. Effect of laxatives and pharmacological therapies in chronic idiopathic constipation: systematic review and meta-analysis. Gut. 2011 Feb;60(2):209-18. doi: 10.1136/gut.2010.227132.
• Background Dellschaft N, Murray K, Ren Y, Marciani L, Gowland P, Spiller R, Hoad C. Assessing Water Content of the Human Colonic Chyme Using the MRI Parameter T1: A Key Biomarker of Colonic Function. Neurogastroenterol Motil. 2025 Apr;37(4):e14999. doi: 10.1111/nmo.14999. Epub 2025 Jan 10.
• Background Dellschaft N, Hoad C, Marciani L, Gowland P, Spiller R. Small bowel water content assessed by MRI in health and disease: a collation of single-centre studies. Aliment Pharmacol Ther. 2022 Feb;55(3):327-338. doi: 10.1111/apt.16673. Epub 2021 Oct 30.
• Background De Lisle RC, Borowitz D. The cystic fibrosis intestine. Cold Spring Harb Perspect Med. 2013 Sep 1;3(9):a009753. doi: 10.1101/cshperspect.a009753.
• Background Corsetti M, Tack J. Linaclotide: A new drug for the treatment of chronic constipation and irritable bowel syndrome with constipation. United European Gastroenterol J. 2013 Feb;1(1):7-20. doi: 10.1177/2050640612474446.
• Background Busby RW, Kessler MM, Bartolini WP, Bryant AP, Hannig G, Higgins CS, Solinga RM, Tobin JV, Wakefield JD, Kurtz CB, Currie MG. Pharmacologic properties, metabolism, and disposition of linaclotide, a novel therapeutic peptide approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. J Pharmacol Exp Ther. 2013 Jan;344(1):196-206. doi: 10.1124/jpet.112.199430. Epub 2012 Oct 22.
• Background Bryant AP, Busby RW, Bartolini WP, Cordero EA, Hannig G, Kessler MM, Pierce CM, Solinga RM, Tobin JV, Mahajan-Miklos S, Cohen MB, Kurtz CB, Currie MG. Linaclotide is a potent and selective guanylate cyclase C agonist that elicits pharmacological effects locally in the gastrointestinal tract. Life Sci. 2010 May 8;86(19-20):760-5. doi: 10.1016/j.lfs.2010.03.015. Epub 2010 Mar 20.
• Background Atluri DK, Chandar AK, Bharucha AE, Falck-Ytter Y. Effect of linaclotide in irritable bowel syndrome with constipation (IBS-C): a systematic review and meta-analysis. Neurogastroenterol Motil. 2014 Apr;26(4):499-509. doi: 10.1111/nmo.12292. Epub 2013 Dec 18.
• Background Aliyu A, Dellschaft N, Hoad C, Williams H, Gaudoin E, Sulaiman S, Crooks C, Gowland P, Aran A, Lange R, Bois De Fer B, Corsetti M, Marciani L, Spiller R. Magnetic Resonance Imaging Reveals Novel Insights into the Dual Mode of Action of Bisacodyl: A Randomized, Placebo-controlled Trial in Constipation. Clin Pharmacol Ther. 2025 May;117(5):1284-1291. doi: 10.1002/cpt.3532. Epub 2024 Dec 16.

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Indications