Proof of Principle Study for an Efficacy Trial of Linaclotide for Cystic Fibrosis (MODEL)
A Randomised, Placebo-controlled Crossover Study Defining the Mode of Action of Linaclotide in Healthy Volunteers Using MRI
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.
Visão geral do estudo
Status
Condições
Intervenção / Tratamento
Descrição detalhada
Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. In CF, defective CFTR may lead to various clinical effects on the gastrointestinal (GI) system; indeed, many CF patients report significant GI symptoms, with the most frequent being attributable to the lower GI tract, including bloating, flatulence, abdominal pain, and borborygmi. Moreover, constipation is another prevalent GI symptom in CF patients. It is estimated that 10-57% of CF patients report constipation symptoms, with an even higher prevalence (approximately 73%) in adults over the age of 30. Symptoms such as constipation are hypothesised to occur due to decreased luminal fluid content resulting from a reduction in anion flow, which ultimately leads to increased amounts of viscous mucus and slowed transit of intestinal contents. Presently, these GI symptoms in CF patients are often treated with laxatives and enemas, and in some cases surgical treatment, which can be uncomfortable and invasive, suggesting that alternative treatments are required.
Linaclotide, a drug approved for safe use across Europe and in the UK, is a synthetic analogue of uroguanylin that activates guanylate cyclase-C (GC-C) receptors located on the luminal surface of intestinal epithelial cells. Activation of GC-C increases intracellular cyclic guanosine monophosphate (cGMP), which stimulates cGMP-dependent protein kinase II (PKGII) and protein kinase A (PKA). Collectively, these kinases activate CFTR, leading to chloride and water secretion into the intestinal lumen. In parallel, elevated cGMP inhibits the sodium-hydrogen exchanger 3 (NHE3), thereby reducing sodium and water absorption. Together, these actions promote fluid secretion and accelerate intestinal transit, leading to linaclotide being commonly prescribed for the treatment of chronic idiopathic constipation and irritable bowel syndrome with chronic constipation (IBS-C).
Meta-analyses confirm linaclotide's clinical benefit in chronic idiopathic constipation and IBS-C; however, its role in CF remains uncertain, though anecdotal reports and animal models suggest therapeutic potential. Linaclotide has less than 1% systemic bioavailability and is degraded in the upper small bowel by carboxypeptidases to an active metabolite, with a small proportion of the administered dose recovered in stool, providing exposure throughout the small and large intestine. However, the primary site of action in humans remains undefined.
Traditional perfusion methods provide only segmental information, limiting assessment of the whole intestine. By contrast, magnetic resonance imaging (MRI) enables non-invasive evaluation of gastrointestinal water content across multiple regions. The Nottingham group has validated MRI techniques for quantifying small bowel water content and assessing colonic chyme hydration via T1 mapping. These methods have been successfully applied to study the effects of various pharmacological agents on gastrointestinal function.
Aim: To define the site of action of linaclotide in healthy volunteers using MRI. Identifying the regional effects of linaclotide will help optimise its future evaluation in CF patients. Based on clinical observations in constipation, stool effects emerge within seven days; however, the investigators hypothesise that small bowel changes occur within 1-2 hours of dosing. Therefore, a one-day pre-dosing regimen is expected to elicit a measurable effect on both the small bowel and colon while minimising participant burden.
Subjects will take 290ug linaclotide /placebo on the day prior to study day (day -1) and on the study day
Tipo de estudo
Inscrição (Estimado)
Estágio
- Fase inicial 1
Contactos e Locais
Contato de estudo
- Nome: Josh Thorley, PhD
- Número de telefone: 07342646598
- E-mail: josh.thorley@nottingham.ac.uk
Locais de estudo
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Nottingham, Reino Unido, NG7 2QX
- Recrutamento
- Sir Peter Mansfield Imaging Centre
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Contato:
- Mahbuba Amhed
- Número de telefone: 0115 95 14747
- E-mail: Mahbuba.Ahmed@nottingham.ac.uk
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Critérios de participação
Critérios de elegibilidade
Idades elegíveis para estudo
- Adulto
- Adulto mais velho
Aceita Voluntários Saudáveis
Descrição
Inclusion Criteria:
Participant is willing and able to give informed consent for participation in the study
Not currently taking any medications (except for selective serotonin reuptake inhibitors, low dose tricyclic antidepressants, antihistamines, and oral contraceptive pill).
Aged between 18-60 years.
Ability to conform to the study protocol, including overnight fasting, dietary and lifestyle restriction, administering linaclotide and placebo intervention, MRI scanning, consuming the rice pudding/blue dye meal, and rating stool frequency and appearance.
Exclusion Criteria:
Contraindication to MRI scanning (i.e. metallic implants, pacemakers, history of metallic foreign body in eye(s) and penetrating eye injury, unable to lie flat and relatively still for less than 5 minutes.)
Pregnancy, lactating, or planning pregnancy during the investigation declared by candidate.
History declared by the candidate of pre-existing gastrointestinal disorder that may affect bowel function.
Reported history of previous resection of the oesophagus, stomach, or intestine (excluding appendix).
Intestinal stoma.
Any medical condition that may potentially compromise participation in the study e.g., known food intolerance to rice pudding, known contraindication to the oral administration of linaclotide or placebo.
Has a body mass index (BMI) value less than 18.5 or greater than 35.
Will not agree to follow dietary and lifestyle restrictions required.
Unable to stop drugs known to alter GI motility including mebeverine, opiates, monoamine oxidase inhibitors, phenothiazines, benzodiazepines, calcium channel antagonists for the duration of the study.
Participants who are currently (or in the past 3 months) taking antibiotics or probiotics as these may impact GI function.
Participation in night shift work the week prior to the study day. Night work is defined as working between midnight and 6.00 AM.
Anyone who in the opinion of the investigator is unlikely to be able to comply with the protocol e.g., cognitive dysfunction, chaotic lifestyle related to substance abuse.
Having taken part in a research study in the last 3 months involving invasive procedures or an inconvenience allowance
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Plano de estudo
Como o estudo é projetado?
Detalhes do projeto
- Finalidade Principal: Tratamento
- Alocação: Randomizado
- Modelo Intervencional: Atribuição cruzada
- Mascaramento: Triplo
Armas e Intervenções
Grupo de Participantes / Braço |
Intervenção / Tratamento |
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Experimental: Linaclotide
290 mcg linaclotide across 2 days
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290 mcg, 2 days dosing, oral capsule form
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Comparador de Placebo: Placebo
Lactose placebo
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Placebo form, oral capsules identical to linaclotide
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O que o estudo está medindo?
Medidas de resultados primários
Medida de resultado |
Descrição da medida |
Prazo |
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Small bowel water content
Prazo: Baseline, and 0, 60, 120, 180, 240, 300, 360 minutes post-dose
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Area under curve (AUC) 0-360 minutes Water content in small bowel as assessed by MRI (mL)
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Baseline, and 0, 60, 120, 180, 240, 300, 360 minutes post-dose
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Medidas de resultados secundários
Medida de resultado |
Descrição da medida |
Prazo |
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Colon water content
Prazo: Baseline, and 0, 60, 120, 180, 240, 300, 360 minutes post-dose
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Area under curve (AUC) 0-360 min Water content in the ascending colonic region as assessed by MRI (mL)
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Baseline, and 0, 60, 120, 180, 240, 300, 360 minutes post-dose
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Colonic regional segmental volumes
Prazo: Baseline, and 0, 60, 120, 180, 240, 300, 360 minutes post-dose
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Total volume of regional colonic segments (ascending, transverse, descending, sigmorectal) as assessed by MRI (mL) at each time point.
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Baseline, and 0, 60, 120, 180, 240, 300, 360 minutes post-dose
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Changes in stool consistency
Prazo: 2 days before intervention, 5 days post-intervention
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Stool consistency rated using Bristol stool scale (type 1-7; 7 being watery stool).
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2 days before intervention, 5 days post-intervention
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Changes in whole gut transit time (WGTT)
Prazo: 1 day post-intervention
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Assessed by time to stool discolouration following administration of blue dye paste.
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1 day post-intervention
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Gastrointestinal symptom rating
Prazo: 2 days pre-intervention and 5 days post-intervention
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Assessing the severity of common gastrointestinal symptoms (flatulence / gas passage, diarrhoea / loose stool, bloating, abdominal pain) via Likert-type scale: 0 = not at all
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2 days pre-intervention and 5 days post-intervention
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Changes in stool frequency
Prazo: 2 days before starting intervention and for 5 days post intervention
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Frequency (per day) of bowel movements (number with exact time)
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2 days before starting intervention and for 5 days post intervention
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Small bowel motility
Prazo: Baseline, and 0, 60, 120, 180, 240, 300, 360 minutes post-dose
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Maximum motility score (A.U) of the small bowel as assessed by MRI
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Baseline, and 0, 60, 120, 180, 240, 300, 360 minutes post-dose
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Colaboradores e Investigadores
Patrocinador
Publicações e links úteis
Publicações Gerais
- 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
- Stefano, M. A., Sandy, N. S., Zagoya, C., Duckstein, F., Ribeiro, A. F., Mainz, J. G., & Lomazi, E. A. (2022). Diagnosing constipation in patients with cystic fibrosis applying ESPGHAN criteria. Journal of Cystic Fibrosis, 21(3), 497-501. https://doi.org/10.1016/j.jcf.2021.08.021
- Stefano, M. A., Poderoso, R. E., Mainz, J. G., Ribeiro, J. D., Ribeiro, A. F., & Lomazi, E. A. (2020). Prevalence of constipation in cystic fibrosis patients: a systematic review of observational studies. Jornal de Pediatria, 96(6), 686-692. https://doi.org/10.1016/j.jped.2020.03.004
- Rubinstein, S., Moss, R., & Lewiston, N. (1986). Constipation and Meconium Ileus Equivalent in Patients With Cystic Fibrosis. Pediatrics, 78(3), 473-479. https://doi.org/10.1542/PEDS.78.3.473
- McHugh, D. R., Cotton, C. U., Moss, F. J., Vitko, M., Valerio, D. M., Kelley, T. J., Hao, S., Jafri, A., Drumm, M. L., Boron, W. F., Stern, R. C., McBennett, K., & Hodges, C. A. (2018). Linaclotide improves gastrointestinal transit in cystic fibrosis mice by inhibiting sodium/hydrogen exchanger 3. American Journal of Physiology - Gastrointestinal and Liver Physiology, 315(5), G868. https://doi.org/10.1152/AJPGI.00261.2017
- arciani, L., Wright, J., Foley, S., Hoad, C. L., Totman, J. J., Bush, D., Hartley, C., Armstrong, A., Manby, P., Blackshaw, E., Perkins, A. C., Gowland, P. A., & Spiller, R. C. (2010). Effects of a 5-HT(3) antagonist, ondansetron, on fasting and postprandial small bowel water content assessed by magnetic resonance imaging. Alimentary Pharmacology & Therapeutics, 32(5), 655-663. https://doi.org/10.1111/J.1365-2036.2010.04395.X
- Marciani, L., Garsed, K. C., Hoad, C. L., Fields, A., Fordham, I., Pritchard, S. E., Placidi, E., Murray, K., Chaddock, G., Costigan, C., Lam, C., Jalanka-Tuovinen, J., De Vos, W. M., Gowland, P. A., & Spiller, R. C. (2014). Stimulation of colonic motility by oral PEG electrolyte bowel preparation assessed by MRI: comparison of split vs single dose. Neurogastroenterology and Motility, 26(10), 1426-1436. https://doi.org/10.1111/NMO.12403
- Luo, M., Liu, Y., Nikolovska, K., Riederer, B., Patrucco, E., Hofmann, F., & Seidler, U. (2024). cGMP-dependent kinase 2, Na+/H+ exchanger NHE3, and PDZ-adaptor NHERF2 co-assemble in apical membrane microdomains. Acta Physiologica, 240(4), e14125. https://doi.org/10.1111/APHA.14125
- Hayee, B., Watson, K. L., Campbell, S., Simpson, A., Farrell, E., Hutchings, P., Macedo, P., Perrin, F., Whelan, K., & Elston, C. (2019). A high prevalence of chronic gastrointestinal symptoms in adults with cystic fibrosis is detected using tools already validated in other GI disorders. United European Gastroenterology Journal, 7(7), 881-888. https://doi.org/10.1177/2050640619841545
- Hannig, G., Tchernychev, B., Kurtz, C. B., Bryant, A. P., Currie, M. G., & Silos-Santiago, I. (2014). Guanylate cyclase-C/cGMP: an emerging pathway in the regulation of visceral pain. Frontiers in Molecular Neuroscience, 7(1 APR), 31. https://doi.org/10.3389/FNMOL.2014.00031
- Ford, A. C., & Suares, N. C. (2011). Effect of laxatives and pharmacological therapies in chronic idiopathic constipation: systematic review and meta-analysis. Gut, 60(2), 209-218. https://doi.org/10.1136/GUT.2010.227132
- Dellschaft, N., Murray, K., Ren, Y., Marciani, L., Gowland, P., Spiller, R., & Hoad, C. (2025). Assessing Water Content of the Human Colonic Chyme Using the MRI Parameter T1: A Key Biomarker of Colonic Function. Neurogastroenterology and Motility, 37(4). https://doi.org/10.1111/NMO.14999
- Dellschaft, N., Hoad, C., Marciani, L., Gowland, P., & Spiller, R. (2022). Small bowel water content assessed by MRI in health and disease: a collation of single-centre studies. Alimentary Pharmacology & Therapeutics, 55(3), 327-338. https://doi.org/10.1111/APT.16673
- e Lisle, R. C., & Borowitz, D. (2013). The Cystic Fibrosis Intestine. Cold Spring Harbor Perspectives in Medicine, 3(9), a009753. https://doi.org/10.1101/CSHPERSPECT.A009753
- Corsetti, M., & Tack, J. (2013). Linaclotide: A new drug for the treatment of chronic constipation and irritable bowel syndrome with constipation. United European Gastroenterology Journal, 1(1), 7-20. https://doi.org/10.1177/2050640612474446
- Busby, R. W., Kessler, M. M., Bartolini, W. P., Bryant, A. P., Hannig, G., Higgins, C. S., Solinga, R. M., Tobin, J. V., Wakefield, J. D., Kurtz, C. B., & Currie, M. G. (2013). 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. The Journal of Pharmacology and Experimental Therapeutics, 344(1), 196-206. https://doi.org/10.1124/JPET.112.199430
- Bryant, A. P., Busby, R. W., Bartolini, W. P., Cordero, E. A., Hannig, G., Kessler, M. M., Pierce, C. M., Solinga, R. M., Tobin, J. V., Mahajan-Miklos, S., Cohen, M. B., Kurtz, C. B., & Currie, M. G. (2010). Linaclotide is a potent and selective guanylate cyclase C agonist that elicits pharmacological effects locally in the gastrointestinal tract. Life Sciences, 86(19-20), 760-765. https://doi.org/10.1016/J.LFS.2010.03.015
- Atluri, D. K., Chandar, A. K., Bharucha, A. E., & Falck-Ytter, Y. (2014). Effect of linaclotide in irritable bowel syndrome with constipation (IBS-C): a systematic review and meta-analysis. Neurogastroenterology and Motility, 26(4), 499-509. https://doi.org/10.1111/NMO.12292
- 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. (2025). Magnetic Resonance Imaging Reveals Novel Insights into the Dual Mode of Action of Bisacodyl: A Randomized, Placebo-controlled Trial in Constipation. Clinical Pharmacology and Therapeutics, 117(5), 1284-1291. https://doi.org/10.1002/CPT.3532
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