MRI Parameters as Biomarkers in Cystic Fibrosis (FEMPTO)

Background: The recent James Lind Alliance priority setting listed "How can we relieve gastro-intestinal symptoms, such as stomach pain, bloating and nausea?" as number 3 priority despite treatment with CFTR modulators. The investigators have shown using magnetic resonance imaging (MRI) that pwCF have abnormal small bowel contents which empty more slowly into the colon. This is most likely due to impaired pancreatic, biliary and intestinal secretions leading to hyperviscosity of contents. Linaclotide is a drug which stimulates bicarbonate secretion in the small intestine which has been shown to accelerate transit in mice models of CF but not in patients. Its action would be predicted to reduce mucus viscosity and normalise small bowel contents and transit.

Aims: to perform a mechanistic pilot study using MRI to show that linaclotide normalises small bowel contents and transit times.

Methods: A randomised, placebo-controlled trial of linaclotide in pwCF. Linaclotide 290ug will be taken on the day before and on the MRI study day. Patients will then undergo serial MRI scanning for 6 hours following dosing at time T 0 , with a standard rice pudding meal at time T60 and a second 700kcal meal at T 300 minutes with the final scan at time T360minutes as the investigators have done previously. The investigators will measure small bowel water content (SBWC) as well as time for chyme to enter the colon (orocaecal transit time [OCTT]) and T1 ascending colon(T1AC), a measure of colonic water content. Primary endpoint: SBWC AUC 0-6hours . Secondary endpoints: change in SBWC after second meal from T300 to T360 ( ∆ SBWC), OCTT, T1 AC AUC 0-6 hours, bowel frequency and stool consistency on study day and the following 3 days.

Impact: If successful this will provide a mechanistic rationale for a full 12 week clinical study of linaclotide as adjunctive treatment for pwCF.

Inclusion criteria

• • Participant is willing and able to give informed consent for participation in the study.

• Proven diagnosis of CF.
• 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 two study meals and blue muffins, and rating stool frequency and appearance.

Exclusion criteria

• Pregnant (current or planned during the study duration) or breastfeeding
• Currently taking regular medicines (i.e., pain relief medication like ibuprofen/paracetamol) apart from cystic fibrosis medicines (i.e., pancreatic enzyme replacement therapy (PERT) medication, CFTR modulators). There are some other medicines it is OK to take such as:
• Some antidepressants (SSRIs or low-dose tricyclics)
• Antihistamines (for allergies)
• The contraceptive pill
• Any resections (surgery) of the intestines, not including removal of the appendix
• Serious medical conditions including any other digestive disorder unrelated to CF.
• Taken a course of intravenous or oral antibiotics in the last 2 weeks (except prophylactic antibiotics such as azithromycin).
• Inability to stop opiates
• Inability to have MRI scans (this could be due to some metallic implants, pacemaker, history of metallic foreign body in your eye and penetrating eye injury)
• Night shift work during the week before study days
• BMI under 18.5 or above 35 kg/m2.
• Taken part in a CTIMP study in the last 4 weeks involving invasive procedures.
• currently has chronic diarrhoea symptoms.