Gastro-intestinal transit and safety of tirzepatide in people with Prader-Willi Syndrome

This is a 12-week pilot study in 10 people with PWS and obesity with or without type 2 diabetes (aim is to enrol 50% with T2D). There will be no placebo group as this is a preliminary trial. All participants will receive tirzepatide dose of 2.5 mg once weekly for 4 weeks. The dose will be increased to 5 mg once weekly for a further 4 weeks and then to a final dose of 10 mg once weekly for 4 weeks. The study drug will be self administered via subcutaneous injection using pre-loaded vials. Study drug returns will be collected at each clinic visit to monitor adherence. A single-isotope gastric emptying study will be performed at baseline, 4 weeks and 12 weeks to assess gastric emptying and caecal arrival time (CAT). Participants will ingest a test meal with total caloric value 255 kcal and nutritional composition 72% carbohydrate, 24% protein, 2% fat and 2% fibre. The meal comprises 2 slices of bread, 30g strawberry jam and 2 egg whites (120g) radiolabelled with 0.5-1 mCi 99mTc-sulphur colloid and 120 ml water. Images will be acquired immediately after ingestion and at hourly intervals up to 6 hours to assess gastric emptying and caecal arrival time. Participants will need to fast for 10 hours before and up to 6 hours following the 99mTc-sulphur colloid labelled meal. At baseline and week 12, directly after ingestion of the 99mTc-sulphur colloid labelled meal, participants will ingest a gas sensing capsule (Atmo Biosciences), a single-use, non-digestible capsule (28x11 mm). This capsule measures concentrations of hydrogen and carbon dioxide, temperature, capsule orientation and changes in the physical electromagnetic properties of the environment surrounding the capsule. Measurements are transmitted from the capsule at a frequency of 434 MHz to a patient-worn data receiver and subsequently uploaded to secure cloud storage via mobile device for analysis and review. The receiver, which allows for bowel movements to be recorded, is worn by participants until the capsule is excreted. The totality of this system provides a measurement of regional and whole gut transit time. It has been validated against the FDA-approved wireless motility capsule but not against scintigraphy. Unlike water-labelled 67Ga-EDTA studies, the current gold standard for measurement of colonic transit, the gas sensing capsule does not involve any radiation exposure nor do patients need to represent for images at 24, 48 and 72 hours. To further assess lower bowel function, participants will be asked to complete a stool chart for 1 week before starting tirzepatide, at weeks 4, 8 and 12 of the study. They will also be asked to complete a validated questionnaire, with assistance from their carer, in plain language covering the Rome IV constipation criteria at week -1, weeks 5, 9 and 13. At each study visit (baseline, week 4, week 8 and week 12), participants will be asked about gastro-intestinal symptoms. To test the efficacy of tirzepatide on weight loss and effects on appetite and behaviour, anthropometry, hyperphagia score, behaviour questionnaires will be taken at baseline and study completion (ie week 12). Arterial stiffness will be assessed at baseline, each dose escalation visit and the final study visit to assess if tirzepatide changes these parameters. Appetite and fullness will be assessed during the scintigraphic studies using validated visual analogue scales (VAS). To assess effects of tirzepatide on metabolic parameters a fasting blood test (to measure glucose, lipids, HbA1c and liver function) will be done at baseline and week 12. To assess whether tirzepatide improves sleep apnoea, overnight pulse oximetry will be assessed at baseline (before starting tirzepatide) and in the week before the final visit at the patient’s abode. Sleep apnoea is characterised by temporary disruptions in breathing, leading to decreased blood oxygen levels. Oximeters, worn on the finger or wrist, continuously monitor oxygen saturation levels throughout the night, and can thereby demonstrate whether there are any changes in the degree of sleep apnoea.