None listed
Conditions
Brief summary
‘GLY-200' is an orally-administered, pH-dependent, gut-restricted therapeutic polymer developed by Glyscend Therapeutics. GLY-200 interacts with the mucus on the surface of the duodenum (the first part of the small intestine) to form a temporary barrier that lasts several hours. This mimics the effects of gastric bypass surgery – a very effective surgical procedure for type 2 diabetes and obesity – where the duodenum is removed from contact with meal contents. We don’t fully understand how excluding the duodenum from contact with nutrients results in lowering of blood glucose or body weight, but possible mechanisms include slowing of stomach emptying or passage of contents through the small intestine, reduction in glucose absorption from the duodenum, or changes in the levels of hormones secreted by the small intestine. This study is designed to investigate these possible mechanisms, in both healthy volunteers and people with type 2 diabetes treated only with diet or metformin.
Interventions
Participants who pass the screening visit will be randomised in a schedule determined by the Investigational Drugs Pharmacy, Royal Adelaide Hospital, in a double-blind, crossover design. After a 14-day run-in, including cessation of metformin for those usually metformin-treated, participants will undergo 2 treatment periods of 7 days each, separated by an interval of at least 14 days. The treatments will consist of GLY-200 2.0 g or placebo, given twice daily with 100 mL water, one hour before br
Participants who pass the screening visit will be randomised in a schedule determined by the Investigational Drugs Pharmacy, Royal Adelaide Hospital, in a double-blind, crossover design. After a 14-day run-in, including cessation of metformin for those usually metformin-treated, participants will undergo 2 treatment periods of 7 days each, separated by an interval of at least 14 days. The treatments will consist of GLY-200 2.0 g or placebo, given twice daily with 100 mL water, one hour before breakfast and dinner, provided in four matching gelatin capsules each containing 0.5 g GLY-200 or 0.5 g microcrystalline cellulose. During each treatment period, and for 3 days before and after, participants will keep a daily record of upper gastrointestinal (GI) symptoms (using the Gastroparesis Cardinal Symptom Index Daily Diary (GCSI-DD)), and stool frequency and form (using the Bristol Stool Form Scale (BSFS)). Scores pertaining to the previous 24 hours will be recorded each evening, with daily reminder prompts by SMS. During each treatment week, participants will also have a daily telephone call with one of the investigators to reinforce compliance and monitor adverse events. Participants will attend the clinical research facility (CRF) at Adelaide Health and Medical Science Building (AHMS) on the final day of each treatment period. On the evening preceding each of these study days (~1900h), participants will be given a standardised evening meal (McCain’s frozen beef lasagne (McCain Foods Proprietary Ltd, Victoria, Australia; or vegetarian lasagne for participants who are vegetarians) to consume with water. Following this meal, participants will be asked to fast from solids and liquids (water may be consumed until 10 pm) until the following morning, when they will attend the CRF of the AHMS building at 0800h. On each study day, participants will attend the CRF at 0800h. Participants receiving treatment for hypertension will withhold their antihypertensive medication on the morning of the study. An intravenous cannula will be placed into a forearm vein for blood sampling (t = -80 min) and participants will then be seated with their back against a gamma camera. After 20 min quiet rest time to accommodate to laboratory conditions, participants will swallow the 4 capsules containing study drug or placebo, according to their current treatment phase, together with 100 mL water (t = -60 min). At t = -5 min, participants will be given a mashed potato meal consisting of 65 g powdered mashed potato (Deb Instant; Continental, Sydney, Australia), 45 g margarine (Flora Original; Unilever, Sydney, Australia), 20 g glucose, 3 g of the non-metabolised glucose analogue 3-O-methylglucose (3-OMG), and 200 mL water, and the meal will be radiolabelled with 20 MBq 99mTc-calcium phytate. They will consume the meal over 5 min, together with a drink of 100 mL water. The meal will contain 2,687 kJ (642 kcal), with 72.3 g carbohydrate, 35.5 g fat, and 8.1 g protein. Scintigraphic images will be acquired every minute for the first hour (t = 0 – 60 min), then at 3-min intervals for another 5 hours (t = 60 – 360 min). A left lateral image of the stomach will be acquired to correct for gamma-ray attenuation, and data will also be corrected for radioactive decay and subject movement. A region of interest will be drawn around the stomach, and percent retention determined at 0, 15, 30, 45, 60, 75, 90, 105, 120, 150, 210, 240, 270, 300, 330, and 360 min. The time taken for the stomach to empty 50% (T50) will also be calculated. Proximal and distal regions of the stomach will be defined, in order to evaluate intragastric meal distribution, as previously described. A region of interest will also be drawn around the colon using a composite image, and used to identify the caecal arrival time as a measure of small intestinal transit. Blood will be sampled from the intravenous (IV) cannula, with the arm kept warm with a heat pad, at t = -65, -10, 15, 30, 60, 90, 120, 180, 240, 300, and 360 min (20 mL per time point, total 220 mL per study day). Gastrointestinal symptoms and appetite perceptions will be monitored using 100mm visual analogue scales at the same intervals as blood sampling. Heart rate and blood pressure will also be monitored every 15 min throughout the study, increasing to every 5 min during t = 0 to 120 min, by an automated sphygmomanometer. The mean of the 3 fasting measurements preceding the meal will be used as a baseline. At t = 360 min, a buffet meal will be provided from which participants will be allowed to eat as much as they wish for 30 min, from which energy intake will be quantified. The IV cannula will then be removed and participants will be able to leave the facility.
Sponsors
The University of Adelaide
Study design
Allocation
Randomised controlled trial
Intervention model
Crossover
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
40 Years to 79 Years
Healthy volunteers
Yes
Inclusion criteria
Healthy Volunteers • Healthy males and females aged between 40 to 79 years • Body mass index (BMI) between 19 to 32 kg/m2 • HbA1c less than 5.7% • Fasting blood glucose less than 5.6 mmol/L T2D patients • Type 2 diabetes (T2D, World Health Organisation criteria) • Males and females aged from 40 to 79 years • BMI from 20 to 40 kg/m2 (i.e. a higher range than in the healthy participants to allow for the greater tendency for overweight/obesity in people with T2D) • HbA1c less than 8.5% on stable (over 3 months) treatment with diet and/or metformin alone
Exclusion criteria
• Use of any medication that may influence gastrointestinal motor function, body weight or appetite (opiates, anticholinergics, levodopa, clonidine, nitrates, phosphodiesterase type 5 inhibitors, sumatriptan, GLP-1 receptor agonists, metoclopramide, domperidone, prucalopride, or erythromycin) • Use of medications that raise gastric pH, including proton pump inhibitors and H2 receptor antagonists • Evidence of drug abuse, or consumption of more than 20 g alcohol, or 10 cigarettes, daily • History of gastrointestinal disease, including significant upper or lower gastrointestinal symptoms (once weekly or more, or any history of swallowing difficulties, on the Digestive Health and Wellbeing Survey Short Form) or previous gastrointestinal surgery (other than uncomplicated appendicectomy or cholecystectomy) • History of any form of heart disease or symptoms of syncope or pre-syncope (including feeling lightheaded or dizzy, feeling unsteady when standing, unexplained falls, fainting, unexplained changes in vision, such as blurring or tunnel vision) • Other significant illness, including epilepsy or respiratory disease • Haemoglobin below the lower limit of the normal range (ie. less than 135 g/L for men and 115 g/L for women), and ferritin below the lower limit of normal (ie. less than 30 mg/mL) • Impaired renal or liver function (as assessed by calculated estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73m2 or abnormal liver function tests (more than 1.5 times upper limit of normal range)) • Donation of blood within the previous 3 months • Participation in any other research studies within the previous 3 months • Exposure to ionising radiation for research purposes that exceeds 3.5 mSv within the previous 12 months • Inability to give informed consent • Female participants who are pregnant or planning for pregnancy, or are lactating
Outcome results
None listed