The effects of encapsulated oral formulation of semaglutide, which is a diabetes medication, on stomach emptying, blood sugar, and body weight in people who are overweight or obese, with or without type 2 diabetes (Oral-SAGE study)

Oral semaglutide capsule, Oraglutide 3-14mg, or matching placebo once weekly for 12 weeks. Oraglutide will be up titrated from 3mg for 4 weeks (weeks 1-4), followed by 7mg for 4 weeks (weeks 5-8) and then 14mg for 4 weeks (weeks 0-12). Oraglutide, has been developed by Diabetology Ltd under Good Manufacturing Practice – Pharmaceutical Inspection Convention Scheme (GMP PICS) guidelines, and has been approved and released for use in this study. Oraglutide is an enteric-coated capsule which contains 3-14 mg of glucagon-like peptide-1 (GLP-1) receptor agonist, semaglutide, with “generally regarded as safe” (GRAS) substances (namely 70.6mg sodium chenodeoxycholate, 33.33mg propyl gallate,1.08mg fumed silica, 9.69mg sodium starch, and 5mg sodium salt). The capsule is to be kept refrigerated at -2 to -8 degrees Celsius prior to use. Screening visit Participants will attend the Clinical Research Facility at the University of Adelaide, Adelaide Health and Medical Sciences Building, for screening visits, after an overnight fast from solids and liquids, in order to review their medical history and current medications and to record their height and weight. Body composition will be measured using the bioelectrical impedance method. Individuals will have the opportunity to read the Participant Information Sheet and an investigator brochure and to discuss their participation with their family and friends. Gastrointestinal symptoms will be assessed using a standardised questionnaire and The Patient Assessment of Upper Gastrointestinal Disorders Symptom Severity Index (PAGI-SYM) questionnaire. An intravenous cannula will be placed into a forearm vein for blood sampling. A baseline blood sample will be taken for complete blood picture, biochemistry, iron studies, glycosylated haemoglobin (HbA1c) and blood glucose. A urine sample will be collected for the urinary/albumin ratio. For female participants, a serum pregnancy test will be performed. For participants with type 2 diabetes (T2D), autonomic nerve function will also be assessed at the screening visit using standardised cardiovascular reflex tests. Parasympathetic function will be evaluated by the variation (R-R interval) of the HR during deep breathing and the immediate response to standing (“30:15” ratio). The R-R interval will be measured by electrocardiography (ECG). Sympathetic function will be assessed by the fall in systolic blood pressure (BP) in response to standing. Participants will receive instructions on completing patient diaries and self-administered questionnaires. Baseline HbA1c will be determined during the first week of this phase. Double-blind Treatment Phase (12 weeks) Participants who meet the inclusion and exclusion criteria and provide informed consent (prior to any screening procedures) will then be enrolled in the study. Because metformin may increase plasma GLP-1 modestly, individuals taking metformin will cease it 48h prior to the gastric emptying studies (Visits 1 and 4). Baseline study visit (Visit 1) Participants will attend the University of Adelaide, Clinical Research Facility at the Adelaide Health and Medical Sciences Building at 0800h. On the day prior to each study visit, participants will be required to eat a standardised meal (McCain's frozen lasagne) with water only in the evening at approximately 7 pm. 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 Research Facility at 0800h. For female participants, a urine pregnancy test will be performed. Height, weight and body composition will be measured and a gastrointestinal questionnaire will be collected. Then, an intravenous cannula will be placed into a forearm vein for blood sampling. A baseline blood sample (25 mL) will be taken (to measure fasting plasma concentrations of glucose, insulin, C-peptide, glucagon, and gut hormones (glucose-dependent Insulinotropic Polypeptide, glucagon-like peptide-1 (GLP-1),) cholesterol and, triglycerides and inflammatory markers, the participant will complete a visual analogue scale questionnaire to assess gastrointestinal symptoms. Then, participants will consume, within 5 min, a standardised mashed potato meal (369 kcal) comprising 65 g powdered potato and 20 g glucose reconstituted with 250 ml boiling water and labelled with 150 mg of a safe, non-radioactive carbon tracer (13C-acetate) that allows measurement of how quickly the stomach empties by analysing carbon dioxide in the breath. Breath samples will be collected in sealed tubes at baseline (prior to the meal) and at regular intervals (every 5 min for the first hour and then 15 min for the subsequent two hours) between t = 0 to t = 180 min, for subsequent analysis of Carbon dioxide containing a naturally occurring, harmless tracer of carbon (13CO2). 15-mL blood samples for the measurement of plasma concentrations of glucose, insulin, C-peptide, glucagon, gut hormones and visual analogue scale scores, will be collected regularly after the meal (at t=30, 60, 90, 120, 150, 180) to assess postprandial effects. At t = 180 min, after collecting final blood and breath samples, the intravenous cannula will be removed, and participants will then be presented with a standardised cold, buffet-style meal, which is used to assess subsequent energy intake. The meal comprises 4 slices (~120 g) of whole-meal bread, 4 slices (~120 g) of white bread, 100 g sliced ham, 100 g sliced chicken, 85 g sliced cheddar cheese, 100 g lettuce, 100 g sliced tomato, 100 g sliced cucumber, 22 g mayonnaise, 20 g margarine, 1 apple (~170 g), 1 banana (~190 g), 175 g strawberry yogurt, 100 g chocolate custard, 120 g fruit salad, 375 mL iced coffee, 300 mL orange juice, and 600 mL water. The meal has a total energy content of ~2300 kcal (~27% fat, ~52% carbohydrate, and ~21% protein) and weight of ~2924 g. Participants will be allowed 30 min to freely consume food until they are comfortably full. Each food item will be weighed before and after being offered to the participants and energy intake and macronutrient composition calculated using commercially available software (Foodworks 8.0, Xyris Software, Highgate Hill, QLD, Australia). Then, at t = 210 min, the final visual analogue scale measurements will be collected. Blood glucose concentrations will be measured immediately using a glucose oxidase analyser (Yellow Springs Institute, USA). Plasma will be separated from the remainder of each sample and stored at – 80 degrees Celsius for subsequent measurements of plasma markers. At the conclusion of the baseline study, participants will be randomised to receive the first dose of oraglutide QW or placebo and will be observed for 15 minutes and will be allowed to leave the facility when symptom-free and blood glucose level </= 5 mmol/L. The treatment kits will be distributed to everyone, who will be advised to take one capsule orally with a glass of water once per week. Study diaries will be dispensed to all research participants to record medication intake and any potential side effects. Intervention period (Interim study visits at 4 weeks (Visit 2) and 8 weeks (Visit 3) of intervention) Commencing day 0 (Visit 1), each participant will take weekly oraglutide QW or placebo following their gastric emptying measurement (compliance will be checked by phone calls, capsule counts and review of the research participant diary at each study visit). Oraglutide QW will be up titrated in weekly doses from 3 mg for the first 4 weeks, followed by 7mg for the following 4 weeks and then 14mg for the last 4 weeks. At 4 and 8 weeks post-treatment, participants will again attend the University of Adelaide, Clinical Research Facility at the Adelaide Health and Medical Sciences Building after an overnight fast from solids and liquids to check their body weight and composition, and receive a new vial of medication. On each visit, an intravenous cannula will be placed into a forearm vein, and a 17-mL blood sample will be taken to measure plasma semaglutide, fasting glucose and insulin levels. Furthermore, during these clinic visits, the individuals will also undergo a follow-up review of medical history and concomitant medication use, as well as an assessment of adverse events. Participant diaries will be collected and reviewed during the clinic visits, and individuals will be asked to complete the self-administered questionnaires. Post-treatment study visit (Visit 4) (12 weeks of intervention) Participants will again attend the University of Adelaide, Clinical Research Facility at the Adelaide Health and Medical Sciences Building at 0800h, having consumed a standardised meal (McCain's frozen lasagne) with water only in the evening at approximately 7 pm, then fasted overnight, for an identical study as on day 0 (Visit 1), with an extra 5-mL blood sample will be collected at the baseline to measure plasma semaglutide levels. For participants with T2D, autonomic nerve function will also be assessed again same as at the screening visit using standardised cardiovascular reflex tests. Those who discontinue the study early during the double-blind treatment phase will undergo final safety assessments at 12 weeks. Follow-up visit (Visit 5) (16 weeks of intervention) Participants will again attend the Clinical Research Facility 4 weeks after study visit 4 to check their body weight and composition. An intravenous cannula will be placed into a forearm vein, and a 17-mL blood sample will be taken to measure complete blood picture, biochemistry, iron studies, HbA1c and blood glucose, insulin and lipid profile and inflammatory marker levels. A urine sample will be collected for the urinary/albumin ratio. Furthermore, the individuals will also undergo a follow-up review of medical history and concomitant medication use, as well as an assessment of adverse events. Participant compliance with the study medication will be closely monitored throughout the study using multiple strategies. Tablet counts will be conducted at each study visit to confirm adherence to the dosing schedule. Weekly phone calls will be made to participants to reinforce compliance, address any questions, and monitor for potential adverse events. Participants will also maintain a diary recording the date and time of each dose. Any missed doses or deviations from the prescribed regimen will be documented in the study records.