Trial ID: ISRCTN58098350
Other - Phase 2 - No longer available
Background and study aims Type 1 diabetes (T1D) affects around 400,000 people in the UK, and is caused by a nearly complete loss of insulin-producing cells in the pancreas. Managing blood sugar levels with insulin injections can be challenging in T1D, and very low blood sugar (hypos) are one of the most feared complications. Disruption of other hormones such as glucagon, which raises blood sugar and counter-balances the effects of insulin during hypos, is now also recognised as part of the disorder. How this happens is not clear, and a better understanding of this mechanism could lead to treatments aimed at reducing the risk of hypos. Glibenclamide (sulfonylurea) is a type of anti-diabetic medication that is commonly used to increase the amount of insulin released by the pancreatic beta-cells. Preclinical studies have shown that sulfonylureas can also improve glucagon levels when used in very small doses by working on pancreatic alpha cells, which release glucagon. In addition, another type of anti-diabetic medication called dapagliflozin has also been shown to work on pancreatic alpha cells. A small pilot study suggested that low doses of glibenclamide (0.3 mg/day) could alter glucagon release in some people with type 2 diabetes without increasing the risk of hypos. The aim of this study is to find out whether similar doses of glibenclamide or a single dose of dapagliflozin could restore glucagon release in people with T1D. It is hoped that add-on therapies such as these may become a new way of helping people with T1D prevent hypo episodes. Who can participate? People with T1D and a control group (non-DM group) without diabetes What does the study involve? People with T1D will be given a liquid form of glibenclamide for a maximum of 54 days, followed by a single dose of dapagliflozin, and undergo five controlled hypoglycaemia challenges (hypo clamps) over 8-10 weeks. The control group (non-DM group) without diabetes will undergo one hypoglycaemia challenge without extra medication What are the possible benefits and risks of participating? As this is a new method of using glibenclamide and dapagliflozin, the researchers are not sure whether it will make a difference to blood sugar levels. For participants with type 1 diabetes, the researchers can provide a print-out of the Libre 2 report at the end of each study step, which will display the blood sugar levels day and night throughout the trial time frame. Although this study at present might not change the way diabetes is managed, it will help get a better understanding of the mechanisms underlying hypoglycaemia in type 1 diabetes and whether these commonly used medications might have a new role in helping people with type 1 diabetes prevent hypoglycaemia episodes in the future. The main serious side-effect of glibenclamide is hypoglycaemia, but the overall risk is low and is dose-dependent. In addition, it is not expected to have any effect on insulin release in participants with type 1 diabetes, as they will have lost most of their insulin-producing cells due to their condition. However, in case of hypoglycaemia, the symptoms can be managed by immediately having a glass of fruit juice (or a sugary drink), then having something to eat such as a banana, a slice of toast or your normal meal. Other possible side effects of glibenclamide (relating to doses higher than those used in this study) include skin rashes, nausea and abdominal discomfort, particularly after drinking alcohol. Dapagliflozin can be associated with increased frequency in passing urine, dizziness or a mild skin rash, but these side effects are usually related to regular dosing rather than as a single dose. The trial will be divided into four 2-week blocks (steps) and each will include a set-up visit and an induced hypoglycaemia challenge. It is not required to complete blocks back to back. The hypoglycaemia challenge (hyperinsulinaemic hypoglycaemic clamp) involves continuous intravenous infusion of insulin and glucose, along with frequent (5 min) blood sampling to maintain blood glucose levels within specific targets. After a period of euglycaemia (target blood glucose 6 mmol/L), glucose levels will be gradually dropped and maintained at the hypoglycaemic range (target 2.5 mmol/L) for a total of 40 min, before glucose levels are then recovered back to euglycaemia. While this is a well-established procedure, the induction of hypoglycaemia can be stressful and the symptoms (sweating, palpitations, agitation, confusion) will likely not have been experienced previously by participants without diabetes. All participants will be screened for high-risk conditions, such as a history of seizures, significant ischaemic heart disease, hypertension or arrhythmias, and they will be monitored closely during the entire procedure. Although only a small amount of blood is taken during each visit of the study and as such no significant after-effects are predicted, however, some people feel dizzy and faint during and after the blood sample is taken or develop an infection from where the blood is drawn. In addition, they might have a small bruise where the needle went in. To minimise these effects, the researchers will use aseptic techniques and appropriate venepuncture methods, as described within the NHS guidelines. Bruises can be painful, but are usually harmless and fade over the next few days. Some individuals may be sensitive to the adhesive that keeps the FreeStyle Libre Sensor (glucose monitoring sensor) attached to the skin. If significant skin irritation around or under your Sensor is noticed, participants will be advised to remove the Sensor and stop using the FreeStyle Libre system. Where is the study run from? University of Oxford (UK) When is the study starting and how long is it expected to run for? July 2023 to May 2025 Who is funding the study? University of Oxford (UK) Who is the main contact? Dr Nkemjika Abiakam, legend-d@dtu.ox.ac.uk
University of Oxford
Source: https://www.isrctn.com/