Effect of Dapagliflozin on IAH in T1DM

Study Overview
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Brief Summary
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Approximately 25% of patients with type 1 diabetes have lost the capacity to timely detect hypoglycaemia, a condition referred to as impaired awareness of hypoglycaemia (IAH) that causes a six-fold higher risk of severe, potentially hazardous, hypoglycaemia. IAH is usually the end-result of a process of habituation to recurrent hypoglycaemia that is potentially reversible. Treatment with sodium glucose cotransporter (SGLT)-2 inhibitors (SGLT-2i) in addition to insulin therapy may decrease the incidence of hypoglycaemia in patients with type 1 diabetes. This study will test the hypothesis that treatment with the SGLT-2 inhibitor, dapagliflozin, added to basal-bolus insulin therapy will improve awareness of hypoglycaemia in patients with type 1 diabetes and IAH. In a randomized doubleblind placebo-controlled cross-over trial, patients will be treated for 8 weeks with dapagliflozin (or placebo), after which hypoglycemic symptoms and counterregulatory hormone responses will be examined during a hyperinsulinemic hypoglycemic glucose clamp study.

Official Title
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Effect of the SGLT-2 Inhibitor Dapagliflozin on Impaired Awareness of Hypoglycemia in Type 1 Diabetes

Conditions
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Diabetes Mellitus, Type 1, Hypoglycemia, Hypoglycemia Unawareness

Intervention / Treatment
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* Drug: Dapagliflozin
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 diabetes, disease duration >1 year Age >18 years, <75 years BMI 19-40 kg/m^2 Insulin treatment according to basal-bolus insulin regimen (injections or insulin pump) Impaired awareness of hypoglycemia as assessed by a score of 3 or more on the modified Dutch translation of the Clarke questionnaire Glycated haemoglobin (HbA1c) ≥42 mmol/mol (6%) and ≤75 mmol/mol (9.0%) Ability to provide informed consent Exclusion Criteria: Treatment with SGLT-2 inhibitors Known intolerance to SGLT-2 inhibitors Treatment with loop diuretics or other anti-hypertensive agents Treatment with glucose-modifying (other than insulin) or immune-modifying agents (e.g. prednisolon) Treatment with pioglitazone Use of statins A history of cardiovascular disease (e.g. myocardial infarction, stroke, heart failure) or hypotension A history of galactose-intolerance, lactase deficiency, glucose-galactose malabsorption History of diabetic ketoacidosis requiring medical intervention within 1 month before screening Admission to the hospital for hyperglycemia or hypoglycemia within 1 month before screening Frequent episodes of severe hypoglycemia within 1 month before screening Laser coagulation for proliferative retinopathy (past 6 months) Proliferative retinopathy Diabetic nephropathy as reflected by an albumin-creatinin ratio ˃ 30 mmol/mg or an estimated glomerular filtration rate (by MDRD) ˂60ml/min/1.73m2 History of pancreatitis (acute or chronic) or pancreatic cancer Use of premixed insulin or of long-acting insulin alone Total daily insulin dose requirements <20 units unless on pump treatment Pregnancy or unwillingness to undertake measures for birth control

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dapagliflozin<br>Dapagliflozin 10 mg capsule once daily for 8 weeks | Drug: Dapagliflozin<br>* 8 weeks treatment with dapagliflozin on top of insulin treatment<br>* Other names: Forxiga;|
| Placebo Comparator: Placebo oral capsule<br>Placebo matched to dapagliflozin 10 mg capsule once daily for 8 weeks | Drug: Placebo oral capsule<br>* 8 weeks treatment with placebo capsules on top of insulin treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptom score in response to insulin-induced hypoglycaemia | Symptom scores (autonomic, neuroglycopenic and general) measured during hyperinsulinemic hypoglycaemic glucose clamps. This questionnaire consists of 18 symptoms, which can be scored between 0 (none) to 6 (severe). Total scores range between 0 and 108, the higher the score, the more symptoms patients have during and after hypoglycemia. | 45 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Counterregulatory hormone responses to insulin-induced hypoglycaemia | (nor)adrenaline, glucagon, insulin, growth hormone and cortisol responses to hypoglycaemia measured during hyperinsulinemic hypoglycaemic glucose clamps | 45 minutes | 
| Time until glycaemic recovery from hypoglycaemia | measured during hyperinsulinemic hypoglycaemic glucose clamps | 45 minutes | 
| Maximal glucose excursion post-hypoglycaemia | Maximal glucose level (mmol/l) measured during the 90 minutes after ending the hypoglycaemic phase of the clamp (during restoration of euglycaemia) | 45 minutes | 
| Time until glucose peak post-hypoglycaemia | measured during hyperinsulinemic hypoglycaemic glucose clamps | 45 minutes | 
| Area under the glucose concentration curve post-hypoglycaemia | measured during hyperinsulinemic hypoglycaemic glucose clamps | 45 minutes | 
| Number of severe hypoglycaemic events during follow-up | measured during follow-up | 16 weeks | 
| Number of nocturnal hypoglycaemic events during follow-up | measured during follow-up | 16 weeks | 
| Number of any hypoglycaemic events during follow-up | measured during follow-up | 16 weeks | 
| Time spent under hypoglycaemic conditions measured by glucose sensor monitoring | measured during follow-up | 2 weeks | 
| Glucose variability as measured by glucose sensor monitoring | measured during follow-up | 2 weeks |