Effect of Dapagliflozin on IAH in T1DM

Diabetes Mellitus, Type 1 Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03556033
• Other study ID #: T1DM_IAH_dapa
• Status: Completed
• Phase: Phase 2
• Start date: November 23, 2018
• Est. completion date: December 20, 2019

Study information

• Verified date: September 2019
• Source: Radboud University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: December 20, 2019
• Est. primary completion date: December 20, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 1
• Hypoglycemia
• Hypoglycemia Unawareness

Intervention

Drug:
• Dapagliflozin
8 weeks treatment with dapagliflozin on top of insulin treatment
• Placebo oral capsule
8 weeks treatment with placebo capsules on top of insulin treatment

Locations

Country	Name	City	State
Netherlands	Radboud university medical center	Nijmegen

Sponsors (1)

Lead Sponsor	Collaborator
Radboud University

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Inflammatory/atherogenic phenotype of circulating monocytes from the participating patients	measured during hyperinsulinemic hypoglycaemic glucose clamps	45 minutes
Primary	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	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
Secondary	Time until glycaemic recovery from hypoglycaemia	measured during hyperinsulinemic hypoglycaemic glucose clamps	45 minutes
Secondary	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
Secondary	Time until glucose peak post-hypoglycaemia	measured during hyperinsulinemic hypoglycaemic glucose clamps	45 minutes
Secondary	Area under the glucose concentration curve post-hypoglycaemia	measured during hyperinsulinemic hypoglycaemic glucose clamps	45 minutes
Secondary	Number of severe hypoglycaemic events during follow-up	measured during follow-up	16 weeks
Secondary	Number of nocturnal hypoglycaemic events during follow-up	measured during follow-up	16 weeks
Secondary	Number of any hypoglycaemic events during follow-up	measured during follow-up	16 weeks
Secondary	Time spent under hypoglycaemic conditions measured by glucose sensor monitoring	measured during follow-up	2 weeks
Secondary	Glucose variability as measured by glucose sensor monitoring	measured during follow-up	2 weeks