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Effect of Dapagliflozin on IAH in T1DM

Primary Purpose

Diabetes Mellitus, Type 1, Hypoglycemia, Hypoglycemia Unawareness

Status
Completed
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
Dapagliflozin
Placebo oral capsule
Sponsored by
Radboud University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diabetes Mellitus, Type 1

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Radboud university medical center

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Dapagliflozin

Placebo oral capsule

Arm Description

Dapagliflozin 10 mg capsule once daily for 8 weeks

Placebo matched to dapagliflozin 10 mg capsule once daily for 8 weeks

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Counterregulatory hormone responses to insulin-induced hypoglycaemia
(nor)adrenaline, glucagon, insulin, growth hormone and cortisol responses to hypoglycaemia measured during hyperinsulinemic hypoglycaemic glucose clamps
Time until glycaemic recovery from hypoglycaemia
measured during hyperinsulinemic hypoglycaemic glucose clamps
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)
Time until glucose peak post-hypoglycaemia
measured during hyperinsulinemic hypoglycaemic glucose clamps
Area under the glucose concentration curve post-hypoglycaemia
measured during hyperinsulinemic hypoglycaemic glucose clamps
Number of severe hypoglycaemic events during follow-up
measured during follow-up
Number of nocturnal hypoglycaemic events during follow-up
measured during follow-up
Number of any hypoglycaemic events during follow-up
measured during follow-up
Time spent under hypoglycaemic conditions measured by glucose sensor monitoring
measured during follow-up
Glucose variability as measured by glucose sensor monitoring
measured during follow-up

Full Information

First Posted
May 17, 2018
Last Updated
March 20, 2020
Sponsor
Radboud University Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT03556033
Brief Title
Effect of Dapagliflozin on IAH in T1DM
Official Title
Effect of the SGLT-2 Inhibitor Dapagliflozin on Impaired Awareness of Hypoglycemia in Type 1 Diabetes
Study Type
Interventional

2. Study Status

Record Verification Date
September 2019
Overall Recruitment Status
Completed
Study Start Date
November 23, 2018 (Actual)
Primary Completion Date
December 20, 2019 (Actual)
Study Completion Date
December 20, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Radboud University Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus, Type 1, Hypoglycemia, Hypoglycemia Unawareness

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Dapagliflozin
Arm Type
Active Comparator
Arm Description
Dapagliflozin 10 mg capsule once daily for 8 weeks
Arm Title
Placebo oral capsule
Arm Type
Placebo Comparator
Arm Description
Placebo matched to dapagliflozin 10 mg capsule once daily for 8 weeks
Intervention Type
Drug
Intervention Name(s)
Dapagliflozin
Other Intervention Name(s)
Forxiga
Intervention Description
8 weeks treatment with dapagliflozin on top of insulin treatment
Intervention Type
Drug
Intervention Name(s)
Placebo oral capsule
Intervention Description
8 weeks treatment with placebo capsules on top of insulin treatment
Primary Outcome Measure Information:
Title
Symptom score in response to insulin-induced hypoglycaemia
Description
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.
Time Frame
45 minutes
Secondary Outcome Measure Information:
Title
Counterregulatory hormone responses to insulin-induced hypoglycaemia
Description
(nor)adrenaline, glucagon, insulin, growth hormone and cortisol responses to hypoglycaemia measured during hyperinsulinemic hypoglycaemic glucose clamps
Time Frame
45 minutes
Title
Time until glycaemic recovery from hypoglycaemia
Description
measured during hyperinsulinemic hypoglycaemic glucose clamps
Time Frame
45 minutes
Title
Maximal glucose excursion post-hypoglycaemia
Description
Maximal glucose level (mmol/l) measured during the 90 minutes after ending the hypoglycaemic phase of the clamp (during restoration of euglycaemia)
Time Frame
45 minutes
Title
Time until glucose peak post-hypoglycaemia
Description
measured during hyperinsulinemic hypoglycaemic glucose clamps
Time Frame
45 minutes
Title
Area under the glucose concentration curve post-hypoglycaemia
Description
measured during hyperinsulinemic hypoglycaemic glucose clamps
Time Frame
45 minutes
Title
Number of severe hypoglycaemic events during follow-up
Description
measured during follow-up
Time Frame
16 weeks
Title
Number of nocturnal hypoglycaemic events during follow-up
Description
measured during follow-up
Time Frame
16 weeks
Title
Number of any hypoglycaemic events during follow-up
Description
measured during follow-up
Time Frame
16 weeks
Title
Time spent under hypoglycaemic conditions measured by glucose sensor monitoring
Description
measured during follow-up
Time Frame
2 weeks
Title
Glucose variability as measured by glucose sensor monitoring
Description
measured during follow-up
Time Frame
2 weeks
Other Pre-specified Outcome Measures:
Title
Inflammatory/atherogenic phenotype of circulating monocytes from the participating patients
Description
measured during hyperinsulinemic hypoglycaemic glucose clamps
Time Frame
45 minutes

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Facility Information:
Facility Name
Radboud university medical center
City
Nijmegen
ZIP/Postal Code
6500HB
Country
Netherlands

12. IPD Sharing Statement

Plan to Share IPD
No

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Effect of Dapagliflozin on IAH in T1DM

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