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Effect of Dapagliflozin on IAH in T1DM

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ClinicalTrials.gov Identifier: NCT03556033
Recruitment Status : Not yet recruiting
First Posted : June 14, 2018
Last Update Posted : June 14, 2018
Sponsor:
Information provided by (Responsible Party):
Radboud University

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.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 1 Hypoglycemia Hypoglycemia Unawareness Drug: Dapagliflozin Drug: Placebo oral capsule Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effect of the SGLT-2 Inhibitor Dapagliflozin on Impaired Awareness of Hypoglycemia in Type 1 Diabetes
Estimated Study Start Date : August 2018
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Dapagliflozin
Dapagliflozin 10 mg capsule once daily for 8 weeks
Drug: Dapagliflozin
8 weeks treatment with dapagliflozin on top of insulin treatment
Other Name: Forxiga

Placebo Comparator: Placebo oral capsule
Placebo matched to dapagliflozin 10 mg capsule once daily for 8 weeks
Drug: Placebo oral capsule
8 weeks treatment with placebo capsules on top of insulin treatment




Primary Outcome Measures :
  1. Symptom score in response to insulin-induced hypoglycaemia [ Time Frame: 45 minutes ]
    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 :
  1. Counterregulatory hormone responses to insulin-induced hypoglycaemia [ Time Frame: 45 minutes ]
    (nor)adrenaline, glucagon, insulin, growth hormone and cortisol responses to hypoglycaemia measured during hyperinsulinemic hypoglycaemic glucose clamps

  2. Time until glycaemic recovery from hypoglycaemia [ Time Frame: 45 minutes ]
    measured during hyperinsulinemic hypoglycaemic glucose clamps

  3. Maximal glucose excursion post-hypoglycaemia [ Time Frame: 45 minutes ]
    Maximal glucose level (mmol/l) measured during the 90 minutes after ending the hypoglycaemic phase of the clamp (during restoration of euglycaemia)

  4. Time until glucose peak post-hypoglycaemia [ Time Frame: 45 minutes ]
    measured during hyperinsulinemic hypoglycaemic glucose clamps

  5. Area under the glucose concentration curve post-hypoglycaemia [ Time Frame: 45 minutes ]
    measured during hyperinsulinemic hypoglycaemic glucose clamps

  6. Number of severe hypoglycaemic events during follow-up [ Time Frame: 16 weeks ]
    measured during follow-up

  7. Number of nocturnal hypoglycaemic events during follow-up [ Time Frame: 16 weeks ]
    measured during follow-up

  8. Number of any hypoglycaemic events during follow-up [ Time Frame: 16 weeks ]
    measured during follow-up

  9. Time spent under hypoglycaemic conditions measured by glucose sensor monitoring [ Time Frame: 2 weeks ]
    measured during follow-up

  10. Glucose variability as measured by glucose sensor monitoring [ Time Frame: 2 weeks ]
    measured during follow-up


Other Outcome Measures:
  1. Inflammatory/atherogenic phenotype of circulating monocytes from the participating patients [ Time Frame: 45 minutes ]
    measured during hyperinsulinemic hypoglycaemic glucose clamps



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03556033


Contacts
Contact: L. van Meijel +312410846 Lian.vanMeijel@radboudumc.nl
Contact: B. de Galan, Dr. +31243618819 Bastiaan.deGalan@radboudumc.nl

Locations
Netherlands
Radboud university medical center Not yet recruiting
Nijmegen, Netherlands, 6500HB
Contact: L. van Meijel         
Sponsors and Collaborators
Radboud University

Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT03556033     History of Changes
Other Study ID Numbers: T1DM_IAH_dapa
First Posted: June 14, 2018    Key Record Dates
Last Update Posted: June 14, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Hypoglycemia
Unconsciousness
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Consciousness Disorders
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms