Dipeptidyl Peptidase-4 Inhibitors and Alpha-cell Recovery (DARE)

This study has been completed.
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
F Holleman, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier:
NCT01272583
First received: January 5, 2011
Last updated: February 14, 2014
Last verified: February 2014
  Purpose

Hypoglycaemia is a well-known complication of insulin treated diabetes. The counterregulatory response to hypoglycaemia, with glucagon as the most important mediator, is initially diminished within a few years of onset of Type 1 diabetes and subsequently lost and thus increasing the risk of hypoglycaemia. Dipeptidyl Peptidase (DPP)-4 inhibitors augment the glucagon response to insulin-induced hypoglycaemia in type 2 diabetes. The investigators hypothesize that treatment with a DPP-4 inhibitor in patients with type 1 diabetes will recover the alpha cell response to hypoglycaemia.


Condition Intervention
Type 1 Diabetes
Hypoglycemia
Drug: Sitagliptin
Drug: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Official Title: Effects of 6 Weeks Treatment With a Dipeptidyl Peptidase 4 Inhibitor on Counterregulatory and Incretin Hormones During Acute Hypoglycaemia in Patients With Type 1 Diabetes: a Randomized Double Blind Placebo-controlled Cross-over Study

Resource links provided by NLM:


Further study details as provided by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):

Primary Outcome Measures:
  • Glucagon Response to Acute Hypoglycaemia [ Time Frame: Change from initialisation phase to 40 minutes after onset of hypoglycaemia ] [ Designated as safety issue: No ]
    Change in glucagon concentration from the initialisation phase to 40 minutes after occurrence of the autonomic reaction to hypoglycaemia

  • Glucagon Response to Acute Hypoglycaemia [ Time Frame: 0, 10, 20 and 40 minutes ] [ Designated as safety issue: No ]
    Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method.


Secondary Outcome Measures:
  • Intact and Total Glucagon Like Peptide-1 (GLP-1), Intact and Total Gastric Inhibitory Peptide (GIP) Response to Acute Hypoglycaemia [ Time Frame: 0, 10, 20, 40 minutes ] [ Designated as safety issue: No ]
    Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method.

  • Epinephrine Response to Acute Hypoglycaemia [ Time Frame: 0, 10, 20, 40 minutes ] [ Designated as safety issue: No ]
    Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method.

  • Norepinephrine Response to Acute Hypoglycaemia [ Time Frame: 0, 10, 20, 40 minutes ] [ Designated as safety issue: No ]
    Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method.

  • Growth Hormone Response to Acute Hypoglycaemia [ Time Frame: 0, 10, 20, 40 minutes ] [ Designated as safety issue: No ]
    Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method.

  • Cortisol Response to Acute Hypoglycaemia [ Time Frame: 0, 10, 20, 40 minutes ] [ Designated as safety issue: No ]
    Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method.

  • Symptomatic Hormone Responses to Acute Hypoglycaemia. [ Time Frame: Change from baseline symptomatic response at hypoglycaemia and 30 minutes after hypoglycaemia ] [ Designated as safety issue: No ]
    The symptomatic responses to hypoglycaemia were assessed using a standard validated symptom questionnaire adapted for experimental hypoglycaemia (McCrimmon et al (2003) Diabet.Med. 20: 507-509). A 7-point Likert scale (1=symptom absent; 7=symptom experienced with great intensity) was used to score presence and intensity of autonomic and neuroglycopenic symptoms of hypoglycaemia. Symptom scores were obtained during the initialisation phase, at occurrence of autonomic reaction and again 30 minutes later. For analyses the scale was considered as a continuous variable.


Enrollment: 16
Study Start Date: March 2011
Study Completion Date: October 2012
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Sequence A (sitagliptin→placebo)
Cross-over, both arms reveived the same intervention in different order.
Drug: Sitagliptin
100 mg once daily for six weeks
Other Name: Januvia
Drug: Placebo
placebo, once daily for six weeks
Other Name: Placebo
Sequence B (placebo→sitagliptin)
Cross-over, both arms reveived the same intervention in different order.
Drug: Sitagliptin
100 mg once daily for six weeks
Other Name: Januvia
Drug: Placebo
placebo, once daily for six weeks
Other Name: Placebo

Detailed Description:

The 16 type 1 patients will be randomised to one of two treatment sequences: DPP-4 inhibitor followed by placebo or placebo followed by a DPP-4 inhibitor. Each treatment period lasts 6 weeks, so all patients will receive treatment for 12 weeks in total. Induction of hypoglycaemia will take place at 0 weeks, 6 weeks and 12 weeks to determine the glucagon response.

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Type 1 Diabetes Mellitus 5-20 years duration
  • C-peptide negative
  • Willing and able to give written informed consent

Exclusion Criteria:

  • Impaired awareness of hypoglycaemia
  • BMI > 27 kg/m2
  • Evidence of severe diabetes complications (autonomic neuropathy, macroalbuminuria, proliferative retinopathy)
  • Acute illness within 3 months before the study
  • Significant renal impairment (creatinine clearance < 50ml/min)
  • Use of beta-adrenoreceptor blockers
  • Cardiac history (previous arrhythmia)
  • History of epilepsy
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01272583

Locations
Netherlands
Academic Medical Center
Amsterdam, Noord Holland, Netherlands, 1100DD
Sponsors and Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Frits Holleman, MD,PhD Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
  More Information

No publications provided

Responsible Party: F Holleman, PhD, MD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier: NCT01272583     History of Changes
Other Study ID Numbers: DARE_2010
Study First Received: January 5, 2011
Results First Received: October 15, 2013
Last Updated: February 14, 2014
Health Authority: Netherlands: Medical Ethics Review Committee (METC)
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):
Type 1 diabetes
DPP-4 inhibitor
Glucagon

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Hypoglycemia
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Sitagliptin
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Hypoglycemic Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on April 16, 2014