Dipeptidyl Peptidase-4 Inhibitors and Alpha-cell Recovery

Type 1 Diabetes Clinical Trial

— DARE  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01272583
• Other study ID #: DARE_2010
• Status: Completed
• Phase: N/A
• First received: January 5, 2011
• Last updated: February 14, 2014
• Start date: March 2011
• Est. completion date: October 2012

Study information

• Verified date: February 2014
• Source: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: Medical Ethics Review Committee (METC)Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 16
• Est. completion date: October 2012
• Est. primary completion date: June 2012
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 55 Years

Eligibility

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

Study Design

Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator)

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 1
• Hypoglycemia
• Type 1 Diabetes

Intervention

Drug:
• Sitagliptin
100 mg once daily for six weeks
• Placebo
placebo, once daily for six weeks

Locations

Country	Name	City	State
Netherlands	Academic Medical Center	Amsterdam	Noord Holland

Sponsors (2)

Lead Sponsor	Collaborator
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)	Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Glucagon Response to Acute Hypoglycaemia	Change in glucagon concentration from the initialisation phase to 40 minutes after occurrence of the autonomic reaction to hypoglycaemia	Change from initialisation phase to 40 minutes after onset of hypoglycaemia	No
Primary	Glucagon Response to Acute Hypoglycaemia	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.	0, 10, 20 and 40 minutes	No
Secondary	Intact and Total Glucagon Like Peptide-1 (GLP-1), Intact and Total Gastric Inhibitory Peptide (GIP) Response to Acute Hypoglycaemia	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.	0, 10, 20, 40 minutes	No
Secondary	Epinephrine Response to Acute Hypoglycaemia	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.	0, 10, 20, 40 minutes	No
Secondary	Norepinephrine Response to Acute Hypoglycaemia	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.	0, 10, 20, 40 minutes	No
Secondary	Growth Hormone Response to Acute Hypoglycaemia	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.	0, 10, 20, 40 minutes	No
Secondary	Cortisol Response to Acute Hypoglycaemia	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.	0, 10, 20, 40 minutes	No
Secondary	Symptomatic Hormone Responses to Acute Hypoglycaemia.	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.	Change from baseline symptomatic response at hypoglycaemia and 30 minutes after hypoglycaemia	No