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Investigating the Effect of Liraglutide on the Endogenous Glucose Production During in Tye 1 Diabetes Subjects

Primary Purpose

Type 1 Diabetes Mellitus

Status

Completed

Phase

Phase 2

Locations

Austria

Study Type

Interventional

Intervention

Liraglutide

Placebo

Mixed Meal Tolerance Test with paracetamol

About this trial

This is an interventional basic science trial for Type 1 Diabetes Mellitus focused on measuring Endogenous Glucose Production, Hypoglycemic clamp, Tracer to Tracee Technique, Type 1 diabetes mellitus

Eligibility Criteria

18 Years - 64 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial
Type 1 diabetes mellitus as diagnosed (including I - III):
I. history of type 1 diabetes mellitus manifestation with acute hyperglycaemia and ketonuria II. positive results for at least one of four islet antibodies (glutamic acid decarboxylase, protein tyrosine phosphatase, zinc transporter 8, or islet cell antibodies) III. residual basal fasting C-peptide of ≥ 0.1 nmol/L
Male or female, aged 18 - 64 years (both inclusive)
Body mass index (BMI) 20.0 - 25.0 kg/m2 (both inclusive)
HbA1c 42 - 80 mmol/mol (6.0-9.5%)
Treated with daily insulin injections or continuous s.c. insulin infusion (CSII) ≥ 1 months. Stable insulin dose as judged by the investigator

Exclusion Criteria:

Known or suspected hypersensitivity to trial product(s) or related products
Use of liraglutide or exenatide within 3 months before screening
Severe hypoglycaemia within 1 month of screening
Hypoglycaemia unawareness as judged by the Investigator or hospitalisation for diabetic ketoacidosis during the previous 2 months
Clinically significant abnormal haematology, biochemistry, lipids, or urinalysis or coagulation screening tests, as judged by the investigator and any of the following laboratory safety results:
- Aspartate transaminase(=AST), alanine aminotransferase (=ALT), lipase, alkaline phosphatase > 2.0 times upper limit of reference range (ULN)
- Haemoglobin < 8.0 mmol/L (male) or < 6.4 mmol/L (female), total leukocyte count <3.0 x 109/L, thrombocytes <100 x 109/L
- Serum creatinine levels ≥ 126 μmol/L (male) or ≥ 111 μmol/L (female)
- Amylase outside normal range
Screening calcitonin > 50 ng/L
Personal history of non-familial medullary thyroid carcinoma
History of chronic or idiopathic acute pancreatitis Suffer from or history of a life threatening disease (e.g. cancer except basal cell skin cancer or squamous cell skin cancer), or any clinically significant respiratory, metabolic, renal, hepatic, gastrointestinal, endocrinological (with the exception of diabetes mellitus and euthyroid struma), haematological, dermatological, venereal, neurological, psychiatric diseases or other major disorders as judged by the investigator.
Proliferative retinopathy or maculopathy and/or severe neuropathy, in particular autonomic neuropathy, as judged by the investigator.
Any disease or condition that, in the opinion of the investigator, would represent an unacceptable risk for the subject's safety.
Any condition that would interfere with trial participation or evaluation of results, as judged by the investigator.
Female of child-bearing potential who is pregnant, breast-feeding or intend to become pregnant or is not using adequate contraceptive methods (adequate contraceptive methods include sterilisation, hormonal intrauterine devices, oral contraceptives, sexual abstinence or vasectomised partner).
Severe acute and/or chronic diseases

Sites / Locations

Medical University Graz

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Liraglutide

Placebo

Arm Description

3-month treatment of liraglutide

3-month treatment of placebo

Outcomes

Primary Outcome Measures

Area under the curve of the endogenous glucose production from (=EGP) from begin of the hypoglycaemic clamp 5.5 mmol/L period until the end of recovery period (4.0 mmol/L), calculated from stable isotope labelled plasma glucose

Secondary Outcome Measures

Area under the curve of peripheral glucose uptake (=PGU), calculated from labelled PG from begin of the hypoglycaemic clamp period 5.5mmol/L until end of recovery period (4.0 mmol/L)

Area under the glucose infusion rate curve from begin of the hypoglycaemic clamp period 5.5mmol/L until end of recovery period (4.0 mmol/L)

Change in mean plasma glucagon concentrations from begin of the hypoglycaemic clamp period 5.5 mmol/L to 3.5 mmol/L to nadir and to recovery phase

Change in mean values of adrenaline from begin of the hypoglycaemic clamp period 5.5 mmol/L to 3.5 mmol/L to nadir and to recovery phase

Change in mean values of noradrenaline from begin the hypoglycaemic clamp period 5.5 mmol/L to 3.5 mmol/L to nadir and to recovery phase

Change in mean values of cortisol from begin the hypoglycaemic clamp period 5.5 mmol/L to 3.5 mmol/L to nadir and to recovery phase

Change in mean values of growth hormone from begin the hypoglycaemic clamp period 5.5 mmol/L to 3.5 mmol/L to nadir and to recovery phase

Change in number of regulatory T-cells detected by blood (fasting) and measured by a laboratory

Change in function of regulatory T-cells detected by blood (fasting) and measured by a laboratory

Area under the glucose curve during the Mixed Meal Tolerance Test

Area under the c-peptid concentration curve during the Mixed Meal Tolerance Test

Area under the paracetamol concentration curve to calculate gastric emptying during the Mixed Meal Tolerance Test

Area under the insulin curve during the Mixed Meal Tolerance Test

Area under the glucagon curve during the Mixed Meal Tolerance Test

Change in HbA1c during each period detected by blood (fasting) at the begin of the visits and measured by a laboratory (tube: K3 EDTA Plasma)

Change in fasting plasma glucose during each period detected by blood at the begin of the visits and measured by a laboratory (tube: lithium heparin plasma)

Full Information

NCT ID

NCT02408705

First Posted

January 28, 2015

Last Updated

September 9, 2016

Sponsor

Medical University of Graz

Collaborators

Novo Nordisk A/S

1. Study Identification

Unique Protocol Identification Number

NCT02408705

Brief Title

Investigating the Effect of Liraglutide on the Endogenous Glucose Production During in Tye 1 Diabetes Subjects

Official Title

A Randomized, Double Blind, Two-period Cross-over Trial Investigating the Effect of Liraglutide as Add on to Intensive Insulin Treatment on the Endogenous Glucose Production in Subjects With C-peptide Positive Type 1 Diabetes Mellitus

Study Type

Interventional

2. Study Status

Record Verification Date

September 2016

Overall Recruitment Status

Completed

Study Start Date

January 2015 (undefined)

Primary Completion Date

May 2016 (Actual)

Study Completion Date

May 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Medical University of Graz

Collaborators

Novo Nordisk A/S

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Each subject will be allocated to 2 periods of 3 months of once daily dosing with either liraglutide (1.2 mg) or placebo treatment (in random sequence) as add on to usual intensive insulin treatment. Wash-out period between treatments will be 1 month. The trial can be divided into the following periods: Screening Treatment period 1 Washout period Treatment period 2 Follow up Visit Mixed Meal Tolerance Test (MMTT) enriched with paracetamol: At the beginning and end of each period a MMTT (Fortimel complete) enriched with paracetamol will be performed to assess the remaining beta-cell function via obtained maximal plasma C-peptide levels as well as the gastric emptying. Experimental / Hypoglycaemic clamp : At the end of each period (Visit 8, 15) a hypoglycaemic clamp will be performed. After the subject completed the MMTT on day 1, the subject will stay in the clinical unit to prepare for the hypoglycaemic clamp with an variable insulin infusion intravenously in order to obtain a steady state of a plasma glucose (PG) level of 5.5 mmol/L overnight until approximately 08:00. At 05:00 hours 10%-[6,6-2H2] glucose solution will be given i.v. as a primed (9.6mg/kg/min) for one minute and a constant (0.08 mg/kg/min) infusion until the last blood sampling of the plateau 4.0 mmol/L will be performed. At 08:00 hours in the morning at day 2, insulin infusion will be increased to 1.5 mU/kg/min for each subject and the PG will be kept at a plateau of 5.5 mmol/L by a controlled variable intravenous infusion of glucose (10% glucose enriched with 4mg [6,6-2H2] glucose /ml) for one hour. Afterwards, PG is allowed to fall to a plateau of 3.5 mmol/L, then to a nadir of 2.5 mmol/L, then to a blood glucose of 4.0 mmol/L and finally back to a level of 5.5 mmol/L for safety reasons. Blood sampling for measurement of [6,6-2H2] glucose, glucagon, insulin, counterregulatory hormones, lactate, free fatty acids, glycerol, vital signs, hypoglycaemic symptoms questionnaire and hypoglycaemic awareness will be performed at each PG plateau.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Type 1 Diabetes Mellitus

Keywords

Endogenous Glucose Production, Hypoglycemic clamp, Tracer to Tracee Technique, Type 1 diabetes mellitus

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 2

Interventional Study Model

Crossover Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

14 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Liraglutide

Arm Type

Active Comparator

Arm Description

3-month treatment of liraglutide

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

3-month treatment of placebo

Intervention Type

Drug

Intervention Name(s)

Liraglutide

Other Intervention Name(s)

Victoza

Intervention Description

They are receiving liraglutide for 3 months. Dose escalation: 0.3 mg - 0.6mg - 0.9mg - 1.2mg (over 4 weeks)

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

They are receiving placebo for 3 months. Dose escalation: 0.3 mg - 0.6mg - 0.9mg - 1.2mg (over 4 weeks)

Intervention Type

Drug

Intervention Name(s)

Mixed Meal Tolerance Test with paracetamol

Other Intervention Name(s)

MMTT

Intervention Description

At the beginning and end of each period (Visit 2a, 8, 9a, 15) a Mixed Meal Tolerance Test enriched paracetamol will be performed.

Primary Outcome Measure Information:

Title

Time Frame