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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Drug: Liraglutide
* Drug: Placebo
* Drug: Mixed Meal Tolerance Test with paracetamol


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Liraglutide<br>3-month treatment of liraglutide | Drug: Liraglutide<br>* They are receiving liraglutide for 3 months. Dose escalation: 0.3 mg - 0.6mg - 0.9mg - 1.2mg (over 4 weeks)<br>* Other names: Victoza;Drug: Mixed Meal Tolerance Test with paracetamol<br>* At the beginning and end of each period (Visit 2a, 8, 9a, 15) a Mixed Meal Tolerance Test enriched paracetamol will be performed.<br>* Other names: MMTT;|
| Placebo Comparator: Placebo<br>3-month treatment of placebo | Drug: Placebo<br>* They are receiving placebo for 3 months. Dose escalation: 0.3 mg - 0.6mg - 0.9mg - 1.2mg (over 4 weeks)<br>Drug: Mixed Meal Tolerance Test with paracetamol<br>* At the beginning and end of each period (Visit 2a, 8, 9a, 15) a Mixed Meal Tolerance Test enriched paracetamol will be performed.<br>* Other names: MMTT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  | After 12 weeks and 2 days of treatment in each treatment period (day 86 and day 198) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) |  | After 12 weeks and 2 days of treatment in each treatment period (day 86 and day 198) | 
| 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) |  | After 12 weeks and 2 days of treatment in each treatment period (day 86 and day 198) | 
| 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 |  | After 12 weeks and 2 days of treatment in each treatment period (day 86 and day 198) | 
| 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 |  | After 12 weeks and 2 days of treatment in each treatment period (day 86 and day 198) | 
| 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 |  | After 12 weeks and 2 days of treatment in each treatment period (day 86 and day 198) | 
| 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 |  | After 12 weeks and 2 days of treatment in each treatment period (day 86 and day 198) | 
| 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 |  | After 12 weeks and 2 days of treatment in each treatment period (day 86 and day 198) | 
| Change in number of regulatory T-cells detected by blood (fasting) and measured by a laboratory |  | After 12 weeks and 2 days of treatment just before the hypoglycaemic clamp in each treatment period (day 86 and day 198) | 
| Change in function of regulatory T-cells detected by blood (fasting) and measured by a laboratory |  | After 12 weeks and 2 days of treatment just before the hypoglycaemic clamp in each treatment period (day 86 and day 198) | 
| Area under the glucose curve during the Mixed Meal Tolerance Test |  | Period 1: Visit 2a (Day 1) versus Visit 8 (Day 85) ; Period 2: Visit 9a (Day 113) versus Visit 15 (Day 197) | 
| Area under the c-peptid concentration curve during the Mixed Meal Tolerance Test |  | Period 1: Visit 2a (Day 1) versus Visit 8 (Day 85) ; Period 2: Visit 9a (Day 113) versus Visit 15 (Day 197) | 
| Area under the paracetamol concentration curve to calculate gastric emptying during the Mixed Meal Tolerance Test |  | Period 1: Visit 2a (Day 1) versus Visit 8 (Day 85) ; Period 2: Visit 9a (Day 113) versus Visit 15 (Day 197) | 
| Area under the insulin curve during the Mixed Meal Tolerance Test |  | Period 1: Visit 2a (Day 1) versus Visit 8 (Day 85) ; Period 2: Visit 9a (Day 113) versus Visit 15 (Day 197) | 
| Area under the glucagon curve during the Mixed Meal Tolerance Test |  | Period 1: Visit 2a (Day 1) versus Visit 8 (Day 85) ; Period 2: Visit 9a (Day 113) versus Visit 15 (Day 197) | 
| 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) |  | Period 1: Visit 2a (Day 1) versus at Visit 8 (Day 85) ; Period 2: Visit 9a (Day 113) versus Visit 15 (Day 197) | 
| 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) |  | Period 1: Visit 2a (Day 1) versus Visit 8 (Day 85) ; Period 2: Visit 9a (Day 113) versus Visit 15 (Day 197) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endogenous Glucose Production, Hypoglycemic clamp, Tracer to Tracee Technique, Type 1 diabetes mellitus