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

NCT ID: NCT02408705

Last Updated: 2016-09-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 14 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-01-31
• Study Completion Date: 2016-05-31

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.

Conditions

Type 1 Diabetes Mellitus

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: TRIPLE

Study Groups

Liraglutide

3-month treatment of liraglutide

Group Type: ACTIVE_COMPARATOR

Liraglutide

Intervention Type: DRUG

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

Mixed Meal Tolerance Test with paracetamol

Intervention Type: DRUG

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

Placebo

3-month treatment of placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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

Mixed Meal Tolerance Test with paracetamol

Intervention Type: DRUG

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

Interventions

Liraglutide

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

Intervention Type: DRUG

Placebo

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

Intervention Type: DRUG

Mixed Meal Tolerance Test with paracetamol

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

Intervention Type: DRUG

Other Intervention Names

Victoza; MMTT

Eligibility Criteria

Inclusion Criteria

1. 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

2. 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

3. Male or female, aged 18 - 64 years (both inclusive)

4. Body mass index (BMI) 20.0 - 25.0 kg/m2 (both inclusive)

5. HbA1c 42 - 80 mmol/mol (6.0-9.5%)

6. Treated with daily insulin injections or continuous s.c. insulin infusion (CSII) ≥ 1 months. Stable insulin dose as judged by the investigator

Exclusion Criteria

1. Known or suspected hypersensitivity to trial product(s) or related products

2. Use of liraglutide or exenatide within 3 months before screening

3. Severe hypoglycaemia within 1 month of screening

4. Hypoglycaemia unawareness as judged by the Investigator or hospitalisation for diabetic ketoacidosis during the previous 2 months

5. 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

6. Screening calcitonin > 50 ng/L

7. Personal history of non-familial medullary thyroid carcinoma

8. 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.

9. Proliferative retinopathy or maculopathy and/or severe neuropathy, in particular autonomic neuropathy, as judged by the investigator.

10. Any disease or condition that, in the opinion of the investigator, would represent an unacceptable risk for the subject's safety.

11. Any condition that would interfere with trial participation or evaluation of results, as judged by the investigator.

12. 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).

13. Severe acute and/or chronic diseases

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 64 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novo Nordisk A/S

INDUSTRY

Sponsor Role: collaborator

Medical University of Graz

OTHER

Sponsor Role: lead

Responsible Party

Pieber Thomas, MD

Univ.Prof. Dr.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Thomas R. Pieber, MD

Role: PRINCIPAL_INVESTIGATOR

Medical University of Graz

Locations

Medical University Graz

Graz, , Austria

Countries

Austria

References

Zenz S, Regittnig W, Boulgaropoulos B, Augustin T, Brunner M, Korsatko S, Munzker J, Narath SH, Raml R, Magnes C, Pieber TR. Effect of Liraglutide Treatment on Whole-body Glucose Fluxes in C-peptide-Positive Type 1 Diabetes During Hypoglycemia. J Clin Endocrinol Metab. 2022 Aug 18;107(9):e3583-e3593. doi: 10.1210/clinem/dgac369.

Reference Type: DERIVED

PMID: 35833597 (View on PubMed)

Related Links

http://www.medunigraz.at

Medical University of Graz

Other Identifiers

LG_T1_EGP

Identifier Type: -

Identifier Source: org_study_id