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

NCT02408705 | Completed Phase 2 DMC

• 1 other identifier: LG_T1_EGP
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

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

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (16)

• 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)

Other Outcomes (2)

• Number of treatment emergent adverse events

  From begin of the trial (Day 1) until the end of the trial (Day 204)

• Number of self-reported hypoglycaemic episodes during each period

  Day 1 until Day 86 (Period 1) compared with Day 113 until day 198 (Period 2)

Study Arms (2)

Liraglutide

ACTIVE COMPARATOR

3-month treatment of liraglutide

Drug: Liraglutide; Drug: Mixed Meal Tolerance Test with paracetamol

Placebo

PLACEBO COMPARATOR

3-month treatment of placebo

Drug: Placebo; Drug: Mixed Meal Tolerance Test with paracetamol

Interventions

Liraglutide DRUG

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

Also known as: Victoza

Liraglutide

Placebo DRUG

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

Placebo

Mixed Meal Tolerance Test with paracetamol DRUG

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

Also known as: MMTT

Liraglutide; Placebo

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Medical University of Graz: lead
• Novo Nordisk A/S: collaborator

Study Sites (1)

Medical University Graz

Graz, 8036, Austria

Location

Related Publications (1)

• 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.

  PMID: 35833597 DERIVED

Related Links

• Medical University of Graz

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

Liraglutide; Acetaminophen

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Glucagon-Like Peptide 1; Glucagon-Like Peptides; Proglucagon; Gastrointestinal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines

Study Officials

• Thomas R. Pieber, MD

  Medical University of Graz

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Univ.Prof. Dr.

Study Record Dates

• First Submitted: January 28, 2015
• First Posted: April 3, 2015
• Study Start: January 1, 2015
• Primary Completion: May 1, 2016
• Study Completion: May 1, 2016
• Last Updated: September 12, 2016

Record last verified: 2016-09

Locations

AU (1)