Effect of Liraglutide on Cardiovascular Endpoints in Diabetes Mellitus Type 2 Patients (MAGNA VICTORIA)

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2013 by Leiden University Medical Center
Sponsor:
Collaborator:
Novo Nordisk A/S
Information provided by (Responsible Party):
M.B. Bizino, MD, principal investigator, Leiden University Medical Center
ClinicalTrials.gov Identifier:
NCT01761318
First received: December 20, 2012
Last updated: November 28, 2013
Last verified: November 2013
  Purpose

The most important cause of mortality amongst DM2 patients is cardiovascular disease. An early finding of cardiovascular disease in DM2 and obesity is diastolic dysfunction. Diastolic dysfunction is an independent predictor of mortality and has been shown to improve in patients on a low calorie diet. The improvement of diastolic function was associated with a reduction in triglyceride accumulation in the heart and liver. A relatively new widely prescribed therapeutic agent for DM2 patients is Liraglutide (Victoza®). Liraglutide is a Glucagon Like Peptide - 1 homologue that improves glucose homeostasis and reduces blood pressure and body weight. Next to the induction of weight loss, which is potentially beneficial for cardiac function, GLP-1 therapy might have a direct advantageous effect on the cardiovascular system. However, the effect of Liraglutide on cardiovascular function has not been investigated yet. The investigators hypothesize that treatment of DM2 patients with Liraglutide is associated with improvement of cardiovascular function and a reduction of triglyceride accumulation in end-organs.


Condition Intervention Phase
Diabetes Mellitus Type 2
Metabolic Syndrome
Cardiovascular Disease
Diastolic Dysfunction
Fatty Liver
Drug: Liraglutide
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Magnetic Resonance Assessment of Victoza Efficacy in the Regression of Cardiovascular Dysfunction In Type 2 Diabetes Mellitus

Resource links provided by NLM:


Further study details as provided by Leiden University Medical Center:

Primary Outcome Measures:
  • Stroke volume [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline in ml: difference between groups

  • Ejection Fraction [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline in percentage: difference between groups

  • Cardiac output [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline in L/min: difference between groups

  • Cardiac index [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline in L/min/m2: difference between groups

  • Peak ejection rate [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline in ml end-diastolic volume/sec: difference between groups

  • Early peak filling rate [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline in ml end-diastolic volume/sec: difference between groups

  • Early deceleration peak [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline in ml/sec: difference between groups

  • Atrial peak filling rate [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline in ml/sec: difference between groups

  • Early deceleration peak / Atrial peak filling rate (E/A ratio) [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline of the ratio: difference between groups

  • Peak mitral annulus longitudinal motion [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline in cm/sec: difference between groups

  • Left ventricular filling pressure (= early peak filling rate / peak mitral annulus longitudinal motion) [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline in mmHg: difference between groups


Secondary Outcome Measures:
  • Aorta and carotid vessel wall imaging [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline of total vessel wall area in mm2: difference between groups

  • Aorta and carotid vessel wall imaging [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline of average vessel wall thickness in mm: difference between groups

  • Aorta and carotid vessel wall imaging [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline of aminimum vessel wall thickness in mm: difference between groups

  • Aorta and carotid vessel wall imaging [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline of maximum vessel wall thickness in mm: difference between groups

  • Aorta and carotid vessel wall imaging [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline of vascular distensibility (pulse wave velocity): difference between groups

  • Adipose tissue distribution [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline of the ratio subcutaneous fat / visceral abdominal fat: difference between groups

  • Total body fat [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline of total fat volume in ml: difference between groups

  • Epicardial fat volume [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline in cm3: difference between groups

  • Magnetic Resonance Spectroscopy of the heart [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline in percentage: difference between groups

  • Magnetic Resonance Spectroscopy of the liver [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline in percentage: difference between groups

  • Magnetic Resonance Spectroscopy of the kidney [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline in percentage: difference between groups

  • HBA1C [ Time Frame: 0,8, 12, 16 and 26 weeks ] [ Designated as safety issue: No ]

    Measurements will be used to guide therapeutic management

    The outcome measure glycemic control will be based on the average HBA1C level of all measurements and regards: difference between groups.


  • Fasting blood glucose level [ Time Frame: 0, 4, 8, 12, 16, 20, 26 weeks ] [ Designated as safety issue: Yes ]

    Fasting blood glucose levels will be used to guide therapeutic management and for safety reasons.

    Outcome measure: the difference between groups of the average of all measurements.


  • Myocardial T1 - mapping [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseling of myocardial T1 - values before and after contrast: difference between groups


Other Outcome Measures:
  • Anthropometric measurements [ Time Frame: 0, 4, 8, 12, 16, 20, 26 weeks ] [ Designated as safety issue: No ]

    Lenght, body weight and calculated BMI.

    Outcome measure: Change from baseline in kg (body weight) or kg/m2 (BMI): difference between groups


  • Waist / hip ratio [ Time Frame: 0, 4, 8, 12, 16, 20, 26 weeks ] [ Designated as safety issue: No ]

    Waist circumference divided by hip circumference.

    Outcome measure: change from baseline: difference between groups


  • Systolic blood pressure [ Time Frame: 0, 4, 8, 12, 16, 20, 26 weeks ] [ Designated as safety issue: No ]

    Measurements for routine clinical management

    Outcome measure: change from baseline in mmHg: difference between groups


  • Diastolic blood pressure [ Time Frame: 0, 4, 8, 12, 16, 20, 26 weeks ] [ Designated as safety issue: No ]

    Measurements for routine clinical management

    Outcome measure: change from baseline in mmHg: difference between groups


  • Resting Energy Expenditure [ Time Frame: 0, 4, 12, 26 weeks ] [ Designated as safety issue: No ]

    Change from baseline: difference between groups

    Measurement with indirect calorimetry (Jaeger, OxyconPro)


  • Immunological analysis [ Time Frame: 0, 26 weeks ] [ Designated as safety issue: No ]

    Fluorescence-Activated Cell Sorting (FACS).

    Change from baseline: difference between groups.


  • Immunological analysis [ Time Frame: 0, 26 weeks ] [ Designated as safety issue: No ]

    Peripheral Blood Mononuclear Cell isolation to analyze immunological activation and status of subjects. Both quantification of white blood cells (T-cells, B-cells, macrophages) and functional analysis will be performed.

    Change from baseline: difference between groups


  • Fasting insulin level [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline: difference between groups

  • Leptin [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline: difference between groups

  • Glucagon [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline: difference between groups

  • Adiponectin [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline: difference between groups

  • CETP [ Time Frame: 0, 4, 12 and 26 weeks ] [ Designated as safety issue: No ]

    Cholesteryl ester transfer protein

    Change from baseline: difference between groups


  • High Sensitive C Reactive Protein [ Time Frame: 0, 4, 12 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline: difference between groups

  • Free Fatty Acids [ Time Frame: 0, 4, 12 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline: difference between groups

  • Cholesterol level (total, HDL and LDL) [ Time Frame: 0, 4, 12 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline: difference between groups

  • Liver function tests (ALT, AST, AF, GGT) [ Time Frame: 0, 4, 12 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline: difference between groups

  • Triglycerides [ Time Frame: 0, 4 , 12 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline: difference between groups

  • QUICKI [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]

    Quantitative Insulin Sensitivity Check Index

    Change from baseline: difference between groups


  • Albuminuria [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Change from baseline of urinary albumine / kreatinine ration: difference between groups

  • Immunological analysis [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Immunological status as assessed by RNA profiling. Change from baseline: difference between groups

  • Metabolomics [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
    Metabolomics in urine and blood sample. Change from baseline: difference between groups


Estimated Enrollment: 50
Study Start Date: August 2013
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Liraglutide

Liraglutide: Solution for subcutaneous injection 6 mg/ml; Flexpen 3 ml.

Dose: s.c. 0,6 mg (0,1 mL) once daily. After 1 week, the dose will be increased to 1,2 mg (0,2 mL) once daily. If tolerated, after 1 week, dose will be increased to 1.8 mg (0,3 mL) once daily. In case of a hypoglycaemic episode, the dosage of oral blood glucose lowering medicaments will be adjusted first. If hypoglycaemia persists, Liraglutide / Liraglutide placebo will be adjusted on the basis of clinical parameters.

Duration: 26 weeks

Drug: Liraglutide

Preparation and labelling of Investigational Medicinal Product:

Liraglutide and placebo will be packed and labeled by Novo Nordisk A/S and provided in non-subject specific boxes. Labeling will be in accordance with Annex 13, local law and trial requirements. The examples of labels are not readily available, but will be supplied when received from Novo Nordisk.

Drug accountability:

Drug accountability will be cared for by the Department of Clinical Pharmacy of the LUMC. The trial product will be dispensed to each subject as required according to treatment group by the clinical pharmacist. No trial product will be dispensed to any person not enrolled in the trial.

Other Names:
  • Trade name: Victoza
  • EV Product Code: SUB25238
  • Name of the Marketing Authorisation Holder: Novo Nordisk
  • Marketing Authorisation number: EU/1/09/529/001
  • ATC code: A10BX07
  • CAS number 204656-20-2
Placebo Comparator: Liraglutide-placebo

Liraglutide placebo: Solution for injection; Flexpen 3 ml.

Dosage: same as Liraglutide

Duration: 26 weeks


  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 69 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Informed consent
  • Age > 18 years and < 70 years
  • BMI > 25 kg/m2
  • DM2 treated with metformin for at least 3 months in the maximum tolerable dosage
  • HbA1c ≥7% and ≤ 10.0 %
  • EGFR > 60 ml/min
  • Normal sitting blood pressure < 150/85 mm Hg and stable for at least one month

Exclusion Criteria:

  • Use of insulin, thiazolidinediones (TZD), SU derivatives, GLP-1 analogues, DPP-IV inhibitors, fibrates, prednisone, cytostatic o antiretroviral therapy within 6 months prior to the study
  • Hereditary lipoprotein disease
  • Psychiatric disorders and / or use of antipsychotic or antidepressant drugs at present or in the past
  • Hepatic disease (AST/ALT > 2 times reference values)
  • Endocrine disease other than diabetes mellitus type 2
  • History or presence of cardiovascular disease
  • Any significant chronic disease (e.g. inflammatory bowel disease)
  • Any significant abnormal laboratory results found during the medical screening procedure
  • Gastrointestinal surgery (e.g. gastric bypass)
  • Pregnant woman or a woman who is breast-feeding
  • Female of child-bearing potential intending to become pregnant or is not using adequate contraceptive methods while sexually active
  • Allergy to intravenous contrast
  • Known or suspected hypersensitivity to trial products or related products
  • Chronic pancreatitis or previous acute pancreatitis
  • Personal history or family history of medullary thyroid carcinoma or personal history of multiple endocrine neoplasia type 2
  • Claustrophobia
  • Metal implants or other contraindications for MRI
  • Recent participation in other research projects within the last 3 months or participation in 2 or more projects in one year
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01761318

Contacts
Contact: Maurice B Bizino, MD +31715263953 m.b.bizino@lumc.nl
Contact: Hildo J Lamb, MD PhD +31715266387 h.j.lamb@lumc.nl

Locations
Netherlands
Leiden University Medical Center Recruiting
Leiden, Netherlands, 2333 ZA
Contact: Maurice Bizino, MD    0031715263953    m.b.bizino@lumc.nl   
Sponsors and Collaborators
Leiden University Medical Center
Novo Nordisk A/S
Investigators
Principal Investigator: Maurice B Bizino, MD Leiden University Medical Center
Study Chair: Jan WA Smit, MD PhD University Nijmegen Medical Centre
Study Director: Hildo J Lamb, MD PhD Leiden University Medical Center
Study Chair: Albert de Roos, MD PhD Leiden University Medical Center
Study Chair: Ingrid M Jazet, MD PhD Leiden University Medical Center
  More Information

Publications:
Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr; International Diabetes Federation Task Force on Epidemiology and Prevention; Hational Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009 Oct 20;120(16):1640-5. doi: 10.1161/CIRCULATIONAHA.109.192644. Epub 2009 Oct 5.

Responsible Party: M.B. Bizino, MD, principal investigator, M.B. Bizino, MD, Leiden University Medical Center
ClinicalTrials.gov Identifier: NCT01761318     History of Changes
Other Study ID Numbers: 379, 2012-001623-12
Study First Received: December 20, 2012
Last Updated: November 28, 2013
Health Authority: European Union: European Medicines Agency

Keywords provided by Leiden University Medical Center:
Diabetes mellitus type 2
Glucagon-Like Peptide 1
Magnetic Resonance Imaging
Magnetic Resonance Spectroscopy
Steatosis

Additional relevant MeSH terms:
Cardiovascular Diseases
Diabetes Mellitus
Diabetes Mellitus, Type 2
Fatty Liver
Metabolic Syndrome X
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Liver Diseases
Digestive System Diseases
Insulin Resistance
Hyperinsulinism
Glucagon-Like Peptide 1
Liraglutide
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Hypoglycemic Agents

ClinicalTrials.gov processed this record on August 19, 2014