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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02660047
Recruitment Status : Completed
First Posted : January 21, 2016
Last Update Posted : March 21, 2018
Sponsor:
Collaborator:
Novo Nordisk A/S
Information provided by (Responsible Party):
MalouPaiman, Leiden University Medical Center

Brief Summary:

Among South Asians, in comparison to Western Europeans, there is an increased risk of type 2 diabetes mellitus (DM2) and DM2-related cardiovascular disease. The effect of Liraglutide (Victoza®) on cardiovascular function is therefore investigated in the DM2 patient group of South Asian descent specifically.

Liraglutide is a new widely prescribed therapeutic agent for DM2 patients. It is a Glucagon Like Peptide - 1 homologue that improves glucose homeostasis and reduces blood pressure and body weight. The disadvantageous metabolic phenotype as seen in South Asians includes a relatively large total fat mass, with predominately visceral relative to subcutaneous adipose tissue and lower brown adipose tissue volume and activity, accompanied by increased lipid levels. The key elements in the mechanism of action of Liraglutide seem to correspond to the differences in metabolic profile between South Asians and Western Europeans. Diastolic dysfunction, an early finding of cardiovascular disease in DM2 and obesity and an independent predictor of mortality, has been shown to be associated with the amount of triglyceride accumulation in the heart and liver. The investigators hypothesize that Liraglutide has direct advantageous cardiovascular effects and reduces triglyceride accumulation in end-organs, specifically for DM2 patients of South Asian descent.


Condition or disease Intervention/treatment Phase
Diabetes Mellitus Type 2 Metabolic Syndrome Cardiovascular Disease Diastolic Dysfunction Fatty Liver Drug: Liraglutide Drug: Liraglutide - Placebo Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 51 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, 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 and South Asian Descent
Study Start Date : August 2015
Actual Primary Completion Date : March 9, 2018
Actual Study Completion Date : March 9, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Liraglutide

Arm Intervention/treatment
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

Drug: Liraglutide

Preparation and labelling of Investigational Medicinal Product:

Liraglutide 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.

Dose: same as Liraglutide

Duration: 26 weeks

Drug: Liraglutide - Placebo

Drug: Liraglutide - Placebo

Preparation and labelling of Investigational Medicinal Product:

Liraglutide - 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 Name: Placebo




Primary Outcome Measures :
  1. Stroke volume [ Time Frame: 0 and 26 weeks ]
    Change from baseline in ml: difference between groups

  2. Ejection Fraction [ Time Frame: 0 and 26 weeks ]
    Change from baseline in percentage: difference between groups

  3. Cardiac output [ Time Frame: 0 and 26 weeks ]
    Change from baseline in L/min: difference between groups

  4. Cardiac index [ Time Frame: 0 and 26 weeks ]
    Change from baseline in L/min/m2: difference between groups

  5. Peak ejection rate [ Time Frame: 0 and 26 weeks ]
    Change from baseline in ml end-diastolic volume/sec: difference between groups

  6. Early peak filling rate [ Time Frame: 0 and 26 weeks ]
    Change from baseline in ml end-diastolic volume/sec: difference between groups

  7. Early deceleration peak [ Time Frame: 0 and 26 weeks ]
    Change from baseline in ml/sec: difference between groups

  8. Atrial peak filling rate [ Time Frame: 0 and 26 weeks ]
    Change from baseline in ml/sec: difference between groups

  9. Early deceleration peak / Atrial peak filling rate (E/A ratio) [ Time Frame: 0 and 26 weeks ]
    Change from baseline of the ratio: difference between groups

  10. Peak mitral annulus longitudinal motion [ Time Frame: 0 and 26 weeks ]
    Change from baseline in cm/sec: difference between groups

  11. Left ventricular filling pressure (= early peak filling rate / peak mitral annulus longitudinal motion) [ Time Frame: 0 and 26 weeks ]
    Change from baseline in mmHg: difference between groups


Secondary Outcome Measures :
  1. Aorta vessel wall imaging [ Time Frame: 0 and 26 weeks ]
    Change from baseline of vascular distensibility (pulse wave velocity): difference between groups

  2. Carotid vessel wall imaging [ Time Frame: 0 and 26 weeks ]
    Change from baseline of average vessel wall thickness in mm: difference between groups

  3. Adipose tissue distribution [ Time Frame: 0 and 26 weeks ]
    Change from baseline of the ratio subcutaneous fat / visceral abdominal fat: difference between groups

  4. Total body fat [ Time Frame: 0 and 26 weeks ]
    Change from baseline of total fat volume in ml: difference between groups

  5. Epicardial fat volume [ Time Frame: 0 and 26 weeks ]
    Change from baseline in cm3: difference between groups

  6. Magnetic Resonance Spectroscopy of the heart [ Time Frame: 0 and 26 weeks ]
    Change from baseline in percentage: difference between groups

  7. Magnetic Resonance Spectroscopy of the liver [ Time Frame: 0 and 26 weeks ]
    Change from baseline in percentage: difference between groups

  8. Magnetic Resonance Spectroscopy of the kidney [ Time Frame: 0 and 26 weeks ]
    Change from baseline in percentage: difference between groups

  9. HBA1C [ Time Frame: Time Frame: 0,8, 12, 16 and 26 weeks ]
    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.

  10. Fasting blood glucose level [ Time Frame: 0, 4, 8, 12, 16, 20, 26 weeks ]
    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.

  11. Myocardial T1 - mapping [ Time Frame: 0 and 26 weeks ]
    Change from baseline of myocardial T1 - values before and after contrast: difference between groups

  12. Brown adipose tissue [ Time Frame: 0 and 26 weeks ]
    Change from baseline of brown adipose tissue volume in cm3: difference between groups


Other Outcome Measures:
  1. Anthropometric measurements [ Time Frame: 0, 4, 8, 12, 16, 20, 26 weeks ]
    Length, body weight and calculated BMI. Outcome measure: Change from baseline in kg (body weight) or kg/m2 (BMI): difference between groups

  2. Waist / hip ratio [ Time Frame: 0, 4, 8, 12, 16, 20, 26 weeks ]
    Waist circumference divided by hip circumference. Outcome measure: change from baseline: difference between groups

  3. Systolic blood pressure [ Time Frame: 0, 4, 8, 12, 16, 20, 26 weeks ]
    Measurements for routine clinical management Outcome measure: change from baseline in mmHg: difference between groups

  4. Diastolic blood pressure [ Time Frame: 0, 4, 8, 12, 16, 20, 26 weeks ]
    Measurements for routine clinical management Outcome measure: change from baseline in mmHg: difference between groups

  5. Resting Energy Expenditure [ Time Frame: 0, 4, 12, 26 weeks ]
    Change from baseline: difference between groups Measurement with indirect calorimetry (Jaeger, OxyconPro)

  6. Immunological analysis [ Time Frame: 0, 26 weeks ]
    Fluorescence-Activated Cell Sorting (FACS). Change from baseline: difference between groups.

  7. Immunological analysis [ Time Frame: 0, 26 weeks ]
    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

  8. Fasting insulin level [ Time Frame: 0 and 26 weeks ]
    Change from baseline: difference between groups

  9. Leptin [ Time Frame: 0 and 26 weeks ]
    Change from baseline: difference between groups

  10. Adiponectin [ Time Frame: 0 and 26 weeks ]
    Change from baseline: difference between groups

  11. CETP [ Time Frame: 0, 4, 12 and 26 weeks ]
    Cholesteryl ester transfer protein Change from baseline: difference between groups

  12. High Sensitive C Reactive Protein [ Time Frame: Change from baseline: difference between groups ]
    0, 4, 12 and 26 weeks

  13. Free Fatty Acids [ Time Frame: 0, 4, 12 and 26 weeks ]
    Change from baseline: difference between groups

  14. Cholesterol level (total, HDL and LDL) [ Time Frame: 0, 4, 12 and 26 weeks ]
    Change from baseline: difference between groups

  15. Liver function tests (ALT, AST, AF, GGT) [ Time Frame: 0, 4, 12 and 26 weeks ]
    Change from baseline: difference between groups

  16. Triglycerides [ Time Frame: 0, 4 , 12 and 26 weeks ]
    Change from baseline: difference between groups

  17. QUICKI [ Time Frame: 0 and 26 weeks ]
    Quantitative Insulin Sensitivity Check Index Change from baseline: difference between groups

  18. Albuminuria [ Time Frame: 0 and 26 weeks ]
    Change from baseline of urinary albumin / creatinine ration: difference between groups

  19. Immunological analysis [ Time Frame: 0 and 26 weeks ]
    Immunological status as assessed by RNA profiling. Change from baseline: difference between groups

  20. Metabolomics [ Time Frame: 0 and 26 weeks ]
    Metabolomics in urine and blood sample. Change from baseline: difference between groups

  21. Insulin dose [ Time Frame: 0 and 26 weeks ]
    Total daily dose (units) of insulin. Change from baseline: difference between groups

  22. Hypoglycaemic episodes [ Time Frame: Between week 0 and 26 ]
    Number of grade 1, 2 and 3 hypoglycaemic episodes as detected with self measurement by participants. Comparison between groups.



Information from the National Library of Medicine

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Ages Eligible for Study:   19 Years to 74 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Informed consent
  • Age > 18 years and < 75 years
  • BMI > 23 kg/m2
  • DM2 treated with metformin and/or SU derivative and/or insulin for at least 3 months in stable dosage
  • HbA1c ≥ 6.5% and ≤ 11.0% (≥ 47.5 mmol/mol and ≤ 97.4 mmol/mol)
  • EGFR > 30 ml/min
  • Ethnicity: South Asian descent (i.e. Hindustani Surinamese), based on self-identified ethnicity and self-reported origin of the mother, the father and the mother's and father's ancestors. Both parents and the mother's and father's ancestors should be South Asian for inclusion.

Exclusion Criteria:

  • Use of thiazolidinediones (TZD), GLP-1 analogues, DPP-IV inhibitors, fibrates, prednisone, cytostatic or antiretroviral therapy within 6 months prior to the study
  • Uncontrolled treated or untreated hypertension (systolic blood pressue ≥ 180 mmHg and/or diastolic blood pressue ≥ 110 mmHg)
  • Acute coronary or cerebrovascular event within 30 days prior to study
  • Congestive heart failure NYHA III-IV
  • 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
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02660047


Locations
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Netherlands
Leiden University Medical Center
Leiden, Albinusdreef 2, Netherlands, 2333 ZA
Sponsors and Collaborators
Leiden University Medical Center
Novo Nordisk A/S
Investigators
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Principal Investigator: Elisabeth HM Paiman, MD Leiden University Medical Center
Principal Investigator: Huub J van Eyk, MD Leiden University Medical Center
Study Director: Hildo J Lamb, MD PhD Leiden University Medical Center
Study Chair: Jan W Smit, MD PhD University Nijmegen Medical Centre
Study Chair: Ingrid M Jazet, MD PhD Leiden University Medical Center
Study Chair: Albert M de Roos, MD PhD Leiden University Medical Center
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: MalouPaiman, MD, Leiden University Medical Center
ClinicalTrials.gov Identifier: NCT02660047    
Other Study ID Numbers: 2012-001623-12
First Posted: January 21, 2016    Key Record Dates
Last Update Posted: March 21, 2018
Last Verified: March 2018
Keywords provided by MalouPaiman, Leiden University Medical Center:
South Asian descent
Additional relevant MeSH terms:
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Fatty Liver
Cardiovascular Diseases
Diabetes Mellitus
Metabolic Syndrome
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Insulin Resistance
Hyperinsulinism
Liver Diseases
Digestive System Diseases
Liraglutide
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists