E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The aim of this study is to elucidate the mechanisms underlying the positive effect of incretin therapy on lipoprotein metabolism, liver fat and cardiovascular risk markers.
1) To examine the effect of liraglutide on triglycerides (TG) and apoB48 production rates (PR) and/or fractional catabolic rates (FRC) in the lipoprotein fraction chylomicrons (Sf>400) in patients with T2DM. This will be fulfilled by kinetic modeling during a standardized fat-rich mixed-meal test.
2) To evaluate the in humans the effect of treatment with liraglutide compared to baseline on hepatic de novo lipogenesis and liver fat content in patients with T2DM, assessed during a standardized fat-rich mixed meal test.
|
Tutkia liraglutidin vaikutusmekanismeja lipoproteiiniaineenvaihduntaan, maksan rasvoittumiseen ja kardiovaskulaariskin merkkiaineisiin.
1) Liraglutidin vaikutus triglyseridien ja apoB-48:n tuotantonopeuteen ja katabolian nopeuteen kylomikronifraktiossa käyttäen aterianjälkeistä kinetiikkamallinnusta tyypin 2 diabetesta sairastavilla
2) Liraglutidin vaikutus maksan rasvojen uudismuodostukseen ja maksan rasvoittumiseen tyypin 2 diabetesta sairastavilla |
|
E.2.2 | Secondary objectives of the trial |
To evaluate the effect of treatment with liraglutide compared to baseline in patients with T2DM, assessed during a standardized fat-rich mixed-meal test combined with stable isotope administration on:
-production rates (PR) of TG, apo-B48 and apo-B100 in the lipoprotein fractions VLDL1 (Sf 60–400) and VLDL2 (Sf 20–60)
-fractional catabolic rates (FCRs) of TG, ap-B48 and apo-B100 in the lipoprotein fraction VLDL1 (Sf 60–400) and VLDL2 (sf 20–60)
-fasting and postprandial serum total TG, total cholesterol, and total apo-B, apo-B48, RLP-chol and RLP-TG, apo-CIII and apo-A5 as well as fasting LDL and HDL size. RLP-chol and RLP-TG are surrogate markers of remnants. Apo-CIII and apo-A5 are key regulators of the lipolytic cascade.
-TRL clearance assessed as effect on post-heparin lipoprotein lipase (LPL) and hepatic lipase (HL) activities. LPL and HL are the key enzymes regulating lipolysis of TRLs and remnant removal by the liver.
- fasting and postprandial glucose, insulin and C-pept |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Obese subjects with T2D and a large waist (waist > 88 cm in women and > 92 cm in men, BMI 27–40 kg/m2, triglycerides between 1.0 – 4.0 mmol/L and LDL < 4.5 mmol/l) treated with a lifestyle or metformin (any dose) (HbA1c 6.5-9% ) and aged 30 – 75 years will be included. Subjects may or may not use statins |
|
E.4 | Principal exclusion criteria |
● Type 1 diabetes
● Apo E2/2 phenotype
● ALT/AST > 3x ULN
● GFR < 60 ml/min, clinically significant TSH outside normal range
● Lipid-lowering drugs other than statins within 6 months
● Treatment with pioglitazone, insulin, sulphonylureas, gliptines, glinides, SGLT-2 inhibitors or thiazide diuretics (at a dose of > 25 mg / day) within 6 months
● Blood pressure > 160 mmHg systolic and/or > 105 diastolic
● History of pancreatitis or stomach / other major bleeding, thyroid neoplasia, persistent hypothyroidism or persistent hyperthyroidism
● Any medical condition that puts the patient in the risk of dehydration
● Concurrent medical condition that may interfere with the interpretation of efficacy and safety data during the study.
● Females of childbearing potential who are not using adequate contraceptive methods
● Subjects who have experienced side-effects previously from GLP-1 agonists
● Non-compliance or withdrawal of consent
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
1) effect of liraglutide on triglycerides (TG) and apoB48 production rates (PR) and/or fractional catabolic rates (FRC) in the lipoprotein fraction chylomicrons (Sf>400) in patients with T2DM. This will be fulfilled by kinetic modeling during a standardized fat-rich mixed-meal test.
2) effect of treatment with liraglutide compared to baseline on hepatic de novo lipogenesis and liver fat content in patients with T2DM, assessed during a standardized fat-rich mixed meal test.
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
baseline vs 3.5 months after treatment |
|
E.5.2 | Secondary end point(s) |
The effect of treatment with liraglutide compared to baseline in patients with T2DM, assessed during a standardized fat-rich mixed-meal test combined with stable isotope administration on:
-production rates (PR) of TG, apo-B48 and apo-B100 in the lipoprotein fractions VLDL1 (Sf 60–400) and VLDL2 (Sf 20–60)
-fractional catabolic rates (FCRs) of TG, ap-B48 and apo-B100 in the lipoprotein fraction VLDL1 (Sf 60–400) and VLDL2 (sf 20–60)
-fasting and postprandial serum total TG, total cholesterol, and total apo-B, apo-B48, RLP-chol and RLP-TG, apo-CIII and apo-A5 as well as fasting LDL and HDL size. RLP-chol and RLP-TG are surrogate markers of remnants. Apo-CIII and apo-A5 are key regulators of the lipolytic cascade.
-TRL clearance assessed as effect on post-heparin lipoprotein lipase (LPL) and hepatic lipase (HL) activities. LPL and HL are the key enzymes regulating lipolysis of TRLs and remnant removal by the liver.
-fasting and postprandial glucose, insulin and C-peptide, assessed also during an OGTT.
-fasting visceral andsubcutaneous fat depots assessed by MRS in both fasting and in postprandial period.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
baseline vs 3.5 months after treatment |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | Yes |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
Trial end is the last day of the use of the investigational drug |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |