Trial record 2 of 11 for:    lixisenatide | Open Studies

Lixisenatide-The Effects on Glucose and Lipid Metabolism in Type 2 Diabetes

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by University of Surrey
Sponsor:
Collaborator:
Sanofi
Information provided by (Responsible Party):
University of Surrey
ClinicalTrials.gov Identifier:
NCT02049034
First received: December 18, 2013
Last updated: January 27, 2014
Last verified: January 2014
  Purpose

GLP-1 analogues are a new treatment for type 2 diabetes, which have recently been shown to have beneficial effects on weight, glycaemic control and postprandial triglyceride concentrations. Postprandial hypertriglyceridaemia, which is associated with an increased risk of cardiovascular disease, is a feature of type 2 diabetes. Hypertriglyceridaemia is due to excess triglyceride-rich lipoproteins (TRL) which consist of very low-density lipoproteins, (VLDL) synthesised by the liver which contain the higher molecular weight form of apolipoproteinB (apoB), apoB-100, and chylomicrons which are synthesised in the intestine in response to an intake of dietary fat and contain the lower molecular weight form of apoB, apoB-48. A recent study has shown that GLP-1 receptor signalling is required for the control of postprandial lipoprotein synthesis and secretion in hamsters and mice. GLP-1 was shown to reduce apoB-48 TRL production while a GLP-1 receptor antagonist increased apoB-48 TRL production.

This study will investigate the effect of the GLP-1 analogue lixisenatide compared with placebo, in a double blind crossover study, on postprandial triglyceride metabolism in 12 patients with type 2 diabetes. Chylomicron and VLDL production and clearance rates will be measured in a repeated meal study by labelling apoB-100 and apoB-48 and by labelling triglycerides using stable isotope methodology. Glucose flux in response to a mixed fluid meal will also be investigated using stable isotope methodology. Gastric emptying and post heparin LPL activity will be measured.

The hypothesis is that i] lixisenatide will lower postprandial glycaemia due to a decrease in endogenous glucose output and an increase in glucose clearance by peripheral tissues as a result of an improvement in insulin sensitivity.


Condition Intervention Phase
Type 2 Diabetes
Other: Lixisenatide
Other: Placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Official Title: The Effect of Lixisenatide on Postprandial Lipid and Glucose Metabolism in Patients With Type 2 Diabetes

Resource links provided by NLM:


Further study details as provided by University of Surrey:

Primary Outcome Measures:
  • Postprandial glucose kinetics [ Time Frame: Two years ] [ Designated as safety issue: No ]
    The study is a double blind cross over study comparing placebo injection with lixisenatide injection. The results will not be known until the investigator is unblinded. An intravenous infusion of [6,6 2H2] glucose will enable the quantification of endogenous hepatic glucose output while addition of [U13C] glucose to a mixed meal will enable the calculation of the contribution of meal derived glucose to postprandial glucose. Enrichment of plasma samples with 2H2 glucose and 13C glucose will be measured by GCMS. Glucose uptake during the postprandial period will then be determined from these measures of glucose output and the glucose concentration at each time point. During this study, gastric emptying will be measured by oral administration of 1000mg acetominophene.


Secondary Outcome Measures:
  • Postprandial and intestinal triglyceride-rich lipoproteins (TRL) kinetics [ Time Frame: Two years ] [ Designated as safety issue: No ]
    Triglyceride kinetics in TRLs will be measured by intravenous injection of isotopically labelled glycerol which will be incorporated into nascent triglyceride molecules which is then incorporated into TRL particles (endogenous pathway) and oral administration of 13C triolein which will be incorporated as fatty acids into triglycerides and then become integrated into lipoprotein particles (exogenous pathway). The study uses a feeding protocol which maintains a steady state triglyceride concentration throughout the study. Repeated blood samples will be taken over many hours after administration of the tracers. Hepatic TRL (apoB-100) will be separated from intestinal TRL (ApoB48) using an immunoaffinity method. Measuring the glycerol and 13C oleate enrichments of the triglyceride isolated from lipoproteins, will allow the calculation of the production and clearance rates of triglycerides in both hepatic and intestinal TRLs.


Other Outcome Measures:
  • Postheparin lipoprotein lipase activity [ Time Frame: Two years ] [ Designated as safety issue: No ]

    A basal sample will be take. Then a heparin will be administered at 50IU/kg. another blood sample will be taken 15 minutes pot heparine injection. Pre and post heparin lipase activity in plasma will be measured using a commercially available kit.

    Both improved β cell function and insulin sensitivity could lead to an increase in LPL activity, increasing the clearance of TRL from the circulation. Improved insulin sensitivity would reduce hepatic TRL synthesis due to direct effects at the liver or indirectly by increasing the insulin sensitivity of lipolysis, thus reducing fatty acid delivery to the liver and intestine. The latter may also impact on intestinal TRL synthesis.



Estimated Enrollment: 12
Study Start Date: January 2014
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo
Placebo for lixisenatide is supplied as green and purple colored disposable pen-injectors containing 3 mL of a sterile aqueous solution.
Other: Lixisenatide

Lixisenatide and placebo are considered as investigational medicinal product (IMP). Metformin is not considered an investigational product but concomitant allowed antidiabetic medications.

Lixisenatide is supplied as disposable pre-filled pen for subcutaneous injection: 10mcg Lixisenatide green pens; 20 mcg Lixisenatide purple pens. Dose titration-10mcg Lixisenatide for 14 days, 20 mcg for 14 days.

Other Names:
  • GLP-1 agonist
  • Lyxumia
Other: Placebo
Placebo for lixisenatide is supplied as green and purple colored disposable pen-injectors containing 3 mL of a sterile aqueous solution.
Experimental: Lixisenatide

Lixisenatide and placebo are considered as investigational medicinal product (IMP). Metformin is not considered an investigational product but concomitant allowed antidiabetic medications.

Lixisenatide is supplied as disposable pre-filled pen for subcutaneous injection: 10mcg Lixisenatide green pens; 20 mcg Lixisenatide purple pens. Dose titration-10mcg Lixisenatide for 14 days, 20 mcg for 14 days.

Other: Lixisenatide

Lixisenatide and placebo are considered as investigational medicinal product (IMP). Metformin is not considered an investigational product but concomitant allowed antidiabetic medications.

Lixisenatide is supplied as disposable pre-filled pen for subcutaneous injection: 10mcg Lixisenatide green pens; 20 mcg Lixisenatide purple pens. Dose titration-10mcg Lixisenatide for 14 days, 20 mcg for 14 days.

Other Names:
  • GLP-1 agonist
  • Lyxumia
Other: Placebo
Placebo for lixisenatide is supplied as green and purple colored disposable pen-injectors containing 3 mL of a sterile aqueous solution.

Detailed Description:

GLP-1 analogues are a new treatment for type 2 diabetes, which have recently been shown to have beneficial effects on weight, glycaemic control and postprandial triglyceride concentrations. Postprandial hypertriglyceridaemia, which is associated with an increased risk of cardiovascular disease, is a feature of type 2 diabetes. Hypertriglyceridaemia is due to excess triglyceride-rich lipoproteins (TRL) which consist of very low-density lipoproteins, (VLDL) synthesised by the liver which contain the higher molecular weight form of apolipoproteinB (apoB), apoB-100, and chylomicrons which are synthesised in the intestine in response to an intake of dietary fat and contain the lower molecular weight form of apoB, apoB-48. A recent study has shown that GLP-1 receptor signalling is required for the control of postprandial lipoprotein synthesis and secretion in hamsters and mice. GLP-1 was shown to reduce apoB-48 TRL production while a GLP-1 receptor antagonist increased apoB-48 TRL production.

This study will investigate the effect of the GLP-1 analogue lixisenatide compared with placebo, in a double blind crossover study, on postprandial triglyceride metabolism in 12 patients with type 2 diabetes. Chylomicron and VLDL production and clearance rates will be measured in a repeated meal study (Visits 4 and 8) by labelling apoB-100 and apoB-48 with 1-13C leucine (infusion for 8 hours) and by labelling triglycerides with [1,1,2,3,3-2H5 ]glycerol (as a bolus injection) and 13C triolein. Blood samples will be taken for 4 hours prior to during the 8 hr isotopic infusion to measure the enrichment of apoB-100 and apoB-48 with 1-13C leucine by gas chromatography mass spectrometry.

At Visits 3 and 7, glucose flux in response to a mixed fluid meal containing U-13C glucose will be investigated. Endogenous glucose production will also be measured by infusing [6,6-2H2] glucose for 6hours.

Gastric emptying will be measured by acetaminophen (1000 mg) absorption. Patients will also receive heparin (50U/kg) at the end of the study after 15 minutes a blood sample will be taken to determine post heparin LPL activity.

During the study the patients will be asked to monitor their blood glucose for three days with continuous glucose monitoring and to fill in a 7 day food diary.

The hypothesis is that i] lixisenatide will lower postprandial glycaemia due to a decrease in endogenous glucose output and an increase in glucose clearance by peripheral tissues as a result of an improvement in insulin sensitivity.

ii] lixisenatide will reduce postprandial triglycerides due to a decrease in chylomicron production as a result of a direct effect on enterocyte chylomicron assembly and will also reduce VLDL secretion from the liver as a result of an improvement in insulin sensitivity.

  Eligibility

Ages Eligible for Study:   40 Years to 65 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects with type 2 diabetes inadequately controlled by metformin.
  • Stable diabetes management over last 3 months: metformin dose unchanged. HbA1c not known to have changed by >0.5% over 3 months.
  • Caucasian
  • Male
  • 40-65 years (inclusive)
  • HbA1c 7.5-8.5% (inclusive)
  • BMI 30-35 kg/m2 (inclusive)
  • Able and willing to self-administer placebo/lixisenatide injection
  • Able and willing to perform self-blood glucose monitoring.
  • Able and willing to wear a Continuous Glucose Monitoring System (CGMS) for 3 days

Exclusion Criteria:

  • Subjects treated with insulin, any OHA (other than metformin), any insulin secretagogue or TZDs
  • A history of heavy alcohol use (>12 to 15 g of alcohol per day)
  • Arteriopathy

    • History of significant coronary artery disease (myocardial infarction, surgical or percutaneous [balloon and/or stent] coronary revascularization procedure, or coronary angiography showing at least one stenosis ≥ 50% in a major epicardial artery or branch vessel)
    • Ischemic cerebrovascular disease, including:

      • History of ischemic stroke.
      • History of carotid arterial disease as documented by ≥ 50 % stenosis documented by carotid ultrasound, magnetic resonance imaging or angiography, with or without neurological sequelae.
    • Atherosclerotic peripheral arterial disease, as documented by history of amputation due to vascular disease; history of surgical or percutaneous revascularization procedure; current symptoms of intermittent claudication confirmed by an ankle-brachial pressure index less than 0.9
  • Hepatic disease: ALT >3 times upper limit of normal (ULN)
  • Renal disease: estimated glomerular filtration rate (Cockroft-Gault equation) less than 40ml/minute.
  • Subjects receiving fibrates or weight reducing drugs
  • Mental incapacity
  • Unwillingness or a language barrier precluding adequate understanding or co-operation
  • Fasting plasma triglycerides >4.0 mmol/l
  • Systolic blood pressure >160 mmHg on 2 occasions, measured at least 10-minutes apart
  • Screening amylase and/or lipase > 3 times ULN or P-calcitonin ≥20 pg/ml (5.9 pmol/L).
  • Personal or immediate family history of medullary thyroid cancer (MTC) or genetic condition that predisposes to MTC (e.g. multiple endocrine neoplasia syndromes).
  • History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy.
  • Any stomach/gastric surgery other than minor endoscopic procedures such as peptic ulcer injection
  • Allergic reaction to any GLP-1 receptor agonist or to metacresol.
  • Clinically relevant history of gastrointestinal disease associated with prolonged nausea and vomiting.
  • Current use of beta blockers.
  • Current smokers
  • Subject enrolled in another experimental protocol which involves the use of an investigational drug or device
  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: NCT02049034

Contacts
Contact: Fariba Shojaee-Moradie, PhD ++44(0)1483 688644 f.shojaee-moradie@surrey.ac.uk
Contact: Margot Umpleby, PhD ++44(0)1483 688579 m.umpleby@surrey.ac.uk

Locations
United Kingdom
University of Surrey FHMS Diabetes and Metabolic Medicine Recruiting
Guildford, Surrey, United Kingdom, GU2 7WG
Contact: Fariba Shojaee-Moardie, PhD    +44 1483 688644    f.shojaee-moradie@surrey.ac.uk   
Contact: Margot AM Umpleby, PhD    +44 1483 688579    m.umpleby@surrey.ac.uk   
Principal Investigator: David Russell-Jones, MBBS PhD         
Sub-Investigator: Margot Umpleby, PhD         
Sub-Investigator: Martin Whyte, MBBS PhD         
Sub-Investigator: Fariba Shojaee-Moardie, PhD         
Sub-Investigator: Barbara Fielding, PhD         
Sponsors and Collaborators
University of Surrey
Sanofi
Investigators
Study Chair: David Russell-Jones, MBBS PhD Royal Surrey County Hospital
Study Director: Margot Umpleby, BA, PhD University of Surrey
Principal Investigator: Martin Whyte, MBBS, PhD University of Surrey
Principal Investigator: Fariba Shojaee-Moradie, BSc, PhD Royal Surrey County Hospital & University of Surrey
  More Information

No publications provided

Responsible Party: University of Surrey
ClinicalTrials.gov Identifier: NCT02049034     History of Changes
Other Study ID Numbers: LIXISL06684, 2013-002826-22
Study First Received: December 18, 2013
Last Updated: January 27, 2014
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by University of Surrey:
GLP-1 agonist
Lixisenatide
Postprandial glucose metabolism
Postprandial lipid metabolism
Gastric emptying
Lipoprotein lipase activity

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases

ClinicalTrials.gov processed this record on August 21, 2014