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Liraglutide to Improve corONary Haemodynamics During Exercise streSS (LIONESS)

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ClinicalTrials.gov Identifier: NCT02315001
Recruitment Status : Completed
First Posted : December 11, 2014
Last Update Posted : May 20, 2015
Sponsor:
Collaborator:
Guy's and St Thomas' NHS Foundation Trust
Information provided by (Responsible Party):
King's College London

Brief Summary:
A single-centre double-blind placebo-controlled crossover randomised controlled trial to determine the physiological basis of glucagon-like peptide-1 receptor activation on exercise haemodynamics, as manifest through specific electrophysiological parameters measured by serial exercise stress testing, in those patients with reversible myocardial ischaemia and obstructive coronary artery disease confirmed by a baseline exercise test and coronary angiography respectively.

Condition or disease Intervention/treatment Phase
Ischaemic Heart Disease Coronary Heart Disease Chronic Stable Angina Drug: Liraglutide Other: Placebo Phase 2

Detailed Description:

Glucagon-like peptide-1 (GLP-1), an endogenous incretin hormone, is secreted by the gut in response to enteral nutrition and is responsible primarily for normal glucose homeostasis. There is a defective incretin effect in Type II diabetes mellitus such that meal-stimulated GLP-1 secretion is markedly impaired. However, a continuous infusion of exogenous GLP-1 can result in near normal insulin responses to a glucose load, suggesting preservation of insulinotropic activity. Liraglutide, a synthetic analogue that shares 97% structural homology to native GLP-1, is now a guideline-mandated antidiabetic therapy given as a once-daily subcutaneous injection.

Evidence emerging from animal and latterly human studies suggest GLP-1, independent of its effect on glycemic control and weight loss, may protect the heart from myocardial ischaemia/reperfusion injury and could potentially modulate the metabolic and haemodynamic outcomes of patients with coronary artery disease and left ventricular systolic dysfunction.

The investigators aim to determine whether chronic GLP-1 receptor occupancy has any effect on exercise haemodynamics in patients with known chronic stable angina, evidence of reversible ischaemia on exercise stress testing and angiographic evidence of obstructive coronary artery disease. Each study participant will be randomised to enter either a GLP-1 treatment arm or volume-matched saline placebo arm. Those randomised to GLP-1 will have a week's run-in phase with 0.6 mg Liraglutide followed by a week's course of 1.2 mg Liraglutide. At the end of Week 2, patients in the treatment arm will have their first exercise tolerance test (ETT). They will then be up-titrated to high dose 1.8 mg Liraglutide for another week before performing a Week 3 ETT. Patients in the placebo arm will have matched volume saline injections for the first two weeks before the Week 2 ETT and then another week of saline injections before the Week 3 ETT.

At the end of Week 3 patients will crossover so that those in the GLP-1 treatment arm cross to the placebo arm and vice versa. By incorporating a run-in phase followed by a step-wise increase in Liraglutide therapy over a 3-week period the investigators aim to minimise the occurrence of adverse reactions and also hope to observe a dose-response effect on exercise haemodynamics. The crossover design will allow study participants to effectively act as their own controls.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 26 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Official Title: The Physiological Effects of GLP-1 on Haemodynamics During Exercise in Patients With Ischaemic Heart Disease
Study Start Date : January 2014
Actual Primary Completion Date : March 2015
Actual Study Completion Date : March 2015

Resource links provided by the National Library of Medicine

Drug Information available for: Liraglutide

Arm Intervention/treatment
Active Comparator: Liraglutide

Week 1 Run-In Phase = 0.6 mg (0.1 ml) Liraglutide once daily via subcutaneous injection

Week 2 Low-Dose Phase = 1.2 mg (0.2 ml) Liraglutide once daily via subcutaneous injection

Week 3 High-Dose Phase = 1.8 mg (0.3 ml) Liraglutide once daily via subcutaneous injection

Drug: Liraglutide
GLP-1 receptor agonist administered via subcutaneous injection
Other Name: Victoza

Placebo Comparator: Saline Placebo

Week 1 Run-In Phase = 0.1 ml normal saline once daily via subcutaneous injection

Week 2 Low-Dose Phase = 0.2 ml normal saline once daily via subcutaneous injection

Week 3 High-Dose Phase = 0.3 ml normal saline once daily via subcutaneous injection

Other: Placebo
Volume-matched normal saline placebo administered via subcutaneous injection




Primary Outcome Measures :
  1. Change in rate pressure product at 0.1 mV ST-segment depression [ Time Frame: Following consecutive exercise treadmill tests performed at Week 2, Week3, Week 5 and Week 6 of a 6-week study protocol ]
  2. Change in degree of ST-segment depression at peak exercise [ Time Frame: Following consecutive exercise treadmill tests performed at Week 2, Week3, Week 5 and Week 6 of a 6-week study protocol ]

Secondary Outcome Measures :
  1. Change in total exercise duration [ Time Frame: Following consecutive exercise treadmill tests performed at Week 2, Week3, Week 5 and Week 6 of a 6-week study protocol ]
  2. Change in time to 0.1 mV ST-segment depression [ Time Frame: Following consecutive exercise treadmill tests performed at Week 2, Week3, Week 5 and Week 6 of a 6-week study protocol ]
  3. Change in recovery time to 0.05 mV ST-segment depression [ Time Frame: Following consecutive exercise treadmill tests performed at Week 2, Week3, Week 5 and Week 6 of a 6-week study protocol ]
  4. Evidence of hypoglycaemia [ Time Frame: During 6-week study protocol ]
    Monitored via twice daily home glucose monitoring and once weekly random serum glucose measurements

  5. Evidence of renal dysfunction [ Time Frame: During 6-week study protocol ]
    Monitored via once weekly measurement of serum creatinine, electrolytes and estimated glomerular filtration rate

  6. Evidence of acute pancreatitis [ Time Frame: During 6-week study protocol ]
    Monitored via once weekly measurement of serum amylase along with telephone and once weekly face-to-face interviews

  7. Change in time to maximum ST-segment depression [ Time Frame: Following consecutive exercise treadmill tests performed at Week 2, Week3, Week 5 and Week 6 of a 6-week study protocol ]


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Men and women aged 18-80
  2. Patients with a recent abnormal exercise tolerance test demonstrating >0.1 mV of planar or down-sloping ST-segment depression.
  3. Patients with known coronary artery disease and angiographic evidence of a >70% stenosis in a main epicardial artery, with or without coronary stenoses elsewhere.
  4. Patients must be able to walk confidently on a treadmill.
  5. Patients must have a normal resting electrocardiogram (ECG) in sinus rhythm without bundle branch aberration or other conduction disturbance.
  6. Patients must have normal left ventricular function.

Exclusion Criteria:

  1. An abnormal resting ECG including atrial fibrillation, bundle branch aberration or other conduction disturbance.
  2. Pre-existing left ventricular systolic dysfunction.
  3. Pre-existing ischaemic or non-ischaemic cardiomyopathy.
  4. Pre-existing valvular heart disease.
  5. Inability to safely negotiate an exercise treadmill.
  6. Type I diabetes mellitus.
  7. Type II diabetes mellitus taking oral or subcutaneous anti diabetic therapy.

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): NCT02315001


Locations
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United Kingdom
Guy's and St Thomas' NHS Foundation Trust
London, Greater London, United Kingdom, SE17EH
Sponsors and Collaborators
King's College London
Guy's and St Thomas' NHS Foundation Trust
Investigators
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Principal Investigator: Michael Marber, PhD FRCP King's College London
Principal Investigator: Simon Redwood, MD FRCP King's College London

Additional Information:
Publications:
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Responsible Party: King's College London
ClinicalTrials.gov Identifier: NCT02315001     History of Changes
Other Study ID Numbers: RJ112/N131
FS/11/70/28917 ( Other Grant/Funding Number: British Heart Foundation )
First Posted: December 11, 2014    Key Record Dates
Last Update Posted: May 20, 2015
Last Verified: May 2015
Keywords provided by King's College London:
Liraglutide
GLP-1
Ischaemic heart disease
Coronary heart disease
Chronic stable angina
Additional relevant MeSH terms:
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Heart Diseases
Coronary Disease
Coronary Artery Disease
Myocardial Ischemia
Angina, Stable
Ischemia
Pathologic Processes
Cardiovascular Diseases
Vascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Angina Pectoris
Chest Pain
Pain
Neurologic Manifestations
Signs and Symptoms
Liraglutide
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists