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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

Tracking Information
First Submitted Date  ICMJE November 10, 2014
First Posted Date  ICMJE December 11, 2014
Last Update Posted Date May 20, 2015
Study Start Date  ICMJE January 2014
Actual Primary Completion Date March 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 29, 2015)
  • 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 ]
  • 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 ]
Original Primary Outcome Measures  ICMJE
 (submitted: December 9, 2014)
  • 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 ]
  • Change in degree of ST-segment depression at peak exercise at equivalent workloads [ Time Frame: Following consecutive exercise treadmill tests performed at Week 2, Week3, Week 5 and Week 6 of a 6-week study protocol ]
Change History Complete list of historical versions of study NCT02315001 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 29, 2015)
  • 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 ]
  • 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 ]
  • 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 ]
  • Evidence of hypoglycaemia [ Time Frame: During 6-week study protocol ]
    Monitored via twice daily home glucose monitoring and once weekly random serum glucose measurements
  • 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
  • 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
  • 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: December 9, 2014)
  • 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 ]
  • 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 ]
  • 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 ]
  • Evidence of hypoglycaemia [ Time Frame: During 6-week study protocol ]
    Monitored via twice daily home glucose monitoring and once weekly random serum glucose measurements
  • 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
  • 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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Liraglutide to Improve corONary Haemodynamics During Exercise streSS
Official Title  ICMJE The Physiological Effects of GLP-1 on Haemodynamics During Exercise in Patients With Ischaemic Heart Disease
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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Condition  ICMJE
  • Ischaemic Heart Disease
  • Coronary Heart Disease
  • Chronic Stable Angina
Intervention  ICMJE
  • Drug: Liraglutide
    GLP-1 receptor agonist administered via subcutaneous injection
    Other Name: Victoza
  • Other: Placebo
    Volume-matched normal saline placebo administered via subcutaneous injection
Study Arms  ICMJE
  • 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

    Intervention: Drug: Liraglutide
  • 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

    Intervention: Other: Placebo
Publications * Myat A, Arri S, Bhatt DL, Gersh BJ, Redwood SR, Marber MS. Design and rationale for the randomised, double-blinded, placebo-controlled Liraglutide to Improve corONary haemodynamics during Exercise streSS (LIONESS) crossover study. Cardiovasc Diabetol. 2015 Feb 19;14:27. doi: 10.1186/s12933-015-0193-4.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 19, 2015)
26
Original Estimated Enrollment  ICMJE
 (submitted: December 9, 2014)
22
Actual Study Completion Date  ICMJE March 2015
Actual Primary Completion Date March 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02315001
Other Study ID Numbers  ICMJE RJ112/N131
FS/11/70/28917 ( Other Grant/Funding Number: British Heart Foundation )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party King's College London
Study Sponsor  ICMJE King's College London
Collaborators  ICMJE Guy's and St Thomas' NHS Foundation Trust
Investigators  ICMJE
Principal Investigator: Michael Marber, PhD FRCP King's College London
Principal Investigator: Simon Redwood, MD FRCP King's College London
PRS Account King's College London
Verification Date May 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP