A Multi-center, Placebo-controlled Study to Evaluate the Safety of GSK716155 and Its Effects on Myocardial Metabolism, Myocardial Function, and Exercise Capacity in Patients With NYHA Class II/III Congestive Heart Failure

Heart Failure, Congestive Clinical Trial

Official title:

A Multi-center, Placebo-controlled Study to Evaluate the Safety of GSK716155 and Its Effects on Myocardial Metabolism, Myocardial Function, and Exercise Capacity in Patients With NYHA Class II/III Congestive Heart Failure

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01357850
• Other study ID #: 112670
• Status: Completed
• Phase: Phase 2
• First received: November 11, 2010
• Last updated: June 4, 2015
• Start date: September 2010
• Est. completion date: September 2012

Study information

• Verified date: June 2015
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationEurope: European Medicines Agency
• Study type: Interventional

Clinical Trial Summary

This exploratory proof of concept study will be conducted in patients with stable New York Heart Association (NYHA) Class II-III heart failure. The focus of the efficacy endpoints is to test the hypothesis that GSK716155 administration will increase glucose uptake and utilization in the myocardium, resulting in increased myocardial efficiency and increased exercise capacity. A positive result, defined as either statistically significant effects on one or more of the efficacy endpoints or as an overall signal suggesting a clinically relevant effect on myocardial physiology, would provide evidence for potential progression into further development in a chronic heart failure population.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 82
• Est. completion date: September 2012
• Est. primary completion date: September 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 21 Years to 75 Years

Eligibility

Inclusion Criteria:

• Chronic dilated cardiomyopathy of ischemic or non-ischemic origin

• Clinically stable on optimal therapies for at least 3 months prior to screening/baseline visit.

• Left ventricular ejection fraction greater than or equal to 40% as assessed by any measurement in the previous 24 months.

• NYHA Class II/III heart failure for a minimum of 6 months prior to enrolment

• Male or female between 21 and 75 years of age inclusive, at the time of signing the informed consent. However the optimal age range for this study will be 40 to 65 years of age.

• A female subject is eligible to participate if she is of:

Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<140 pmol/L) is confirmatory].

Child-bearing potential and agrees to use one of the contraception methods listed in Section 8.1 for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until the follow-up visit ~28 days post-last dose.

• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

• Confirmed QTcB or QTcF < 480 msec; or QTc < 500 msec in subjects with Bundle Branch Block.

• AST and ALT < 2xULN; alkaline phosphatase and bilirubin greater than or equal to 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

• Subjects must be able to perform performance/exercise testing

Exclusion Criteria:

• A subject will not be eligible for inclusion in this study if any of the following criteria apply:

• Active ischemia manifest as a history of myocardial infarction or unstable angina in the past 12 months or a history of coronary revascularization (percutaneous coronary intervention and/or coronary artery bypass grafting) in the past 6 months.

-. High suspicion of active myocardial ischemia, in the opinion of the treating physician

• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening

• History of drug/alcohol abuse.

• A positive test for HIV antibody.

• Calcitonin > 100 pg./mL

• Triglycerides > 850 mg/dL

• History of significant gastrointestinal surgery, including gastric bypass and banding, antrectomy, Roux-en-Y bypass, gastric vagotomy, small bowel resection, or surgeries thought to significantly affect upper gastrointestinal function.

• History of regular alcohol consumption within 6 months of the study defined as:

For UK: an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits.

For US: an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 ml) of beer, 5 ounces (150 ml) of wine or 1.5 ounces (45 ml) of 80 proof distilled spirits.

• The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).

• Exposure to more than four new chemical entities within 12 months prior to the first dosing day.

• Known allergy or history of sensitivity to albiglutide, any other GLP-1 analogue, , or Baker's yeast.

• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.

• Pregnant females as determined by positive serum or urine hCG test at screening or prior to dosing.

• Lactating females.

• Unwillingness or inability to follow the procedures outlined in the protocol (e.g.. related to psychiatric disorder)

• Subject is mentally or legally incapacitated.

• Known diagnosis of diabetes mellitus, fasting glucose >140mg/dL, or HbA1c > 7%.

• Uncorrected thyroid disease manifest as an abnormal thyroid-stimulating hormone (TSH) (outside reference range at screening).

• Other medical problems with life expectancy less than 1yr.

• Other causes of cardiomyopathy or left ventricular dysfunction including:

Uncorrected primary obstructive or regurgitant valvular disease Restrictive cardiomyopathy due to amyloidosis, hemochromatosis, sarcoidosis or other cause Cardiac hypertrophy with wall thickness >1.5cm Alcohol-induced cardiomyopathy Women with heart failure during the 12 months following childbirth. Complex congenital heart disease Anthracycline induced cardiomyopathy

• Subjects with genetic disorders of skeletal muscle (e.g. Duchenne muscular dystrophy)

• Clinically significant pericardial disease.

• Listed as a status 1A or 1B on heart transplant waiting list.

• History of deep vein thrombosis or a known coagulation disorder

• History of pancreatitis

• History of or family history of medullary thyroid carcinoma

• History of or family history of multiple endocrine neoplasia type 2

• History of renal dysfunction with estimated GFR < 40 ml/min at screening

• Resting systolic blood pressure < 85 mmHg or >170 mmHg; or diastolic blood pressure >110 mgHg at screening.

• Inability of the patient to lie flat for a combined total of up to 4 hours to complete imaging assessments.

• No subjects will be enrolled at the single site performing the CMR sub-study who have contraindications to MRI scanning including, but not limited to:

Intracranial aneurysm clips with an appropriate operative conformation History of intra- orbital metal fragments Pacemakers or non-MR compatible heart valves Inner ear implants History of claustrophobia deemed significant by the investigator

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure, Congestive

Intervention

Drug:
• GSK716155
GSK716155
• Placebo
Placebo

Locations

Country	Name	City	State
United Kingdom	GSK Investigational Site	Cambridge	Cambridgeshire
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	Oxford
United States	GSK Investigational Site	Auburn	Maine
United States	GSK Investigational Site	Baltimore	Maryland
United States	GSK Investigational Site	Columbus	Ohio
United States	GSK Investigational Site	Detroit	Michigan
United States	GSK Investigational Site	Metairie	Louisiana
United States	GSK Investigational Site	Minneapolis	Minnesota
United States	GSK Investigational Site	New York	Pennsylvania
United States	GSK Investigational Site	Newark	New Jersey
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Savannah	Georgia
United States	GSK Investigational Site	St Louis	Missouri
United States	GSK Investigational Site	Stony Brook	New York

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Myocardial Glucose Utilization as Assessed by [18F]Fluoro-2-deoxy-glucose Positron Emission Tomography (FDG-PET) Imaging	FDG-PET imaging was performed at Baseline and Week 13 to assess myocardial glucose uptake. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Based on analysis using a mixed effects analysis of variance (ANOVA) model, fitting terms for treatment, visit and interaction of treatment and visit, with participants as random effects.	Baseline and Week 13	No
Primary	Change From Baseline in Myocardial Efficiency (Work Performed/Myocardial Oxygen Consumption [MVO2]) Assessed at Rest	MVO2 was estimated by measuring the rate of myocardial clearance of 11C-activity which represents overall myocardial oxidative flux through the TCA cycle. Cardiac work was measured by echocardiography and cardiac efficiency index was calculated as work (by echocardiography) divided by MVO2. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Based on analysis using a mixed effects ANOVA model, fitting terms for treatment, visit and interaction of treatment and visit, with participants as random effects.	Baseline and Week 13	No
Primary	Change From Baseline in Peak Oxygen Uptake (Peak VO2) as Assessed by Bicycle Cardiopulmonary Exercise Testing	Peak VO2 was measured at Baseline and Week 13. Participants performed a maximal exercise test limited by dyspnea or fatigue on a cycle ergometer. After a rest period, the workloads were increased in a step fashion by 25 watts every 3 minutes. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Based on analysis using a mixed effects ANOVA model, fitting terms for treatment, visit and interaction of treatment and visit, with participants as random effects.	Baseline and Week 13	No
Secondary	Change From Baseline in Left Ventricular Ejection Fraction (LVEF) as Assessed by Echocardiogram	Echocardiography was performed at Baseline and Week 13 using pulse-wave, continuous-wave, and tissue Doppler. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.	Baseline and Week 13	No
Secondary	Change From Baseline in Left Ventricular (LV) Volumes in Systole and Diastole as Assessed by Echocardiogram	Echocardiography was performed at Baseline and Week 13 using pulse-wave, continuous-wave and tissue Doppler. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.	Baseline and Week 13	No
Secondary	Change From Baseline in LV and RV Function Assessed by Cardiac Magnetic Resonance (CMR) (LVEF), Myocardial Strain Assessed by Myocardial Tagging Indices	Non-contrast CMR to assess left ventricular (LV) and right ventricular (RV) ejection fraction, volume, mass, and strain was performed following a period of rest after exercise testing at Baseline and after the Week 13 treatment phase. A 3Tesla magnetic resonance imagine (MRI) examination was performed including sequences for evaluation of LV structure and function. Only those participants available at the specified time points were analyzed. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.	Baseline and Week 13	No
Secondary	Change From Baseline in LV and RV Function Assessed by CMR (LV and RV Volumes in Systole and Diastole), Myocardial Strain Assessed by Myocardial Tagging Indices	Non-contrast CMR to assess LV and RV ejection fraction, volume, mass, and strain was performed following a period of rest after exercise testing at Baseline and after the Week 13 treatment phase. A 3Tesla magnetic resonance imagine (MRI) examination was performed including sequences for evaluation of LV structure and function. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.	Baseline and Week 13	No
Secondary	Change From Baseline in LV and RV Function Assessed by CMR (LV Mass), Myocardial Strain Assessed by Myocardial Tagging Indices	Non-contrast CMR to assess left/right ventricular ejection fraction, volume, mass, and strain was performed following a period of rest after exercise testing at Baseline and after the Week 13 treatment phase. A 3Tesla magnetic resonance imagine (MRI) examination was performed including sequences for evaluation of LV structure and function. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.	Baseline and Week 13	No
Secondary	Change From Baseline in Cardiac Energetics (PCr/ATP) Measured by 31P Magnetic Resonance Spectroscopy (MRS)	Participants underwent a CMR scan performed on a 3 Tesla MR system at Baseline and Week 13 to assess cardiac mass, volumes (global function and dilatation), strain and torsion, cardiac and liver lipid content and cardiac energy metabolism. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.	Baseline and Week 13	No
Secondary	Change From Baseline in Cardiac and Liver Fat by Proton Spectroscopy (1H MRS)	Change in Baseline in cardiac and liver fat by proton spectroscopy was planned at Baseline and Week 13. The protocol allowed for sites to perform all or only efficacy assessments, depending on site designation, capability and feasibility. No sites that enrolled participants into this study were able to perform this outcome measure.	Baseline and Week 13	No
Secondary	Change From Baseline in Exercise Capacity Assessed by 6-minute Walk Test	The six minute walk test was performed at Baseline and Week 13. All participantss were given standardized instructions and the distance walked was measured. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.	Baseline and Week 13	No
Secondary	Change From Baseline in Serum N-terminal Fragment Brain Natriuretic Peptide (NT-BNP) Level	Baseline is defined as the last available assessment on or prior to the first dose of study medication. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.	Change from Baseline at Week 13	No
Secondary	Change From Baseline in Plasma Levels of Glucose, and Free Fatty Acids (FFA)	Blood samples for biomarker analysis of fasting levels of glucose and FFA were collected at Weeks 1, 7 and 13; glucose was also collected at Weeks 2, 4, 6, 8, 10, and 12. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.	Baseline and Week 13	No
Secondary	Change From Baseline in Plasma Levels of Insulin	Blood samples for biomarker analysis of fasting levels of insulin were collected at Weeks 1, 7 and 13. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.	Baseline and Week 13	No
Secondary	Change From Baseline in Quality of Life as Assessed by the Minnesota Living With Heart Failure Questionnaire	Minnesota living with heart failure questionnaire (MLHFQ) is a validated instrument to measure participant-reported quality of life at Baseline and Week 13. For each of 21 items, participants rated the effects of heart failure and its treatment on physical, socioeconomic and psychological aspects of their life. To measure the effects of symptoms, functional limitations, psychological distress on an individual's quality of life, the MLHF questionnaire asks each participant to indicate their response using a 6-point scale (ranging from 0 to 5, 0=no, 1=very little, and 5=very much). The min and max scores can range from 0 to 105. The likert scale measures the effect of heart failure and treatments for heart failure on an individual's ability to live as they want. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.	Baseline and Week 13	No
Secondary	Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. Please refer to the AE/SAE section for further details.	Baseline and Week 13	No
Secondary	Number of Participants With Adverse Events by the Indicated Severity	An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. Severity categories: Mild: an event that was easily tolerated by the participant, causing minimal discomfort and not interfering with everyday activities;Moderate: an event that was sufficiently discomforting to interfere with normal everyday activities; Severe: an event that prevents normal everyday activities.	Baseline and Week 13	No