| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| NYHA Class II/III congestive heart failure. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010684 |
| E.1.2 | Term | Congestive heart failure |
|
| 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 |
1. To determine the treatment effect across doses of GSK716155 relative to placebo on myocardial glucose uptake in patients with NYHA Class II/III heart failure over a 3 month period.
2. To determine the treatment effect across doses of GSK716155 relative to placebo on myocardial efficiency in patients with NYHA Class II/III heart failure over a 3 month period.
3. To determine the treatment effect across doses of GSK716155 relative to placebo on maximum exercise performance in patients with NYHA Class II/III heart failure over a 3 month period
|
|
| E.2.2 | Secondary objectives of the trial |
1. To determine the treatment effect across doses of GSK716155 relative to placebo on left ventricular function using echocardiography.
2. To determine the treatment effect across doses of GSK716155 relative to placebo on cardiac size, function, mass and strain using cardiac magnetic resonance imaging (CMR).
3. To measure cardiac energetics using 31P MRS.
4. To measure cardiac and hepatic fat by proton MRS.
5. To determine the treatment effect across doses of GSK716155 relative to placebo on 6-minute walking distance.
6. To determine the treatment effect across doses of GSK716155 relative to placebo on serum BNP, a marker of severity of CHF.
7. To determine the treatment effect across doses of GSK716155 relative to placebo on biomarkers of glucose metabolism.
8. To determine the treatment effect across doses of GSK716155 relative to placebo on quality of life measures.
For secondary objectives 9 and 10 please refer to Protocol Amendment 01, Page 24 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Chronic heart failure due to cardiomyopathy of ischemic or non-ischemic origin.
2. Clinically stable on optimal therapies for at least 3 months prior to screening/baseline visit.
3. Left ventricular ejection fraction ≤ 40 % as assessed by any measurement in the previous 24 months.
4. NYHA Class II/III heart failure for a minimum of 6 months prior to enrolment
5. 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.
6. 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]. [Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in Section 8.1 if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, method.]
• 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.
7. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
8. Confirmed QTcB or QTcF < 480 msec; or QTc < 500 msec in subjects with Bundle
Branch Block.
9. AST and ALT < 2xULN; alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated
bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
10. Subjects must be able to perform performance/exercise testing |
|
| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply
1. 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.
2. High suspicion of active myocardial ischemia, in the opinion of the treating physician.
3. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
result within 3 months of screening.
4. History of drug/alcohol abuse.
5. A positive test for HIV antibody.
6. Calcitonin > 100 pg/mL
7. Triglycerides > 850 mg/dL
8. History of significant gastrointestinal surgery, including gastric bypass and banding, antrectomy, Roux-en-Y bypass, gastric vagotomy, small bowel resection, or surgeries thought to significantlyaffect upper gastrointestinal function.
9. 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.
10. 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).
11. Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
12. Known allergy or history of sensitivity to albiglutide, any other GLP-1 analogue, or
Baker’s yeast.
13. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
14. Pregnant females as determined by positive serum or urine hCG test at screening or prior to dosing.
15. Lactating females.
16. Unwillingness or inability to follow the procedures outlined in the protocol (e.g.,
related to psychiatric disorder).
17. Subject is mentally or legally incapacitated.
18. Known diagnosis of diabetes mellitus, fasting glucose >140mg/dL, or HbA1c >7%.
19. Uncorrected thyroid disease manifest as an abnormal thyroid-stimulating hormone (TSH) (outside reference range at screening).
20. Other medical problems with life expectancy less than 1yr.
21. 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
22. Subjects with genetic disorders of skeletal muscle (e.g., Duchenne muscular
dystrophy).
23. Clinically significant pericardial disease.
24. Listed as a status 1A or 1B on heart transplant waiting list.
25. History of deep vein thrombosis or a known coagulation disorder.
26. History of pancreatitis.
27. History of or family history of medullary thyroid carcinoma.
28. History of or family history of multiple endocrine neoplasia type 2.
29. History of renal dysfunction with estimated GFR < 40 ml/min at screening.
30. Resting systolic blood pressure < 85 mmHg or >170 mmHg; or diastolic blood
pressure >110 mgHg at screening.
31. Inability of the patient to lie flat for a combined total of up to 4 hours to complete
imaging (PET/MR) assessments.
32. No subjects will undergo CMR or MRS imaging who have contraindications to
MRI scanning including, but not limited to:
• Intracranial aneurysm clips (except Sugita) 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Myocardial glucose utilization as assessed by FDG-PET imaging
2. Myocardial efficiency (work performed/MVO2) assessed at rest:
a. Work calculated by cardiac echo
b. MVO2 accessed via 11C-acetate PET imaging
3. Peak oxygen uptake (VO2 max) as assessed by bicycle cardiopulmonary exercise
testing. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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 | Yes |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| 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
|
| The end of the study is defined as the last subject’s last visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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