| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute decompensated heart failure (adHF) |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 7.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000803 |
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| 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 |
The objectives of this study are to assess the efficacy and safety of IV nesiritide versus placebo, in addition to background care, in the treatment of subjects with adHF managed in an inpatient setting reflecting mainstream clinical practice.
Primary Objective
• To evaluate the efficacy of nesiritide versus placebo, in addition to background care by assessing dyspnoea and well-being at 3 hours and 6 hours after the start of investigational product.
The study will be considered a success if improvement in subject self-assessed dyspnoea (at either 3 or 6 hours, or both) and in subject self-assessed well-being (at either 3 or 6 hours, or both) is shown.
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| E.2.2 | Secondary objectives of the trial |
• To assess the effect of nesiritide versus placebo, in addition to background care, on other efficacy parameters including mortality and readmissions, clinical status and endpoints relating to length of hospital stay and degree of care required
• To assess the safety of nesiritide versus placebo, in addition to background care, in subjects with adHF
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
A subject will be considered eligible for inclusion in this study only if all of the
following criteria apply:
1. Male or female, at least 18 years of age and who has been hospitalised for the management of a primary diagnosis of adHF. Note for the small number of female subjects of childbearing potential who may enter the study an effective method of contraception must be used for the duration of the study (up to Day 30)
2. The underlying primary aetiology of adHF and the presenting symptoms should be cardiac disease, rather than pulmonary disease (e.g. not cor pulmonale, nor pneumonia in addition to chronic HF)
3. In relation to the acute episode, subjects must have at least one sign of heart failure as detailed below:
• tachypnoea (> 20 breaths/minute)
• increased jugular venous pressure (JVP), or 3rd/4th heart sound, or recent clinically significant weight gain indicative of oedema, or hepatic congestion.
• crackles/rales or pulmonary effusion evident on chest auscultation/ examination.
4. In relation to the acute episode, subjects must have at least one piece of investigational evidence consistent with heart failure as detailed below:
• a chest X-ray upon admission with evidence of pulmonary congestion
• Left ventricular systolic ejection fraction performed within the past 12 months - Left ventricular ejection fraction should be ≤45% or the equivalent rating of at least moderately impaired left ventricular systolic function.
5. Subjects must still have dyspnoea at rest or on minimal exertion (e.g. on sitting up) at the time of randomisation
6. Subjects must have received at least one but not more than two doses of IV bolus diuretic within 24 hours prior to randomisation AND/OR, have been receiving a continuous infusion of IV diuretics for at least 2 hours immediately prior to randomisation at a constant dose. Bolus IV diuretic is not permitted within 1 hour prior to randomisation. The subject must be randomised within 24 hours of the initiation of IV treatment for HF.
7. Chronicity of HF must be substantiated by: 1) documented clinical history of chronic HF and 2) investigational evidence of left ventricular systolic dysfunction (e.g. by echocardiography, ventriculography or nuclear cardiography) within the last 12 months. A current assessment (e.g. echocardiographic) can be performed if this information is not available from the medical history at the time of screening. NB: Left ventricular ejection fraction should be ≤45% or the equivalent rating of at least moderately impaired left ventricular systolic function
8. The subject or legal representative must fully understand and sign the written informed consent prior to initiation of protocol-specified procedures.
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| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1. Initiation of IV treatment for HF > 24 hours prior to randomisation
2. Hospitalised for ≥48 hours prior to randomisation
3. Baseline SBP
a. Subjects who have not received or are not receiving either IV vasodilators (e.g. nitrates) or inotropes prior to randomisation are excluded if SBP ≤ 100mmHg.
b. Subjects who have received or are receiving either IV vasodilators (e.g. nitrates) or inotropes prior to randomisation are excluded if SBP < 120mmHg
4. a. Subjects receiving continuous iv diuretics, iv vasodilators, or iv inotropes prior to randomisation whose dose has not remained stable for 2 hours prior to randomisation.
b. Subjects receiving iv vasodilators, or iv inotropes whose SBP is unstable (e.g. progressively falling) or has fallen below 120mmHg within 2 hours prior to randomisation.
5. Known or suspected acute coronary syndrome (ST-elevation or non-ST elevation myocardial infarction (MI) or unstable angina pectoris) within the past 2 weeks.
6. Cardiogenic shock, evidence of uncorrected volume or sodium depletion (e.g. excessive diuresis or clinical signs of dehydration) or other clinical condition that would contraindicate the administration of IV vasoactive agents
7. Evidence of malignant hypertension or severe persistent uncontrolled hypertension (blood pressure >190/115 mmHg).
8. History of unexplained syncope
9. Requiring mechanical ventilation, or mechanical circulatory support (e.g. intraaortic balloon pump, left ventricular assist devices) (subjects receiving CPAP prior to randomisation may be recruited), or likely to require dialysis or other renal replacement therapy post randomisation, or likely to undergo percutaneaous coronary intervention (PCI) or emergency surgery during admission.
10. Subjects who have been resuscitated or received defibrillation during the admission prior to randomisation.
11. Known allergic reaction to nesiritide or other IV therapy that may be critical to successful management of adHF (e.g. nitrate, inotropes, diuretics)
12. The following co-morbidities: cardiac valvular stenosis, restrictive cardiomyopathy, hypertrophic obstructive cardiomyopathy, pericardial tamponade or any condition likely to cause intolerance to vasodilators, severe pulmonary disease, concurrent pneumonia,
13. adHF associated with: underlying congenital heart disease, thyrotoxicosis (or other conditions associated with high output cardiac failure), active myocarditis; or with uncontrolled haemodynamically relevant atrial fibrillation/flutter; or with ventricular rhythm disturbances or secondary to clinical evidence of digoxin toxicity or any other drug-related toxicity.
14. Subjects with other significant, non-cardiac, co-morbidities (e.g. cancer) who are not anticipated to survive the 6 month follow-up
15. Subjects whose condition requires long term IV vasoactive support (e.g. heart transplant candidate) or subjects whose acute cardiovascular condition is unlikely to be sufficiently improved to enable the subject to be discharged following study therapy
16. Subjects who have undergone a heart transplant or who are waiting to undergo transplant surgery
17. Subjects who have undergone coronary artery bypass graft (CABG) surgery or other cardiac/ major non-cardiac surgery within the past 30 days
18. Therapy with another investigational drug within 5 half lives prior to the time of study entry which had not been pre-approved by GSK
19. Prior therapy with nesiritide
20. Pregnancy, suspected pregnancy or breast feeding
21. Unwillingness or inability to comply with study requirements
22. This note is applicable to French-participating centres only:
A subject will not be eligible for inclusion into this study if any of the following criteria apply:
• The subject is not either affiliated to or beneficiary of a social security category.
• The subject will participate simultaneously in another clinical trial.
The exclusion period after the completion of this study (Day 30) will be 5 months.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Co-Primary Endpoints:
• Subject self-assessed dyspnoea at 3 hours
• Subject self-assessed dyspnoea at 6 hours
• Subject self-assessed well being at 3 hours
• Subject self-assessed well being at 6 hours
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| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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.8.5 | The trial involves multiple Member States | Yes |
| 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 |
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| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
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As per protocol: All subjects will be considered to have completed the study upon completion of assessments and procedures up to and including the Day 30 visit (Day 30 post randomistiaon) or if the subject dies prior to the Day 30 follow up.
A long term follow-up of subjects will involve monthly collection of survival status up to Day 180 post randomisation. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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