| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Decompensated Heart Failure |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064653 |
| E.1.2 | Term | Acute decompensated 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 |
| To compare the effect of four intravenous (I.V.) SLV320 doses with placebo on the change in serum creatinine from Baseline to Day 14. |
|
| E.2.2 | Secondary objectives of the trial |
1. Compare the effect of four I.V. SLV320 doses with placebo on the change in the variables from Baseline to various time points.
2. Compare the effect of four I.V. doses of SLV320 with placebo using the trichotomous endpoint of treatment success, treatment failure, or no change.
3. Compare the effect of four I.V. doses of SLV320 with placebo on total loop diuretic dose.
4. Compare the effect of four I.V. doses of SLV320 with placebo on using a composite endpoint of all-cause mortality, cardiovascular hospitalization or hospitalization for worsening renal function, in time to event and frequency, during the follow-up period.
5. Determine the pharmacokinetic (PK) profile of I.V. SLV320 and its active metabolites.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
In order to be eligible for the study, subjects should fulfill the following criteria at the Screening visit:
1. Be capable of understanding the nature of the study and be willing to participate, as documented by signed written informed consent or signed informed consent by a legally authorized representative.
2 .Be 18 years or older (male or female).
3. If female, be surgically sterile (bilateral oophorectomy and/or hysterectomy) or be at least one year postmenopausal as judged by the Investigator.
4. Have renal dysfunction (defined as estimated eGFR of 20–80 mL/min [Cockcroft-Gault formula]).
5.Have BNP ≥400 pg/mL or NT-pro-BNP >2000 pg/mL.
6. Have a history of systolic or diastolic chronic heart failure of at least 14 days duration for which loop diuretic therapy has been prescribed.
7. Have clinical evidence of volume overload manifested by at least two of the following features:
(a) dyspnea
(b) rales
(c) peripheral edema and/or pre-sacral edema
(d) increased jugular venous distension (>8 cm)
(e) chest X-ray consistent with CHF.
8. Require hospitalization for treatment of the current episode of ADHF with I.V. diuretics and
-Have received at least 40 mg I.V. furosemide (or equivalent) for the treatment of the current episode of ADHF prior to the start of the initial study drug infusion unless a rationale for a lower dose is provided by the enrolling Investigator, and
-Receives the first study treatment within 24 hours (± four hours) following presentation to the hospital (including the emergency department) for this episode of ADHF.
9. Anticipated need for I.V. furosemide ≥40 mg/day (or equivalent dose of I.V. loop diuretic) for at least 24 hours after start of study drug |
|
| E.4 | Principal exclusion criteria |
Subjects are excluded from participating in the study if they:
1. Are women of child-bearing potential.
2. Have low output syndrome, defined as having the need for treatment with I.V. inotropes or vasopressors.
3. Have systolic blood pressure <95 mmHg at the time of randomization.
4. Have body temperature >38°C (100.4°F) at the time of randomization.
5. Need mechanical ventilation.
6. Have significant stenotic valvular disease (severe aortic or mitral stenosis).
7. Have clinical evidence of acute coronary syndromes in the two weeks prior to screening.
8. Have myocardial infarction or hemodynamically destabilizing significant arrythmias (ventricular tachycardia, bradyarrythmias with slow ventricular rate [<45 bpm] or atrial fibrillation/flutter with a rapid ventricular response of >130 bpm), or electrocardiographic evidence of 2nd degree heart block (Mobitz Type II) or 3rd degree AV-block in the absence of a pacemaker, within 30 days of screening.
9. Have acute myocarditis or hypertrophic obstructive, restrictive, or constrictive cardiomyopathy.
10. Have serum potassium <3.5 mEq/L and/or serum sodium <130 mEq/L. Serum potassium 3.0–3.4 mEq/L will be allowed if parenteral supplemental potassium is being administered.
11. Have aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3 times the upper limit of normal; and/or total bilirubin >3 mg/dL.
12. Have clinically significant laboratory abnormalities or medical conditions which, in the opinion of the Investigator, make them unsuitable for evaluation in the study.
13. Any heart, lung, kidney, or liver transplant recipient or are admitted for these transplantations.
14. Have ongoing or planned treatment with ultrafiltration, hemofiltration or dialysis.
15. Have implantation of a cardiac defibrillator or cardiac resynchronization device (pacemaker) or temporary pacing wire within seven days of screening.
16.Have non-cardiac pulmonary edema, including suspected sepsis
17. Have a known risk for seizures with history of any of the following:
- stroke within two years, or transient ischemic attack within six months, prior to screening.
- seizures (except febrile seizure)
- brain tumor of any etiology (or current brain tumor)
- encephalitis/meningitis within the previous two years
- penetrating head trauma
- closed head injury with loss of consciousness of over 30 minutes within the previous two years
- brain surgery within the previous two years
- alcohol withdrawal seizures (or are at risk of alcohol withdrawal seizures)
18. Have an increased risk for seizure (as determined by the Investigator) due to unstable condition resulting in widely fluctuating oxygen, glucose or electrolyte levels.
19. Have advanced Alzheimer's disease.
20. Have advanced multiple sclerosis.
21.Have a history of hypoglycemia unawareness.
22. Have received I.V. contrast dye within two weeks prior to Day 1, or are expected to receive I.V. contrast during the treatment period of the study.
23. Have a history of acute contrast-induced nephropathy (increase of serum creatinine >0.5 mg/dL within 48 hours of contrast exposure).
24. Have had administration of an investigational drug or device, or have participated in an investigational trial, within 30 days prior to randomization.
25. Have evidence of malignancy, within 6 months prior to screening. Subjects with a history of stable prostate cancer, basal cell carcinoma, or fewer than three squamous cell carcinomas of the skin are eligible.
26. Have known hypersensitivity to adenosine A1 antagonists or any of SLV320's components.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The trichotomous endpoint of treatment success, treatment failure or no change will be assessed, using the following criteria on Day 14:
- Treatment success is dyspnea reported by the subject as 'moderately' or 'markedly' better at both Day 2 and Day 3 compared to start of treatment, and the absence of treatment failure.
- Treatment failure is any one of the following:
- Death from heart failure, readmission to the hospital for heart failure, or unexpected post-discharge visits for heart failure e.g., emergency department visit through Day 14.
- Worsening of heart failure requiring the use of I.V. rescue therapy more than 24 hours following the start of the first infusion of SLV320 or placebo to discharge from hospital or Day 7 (whichever is earliest)
- Persistent renal impairment (the worsening of renal function defined by an increase of >0.3 mg/dL in serum creatinine from Baseline to Day 7, confirmed at Day 14.
The composite endpoint of death or cardiovascular or renal hospitalization will be assessed at all visits (Days 7, 14, 30, 60, 90 and 180). |
|
| 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 | No |
| 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 | 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) | 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 | 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.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 85 |
| 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 | Yes |
| 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
| |
| 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 | 13 |
| 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 | 13 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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