E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients being admitted to hospital for acute heart failure (AHFS) with volume overload and renal impairment. |
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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 | 10000803 |
E.1.2 | Term | Acute heart failure |
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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 main objective of this study is to evaluate the effect of KW-3902IV in addition to IV loop diuretic therapy on heart failure signs and symptoms, persistent renal function, morbidity and mortality, and safety in subjects hospitalised with acute heart failure syndrome, volume overload, and renal impairment. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to evaluate the safety of KW-3902IV in subjects hospitalised with AHFS, volume overload and renal impairment and to estimate and compare within trial medical resource utilization and direct medical costs between patients treated with KW-3902IV and placebo. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. In Germany, subjects entering into the clinical trial must provide their own actual informed consent. Institutionalised patients and patients that require a legally authorised representative must be excluded. 2. Male or female 18 years of age or greater 3. History of heart failure of at least 14 days duration for which diuretic therapy has been prescribed 4. Hospitalized for AHFS requiring IV diuretic therapy. AHFS is defined as dyspnea at rest or with minimal exertion and signs of fluid overload manifested by at least one of the following at time of randomization: • JVP >8 cm, or • Pulmonary rales ≥1/3 up the lung fields, not clearing with cough, or • ≥2+ peripheral edema, or pre-sacral edema 5. Eligible for randomization within 24-hours of presentation to the hospital (including time spent in the emergency department. Study drug infusion should start as soon as possible following randomization, preferably in the morning hours. 6. Anticipated need for IV furosemide ≥40 mg/day (or equivalent dose of IV loop diuretic) for at least 24 hours after start of study drug 7. Impaired renal function defined as a creatinine clearance on admission between 20-80 mL/min using the Cockcroft-Gault equation for estimating creatinine clearance (corrected for height in edematous or obese subjects ≥100 kg) 8. Systolic blood pressure ≥95 mmHg (subjects with a systolic blood pressure of 90 –94 mmHg at randomization may be included if their usual systolic blood pressure measurements are consistently within this range while clinically stable) |
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E.4 | Principal exclusion criteria |
9. Pregnant or breast feeding women. Women of child bearing potential must have a negative urine or serum pregnancy test prior to enrollment. 10. Acute contrast induced nephropathy 11. Temperature >38°C (oral or equivalent) or sepsis or active infection requiring IV anti-microbial treatment 12. Serum potassium <3.5 mEq/L (3.0-3.4 mEq/L will be allowed if parenteral supplemental potassium is being administered) 13. Ongoing or planned IV therapy for AHFS with positive inotropic agents, vasopressors, vasodilators, or mechanical support (intraaortic balloon pump, endotracheal intubation, ventricular assist device) with the exception of IV nitrates 14. BNP <500 pg/mL or NT-pro-BNP <2000 pg/mL 15. Ongoing or planned treatment with ultrafiltration, hemofiltration, or dialysis 16. Severe pulmonary disease (as evidenced by pre-admission or current oral steroid dependency, current treatment with IV steroids, or previous history of CO2 retention or intubation for acute exacerbation) 17. Significant stenotic valvular disease (severe aortic stenosis, mitral stenosis) 18. Heart transplant recipient or admitted for cardiac transplantation 19. Clinical evidence of acute coronary syndrome in the 2 weeks prior to screening 20. AHFS due to significant arrhythmias (ventricular tachycardia, bradyarrhythmias with slow ventricular rate [<45 beats per minute] or atrial fibrillation/flutter with a rapid ventricular response of >120 beats per minute) 21. Acute myocarditis or hypertrophic obstructive, restrictive, or constrictive cardiomyopathy. This criterion does not include restrictive patterns seen on Doppler. 22. Known hepatic impairment (total bilirubin >3 mg/dL, albumin <2.8 mg/dL, or increased ammonia levels if performed) 23. Non-cardiac pulmonary edema, including suspected sepsis 24. Administration of an investigational drug or device, or participation in another trial, within 30 days before randomization 25. Current or anticipated therapy with atanazavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole 26. Systolic blood pressure >160 mmHg at randomization 27. Inability to follow instructions or comply with follow-up procedures 28. Allergy to soybean oil or eggs or benzodiazepines 29. History of seizure (except febrile seizure) 30. Stroke within 2 years 31. History of or current brain tumor of any etiology 32. Brain surgery within 2 years 33. Encephalitis/meningitis within 2 years 34. History of penetrating head trauma 35. Closed head injury with loss of consciousness (LOC) over 30 minutes within 2 years 36. History of drug or alcohol abuse or at risk for alcohol withdrawal seizures 37. Advanced Alzheimer’s disease 38. Advanced multiple sclerosis 39. Hgb <8 g/dL, or Hct <25%, or the need for a blood transfusion 40. Previous exposure to KW-3902 |
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E.5 End points |
E.5.1 | Primary end point(s) |
A three category, ordered outcome of treatment success, patient unchanged, or treatment failure based on the following definitions: • Treatment success (determined at 24 and 48 hours after the start of study drug [Day 2 and 3] or the day of discharge if earlier): o Dyspnea reported by the patient using a 7-point Likert scale as moderately or markedly better compared to study start, AND o Not a treatment failure • Patient Unchanged: Neither treatment success or treatment failure • Treatment failure (includes any 1 of the following criteria): Death or readmission for heart failure any time through Day 7; OR Worsening symptoms and/or signs of heart failure occurring >24 hours after the start of study drug to Day 7 or discharge, whichever occurs first, such that there is a need for any one of the following types of “rescue therapy”: an increase in the dose or reinstitution of IV loop diuretic therapy, or initiation of oral metolazone or IV chlorothiazide as accompanying therapy to loop diuretics or initiation of ultrafiltration or initiation of IV positive inotropes, vasopressors, or IV vasodilators or initiation of mechanical ventilatory (including BiPAP or CPAP) or circulatory support OR Persistent renal impairment as defined by a serum creatinine (SCr) increase of ≥0.3 mg/dL from randomization to Day 7, confirmed at Day 14, or the initiation of hemofiltration or dialysis through Day 7. Data from the Phase 3 studies CKI-301 and CKI-302 will be combined for this analysis. |
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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 | No |
E.6.11 | Pharmacogenomic | No |
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 | No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 75 |
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 | 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
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Patients will be followed a minimum of 60 days and up to a maximum of 180 days from start of first study drug dose. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |