E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with heart failure and renal impairment, who require loop diuretic therapy and at least 12 hours of hemodynamic monitoring in the period after screening, and who satisfy the eligibility criteria. |
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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 | HLGT |
E.1.2 | Classification code | 10007539 |
E.1.2 | Term | Cardiac disorder signs and symptoms |
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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 estimate the effects of rolofylline, alone and in addition to loop diuretic therapy, on pulmonary capillary wedge pressure, as well as other hemodynamic parameters, and to estimate the effects of rolofylline on diuresis and natriuresis in patients with heart failure and renal impairment. |
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E.2.2 | Secondary objectives of the trial |
Change in CO, SVR, PVR, pulmonary pressure and right atrial pressure at 4 and 8 hours after initiation of study drug Change in urine output, fractional excretion of sodium, potassium, urea, uric acid, creatinine, FiO2, blood pressure, and heart rate during and after study drug administration, up to 8 hours after initiation of study drug |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Able to provide written informed consent 2. Male or female 18 years of age or greater 3. Current use of oral furosemide ≥80 mg/day or IV furosemide ≥40 mg/day (or equivalent dose of oral/IV loop diuretic) 4. Stable heart failure therapy (excluding diuretics) for ≥24 hours prior to screening (treatment with ACE inhibitors, ARBS, digoxin, aldosterone blockers, nitrates, hydralazine, and other diuretics are allowed as long as doses are stable for at least 24 hours prior to screening) 5. Impaired renal function defined as a creatinine clearance between 20-80 mL/min using the Cockcroft-Gault equation (corrected for height in edematous or obese patients ≥100 kg) based on serum creatinine measurements done within 24 hours of screening 6. BNP >500 pg/mL OR NT-pro-BNP >2000 pg/mL within 24 hours of screening 7. Systolic blood pressure ≥95 mmHg (patients 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) 8. Patients require at least 12 hours of hemodynamic monitoring in the period after screening. |
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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 >38C or sepsis or active infection requiring IV antimicrobial treatment 12. Administration of oral or IV loop diuretic within 3 hours prior to the initial screening 13. Serum potassium <3.5 mEq/L 14. Ongoing, recent (within 48 hours), or planned treatment with ultrafiltration, hemofiltration, or dialysis, or mechanical support (intra-aortic balloon pump, endotracheal intubation, ventricular assist device) during this hospitalization 15. Rapidly progressive acute renal failure as manifested by an increase in SCr ≥0.7 mg/dL in a 24-hour period 16. Evidence of acute tubular necrosis or post-obstructive nephropathy or other exogenous causes of acute kidney injury, unrelated to heart failure or its treatment 17. Severe pulmonary disease 18. Severe aortic or mitral stenosis or regurgitation 19. Heart transplant recipient or admitted for imminent cardiac transplantation or LVAD surgery (i.e., expected within 72 hours) 20. Any major surgery within 2 weeks prior to screening 21. Clinical evidence of acute coronary syndrome in the 2 weeks prior to screening 22. Significant arrhythmias 23. Acute myocarditis or hypertrophic obstructive, restrictive, or constrictive cardiomyopathy. This criterion does not include restrictive patterns seen on Doppler. 24. Known hepatic impairment with a total bilirubin >3 mg/dL, or an albumin <2.8 mg/dL, or increased ammonia levels (if available) 25. Body Mass Index (BMI) >35 kg/m2 26. Hgb <8 g/dL or Hct <25%, or the need for a blood transfusion 27. Non-cardiac pulmonary edema, including suspected sepsis 28. Administration of an investigational drug or device, or participation in another trial, within 30 days before randomization 29. Current or anticipated therapy with atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole 30. Systolic blood pressure ≥160 mmHg at randomization 31. Inability to follow instructions or comply with follow-up procedures 32. Allergy to soybean oil, eggs, or benzodiazepines 33. History of seizure (except febrile seizure) 34. Stroke within 2 years 35. History of or current brain tumor of any etiology 36. Brain surgery within 2 years 37. Encephalitis/meningitis within 2 years 38. History of penetrating head trauma 39. Closed head injury with loss of consciousness (LOC) over 30 minutes within 2 years 40. History of drug or alcohol abuse or at risk for alcohol withdrawal seizures 41. Advanced Alzheimers disease 42. Advanced multiple sclerosis
Baseline Period Criteria Exclusion Criteria (at least 1 hour prior to dosing): 43. Balloon thermodilution catheter in place <3 hours 44. Wedge pressure ≤18 mmHg |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in PCWP 4 and 8 hours after initiation of study drug |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
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 | 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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
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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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 | 7 |
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 | 7 |