E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated | |
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 | 10021038 | E.1.2 | Term | Hyponatremia | |
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 primary objective of this study is to determine whether administration of lixivaptan can effectively and safely produce an increase in serum sodium from Baseline in HF patients with volume overload and hyponatremia. | |
E.2.2 | Secondary objectives of the trial | The secondary objectives of this study are that lixivaptan: a. Demonstrates improvement in serum sodium concentrations (AUC) up to Day 60 within the double-blind on-therapy period for hyponatremic patients with serum sodium <135 mEq/L at Baseline. b. Is associated with improvement in clinical status as measured by: i. Changes in the Trail Making Test, part B following 28 days of dosing. ii. Days alive and out of the hospital (for cardiovascular causes) within 60-Days of randomisation. c. Prevents worsening of hyponatremia d. Improves the percentage of patients with normalized serum sodium. | |
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives | Pharmacoeconomic Study - US only. Full details and study objectives of the sub-study are contained in the protocol. | |
E.3 | Principal inclusion criteria | 1. Men and Women with age greater than or equal to 18 years. 2. Baseline Serum sodium concentration < 135 mEq/L. Repeat measures of serum sodium are alllowed; the last serum sodium result within 24 hours prior to randomization will serve as the qualifying measurement. 3. Current hospitalization for worsening of chronic congestive heart failure. a) Chronic heart failure is defined as requiring treatment for a minimum of 30-Days prior to hospitalization. Study patients are expected to be on standard background therapy for Congestive Heart Failure. 4. The patient has clinical evidence of volume overload with at least two of the following: a) dyspnea, b) pulmonary congestion (rales), c) peripheral edema, d) increased jugular venous pressure and/or hepatic congestion with ascites, e) chest x-ray consistent with CHF, or f) plasma BNP ≥ 150 pg/mL or NT pro-BNP ≥ 450 pg/mL. 5. The patient has documented Left Ventricular Ejection Fraction (LVEF) within the past year. 6. Supine systolic arterial blood pressure ≥ 90 mmHg. | |
E.4 | Principal exclusion criteria | 1. Previous participation in this or any other lixivaptan clinical trial. 2. Participation in any other investigational study of drugs or devices within 30-Days prior to Screening. 3. Women who will not adhere to the reproductive precautions as outlined in section 4.3 of the protocol and in the informed consent form. 4. Positive urine pregnancy test. 5. Inability to provide informed consent. 6. Inability to respond to thirst. 7. Inability to take oral medications. 8. Acute severe hyponatremia. 9. Overt symptoms of hyponatremia requiring immediate medical intervention (e.g., severe lethargy, coma, seizures). 10. Hemodynamically significant uncorrected primary cardiac valvular disease. 11. Hypertrophic cardiomyopathy (obstructive or non-obstructive). 12. CHF due to uncorrected thyroid disease (i.e., T4 above or below the limits of the reference range), active myocarditis or known amyloid cardiomyopathy. 13. History of sustained ventricular tachycardia or ventricular fibrillation within 30 days, unless in the presence of an automatic implantable cardioverter defibrillator. 14. ST-segment elevation myocardial infarction (STEMI) within 30-Days or active myocardial ischemia at the time of enrollment. 15. History of stroke within 30-Days prior to screening. 16. History of a cardiac revascularization procedure within 30-Days prior to screening. 17. Subjects who are on cardiac mechanical support. 18. History of bi-ventricular pacer placement within the last 30-Days. 19. Planned revascularization procedures, electrophysiologic (EP) device implantation, cardiac mechanical support implantation, ultrafiltration or dialysis, or other cardiac surgery within 30 days following study enrollment. 20. Serum creatinine > 3.0 mg/dL/265.2 mol/L. 21. Uncontrolled diabetes mellitus as defined by the Investigator (e.g. HbA1c > 9%). 22. Adrenal insufficiency, whether treated or not. If serum cortisol is less than the lower limit of the reference range, the patient is excluded and should be referred for follow-up evaluation. 23. History of primary significant liver disease or acute hepatic failure, as defined by the Investigator. 24. History of chronic drug/medication abuse within the 6 months, or current alcohol abuse. 25. Co-morbid condition with an expected survival less than six months. Specific requirements for females Women of child-bearing potential must demonstrate a negative urine pregnancy test prior to randomization and at the final study visit 30 days after the last dose of study drug. In addition, women of child-bearing potential must agree to use one of the methods of birth control detailed in 4.3 of the protocol for the entire study period including screening, the titration and treatment phases and the 30-day follow-up period. | |
E.5 End points |
E.5.1 | Primary end point(s) | The change from baseline in serum sodium concentrations at day 7 of the double-blind on-therapy period for hyponatremic patients with serum sodium of <135 mEq/L at baseline. | |
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 | Yes |
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 | 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) | 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.8.4.1 | Number of sites anticipated in Member State concerned | 25 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 100 |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
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 |
E.8.9.2 | In all countries concerned by the trial days | 0 |