E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hyponatremia
Hiponatremia |
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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 | 10021038 |
E.1.2 | Term | Hyponatremia |
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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 primary objective of this study is to determine whether administration of lixivaptan can effectively and safely produce an increase in serum sodium from in the full study cohort with patients with baseline in HF subjects with volume overload and hyponatremia (Baseline serum sodium ≥ 120 mEq/L to <130 mEq/L). |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to determine whether: • Administration of lixivaptan can effectively and safely produce an increase in serum sodium from in the full study cohort of subjects, baseline in HF subjects with volume overload and hyponatremia (Baseline serum sodium ≥ 120 mEq/L to <135 mEq/L). • In subjects with Baseline serum sodium ≥ 120 mEq/L to <135 mEq/L, lixivaptan administration is associated with an improvement in clinical status as measured by days dead or hospitalized for cardiovascular causes within 60 days of randomization. • Lixivaptan therapy demonstrates acute effects on body weight. |
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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 |
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E.3 | Principal inclusion criteria |
1. Men and Women with age greater than or equal to 18 years. 2. Current hospitalization for chronic congestive heart failure with admission up to 48 hours prior to randomization. Chronic heart failure is defined as requiring treatment for a minimum of 30 days prior to hospitalization. 3. NYHA Class III or IV at the time of hospitalization (appendix II). 4. The subject has clinical evidence of volume overload with at least two of the following: dyspnea, pulmonary congestion, peripheral edema, increased jugular venous pressure and/or hepatic congestion with ascites. 5. LVEF < 40% within the past year. 6. Baseline Serum sodium concentration ≥120 mEq/L to < 135 mEq/L. Also, female subjects are eligible to participate in this study if they are not pregnant or lactating, and are at least one of the following: • Surgically sterile (via hysterectomy or bilateral tubal ligation ≥6 months prior to enrollment). • Post-menopausal (last menstrual period ≥12 months prior to enrollment). • For women of child-bearing potential: o Use of an intrauterine device; or use of a double barrier method of pregnancy prevention (e.g., diaphragm plus spermicide) for 2 weeks prior to screening and during the Screening Period, or o Use of oral, injectable, topical or subcutaneous hormonal contraceptives for 2 weeks prior to screening and during the Screening Period, and o Agrees to continue the same contraceptive method for the duration of the Treatment Period and for 30 days from the last dose of lixivaptan administration, and o Demonstrates a negative urine pregnancy test result prior to the first lixivaptan administration. o Abstinence is an acceptable means of birth control. |
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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 the informed consent form. 4. Positive urine pregnancy test. 5. Inability to provide informed consent. 6. Inability to take oral medications. 7. Symptomatic hyponatremia (e.g., severe lethargy, coma, seizures, mental status changes attributable to hyponatremia). 8. Uncontrolled diabetes mellitus (glucose ≥220 mg/dL). 9. Hemodynamically significant uncorrected primary cardiac valvular disease. 10. Hypertrophic cardiomyopathy (obstructive or non-obstructive). 11. CHF due to uncorrected thyroid disease (i.e., T4 above or below the limits of the reference range), active myocarditis or known amyloid cardiomyopathy. 12. History of sustained ventricular tachycardia or ventricular fibrillation within 30 days, unless in the presence of an automatic implantable cardioverter defibrillator. 13. History of myocardial infarction, unstable angina or evidence of active ischemia within 30 days prior to screening. 14. History of stroke within 30 days prior to screening. 15. History of a cardiac revascularization procedure within 30 days prior to screening. 16. Subjects who are on cardiac mechanical support. 17. History of bi-ventricular pacer placement within the last 30 days. 18. Planned revascularization procedures, electrophysiologic (EP) device implantation, cardiac mechanical support implantation, ultrafiltration or dialysis, cardiac transplantation, or other cardiac surgery within 30 days following study enrollment. 19. Supine systolic arterial blood pressure < 90 mmHg. 20. Serum creatinine > 3.0 mg/dL 21. History of primary significant liver disease or acute hepatic failure, as defined by the Investigator. 22. History of drug or medication abuse within the past year, or current alcohol abuse. 23. Co-morbid condition with an expected survival less than six months. 24. Adrenal insufficiency, whether treated or not. If serum cortisol is less than the lower limit of the reference range, the subject is excluded and should be referred for a follow-up evaluation. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint, time-normalized AUC for change from Baseline in serum sodium over the time course of 0 72 hours (nAUC0 72) will be calculated for the Modified Intent-to-Treat (MITT) subjects with Baseline serum sodium of <130 mEq/L. |
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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 | 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.8.5 | 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 |
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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 | 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 |