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    Summary
    EudraCT Number:2005-002306-39
    Sponsor's Protocol Code Number:156-03-236
    National Competent Authority:Lithuania - SMCA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2005-06-07
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedLithuania - SMCA
    A.2EudraCT number2005-002306-39
    A.3Full title of the trial
    Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Long Term Efficacy and Safety of Oral Tolvaptan Tablets in Subjects Hospitalized with
    Worsening Congestive Heart Failure
    A.3.2Name or abbreviated title of the trial where available
    EVEREST
    A.4.1Sponsor's protocol code number156-03-236
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorOtsuka Maryland Research Institute, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Information not present in EudraCT
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTolvaptan
    D.3.2Product code OPC-41061
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTolvaptan
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Subjects hospitalized with worsening congestive heart failure (CHF).
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare the efficacy of tolvaptan or placebo in conjunction with optimal
    (as determined by the investigator) current therapy on the time to all-cause mortality in subjects hospitalized with worsening CHF.

    To compare the efficacy of tolvaptan or placebo in conjunction with optimal (as
    determined by the investigator) current therapy on the time to first occurrence of CV
    mortality or hospitalization for heart failure.

    Embedded Trials (Trial A and Trial B):
    To compare the efficacy of tolvaptan or placebo in conjunction with optimal
    (as determined by the investigator) current therapy on the change from baseline in
    patient-assessed global clinical status at Inpatient Day 7 or discharge, if earlier.
    E.2.2Secondary objectives of the trial
    To compare the efficacy of tolvaptan or placebo in conjunction with optimal
    (as determined by the investigator) current therapy.

    To assess the safety of tolvaptan or placebo in conjunction with optimal (as determined by the investigator) current therapy by comparing:

    Embedded Trials (Trial A and Trial B):
    To compare the efficacy of tolvaptan or placebo in conjunction with optimal current therapy
    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal inclusion criteria
    1. 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. The subject must have signs of extracellular volume expansion, defined as two or more of the following: a) jugular venous distention; b) pitting edema (>1+); or c) dyspnea at the time of randomization.
    4. NYHA Class III or IV at the time of hospitalization.
    5. Most recent LVEF < 40% within one year.
    E.4Principal exclusion criteria
    1. Women who will not adhere to the reproductive precautions as outlined in the Informed Consent form.
    2. Positive urine pregnancy test.
    3. Inability to provide written informed consent.
    4. Cardiac surgery within 60 days of potential study enrollment, excluding percutaneous coronary interventions.
    5. Planned revascularization procedures, electrophysiologic (EP) device implantation, cardiac mechanical support implantation, cardiac transplantation, or other cardiac surgery within 30 days following study enrollment.
    6. Subjects who are on cardiac mechanical support.
    7. History of bi-ventricular pacer placement within the last 60 days.
    8. Co-morbid condition with an expected survival less than six months.
    9. Subjects with acute ST segment elevation myocardial infarction at the time of hospitalization.
    10. History of sustained ventricular tachycardia or ventricular fibrillation within 30 days, unless in the presence of an automatic implantable cardioverter defibrillator.
    11. History of a cerebrovascular accident within the last 30 days.
    12. Hemodynamically significant uncorrected primary cardiac valvular disease.
    13. Hypertrophic cardiomyopathy (obstructive or non-obstructive).
    14. CHF due to uncorrected thyroid disease, active myocarditis or known amyloid cardiomyopathy.
    16. History of primary significant liver disease or acute hepatic failure, as defined by the investigator.
    17. Chronic uncontrolled diabetes mellitus as determined by the investigator.
    18. Morbid obesity, defined as > 159 kg (or 350 lbs) or BMI > 42.
    19. Supine systolic arterial blood pressure < 90 mmHg.
    20. Serum creatinine > 3.5 mg/dL or > 309.4 µmol/L.
    21. Serum potassium > 5.5 mEq/L or > 5.5 mmol/L.
    22. Hemoglobin < 9 g/dL or < 90 g/L or 5.586 mmol/L.
    23. History of hypersensitivity and/or idiosyncratic reaction to benzazepine derivatives (such as benazapril).
    24. History of drug or medication abuse within the past year, or current alcohol abuse.
    25. Inability to take oral medications.
    26. Participation in another clinical drug or device trial where the last dose of drug was within the past
    30 days or an investigational medical device is currently implanted.
    27. Previous participation in this or any other tolvaptan clinical trial.
    28. Subjects with refractory, end-stage, heart failure defined as subjects who are appropriate candidates for specialized treatment strategies, such as ventricular assist devices, continuous positive IV inotropic therapy, or hospice care.
    29. Subjects currently treated with hemofiltration or dialysis.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint in the primary outcome study is the time to all-cause
    mortality or the time to first occurrence of CV mortality or heart failure hospitalization.

    The primary efficacy endpoint in the embedded trials is the change from baseline in
    patient-assessed global clinical status at Inpatient Day 7 or discharge, if earlier.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Information not present in EudraCT
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Information not present in EudraCT
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) Information not present in EudraCT
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other 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.8.5The trial involves multiple Member States Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial has a data monitoring committee Information not present in EudraCT
    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
    The End of Study Date will be called the Study Termination Date. The Study
    Termination Date will be determined by the sponsor and will occur after the 1065th death and a minimum of 60 days of therapy for all current subjects.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months11
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Information not present in EudraCT
    F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2005-06-07. Yes
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state100
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1600
    F.4.2.2In the whole clinical trial 3600
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    All subjects will continue to receive conventional therapy.

    A follow-up visit will occur 7 days after the last dose of study drug for all
    subjects to allow for adjustments in concomitant diuretic therapy. A follow-up telephone
    call will be made 14 days after the last dose of study drug for all subjects to collect safety
    information.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2005-07-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2005-06-22
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2006-07-05
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