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    Summary
    EudraCT Number:2010-023104-28
    Sponsor's Protocol Code Number:MEIN/10/Neb+HCTZ-Hyp/001
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-06-29
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2010-023104-28
    A.3Full title of the trial
    A multicentre randomised, double blind, active controlled, parallel group comparison of Nebivolol plus HCTZ and Irbesartan plus HCTZ in the treatment of isolated systolic hypertension in elderly patients.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study in multiple centres investigating the effect of two different active treatments for raised bloodpressure in elderly patients where it is unknown during the study which of both treatments is administered.
    A.3.2Name or abbreviated title of the trial where available
    The NEHIS Study
    A.4.1Sponsor's protocol code numberMEIN/10/Neb+HCTZ-Hyp/001
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMenarini International Operations Luxembourg S.A.
    B.1.3.4CountryLuxembourg
    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 supportMenarini International Operations Luxembourg S.A.
    B.4.2CountryLuxembourg
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationA. Menarini Farmaceutica Internazionale
    B.5.2Functional name of contact pointMarilena Grana
    B.5.3 Address:
    B.5.3.1Street Addressvia Sette Santi, 1
    B.5.3.2Town/ cityFirenze
    B.5.3.3Post code50131
    B.5.3.4CountryItaly
    B.5.4Telephone number003905556809993
    B.5.5Fax number00390555680484
    B.5.6E-mailmgrana@menarini.it
    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 Yes
    D.2.1.1.1Trade name Nebilet Plus
    D.2.1.1.2Name of the Marketing Authorisation holderMenarini International Operations Luxembourg S.A.
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 152520-56-4
    D.3.9.3Other descriptive nameNEBIVOLOL HYDROCHLORIDE
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHYDROCHLOROTHIAZIDE
    D.3.9.1CAS number 58-93-5
    D.3.9.4EV Substance CodeSUB08062MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number12,5
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.1.1.1Trade name Karvezide
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    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.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.3Other descriptive nameIRBESARTAN HYDROCHLORIDE
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHYDROCHLOROTHIAZIDE
    D.3.9.1CAS number 58-93-5
    D.3.9.4EV Substance CodeSUB08062MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number12,5
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Isolated Systolic Hypertension
    E.1.1.1Medical condition in easily understood language
    Isolated raised systolic bloodpressure
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level LLT
    E.1.2Classification code 10050591
    E.1.2Term Isolated systolic hypertension
    E.1.2System Organ Class 10047065 - Vascular disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate the superiority of the combination Nebivolol plus HCTZ versus Irbesartan plus HCTZ in term of SBP reduction after 12 weeks of treatment in elderly patients with isolated systolic hypertension.
    E.2.2Secondary objectives of the trial
    To investigate the tolerability of the combination Nebivolol plus HCTZ versus Irbesartan plus HCTZ.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Male or female aged at least 60 years;
    • Office systolic blood pressure >140 mmHg and office diastolic blood pressure ≤ 90 mmHg;
    • Subjects should have at least 2 additional risk factors
    • Willing to give written informed consent.
    E.4Principal exclusion criteria
    · Systolic blood pressure equal to or greater than 180 mmHg at the end of washout (visit 2) or run-in period (visit 3b);
    · Differences >20mmHg for SBP and >10mmHg for DBP on 3 consecutive readings at baseline
    · Current treatment with more than 2 antihypertensive agents within the last 6 months;
    · History of stroke, myocardial infarction, PCI or coronary bypass surgery within the last 12 months
    · Symptomatic lower limb ischemia i.e. claudicatio intermittens
    · Secondary hypertension (i.e.renovascular, adrenal, endocrine, tumor ..);
    · Serum creatinine > 150 ╬╝mol/L
    · Hepatic impairment defined as ASAT or ALAT >2 x upper normal limit;
    · Chronic administration of any medication known to affect blood pressure.
    · bradycardia (heart rate < 60 bpm prior to start therapy).
    · Acute heart failure, cardiogenic shock or episodes of heart failure decompensation requiring i.v. inotropic therapy;
    · Clinically significant ECG abnormalities at baseline.
    · Any other medical or mental condition or laboratory abnormality that makes the patient unsuitable for the study in the opinion of the investigator.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy variable will be the change from baseline (Day 0) to the end of treatment (Day +84) in systolic blood pressure.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 84
    E.5.2Secondary end point(s)
    · To investigate the tolerability of the combination Nebivolol plus HCTZ versus Irbesartan plus HCTZ.
    · Furthermore secondary efficacy criteria:
    · Percentage of normalized patients (mean SBP ≤ 140 mmHg) at the end of treatment (Day +84);
    · Percentage of responding patients (decrease of mean SBP ≥ 20 mmHg) at the end of treatment (Day +84);
    · Change from baseline to the end of treatment (Day +84) in the 24-hour mean SBP, measured by ABPM;
    · Change from baseline to the end of treatment (Day +84) in the 24-hour mean DBP, measured by ABPM;
    · Change from baseline to the end of treatment (Day +84) in SBP in the last six hours of the 24- hour dose period (as measured by 24-hour ABPM);
    · Change from baseline to the end of treatment (Day +84) in DBP in the last six hours of the 24-
    hour dose period (as measured by 24-hour ABPM);
    · Change from baseline to the end of treatment (Day +84) in SBP and DBP for other time intervals [i.e. daytime mean (06:00-00:00), and night-time mean (00:00-6:00)] (as measured by 24-hour ABPM).
    · Change from baseline to the end of treatment (Day +84) in arterial stiffness/distensibility
    · To investigate the effect of Nebivolol + HCTZ as compared to Irbesartan + HCTZ on the arterial stiffness parameters (details in section 24.2 (Appendix 2).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Day 84
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Irbesartan/hydrochlorothiazide
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days14
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days14
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 120
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state70
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    F.4.2.2In the whole clinical trial 150
    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)
    Patients will be restored to standard care for systolic hypertension.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-06-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-10-20
    P. End of Trial
    P.End of Trial StatusCompleted
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