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    Summary
    EudraCT Number:2004-004863-32
    Sponsor's Protocol Code Number:BCBE/04/NEB-PAO/087
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2006-02-21
    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 ConcernedAustria - BASG
    A.2EudraCT number2004-004863-32
    A.3Full title of the trial
    EFFECTS OF NEBIVOLOL ON THE WALKING ABILITY IN PATIENTS WITH ESSENTIAL HYPERTENSION AND PERIPHERAL ARTERIAL DISEASE INTERMITTENT CLAUDICATION
    A.4.1Sponsor's protocol code numberBCBE/04/NEB-PAO/087
    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 SponsorBerlin-Chemie Menarini
    B.1.3.4CountryGermany
    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 nameNebilet
    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 INNNebivolol
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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.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 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 nameHCT Hexal
    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 INNHydrochlorothiazid
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    ESSENTIAL HYPERTENSION AND PERIPHERAL ARTERIAL DISEASE INTERMITTENT CLAUDICATION
    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
    The primary objective of this clinical trial is to evaluate the clinical efficacy (ICD) and tolerability of nebivolol in comparison with hydrochlorothiazide in the treatment of patients with PAD intermittent claudication (Fontaine’s stage II (a+b)) and essential hypertension.
    E.2.2Secondary objectives of the trial
    -Initial claudication distance (ICD) after 12 weeks treatment
    -Absolute claudication distance (ACD) after 12 weeks and 24 weeks treatment
    -ICD and ACD responders after 24 weeks of treatment
    -Ankle-brachial pressure index (ABPI) after 12 weeks and 24 weeks treatment
    -Lipid profile after 24 weeks treatment
    -sCRP (sensitive C-reactive protein) after 24 weeks treatment
    -Quality of life (QoL) (“Periphere Arterielle Verschlusskranktheit 86 Scale”) after 24 weeks treatment
    -All-cause mortality
    -Cardiovascular mortality
    -Cardiovascular morbidity
    -Proportion of cardiac catheter examinations, coronary angiography and hospitalizations.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Screening inclusion criteria
    2. ≥40 years to 75 years
    3.PAD Fontaine’s stage II with:
    •a history of typical intermittent claudication for at least 6 months with documented lesions by duplex sonography or angiography within the last 36 months prior to inclusion,
    •actual proven PAD by objective means such as haemodynamics and non-invasive imaging or angiography,
    •a history (> 1 month before study inclusion) of previous peripheral (lower extremity) vascular intervention such as surgical endarterectomy, by pass grafting or aortic abdominal aneurysm repair or PTA with or without stenting is allowed,
    •an ankle-brachial pressure index (ABPI) of the worse leg < 0.90,
    •advice on smoking cessation has been given and documented prior to inclusion in the trial; smoking habit is stable for at least 3 months prior to inclusion in the trial.
    4.No further improvement in previous exercise training or failure of previous tried exercise training or experience of patient’s lack of compliance regarding exercise training or patients unable to perform exercise training. Walking training must be applied during the trial.
    5.Hypertension according to the Joint National Committee on Hypertension (JNC) (systolic blood pressure (SBP) 140-159 mmHg and/or diastolic blood pressure (DBP) 90-99 mmHg) with or without treatment with antihypertensive drugs

    Baseline inclusion criteria
    6. ASA 100 mg and/or Clopidogrel 75 mg or Phenprocoumon (Phenprocoumon stable at least three months prior screening visit) and stable background medication for the prevention or therapy of cardiovascular events like ACE inhibitors and/or AT1 inhibitors and/or calcium-channel blockers and/or statins (statins stable for >/= 3 month before study inclusion)
    7.Treadmill variability in ACD of ≤ 25% between treadmill test at visit 2 (screening control) and visit 3 (baseline)
    8.ACD between 100 m and 300 m at visit 3 (baseline)
    9.SBP > 130mmHg and/or DBP > 85 at baseline (Visit 3)
    E.4Principal exclusion criteria
    1.PAD with rest pain or leg ulcer or gangrene (Fontaine stage III –IV resp. critical limb ischemia (CLI): systolic ankle pressure ≤ 50 mmHg or systolic toe pressure ≤ 30
    mmHg or transcutaneous partial oxygen pressure (tcpO2) ≤ 10 %)
    2.Any concomitant disease limiting the exercise capacity of the patient (e.g. but not limited to: angina pectoris, heart failure, respiratory disease, orthopaedic disease, neurological disorder)
    3.Standardized exercise training during the study (e.g. supervised physical group-training or individual training) or walking exercises during the study exceeding the all-day habits of the patient as compared to the patient’s habits prior to study inclusion
    4.Poorly controlled diabetes mellitus (HbA1c > 8.5%)
    5.Orthopedic, neurological or pulmonary concomitant diseases, which limit or may limit the walking distance.
    6.Anticipated need for limb, coronary, or carotid vascular surgery or angioplasty during the trial
    7.Previous treatment within the last 4 weeks prior to screening or concomitant treatment with rheologic agents (including herbal substances like Ginkgo Biloba (or Padma28) ) or substances that may influence the progression of the PAD or the walking distances except for the trial medication and the background medication
    8.Treatment with alpha-blockers or vasodilators as prostaglandin E1, prostaglandin I2 analoga, pentoxiphyllin, naftidrofuryl and buflomedil < 3 month stable before Visit 1.
    9.Regular use of analgesics with anti-inflammatory potential, i.e. NSAIDs. Treatment on demand and  7 days, e.g. for headache is allowed.
    10.Treatment with COXII-Inhibitors
    11.Anticipated need of newly prescribed treatment with nitrates during the study in patients not pre-treated with those agents at screening stable for  3 month
    12.Newly diagnosed or unstable angina pectoris (acute coronary syndrome)
    13.Concomitant treatment with other beta-blockers (pre treatment can be discontinued until visit 2) or HCT (including combinations) except for the study medication started at visit 3
    14.Contraindication to the study drugs:
    •Cardiogenic Shock
    •heart failure NYHA class III or IV,
    •sick-sinus-syndrome including heart blocks (SA node) and/or AV block 2nd and 3rd degree and/or significant arrhythmia and/or bradycardia < 50 bpm,
    •Hypotension with systolic blood pressure < 100 mmHg
    •bronchial hyperreagibility, bronchial asthma, or history of bronchospasm,
    •patients with known SGPT (ALAT) and SGOT (ASAT) levels exceeding three times the upper limit of the investigator's normal range, known serum bilirubin > 1.75 mg/dl (> 30 µmol/l) or clinical evidence of severe hepatic disease or hepatic failure,
    •untreated phaeocromocytoma,
    •known metabolic acidosis
    •known severe renal disease (renal failure with oliguria or unuria, creatinine clearance < 30 ml/min and/or serum creatinine level > 150 µmol/l [1.8 mg/100ml])
    •known acute glomerulonephritis
    •known coma and praecoma hepaticum
    •known articular gout
    •known hypocaliaemia, hypoatriaemia, hypovolaemia, hypocalcaemia
    •Fructose incompatibility
    15.Acute myocardial infarction and/or stroke during the last 6 months prior to screening
    16.Acute pathologic hemorrhage
    17.Known Hyperthyroidism
    18.Patients with psychiatric diseases
    19.Known hypersensitivity to nebivolol or HCT or to any of the ingredients of the study drugs, or any known hypersensitivity to beta-blocker or HCT
    20. Prior or active malignancy in the previous 5 years except adequately treated basal cell/ squamous cell carcinoma of the skin or carcinoma in situ of the cervix
    21. Women of childbearing potential without adequate contraception; medically acceptable methods are contraceptive implant (contraceptive injection, intrauterine device (IUD), or oral contraceptives taken for at least 3 months, which the patient agrees to continue using during the study.
    22.Applies for female patients with childbearing potential: pregnancy or lactation (pregnancy should be ruled out by pregnancy test)
    23.Patients with a history of alcohol and/or drug abuse
    24.Patients who are currently participating in another clinical study or who have received an investigational drug within 30 days prior to entering the study or who have participated in this trial before
    25.Patients who are unwilling or unable to provide informed consent or to participate satisfactorily for the entire trial period.
    E.5 End points
    E.5.1Primary end point(s)
    Primary efficacy variable:
    • Change in the initial claudication distance (ICD) between baseline (visit 3) and end of double-blind treatment (visit 6) as measured by treadmill testing.
    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 No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    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) 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 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 No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    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
    last visit of last patient, closure of data bank
    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 months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    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 2006-02-21. 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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 200
    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)
    The investigator will discuss the importance of a subsequent antihypertensive therapy at visit 6 with the patient and if needed with the patient’s family doctor or clinic physician (see Protocol 9.4.7)
    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 Decision2006-05-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-05-19
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2009-03-31
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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