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    Summary
    EudraCT Number:2008-007149-30
    Sponsor's Protocol Code Number:4500
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-01-19
    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 ConcernedUK - MHRA
    A.2EudraCT number2008-007149-30
    A.3Full title of the trial
    Optimal Treatment of Drug Resistant Hypertension
    A.3.2Name or abbreviated title of the trial where available
    Optimal Treatment of Drug Resistant Hypertension
    A.4.1Sponsor's protocol code number4500
    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 SponsorCambridge University Hospitals NHS Foundation Trust and University of Cambridge
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBritish Heart Foundation
    B.4.2CountryUnited Kingdom
    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
    B.Sponsor: 2
    B.1.1Name of SponsorCambridge Clinical Trials Unit
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    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 Yes
    D.2.1.1.1Trade name Spironolactone
    D.2.1.1.2Name of the Marketing Authorisation holderActavis
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 namespironolactone
    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.3.8INN - Proposed INNspironolactone
    D.3.9.1CAS number 52-01-7
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number25 to 50
    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 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 Cardozin XL
    D.2.1.1.2Name of the Marketing Authorisation holderArrow Generics
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 namedoxazosin
    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.3.8INN - Proposed INNdoxazosin
    D.3.9.1CAS number 74191-85-8
    D.3.9.3Other descriptive nameDoxazosin mesilate
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number4 to 8
    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: 3
    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 Bisoprolol
    D.2.1.1.2Name of the Marketing Authorisation holderRelonchem Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 namebisoprolol
    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.3.8INN - Proposed INNbisoprolol
    D.3.9.1CAS number 66722-44-9
    D.3.9.3Other descriptive namebisoprolol fumarate
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number5 to 10
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    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
    Hypertension
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 15.0
    E.1.2Level PT
    E.1.2Classification code 10020772
    E.1.2Term 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
    The primary objective is to test our primary hypothesis which states that the commonest cause of resistant hypertension is excessive sodium retention, and that further diuretic therapy, i.e. spironolactone will be superior to other potential "add-on drugs" for people with inadequate blood pressure control despite treatment with three drugs, i.e. Ace Inhibitors, Calcium Channel Blockers and Diuretics (A+C+D).
    E.2.2Secondary objectives of the trial
    The secondary outcome will be the difference in home BP between the best drug predicted by the patient’s plasma renin and the observed best drug. (High-renin, i.e. highest tertile, predicts beta-blocker (bisoprolol) best; low-renin, i.e. lowest tertile, predicts further-diuretic (spironolactone) best; normal-renin (i.e. middle tertile) predicts alpha-blocker (doxazosin) best.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion criteria:

    • Patients aged 18-79 years;
    • Patients will all have hypertension that is not controlled to target: clinic systolic BP ≥ 5 mmHg above target (i.e. ≥ 140 mmHg for non-diabetic hypertensives or ≥ 135 mmHg for diabetics), under one of the following conditions:
    a) Treatment for at least 3 months with lisinopril 20 mg (A) + amlodipine 10 mg (C)+bendroflumethiazide 2.5 mg (D) or their equivalents‡
    b) Patients who have received the three drugs or equivalents specified in a), and are either intolerant to one category, or tolerate only a lower dose (e.g. amlodipine 5 mg or lisinopril 10 mg)
    c) Patients receiving the three drugs or equivalents specified in a), who are receiving additional drugs for their hypertension, may be included if the investigator 1) feels it is appropriate to stop these additional drugs at the screening visit and 2) anticipates that the BP criteria for inclusion will be met when re-checked at the baseline visit
    Patients may be included if the PI anticipates BP criteria for inclusion will be met at randomisation.
    3. Patients with a home systolic BP average of >130 mmHg or within 15mmHg of clinic BP over the 4 days prior to the baseline visit.
    E.4Principal exclusion criteria
    1. Inability to give informed consent;
    2. Participation in a clinical study involving an investigational drug or device within 4 weeks of screening;
    3. Secondary or accelerated hypertension;
    4. Type 1 diabetes;
    5. eGFR<45 mls/min;
    6. Plasma potassium outside of normal range on two successive measurements during screening;
    7. Pregnancy, planning to conceive, or women of child-bearing potential, i.e. not using barrier effective contraception;
    8. Anticipated change of medical status during the trial (e.g. surgical intervention requiring >2 weeks convalescence);
    9. Absolute contra-indication to study drugs (e.g. asthma) or previous intolerance of trial therapy;
    10. Sustained atrial fibrillation;
    11. Recent (<6 months) cardiovascular event requiring hospitalisation (e.g. myocardial infarction or stroke);
    12. Suspected non-adherence to antihypertensive treatment (see above);
    13. Requirement for study drug for reason other than to treat hypertension, (e.g. β-blockers for angina or diuretics other than those to treat hypertension);
    14. Current therapy for cancer;
    15. Concurrent chronic illness, or other reasons likely to preclude 40 week participation in the study;
    16. Clinic Systolic BP >200 mmHg or diastolic BP >120mmHg, with PI discretion to override if home BP measurements are lower
    17. Any concomitant condition that, in the opinion of the investigator, may adversely affect the safety and/or efficacy of the study drug or severely limit that patients life-span or ability to complete the study (e.g. alcohol or drug abuse, disabling or terminal illness, mental disorders);
    18. Treatment with any of the following medications;
    a. Oral corticosteroids within 3 months of screening. Treatment with systemic corticosteroids is also prohibited during study participation;
    b. Chronic stable use, or unstable use of NSAIDs (other than low dose aspirin) is prohibited. Chronic use is defined as >3 consecutive or non-consecutive days of treatment per week. In addition intermittent use of NSAIDs is strongly discouraged throughout the study and NSAIDs if required, must not be used for more than a total of 2 days. For those requiring analgesics during the study, paracetamol is recommended.
    c. The use of short acting nitrates (e.g. sublingual nitroglycerin) is permitted. However, participants should not take
    P2 Protocol v7.1 26 May 11 Page 14 of 69
    short acting oral nitrates within 4 hours of screening or an subsequent visit;
    d. The use of long acting nitrates (e.g. Isordil) is permitted but the dose must be stable for at least 2 weeks prior to screening and randomisation;
    e. The use of sympathomimetic decongestants is permitted , however, not within 1 day prior to any study visit/BP assessment;
    f. The use of theophylline is permitted but the dose must be stable for at least 4 weeks prior to screening and throughout the study;
    g. The use of phosphodiesterase type V inhibitors is permitted; however study participants must refrain from taking these medications for at least 1 day prior to screening or any subsequent study visits;
    h. The use of alpha-blockers is not permitted, with the exception of afluzosin and tamsulosin for prostatic symptoms
    19. A pill count will be made at the end of the 4 week run-in period and those with adherence <70% will be excluded from randomisation
    E.5 End points
    E.5.1Primary end point(s)
    The Primary Outcome Measure will be the difference in home systolic BP averages between each active drug and placebo, at the end of the 12 week treatment cycle, when each drug is taken at maximum tolerated dose.


    E.5.1.1Timepoint(s) of evaluation of this end point
    End of 12 week treatment cycle
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    An open label cohort will be included to cover expired double blind medication.
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    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.8.4.1Number of sites anticipated in Member State concerned16
    E.8.5The trial involves multiple Member States No
    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 years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days29
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 0
    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 state346
    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 the investigational drugs - spironolactone, bisoprolol, doxazosin - are cheap generic drugs which are already routine and frequent prescriptions within primary care. What is unknown is whether one of these is on average superior to the others; and/or whether our biochemical (plasma renin) or haemodynamic tests at baseline will allow the best drug for individual patients to be predicted without a trial-and-error rotation (which in everyday practice is rarely either systematic or complete).
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation West Anglia CLRN
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2009-01-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-01-14
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-06-26
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