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    Summary
    EudraCT Number:2017-000896-99
    Sponsor's Protocol Code Number:AC16148
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2018-05-04
    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 number2017-000896-99
    A.3Full title of the trial
    A multicentre prospective randomised open-label blinded end-point controlled trial of high-sensitivity cardiac troponin I-guided combination angiotensin receptor blockade and beta blocker therapy to prevent cardiac toxicity in breast cancer and lymphoma patients receiving anthracycline adjuvant therapy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A randomised trial with breast cancer and lymphoma patients to test if medication can prevent cardiac damage caused by anthracycline chemotherapy.
    A.3.2Name or abbreviated title of the trial where available
    Cardiac CARE
    A.4.1Sponsor's protocol code numberAC16148
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN24439460
    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 SponsorUniversity of Edinburgh
    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 supportNIHR EME
    B.4.2CountryUnited Kingdom
    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 organisationUniversity of Edinburgh
    B.5.2Functional name of contact pointMorag MacLean
    B.5.3 Address:
    B.5.3.1Street AddressEdinburgh Clinical Trials Unit
    B.5.3.2Town/ cityUsher Institute, 9 Edinburgh Bioquarter
    B.5.3.3Post codeEH16 4UX
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number0131 6519914
    B.5.6E-mailmorag.maclean@ed.ac.uk
    B.Sponsor: 2
    B.1.1Name of SponsorNHS Lothian
    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 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 nameCandesartan Cilexetil
    D.3.4Pharmaceutical form Tablet
    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 INNcandesartan
    D.3.9.1CAS number 139481-59-7
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number8
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INN139481-59-7
    D.3.9.1CAS number 139481-59-7
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number16
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INN139481-59-7
    D.3.9.1CAS number 139481-59-7
    D.3.9.4EV Substance CodeAS3
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number32
    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 Information not present in EudraCT
    D.2.1.1.2Name of the Marketing Authorisation holderActavis UK 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 nameCarvedilol
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNCarvedilol
    D.3.9.1CAS number 72956-09-3
    D.3.9.4EV Substance CodeAS4
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3.125
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCarvedilol
    D.3.9.1CAS number 72956-09-3
    D.3.9.4EV Substance CodeAS5
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6.25
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCarvedilol
    D.3.9.1CAS number 72956-09-3
    D.3.9.4EV Substance CodeAS6
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number12.5
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCarvedilol
    D.3.9.1CAS number 72956-09-3
    D.3.9.4EV Substance CodeAS7
    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) 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Myocardial toxicity and the development of left ventricular systolic dysfunction
    E.1.1.1Medical condition in easily understood language
    A decrease in how well the heart muscles function
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10007612
    E.1.2Term Cardiac troponin I increased
    E.1.2System Organ Class 100000004848
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10069501
    E.1.2Term Left ventricular systolic dysfunction
    E.1.2System Organ Class 100000004849
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine whether known treatments for heart failure can prevent or reduce myocardial injury and the development of left ventricular systolic dysfunction.
    E.2.2Secondary objectives of the trial
    To establish whether a novel highly sensitive plasma marker of myocardial injury can anticipate the development and monitor progression of left ventricular systolic dysfunction.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Female or male aged ≥18 years
    • Histological diagnosis of invasive breast cancer or non-Hodgkin lymphoma
    • ECOG performance status 0-1
    • Planned to commence anthracycline containing therapy
    o for adjuvant or neo-adjuvant treatment of breast cancer. Breast cancer patients scheduled for ≥300 mg/m2 cumulative dose epirubicin, or equivalent, over 3, 4 or 6 cycles
    or
    o NHL patients planned to commence ≥3 cycles of CHOP or R-CHOP therapy containing ≥300mg/m2 epirubicin equivalent cumulative dose of anthracycline.
    • A life expectancy of at least 12 months
    • LVEF ≥ 50% on baseline MRI
    • Systolic blood pressure ≥ 105 mmHg and ≤170 mmHg
    • An eGFR >45 mL/min/1.73 m2
    • Provide written consent to take part in the study
    E.4Principal exclusion criteria
    • Pregnancy or breastfeeding
    • HER2 positive breast disease with planned trastuzumab therapy
    • Uncontrolled arterial hypertension defined as systolic blood pressure on treatment of >170 mmHg
    • Patients already taking B-blockers, ACEi or ARBs
    • Contra-indication to ARBs (eGFR ≤ 45 mL/min/1.73 m2, previous hypersensitivity, renal artery stenosis) or B-blockers (asthma, pathological heart block and, pathological sinus bradycardia.
    • Clinically proven intolerance to lactose monohydrate
    • A history of symptomatic heart failure
    • Contraindication to or inability to tolerate MRI scanning
    • Suspected poor drug compliance
    • Active alcohol or drug abuse
    • Patients previously treated with anthracyclines or trastuzumab
    • Uncontrolled concomitant serious illness, as determined by the investigator
    • Female or male aged < 18 years
    • Not provided written consent to take part in the study
    • Previously randomised into this trial
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measure will be a change in LVEF on cardiac MRI scan conducted 6 months after final anthracycline dose compared to baseline cardiac MRI scan conducted before anthracycline therapy starts between (randomised) treatment groups.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Six months after the final anthracycline dose.
    E.5.2Secondary end point(s)
    1. Specificity of cTnI assay for left ventricular dysfunction: Post treatment LVEF will be recorded with cardiac MRI in all non-randomised patients and compared to baseline LVEF to define the specificity of the hs-cTnI assay for identifying low-risk patients who do not develop left ventricular systolic dysfunction.
    2. The development of asymptomatic left ventricular dysfunction (a 10 percentage point fall or an LVEF less than 50%).
    3. Resolution of myocardial injury. Where plasma cTnI concentrations return to the normal reference range (less than 5 ng/L) at 2, 4 and 6 months after chemotherapy.
    4. Clinical endpoints of death, cardiovascular death and heart failure. Heart failure will be defined by the diagnosis of clinical (symptomatic) heart failure (see below for definition).
    5. Health economics for all enrolled patients: Confirm the feasibility of data capture and assess the quality of data obtainable in this patient population. Provide information that can inform the design of further research including sample size calculation and/or value of information analysis.
    6. Heart rate and blood pressure at 2, 4 & 6 months following final dose of anthracycline.
    7. Clinical endpoints of Hypotension, Bradycardia, Hyperkalaemia, Worsening renal function, Acute kidney injury, Fatigue grade ≥2 by CTCAE classification, New diagnosis of Atrial Fibrillation
    E.5.2.1Timepoint(s) of evaluation of this end point
    2 months and 6 months after the final anthracycline dose.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis Yes
    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 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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    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 No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Open-label blinded end point
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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 concerned11
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA11
    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 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days1
    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: 160
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 8
    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 state168
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 168
    F.4.2.2In the whole clinical trial 168
    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)
    In the UK these drugs are only licensed for patients with high blood pressure or heart failure so are not normally prescribed to this patient group.

    Drug treatment will continue until the final MRI scan. If LVEF is normal the medication will be stopped after the scan has been reported. ARB and B-blocker may be continued at the discretion of the supervising clinician if there is concern with respect to the presence of left ventricular dysfunction.
    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 Decision2017-06-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-06-19
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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