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    Summary
    EudraCT Number:2021-006953-77
    Sponsor's Protocol Code Number:27-12-2021
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-01-31
    Trial 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 ConcernedDenmark - DHMA
    A.2EudraCT number2021-006953-77
    A.3Full title of the trial
    Treatment effects of Bisoprolol and Verapamil in symptomatic patients with non-obstructive hypertrophic cardiomyopathy
    Effekten af Bisoprolol og Verapamil hos symptomatiske patienter med hypertrofisk kardiomyopati uden udløbsobstruktion
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The effect of Bisoprolol and Verapamil in non-obstructive hypertrophic cardiomyopathy
    Effekten af Bisoprolol og Verapamil hos patienter med hypertrofisk kardiomyopati uden udløbsobstruktion
    A.3.2Name or abbreviated title of the trial where available
    TEMPO II
    TEMPO II
    A.4.1Sponsor's protocol code number27-12-2021
    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 SponsorAarhus University Hospital
    B.1.3.4CountryDenmark
    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 supportDanske Regioners medicin og behandlingspulje
    B.4.2CountryDenmark
    B.4.1Name of organisation providing supportNovo Nordisk Foundation
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAarhus University Hospital
    B.5.2Functional name of contact pointMorten Steen Kvistholm Jensen
    B.5.3 Address:
    B.5.3.1Street AddressPalle Juul-Jensens Boulevard 00
    B.5.3.2Town/ cityAarhus N
    B.5.3.3Post code8200
    B.5.3.4CountryDenmark
    B.5.4Telephone number004540145482
    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 Bisoprolol
    D.2.1.1.2Name of the Marketing Authorisation holderKrka
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    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 Modified-release 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 INNBISOPROLOL
    D.3.9.1CAS number 66722-44-9
    D.3.9.4EV Substance CodeSUB13096MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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 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 Isoptin
    D.2.1.1.2Name of the Marketing Authorisation holderRetard
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    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 Modified-release 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 INNVERAPAMIL HYDROCHLORIDE
    D.3.9.1CAS number 99300-78-4
    D.3.9.4EV Substance CodeSUB05088MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number240
    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 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
    Non-obstructive Hypertrophic cardiomyopathy
    E.1.1.1Medical condition in easily understood language
    Hypertrophic cardiomyopathy (HCM) is a condition in which a portion of the heart becomes thickened without an obvious cause. This results in the heart being less able to pump effectively.
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10007636
    E.1.2Term Cardiomyopathy
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10049813
    E.1.2Term Non-obstructive cardiomyopathy
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 27.0
    E.1.2Level PT
    E.1.2Classification code 10020871
    E.1.2Term Hypertrophic cardiomyopathy
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10061029
    E.1.2Term Cardiomyopathy primary
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    We want to quantify the effect of Bisoprolol and Verapamil on maximal oxygen consumption (VO2 max), left ventricular end diastolic volume and the incidence of non-sustained ventricular tachycardia in patients with non-obstructive hypertrophic cardiomyopathy.
    E.2.2Secondary objectives of the trial
    Not Applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Informed consent
    - Age ≥ 18 years
    - Maximal wall thickness ≥ 15 mm unrelated to hypertension, valve diseases or storage diseases.
    - And one of the following:
    1. New York Heart Association – functional class (NYHA) ≥ II
    2. A history of NYHA class ≥ II before treatment with BB or CCB
    3. pro-BNP>300 ng/l/35>nmol/l or BNP >100ng/l/>29nmol/l
    4. Non-sustained VT (>120 min-1, ≥3 cycles) documented within the last 2 years of screening
    E.4Principal exclusion criteria
    - Left ventricular ejection fraction < 50%
    - LVOT gradient >30 mmHg at rest or during Valsalva maneuver after discontinuation of BB or CCB respectively
    - Previous history of LVOT gradient >30 mmHg at rest, during exercise or during Valsalva maneuver.
    - Permanent atrial fibrillation
    - Permanent right ventricular pacing
    - Previous intolerance for Bisoprolol (BB) or Verapamil (CCB)
    - Known present obstructive coronary disease (previous percutaneous coronary intervention is accepted)
    - eGFR < 40 ml/min
    - Fertile women (<50 years) who are pregnant (Positive Plasma-HCG), breastfeeding or not using anticonceptions.
    - Significant liver failure, severe valvular disease, bradycardia (40bpm) or hypotension (systolic <100mmHg), other significant comorbidity or risks associated with discontinuation of BB or CCB after individual judgement by the investigators.
    - Unable to understand patient information intellectually or linguistically
    - Unable to perform exercise test.
    - Unable to speak and/or understand Danish.

    Additional exclusion criteria for CMRI sub-study:
    - Implantable cardioverter defibrillator (any kind)
    - Pacemaker (any kind)
    - Metal implants like to affect image quality
    - Metal implants that poses a risk during CMR
    - Inability to cope with being in the scanner.
    E.5 End points
    E.5.1Primary end point(s)
    - Phase 1: The maximal oxygen consumption (VO2 max) is different (ΔVO2 max ≥1 ml/kg/min) between treatments in non-obstructive HCM patients
    - Phase 2: The left ventricular end diastolic volume (LV vol) is different between treatments in non-obstructive HCM patients.
    - Phase 3: The incidence of non-sustained ventricular tachycardia (NSVT) is different (Hazard ratio ≥ 0.5) between treatments in non-obstructive HCM patients.
    E.5.1.1Timepoint(s) of evaluation of this end point
    - Phase 1: The team may decide to unblind the treatment in patients, who are tested with CPX, after minimum 26 patients have completed all three treatment periods. Interim analyses of event rates in the ambulatory ECG monitoring (Phase three) will be performed and an adjusted sample size calculation for the arrhythmic endpoint may be applied (Ultimo 2024)
    - Phase 2: The team may decide to unblind the treatment in all patients after 30-50 patients have finished the CMRI in all three treatment periods. (Ultimo 2025)
    - Phase 3: The team may decide to unblind the remaining patients, after 82-140 patients have finished the study. A different sample size may be applied after interim analyses of event rates in phase one. (Ultimo 2026)
    E.5.2Secondary end point(s)
    Clinical
    - Sex specific analyses of effect parameters
    - Kansas City Cardiomyopathy Questionnaire (KCCQ) score
    - New York Heart Association (NYHA) functional classification
    - Canadian Cardiovascular Society (CCS)
    - Tolerable dose
    Biomarkers
    - Pro-BNP/BNP
    - High sensitive Troponin I/Troponin T
    Cardiopulmonary exercise test
    - Recovery time
    - VO2 max at anaerobic threshold
    - Percent predicted VO2 max
    - Ventilatory equivalent for carbon dioxide VE/VCO2
    - Metabolic equivalent of task (METs)
    Echocardiography
    - Left ventricular end-diastolic dimension
    - Myocardial deformation imaging (Strain)
    - Left ventricular outflow tract time velocity intergral (VTI)
    - Left atrial dimension
    Cardiac magnetic resonance imaging sub-study (optional)
    - Left ventricular systolic function
    - Right ventricular dimensions
    - Right ventricular systolic function
    - Stroke volume (Aortic flow)
    - Coronary sinus flow
    - Dimension of inferior and superior caval vein
    - Left atrial dimension
    Ambulatory ECG recordings
    - Atrial fibrillation (Ambulatory ECG monitoring)
    - Estimation of ventricular ectopic beats (Ambulatory ECG monitoring)
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Phase 1: The team may decide to unblind the treatment in patients, who are tested with CPX, after minimum 26 patients have completed all three treatment periods. Interim analyses of event rates in the ambulatory ECG monitoring (Phase three) will be performed and an adjusted sample size calculation for the arrhythmic endpoint may be applied (Ultimo 2024)
    - Phase 2: The team may decide to unblind the treatment in all patients after 30-50 patients have finished the CMRI in all three treatment periods. (Ultimo 2025)
    - Phase 3: The team may decide to unblind the remaining patients, after 82-140 patients have finished the study. A different sample size may be applied after interim analyses of event rates in phase one. (Ultimo 2026)
    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 No
    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 No
    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 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.8.2.4Number of treatment arms in the trial3
    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 concerned4
    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
    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: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state140
    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)
    None
    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 Decision2022-04-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-04-11
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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