Non-obstructive Hypertrophic CardiomyopathyPhase 4TEMPO IINCT05569382
Treatment Effects of Bisoprolol and Verapamil in Symptomatic Patients With Non-obstructive Hypertrophic Cardiomyopathy
A Phase 4 study testing Verapamil and Bisoprolol in people with Non-obstructive Hypertrophic Cardiomyopathy, run by Morten Steen Kvistholm Jensen at 4 sites in Denmark.
Trial summary
Aim: to compare the treatment effects of Bisoprolol (beta 1 receptor specific beta blocker (BB)) and Verapamil (cardio-specific calcium channel blockers (CCB)) in patients with non-obstructive hypertrophic cardiomyopathy (HCM). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Non-obstructive Hypertrophic Cardiomyopathy
- What is being tested?
- Verapamil and Bisoprolol
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 100 participants
- Where
- 4 sitesDenmark
- Study dates
- 10 Aug 2022to 31 Dec 2027
- Phase
- Phase 4
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age ≥ 18 years
- Maximal wall thickness ≥ 15 mm unrelated to hypertension, valve diseases or storage diseases. And one of the following:
- New York Heart Association - functional class (NYHA) ≥ II
- A history of NYHA class ≥ II before treatment with BB or CCB
- Pro-BNP>300 ng/l/35>nmol/l or BNP >100ng/l/>29nmol/l
- Non-sustained VT (>120 min-1, ≥3 cycles) documented within the last 2 years of screening
Who cannot join
- Left ventricular ejection fraction < 50%
- LVOT gradient >30 mmHg at rest or during Valsalva maneuver after discontinuation of BB or CCB respectively
- 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)
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- 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 anticonception.
- Significant liver failure
- Severe valvular disease
- Bradycardia (40bpm)
- 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 CMR 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.
Trial locations and contacts
4 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Denmark4 sites, 4 recruiting
- Recruiting
Department of Cardiology, Aarhus University Hospital
Aarhus N, 8200
Morten SK Jensen, 004540145482, morten.jensen@rm.dk
Louise Bjerregaard, 004540429833, lbjer@clin.au.dk
- Recruiting
Department of Cardiology, Odense University Hospital
Odense, 5000
Lotte Saaby
- Not yet recruiting
Department of Cardiology, Zealand University Hospital
Roskilde, 4000
Martin Snoer
- Not yet recruiting
Department of Cardiology, Regional Hospital Viborg
Viborg, 8800
Erik S Nielsen
About this study
Aim: to compare the treatment effects of Bisoprolol (beta 1 receptor specific beta blocker (BB)) and Verapamil (cardio-specific calcium channel blockers (CCB)) in patients with non-obstructive hypertrophic cardiomyopathy (HCM).
Background: Hypertrophic cardiomyopathy (HCM) is characterized by hypertrophy of the left ventricular wall and a hypercontracted state of the sarcomeres. This narrows the left ventricular cavity, but though the left ejection fraction is increased the stroke volume and the cardiac output cannot be fully compensated. The disease manifestations can be mild or develop into severe functional limitations and devastating complications at early age. Dyspnea, chest pain, palpitations and syncope are the most common symptoms, and patients are at risk of supraventricular and ventricular arrhythmias. Arrhythmias and sudden cardiac deaths may precede heart failure symptoms. Patients with symptomatic HCM are treated initially with beta blockers and calcium channel blockers. However, there is limited evidence supporting the effectiveness of this guideline-recommended treatment in HCM.
Read more
Methods: The study is a multicenter, double-blinded, randomized, placebo-controlled cross-over trial. Patients are randomized in to three 35-days treatment periods with Bisoprolol, Verapamil and Placebo. Each treatment period includes a 7-days up titration period, a 21-days target dose period and a 7-days down titration period. Between treatment periods 45 days treatment pause is allowed. End point will be evaluated at day 21 (- 4 days). Patients will be evaluated by cardiopulmonary exercise test, echocardiography, 7 day Holter-monitoring, biomarkers and the Kansas City Cardiomyopathy Questionnaire (KCCQ). A subgroup of patients will also be evaluated with cardiac magnetic resonance imaging.
Hypotheses: Three separate phases each with one primary effect parameters will be analyzed between treatment with Bisoprolol and Verapamil:
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 enddiastolic volume (LVvol) is different (ΔLVvol ≥3 ml) 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.
The trial will be performed and analyzed in three phases, and each phase may be unblinded and analyzed separately.
- Being tested
- Verapamil, Bisoprolol, Placebo
- Keywords
- Hypertrophic cardiomyopathy, Bisoprolol, Verapamil, Beta Blocker, Calcium-channel Blocker
- Medical subject headings
- Cardiomyopathy, Hypertrophic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VerapamilDrug
Also called Isoptin Retard 240 MG, Verapamil Hydrochloride 240 MG
- week: uptitration with 120 mg capsules per day, until maximum dosage of 360 mg´s/day.
2-4. week: steady state treatment with the maximum tolerated dose.
- week: downtitration
BisoprololDrug
Also called Bisoprolol "Krka" 2.5 MG, Bisoprolol Fumarate 2.5 MG
- week: uptitration with 2.5 mg capsules per day, until maximum dosage of 7.5 mg´s/day.
2-4. week: steady state treatment with the maximum tolerated dose.
- week: downtitration
PlaceboDrug
Also called Placebo oral capsule
- week: uptitration with one capsules per day, until maximum dosage of three capsules/day.
2-4. week: steady state treatment with the maximum tolerated dose.
- week: downtitration
| Study group | Role | What they receive |
|---|---|---|
| Verapamil | Active comparator | Maximal tolerable dose (up to 360 mg per day) Receives: Drug: Verapamil |
| Bisoprolol | Active comparator | Maximal tolerable dose (up to 7,5 mg per day) Receives: Drug: Bisoprolol |
| Placebo | Placebo comparator | Matching placebo Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximal oxygen consumption (VO2 max)
Changes in VO2 max estimated during cardiopulmonary exercise test
Measured: Changes will be evaluated at day 21 in each treatment arm
Left ventricular enddiastolic volume (LVvol)
Changes in enddiastolic volume (LVvol) estimated during cardiac MRI
Measured: Changes will be evaluated at day 21 in each treatment arm
Incidence of non-sustained ventricular tachycardia (NSVT
Changes in NSVT estimated during ECG monitoring
Measured: Changes will be evaluated at day 21 +7 days in each treatment arm
Secondary outcomes (24)
Kansas City Cardiomyopathy Questionnaire (KCCQ) score
Changes in KCCQ assessed by clinical evaluation
Measured: Changes will be evaluated at day 21 in each treatment arm
New York Heart Association (NYHA) functional classification
Changes in NYHA class assessed by clinical evaluation
Measured: Changes will be evaluated at day 21 in each treatment arm
Canadian Cardiovascular Society (CCS) class
Changes in CCS class assessed by clinical evaluation
Measured: Changes will be evaluated at day 21 in each treatment arm
Pro-BNP/BNP
Changes in level of Pro-BNP/BNP in blood sample
Measured: Changes will be evaluated at day 21 in each treatment arm
High sensitive Troponin I/Troponin T
Changes in level of high sensitive Troponin I/Troponin T in blood sample
Measured: Changes will be evaluated at day 21 in each treatment arm
Metabolic equivalent of task (METs)
Changes in METs measured during cardiopulmonary exercise test
Measured: Changes will be evaluated at day 21 in each treatment arm
Recovery time
Changes in recovery time measured during cardiopulmonary exercise test
Measured: Changes will be evaluated at day 21 in each treatment arm
VO2 max Anaerobic threshold
Changes in VO2 max at anaerobic threshold measured during cardiopulmonary exercise test
Measured: Changes will be evaluated at day 21 in each treatment arm
Percent predicted VO2 max
Changes in percent predicted VO2 max measured during cardiopulmonary exercise test
Measured: Changes will be evaluated at day 21 in each treatment arm
Ventilatory equivalent for carbon dioxide VE/VCO2
Changes in VE/VCO2 measured during cardiopulmonary exercise test
Measured: Changes will be evaluated at day 21 in each treatment arm
Echocardiographic left ventricular end-diastolic dimension
Changes in left ventricular end-diastolic dimension measured during echocardiography
Measured: Changes will be evaluated at day 21 in each treatment arm
Echocardiographic global longitudinal strain (GLS) for LV function
Changes in GLS measured during echocardiography
Measured: Changes will be evaluated at day 21 in each treatment arm
Echocardiographic left ventricular outflow tract time velocity intergral (LVOT VTI) for LV function
Changes in LVOT VTI measured during echocardiography
Measured: Changes will be evaluated at day 21 in each treatment arm
Echocardiographic dimension of left atrial
Changes in left atrial dimension measured during echocardiography
Measured: Changes will be evaluated at day 21 in each treatment arm
Episodes of atrial fibrillation (AFIB) on Holter monitoring
Changes in episodes of AFIB measured during Holter monitoring
Measured: Changes will be evaluated at day 21 +7 days in each treatment arm
Number of ventricular ectopic beats on Holter monitoring
Changes in number of ventricular ectopic beats measured during Holter monitoring
Measured: Changes will be evaluated at day 21 +7 days in each treatment arm
Left ventricular systolic function on Cardiac MRI
Changes in left ventricular systolic function on Cardiac MRI
Measured: Changes will be evaluated at day 21 in each treatment arm
Right ventricular dimensions on Cardiac MRI
Changes in right ventricular dimensions on Cardiac MRI
Measured: Changes will be evaluated at day 21 in each treatment arm
Right ventricular systolic function on Cardiac MRI
Changes in right ventricular systolic function on Cardiac MRI
Measured: Changes will be evaluated at day 21 in each treatment arm
Stroke volume (Aortic flow) on Cardiac MRI
Changes in stroke volume (Aortic flow) on Cardiac MRI
Measured: Changes will be evaluated at day 21 in each treatment arm
Coronary sinus flow on Cardiac MRI
Changes in coronary sinus flow on Cardiac MRI
Measured: Changes will be evaluated at day 21 in each treatment arm
Dimension of inferior and superior caval vein on Cardiac MRI
Changes in dimension of inferior and superior caval vein on Cardiac MRI
Measured: Changes will be evaluated at day 21 in each treatment arm
Dimension of left atrium on cardiac MRI
Changes in dimension of left atrium on cardiac MRI
Measured: Changes will be evaluated at day 21 in each treatment arm
Sex specific analyses of outcome measures
Changes in outcome measures between male and female
Measured: Changes will be evaluated at day 21 in each treatment arm
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Oct 2022
- Study start10 Aug 2022
- Primary completion1 Apr 2027 (estimated)
- Study completion31 Dec 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Non-obstructive Hypertrophic CardiomyopathyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- The trial will be performed and analyzed in three phases, and each phase may be unblinded and analyzed separately. Phase one: More than 26 patients must have completed all three treatment periods. Functional analyses of VO2 max from CPX tests and secondary functional effect parameters (KCCQ, NYHA, CCS), echocardiographic parameters, biomarkers (TNI/TNT, pro-BNP/BNP). Phase two: Between 30 to 50 patients must have completed all three treatment periods and have CMR performed in each period. Structural and hemodynamic analyses of cardiac dimensions and hemodynamic effect parameters (CMR). Sex specific analyses of functional, structural and hemodynamic effect parameters will be performed. Phase three (n \> 82): Arrhythmic effect parameters will be analyzed from ambulatory ECG monitoring.
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 100 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Morten Steen Kvistholm Jensen
- Sponsor type
- University, hospital or other
- Collaborators
- Viborg Regional Hospital, Zealand University Hospital, Odense University Hospital
- Responsible party
- Sponsor-investigator, Morten Steen Kvistholm Jensen, Aarhus University Hospital Skejby
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05569382
- Sponsor's protocol ID
- 490-73-6795
- Other IDs
- 2021-006953-77
- Acronym
- TEMPO II
- Status last verified
- Mar 2025
- First submitted
- 4 Oct 2022
- Last updated
- 20 Mar 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No