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NCT Number: NCT05569382

Treatment Effects of Bisoprolol and Verapamil in Symptomatic Patients With Non-obstructive Hypertrophic Cardiomyopathy

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.

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.

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Key information

Conditions

Non-obstructive Hypertrophic Cardiomyopathy Aortic Stenosis, Subvalvular Aortic Valve Disease Aortic Valve Stenosis Cardiomyopathies Cardiomyopathy, Hypertrophic Cardiovascular Diseases Heart Diseases Heart Valve Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • 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

Exclusion criteria

  • 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)
  • 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.

Treatment and study plan

Verapamil

Drug
  • 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

Other names: Isoptin Retard 240 MG, Verapamil Hydrochloride 240 MG

Bisoprolol

Drug
  • 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

Other names: Bisoprolol "Krka" 2.5 MG, Bisoprolol Fumarate 2.5 MG

Placebo

Drug
  • 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

Other names: Placebo oral capsule

Primary outcomes

  1. Maximal oxygen consumption (VO2 max)

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in VO2 max estimated during cardiopulmonary exercise test

  2. Left ventricular enddiastolic volume (LVvol)

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in enddiastolic volume (LVvol) estimated during cardiac MRI

  3. Incidence of non-sustained ventricular tachycardia (NSVT

    Time frame: Changes will be evaluated at day 21 +7 days in each treatment arm

    Changes in NSVT estimated during ECG monitoring

Secondary outcomes

  1. Kansas City Cardiomyopathy Questionnaire (KCCQ) score

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in KCCQ assessed by clinical evaluation

  2. New York Heart Association (NYHA) functional classification

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in NYHA class assessed by clinical evaluation

  3. Canadian Cardiovascular Society (CCS) class

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in CCS class assessed by clinical evaluation

  4. Pro-BNP/BNP

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in level of Pro-BNP/BNP in blood sample

  5. High sensitive Troponin I/Troponin T

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in level of high sensitive Troponin I/Troponin T in blood sample

  6. Metabolic equivalent of task (METs)

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in METs measured during cardiopulmonary exercise test

  7. Recovery time

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in recovery time measured during cardiopulmonary exercise test

  8. VO2 max Anaerobic threshold

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in VO2 max at anaerobic threshold measured during cardiopulmonary exercise test

  9. Percent predicted VO2 max

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in percent predicted VO2 max measured during cardiopulmonary exercise test

  10. Ventilatory equivalent for carbon dioxide VE/VCO2

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in VE/VCO2 measured during cardiopulmonary exercise test

  11. Echocardiographic left ventricular end-diastolic dimension

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in left ventricular end-diastolic dimension measured during echocardiography

  12. Echocardiographic global longitudinal strain (GLS) for LV function

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in GLS measured during echocardiography

  13. Echocardiographic left ventricular outflow tract time velocity intergral (LVOT VTI) for LV function

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in LVOT VTI measured during echocardiography

  14. Echocardiographic dimension of left atrial

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in left atrial dimension measured during echocardiography

  15. Episodes of atrial fibrillation (AFIB) on Holter monitoring

    Time frame: Changes will be evaluated at day 21 +7 days in each treatment arm

    Changes in episodes of AFIB measured during Holter monitoring

  16. Number of ventricular ectopic beats on Holter monitoring

    Time frame: Changes will be evaluated at day 21 +7 days in each treatment arm

    Changes in number of ventricular ectopic beats measured during Holter monitoring

  17. Left ventricular systolic function on Cardiac MRI

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in left ventricular systolic function on Cardiac MRI

  18. Right ventricular dimensions on Cardiac MRI

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in right ventricular dimensions on Cardiac MRI

  19. Right ventricular systolic function on Cardiac MRI

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in right ventricular systolic function on Cardiac MRI

  20. Stroke volume (Aortic flow) on Cardiac MRI

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in stroke volume (Aortic flow) on Cardiac MRI

  21. Coronary sinus flow on Cardiac MRI

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in coronary sinus flow on Cardiac MRI

  22. Dimension of inferior and superior caval vein on Cardiac MRI

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in dimension of inferior and superior caval vein on Cardiac MRI

  23. Dimension of left atrium on cardiac MRI

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in dimension of left atrium on cardiac MRI

  24. Sex specific analyses of outcome measures

    Time frame: Changes will be evaluated at day 21 in each treatment arm

    Changes in outcome measures between male and female

Study contacts

Contact information is provided by the study sponsor or research team.

Louise Bjerregaard

CONTACT

[email protected]

004540429833

Morten SK Jensen

CONTACT

[email protected]

004540145482

Sponsors and collaborators

Lead sponsor

Morten Steen Kvistholm Jensen

Other

Collaborators

  • Odense University Hospital
  • Viborg Regional Hospital
  • Zealand University Hospital

Registry information

Acronym: TEMPO II

Important dates

Study start
2022
Primary completion
2027
Study completion
2027
First posted
Oct 6, 2022
Registry last updated
Mar 20, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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