Treatment Effects of Bisoprolol and Verapamil in Symptomatic Patients With Non-obstructive Hypertrophic Cardiomyopathy (TEMPO II)

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.

Study Overview

• Status: Recruiting
• Conditions: Non-obstructive Hypertrophic Cardiomyopathy
• Intervention / Treatment: Drug: Verapamil; Drug: Bisoprolol; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Morten SK Jensen; Phone Number: 004540145482; Email: morten.jensen@rm.dk
• Study Contact Backup: Name: Louise Bjerregaard; Phone Number: 004540429833; Email: lbjer@clin.au.dk

Study Locations

• Denmark
  • Aarhus N, Denmark, 8200
    • Recruiting
    • Department of Cardiology, Aarhus University Hospital
    • Contact: Morten SK Jensen; Phone Number: 004540145482; Email: morten.jensen@rm.dk
    • Contact: Louise Bjerregaard; Phone Number: 004540429833; Email: lbjer@clin.au.dk
    • Principal Investigator: Morten SK Jensen
    • Sub-Investigator: Steen H Poulsen
    • Sub-Investigator: Louise Bjerregaard
  • Odense, Denmark, 5000
    • Recruiting
    • Department of Cardiology, Odense University Hospital
    • Contact: Lotte Saaby
  • Roskilde, Denmark, 4000
    • Not yet recruiting
    • Department of Cardiology, Zealand University Hospital
    • Contact: Martin Snoer
  • Viborg, Denmark, 8800
    • Not yet recruiting
    • Department of Cardiology, Regional Hospital Viborg
    • Contact: Erik S Nielsen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Matching placebo	Drug: Placebo; 1. 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. 5. week: downtitration; Other Names: Placebo oral capsule
Active Comparator: Verapamil; Maximal tolerable dose (up to 360 mg per day)	Drug: Verapamil; 1. 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. 5. week: downtitration; Other Names: Isoptin Retard 240 MG; Verapamil Hydrochloride 240 MG
Active Comparator: Bisoprolol; Maximal tolerable dose (up to 7,5 mg per day)	Drug: Bisoprolol; 1. 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. 5. week: downtitration; Other Names: Bisoprolol "Krka" 2.5 MG; Bisoprolol Fumarate 2.5 MG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximal oxygen consumption (VO2 max)	Changes in VO2 max estimated during cardiopulmonary exercise test	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	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	Changes will be evaluated at day 21 +7 days in each treatment arm

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Kansas City Cardiomyopathy Questionnaire (KCCQ) score	Changes in KCCQ assessed by clinical evaluation	Changes will be evaluated at day 21 in each treatment arm
Canadian Cardiovascular Society (CCS) class	Changes in CCS class assessed by clinical evaluation	Changes will be evaluated at day 21 in each treatment arm
Pro-BNP/BNP	Changes in level of Pro-BNP/BNP in blood sample	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	Changes will be evaluated at day 21 in each treatment arm
Metabolic equivalent of task (METs)	Changes in METs measured during cardiopulmonary exercise test	Changes will be evaluated at day 21 in each treatment arm
Recovery time	Changes in recovery time measured during cardiopulmonary exercise test	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	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	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	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	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	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	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	Changes will be evaluated at day 21 in each treatment arm
Echocardiographic dimension of left atrial	Changes in left atrial dimension measured during echocardiography	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	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	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	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	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	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	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	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	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	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	Changes will be evaluated at day 21 in each treatment arm

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left ventricular dimensions	On Cardiac MRI	Day 21 in each treatment arm
Left ventricular systolic function	On Cardiac MRI	Day 21 in each treatment arm
Right ventricular dimensions	On Cardiac MRI	Day 21 in each treatment arm
Right ventricular systolic function	On Cardiac MRI	Day 21 in each treatment arm
Stroke volume (Aortic flow)	On Cardiac MRI	Day 21 in each treatment arm
Coronary sinus flow	On Cardiac MRI	Day 21 in each treatment arm
Dimension of inferior and superior caval vein	On Cardiac MRI	Day 21 in each treatment arm
Left atrial dimension	On Cardiac MRI	Day 21 in each treatment arm
Left ventricular end-diastolic volume	On Cardiac MRI	Day 21 in each treatment arm

Collaborators and Investigators

• Sponsor: Morten Steen Kvistholm Jensen
• Collaborators: Odense University Hospital; Zealand University Hospital; Viborg Regional Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 10, 2022
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: October 4, 2022
• First Submitted That Met QC Criteria: October 4, 2022
• First Posted (Actual): October 6, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 17, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Bisoprolol; Verapamil; Hypertrophic cardiomyopathy; Beta Blocker; Calcium-channel Blocker
• Additional Relevant MeSH Terms: Aortic Valve Disease; Cardiovascular Diseases; Pathological Conditions, Anatomical; Heart Diseases; Heart Valve Diseases; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Cardiomyopathies; Cardiomyopathy, Hypertrophic; Hypertrophy; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Agents; Anti-Arrhythmia Agents; Membrane Transport Modulators; Adrenergic Agents; Calcium Channel Blockers; Vasodilator Agents; Antihypertensive Agents; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Adrenergic beta-Antagonists; Adrenergic Antagonists; Bisoprolol; Verapamil
• Other Study ID Numbers: 490-73-6795; 2021-006953-77 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No