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

Aim: To compare treatment effects of Bisoprolol and Verapamil in 140 patients with non-obstructive hypertrophic cardiomyopathy. The overall clinical purpose is to reduce the symptomatic burden and arrhythmic complications.

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 1-30 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 equal independent primary effect parameters will be analyzed between treatment with Bisoprolol and Verapamil:

1. The incidence of non-sustained ventricular tachycardia (NSVT) is different between treatment in non-obstructive HCM patients.
2. The left ventricular outflow tract (LVOT) time velocity integral (VTI) is different between treatment in non-obstructive HCM patients.
3. The maximal oxygen consumption (VO2 max) is different between treatments in non-obstructive HCM patients.

Study Overview

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

• Study Type: Interventional
• Enrollment (Anticipated): 140
• 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
  • Copenhagen, Denmark, 2100
    • Not yet recruiting
    • Department of Cardiology, Rigshospital
  • Frederiksberg, Denmark, 2000
    • Not yet recruiting
    • Department of Cardiology, Bispebjerg Hospital
    • Contact: Jens J Thune
  • Hellerup, Denmark, 2900
    • Not yet recruiting
    • Department of Cardiology, Gentofte University Hospital
    • Contact: Alex Christensen
  • Odense, Denmark, 5000
    • Not yet 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
• Genders Eligible for Study: All

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
• 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 < 60 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	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	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	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
Non-sustained ventricular tachycardia (NSVT) in 7-Day Holter Monitoring	Changes in the incidence of non-sustained ventricular tachycardia (NSVT) in 7-Day Holter Monitoring	7-Day Holter-monitoring starts at day 21 in each treatment arm. Subsequently, the Holter report will be analyzed.
Left ventricular outflow tract (LVOT) time velocity integral (VTI)	Changes in LVOT VTI estimated during echocardiography	Changes will be evaluated at day 21 in each treatment arm
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

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
New York Heart Association (NYHA) class	Changes in NYHA class 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
Anaerobe threshold	Changes in anaerobe threshold measured during cardiopulmonary exercise test	Changes will be evaluated at day 21 in each treatment arm
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
Strain in hypertrophied segment	Changes in strain in hypertrophied segment calculated during echocardiography	Changes will be evaluated at day 21 in each treatment arm
Strain in non-hypertrophied segment	Changes in strain in non-hypertrophied segment calculated during echocardiography	Changes will be evaluated at day 21 in each treatment arm
Left atrial dimension	Left atrial dimension measured during echocardiography	Day 21 in each treatment arm
Atrial fibrillation in 7-Day Holter Monitoring	Changes in the incidence of atrial fibrillation in 7-Day Holter Monitoring	7-Day Holter-monitoring starts at day 21 in each treatment arm. Subsequently, the Holter report will be analyzed.
Ventricular ectopic beats in 7-Day Holter Monitoring	Changes in the incidence of ventricular ectopic beats in 7-Day Holter Monitoring	7-Day Holter-monitoring starts at day 21 in each treatment arm. Subsequently, the Holter report will be analyzed.

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; Rigshospitalet, Denmark; Bispebjerg Hospital; Gentofte University Hospital; Viborg Regional Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 10, 2022
• Primary Completion (Anticipated): June 1, 2025
• Study Completion (Anticipated): June 1, 2025

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 (Estimate): December 7, 2022
• Last Update Submitted That Met QC Criteria: December 5, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

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