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

Sponsor

Morten Steen Kvistholm Jensen (Other)

Overall Status

Recruiting

CT.gov ID

NCT05569382

Collaborator

Gentofte University Hospital (Other), Bispebjerg Hospital (Other), Rigshospitalet, Denmark (Other), Viborg Regional Hospital (Other), Zealand University Hospital (Other), Odense University Hospital (Other)

140

Enrollment

Locations

Arms

33.7

Anticipated Duration (Months)

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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:

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

Condition or Disease	Intervention/Treatment	Phase
Non-obstructive Hypertrophic Cardiomyopathy	Drug: Verapamil Drug: Bisoprolol Drug: Placebo	Phase 4

Study Design

Study Type:

Interventional

Anticipated Enrollment :

140 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Aug 10, 2022

Anticipated Primary Completion Date :

Jun 1, 2025

Anticipated Study Completion Date :

Jun 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
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
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

Arm

Intervention/Treatment

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

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

Outcome Measures

Primary Outcome Measures

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.]
Changes in the incidence of non-sustained ventricular tachycardia (NSVT) in 7-Day Holter Monitoring
Left ventricular outflow tract (LVOT) time velocity integral (VTI) [Changes will be evaluated at day 21 in each treatment arm]
Changes in LVOT VTI estimated during echocardiography
Maximal oxygen consumption (VO2 max) [Changes will be evaluated at day 21 in each treatment arm]
Changes in VO2 max estimated during cardiopulmonary exercise test

Secondary Outcome Measures

Kansas City Cardiomyopathy Questionnaire (KCCQ) score [Changes will be evaluated at day 21 in each treatment arm]
Changes in KCCQ assessed by clinical evaluation
New York Heart Association (NYHA) class [Changes will be evaluated at day 21 in each treatment arm]
Changes in NYHA class assessed by clinical evaluation
Canadian Cardiovascular Society (CCS) class [Changes will be evaluated at day 21 in each treatment arm]
Changes in CCS class assessed by clinical evaluation
Pro-BNP/BNP [Changes will be evaluated at day 21 in each treatment arm]
Changes in level of Pro-BNP/BNP in blood sample
High sensitive Troponin I/Troponin T [Changes will be evaluated at day 21 in each treatment arm]
Changes in level of high sensitive Troponin I/Troponin T in blood sample
Metabolic equivalent of task (METs) [Changes will be evaluated at day 21 in each treatment arm]
Changes in METs measured during cardiopulmonary exercise test
Recovery time [Changes will be evaluated at day 21 in each treatment arm]
Changes in recovery time measured during cardiopulmonary exercise test
Anaerobe threshold [Changes will be evaluated at day 21 in each treatment arm]
Changes in anaerobe threshold measured during cardiopulmonary exercise test
Left ventricular end-diastolic dimension [Changes will be evaluated at day 21 in each treatment arm]
Changes in left ventricular end-diastolic dimension measured during echocardiography
Strain in hypertrophied segment [Changes will be evaluated at day 21 in each treatment arm]
Changes in strain in hypertrophied segment calculated during echocardiography
Strain in non-hypertrophied segment [Changes will be evaluated at day 21 in each treatment arm]
Changes in strain in non-hypertrophied segment calculated during echocardiography
Left atrial dimension [Day 21 in each treatment arm]
Left atrial dimension measured during echocardiography
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.]
Changes in the incidence of atrial fibrillation in 7-Day Holter Monitoring
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.]
Changes in the incidence of ventricular ectopic beats in 7-Day Holter Monitoring

Other Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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
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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Department of Cardiology, Aarhus University Hospital	Aarhus N	Denmark	8200
2	Department of Cardiology, Rigshospital	Copenhagen	Denmark	2100
3	Department of Cardiology, Bispebjerg Hospital	Frederiksberg	Denmark	2000
4	Department of Cardiology, Gentofte University Hospital	Hellerup	Denmark	2900
5	Department of Cardiology, Odense University Hospital	Odense	Denmark	5000
6	Department of Cardiology, Zealand University Hospital	Roskilde	Denmark	4000
7	Department of Cardiology, Regional Hospital Viborg	Viborg	Denmark	8800