Clinical trial NCT05569382: Treatment Effects of Bisoprolol and Verapamil in Symptomatic Patients With Non-obstructive Hypertrophic Cardiomyopathy
Official title: Treatment Effects of Bisoprolol and Verapamil in Symptomatic Patients With Non-obstructive Hypertrophic Cardiomyopathy
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Non-obstructive Hypertrophic Cardiomyopathy
Keywords: Hypertrophic cardiomyopathy
Bisoprolol
Verapamil
Beta Blocker
Calcium-channel Blocker
Lead sponsor: Aarhus University Hospital Skejby
Sponsor class: OTHER
Collaborators: name: Viborg Regional Hospital
name: Zealand University Hospital
name: Odense University Hospital
First posted: 2022-10-06
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention 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.
Primary purpose: TREATMENT

Brief 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).

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Maximal oxygen consumption (VO2 max)
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: Left ventricular enddiastolic volume (LVvol)
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: Incidence of non-sustained ventricular tachycardia (NSVT
timeFrame: Changes will be evaluated at day 21 +7 days in each treatment arm
Secondary outcomes:
measure: Kansas City Cardiomyopathy Questionnaire (KCCQ) score
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: New York Heart Association (NYHA) functional classification
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: Canadian Cardiovascular Society (CCS) class
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: Pro-BNP/BNP
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: High sensitive Troponin I/Troponin T
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: Metabolic equivalent of task (METs)
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: Recovery time
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: VO2 max Anaerobic threshold
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: Percent predicted VO2 max
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: Ventilatory equivalent for carbon dioxide VE/VCO2
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: Echocardiographic left ventricular end-diastolic dimension
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: Echocardiographic global longitudinal strain (GLS) for LV function
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: Echocardiographic left ventricular outflow tract time velocity intergral (LVOT VTI) for LV function
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: Echocardiographic dimension of left atrial
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: Episodes of atrial fibrillation (AFIB) on Holter monitoring
timeFrame: Changes will be evaluated at day 21 +7 days in each treatment arm
measure: Number of ventricular ectopic beats on Holter monitoring
timeFrame: Changes will be evaluated at day 21 +7 days in each treatment arm
measure: Left ventricular systolic function on Cardiac MRI
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: Right ventricular dimensions on Cardiac MRI
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: Right ventricular systolic function on Cardiac MRI
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: Stroke volume (Aortic flow) on Cardiac MRI
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: Coronary sinus flow on Cardiac MRI
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: Dimension of inferior and superior caval vein on Cardiac MRI
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: Dimension of left atrium on cardiac MRI
timeFrame: Changes will be evaluated at day 21 in each treatment arm
measure: Sex specific analyses of outcome measures
timeFrame: Changes will be evaluated at day 21 in each treatment arm
Other outcomes:
Locations:
city: Aarhus N
country: Denmark
facility: Department of Cardiology, Aarhus University Hospital
city: Odense
country: Denmark
facility: Department of Cardiology, Odense University Hospital
city: Roskilde
country: Denmark
facility: Department of Cardiology, Zealand University Hospital
city: Viborg
country: Denmark
facility: Department of Cardiology, Regional Hospital Viborg
Study officials:
References: