Treatment Effects of Bisoprolol and Verapamil in Symptomatic Patients With Non-obstructive Hypertrophic Cardiomyopathy
NCT ID: NCT05569382
Last Updated: 2025-03-20
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE4
100 participants
INTERVENTIONAL
2022-08-10
2027-12-31
Brief Summary
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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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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
CROSSOVER
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.
TREATMENT
TRIPLE
Study Groups
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Verapamil
Maximal tolerable dose (up to 360 mg per day)
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
Bisoprolol
Maximal tolerable dose (up to 7,5 mg per day)
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
Placebo
Matching placebo
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
Interventions
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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
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
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 Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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.
* 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.
18 Years
ALL
No
Sponsors
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Viborg Regional Hospital
OTHER
Zealand University Hospital
OTHER
Odense University Hospital
OTHER
Morten Steen Kvistholm Jensen
OTHER
Responsible Party
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Morten Steen Kvistholm Jensen
Consultant, PhD, Associated professor
Locations
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Department of Cardiology, Aarhus University Hospital
Aarhus N, , Denmark
Department of Cardiology, Odense University Hospital
Odense, , Denmark
Department of Cardiology, Zealand University Hospital
Roskilde, , Denmark
Department of Cardiology, Regional Hospital Viborg
Viborg, , Denmark
Countries
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Central Contacts
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Facility Contacts
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Lotte Saaby
Role: primary
Martin Snoer
Role: primary
Erik S Nielsen
Role: primary
Other Identifiers
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2021-006953-77
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
490-73-6795
Identifier Type: -
Identifier Source: org_study_id
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