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

NCT05569382 | Recruiting Phase 4

• 2 other identifiers: 490-73-67952021-006953-77
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 4

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.

Conditions

Non-obstructive Hypertrophic Cardiomyopathy

Keywords

Hypertrophic cardiomyopathy; Bisoprolol; Verapamil; Beta Blocker; Calcium-channel Blocker

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (24)

• Kansas City Cardiomyopathy Questionnaire (KCCQ) score

  Changes will be evaluated at day 21 in each treatment arm

• New York Heart Association (NYHA) functional classification

  Changes will be evaluated at day 21 in each treatment arm

• Canadian Cardiovascular Society (CCS) class

  Changes will be evaluated at day 21 in each treatment arm

• Pro-BNP/BNP

  Changes will be evaluated at day 21 in each treatment arm

• High sensitive Troponin I/Troponin T

  Changes will be evaluated at day 21 in each treatment arm

Study Arms (3)

Verapamil

ACTIVE COMPARATOR

Maximal tolerable dose (up to 360 mg per day)

Drug: Verapamil

Bisoprolol

ACTIVE COMPARATOR

Maximal tolerable dose (up to 7,5 mg per day)

Drug: Bisoprolol

Placebo

PLACEBO COMPARATOR

Matching placebo

Drug: Placebo

Interventions

Verapamil DRUG

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

Also known as: Isoptin Retard 240 MG, Verapamil Hydrochloride 240 MG

Verapamil

Bisoprolol DRUG

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

Also known as: Bisoprolol "Krka" 2.5 MG, Bisoprolol Fumarate 2.5 MG

Bisoprolol

Placebo DRUG

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

Also known as: Placebo oral capsule

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Morten Steen Kvistholm Jensen: lead
• Viborg Regional Hospital: collaborator
• Zealand University Hospital: collaborator
• Odense University Hospital: collaborator

Study Sites (4)

Department of Cardiology, Aarhus University Hospital

Aarhus N, 8200, Denmark

RECRUITING

Department of Cardiology, Odense University Hospital

Odense, 5000, Denmark

RECRUITING

Department of Cardiology, Zealand University Hospital

Roskilde, 4000, Denmark

NOT YET RECRUITING

Department of Cardiology, Regional Hospital Viborg

Viborg, 8800, Denmark

NOT YET RECRUITING

MeSH Terms

Conditions

Cardiomyopathy, Hypertrophic

Interventions

Verapamil; Bisoprolol

Condition Hierarchy (Ancestors)

Cardiomyopathies; Heart Diseases; Cardiovascular Diseases; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Aortic Valve Disease; Heart Valve Diseases

Intervention Hierarchy (Ancestors)

Phenethylamines; Ethylamines; Amines; Organic Chemicals; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Propanols

Central Study Contacts

Morten SK Jensen

CONTACT

004540145482; morten.jensen@rm.dk

Louise Bjerregaard

CONTACT

004540429833; lbjer@clin.au.dk

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Consultant, PhD, Associated professor

Model Details: 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.

Study Record Dates

• First Submitted: October 4, 2022
• First Posted: October 6, 2022
• Study Start: August 10, 2022
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: March 20, 2025

Record last verified: 2025-03

Locations

DK (4)