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

Non-obstructive Hypertrophic Cardiomyopathy Clinical Trial

— TEMPO II  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05569382
• Other study ID #: 490-73-6795
• Secondary ID: 2021-006953-77
• Status: Recruiting
• Phase: Phase 4
• Start date: August 10, 2022
• Est. completion date: June 1, 2027

Study information

• Verified date: June 2024
• Source: Aarhus University Hospital Skejby
• Contact: Morten SK Jensen
• Phone: 004540145482
• Email: morten.jensen[@]rm.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: June 1, 2027
• Est. primary completion date: June 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cardiomyopathies
• Cardiomyopathy, Hypertrophic
• Hypertrophy
• Non-obstructive Hypertrophic Cardiomyopathy

Intervention

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
• 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

Locations

Country	Name	City	State
Denmark	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

Sponsors (4)

Lead Sponsor	Collaborator
Morten Steen Kvistholm Jensen	Odense University Hospital, Viborg Regional Hospital, Zealand University Hospital

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	Kansas City Cardiomyopathy Questionnaire (KCCQ) score	Changes in KCCQ assessed by clinical evaluation	Changes will be evaluated at day 21 in each treatment arm
Secondary	New York Heart Association (NYHA) functional classification	Changes in NYHA class assessed by clinical evaluation	Changes will be evaluated at day 21 in each treatment arm
Secondary	Canadian Cardiovascular Society (CCS) class	Changes in CCS class assessed by clinical evaluation	Changes will be evaluated at day 21 in each treatment arm
Secondary	Pro-BNP/BNP	Changes in level of Pro-BNP/BNP in blood sample	Changes will be evaluated at day 21 in each treatment arm
Secondary	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
Secondary	Metabolic equivalent of task (METs)	Changes in METs measured during cardiopulmonary exercise test	Changes will be evaluated at day 21 in each treatment arm
Secondary	Recovery time	Changes in recovery time measured during cardiopulmonary exercise test	Changes will be evaluated at day 21 in each treatment arm
Secondary	VO2 max Anaerobic threshold	Changes in VO2 max at anaerobic threshold measured during cardiopulmonary exercise test	Changes will be evaluated at day 21 in each treatment arm
Secondary	Percent predicted VO2 max	Changes in percent predicted VO2 max measured during cardiopulmonary exercise test	Changes will be evaluated at day 21 in each treatment arm
Secondary	Ventilatory equivalent for carbon dioxide VE/VCO2	Changes in VE/VCO2 measured during cardiopulmonary exercise test	Changes will be evaluated at day 21 in each treatment arm
Secondary	Echocardiographic 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
Secondary	Echocardiographic global longitudinal strain (GLS) for LV function	Changes in GLS measured during echocardiography	Changes will be evaluated at day 21 in each treatment arm
Secondary	Echocardiographic left ventricular outflow tract time velocity intergral (LVOT VTI) for LV function	Changes in LVOT VTI measured during echocardiography	Changes will be evaluated at day 21 in each treatment arm
Secondary	Echocardiographic dimension of left atrial	Changes in left atrial dimension measured during echocardiography	Changes will be evaluated at day 21 in each treatment arm
Secondary	Episodes of atrial fibrillation (AFIB) on Holter monitoring	Changes in episodes of AFIB measured during Holter monitoring	Changes will be evaluated at day 21 +7 days in each treatment arm
Secondary	Number of ventricular ectopic beats on Holter monitoring	Changes in number of ventricular ectopic beats measured during Holter monitoring	Changes will be evaluated at day 21 +7 days in each treatment arm
Secondary	Left ventricular systolic function on Cardiac MRI	Changes in left ventricular systolic function on Cardiac MRI	Changes will be evaluated at day 21 in each treatment arm
Secondary	Right ventricular dimensions on Cardiac MRI	Changes in right ventricular dimensions on Cardiac MRI	Changes will be evaluated at day 21 in each treatment arm
Secondary	Right ventricular systolic function on Cardiac MRI	Changes in right ventricular systolic function on Cardiac MRI	Changes will be evaluated at day 21 in each treatment arm
Secondary	Stroke volume (Aortic flow) on Cardiac MRI	Changes in stroke volume (Aortic flow) on Cardiac MRI	Changes will be evaluated at day 21 in each treatment arm
Secondary	Coronary sinus flow on Cardiac MRI	Changes in coronary sinus flow on Cardiac MRI	Changes will be evaluated at day 21 in each treatment arm
Secondary	Dimension of inferior and superior caval vein on Cardiac MRI	Changes in dimension of inferior and superior caval vein on Cardiac MRI	Changes will be evaluated at day 21 in each treatment arm
Secondary	Dimension of left atrium on cardiac MRI	Changes in dimension of left atrium on cardiac MRI	Changes will be evaluated at day 21 in each treatment arm
Secondary	Sex specific analyses of outcome measures	Changes in outcome measures between male and female	Changes will be evaluated at day 21 in each treatment arm