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The Effect of Metoprolol in Patients With Hypertrophic Obstructive Cardiomyopathy. (TEMPO)

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ClinicalTrials.gov Identifier: NCT03532802
Recruitment Status : Recruiting
First Posted : May 22, 2018
Last Update Posted : May 22, 2018
Sponsor:
Information provided by (Responsible Party):
Steen Hvitfeldt Poulsen, Aarhus University Hospital Skejby

Brief Summary:
Hypertrophic obstructive cardiomyopathy (HOCM) patients often develop disabling symptoms of heart failure. Current treatment strategies are predicated on the empirical use of long-standing drugs, such as beta-adrenergics, although with little evidence supporting their clinical benefit in this disease. Metoprolol is currently the most widely used beta-blocker in symptomatic HOCM patients, but a randomized, placebo-controlled trial, that looks at the effect in HOCM patients has never been conducted. No studies of HOCM combine invasive pressure measurement with exercise and echocardiography. All previous studies, both invasive and echocardiographic, have been conducted during rest, and not during exercise. Symptoms of HOCM patients are function-related, and exercise testing is essential to assess the condition and the effect of drugs.

Condition or disease Intervention/treatment Phase
Hypertrophic Cardiomyopathy Drug: Metoprolol Succinate Drug: Placebo oral capsule Phase 2

Detailed Description:

Background Hypertrophic cardiomyopathy (HCM) is characterized by an increase in left-ventricular wall thickness, typically localized at the interventricular septum. The hypertrophy can increase to an extend that causes a dynamic obstruction of the left ventricular outflow tract (LVOTO); these patients have hypertrophic obstructive cardiomyopathy (HOCM). Due to the obstruction, patients develop high interventricular pressure gradients, which may overtime become detrimental to the left ventricular function.

HOCM patients often develop disabling symptoms of heart failure. Current treatment strategies are predicated on the empirical use of long-standing drugs, such as beta-adrenergics, although with little evidence supporting their clinical benefit in this disease. Metoprolol is currently the most widely used beta-blocker in symptomatic HOCM patients, but a randomized, placebo-controlled trial, that looks at the effect in HOCM patients has never been conducted. No studies of HOCM combine invasive pressure measurement with exercise and echocardiography. All previous studies, both invasive and echocardiographic, have been conducted during rest, and not during exercise. Symptoms of HOCM patients are function-related, and exercise testing is essential to assess the condition and the effect of drugs.

Objective We want to quantify the effects of metoprolol on myocardial function and perfusion, hemodynamics and heart failure symptoms in patients with HOCM.

Hypotheses

Primary

• Metoprolol treatment reduces ∆ pulmonary capillary wedge pressure (PCWP) (rest-exercise)

Secondary

  • Metoprolol treatment reduces PCWP at rest
  • Metoprolol treatment increases maximal oxygen consumption (VO2-max) .
  • Metoprolol treatment reduces LVOT gradient during exercise
  • Metoprolol treatment increases the coronary flow reserve
  • Metoprolol treatment decrease External Work
  • Metoprolol treatment reduces heart failure symptoms, estimated by the Kansas City Cardiomyopathy Questionnaire

Design and methods

A randomized, double-blinded, placebo-controlled, crossover study. We will examine 32 patients with HOCM both during treatment with metoprolol and placebo.

Patients will be examined in a set-up of simultaneous 1) right heart catheterization 2) cardiopulmonary exercise test and 3) transthoracic echocardiography. The set-up allows us to evaluate the hemodynamic values during rest and maximum exercise.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: The Effect of Metoprolol on Myocardial Function, Perfusion, Hemodynamics and Heart Failure Symptoms in Patients With Hypertrophic Obstructive Cardiomyopathy.
Actual Study Start Date : May 1, 2018
Estimated Primary Completion Date : December 1, 2019
Estimated Study Completion Date : May 1, 2021


Arm Intervention/treatment
Active Comparator: Metoprolol Succinate
Metoprololsuccinat
Drug: Metoprolol Succinate
  1. week: uptitration with 50 mg capsules per day, until maximum dosage of 150 mg´s/day.
  2. week: steady state treatment with the maximum tolerated dose of the 1.week.

Placebo Comparator: Placebo oral capsule
Placebo
Drug: Placebo oral capsule
  1. week: uptitration with 1 capsule per day, until maximum tolerated dosage of 3 capsules/day.
  2. week: steady state treatment with the maximum tolerated dose of the 1. week




Primary Outcome Measures :
  1. ∆Pulmonary capillary wedge pressure (rest-exercise) [ Time Frame: Changes will be evaluated after an expected average of 2 weeks of treatment in both treatment arms ]
    Changes in pulmonary capillary wedge pressure in mmHg from rest to exercise, measured during right heart catheterization


Secondary Outcome Measures :
  1. Pulmonary capillary wedge pressure at rest [ Time Frame: Changes will be evaluated after an expected average of 2 weeks of treatment in both treatment arms ]
    Changes in pulmonary capillary wedge pressure in mmHg during rest, measured during right heart catheterization

  2. VO2-max [ Time Frame: Changes will be evaluated after an expected average of 2 weeks of treatment in both treatment arms ]
    Changes in maximal oxygen consumption (L/min) measured during cardiopulmonary exercise test

  3. LVOT gradient during maximum exercise [ Time Frame: Changes will be evaluated after an expected average of 2 weeks of treatment in both treatment arms ]
    Changes of the LVOT gradient during maximum exercise, measured in mmHg during 2D echocardiography

  4. Coronary flow reserve [ Time Frame: Changes will be evaluated after an expected average of 2 weeks of treatment in both treatment arms ]
    Changes in the ratio of maximum coronary blood flow (induced by infusion of adenosin) to resting coronary blood flow, estimated by 2D doppler echocardiography

  5. N-terminal prohormone of brain natriuretic peptide [ Time Frame: Changes will be evaluated after an expected average of 2 weeks of treatment in both treatment arms ]
    Changes in level of N-terminal prohormone of brain natriuretic peptide (ng/L) in blood sample

  6. Changes of symptoms and quality of life with Kansas City Cardiomyopathy Questionnaire [ Time Frame: Changes will be evaluated after an expected average of 2 weeks of treatment in both treatment arms ]
    Changes of symptoms and quality of life with Kansas City Cardiomyopathy Questionnaire assessed by clinical evaluation



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Wall thickness ≥ 15 mm in one or more myocardial segments that is not explained by loading conditions.
  • LVOT gradient > 30 mmHg at rest and/or > 50 mmHg at Valsalva's maneuver or exercise
  • New York Heart Association Functional class (NYHA) ≥ II

Exclusion Criteria:

  • Age < 18 years
  • Known allergy to trial medicine
  • Contraindications to beta-blocker treatment
  • Contraindications to Magnetic resonans scan, including contraindication to the contrast agent gadolinium.
  • Female patients who are pregnant (positive plasma-HCG), breastfeeding or of child-bearing potential while not practicing effective chemical contraceptive hormones.
  • In case of patients having a pacemaker, they may not be pace-dependent.
  • Treatment with Amiodarone
  • Atrial fibrillation/flutter at the time of examination
  • Bradycardia < 49 beats/min
  • Systolic blood pressure < 100 mmHg
  • Trifascicular block
  • Previous transcoronary ablation of septum hypertrophy (TASH) or myectomy
  • Current abuse of alcohol and/or drugs
  • Significant co-morbidity or issues that makes the patient unsuitable for participation, judged by the investigator
  • Patients who cannot give valid consent (e.g. mental illness or dementia)
  • Patients who do not understand danish

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03532802


Contacts
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Contact: Anne Dybro, MD 0045-26112115 annedybr@rm.dk
Contact: Steen Hvitfeldt Poulsen, DMSc 0045-30922309 steepoul@rm.dk

Locations
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Denmark
Aarhus University Hospital, Department of Cardiology Recruiting
Aarhus N, Danmark, Denmark, 8200
Contact: Anne Dybro, MD    26112115    annedybr@rm.dk   
Contact: Steen Hvitfeldt Poulsen, DMSc    0045-30922309    steepoul@rm.dk   
Sponsors and Collaborators
Steen Hvitfeldt Poulsen
Investigators
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Study Director: Steen Hvitfeldt Poulsen, MD Aa
Study Director: Morten Kvistholm Jensen, MD, PhD Aarhus University Hospital, Department of Cardiology
Study Director: Torsten Bloch Rasmussen, MD, PhD Aarhus University Hospital, Department of Cardiology

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Responsible Party: Steen Hvitfeldt Poulsen, Senior consultant, DMSc, Aarhus University Hospital, Aarhus University Hospital Skejby
ClinicalTrials.gov Identifier: NCT03532802     History of Changes
Other Study ID Numbers: 1-10-72-441-17
First Posted: May 22, 2018    Key Record Dates
Last Update Posted: May 22, 2018
Last Verified: May 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Steen Hvitfeldt Poulsen, Aarhus University Hospital Skejby:
metoprolol
heart diseases
cardiovascular diseases
ventricular outflow obstruction
hemodynamics
Additional relevant MeSH terms:
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Cardiomyopathies
Cardiomyopathy, Hypertrophic
Hypertrophy
Heart Diseases
Cardiovascular Diseases
Pathological Conditions, Anatomical
Aortic Stenosis, Subvalvular
Aortic Valve Stenosis
Heart Valve Diseases
Metoprolol
Anti-Arrhythmia Agents
Antihypertensive Agents
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action