Randomized Trial to Examine a Differential Therapeutic Response in Symptomatic Patients With Non-obstructive Coronary Artery Disease

NCT ID: NCT05294887

Last Updated: 2022-03-24

Study Results

Results pending

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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Recruitment Status

UNKNOWN

Clinical Phase

PHASE4

Total Enrollment

132 participants

Study Classification

INTERVENTIONAL

Study Start Date

2022-03-04

Study Completion Date

2024-06-30

Brief Summary

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EXAMINE-CAD-DZHK22 is a prospective, randomized, double-blind, placebo-controlled, crossover trial investigating the efficacy of beta blocker (bisoprolol) and calcium channel blocker (diltiazem) therapy in symptomatic patients with non-obstructed coronary arteries according to coronary physiological testing results.

Detailed Description

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Patients presenting with recurrent angina but non-obstructed coronary arteries are increasingly recognized and have a high morbidity and symptomatic burden. These patients are often misdiagnosed and discharged without further investigation or treatment. Current European Society of Cardiology (ESC) guidelines for the management of patients with chronic coronary syndromes recommend beta blockers or calcium channel blockers, depending on the presence of abnormal vasodilatation or abnormal vasoconstriction. Scientific evidence to support this recommendation, however, is scarce and no randomized clinical trial of this differential therapy has been performed in these patients. The aim of the EXAMINE-CAD-DZHK22 trial is therefore to compare for the first time the efficacy of beta blocker (bisoprolol) and calcium channel blocker (diltiazem) therapy in reducing angina symptoms in symptomatic patients with non-obstructed coronary arteries according to coronary physiology testing results. This study is the first to investigate whether coronary physiology testing can guide therapeutic management of these patients depending on whether abnormalities of vasodilatation or vasoconstriction are present. The EXAMINE-CAD-DZHK22 trial will thus fill an important knowledge and evidence gap in the treatment of these highly symptomatic patients, and has the potential to pave the way for future large-scale clinical trials in symptomatic patients with non-obstructed coronary arteries.

Conditions

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Coronary Microvascular Dysfunction Microvascular Angina Vasospasm, Coronary Vasospastic Angina Prinzmetal Angina Coronary Artery Disease

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors
Subjects will be randomly assigned to 1 of 6 possible treatment sequences. All treatment sequences will include the consecutive treatment with bisoprolol, diltiazem, and placebo.

Study Groups

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bisoprolol first, diltiazem second

Crossover Design: bisoprolol first, diltiazem second, placebo third

Group Type EXPERIMENTAL

Bisoprolol

Intervention Type DRUG

beta-adrenergic receptor blocker

Diltiazem

Intervention Type DRUG

calcium channel blocker

Placebo

Intervention Type DRUG

Placebo

bisoprolol first, placebo second

Crossover Design: bisoprolol first, placebo second, diltiazem third

Group Type EXPERIMENTAL

Bisoprolol

Intervention Type DRUG

beta-adrenergic receptor blocker

Diltiazem

Intervention Type DRUG

calcium channel blocker

Placebo

Intervention Type DRUG

Placebo

diltiazem first, bisoprolol second

Crossover Design: diltiazem first, bisoprolol second, placebo third

Group Type EXPERIMENTAL

Bisoprolol

Intervention Type DRUG

beta-adrenergic receptor blocker

Diltiazem

Intervention Type DRUG

calcium channel blocker

Placebo

Intervention Type DRUG

Placebo

diltiazem first, placebo second

Crossover Design: diltiazem first, placebo second, bisoprolol third

Group Type EXPERIMENTAL

Bisoprolol

Intervention Type DRUG

beta-adrenergic receptor blocker

Diltiazem

Intervention Type DRUG

calcium channel blocker

Placebo

Intervention Type DRUG

Placebo

placebo first, bisoprolol second

Crossover Design: placebo first, bisoprolol second, diltiazem third

Group Type EXPERIMENTAL

Bisoprolol

Intervention Type DRUG

beta-adrenergic receptor blocker

Diltiazem

Intervention Type DRUG

calcium channel blocker

Placebo

Intervention Type DRUG

Placebo

placebo first, diltiazem second

Crossover Design: placebo first, diltiazem second, bisoprolol third

Group Type EXPERIMENTAL

Bisoprolol

Intervention Type DRUG

beta-adrenergic receptor blocker

Diltiazem

Intervention Type DRUG

calcium channel blocker

Placebo

Intervention Type DRUG

Placebo

Interventions

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Bisoprolol

beta-adrenergic receptor blocker

Intervention Type DRUG

Diltiazem

calcium channel blocker

Intervention Type DRUG

Placebo

Placebo

Intervention Type DRUG

Other Intervention Names

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beta blocker

Eligibility Criteria

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Inclusion Criteria

* Age 18 - 85 years
* Recurrent angina symptoms provoked by exercise and/or repeated attacks of angina at rest (both at least for 4 weeks)
* Absence of flow-limiting coronary artery stenosis (as defined by any coronary artery diameter reduction \>50% or fractional flow reserve ≤0.80)
* Left ventricular ejection fraction (LVEF) \>50%
* Written informed consent

Exclusion Criteria

* Pregnancy, planned pregnancy, or breast-feeding
* Female patients of childbearing potential who are unwilling to use a highly effective contraception method during trial participation according to CTFG. In addition, a negative serum or urine pregnancy test must be available prior to randomization.
* Expected life expectancy \<1 year
* Contraindications to withholding nitrates, calcium channel blockers, and beta blockers for 48 hours before invasive coronary reactivity testing (e.g. clinical need for rate control in case of permanent atrial fibrillation, recurrent angina symptoms without any possibility to wihthold ongoing medication)
* Known hypersensitivity or contraindication to bisoprolol or diltiazem or any of its excipients.
* Concomitant therapy with systemic drugs that are strong inhibitors of both CYP3A4 and P-gp (azole antimycotics such as ketoconazole and itraconazole or HIV protease inhibitors such as ritonavir)
* Concomitant therapy with drugs that are strong CYP3A4 inducers (e.g. carbamazepine, phenytoin, rifampicin, St. John's wort)
* Bradycardia (\<50/min) at time of randomization
* Symptomatic hypotension (\<100 mmHg) at time of randomization
* Cardiogenic shock
* Second and third degree atrioventricular block, sick sinus syndrome, sinoatrial block
* Severe valvular heart disease (grade III)
* Any cardiomyopathy including those with preserved left ventricular ejection fraction (LVEF)
* Chronic obstructive pulmonary disease
* Severe bronchial asthma
* Metabolic acidosis at time of randomization
* Renal failure (creatinine \>2.0 mg/dL)
* N-terminal pro B-type natriuretic peptide (NT-proBNP) \>300 ng/L
* Known significant liver disease (e.g. acute hepatitis, chronic active hepatitis, cirrhosis) which is associated with moderate or severe hepatic impairment (alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥2.0 upper limit of normal (ULN))
* Untreated pheochromocytoma
* Late stage of peripheral arterial disease or Raynaud's syndrome
* Participation in another clinical trial according to AMG or MPG at the time of randomization and the duration of this trial
* Patients who are unwilling to consent to saving and propagation of pseudonymized medical data for study reasons
* Persons who are legally detained in an official institution
* Persons likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of patient's and investigator's knwoledge
* Persons who may dependent on the Sponsor, the Investigator or the trial sites, are not eligible to enter the trial
* Active coronavirus disease 2019 (COVID-19) at time of randomization
Minimum Eligible Age

18 Years

Maximum Eligible Age

85 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)

OTHER

Sponsor Role collaborator

Charite University, Berlin, Germany

OTHER

Sponsor Role lead

Responsible Party

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Ulf Landmesser

Prof. Dr.

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Ulf Landmesser, Prof. Dr.

Role: STUDY_CHAIR

Charité University, Berlin, Germany

Barbara E Stähli, Prof. Dr.

Role: STUDY_CHAIR

Universitätsspital Zürich

Locations

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Kerckhoff-Klinik gGmbH

Bad Nauheim, , Germany

Site Status NOT_YET_RECRUITING

Herz- und Diabeteszentrum NRW

Bad Oeynhausen, , Germany

Site Status NOT_YET_RECRUITING

Charité University Medicine Berlin, Campus Benjamin Franklin

Berlin, , Germany

Site Status RECRUITING

Universitätsklinikum Erlangen

Erlangen, , Germany

Site Status NOT_YET_RECRUITING

Universitätsklinikum Frankfurt

Frankfurt, , Germany

Site Status NOT_YET_RECRUITING

Universitäres Herz- und Gefäßzentrum UKE Hamburg

Hamburg, , Germany

Site Status NOT_YET_RECRUITING

Universitätsklinikum Heidelberg

Heidelberg, , Germany

Site Status NOT_YET_RECRUITING

Universitätsklinikum Schleswig-Holstein, Campus Kiel

Kiel, , Germany

Site Status NOT_YET_RECRUITING

Universitätsklinikum Leipzig

Leipzig, , Germany

Site Status NOT_YET_RECRUITING

Universitätsmedizin der Johannes Gutenberg-Universität Mainz

Mainz, , Germany

Site Status NOT_YET_RECRUITING

Universitätsmedizin Mannheim

Mannheim, , Germany

Site Status NOT_YET_RECRUITING

Deutsches Herzzentrum München des Freistaates Bayern - Klinik an der Technischen Universität München

München, , Germany

Site Status NOT_YET_RECRUITING

Robert-Bosch-Krankenhaus

Stuttgart, , Germany

Site Status NOT_YET_RECRUITING

Inselspital, Universitätsspital Bern

Bern, , Switzerland

Site Status NOT_YET_RECRUITING

Universitäres Herzzentrum Zürich, Universitätsspital Zürich

Zurich, , Switzerland

Site Status NOT_YET_RECRUITING

Countries

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Germany Switzerland

Central Contacts

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Aslihan Erbay, MD

Role: CONTACT

+49 30 450 513 653

Facility Contacts

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Roland Klingenberg, PD Dr.

Role: primary

Tanja Rudolph, Prof. Dr.

Role: primary

Ulf Landmesser, Prof. Dr.

Role: primary

Luise Gaede, PD Dr.

Role: primary

Stephan Fichtlscherer, Prof. Dr.

Role: primary

Peter Clemmensen, Prof. Dr.

Role: primary

Manuela Licka, Dr.

Role: primary

Matthias Lutz, PD Dr.

Role: primary

Karsten Lenk, PD Dr.

Role: primary

Tommaso Gori, Prof. Dr.

Role: primary

Ibrahim Akin, Prof. Dr.

Role: primary

Jens Wiebe, PD Dr.

Role: primary

Ong Peter, Prof. Dr.

Role: primary

Lorenz Räber, Prof. Dr.

Role: primary

Barbara Stähli, Prof. Dr.

Role: primary

Other Identifiers

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2020-004717-12

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

EXAMINE-CAD-DZHK22

Identifier Type: -

Identifier Source: org_study_id

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