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

March 15, 2022 updated by: Ulf Landmesser, Charite University, Berlin, Germany

First Prospective Randomized Trial to Examine a Differential Therapeutic Response in Symptomatic Patients With Non-obstructive Coronary Artery Disease After Coronary Physiological Testing

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
132

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • Germany
      • Bad Nauheim, Germany, 61231
        • Not yet recruiting
        • Kerckhoff-Klinik gGmbH
        • Contact:
          • Roland Klingenberg, PD Dr.
      • Bad Oeynhausen, Germany, 32545
        • Not yet recruiting
        • Herz- und Diabeteszentrum NRW
        • Contact:
          • Tanja Rudolph, Prof. Dr.
      • Berlin, Germany, 12203
        • Recruiting
        • Charité University Medicine Berlin, Campus Benjamin Franklin
        • Contact:
          • Ulf Landmesser, Prof. Dr.
      • Erlangen, Germany, 91054
        • Not yet recruiting
        • Universitätsklinikum Erlangen
        • Contact:
          • Luise Gaede, PD Dr.
      • Frankfurt, Germany, 60590
        • Not yet recruiting
        • Universitätsklinikum Frankfurt
        • Contact:
          • Stephan Fichtlscherer, Prof. Dr.
      • Hamburg, Germany, 20246
        • Not yet recruiting
        • Universitäres Herz- und Gefäßzentrum UKE Hamburg
        • Contact:
          • Peter Clemmensen, Prof. Dr.
      • Heidelberg, Germany, 69120
        • Not yet recruiting
        • Universitatsklinikum Heidelberg
        • Contact:
          • Manuela Licka, Dr.
      • Kiel, Germany, 24105
        • Not yet recruiting
        • Universitätsklinikum Schleswig-Holstein, Campus Kiel
        • Contact:
          • Matthias Lutz, PD Dr.
      • Leipzig, Germany, 04103
        • Not yet recruiting
        • Universitatsklinikum Leipzig
        • Contact:
          • Karsten Lenk, PD Dr.
      • Mainz, Germany, 55131
        • Not yet recruiting
        • Universitätsmedizin der Johannes Gutenberg-Universität Mainz
        • Contact:
          • Tommaso Gori, Prof. Dr.
      • Mannheim, Germany, 68167
        • Not yet recruiting
        • Universitätsmedizin Mannheim
        • Contact:
          • Ibrahim Akin, Prof. Dr.
      • München, Germany, 80636
        • Not yet recruiting
        • Deutsches Herzzentrum München des Freistaates Bayern - Klinik an der Technischen Universität München
        • Contact:
          • Jens Wiebe, PD Dr.
      • Stuttgart, Germany, 70376
        • Not yet recruiting
        • Robert-Bosch-Krankenhaus
        • Contact:
          • Ong Peter, Prof. Dr.
  • Switzerland
      • Bern, Switzerland, 3010
        • Not yet recruiting
        • Inselspital, Universitätsspital Bern
        • Contact:
          • Lorenz Räber, Prof. Dr.
      • Zürich, Switzerland, 8091
        • Not yet recruiting
        • Universitäres Herzzentrum Zürich, Universitätsspital Zürich
        • Contact:
          • Barbara Stähli, Prof. Dr.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 85 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: bisoprolol first, diltiazem second
Crossover Design: bisoprolol first, diltiazem second, placebo third
Drug: Placebo
Placebo
Drug: Bisoprolol
beta-adrenergic receptor blocker
Other Names:
  • beta blocker
Drug: Diltiazem
calcium channel blocker
Experimental: bisoprolol first, placebo second
Crossover Design: bisoprolol first, placebo second, diltiazem third
Drug: Placebo
Placebo
Drug: Bisoprolol
beta-adrenergic receptor blocker
Other Names:
  • beta blocker
Drug: Diltiazem
calcium channel blocker
Experimental: diltiazem first, bisoprolol second
Crossover Design: diltiazem first, bisoprolol second, placebo third
Drug: Placebo
Placebo
Drug: Bisoprolol
beta-adrenergic receptor blocker
Other Names:
  • beta blocker
Drug: Diltiazem
calcium channel blocker
Experimental: diltiazem first, placebo second
Crossover Design: diltiazem first, placebo second, bisoprolol third
Drug: Placebo
Placebo
Drug: Bisoprolol
beta-adrenergic receptor blocker
Other Names:
  • beta blocker
Drug: Diltiazem
calcium channel blocker
Experimental: placebo first, bisoprolol second
Crossover Design: placebo first, bisoprolol second, diltiazem third
Drug: Placebo
Placebo
Drug: Bisoprolol
beta-adrenergic receptor blocker
Other Names:
  • beta blocker
Drug: Diltiazem
calcium channel blocker
Experimental: placebo first, diltiazem second
Crossover Design: placebo first, diltiazem second, bisoprolol third
Drug: Placebo
Placebo
Drug: Bisoprolol
beta-adrenergic receptor blocker
Other Names:
  • beta blocker
Drug: Diltiazem
calcium channel blocker

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Change in angina symptom severity as measured by the Seattle Angina Questionnaire (SAQ) summary score from each period specific baseline to the end of this period (week 4)
Time Frame: from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
Assessment of angina symptom severity as measured by the SAQ summary score resulting from the SAQ physical limitation scale, SAQ angina frequency scale, and SAQ quality of life scale. The score ranges from 0 to 100, with the lower the score, the higher the symptom severity and limitations.
from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
SAQ angina stability scale
Time Frame: from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
Individual SAQ domain to evaluate the disease-specific health status with quantification of patients' symptoms of angina. The score ranges from 0 to 100, with the lower the score, the higher the symptom severity and limitations.
from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
SAQ angina frequency scale
Time Frame: from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
Individual SAQ domain to evaluate the disease-specific health status with quantification of patients' symptoms of angina. The score ranges from 0 to 100, with the lower the score, the higher the symptom severity and limitations.
from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
SAQ treatment satisfaction scale
Time Frame: from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
Individual SAQ domain to evaluate the disease-specific treatment satisfaction. The score ranges from 0 to 100, with the higher the score, the higher the treatment satisfaction.
from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
SAQ physical limitation scale
Time Frame: from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
Individual SAQ domain to evaluate the disease-specific health status with quantification of patients' symptoms of angina and the extent to which their angina affects their functioning. The score ranges from 0 to 100, with the lower the score, the higher the symptom severity and limitations.
from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
SAQ quality of life
Time Frame: from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
Individual SAQ domain to evaluate the disease-specific health status with the extent to which their angina affects their quality of life. The score ranges from 0 to 100, with the higher the score, the higher the quality of life.
from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
Duke Activity Status Index (DASI)
Time Frame: from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
Assessment of functional capacity of patients with cardiovascular disease
from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
Rose dyspnea scale
Time Frame: from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
Assessment of patients' dyspnea level with common activities. Scores range from 0 to 4, where 0 indicates no dyspnea with activity and 4 indicates significant limitations due to dyspnea.
from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
Angina diary (Angina episodes per week)
Time Frame: from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
Assessment of angina frequency
from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
Angina diary (nitroglycerin use per week))
Time Frame: from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
Assessment of need for nitroglycerine
from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
Quality of Life (Short Form 36 health survey questionnaire)
Time Frame: from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
Evaluation of health-related quality of life
from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
Psychological symptoms as assessed by Patient Health Questionnaire (PHQ-9)
Time Frame: from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
Assessment of symptoms for depression in patients with physical illness or physical complaints
from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
Psychological symptoms as assessed by the Hospital Anxiety Depression Scale (HADS))
Time Frame: from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
Assessment of symptoms for depression and anxiety in patients with physical illness or physical complaints
from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
Functional capacity as assessed by bicycle exercise testing
Time Frame: from baseline (visit 1) to the end of each treatment period (4 weeks, 10 weeks, 16 weeks)
Assessment of functional capacity in bicycle exercise testing (i.e. maximum load capacity in watt)
from baseline (visit 1) to the end of each treatment period (4 weeks, 10 weeks, 16 weeks)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Charite University, Berlin, Germany

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Chair: Ulf Landmesser, Prof. Dr., Charite University, Berlin, Germany
  • Study Chair: Barbara E Stähli, Prof. Dr., Universitätsspital Zürich

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
March 4, 2022

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 1, 2024

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 1, 2024

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
February 28, 2022

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 15, 2022

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
March 24, 2022

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 24, 2022

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 15, 2022

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • EXAMINE-CAD-DZHK22
  • 2020-004717-12 (EudraCT Number)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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