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Coronary Microvascular DysfunctionPhase 4EXAMINE-CADNCT05294887

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

A Phase 4 study testing Bisoprolol and Diltiazem in people with Coronary Microvascular Dysfunction and Microvascular Angina, run by Charite University, Berlin, Germany at 15 sites in 2 countries.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 to 85 years
What is being tested?
Bisoprolol and Diltiazem
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
132 participants
Where
15 sitesin 2 countries
Study dates
4 Mar 2022to Jun 2024
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 85 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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)
Show all 27Show fewer
  • 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

Trial locations and contacts

15 sites in 2 countries.

Aslihan Erbay, MD contact

+49 30 450 513 653

examine-cad@charite.de

15 sites in 2 countries

Germany13 sites, 13 recruiting

  • Kerckhoff-Klinik gGmbH

    Bad Nauheim, 61231

    Roland Klingenberg, PD Dr.

    Not yet recruiting

  • Herz- und Diabeteszentrum NRW

    Bad Oeynhausen, 32545

    Tanja Rudolph, Prof. Dr.

    Not yet recruiting

  • Charité University Medicine Berlin, Campus Benjamin Franklin

    Berlin, 12203

    Ulf Landmesser, Prof. Dr.

    Recruiting

  • Universitätsklinikum Erlangen

    Erlangen, 91054

    Luise Gaede, PD Dr.

    Not yet recruiting

  • Universitätsklinikum Frankfurt

    Frankfurt, 60590

    Stephan Fichtlscherer, Prof. Dr.

    Not yet recruiting

  • Universitäres Herz- und Gefäßzentrum UKE Hamburg

    Hamburg, 20246

    Peter Clemmensen, Prof. Dr.

    Not yet recruiting

  • Universitätsklinikum Heidelberg

    Heidelberg, 69120

    Manuela Licka, Dr.

    Not yet recruiting

  • Universitätsklinikum Schleswig-Holstein, Campus Kiel

    Kiel, 24105

    Matthias Lutz, PD Dr.

    Not yet recruiting

  • Universitätsklinikum Leipzig

    Leipzig, 04103

    Karsten Lenk, PD Dr.

    Not yet recruiting

  • Universitätsmedizin der Johannes Gutenberg-Universität Mainz

    Mainz, 55131

    Tommaso Gori, Prof. Dr.

    Not yet recruiting

  • Universitätsmedizin Mannheim

    Mannheim, 68167

    Ibrahim Akin, Prof. Dr.

    Not yet recruiting

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

    München, 80636

    Jens Wiebe, PD Dr.

    Not yet recruiting

  • Robert-Bosch-Krankenhaus

    Stuttgart, 70376

    Ong Peter, Prof. Dr.

    Not yet recruiting

Other trials in Germany

Switzerland2 sites, 2 recruiting

  • Inselspital, Universitätsspital Bern

    Bern, 3010

    Lorenz Räber, Prof. Dr.

    Not yet recruiting

  • Universitäres Herzzentrum Zürich, Universitätsspital Zürich

    Zurich, 8091

    Barbara Stähli, Prof. Dr.

    Not yet recruiting

Other trials in Switzerland

About this study

Official title: 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.

Read the 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.

Being tested
Bisoprolol, Diltiazem, Placebo
Keywords
Coronary Microvascular Dysfunction, Microvascular Angina, Coronary Vasospasm, Vasospastic Angina, Beta Blocker, Calcium Channel Blocker
Medical subject headings
Microvascular Angina, Coronary Vasospasm, Angina Pectoris, Variant, Coronary Artery Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BisoprololDrug

    Also called beta blocker

    beta-adrenergic receptor blocker

  • DiltiazemDrug

    calcium channel blocker

  • PlaceboDrug

    Placebo

Study groups in NCT05294887
Study groupRoleWhat they receive
bisoprolol first, diltiazem secondExperimentalCrossover Design: bisoprolol first, diltiazem second, placebo third
Receives: Drug: Bisoprolol; Drug: Diltiazem; Drug: Placebo
bisoprolol first, placebo secondExperimentalCrossover Design: bisoprolol first, placebo second, diltiazem third
Receives: Drug: Bisoprolol; Drug: Diltiazem; Drug: Placebo
diltiazem first, bisoprolol secondExperimentalCrossover Design: diltiazem first, bisoprolol second, placebo third
Receives: Drug: Bisoprolol; Drug: Diltiazem; Drug: Placebo
diltiazem first, placebo secondExperimentalCrossover Design: diltiazem first, placebo second, bisoprolol third
Receives: Drug: Bisoprolol; Drug: Diltiazem; Drug: Placebo
placebo first, bisoprolol secondExperimentalCrossover Design: placebo first, bisoprolol second, diltiazem third
Receives: Drug: Bisoprolol; Drug: Diltiazem; Drug: Placebo
placebo first, diltiazem secondExperimentalCrossover Design: placebo first, diltiazem second, bisoprolol third
Receives: Drug: Bisoprolol; Drug: Diltiazem; Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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)

    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.

    Measured: 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 outcomes (13)

  1. SAQ angina stability scale

    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.

    Measured: 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

  2. SAQ angina frequency scale

    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.

    Measured: 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

  3. SAQ treatment satisfaction scale

    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.

    Measured: 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

  4. SAQ physical limitation scale

    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.

    Measured: 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

  5. SAQ quality of life

    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.

    Measured: 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

  6. Duke Activity Status Index (DASI)

    Assessment of functional capacity of patients with cardiovascular disease

    Measured: 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

  7. Rose dyspnea scale

    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.

    Measured: 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

  8. Angina diary (Angina episodes per week)

    Assessment of angina frequency

    Measured: 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

  9. Angina diary (nitroglycerin use per week))

    Assessment of need for nitroglycerine

    Measured: 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

  10. Quality of Life (Short Form 36 health survey questionnaire)

    Evaluation of health-related quality of life

    Measured: 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

  11. Psychological symptoms as assessed by Patient Health Questionnaire (PHQ-9)

    Assessment of symptoms for depression in patients with physical illness or physical complaints

    Measured: 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

  12. Psychological symptoms as assessed by the Hospital Anxiety Depression Scale (HADS))

    Assessment of symptoms for depression and anxiety in patients with physical illness or physical complaints

    Measured: 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

  13. Functional capacity as assessed by bicycle exercise testing

    Assessment of functional capacity in bicycle exercise testing (i.e. maximum load capacity in watt)

    Measured: from baseline (visit 1) to the end of each treatment period (4 weeks, 10 weeks, 16 weeks)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Mar 2022
  2. Study start4 Mar 2022
  3. Primary completionJun 2024 (estimated)
  4. Study completionJun 2024 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Crossover
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
132 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05294887
Sponsor's protocol ID
EXAMINE-CAD-DZHK22
Other IDs
2020-004717-12
Acronym
EXAMINE-CAD
Status last verified
Mar 2022
First submitted
28 Feb 2022
Last updated
24 Mar 2022
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Bisoprolol and Diltiazem in people with Coronary Microvascular Dysfunction and Microvascular Angina, run by Charite University, Berlin, Germany at 15 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 24 Mar 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 15 sites in Germany, Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Aslihan Erbay, MD (+49 30 450 513 653, examine-cad@charite.de), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05294887.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Mar 2022.

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