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

NCT05294887 | Unknown Phase 4 DMC

• 2 other identifiers: EXAMINE-CAD-DZHK222020-004717-12
• Study Type: interventional
• Target: 132
• Locations: 2 countries
• Sites: 15

Brief 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.

Conditions

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

Keywords

Coronary Microvascular Dysfunction; Microvascular Angina; Coronary Vasospasm; Vasospastic Angina; Beta Blocker; Calcium Channel Blocker

Outcome Measures

Primary Outcomes (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.

  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)

• SAQ angina stability scale

  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

  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

  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

  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

  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

Study Arms (6)

bisoprolol first, diltiazem second

EXPERIMENTAL

Crossover Design: bisoprolol first, diltiazem second, placebo third

Drug: Bisoprolol; Drug: Diltiazem; Drug: Placebo

bisoprolol first, placebo second

EXPERIMENTAL

Crossover Design: bisoprolol first, placebo second, diltiazem third

Drug: Bisoprolol; Drug: Diltiazem; Drug: Placebo

diltiazem first, bisoprolol second

EXPERIMENTAL

Crossover Design: diltiazem first, bisoprolol second, placebo third

Drug: Bisoprolol; Drug: Diltiazem; Drug: Placebo

diltiazem first, placebo second

EXPERIMENTAL

Crossover Design: diltiazem first, placebo second, bisoprolol third

Drug: Bisoprolol; Drug: Diltiazem; Drug: Placebo

placebo first, bisoprolol second

EXPERIMENTAL

Crossover Design: placebo first, bisoprolol second, diltiazem third

Drug: Bisoprolol; Drug: Diltiazem; Drug: Placebo

placebo first, diltiazem second

EXPERIMENTAL

Crossover Design: placebo first, diltiazem second, bisoprolol third

Drug: Bisoprolol; Drug: Diltiazem; Drug: Placebo

Interventions

Bisoprolol DRUG

beta-adrenergic receptor blocker

Also known as: beta blocker

bisoprolol first, diltiazem second; bisoprolol first, placebo second; diltiazem first, bisoprolol second; diltiazem first, placebo second; placebo first, bisoprolol second; placebo first, diltiazem second

Diltiazem DRUG

calcium channel blocker

bisoprolol first, diltiazem second; bisoprolol first, placebo second; diltiazem first, bisoprolol second; diltiazem first, placebo second; placebo first, bisoprolol second; placebo first, diltiazem second

Placebo DRUG

Placebo

bisoprolol first, diltiazem second; bisoprolol first, placebo second; diltiazem first, bisoprolol second; diltiazem first, placebo second; placebo first, bisoprolol second; placebo first, diltiazem second

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Charite University, Berlin, Germany: lead
• Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK): collaborator

Study Sites (15)

Kerckhoff-Klinik gGmbH

Bad Nauheim, 61231, Germany

NOT YET RECRUITING

Herz- und Diabeteszentrum NRW

Bad Oeynhausen, 32545, Germany

NOT YET RECRUITING

Charité University Medicine Berlin, Campus Benjamin Franklin

Berlin, 12203, Germany

RECRUITING

Universitätsklinikum Erlangen

Erlangen, 91054, Germany

NOT YET RECRUITING

Universitätsklinikum Frankfurt

Frankfurt, 60590, Germany

NOT YET RECRUITING

Universitäres Herz- und Gefäßzentrum UKE Hamburg

Hamburg, 20246, Germany

NOT YET RECRUITING

Universitätsklinikum Heidelberg

Heidelberg, 69120, Germany

NOT YET RECRUITING

Universitätsklinikum Schleswig-Holstein, Campus Kiel

Kiel, 24105, Germany

NOT YET RECRUITING

Universitätsklinikum Leipzig

Leipzig, 04103, Germany

NOT YET RECRUITING

Universitätsmedizin der Johannes Gutenberg-Universität Mainz

Mainz, 55131, Germany

NOT YET RECRUITING

Universitätsmedizin Mannheim

Mannheim, 68167, Germany

NOT YET RECRUITING

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

München, 80636, Germany

NOT YET RECRUITING

Robert-Bosch-Krankenhaus

Stuttgart, 70376, Germany

NOT YET RECRUITING

Inselspital, Universitätsspital Bern

Bern, 3010, Switzerland

NOT YET RECRUITING

Universitäres Herzzentrum Zürich, Universitätsspital Zürich

Zurich, 8091, Switzerland

NOT YET RECRUITING

MeSH Terms

Conditions

Microvascular Angina; Coronary Vasospasm; Angina Pectoris, Variant; Coronary Artery Disease

Interventions

Bisoprolol; Adrenergic beta-Antagonists; Diltiazem

Condition Hierarchy (Ancestors)

Angina Pectoris; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Coronary Disease; Angina, Unstable; Chest Pain; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Arteriosclerosis; Arterial Occlusive Diseases

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Physiological Effects of Drugs; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Ulf Landmesser, Prof. Dr.

  Charité University, Berlin, Germany

  STUDY CHAIR

• Barbara E Stähli, Prof. Dr.

  Universitätsspital Zürich

  STUDY CHAIR

Central Study Contacts

Aslihan Erbay, MD

CONTACT

+49 30 450 513 653; examine-cad@charite.de

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr.

Study Record Dates

• First Submitted: February 28, 2022
• First Posted: March 24, 2022
• Study Start: March 4, 2022
• Primary Completion: June 1, 2024
• Study Completion: June 1, 2024
• Last Updated: March 24, 2022

Record last verified: 2022-03

Locations

DE (13); CH (2)