Clinical trial NCT05294887: Randomized Trial to Examine a Differential Therapeutic Response in Symptomatic Patients With Non-obstructive Coronary Artery Disease
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
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
Lead sponsor: Charite University, Berlin, Germany
Sponsor class: OTHER
Collaborators: name: Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)
First posted: 2022-03-24
Enrollment: 132
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
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)
timeFrame: 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:
measure: SAQ angina stability scale
timeFrame: 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
measure: SAQ angina frequency scale
timeFrame: 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
measure: SAQ treatment satisfaction scale
timeFrame: 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
measure: SAQ physical limitation scale
timeFrame: 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
measure: SAQ quality of life
timeFrame: 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
measure: Duke Activity Status Index (DASI)
timeFrame: 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
measure: Rose dyspnea scale
timeFrame: 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
measure: Angina diary (Angina episodes per week)
timeFrame: 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
measure: Angina diary (nitroglycerin use per week))
timeFrame: 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
measure: Quality of Life (Short Form 36 health survey questionnaire)
timeFrame: 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
measure: Psychological symptoms as assessed by Patient Health Questionnaire (PHQ-9)
timeFrame: 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
measure: Psychological symptoms as assessed by the Hospital Anxiety Depression Scale (HADS))
timeFrame: 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
measure: Functional capacity as assessed by bicycle exercise testing
timeFrame: from baseline (visit 1) to the end of each treatment period (4 weeks, 10 weeks, 16 weeks)
Other outcomes:
Locations:
city: Bad Nauheim
country: Germany
facility: Kerckhoff-Klinik gGmbH
city: Bad Oeynhausen
country: Germany
facility: Herz- und Diabeteszentrum NRW
city: Berlin
country: Germany
facility: Charité University Medicine Berlin, Campus Benjamin Franklin
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen
city: Frankfurt
country: Germany
facility: Universitätsklinikum Frankfurt
city: Hamburg
country: Germany
facility: Universitäres Herz- und Gefäßzentrum UKE Hamburg
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein, Campus Kiel
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universität Mainz
city: Mannheim
country: Germany
facility: Universitätsmedizin Mannheim
city: München
country: Germany
facility: Deutsches Herzzentrum München des Freistaates Bayern - Klinik an der Technischen Universität München
city: Stuttgart
country: Germany
facility: Robert-Bosch-Krankenhaus
city: Bern
country: Switzerland
facility: Inselspital, Universitätsspital Bern
city: Zürich
country: Switzerland
facility: Universitäres Herzzentrum Zürich, Universitätsspital Zürich
Study officials:
affiliation: Charité University, Berlin, Germany
name: Ulf Landmesser, Prof. Dr.
role: STUDY_CHAIR
affiliation: Universitätsspital Zürich
name: Barbara E Stähli, Prof. Dr.
role: STUDY_CHAIR
References: