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

Coronary Artery Disease Clinical Trial

— EXAMINE-CAD  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05294887
• Other study ID #: EXAMINE-CAD-DZHK22
• Secondary ID: 2020-004717-12
• Status: Recruiting
• Phase: Phase 4
• Start date: March 4, 2022
• Est. completion date: June 2024

Study information

• Verified date: March 2022
• Source: Charite University, Berlin, Germany
• Contact: Aslihan Erbay, MD
• Phone: +49 30 450 513 653
• Email: examine-cad[@]charite.de
• Is FDA regulated: No
• Study type: Interventional

Clinical 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 132
• Est. completion date: June 2024
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

• Angina Pectoris
• Angina Pectoris, Variant
• Coronary Artery Disease
• Coronary Disease
• Coronary Microvascular Dysfunction
• Coronary Vasospasm
• Microvascular Angina
• Myocardial Ischemia
• Vasospastic Angina

Intervention

Drug:
• Bisoprolol
beta-adrenergic receptor blocker
• Diltiazem
calcium channel blocker
• Placebo
Placebo

Locations

Country	Name	City	State
Germany	Kerckhoff-Klinik gGmbH	Bad Nauheim
Germany	Herz- und Diabeteszentrum NRW	Bad Oeynhausen
Germany	Charité University Medicine Berlin, Campus Benjamin Franklin	Berlin
Germany	Universitätsklinikum Erlangen	Erlangen
Germany	Universitätsklinikum Frankfurt	Frankfurt
Germany	Universitäres Herz- und Gefäßzentrum UKE Hamburg	Hamburg
Germany	Universitätsklinikum Heidelberg	Heidelberg
Germany	Universitätsklinikum Schleswig-Holstein, Campus Kiel	Kiel
Germany	Universitätsklinikum Leipzig	Leipzig
Germany	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz
Germany	Universitätsmedizin Mannheim	Mannheim
Germany	Deutsches Herzzentrum München des Freistaates Bayern - Klinik an der Technischen Universität München	München
Germany	Robert-Bosch-Krankenhaus	Stuttgart
Switzerland	Inselspital, Universitätsspital Bern	Bern
Switzerland	Universitäres Herzzentrum Zürich, Universitätsspital Zürich	Zürich

Sponsors (2)

Lead Sponsor	Collaborator
Charite University, Berlin, Germany	Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)

Countries where clinical trial is conducted

Germany,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.	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	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.	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	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.	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	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.	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	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.	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	Duke Activity Status Index (DASI)	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
Secondary	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.	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	Angina diary (Angina episodes per week)	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
Secondary	Angina diary (nitroglycerin use per week))	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
Secondary	Quality of Life (Short Form 36 health survey questionnaire)	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
Secondary	Psychological symptoms as assessed by Patient Health Questionnaire (PHQ-9)	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
Secondary	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	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	Functional capacity as assessed by bicycle exercise testing	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)