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

Sponsor

Charite University, Berlin, Germany (Other)

Overall Status

Recruiting

CT.gov ID

NCT05294887

Collaborator

Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) (Other)

132

Enrollment

Locations

Arms

26.9

Anticipated Duration (Months)

8.8

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Coronary Microvascular Dysfunction Microvascular Angina Vasospasm, Coronary Vasospastic Angina Prinzmetal Angina Coronary Artery Disease	Drug: Bisoprolol Drug: Diltiazem Drug: Placebo	Phase 4

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 Design

Study Type:

Interventional

Anticipated Enrollment :

132 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

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.

Primary Purpose:

Treatment

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

Actual Study Start Date :

Mar 4, 2022

Anticipated Primary Completion Date :

Jun 1, 2024

Anticipated Study Completion Date :

Jun 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: bisoprolol first, diltiazem second Crossover Design: bisoprolol first, diltiazem second, placebo third	Drug: Bisoprolol beta-adrenergic receptor blocker Other Names: beta blocker Drug: Diltiazem calcium channel blocker Drug: Placebo Placebo
Experimental: bisoprolol first, placebo second Crossover Design: bisoprolol first, placebo second, diltiazem third	Drug: Bisoprolol beta-adrenergic receptor blocker Other Names: beta blocker Drug: Diltiazem calcium channel blocker Drug: Placebo Placebo
Experimental: diltiazem first, bisoprolol second Crossover Design: diltiazem first, bisoprolol second, placebo third	Drug: Bisoprolol beta-adrenergic receptor blocker Other Names: beta blocker Drug: Diltiazem calcium channel blocker Drug: Placebo Placebo
Experimental: diltiazem first, placebo second Crossover Design: diltiazem first, placebo second, bisoprolol third	Drug: Bisoprolol beta-adrenergic receptor blocker Other Names: beta blocker Drug: Diltiazem calcium channel blocker Drug: Placebo Placebo
Experimental: placebo first, bisoprolol second Crossover Design: placebo first, bisoprolol second, diltiazem third	Drug: Bisoprolol beta-adrenergic receptor blocker Other Names: beta blocker Drug: Diltiazem calcium channel blocker Drug: Placebo Placebo
Experimental: placebo first, diltiazem second Crossover Design: placebo first, diltiazem second, bisoprolol third	Drug: Bisoprolol beta-adrenergic receptor blocker Other Names: beta blocker Drug: Diltiazem calcium channel blocker Drug: Placebo Placebo

Outcome Measures

Primary Outcome Measures

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) [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.

Secondary Outcome Measures

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]
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.
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]
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.
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]
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.
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]
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.
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]
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.
Duke Activity Status Index (DASI) [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
Rose dyspnea 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]
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.
Angina diary (Angina episodes per week) [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
Angina diary (nitroglycerin use per week)) [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
Quality of Life (Short Form 36 health survey questionnaire) [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
Psychological symptoms as assessed by Patient Health Questionnaire (PHQ-9) [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
Psychological symptoms as assessed by the Hospital Anxiety Depression Scale (HADS)) [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
Functional capacity as assessed by bicycle exercise testing [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)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 85 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Kerckhoff-Klinik gGmbH	Bad Nauheim	Germany	61231
2	Herz- und Diabeteszentrum NRW	Bad Oeynhausen	Germany	32545
3	Charité University Medicine Berlin, Campus Benjamin Franklin	Berlin	Germany	12203
4	Universitätsklinikum Erlangen	Erlangen	Germany	91054
5	Universitätsklinikum Frankfurt	Frankfurt	Germany	60590
6	Universitäres Herz- und Gefäßzentrum UKE Hamburg	Hamburg	Germany	20246
7	Universitätsklinikum Heidelberg	Heidelberg	Germany	69120
8	Universitätsklinikum Schleswig-Holstein, Campus Kiel	Kiel	Germany	24105
9	Universitätsklinikum Leipzig	Leipzig	Germany	04103
10	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz	Germany	55131
11	Universitätsmedizin Mannheim	Mannheim	Germany	68167
12	Deutsches Herzzentrum München des Freistaates Bayern - Klinik an der Technischen Universität München	München	Germany	80636
13	Robert-Bosch-Krankenhaus	Stuttgart	Germany	70376
14	Inselspital, Universitätsspital Bern	Bern	Switzerland	3010
15	Universitäres Herzzentrum Zürich, Universitätsspital Zürich	Zürich	Switzerland	8091