Ignite Creation Date:
2024-05-06 @ 3:50 PM
Last Modification Date:
2024-10-26 @ 1:58 PM
Study NCT ID:
NCT04777045
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2023-03-30
First Post:
2021-02-18
Brief Title:
Efficacy of Diltiazem to Improve Coronary Microvascular Dysfunction a Randomized Clinical Trial
Sponsor:
Radboud University Medical Center
Organization:
Radboud University Medical Center
Study Overview
Official Title:
Efficacy of Diltiazem to Improve Coronary Microvascular Dysfunction a Randomized Clinical Trial
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2022-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
EDIT-CMD
Brief Summary:
Rationale Up to 40 of patients undergoing a coronary angiogram for symptomssigns of ischemia do not have obstructive coronary artery disease CAD In about half of them the mechanism underlying cardiac ischemia is coronary microvascular dysfunction CMD In CMD myocardial ischemia is caused by impaired endothelial andor non-endothelial coronary vasoreactivity resulting in the coronary microvasculature not dilating properly or becoming vasospastic Recently published diagnostic criteria state that to confirm the diagnosis CMD patients should either have an impaired coronary flow reserve CFR increased microvascular resistance IMR or have evidence of microvascular spasms Hence invasive coronary function testing CFT is considered the reference standard for a definitive diagnosis of CMD
Patients with microvascular angina often have continuing episodes of chest pain leading to frequent first aid visits and hospital re-admissions with associated high health care costs Moreover CMD is associated with a worsened cardiovascular prognosis Therefore adequate treatment is paramount However current treatment options are based on a limited number of small studies most of which were not placebo-controlled Based on prior studies and our clinical experience we believe diltiazem a calcium channel blocker CCB could improve coronary microvascular function in patients with CMD
Objective Our primary objective is to assess the effect of diltiazem on coronary microvascular function as assessed by CFT in symptomatic patients with CMD Our secondary objective is to assess the effect of diltiazem on the individual coronary function parameters
Study design This is a clinical multi-center randomized with 11 ratio double-blind placebo-controlled study Patients with chronic angina in the absence of obstructive CAD will be screened for study enrollment Eligible patients will be asked for informed consent after which the screening visit will take place Within 8 weeks after screening they will undergo CFT with the assessment of the coronary flow reserve CFR index of microcirculatory resistance IMR and coronary spasm
Intervention arm if CFT shows either a CFR 20 an IMR 25 andor coronary spasm the patient will continue in the intervention arm of the trial and will be randomized to either diltiazem or placebo treatment for 6 weeks After 6 weeks a CFT will be repeated and the diltiazemplacebo treatment will be discontinued Follow-up will be obtained after 6 weeks of treatment and 1 year and 5 years after treatment discontinuation
Registration arm If the CFT at baseline shows no signs of vascular dysfunction patients will enter in the registration arm of the study These patients will not receive any study medication Follow-up will be obtained after 1 year and 5 years
Study population Adult patients with chronic angina in the absence of obstructive CAD will be screened for participation They will be recruited from the outpatient clinic of the cardiology department of the participating sites Patients with contra-indications for coronary function testing with the use of adenosine and acetylcholine andor diltiazem treatment ie severe AV conduction delay hypersensitivity reduced left ventricular function will not be eligible
Intervention After establishing an abnormal coronary vascular function 6 weeks treatment with either diltiazem 120-360 mg or placebo will be initiated in a double-blind fashion Every two weeks dose titration will be performed if possible under the guidance of patient tolerance dizziness leg oedema etc blood pressure and heart rate
Main study parametersendpoints The proportion of patients having a successful treatment with diltiazem defined as normalization of at least one abnormal parameter and none of the normal parameters becoming abnormal A normal IMR is specified as IMR 25 a normal CFR being a CFR 2 and a normal acetylcholine test is specified as one without ECG abnormalities and without signs of spasm at the same acetylcholine dose used at baseline Main secondary endpoints will be the change in the individual coronary function parameters
Nature and extent of the burden and risks associated with participation benefit and group relatedness The extensive experience with diltiazem and the favourable safety profile in combination with the short duration of treatment make the treatment risk low for participants Related to the study procedure several reports show that CFT is a safe procedure with serious complication rates death myocardial infaction etc ranging from 0 to 07 The first CFT is clinically indicated by the treating physician The second CFT will bring additive risk to the participants in the intervention arm However we believe it is essential to investigate the effect of diltiazem on coronary function to justify its use in CMD patients
Patients with microvascular angina often have continuing episodes of chest pain leading to frequent first aid visits and hospital re-admissions with associated high health care costs Moreover CMD is associated with a worsened cardiovascular prognosis Therefore adequate treatment is paramount However current treatment options are based on a limited number of small studies most of which were not placebo-controlled Based on prior studies and our clinical experience we believe diltiazem a calcium channel blocker CCB could improve coronary microvascular function in patients with CMD
Objective Our primary objective is to assess the effect of diltiazem on coronary microvascular function as assessed by CFT in symptomatic patients with CMD Our secondary objective is to assess the effect of diltiazem on the individual coronary function parameters
Study design This is a clinical multi-center randomized with 11 ratio double-blind placebo-controlled study Patients with chronic angina in the absence of obstructive CAD will be screened for study enrollment Eligible patients will be asked for informed consent after which the screening visit will take place Within 8 weeks after screening they will undergo CFT with the assessment of the coronary flow reserve CFR index of microcirculatory resistance IMR and coronary spasm
Intervention arm if CFT shows either a CFR 20 an IMR 25 andor coronary spasm the patient will continue in the intervention arm of the trial and will be randomized to either diltiazem or placebo treatment for 6 weeks After 6 weeks a CFT will be repeated and the diltiazemplacebo treatment will be discontinued Follow-up will be obtained after 6 weeks of treatment and 1 year and 5 years after treatment discontinuation
Registration arm If the CFT at baseline shows no signs of vascular dysfunction patients will enter in the registration arm of the study These patients will not receive any study medication Follow-up will be obtained after 1 year and 5 years
Study population Adult patients with chronic angina in the absence of obstructive CAD will be screened for participation They will be recruited from the outpatient clinic of the cardiology department of the participating sites Patients with contra-indications for coronary function testing with the use of adenosine and acetylcholine andor diltiazem treatment ie severe AV conduction delay hypersensitivity reduced left ventricular function will not be eligible
Intervention After establishing an abnormal coronary vascular function 6 weeks treatment with either diltiazem 120-360 mg or placebo will be initiated in a double-blind fashion Every two weeks dose titration will be performed if possible under the guidance of patient tolerance dizziness leg oedema etc blood pressure and heart rate
Main study parametersendpoints The proportion of patients having a successful treatment with diltiazem defined as normalization of at least one abnormal parameter and none of the normal parameters becoming abnormal A normal IMR is specified as IMR 25 a normal CFR being a CFR 2 and a normal acetylcholine test is specified as one without ECG abnormalities and without signs of spasm at the same acetylcholine dose used at baseline Main secondary endpoints will be the change in the individual coronary function parameters
Nature and extent of the burden and risks associated with participation benefit and group relatedness The extensive experience with diltiazem and the favourable safety profile in combination with the short duration of treatment make the treatment risk low for participants Related to the study procedure several reports show that CFT is a safe procedure with serious complication rates death myocardial infaction etc ranging from 0 to 07 The first CFT is clinically indicated by the treating physician The second CFT will bring additive risk to the participants in the intervention arm However we believe it is essential to investigate the effect of diltiazem on coronary function to justify its use in CMD patients
Detailed Description:
Primary Objective
To assess the effect of diltiazem on coronary microvascular function in patients with chronic angina and evidence of coronary microvascular dysfunction
Secondary Objectives
To assess the effect of 6 weeks of treatment with diltiazem on the individual coronary function parameters in patients with coronary microvascular dysfunction
Safety objective
To assess the safety of coronary function testing in patients with chronic angina in the absence of obstructive CAD
To assess the safety of treatment with diltiazem in patients with coronary microvascular dysfunction
Exploratory objectives
To assess the effect of 6 weeks of treatment with diltiazem on angina frequency and severity in patients with coronary microvascular dysfunction
To assess the difference in major adverse cardiovascular events MACE in symptomatic patients with and without coronary microvascular dysfunction at 1 and 5 year follow-up
Sample size calculation
There are little data available about the effect of oral diltiazem on coronary non-endothelium dependent and endothelium dependent vasoreactivity
The effect of CCBs on non-endothelium dependent vasoreactivity one randomized placebo-controlled study shows oral treatment with diltiazem improves TIMI frame count on repeat coronary angiography 1 In current practice CFR and IMR quantitative measurements have replaced the TIMI frame count Another non-placebo controlled study shows an improvement of echocardiography-measured CFR in CMD patients treated with 90mg diltiazem2 The effect of CCBs on endothelium dependent vasoreactivity patients who are treated with ultra long-acting CCBs ie amlodipine show less vasoconstriction on baseline coronary angiography and have a lower rate of positive acetylcholine provocation testing compared to patients who dont 41 vs 64 if all of them stop all CCBs 48 hours before the procedure 3 We find a 25 success rate of treatment with diltiazem clinically relevant Based on the previous literature that kind of treatment effect is expected to be feasible we anticipate a 30 success rate in the patients treated with diltiazem compared to a 5 success rate in those treated with placebo To detect this difference with type I error rate of 5 and type II error rate of 80 we need a total of 72 subjects 36 in each group in the study Based on prior research 2 3 we estimate that at least 60 of the screened patients will have an abnormal coronary reactivity test We estimate that 15 of the randomized patients will discontinue the IMP during the treatment phase due to side effects of diltiazem gastro-intestinal side effects peripheral oedema see section 64 or inability to undergo the second coronary reactivity test Therefore a total of 142 patients needs to be screened to reach intended sample size of 72 patients that complete the study protocol as shown in figure 2
An interim analysis will be performed for futility when half of the patients has been recruited in both arms The boundary for futility consideration will be a conditional power of 20 under the alternative hypothesis 4 At conditional power of 20 under original design effect assumption a single assessment of futility when half of the patients has been recruited in both arms we expect very limited inflation in type II error rate 5 6
Statistical analysis
For summarizing patient characteristics continuous variables with a Gaussian distribution will be expressed as mean standard deviation SD and continuous variables with a non-Gaussian distribution as median interquartile range IQR Categorical variables will be summarized with number percentage
Analysis Populations
The full analysis population will consist of all patients who signed informed consent from both the intervention arm and the registration arm
All patients who are enrolled in the intervention arm of the study and are randomly allocated to treatment or placebo group will be included in the primary analysis of efficacy intention-to-treat treat analysis ITT
In a supportive analysis the Per Protocol PP group will consist of all patients from the ITT group without major protocol violations Major protocol violations are
In- or exclusion criteria are not met
Inadequate informed consent
Serious non-compliance of the IMP a drug-compliance 80
Missing data subject who misses primary outcome data from the first andor second CFT acetylcholine testing outcome CFR and IMR data
The safety population will be the as-treated population which will consist of all patients from the intervention group who had at least one dose of trial medication
Data Safety Monitoring Board DSMB
A DSMB will be formed for two analyses one interim look after half of the patients as calculated in the original power analysis completed visit 104 the second coronary reactivity test and one analysis after all 72 patients completed visit 104 The full procedure is described in the DSMB Charter
The DSMB would be responsible for the execution of the interim analysis and for making recommendations to the executive committee based on a clearly defined written charter The objective of the interim analysis will be to assess the following
Safety issue is there any difference in the safety profile between treatment groups If yes are these associated with drug administration
Futility is it unlikely that a relevant treatment difference will be demonstrated
Efficacy do the data show an overt efficacy of diltiazem compared to placebo
Are there any other observations in the accumulated data that should be communicated to the sponsor The advices of the DSMB will be sent to the sponsor of the study Should the sponsor decide not to fully implement the advice of the DSMB the sponsor will send the advice to the reviewing METC including a note to substantiate why part of the advice of the DSMB will not be followed
Regulation statement
The study will be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with ICHGCP and in accordance with the Medical Research Involving Human Subjects Act WMO and other guidelines regulations and Acts
Recruitment and consent
The Principal Investigators will
Ensure each patient is given full and adequate oral and written information about the nature purpose possible risk and benefit of the study
Ensure each patient is notified that they are free to discontinue from the study at any time
Ensure that each patient is given the opportunity to ask questions and allowed time to consider the information provided
Ensure each patient provides signed and dated informed consent before conducting any procedure specifically for the study
Ensure the original signed Informed Consent Forms isare stored in the Investigators Study File
Ensure a copy of the signed Informed Consent Form is given to the patient
Ensure that any incentives for patients who participate in the study as well as any provisions for patients harmed as a consequence of study participation are described in the informed consent form that is approved by an Ethics Committee
Patients with angina in the absence of obstructive CAD will be screened for participation in the study according to the the Inclusion criteria and Exclusion criteria Most of these patients will be identified from the waiting list for a CFT Patients will only be eligible if the treating physician has already agreed with the patient to perform a CFT for hisher angina After the patient has agreed to be informed about the study heshe will be contacted by one of the members of the study team and will receive the patient information Preferably a face-to-face information visit will be planned 1-2 weeks after the patient information was provided but before the coronary reactivity test The alternative would be a telephone visit to explain the patient information Only after the patient is well informed all questions are answered and heshe agrees to participate the screening visit will be planned where the informed consent form will be signed If the patient does not want to participate in the study the coronary reactivity test will still take place
Benefits and risks assessment group relatedness
It is essential to only include patients with properly diagnosed CMD patients without current obstructive CAD and an abnormal coronary reactivity To assess both endothelial-dependent and endothelial-independent coronary vasoreactivity invasive CFT is currently the only diagnostic option
Wei et al report on the safety of invasive CFT in women to diagnose CMD7 Among 293 symptomatic women without obstructive CAD who underwent testing four total adverse events occurred - two of which were deemed serious a coronary dissection and an episode of coronary spasm leading to acute myocardial infarction Over the course of 5 year follow-up the overall rate of major adverse cardiac events in the population was 82 The investigators rightly conclude that the immediate risk of testing is relatively low in comparison to the overall event rate in this population Ong et al also report low risk of coronary function testing using ACH testing in 124 patients without obstructive CAD28 There were no serious complications eg myocardial infarction refractory spasm sustained ventricular arrhythmias or need for resuscitation Transient atrioventricular block was frequently observed and occurred mostly during provocation of the RCA it always resolved within seconds after reducing the speed of the ACH injection due to the short half-life of ACH We will not include testing of the RCA in our protocol
In our clinical experience diltiazem relieves angina in patients with CMD To justify the use of this agent in the treatment of CMD it is essential to prove its effect on coronary reactivity besides its effect on symptoms Diltiazem is widely used cheap and safe Its characteristics are promising with regard to its potential to improve coronary vasoreactivity
Handling and storage of data and documents
The data generated will be encoded and a separate patient identification log will be created The key to the code will only be available to the principal investigator and delegated investigators The acquired encoded data imputed in the eCRF will be accessible with passwords to the researchers involved Personal data will comply to the Dutch Personal Data Protection Act
Monitoring and Quality Assurance
During the study the study sites will be monitored to review study progress Investigator and patient compliance with clinical protocol requirements and any emergent problems The monitor visit will include patient informed consent patient recruitment and follow-up SAE documentation and reporting AE documentation IMP allocation IMP accountability and quality of the data Details will be specified in a monitoring plan
To assess the effect of diltiazem on coronary microvascular function in patients with chronic angina and evidence of coronary microvascular dysfunction
Secondary Objectives
To assess the effect of 6 weeks of treatment with diltiazem on the individual coronary function parameters in patients with coronary microvascular dysfunction
Safety objective
To assess the safety of coronary function testing in patients with chronic angina in the absence of obstructive CAD
To assess the safety of treatment with diltiazem in patients with coronary microvascular dysfunction
Exploratory objectives
To assess the effect of 6 weeks of treatment with diltiazem on angina frequency and severity in patients with coronary microvascular dysfunction
To assess the difference in major adverse cardiovascular events MACE in symptomatic patients with and without coronary microvascular dysfunction at 1 and 5 year follow-up
Sample size calculation
There are little data available about the effect of oral diltiazem on coronary non-endothelium dependent and endothelium dependent vasoreactivity
The effect of CCBs on non-endothelium dependent vasoreactivity one randomized placebo-controlled study shows oral treatment with diltiazem improves TIMI frame count on repeat coronary angiography 1 In current practice CFR and IMR quantitative measurements have replaced the TIMI frame count Another non-placebo controlled study shows an improvement of echocardiography-measured CFR in CMD patients treated with 90mg diltiazem2 The effect of CCBs on endothelium dependent vasoreactivity patients who are treated with ultra long-acting CCBs ie amlodipine show less vasoconstriction on baseline coronary angiography and have a lower rate of positive acetylcholine provocation testing compared to patients who dont 41 vs 64 if all of them stop all CCBs 48 hours before the procedure 3 We find a 25 success rate of treatment with diltiazem clinically relevant Based on the previous literature that kind of treatment effect is expected to be feasible we anticipate a 30 success rate in the patients treated with diltiazem compared to a 5 success rate in those treated with placebo To detect this difference with type I error rate of 5 and type II error rate of 80 we need a total of 72 subjects 36 in each group in the study Based on prior research 2 3 we estimate that at least 60 of the screened patients will have an abnormal coronary reactivity test We estimate that 15 of the randomized patients will discontinue the IMP during the treatment phase due to side effects of diltiazem gastro-intestinal side effects peripheral oedema see section 64 or inability to undergo the second coronary reactivity test Therefore a total of 142 patients needs to be screened to reach intended sample size of 72 patients that complete the study protocol as shown in figure 2
An interim analysis will be performed for futility when half of the patients has been recruited in both arms The boundary for futility consideration will be a conditional power of 20 under the alternative hypothesis 4 At conditional power of 20 under original design effect assumption a single assessment of futility when half of the patients has been recruited in both arms we expect very limited inflation in type II error rate 5 6
Statistical analysis
For summarizing patient characteristics continuous variables with a Gaussian distribution will be expressed as mean standard deviation SD and continuous variables with a non-Gaussian distribution as median interquartile range IQR Categorical variables will be summarized with number percentage
Analysis Populations
The full analysis population will consist of all patients who signed informed consent from both the intervention arm and the registration arm
All patients who are enrolled in the intervention arm of the study and are randomly allocated to treatment or placebo group will be included in the primary analysis of efficacy intention-to-treat treat analysis ITT
In a supportive analysis the Per Protocol PP group will consist of all patients from the ITT group without major protocol violations Major protocol violations are
In- or exclusion criteria are not met
Inadequate informed consent
Serious non-compliance of the IMP a drug-compliance 80
Missing data subject who misses primary outcome data from the first andor second CFT acetylcholine testing outcome CFR and IMR data
The safety population will be the as-treated population which will consist of all patients from the intervention group who had at least one dose of trial medication
Data Safety Monitoring Board DSMB
A DSMB will be formed for two analyses one interim look after half of the patients as calculated in the original power analysis completed visit 104 the second coronary reactivity test and one analysis after all 72 patients completed visit 104 The full procedure is described in the DSMB Charter
The DSMB would be responsible for the execution of the interim analysis and for making recommendations to the executive committee based on a clearly defined written charter The objective of the interim analysis will be to assess the following
Safety issue is there any difference in the safety profile between treatment groups If yes are these associated with drug administration
Futility is it unlikely that a relevant treatment difference will be demonstrated
Efficacy do the data show an overt efficacy of diltiazem compared to placebo
Are there any other observations in the accumulated data that should be communicated to the sponsor The advices of the DSMB will be sent to the sponsor of the study Should the sponsor decide not to fully implement the advice of the DSMB the sponsor will send the advice to the reviewing METC including a note to substantiate why part of the advice of the DSMB will not be followed
Regulation statement
The study will be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with ICHGCP and in accordance with the Medical Research Involving Human Subjects Act WMO and other guidelines regulations and Acts
Recruitment and consent
The Principal Investigators will
Ensure each patient is given full and adequate oral and written information about the nature purpose possible risk and benefit of the study
Ensure each patient is notified that they are free to discontinue from the study at any time
Ensure that each patient is given the opportunity to ask questions and allowed time to consider the information provided
Ensure each patient provides signed and dated informed consent before conducting any procedure specifically for the study
Ensure the original signed Informed Consent Forms isare stored in the Investigators Study File
Ensure a copy of the signed Informed Consent Form is given to the patient
Ensure that any incentives for patients who participate in the study as well as any provisions for patients harmed as a consequence of study participation are described in the informed consent form that is approved by an Ethics Committee
Patients with angina in the absence of obstructive CAD will be screened for participation in the study according to the the Inclusion criteria and Exclusion criteria Most of these patients will be identified from the waiting list for a CFT Patients will only be eligible if the treating physician has already agreed with the patient to perform a CFT for hisher angina After the patient has agreed to be informed about the study heshe will be contacted by one of the members of the study team and will receive the patient information Preferably a face-to-face information visit will be planned 1-2 weeks after the patient information was provided but before the coronary reactivity test The alternative would be a telephone visit to explain the patient information Only after the patient is well informed all questions are answered and heshe agrees to participate the screening visit will be planned where the informed consent form will be signed If the patient does not want to participate in the study the coronary reactivity test will still take place
Benefits and risks assessment group relatedness
It is essential to only include patients with properly diagnosed CMD patients without current obstructive CAD and an abnormal coronary reactivity To assess both endothelial-dependent and endothelial-independent coronary vasoreactivity invasive CFT is currently the only diagnostic option
Wei et al report on the safety of invasive CFT in women to diagnose CMD7 Among 293 symptomatic women without obstructive CAD who underwent testing four total adverse events occurred - two of which were deemed serious a coronary dissection and an episode of coronary spasm leading to acute myocardial infarction Over the course of 5 year follow-up the overall rate of major adverse cardiac events in the population was 82 The investigators rightly conclude that the immediate risk of testing is relatively low in comparison to the overall event rate in this population Ong et al also report low risk of coronary function testing using ACH testing in 124 patients without obstructive CAD28 There were no serious complications eg myocardial infarction refractory spasm sustained ventricular arrhythmias or need for resuscitation Transient atrioventricular block was frequently observed and occurred mostly during provocation of the RCA it always resolved within seconds after reducing the speed of the ACH injection due to the short half-life of ACH We will not include testing of the RCA in our protocol
In our clinical experience diltiazem relieves angina in patients with CMD To justify the use of this agent in the treatment of CMD it is essential to prove its effect on coronary reactivity besides its effect on symptoms Diltiazem is widely used cheap and safe Its characteristics are promising with regard to its potential to improve coronary vasoreactivity
Handling and storage of data and documents
The data generated will be encoded and a separate patient identification log will be created The key to the code will only be available to the principal investigator and delegated investigators The acquired encoded data imputed in the eCRF will be accessible with passwords to the researchers involved Personal data will comply to the Dutch Personal Data Protection Act
Monitoring and Quality Assurance
During the study the study sites will be monitored to review study progress Investigator and patient compliance with clinical protocol requirements and any emergent problems The monitor visit will include patient informed consent patient recruitment and follow-up SAE documentation and reporting AE documentation IMP allocation IMP accountability and quality of the data Details will be specified in a monitoring plan
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2018-003518-41 | EUDRACT_NUMBER | None | None |