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Efficacy of Diltiazem to Improve Coronary Microvascular Dysfunction: a Randomized Clinical Trial (EDIT-CMD)

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ClinicalTrials.gov Identifier: NCT04777045
Recruitment Status : Recruiting
First Posted : March 2, 2021
Last Update Posted : March 2, 2021
Sponsor:
Information provided by (Responsible Party):
Radboud University Medical Center

Brief Summary:

Rationale: Up to 40% of patients undergoing a coronary angiogram for symptoms/signs 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 and/or 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 1:1 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 ≤ 2.0, an IMR ≥ 25 and/or 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 diltiazem/placebo 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) and/or diltiazem treatment (i.e. 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 parameters/endpoints: 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 0.7%. 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.


Condition or disease Intervention/treatment Phase
Microvascular Angina Coronary Vasospasm Microvascular Ischemia of Myocardium Drug: Diltiazem Hydrochloride Drug: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 85 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

A clinical multi-center randomized with 1:1 ratio, double-blind, placebo-controlled study. Patients with chronic angina in the absence of CAD will be screened for study enrolment. Eligible patients will be asked for informed consent at the screening visit.

Within 8 weeks after screening, participants undergo coronary function testing. If this shows either a CFR ≤ 2.0, an IMR ≥ 25 and/or abnormal acetylcholine testing the patient will continue in the intervention arm and will be randomized to either diltiazem or placebo treatment for 6 weeks. After 6 weeks, coronary function testing will be repeated and the diltiazem/placebo treatment will be discontinued. Follow-up will be obtained 1 month, 1 year and 5 years after treatment discontinuation. If coronary function testing 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.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: The blinding of treatment is ensured by using a double-blind technique. The diltiazem capsules and the respective placebo capsules will have the same look and feel. The bottles with the IMP will be labelled with unique identification numbers. No member of the study team, or anyone handling study data will have access to the randomization scheme during the study. In case of an adverse event (AE), the code should only be broken in circumstances when knowledge of the IMP is required for treating the patient. If possible, contact should be initiated with the principal investigator before breaking the code. Code breaking can be performed at any time by the investigator. A sealed emergency envelope per patient randomization number will be present per patient at the research department. If the blind is broken, the Investigator should document the date, time of the day and the reason for code breaking. If the code is broken, patient must discontinue IMP administration but continues the study.
Primary Purpose: Treatment
Official Title: Efficacy of Diltiazem to Improve Coronary Microvascular Dysfunction: a Randomized Clinical Trial
Actual Study Start Date : October 25, 2019
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2026

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Angina

Arm Intervention/treatment
Experimental: Diltiazem
When signs of vascular dysfunction with the coronary function test.
Drug: Diltiazem Hydrochloride

Diltiazem hydrochloride is a calcium ion influx inhibitor (slow channel blocker or calcium antagonist). It is a white to off-white crystalline powder with a bitter taste. It is freely soluble in water, methanol and chloroform. It has a molecular weight of 450.98.

It provides its therapeutic effects by blocking the influx of calcium ions into vascular smooth and cardiac muscle cells during membrane depolarization. The decrease in intracellular calcium causes relaxation of smooth muscle cells and cardiac myocytes by inhibiting actin-myosin interactions. Vasodilation subsequently results in decreased peripheral vascular resistance. The antihypertensive effect of diltiazem in hypertensives is greater than in normotensives.

Diltiazem is registered for the treatment of hypertension, heart rate control in supraventricular tachycardia, chronic stable angina pectoris and angina pectoris resulting from coronary artery spasm.

Other Names:
  • Molecular Formula: C22H26N2S.HCl
  • Diltiazem HCl Retard 120 mg, Prolonged-Release Tablets
  • CAS 33286-22-5
  • Chemically diltiazem hydrochloride is the hydrochloride salt of (2S, 3S)-5-(2- Dimethylaminoethyl)- 2, 3, 4, 5-tetrahydro-2-(4-methoxyphenyl)-4-oxo-1, 5-benzothiazepin-3- yl-acetate

Placebo Comparator: Placebo
When signs of vascular dysfunction with the coronary function test.
Drug: Placebo
Matching placebo capsules, given QD per oral use. Placebo capsules will be used in the same manner with the same dose titration.




Primary Outcome Measures :
  1. 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. [ Time Frame: 6 weeks ]
    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 spasm, without ischemic ECG abnormalities and without (recognizable) angina at the same acetylcholine dose used at baseline.


Secondary Outcome Measures :
  1. Change in index of microvascular resistance (IMR) [ Time Frame: 6 weeks ]
    the delta between 1st and 2nd coronary function test

  2. Change in Coronary Flow Reserve (CFR) [ Time Frame: 6 weeks ]
    the delta between 1st and 2nd coronary function test

  3. Change in Acetylcholine test parameters [ Time Frame: 6 weeks ]
    his is defined as the difference between the dose of acetylcholine at which the baseline CFT showed signs of spasm, compared to the dose at the second CFT. This will be compared between treatment and placebo group using a multinominal logistic regression. The efficacy population will be used for this analysis.

  4. Change in Absolute flow parameters - flow (Q) (ml/min) [ Time Frame: 6 weeks ]
    These are derived by subtracting the outcome from the second CFT from the outcome of the first CFT. To compare change in CFT parameters between treatment and placebo group, we will use independent sample t-test. Bonferroni correction will be applied to account for multiple testing. The efficacy population will be used for this analysis.

  5. Change in Absolute flow parameters - Resistance (R) [ Time Frame: 6 weeks ]
    These are derived by subtracting the outcome from the second CFT from the outcome of the first CFT. To compare change in CFT parameters between treatment and placebo group, we will use independent sample t-test. Bonferroni correction will be applied to account for multiple testing. The efficacy population will be used for this analysis.


Other Outcome Measures:
  1. Safety endpoints [ Time Frame: 6 weeks ]
    The occurrence of complications related to the coronary angiography and/or CFT will be collected, as well as adverse events related to the IMP.

  2. Follow-up (MACE) [ Time Frame: 5 years ]
    Number of major adverse cardiovascular events (MACE) at 1 and 5 year follow-up. MACE is defined as nonfatal stroke, nonfatal myocardial infarction, cardiovascular death, all-cause death, hospitalization for heart failure.

  3. Change in angina frequency reporting in the patient diary [ Time Frame: 5 years ]
    Change in patient reported outcome measures (PROs). These are derived by subtracting the outcome from the PROs from visit 104 to those from visit 1. The efficacy population will be used for this analysis.To compare change in PROs between treatment and placebo group, we will use independent sample t-test.

  4. Change in the Seattle Angina Questionnaire (SAQ) [ Time Frame: 5 years ]
    Change in patient reported outcome measures (PROs). These are derived by subtracting the outcome from the PROs from visit 104 to those from visit 1. The efficacy population will be used for this analysis.To compare change in PROs between treatment and placebo group, we will use independent sample t-test.

  5. Change in RAND-36 scores [ Time Frame: 5 years ]
    Change in patient reported outcome measures (PROs). These are derived by subtracting the outcome from the PROs from visit 104 to those from visit 1. The efficacy population will be used for this analysis.To compare change in PROs between treatment and placebo group, we will use independent sample t-test.

  6. Change in angina CCS classification [ Time Frame: 5 years ]
    Change in patient reported outcome measures (PROs). These are derived by subtracting the outcome from the PROs from visit 104 to those from visit 1. The efficacy population will be used for this analysis.To compare change in PROs between treatment and placebo group, we will use independent sample t-test.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with chronic angina, defined as symptoms of angina at least 2 times a week despite medical therapy for the last 3 months.
  • No signs of obstructive coronary artery disease (CAD), documented within 5 years* before inclusion by one of the following modalities:

    • Patients with non-obstructive (< 50% stenosis) coronary arteries, or patients with one or more intermediate stenoses (between 50 and 70%) with documented FFR > 0.80 or iFR > 0.89 on angiogram.
    • Coronary computed tomography angiography (CCTA) with finding of non-obstructive coronary arteries
  • Baseline coronary function testing with at least one of the following:

    1. CFR ≤ 2.0
    2. IMR ≥ 25
    3. Abnormal acetylcholine test defined as the presence of (recognizable) angina, ischemic ECG abnormalities with or without epicardial spasm.
  • Signed written informed consent * Note: in cases of clinically suspected progression of atherosclerosis as per the Investigator, more contemporary (i.e., 6 months) evidence should be provided.

Exclusion Criteria:

  • Other cause of angina deemed highly likely by the treating physician.
  • Active use of calcium channel blockers or any use of calcium channel blockers in the previous two weeks or known intolerance for non-dihydropyridine calcium channel blockers.
  • Left ventricular ejection fraction < 50%.
  • Recent PCI within the past 3 months.
  • Patients with history of coronary artery bypass grafting (CABG).
  • Surgically uncorrected significant congenital or valvular heart disease, cardiomyopathy or myocarditis.
  • Significant renal impairment (eGFR < 30).
  • Significant hepatic impairment (history or cirrhosis or abnormal serum ALT or AST 3-fold greater than the upper limit of normal).
  • Pregnant women or women of child bearing potential who are planning to become pregnant within the next 3 months.
  • Prior non-cardiac illness with an estimated life expectancy < 1 year.
  • Contra-indication to coronary function testing:

    1. Contraindication or known hypersensitivity to adenosine.
    2. Contraindication or known hypersensitivity to acetylcholine.
    3. Ongoing dipyridamole treatment.
  • Contra-indication for treatment with CCB: second or third degree AV block, sinus node dysfunction, bradycardia (heart rate < 50 beats/minute) and/or potentially dangerous interaction due to the use of another CYP3A4 substrate in the opinion of the investigator.
  • Symptomatic hypotension or systolic BP < 100 mmHg at screening visit on 2 consecutive measurements.
  • History of hospitalization for asthma and/or current use of ≥ 2 types of pulmonary medications for asthma and/or severe COPD with FEV1 < 50% of predicted.
  • Participation in another clinical study with an IMP within one month prior to enrolment.
  • Inability of the patient, in the opinion of the investigator, to understand and/or comply with study medications, procedures and/or follow-up OR any conditions that, in the opinion of the investigator, may render the patient unable to complete the study.
  • Unable to give informed consent (i.e. due to language barrier).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04777045


Contacts
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Contact: Tijn PJ Jansen, MD +31621171608 tijn.jansen@radboudumc.nl
Contact: Regina E Konst, MD regina.konst@radboudumc.nl

Locations
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Netherlands
Radboud University Medical Center Recruiting
Nijmegen, Gelderland, Netherlands, 6525 GA
Contact: Tijn PJ Jansen, MD         
Principal Investigator: Suzette Elias-Smale, MD, PhD         
Sub-Investigator: Regina E Konst, MD         
Principal Investigator: Niels van Royen, MD, PhD         
Catharina Hospital Recruiting
Eindhoven, Netherlands
Contact: Annemiek de Vos, MD, PhD         
Maasstad Hospital Recruiting
Rotterdam, Netherlands
Contact: Valeria Paradies, MD, PhD         
Sponsors and Collaborators
Radboud University Medical Center
Investigators
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Principal Investigator: Suzette Elias-Smale, MD, PhD Radboud University Medical Center
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Radboud University Medical Center
ClinicalTrials.gov Identifier: NCT04777045    
Other Study ID Numbers: NL67497.091.19
2018-003518-41 ( EudraCT Number )
First Posted: March 2, 2021    Key Record Dates
Last Update Posted: March 2, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Radboud University Medical Center:
Coronary vasospasm
IMR
CFR
Diltiazem
Coronary function testing
Additional relevant MeSH terms:
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Microvascular Angina
Coronary Vasospasm
Ischemia
Pathologic Processes
Angina Pectoris
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Vascular Diseases
Coronary Disease
Diltiazem
Antihypertensive Agents
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs
Vasodilator Agents