Efficacy of Diltiazem to Improve Coronary Microvascular Dysfunction: a Randomized Clinical Trial

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 diltiazem.(2) The effect of CCBs on endothelium dependent vasoreactivity: patients who are treated with ultra long-acting CCBs (i.e. amlodipine) show less vasoconstriction on baseline coronary angiography and have a lower rate of positive acetylcholine provocation testing compared to patients who don't (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 6.4) 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 and/or 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 advice(s) 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 ICH/GCP and in accordance with the Medical Research Involving Human Subjects Act (WMO) and other guidelines, regulations and Acts

Recruitment and consent:

The Principal Investigator(s) 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 Form(s) is/are stored in the Investigator's 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 his/her angina. After the patient has agreed to be informed about the study he/she 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 he/she 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 CMD.(7) 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 8.2%. 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 CAD.(28) There were no serious complications (e.g., 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 it's 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.