Clinical trial NCT04130438
Conditions: Myocardial Bridging
Sponsor: Stanford University
Start date: 2020-10-15; Completion date: 2024-10-17
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The proposed clinical trial is relevant to public health because it is expected to expand the differential diagnosis and provide an evidence--based therapy for the large population of patients with angina in the absence of obstructive CAD who currently remain undiagnosed and untreated. It, therefore, upholds an important part of the mission of the The National Heart, Lung, and Blood Institute (NHLBI), which is to promote the treatment of heart disease and enhance the health of all individuals so that they can live longer and more fulfilling lives.

Detailed description:
Angina in the absence of obstructive coronary artery disease (CAD) affects millions, resulting in a reduced quality of life and a burden on the health care system. Previous work has focused on endothelial and microvascular dysfunction as causes of angina in these patients, but even when these etiologies are tested for, nearly half of patients remain undiagnosed, and proven therapies are lacking. The long--term goal of this research proposal is to improve the lives of patients with angina in the absence of obstructive CAD. These patients have been found to have a disproportionate prevalence of myocardial bridges (MBs) (60% vs. 30% in the general population).

MBs are known to cause angina, and the mechanism by which they do so is also known, but MBs have not been actively studied in the context of patients with angina in the absence of obstructive CAD. Medical therapies for symptomatic MBs, including beta blockers and calcium channel blocker have been suggested, but have never been appropriately tested, and may not be better than placebo. The overall objective of this research proposal is to demonstrate that MBs are an important and treatable cause of angina in patients with non--obstructive CAD.

The investigator will conduct the first--ever randomized, double--blind, placebo--controlled trial of medical therapy in patients with angina and an MB. The rationale is that a proven treatment would significantly expand the paradigm by which patients with angina in the absence of obstructive CAD are evaluated and treated. Our central hypothesis is that beta blockers and calcium channel blockers are effective treatments for reducing angina in patients with an MB compared with placebo. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Determine the efficacy of beta blockers and calcium channel blockers in treating patients with angina and an MB and 2) Identify predictors of efficacy of beta blockers and calcium channel blockers in treating patients with angina and an MB. For Aim #1, the investigator will randomize a total of 360 adult patients with angina and an MB into one of three treatment arms: beta blocker (nebivolol), calcium channel blocker (diltiazem), or placebo (1:1:1).

Efficacy will be determined after 30 days on the study drug by a change in angina, as assessed by the Seattle Angina Questionnaire (SAQ). The investigator will also evaluate changes in exercise capacity, as well as drug adherence and side effects. For Aim #2, the investigator will evaluate MB muscle index (MMI, a product of MB length x depth) by coronary computed tomography angiography, as well as male sex, as predictors of efficacy. Randomization will be stratified on sex, ensuring a balance of women and men in each arm. The proposed research is innovative because it shifts the current clinical perspective on angina in the absence of obstructive CAD by considering myocardial bridging as a potential etiology.

It is also significant because it will substantially increase the number of patients with angina in the absence of obstructive CAD that clinicians are able to diagnose and treat, ultimately leading to improvements in quality of life and a reduction in health care costs.

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Nebivolol intervention 2: Diltiazem intervention 3: Placebo
Intervention descriptions: intervention 1: The intervention to be tested is oral beta blocker (nebivolol 2.5 mg) vs. calcium channel blocker (Diltiazem-SR 120 mg) vs. placebo. Once enrolled, baseline data will be gathered and subjects will be randomly assigned to a treatment arm. Subjects will be instructed to take their assigned study drug once a day for 30 days. intervention 2: The intervention to be tested is oral beta blocker (nebivolol 2.5 mg) vs. calcium channel blocker (Diltiazem-SR 120 mg) vs. placebo. Once enrolled, baseline data will be gathered and subjects will be randomly assigned to a treatment arm. Subjects will be instructed to take their assigned study drug once a day for 30 days. intervention 3: The intervention to be tested is oral beta blocker (nebivolol 2.5 mg) vs. calcium channel blocker (Diltiazem-SR 120 mg) vs. placebo. Once enrolled, baseline data will be gathered and subjects will be randomly assigned to a treatment arm. Subjects will be instructed to take their assigned study drug once a day for 30 days.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
Efficacy of Medical Therapy in Women and Men with 
Angina and Myocardial Bridging 
Study Protocol and Statistical Analysis Plan 
NCT04130438 
December 8, 2020 


CLINICAL PROTOCOL SYNOPSIS 
• 
Protocol Title: Efficacy of Medical Therapy in Women and Men with Angina and Myocardial Bridging 
 
• 
Focus of Study: To determine the efficacy of medical therapy in patients with angina and a 
myocardial bridge (MB). 
 
• 
Objectives: The primary objective is to determine if beta blockers and/or calcium channel blockers will 
improve angina in patients with angina and an MB compared with placebo. The secondary objective is 
to identify predictors of efficacy of beta blockers and calcium channel blockers in treating patients with 
angina and an MB. 
 
• 
Study Design: The design of the study is a randomized, double-blind, placebo-controlled phase II 
clinical trial. 
 
• 
Intervention to Be Tested: The intervention to be tested is oral beta blocker (nebivolol 2.5 mg) vs. 
calcium channel blocker (diltiazem SR 120 mg) vs. placebo. Once enrolled, baseline data will be 
gathered and subjects will be randomly assigned to a treatment arm. Subjects will be instructed to take 
their assigned study drug once a day for 30 days. They will be given a diary in order to note any days 
missed and any side effects. If they stop taking their assigned study drug, they will be asked to note the 
last day the study drug was taken and the reason for stopping. They will also be asked to keep the 
bottle and any unused pills, which they will be instructed to bring back, along with the diary, at the 30­ 
day follow­up visit. Adherence will be defined by the proportion of treatment intervention pills taken, as 
assessed by a pill count. At the 30-day follow-up visit, they will repeat data collection, as well as an 
optional exercise treadmill test (ETT). Following completion of the 30­day follow-up, subjects will be 
unblinded to their study drug and will continue with usual care under the direction of their primary 
physician. They will be contacted again at 6 months for final data collection. Following completion of the 
6-month follow­up, their participation in the study will end. 
 


• 
Primary and Important Secondary Endpoints: The primary endpoint is change in angina after treatment 
as assessed by the Seattle Angina Questionnaire (SAQ) at 30­day follow­up. The secondary endpoints are 
1) change in exercise parameters at 30 days, 2) treatment adherence (pill counts) and self-reported side 
effects at 30 days, 3) occurrence of cardiac events at 30 days, 4) change in angina by SAQ at 6 months, 5) 
occurrence of cardiac events at 6 months,  and  6)  treatment  course  at  6 months, following the 30­day 
treatment period. 
 
 The SAQ is a self­report instrument with 19 items that yields five subscale scores: physical 
limitation, angina stability, angina frequency, treatment satisfaction, and disease perception. 
The range of scores for each of these subscales is 0 to 100, with higher scores indicating a 
higher quality of life. A difference of 10 is considered clinically meaningful. 
 
 Exercise parameters include duration of exercise, METs achieved, percentage of maximal 
predicted heart rate achieved, Duke Activity Status Index (DASI), symptoms (onset and 
duration), and EKG changes (ST­segment changes, arrhythmia, and heart rate recovery). 
 
 Cardiac events include myocardial infarction, sustained ventricular arrhythmia, cardiac arrest, 
cardiac death, and emergency room visits/hospitalizations for angina. 
 
 Treatment course includes 1) if they stayed on the study drug at the initial dose, 2) stayed on 
the study drug at a different dose, 3) switched to an alternate therapy, and/or 4) underwent 
further cardiac testing. 
 
• 
Schedule of Clinical and Laboratory Evaluations: Potential subjects will be  recruited  from  the physician 
investigators’ (Tremmel, Schnittger, and Rogers) outpatient clinics. Informed consent will be sought, and if 
obtained, subjects will be screened for eligibility by reviewing the inclusion and exclusion criteria. If 
successfully enrolled in the trial, they will be scheduled for their baseline visit, which may occur on the same 
day as screening. Baseline data, including demographics, cardiac risk factors, current cardiac medications, 
results of prior cardiac testing, and prior cardiac events will be collected. The subject will also complete the  
SAQ and SF-12.  Following  data  collection, the  subject will be  randomized  to their assigned treatment 
arm. They will be given their study drug and instructed to take their study drug once a day for 30 days. They 
will also be given a diary and instructions for use. Their 30-day visit will be scheduled, along with an optional 
exercise treadmill test. The 30-day visit will need to occur while the subject is still on the study drug, so may 
occur anywhere within days 25 to 30. At 5 days and 2 days prior to their 30­day follow­up visit, subjects will 
be sent HIPAA-compliant reminders via the phone and electronic messaging about their upcoming visit, as 
well as the need to bring their pill bottles, unused study drug (if any), and diary. At the 30-day follow­up visit, 
subjects will repeat the SAQ and SF-12, and complete data collection about adherence (pill count), side 
effects, and subsequent cardiac events. They will also undergo an exercise treadmill test (ETT) if they 
agreed to one being ordered. Once all requirements for the 30­day follow-up visit are complete, the subject 
and their physician will be unblinded to their treatment  assignment.  They will then begin  usual  care  as 
determined by their treating physician. Similar to the 30-day visit, at 5 days and 2 days prior to their 6-
­month follow­up visit, subjects will be sent HIPAA-compliant reminders via the phone and electronic 
messaging about their upcoming visit. At the 6­month follow-up visit, subjects will be asked to complete a 
final SAQ and SF-12, and data will be collected regarding  any  subsequent cardiac  events, as  well as their 
treatment course following unblinding. Once they have  completed  all  requirements  for  their  6 month 
follow-up visit, their participation in the study will end. All variables to be collected are detailed in the Data 
Management Plan. The Schedule of Evaluations is presented in the Figure below. 


Study Visit 
Screening 
Day 0 
(Baseline) 
5 days and 
2 
days 
prior 
to 
follow-­up 
visit 
30-­day visit 
(Between 
Day 25-­30) 
6-­month 
visit 
Informed Consent Form (ICF) 
X 
Inclusion/Exclusion Criteria reviewed 
X 
Subject scheduled for initial visit-­Day 0 (Baseline) 
X 
Demographics 
X 
Cardiac risk factors 
X 
Review of medications 
X 
Results of prior cardiac testing (including exercise 
parameters of exercise stress echo, and CCTA) 
X 
Medical history, including prior cardiac events 
X 
Seattle angina questionnaire (SAQ) and SF-12 
X 
X 
X 
Randomization 
X 
Instructions for study drug and diary 
X 
Schedule 30-­day and 6-month visits 
X 
Reminders via phone and e-­mail about diary, pill 
bottles, and 30-­day/6-­month follow-­up visit 
X 
 
Exercise treadmill test (if applicable) 
X 
Subsequent cardiac events 
X 
X 
Pill count for adherence 
X 
Side effects 
X 
Unblinding 
X 
Treatment course 
 
X 
Study completion 
X 
 
 
 
• 
Study Population: The sample size is 360 subjects. Based on our previous experience, we expect 
60% will be men and 40% will be women. They are expected to range in age from 18 years to 80 years. 
Given our catchment area, the majority of subjects will come from within a 120 mile radius of the San 
Francisco Bay area. Based on our local demographics, the vast majority (70%) will be white (18% of 
which are Hispanic), and approximately 11% will be Asian, with the remainder being Native Indian, 
Pacific Islander, or black. All patients will have stable angina in the absence of obstructive CAD and an 
MB, but will otherwise be relatively healthy. 
 
• 
Statistical Design and Power: We will enroll 120 subjects in each treatment arm for a total of 360 
subjects. The sample size per treatment arm was calculated through a simulation study, using 
ANCOVA models. We found we need 120 subjects per treatment arm (360 total) to find a clinically 
meaningful and statistically significant effect in the primary outcome (>10 change in SAQ), assuming 


moderate variation (standard deviation=4) with at least 0.80 power. To determine the primary endpoint, 
we will evaluate changes (post- minus pre-treatment) in each of the five SAQ subscales with an 
ANCOVA that includes pre-treatment SAQ subscale scores and treatment as explanatory variables. We 
will compare the treatment effect of beta blocker and calcium channel blocker to each other and to the 
control (placebo) for each of the five subscales. This analysis plan adheres to the intent-­to-­treat 
principle; all randomized subjects will be included in the analysis and analyzed according to their 
original treatment assignment. If a subject stops treatment prior to the 30-­day follow-­up, we will only 
use the subject’s baseline measurements in the primary analysis, but will complete a sensitivity 
analysis that evaluates the endpoint in the presence of these measurements by accounting for the 
number of days on the assigned treatment. Subjects will be instructed to take their study drug once a 
day for 30 days. Adherence will be assessed by pill count. With regard to intervention discontinuation, 
subjects may withdraw voluntarily from participation in the study at any time and for any reason. If given 
permission, we will continue to follow subjects even if the study intervention is discontinued. If any 
subject discontinues because of an adverse event or serious adverse event, safety data will continue to 
be collected. 
 
• 
Group Assignment: We will use stratified randomization. Specifically, subjects will be randomly 
assigned to a treatment arm: beta blocker (nebivolol), calcium channel blocker (diltiazem), or placebo 
(1:1:1), stratified on sex to ensure a balance of women and men in each arm. 
 
• 
Subject Participation Duration: 6 months. 
 
• 
Study Duration: Estimated time from when the study opens to enrollment to completion of data 
collection is 51 months. Estimated time from when the study opens to enrollment to final data analyses 
is 54 months.