Myocardial Bridging
Conditions
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.
Interventions
DRUGNebivolol
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.
DRUGDiltiazem
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.
OTHERPlacebo
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.
Sponsors
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Age ≥18 years 2. Stable angina (typical or atypical, based on Diamond criteria (35)) 3. Exercise stress echocardiogram or exercise stress test (with beta blocker or calcium channel blocker held) performed within six months of enrollment 4. CCTA or invasive coronary angiogram confirming the presence of an MB 5. Absence of obstructive CAD, as demonstrated by no ischemia on stress testing and no significant obstructive CAD (coronary stenosis \<50%) on CCTA or invasive coronary angiogram
Exclusion criteria
1. Asymptomatic 2. Status--post heart transplant 3. Presence of another likely explanation of chest pain, such as pulmonary hypertension, hypertrophic obstructive cardiomyopathy, or aortic stenosis 4. Presence of an acute coronary syndrome (unstable angina, NSTEMI, or STEMI), Tako--tsubo, or cardiogenic shock 5. An abnormal left ventricular ejection fraction (EF\<55%) 6. History of a severe adverse reaction to beta blockers or calcium channel blockers (prior minor intolerance or ineffectiveness not exclusion) 7. Use of existing medication that has an unsafe drug--drug interaction with beta blockers or calcium channel blockers 8. Refusal to take beta blockers or calcium channel blockers 9. Resting systolic blood pressure \<100 mmHg or heart rate \<50 beats per minute 10. Inability to provide an informed consent, including an inability to speak, read, or understand English or Spanish 11. A hearing impairment that won't allow for a typical verbal conversation or a visual impairment that won't allow for reading of the written consent 12. A potentially vulnerable subject (including pregnant women, prisoners, economically and educationally disadvantaged, decisionally impaired, and institutionalized individuals)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | baseline and 30 days | Effectiveness of beta blockers and calcium channel blockers for reducing angina in patients with a Myocardial Bridge (MB) compared to placebo determined after 30 days on the study drug by a change in angina, as assessed by the Seattle Angina Questionnaire (SAQ). The SAQ assesses 5 domains: physical limitation, angina stability angina frequency, treatment satisfaction, and quality of life. Each domain score is normalized to a range of 0 to 100, with higher scores corresponding to better outcomes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duke Treadmill Score | baseline, 30 days | The Duke treadmill score is calculated as exercise time × (5 × ST-segment deviation) - (4 × exercise angina), with 0 = no angina, 1 = non-limiting angina, and 2 = exercise-limiting angina. Possible scores range from -25 (highest risk) to +15 (lowest risk). |
| Number of Participants With Cardiac Events | 30 days, 6 months | Major adverse cardiovascular events include death, heart attack, coronary stent or bypass surgery, and stroke. |
| Duke Treadmill Score by Risk Category | baseline, 30 days | Changes in exercise capacity will be measured by difference in exercise time increment between the groups. The Duke treadmill score is calculated as exercise time × (5 × ST-segment deviation) - (4 × exercise angina), with 0 = no angina, 1 = non-limiting angina, and 2 = exercise-limiting angina. Possible scores range from -25 (highest risk) to +15 (lowest risk). Scores are reported by the number of participants in each risk category: low risk (≥+5), moderate risk (-10 to +4) and high risk (≤-11) (Shaw, et al, 1998). |
| Number of Participants With Side Effects | 30 days | Patient self-reported side effects recorded in a diary to be turned in at 30 days. In addition, patients are requested to contact us regarding any serious side effects during the study. Finally, patients are asked about any side effects they experienced during their 30-day follow-up to ensure that symptoms are captured. |
| Treatment Course | 6 months | Number of participants who stayed on the study drug at the initial dose, stayed on the study drug at a different dose, switched to an alternate therapy, and/or underwent further cardiac testing. |
| Drug Adherence. | 30 days | Percentage of drug taken by participants, measured by pill count at the end of 30 days. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Beta Blocker (Nebivolol) Participants receive oral beta blocker (nebivolol 2.5 mg) once a day for 30 days. | 2 |
| Calcium Channel Blocker (Diltiazem) Participants receive oral calcium channel blocker (Diltiazem-SR 120 mg) once a day for 30 days. | 1 |
| Placebo Participants receive placebo once a day for 30 days. | 2 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Beta Blocker (Nebivolol) | Calcium Channel Blocker (Diltiazem) | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 1 | 0 / 2 |
| other Total, other adverse events | 0 / 2 | 0 / 1 | 0 / 2 |
| serious Total, serious adverse events | 0 / 2 | 0 / 1 | 0 / 2 |
Outcome results
Primary
Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ)
Effectiveness of beta blockers and calcium channel blockers for reducing angina in patients with a Myocardial Bridge (MB) compared to placebo determined after 30 days on the study drug by a change in angina, as assessed by the Seattle Angina Questionnaire (SAQ). The SAQ assesses 5 domains: physical limitation, angina stability angina frequency, treatment satisfaction, and quality of life. Each domain score is normalized to a range of 0 to 100, with higher scores corresponding to better outcomes.
Time frame: baseline and 30 days
Population: Participants with data at the respective time point
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Beta Blocker (Nebivolol) | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Physical limitation - baseline | 44.4 score on a scale | Standard Deviation 24.4 |
| Beta Blocker (Nebivolol) | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Physical limitation - 30 days | 53.6 score on a scale | Standard Deviation 24.5 |
| Beta Blocker (Nebivolol) | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Angina stability - baseline | 40 score on a scale | Standard Deviation 0 |
| Beta Blocker (Nebivolol) | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Angina stability - 30 days | 50 score on a scale | Standard Deviation 30 |
| Beta Blocker (Nebivolol) | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Angina frequency - baseline | 70 score on a scale | Standard Deviation 0 |
| Beta Blocker (Nebivolol) | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Angina frequency - 30 days | 80 score on a scale | Standard Deviation 10 |
| Beta Blocker (Nebivolol) | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Treatment satisfaction - baseline | 67.7 score on a scale | Standard Deviation 8.9 |
| Beta Blocker (Nebivolol) | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Treatment satisfaction - 30 days | 64.7 score on a scale | Standard Deviation 11.8 |
| Beta Blocker (Nebivolol) | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Quality of life - baseline | 41.6 score on a scale | Standard Deviation 25 |
| Beta Blocker (Nebivolol) | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Quality of life - 30 days | 54.1 score on a scale | Standard Deviation 20.9 |
| Calcium Channel Blocker (Diltiazem) | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Quality of life - baseline | 41.7 score on a scale | — |
| Calcium Channel Blocker (Diltiazem) | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Physical limitation - baseline | 62.2 score on a scale | — |
| Calcium Channel Blocker (Diltiazem) | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Angina frequency - 30 days | 80 score on a scale | — |
| Calcium Channel Blocker (Diltiazem) | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Angina frequency - baseline | 60 score on a scale | — |
| Calcium Channel Blocker (Diltiazem) | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Physical limitation - 30 days | 68.0 score on a scale | — |
| Calcium Channel Blocker (Diltiazem) | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Quality of life - 30 days | 58.3 score on a scale | — |
| Calcium Channel Blocker (Diltiazem) | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Treatment satisfaction - 30 days | 94.1 score on a scale | — |
| Calcium Channel Blocker (Diltiazem) | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Angina stability - baseline | 40 score on a scale | — |
| Calcium Channel Blocker (Diltiazem) | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Treatment satisfaction - baseline | 100 score on a scale | — |
| Calcium Channel Blocker (Diltiazem) | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Angina stability - 30 days | 60 score on a scale | — |
| Placebo | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Treatment satisfaction - 30 days | 29.4 score on a scale | — |
| Placebo | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Angina stability - 30 days | 20 score on a scale | Standard Deviation 0 |
| Placebo | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Angina frequency - baseline | 75 score on a scale | Standard Deviation 25 |
| Placebo | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Angina frequency - 30 days | 30 score on a scale | — |
| Placebo | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Quality of life - baseline | 37.5 score on a scale | Standard Deviation 20.9 |
| Placebo | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Treatment satisfaction - baseline | 76.5 score on a scale | Standard Deviation 5.85 |
| Placebo | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Physical limitation - baseline | 53.4 score on a scale | Standard Deviation 15.6 |
| Placebo | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Quality of life - 30 days | 25 score on a scale | — |
| Placebo | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Physical limitation - 30 days | 17.8 score on a scale | — |
| Placebo | Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ) | Angina stability - baseline | 80 score on a scale | Standard Deviation 20 |
Secondary
Drug Adherence.
Percentage of drug taken by participants, measured by pill count at the end of 30 days.
Time frame: 30 days
Population: Participants with data through 30 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Beta Blocker (Nebivolol) | Drug Adherence. | 99.5 percentage of drug taken | Standard Deviation 0.5 |
| Calcium Channel Blocker (Diltiazem) | Drug Adherence. | 100 percentage of drug taken | — |
| Placebo | Drug Adherence. | 100 percentage of drug taken | — |
Secondary
Duke Treadmill Score
The Duke treadmill score is calculated as exercise time × (5 × ST-segment deviation) - (4 × exercise angina), with 0 = no angina, 1 = non-limiting angina, and 2 = exercise-limiting angina. Possible scores range from -25 (highest risk) to +15 (lowest risk).
Time frame: baseline, 30 days
Population: Participants with data at the respective time point
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Beta Blocker (Nebivolol) | Duke Treadmill Score | Baseline | 2.3 score on a scale | Standard Deviation 2.35 |
| Beta Blocker (Nebivolol) | Duke Treadmill Score | 30 days | 2 score on a scale | — |
| Calcium Channel Blocker (Diltiazem) | Duke Treadmill Score | Baseline | 3.0 score on a scale | — |
| Calcium Channel Blocker (Diltiazem) | Duke Treadmill Score | 30 days | 10 score on a scale | — |
| Placebo | Duke Treadmill Score | Baseline | 1.5 score on a scale | Standard Deviation 4.95 |
| Placebo | Duke Treadmill Score | 30 days | -11 score on a scale | — |
Secondary
Duke Treadmill Score by Risk Category
Changes in exercise capacity will be measured by difference in exercise time increment between the groups. The Duke treadmill score is calculated as exercise time × (5 × ST-segment deviation) - (4 × exercise angina), with 0 = no angina, 1 = non-limiting angina, and 2 = exercise-limiting angina. Possible scores range from -25 (highest risk) to +15 (lowest risk). Scores are reported by the number of participants in each risk category: low risk (≥+5), moderate risk (-10 to +4) and high risk (≤-11) (Shaw, et al, 1998).
Time frame: baseline, 30 days
Population: Participants with data at the respective time point
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Beta Blocker (Nebivolol) | Duke Treadmill Score by Risk Category | Low risk - baseline | 0 Participants |
| Beta Blocker (Nebivolol) | Duke Treadmill Score by Risk Category | Moderate risk - baseline | 2 Participants |
| Beta Blocker (Nebivolol) | Duke Treadmill Score by Risk Category | High risk - baseline | 0 Participants |
| Beta Blocker (Nebivolol) | Duke Treadmill Score by Risk Category | Low risk - 30 days | 0 Participants |
| Beta Blocker (Nebivolol) | Duke Treadmill Score by Risk Category | Moderate risk - 30 days | 1 Participants |
| Beta Blocker (Nebivolol) | Duke Treadmill Score by Risk Category | High risk - 30 days | 0 Participants |
| Calcium Channel Blocker (Diltiazem) | Duke Treadmill Score by Risk Category | High risk - 30 days | 0 Participants |
| Calcium Channel Blocker (Diltiazem) | Duke Treadmill Score by Risk Category | Low risk - baseline | 0 Participants |
| Calcium Channel Blocker (Diltiazem) | Duke Treadmill Score by Risk Category | Low risk - 30 days | 1 Participants |
| Calcium Channel Blocker (Diltiazem) | Duke Treadmill Score by Risk Category | Moderate risk - 30 days | 0 Participants |
| Calcium Channel Blocker (Diltiazem) | Duke Treadmill Score by Risk Category | Moderate risk - baseline | 1 Participants |
| Calcium Channel Blocker (Diltiazem) | Duke Treadmill Score by Risk Category | High risk - baseline | 0 Participants |
| Placebo | Duke Treadmill Score by Risk Category | Moderate risk - baseline | 2 Participants |
| Placebo | Duke Treadmill Score by Risk Category | High risk - baseline | 0 Participants |
| Placebo | Duke Treadmill Score by Risk Category | High risk - 30 days | 1 Participants |
| Placebo | Duke Treadmill Score by Risk Category | Low risk - 30 days | 0 Participants |
| Placebo | Duke Treadmill Score by Risk Category | Low risk - baseline | 0 Participants |
| Placebo | Duke Treadmill Score by Risk Category | Moderate risk - 30 days | 0 Participants |
Secondary
Number of Participants With Cardiac Events
Major adverse cardiovascular events include death, heart attack, coronary stent or bypass surgery, and stroke.
Time frame: 30 days, 6 months
Population: Participants with data at the respective time point
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Beta Blocker (Nebivolol) | Number of Participants With Cardiac Events | 30 days | 0 Participants |
| Beta Blocker (Nebivolol) | Number of Participants With Cardiac Events | 6 months | 0 Participants |
| Calcium Channel Blocker (Diltiazem) | Number of Participants With Cardiac Events | 30 days | 0 Participants |
| Calcium Channel Blocker (Diltiazem) | Number of Participants With Cardiac Events | 6 months | 0 Participants |
| Placebo | Number of Participants With Cardiac Events | 30 days | 0 Participants |
| Placebo | Number of Participants With Cardiac Events | 6 months | 0 Participants |
Secondary
Number of Participants With Side Effects
Patient self-reported side effects recorded in a diary to be turned in at 30 days. In addition, patients are requested to contact us regarding any serious side effects during the study. Finally, patients are asked about any side effects they experienced during their 30-day follow-up to ensure that symptoms are captured.
Time frame: 30 days
Population: Participants with data at 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Beta Blocker (Nebivolol) | Number of Participants With Side Effects | 0 Participants |
| Calcium Channel Blocker (Diltiazem) | Number of Participants With Side Effects | 0 Participants |
| Placebo | Number of Participants With Side Effects | 0 Participants |
Secondary
Treatment Course
Number of participants who stayed on the study drug at the initial dose, stayed on the study drug at a different dose, switched to an alternate therapy, and/or underwent further cardiac testing.
Time frame: 6 months
Population: Participants with data at 6 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Beta Blocker (Nebivolol) | Treatment Course | Stayed on study drug at the initial dose | 2 Participants |
| Beta Blocker (Nebivolol) | Treatment Course | Stayed on study drug at a different dose | 0 Participants |
| Beta Blocker (Nebivolol) | Treatment Course | Switched to alternate therapy | 0 Participants |
| Beta Blocker (Nebivolol) | Treatment Course | Underwent further cardiac testing | 0 Participants |
| Calcium Channel Blocker (Diltiazem) | Treatment Course | Underwent further cardiac testing | 0 Participants |
| Calcium Channel Blocker (Diltiazem) | Treatment Course | Stayed on study drug at the initial dose | 0 Participants |
| Calcium Channel Blocker (Diltiazem) | Treatment Course | Switched to alternate therapy | 0 Participants |
| Calcium Channel Blocker (Diltiazem) | Treatment Course | Stayed on study drug at a different dose | 1 Participants |
| Placebo | Treatment Course | Underwent further cardiac testing | 0 Participants |
| Placebo | Treatment Course | Stayed on study drug at a different dose | 0 Participants |
| Placebo | Treatment Course | Switched to alternate therapy | 1 Participants |
| Placebo | Treatment Course | Stayed on study drug at the initial dose | 0 Participants |