Using Mirabegron to Increase Blood Pressure in Patients With Postural Orthostatic Tachycardia Syndrome
Phase: PHASE2
Conditions: Postural Orthostatic Tachycardia Syndrome, Chronic Orthostatic Intolerance, Syncope
Sponsor: Cedars-Sinai Medical Center

 
 
 
 
Using Mirabegron to Increase Blood Pressure in Patients 
with Postural Orthostatic Tachycardia Syndrome 
Principal Investigator: Peng-Sheng Chen, MD 
Sponsor: Peng-Sheng Chen, MD 
Funded by: the American Heart Association 
Version Number: 5.0 
12 December 2024 
 
Summary of Changes from the Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
1.1, 1.2, 1.3, 
3.0, 9.1 
 Addition of QOL questionnaire PROMIS SF 8a 
 This questionnaire is a self-reported 
measure of physical, mental, and social 
health in relation to fatigue. We believe 
this may we one of the mechanisms the 
study drug, Mirabegron, has had a positive 
impact on our patient population and 
would use this questionnaire to evaluate 
that relationship. 

  
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 3 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 4 
2 
INTRODUCTION ............................................................................................................................................ 4 
2.1 
Study Rationale .................................................................................................................................... 4 
2.2 
Background........................................................................................................................................... 5 
2.3 
Risk/Benefit Assessment .................................................................................................................... 5 
2.3.1 
Known Potential Risks ..................................................................................................... 5 
2.3.2 
Known Potential Benefits ................................................................................................ 6 
2.3.3 
Assessment of Potential Risks and Benefits ................................................................ 6 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 7 
4 
STUDY DESIGN ............................................................................................................................................. 8 
4.1 
Overall Design ...................................................................................................................................... 8 
4.2 
Scientific Rationale for Study Design................................................................................................ 9 
4.3 
Justification for Dose ........................................................................................................................... 9 
4.4 
End of Study Definition ....................................................................................................................... 9 
5 
STUDY POPULATION .................................................................................................................................. 9 
5.1 
Inclusion Criteria ................................................................................................................................ 10 
5.2 
Exclusion Criteria ............................................................................................................................... 10 
5.3 
Lifestyle Considerations .................................................................................................................... 10 
5.4 
Screen Failures .................................................................................................................................. 11 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 11 
6 
STUDY INTERVENTION ............................................................................................................................ 11 
6.1 
Study Intervention(s) Administration ............................................................................................... 11 
6.1.1 
Study Intervention Description ..................................................................................... 11 
6.1.2 
Dosing and Administration ............................................................................................ 11 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 12 
6.2.1 
Acquisition and accountability ...................................................................................... 12 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 12 
6.2.3 
Product Storage and Stability ....................................................................................... 12 
6.2.4 
Preparation ...................................................................................................................... 12 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 12 
6.4 
Study Intervention Compliance ........................................................................................................ 12 
6.5 
Concomitant Therapy ........................................................................................................................ 13 
6.5.1 
Rescue Medicine ............................................................................................................ 13 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 13 
7.1 
Discontinuation of Study Intervention ............................................................................................. 13 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 13 
7.3 
Lost to Follow-Up ............................................................................................................................... 14 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 14 
8.1 
Efficacy Assessments ....................................................................................................................... 14 
8.2 
Safety and Other Assessments ....................................................................................................... 14 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 15 

  
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 15 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 15 
8.3.3 
Classification of an Adverse Event .............................................................................. 15 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 16 
8.3.5 
Adverse Event Reporting .............................................................................................. 17 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 17 
8.3.7 
Reporting Events to Participants ................................................................................. 18 
8.3.8 
Events of Special Interest ............................................................................................. 18 
8.3.9 
Reporting of Pregnancy ................................................................................................ 18 
8.4 
Unanticipated Problems .................................................................................................................... 18 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 18 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 18 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 19 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 19 
9.1 
Statistical Hypotheses ....................................................................................................................... 19 
9.2 
Sample Size Determination .............................................................................................................. 19 
9.3 
Populations for Analyses .................................................................................................................. 20 
9.4 
Statistical Analyses............................................................................................................................ 20 
9.4.1 
General Approach .......................................................................................................... 20 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 20 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 20 
9.4.4 
Safety Analyses .............................................................................................................. 20 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 20 
9.4.6 
Planned Interim Analyses ............................................................................................. 20 
9.4.7 
Sub-Group Analyses ..................................................................................................... 21 
9.4.8 
Tabulation of Individual participant Data .................................................................... 21 
9.4.9 
Exploratory Analyses ..................................................................................................... 21 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 21 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 21 
10.1.1 
Informed Consent Process ........................................................................................... 21 
10.1.2 
Study Discontinuation and Closure ............................................................................. 22 
10.1.3 
Confidentiality and Privacy ........................................................................................... 22 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 23 
10.1.5 
Key Roles and Study Governance .............................................................................. 23 
10.1.6 
Safety Oversight ............................................................................................................. 23 
10.1.7 
Quality Assurance and Quality Control ....................................................................... 23 
10.1.8 
Data Handling and Record Keeping ............................................................................ 24 
10.1.9 
Protocol Deviations ........................................................................................................ 25 
10.1.10 
Publication and Data Sharing Policy ........................................................................... 25 
10.1.11 
Conflict of Interest Policy .............................................................................................. 25 
10.2 
Additional Considerations ................................................................................................................. 25 
10.3 
Abbreviations ...................................................................................................................................... 27 
10.4 
Protocol Amendment History ........................................................................................................... 29 
11 
REFERENCES ............................................................................................................................................. 31 
 

Using Mirabegron to Increase Blood Pressure in Patients with Postural Orthostatic Tachycardia Syndrome 
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STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
American Heart Association (AHA)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of AHA-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Using mirabegron to prevent syncope in patients with postural orthostatic 
tachycardia syndrome  
Study Description: 
This is a pilot dose-finding study to test the hypothesis that mirabegron 
increases systolic blood pressure (BP), prevents syncope/presyncope and 
improves the quality of life (QOL), functional capacity, chest pain, and 
overactive bladder (OAB) symptoms in patients with postural orthostatic 
tachycardia syndrome (POTS) who have a documented history of 
hypotension inadequately responsive to conventional treatments. We will 
perform 24-hr ambulatory blood pressure monitoring (ABPM) and 
ambulatory skin sympathetic nerve activity (SKNA) recording using a 
Bittium Faros electrocardiogram (ECG) monitor, assess the number of 
syncope and presyncope episodes and determine the symptoms using 
validated questionnaires at baseline. The patients will then be given 
mirabegron (either 25 mg once daily or 50 mg once daily) for 8 weeks. 
Afterwards, the patient will return to clinic for clinical assessments, 
complete questionnaires, ABPM and ambulatory SKNA recording while still 
on treatment. Mirabegron will be stopped when the data collection is 
complete. Because mirabegron has a long half-life, we will schedule a 
video visit with the patient 12 weeks after beginning the treatment and 
inquire about the patient’s symptoms. We will repeat all pertinent 
questionnaires at that time. 

Using Mirabegron to Increase Blood Pressure in Patients with Postural Orthostatic Tachycardia Syndrome 
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Objectives: 
 
Primary Objective:  To test the hypothesis that mirabegron increases 
systolic BP. 
 
Secondary Objectives: To test the hypotheses that mirabegron  
1) Prevents syncope/presyncope 
2) Improves QOL, functional capacity, chest pain, and OAB symptoms  
 
 
Endpoints: 
Primary Endpoint:  
- 
Mirabegron increases the average systolic BP in 24-hr ABPM 
recording. 
 
Secondary Endpoints:  
- 
Reduction in frequencies of syncope and presyncope as 
determined by subject symptom diary 
- 
Reduction of the hypotensive (systolic BP < 90 mmHg) episodes 
during wake time in 24-hr ABPM 
- 
Improvement of QOL as measured by the EQ-5D-5L 
- 
Improvement of functional capacity as measured by the Duke 
Activity Status Index (DASI) 
- 
Improvement of chest pain as measured by Seattle Angina 
Questionnaire (SAQ) 
- 
Improvement in OAB symptoms as measured by the overactive 
bladder questionnaire (OAB-q SF)  
- 
Improvement of POTS symptom severity as measured by the 
Malmö POTS Score (MAPS) 
- 
Improvement of sexual function in female participants as 
measured by the Female Sexual Function Index (FSFI) 
- 
Improvement of fatigue symptoms as measured by PROMIS SF 
Fatigue 8a 
- 
Reduction of postural heart rate elevation 
Study Population: 
This pilot study will enroll 20 patients with POTS who have a documented 
history of hypotension inadequately responsive to conventional 
treatment.  
Phase: 
Pilot 
Description of 
Sites/Facilities Enrolling 
Participants: 
The study will enroll patients treated at the Cedars-Sinai Medical Center.  
This is a single site study. 
 
Description of Study 
Intervention: 
Patients will be randomly assigned 1:1 to receive mirabegron (25 mg or 50 
mg once daily) orally for 8 weeks.  
Study Duration: 
24 months. 
Participant Duration: 
Approximately 14 weeks. 
 
 
 
 

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1.2 
SCHEMA 
 
       
 
 
 
 
 
 
8 Week Follow-Up Visit: 12-lead ECG, Active Standing Test, SKNA monitoring using Faros 
recorder, 24-hour ABPM recording, vitals, EQ-5D-5L, DASI, SAQ, OAB-q SF, MAP, FSFI, 
PROMIS SF Fatigue 8a, symptom diary, assess safety endpoints and adverse events. After the 
visit, the subject has the option to continue mirabegron as part of routine care or discontinue 
Discontinue 
mirabegron and end 
study participation 
No 
Can tolerate 
mirabegron  
Yes
12 Week Follow-Up: assess adverse events and safety endpoints using participant’s preferred 
contact methods (phone, email, or teleconference).  
Baseline Visit: Obtain informed consent, medical history/demographic 
information, 12-lead ECG, Active Standing Test, SKNA monitoring using 
Faros recorder, symptom diary, EQ-5D-5L, DASI, SAQ, OAB-q SF, 
MAP, FSFI, PROMIS SF Fatigue 8a, randomly assigned 1:1 to 25 
mg or 50 mg mirabegron once daily, drug administration 
POTS with Pre-Syncope or Syncope and 
24-hr ABPM showing systolic hypotension 
4 Week Follow-Up: assess adverse events and safety endpoints using participant’s preferred 
contact methods (phone, email, or teleconference).  

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Baseline Visit2 
 
4 Week Follow-
Up (+/- 1 week)4 
8 Week Follow-
Up Visit (+/- 1 
week)3 
 
12 Week 
Follow-Up (+/- 
1 week)4 
Screening and eligibility 
x 
 
 
 
Obtain informed consent 
x 
 
 
 
Medical 
history/demographics 
x 
 
 
 
Concomitant medication 
review 
x 
 
 
 
Vitals 
x 
 
x 
 
12-lead ECG 
x 
 
x 
 
EQ-5D-5L, DASI, SAQ, 
MAP, FSFI, OAB-q SF, and 
PROMIS SF Fatigue 8a8 
x 
 
x 
 
Ambulatory SKNA recording 
and symptom diary5 
x 
 
x 
 
24-hour ABPM6 
x1 
 
x 
 
Active Standing Test7 
x 
 
x 
 
Study drug dispense 
x 
 
 
 
Assess for safety endpoints 
and adverse events 
 
x 
x 
x 
Subject Parking Validation 
x 
 
x 
 
1. 
24-Hour ABPM (conducted as routine clinical care) showing systolic hypotension up to 6 months prior to informed consent 
will be collected and used as part of Baseline visit study data. In this case, 24-Hour ABPM may not need to be repeated at 
Baseline visit. 
2. 
Baseline Visit to be conducted in-person in clinic. Informed consent to be obtained in person or virtually through 
DocuSign. All study activities to be completed in-person, virtually, and/or via mail.  
3. 
8 Week Follow-Up Visit to be conducted in-person in clinic. 8 Week Follow-Up Visit to occur 8 weeks after the subject 
begins the mirabegron treatment.  
4. 
4 Week and 12 Week Follow-Up to be conducted using subjects preferred contact method (phone, email, or 
teleconference). 4 Week Follow-Up will occur 4 weeks after subject begins initial mirabegron treatment. 12 Week Follow-
Up to occur 12 weeks after subject begins initial mirabegron treatment.  
5. 
Ambulatory SKNA recording to be measured for 1-7 days. 
6. 
ABPM recording of at least 24-hours but may be completed for longer than 24-hours. 
7. 
If the patient cannot tolerate the active standing test, it will not be conducted/completed 
8. 
Questionnaires will be administered via REDCap or in person, based on participant preference  
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
Chronic orthostatic intolerance syndrome is a disease that often affects multiple organ systems. 
The cardiovascular involvement leads to the diagnosis of postural orthostatic tachycardia (POTS) or 
postural syndrome without tachycardia (PSWT).1 POTS and PSWT are both characterized by chronic (> 3 
months) orthostatic intolerance without orthostatic hypotension, but only POTS has > 30 bpm increase 
of heart rate during active standing test or tilt table test. Hypotension, labile BP, syncope, pre-syncope 
and severe dizziness are among the most common symptoms suffered by these patients. The prevalence 
of POTS is approximately 0.2% and affects approximately 500,000 people in the US alone2, 3 The 

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prevalence of PSWT is unknown. However, because orthostatic tests are not perfectly sensitive or 
reproducible, the PSWT patients likely have POTS but did not have documented 30 bpm increase of 
heart rate during a clinic visit. Since October 2022, the International Classification of Diseases Tenth 
Edition (ICD-10) added a new code (G90.A) for POTS. That code includes both chronic orthostatic 
intolerance and postural tachycardia syndrome. For the purpose of the current application, we will use 
the ICD-10 definition for POTS and recruit patients with chronic orthostatic intolerance, with or without 
a 30 bpm increase of the heart rate upon standing. 
Most patients present between the ages of 15-25 years and over 75% of them are women. 
Currently available treatment for hypotension is extremely limited. The most commonly used drugs are 
vasoconstrictors (midodrine and droxidopa). Because of the short half-lives the patients need to take 
these drugs 3 times daily. The other approach is to use fludrocortisone to increase one’s blood volume. 
Very little clinical trial data are available to document their efficacy in preventing syncope. Therefore, 
the Heart Rhythm Society consensus statement on POTS does not have a class I recommendation for 
treatment.2 Because mirabegron has an excellent long-term safety profile, is well tolerated, and has a 
very long half-life (50 hours), this therapy could make a large difference in patient’s symptoms. If 
successful, this pilot study may lead to a randomized clinical trial to document the efficacy of 
mirabegron in treating syncope in patients with POTS or PSWT. 
 
2.2 
BACKGROUND  
 
Mirabegron is the first beta-3 receptor stimulator approved by the FDA. The drug is currently 
indicated in treating OAB. A major off-target effect of this drug is to increase BP. While others have 
speculated that mirabegron may be useful in treating patients with orthostatic hypotension and 
dysautonomia,4, 5 none provided evidence to support that hypothesis. Therefore, the present study is an 
innovative approach to managing patients with recurrent syncope. Furthermore, mirabegron may also 
reduce OAB symptoms, which is common in this patient population.  
Three patients seen in the PI’s POTS clinic responded to mirabegron by increasing BP and eliminating 
syncope. The first patient is a 69-year old woman referred for orthostatic hypotension and syncope. The 
patient also suffered from OAB. After treatment with mirabegron for OAB, she had significantly 
improved BP and no longer had syncope or dizziness. The second patient was referred for syncope, low 
BP, and POTS. Treatment with mirabegron resulted in stable BP and no syncopal episodes. The third 
patient is a 20-year-old woman with orthostatic intolerance, labile BP, syncope secondary to orthostatic 
hypotension, suspected Lupus, and iron deficiency anemia. After receiving mirabegron, patient denied 
any syncopal episodes and BP improved. The PI has identified other patients with syncope who might 
benefit from mirabegron. It is possible that mirabegron, by virtue of its stable drug concentration over 
long periods of time, is effective in preventing the intermittent reduction of the BP as shown in the 24-
hour ABPM data, thus prevents syncope. These clinical observations form the basis for this prospective 
study. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
Risks associated with the use of mirabegron include hypersensitivity reactions to mirabegron. 
Use of mirabegron has been associated with increase in BP, urinary retention in patients with bladder 
outlet obstruction and in patients taking muscarinic antagonist drugs for overactive bladder, 

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angioedema, and patients taking drugs metabolized by CYP2D6. Most commonly reported adverse 
reactions were hypertension, nasopharyngitis, urinary tract infection and headache.6  
CYP2D6 interaction. Mirabegron partly acts as a (quasi-) irreversible, metabolism-dependent 
inhibitor of cytochrome p450 2D6 (CYP2D6).7 It should not be given to patients who are taking drugs 
metabolized by CYP2D6. In addition, mirabegron is metabolized by CYP3A and to a minor extent by 
CYP2D6 in humans.8 The mirabegron label notes that CYP2D6 poor metabolizers had increased 
concentrations of the drug as compared to CYP2D6 extensive metabolizers. However, the effect of 
CYP2D6 phenotype on mirabegron exposure is small and likely of limited clinical importance.8  
 
 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
Mirabegron is a beta-3 activator approved by the United States and the European Union in 2012 to treat 
patients with OAB syndrome. In 2017, mirabegron was among the top 200 drugs prescribed in the US, 
with more than one million prescriptions.9 The safety of mirabegron is well documented by randomized 
clinical trials that showed the adjudicated cardiovascular events to be comparable for the placebo and 
mirabegron groups.10, 11 No adverse events of QTc prolongation or proarrhythmic events were noted. A 
randomized clinical trial in patients with heart failure showed promising effects on left ventricular 
ejection fraction and that the treatment is safe and well tolerated.12 The mechanism of action of 
mirabegron in OAB is the activation of the detrusor smooth muscle to increase bladder capacity and 
reduce incontinence. A known off-target (side) effect of mirabegron is the elevation of BP, which may 
prevent recurrent syncope due to hypotension. If successful, this clinical trial may significantly improve 
the management of syncope. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Potential benefits 
The cardiovascular effects of beta-3 stimulation have been studied in both animal models and humans. 
The Principal Investigator’s lab showed that BRL-37344 (a beta-3 stimulator) effectively suppresses the 
ventricular tachycardia in a canine model.13 Dogs receiving BRL-37344 had shorter QTc, lighter heart 
weight, lower protein levels for sodium calcium exchanger and dihydropyridine receptor and higher 
beta-3 adrenoceptor expression than the control dogs. There were no changes in beta 1 or beta 2 
adrenoceptor expression. A randomized clinical trial in patients with heart failure showed promising 
effects on left ventricular ejection fraction and that the treatment is safe and well tolerated.12   
 
 
Potential risks 
Subjects may experience adverse reactions such as hypertension, nasopharyngitis, urinary tract 
infection, and headache. 
 
There is a small risk of skin irritation and redness from the ECG electrodes and the skin preparation.  The 
electrode application sites will be checked at time of study exit. The subject’s participation in the study 
will be terminated if the patients develop symptoms or signs of allergy to the electrode, or when the 
subject voluntarily withdrawal from the study.  
 

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The subject may experience slight discomfort with the ABP monitoring system related to continued 
inflation of the BP cuff. The cuff may also cause skin irritation or a mild rash on the arm that usually goes 
away after removal of the cuff.    
 
A randomized clinical trial with 50 mg or 100 mg once-daily doses of mirabegron showed no adverse 
events of QTc prolongation and no proarrhythmic events of ventricular tachycardia, ventricular 
fibrillation or torsades de pointes.10 Therefore, we do not think QT prolongation is a potential risk of 
mirabegron treatment. 
 
 
 
 
3 
OBJECTIVES AND ENDPOINTS 
 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
 
The primary objective is to test 
the hypothesis that mirabegron 
increases systolic BP.  
 
 
 
 
 
 
The primary endpoint is the 
average systolic BP obtained by 
24-hr ABPM. 
 
A common side effect of 
mirabegron is to increase BP. We 
will use this side effect to 
manage patients with low BP. 
Secondary 
 
 
 
The secondary objective is to 
test the hypothesis that 
mirabegron can reduce 
syncope/pre--syncope, reduce 
transient hypotensive episodes 
and improve the QOL.  
 
The secondary endpoints are: 
1. Reduction of 
frequencies of syncope 
and pre-syncope 
2. Reduction of the 
hypotensive (systolic 
BP < 90 mmHg) 
episodes during wake 
time 
3. Improvement of QOL 
as measured by EQ-5D-
5L score 
4. Improvement of 
functional capacity as 
measured by the Duke 
Activity Status Index 
(DASI) 
 
1. Syncope greatly affects the 
QOL. 
2. 20% of the patients with 
chronic orthostatic intolerance 
have OAB symptoms.  
3.  POTS is characterized by large 
HR elevation upon standing. 
Reduction of HR elevation 
during active standing test is a 
marker of improvement. 
 

Using Mirabegron to Increase Blood Pressure in Patients with Postural Orthostatic Tachycardia Syndrome 
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
5. Improvement of chest 
pain as measured by 
Seattle Angina 
Questionnaire (SAQ) 
score 
6. Improvement in OAB 
symptoms as measured 
by the OAB-q SF  
7. Improvement of POTS 
symptom severity as 
measured by the MAP 
8. Improvement of sexual 
function in female 
participants as 
measured by the 
Female Sexual Function 
Index (FSFI) 
9. Improvement of 
fatigue symptoms as 
measured by PROMIS 
SF Fatigue 8a 
10. Reduce the postural 
heart rate elevation 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
• 
A statement of the hypothesis  
o To test the hypothesis that mirabegron increases BP, prevents syncope/pre-syncope, 
and improves the QOL and OAB symptoms in patients with POTS. 
• 
 Phase of the trial 
o Pilot. 
• 
A description of the type/design of trial to be conducted (e.g., randomized, placebo-controlled, 
double-blinded, parallel design, open-label, dose escalation, dose-ranging, adaptive, cluster 
randomized, group sequential, multi-regional, superiority, or non-inferiority design)   
o This is a dose-ranging pilot study to test the hypothesis that mirabegron increases BP, 
prevents syncope/pre-syncope, and improves QOL in patients with chronic orthostatic 
intolerance syndrome. 
• 
A description of methods to be used to minimize bias 
o We will explain to the participant that this is a pilot study. The benefit of this drug 
remains unknown. 

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• 
The number of study groups/arms and study intervention duration  
o There are two group of patients. The patients are randomly assigned through REDCap to 
receive either 25 mg/day or 50 mg/day of mirabegron for 8 weeks. 
o Concomitant medication review, QOL and OAB Questionnaires are performed at all 
timepoints. 
o Assessment of adverse events, 12-lead ECG, 24-hr ABPM, ambulatory SKNA and ECG 
monitoring are performed at baseline and 8 weeks after the commencement of 
mirabegron therapy. 
• 
Indicate if single site or multi-site 
o This is a single site study. 
• 
Name of study intervention(s) 
o Mirabegron, 25 mg or 50 mg orally once daily. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
It is unclear whether the BP elevation effects of mirabegron observed in clinical trials are applicable to 
patients with syncope or presyncope. All patients will be told that mirabegron has a potential off-target 
effect of raising BP, but whether it can reduce the frequency of syncope remains unclear. In the QT/QTc 
healthy volunteer study, the maximum mean increase in supine systolic BP/diastolic BP (SBP/DBP) at a 
mirabegron dose of 50 mg was ∼4.0/1.6 mmHg greater than placebo. The 24‐hr average increases in 
systolic BP versus placebo were 3.0, 5.5, and 9.7 mmHg for the 50, 100, and 200 mg dose groups. 
Increases in diastolic BP were also dose dependent but were smaller than systolic BP. However, 
mirabegron has never been tested in the population with hypotension and syncope. It is possible that 
mirabegron, by virtue of its stable drug concentration over long period of time, is effective in preventing 
the intermittent reduction of the BP as shown in the 24-hr ABPM measurements even if it has minimal 
effects on the average BP. In theory, preventing intermittent reduction alone is sufficient to prevent 
syncope without changing the average BP. 
 
4.3 
JUSTIFICATION FOR DOSE 
 
Mirabegron is a new and expensive medication that is approved for use only in adult patients with OAB. 
This pilot study will inform the development and implementation of future clinical trials because it will 
allow the investigators to expand the use of mirabegron to patients without OAB. Even in patients with 
OAB, the insurance company often denies the coverage of mirabegron unless the patients fail other 
standard OAB drugs. This trial will streamline the use of mirabegron even in patients with OAB. The 25 
and 50 mg doses are the most commonly used to treat patients with OAB and have proven to be safe in 
previous clinical trials.  
 
4.4 
END OF STUDY DEFINITION 
 
The end of the study is defined as completion of the last visit and the ABPM/SKNA recording as shown in 
the Schedule of Activities.  
 
 
5 
STUDY POPULATION 

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5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all the following criteria: 
1. Provision of signed and dated informed consent form. 
2. Age > 18 years old. 
3. Documented history of chronic (> 3 months) of orthostatic intolerance. 
4. Diagnosis of syncope or pre-syncope and documented intermittent hypotension unresponsive to 
conventional life-style modification therapy. 
a. A history of syncope (complete loss of consciousness) or presyncope (the sensation that 
one is about to pass out). 
b. At least one documented hypotensive episode with systolic BP < 90 mmHg on 24-hr 
ABPM.  
c. Inadequate response to conventional therapies. 
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Patients with other potential etiologies of syncope 
a. Sustained tachyarrhythmias other than sinus tachycardia. Specifically, patients with a 
diagnosis of atrial fibrillation, sustained (> 30 seconds) arrhythmias including paroxysmal 
supraventricular tachycardia, atrial flutter, ventricular tachycardia, ventricular 
fibrillation. 
b. Symptomatic bradycardia before pacemaker implantation.  
2. Heart failure with either preserved or reduced ejection fraction. 
3. Wolff Parkinson-White Syndrome. 
4. Stroke within the past 6 months. 
5. Any history of myocardial infarction. 
6. Active thyrotoxicosis. 
7. Any experimental medication concomitantly or within 4 weeks of participation in the study. 
8. Patients < 18 years old because mirabegron is not approved by FDA for use in children. 
9. People with a history of allergy to ECG electrodes or adhesive tape. 
10. Patients with known contraindications or precautions to mirabegron. 
a. Hypertension 
b. Severe renal impairment (calculated CrCl < 30ml/min) 
c. Hepatic disease (Child-Pugh Class B) 
d. Pregnant or lactation  
e. Geriatric patients in long term care facilities 
f. Patients who are known to be allergic to mirabegron 
g. Patients taking drugs that are CYP2D6 substrates. An extensive list can be found at the 
following website: https://drug-interactions.medicine.iu.edu/MainTable.aspx 
11. Prisoners 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 

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Not applicable. 
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate but are not eligible to participate. 
A minimal set of screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information includes 
demographics, screen failure details, eligibility criteria, and any serious adverse event (SAE). 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
• 
Sample size: 20 subjects – age > 18 years 
• 
Anticipated accrual rate: 2 per month 
• 
All subjects will be enrolled at one US site 
• 
Vulnerable subjects will not be recruited 
• 
All sex, racial and ethnic group members will be recruited to participate in the study  
 
Patients will primarily be recruited through the Cedars Sinai Heart Institute POTS clinic at the time of 
their office visit. Study brochures will be distributed to physicians’ offices and discussed with Cedars-
Sinai physicians to help with patient referral and recruitment. We will also include study information in 
the Smidt Heart Institute Current Research website. Eligible patients will be approached by the 
investigator and coordinator. The patients will be consented by the investigator or one of the co-
investigators utilizing the informed consent form as a guide.  
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
Mirabegron 
Mirabegron is a beta-3 adrenergic agonist indicated for the treatment of OAB with symptoms of urge 
urinary incontinence, urinary urgency, and urinary frequency. A known off-target (side) effect of 
mirabegron is the elevation of BP, which may be detrimental to patients with hypertension. However, 
the off-target effect of BP elevation may be exactly what the patients need to prevent recurrent syncope 
due to hypotension. 
 
6.1.2 DOSING AND ADMINISTRATION 
 
Patients will be randomly assigned to receive mirabegron 25 mg or 50 mg oral once daily. If a dose is 
delayed or missed for less than 12 hours, the participant will be instructed to take the dose as soon as 
possible. If the dose the dose is delayed or missed for 12 hours or longer from the scheduled dose, the 

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participant should skip the dose and take only the next scheduled dose. The participant should 
document the dose that is skipped, and not take a double dose if a dose is missed.  
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
Mirabegron will be obtained from Cedars-Sinai investigational pharmacy.  
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Mirabegron is produced by Astellas Pharma US, Inc. The drug is produced as an oval, yellow, film coated 
tablet, debossed with the Astellas logo. The tablets are labeled “325” for 25 mg dose and “355” for 50 
mg dose.  
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
Mirabegron will be stored per packaging insert guidelines at 25°C with excursions permitted from 15°C 
to 30°C.  
 
 
6.2.4 PREPARATION 
 
12-week supply of study drug (Mirabegron) will be dispensed by the Cedars-Sinai investigational 
pharmacy at baseline visit.  
 
The patient will take the drugs for 8 weeks. The primary and secondary outcomes will be assessed after 
8 weeks on the drug. 12 weeks of drug coverage may be needed in case there are scheduling difficulties 
for follow-up and to allow participants time to obtain the drug themselves if they find it helpful. A 12-
week supply was recommended by the pharmacy, as mirabegron comes in 30-count bottles, dispersing 
the drug for 12 weeks will be easier. 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
This is a dose-finding pilot study with 1:1 randomization into two groups of patients receiving either 25 
mg or 50 mg dose of mirabegron. 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
The study team will assess compliance with the study intervention by: 
• 
Maintaining accurate study records and documentation of all required visit tests and procedures 
• 
All research staff will be trained in all study activities 
• 
All research staff will be trained in using the HIPAA compliant REDCap electronic data capture 
system 
• 
All tests and procedures will be reviewed by a designated research team member 
o Any abnormal result will be reported to the PI immediately 

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• 
Patients will be asked to return any remaining medication at the end of the study for 
accountability 
 
 
6.5 
CONCOMITANT THERAPY 
 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are 
concomitant prescription medications, over-the-counter medications and supplements. Current 
medications will be recorded at the baseline visit. Concomitant medications will be reviewed at each 
visit for accuracy.  
 
 
6.5.1 RESCUE MEDICINE 
 
Not applicable. 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
Discontinuation from the study drug does mean discontinuation from the study, and remaining study 
procedures should not be completed as indicated by the study protocol. If a clinically significant finding 
is identified (including, but not limited to changes from baseline) after enrollment, the investigator or 
qualified designee will determine if any change in participant management is needed. Any new clinically 
relevant finding will be reported as an adverse event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
The reasons for discontinuing the study drug 
• 
Any adverse events, serious adverse events, or unanticipated problems  
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
Pregnancy 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
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The reason for participant discontinuation or withdrawal from the study will be recorded on the Study 
Exit Case Report Form (CRF). Subjects who sign the informed consent form but do not receive the study 
intervention may be replaced.  
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she fails to return for any scheduled visits and 
is unable to be contacted by the study site staff after three attempts.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls, emails, and, if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s medical record or 
study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
 
Procedures/tests/evaluations 
 
• 
Initial screening process will be conducted via medical chart review and participant interview  
• 
Medical history/demographics will be performed by the investigator 
• 
Concomitant medications will be collected by the research team 
• 
12-lead ECG and active standing test will be conducted in clinic using standard operating 
procedures. If participant cannot tolerate the active standing test, it will not be 
conducted/completed. 
• 
QOL and OAB questionnaires will be administered by the research team in person or via REDCap 
• 
The Faros and ABPM recording devices may be mailed back to the investigator with pre-paid 
FedEx packaging 
• 
12-week supply of study drug will be dispensed by the pharmacy. The patient will take the drugs 
for 8 weeks. The primary and secondary outcomes will be assessed after 8 weeks on the drug.  
• 
Results of study specific procedures will be provided to the participant if deemed medically 
necessary by the PI and/or co-investigator(s) 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Based on FDA labeling and published literature, mirabegron is expected to have minimal adverse effects. 
However, patients with POTS have increased probability of having drug allergies. Therefore, safety 
assessments will be conducted at each study visit. The participant will periodically be assessed for 

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serious adverse events and unanticipated problems by telephone calls/text message/emails during the 
8-week period to assess safety. The study team will communicate with subjects at around 4 weeks to ask 
how they are doing, are they having any problems, side effects, problems remembering to take the 
medication. We will ask the participants for their preferred method of communication - telephone call  
or email.  Safety and effectiveness will be assessed at the end of 8 weeks via questionnaires, 7-day ECG 
monitor, and 24-hour ABPM recording. Because mirabegron has a long half-life, we will do a video 
conference 4 weeks after drug stoppage to determine if there are any residual side effects.  
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 SEVERITY OF EVENT 
 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 

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All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
 
 
8.3.3.3 EXPECTEDNESS  
 
The principal investigator will be responsible for determining whether an adverse event (AE) is expected 
or unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the study intervention. 
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 

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All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The principal investigator will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of 
study participation.  At each study visit, the investigator will inquire about the occurrence of AE/SAEs 
since the last visit.  Events will be followed for outcome information until resolution or stabilization. 
 
 
8.3.5 ADVERSE EVENT REPORTING  
 
Adverse events (AEs) will be reported to the IRB following IRB guidelines. Sign off on the adverse event 
will be done in accordance with the IRB guidelines.  
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
 
The study clinician will immediately report to the IRB and sponsor any serious adverse event, whether or 
not considered study intervention related, including those listed in the protocol or investigator brochure 
and must include an assessment of whether there is a reasonable possibility that the study intervention 
caused the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be 
reported in accordance with the protocol unless there is evidence suggesting a causal relationship 
between the study intervention and the event (e.g., death from anaphylaxis). In that case, the 
investigator must immediately report the event to the IRB and sponsor. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting documentation 
of the event may be requested by the Data Coordinating Center (DCC)/study sponsor and should be 
provided as soon as possible. 
 
The study sponsor will be responsible for notifying the Food and Drug Administration (FDA) of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later 
than 7 calendar days after the sponsor's initial receipt of the information.  In addition, the sponsor must 
notify FDA and all participating investigators in an Investigational New Drug (IND) safety report of 

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potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later 
than 15 calendar days after the sponsor determines that the information qualifies for reporting. 
 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
AEs, SAEs, or any significant findings will be reported to the participant by the principal investigator. A 
follow up letter will be sent to the participant’s residence to confirm notification. The PI will coordinate 
with the patient’s physician in managing these AEs and SAEs to ensure patient safety.  
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
Not applicable. 
 
8.3.9 REPORTING OF PREGNANCY  
 
The participant will be withdrawn from the study if they become pregnant.  
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the Data Coordinating Center (DCC)/lead principal investigator (PI). The UP report will 
include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  

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• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DCC/study 
sponsor within 24 hours of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor as soon as possible, but 
no later than 10 business days of the investigator becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) as soon as possible, but no later than 10 business days of 
the IRB’s receipt of the report of the problem from the investigator. 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
The PI will inform the patients of unanticipated problems when they occur and again during the 
routinely scheduled follow up. The PI will coordinate with the patient’s physician in managing these 
unanticipated problems to ensure patient safety.  
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
• 
Primary Efficacy Endpoint(s):  
o An increase of the average systolic BP. 
 
• 
Secondary Efficacy Endpoint(s): 
o Reduction of frequencies of syncope and presyncope 
o Reduction of the hypotensive (systolic BP < 90 mmHg) episodes during wake time 
o Improvement of QOL as measured by EQ-5D-5L score 
o Improvement of functional capacity as measured by the Duke Activity Status Index 
(DASI) 
o Improvement of chest pain as measured by Seattle Angina Questionnaire (SAQ) score 
o Improvement in OAB symptoms as measured by the OAB-q SF  
o Improvement of POTS symptoms severity as measured by the MAP 
o Improvement of sexual function in female participants as measured by the FSFI 
o Improvement of fatigue symptoms as measured by PROMIS SF Fatigue 8a 
o Reduction of postural heart rate elevation 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
This is a pilot study of 20 patients. We did not perform statistical power calculation to determine the 
sample size. 

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9.3 
POPULATIONS FOR ANALYSES 
 
Patients who completed 8 weeks of therapy will be included in the analysis. 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
Student’s t-tests will be used to compare the mean systolic BP, the QOL and OAB questionnaire scores 
and the number of syncopal episodes before and after treatment to test the proposed hypotheses. 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
The primary endpoint is the average systolic BP on 24-hr ABPM recording. This analysis will be 
conducted on participants who complete 8 weeks of therapy. The systolic BP before and after treatment 
will be compared with paired Student’s t-tests if the data are normally distributed with the Kolmogorov-
Smirnov test, or the Shapiro-Wilk test. Wilcoxon signed rank test will be used if the data are not 
normally distributed.  A p-value of ≤ 0.05 will be considered statistically significant. 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
The secondary endpoints are the QOL score, OAB score and the number of syncopal episodes. This 
analysis will be conducted on participants who complete 8 weeks of therapy. The data before and after 
treatment will be compared with paired Student’s t-tests. A p-value of ≤ 0.05 will be considered 
statistically significant. 
 
9.4.4 SAFETY ANALYSES 
 
Safety Endpoints 
• 
Hypertension, defined as any BP measurements of > 140/90 mmHg 
• 
Allergic reaction to mirabegron or skin patch electrodes 
• 
Development of new symptomatic bradycardia or symptomatic 2nd or 3rd degree atrioventricular 
block 
• 
Development of new symptomatic sustained supraventricular or ventricular tachyarrhythmia 
 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
The data will be summarized by mean and standard deviation. 
 
9.4.6 PLANNED INTERIM ANALYSES  
 
No interim analysis is planned. 
 

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9.4.7 SUB-GROUP ANALYSES 
 
No subgroup analysis is planned. 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
The baseline and post-treatment data will be listed according to the time points. 
 
9.4.9 EXPLORATORY ANALYSES 
 
None. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention. The following consent materials are submitted with this 
protocol: informed consent, HIPAA form. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator and/or co-investigator(s) will explain the research study to the participant and answer any 
questions that may arise. A verbal explanation will be provided in terms suited to the participant’s 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
research participants. Participants will have the opportunity to carefully review the written consent 
form and ask questions prior to signing. The participants should have the opportunity to discuss the 
study with their family or surrogates or think about it prior to agreeing to participate. The participant 
will sign the informed consent document prior to any procedures being done specifically for the study. 
Participants must be informed that participation is voluntary and that they may withdraw from the 
study at any time, without prejudice. A copy of the informed consent document will be given to the 
participants for their records. The informed consent process will be conducted and documented in the 
source document (including the date), and the form signed, before the participant undergoes any study-
specific procedures. The rights and welfare of the participants will be protected by emphasizing to them 
that the quality of their medical care will not be adversely affected if they decline to participate in this 
study. 

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10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigator, funding agency, the 
sponsor and regulatory authorities. If the study is prematurely terminated or suspended, the PI will 
promptly inform study participants, the IRB, and sponsor and will provide the reason(s) for the 
termination or suspension. Study participants will be contacted, as applicable, and be informed of 
changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may 
inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the Cedars-Sinai Medical Center. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 

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identified by a unique study identification number. The study data entry and study management 
systems used by clinical sites and by Cedars-Sinai Medical Center research staff will be secured and 
password protected. At the end of the study, all study databases will be de-identified and archived at 
the Cedars-Sinai Medical Center. 
 
 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
All data will be housed in a HIPAA-compliant secure storage system, like REDCap or Box, within the 
Cedars-Sinai network with access restricted to approved members of the research team. All forms-
signed informed consent/authorization forms will be placed in a locked research office and/or file 
cabinet. The records will be stored indefinitely. Data will be used as preliminary data for future grants 
and studies.  
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
 
 
 
 
 
 
 
 
 
10.1.6 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of a Data Safety Monitor who is a faculty member in the 
Department of Cardiology. The data safety monitor will meet with the PI every 3 months to review the 
progress of the study and the safety endpoints. Dr. Bojan Cercek of the Department of Cardiology has 
agreed to serve as the Data Safety Monitor for this study. 
 
10.1.7 QUALITY ASSURANCE AND QUALITY CONTROL 
 
There is only one site for recruitment. The PI will perform internal quality management of study 
conduct, data and biological specimen collection, documentation and completion. An individualized 
quality management plan will be developed to describe a site’s quality management. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), and 
Principal Investigator 
Peng-Sheng Chen, MD 
Cedars Sinai Medical Center  
127 South San Vicente Blvd. 
A3600 
Los Angeles, CA 90048 
310-248-6679 
Peng-sheng.chen@cshs.org 

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reported in compliance with the protocol, International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 
10.1.8 DATA HANDLING AND RECORD KEEPING  
 
10.1.8.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study. Data recorded in the electronic case report 
form (eCRF) derived from source documents should be consistent with the data recorded on the source 
documents.  
 
Data collection for REDCap may be completed through review of the medical record and/or the 
assessment of the clinicians involved in the subject’s care. The following data may be collected: 
• Demographics 
• 12-lead EKG 
•  Clinic ABPM report 
• Diagnoses 
• Medications 
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into REDCap, a 21 CFR Part 11-compliant data capture 
system provided by the Cedars-Sinai Medical Center. The data system includes password protection and 
internal quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the source documents. 
 
10.1.8.2 STUDY RECORDS RETENTION  
 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harmonisation (ICH) region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform 
the investigator when these documents no longer need to be retained. 

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10.1.9 PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations as soon as possible but no later than 10 working days of identification of the protocol 
deviation, or within 10 working days of the scheduled protocol-required activity.  All deviations must be 
addressed in study source documents, uploaded to the REDCap database, and reported to AHA and IRB.  
Protocol deviations must be sent to the reviewing Institutional Review Board (IRB) per their policies. The 
site investigator is responsible for knowing and adhering to the reviewing IRB requirements. Further 
details about the handling of protocol deviations will be included in the MOP.  
 
10.1.10 
PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
The study will comply with the AHA Data Sharing Policy. The American Heart Association (AHA) requires 
that all journal articles resulting from AHA funding be made freely available in PubMed Central (PMC) 
and linked to an AHA award within 12 months of publication. It is the responsibility of the awardee to 
ensure journal articles are deposited into PMC and that all necessary rights are retained in order to do 
so.        
 
10.1.11 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership has established policies and procedures for all study group members to disclose all conflicts 
of interest and will establish a mechanism for the management of all reported dualities of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
 
Not applicable. 
 

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10.3 ABBREVIATIONS 
 
ABPM 
Arterial Blood Pressure Monitoring 
AE 
Adverse Event 
AHA 
American Heart Association 
ANCOVA 
Analysis of Covariance 
BP 
Blood Pressure 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DBP 
Diastolic Blood Pressure 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCS 
Neurocardiogenic Syncope 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
OAB 
Overactive Bladder  
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
POTS 
Postural Orthostatic Tachycardia Syndrome 
QA 
Quality Assurance 
QC 
Quality Control 
QOL 
Quality of Life 

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SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SKNA 
Skin Sympathetic Nerve Activity 
SMC 
Safety Monitoring Committee 
SNA 
Sympathetic Nerve Activity  
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
3.0 
16 February 
2024 
 
the wording "such as midodrine" was 
removed 
Midodrine is not a CYP2D6 
substrate, it is a CYP2D6 
inhibitor, and therefore this 
statement is not correct and the 
drug is not an exclusion. All 
other CYP2D6 substrates listed 
at the linked site in this section of 
the protocol are still valid 
exclusion criteria 
3.0 
16 February 
2024 
 
previously titled "Clinical 
Monitoring" was removed from the 
protocol per IRB guidance 
It is not a condition of our 
funding and cannot be offered by 
the IRB at this time. QC will still 
be implemented and safety 
oversight completed on a routine 
basis. 
4.0 
24 April 
2024 
Addition of active standing test to 
baseline and week 8 SOA 
Active standing test is a standard 
procedure that POTS patients 
undergo when coming in for a 
clinic visit and is a data point we 
would like to collect for 
comparison between Baseline 
and Week 8 FU as mirabegron 
may impact postural heart rate 
elevation. 
5.0 
30 
September 
2024 
Addition of QOL questionnaires, 
Malmö POTS Score (MAPS) and 
Female Sexual Function Index (FSFI), 
at time of other questionnaires 
(baseline and week 8 FU) 
 The Malmö POTS Score 
(MAPS) is a newly developed 
structured evaluation of 
symptom severity in patients with 
POTS. The Female Sexual 
Function Index (FSFI) is the 
most widely used questionnaire 
to evaluate the sexual health in 
female populations. As POTS 
affects mostly females and our 
male participant sample size is 
too small for analysis on this 
secondary endpoint, we would 
like to add only a female-specific 
sexual function survey. We 
believe these questionnaires will 
be beneficial in assessing QOL 
changes in our study population.  
5.0 
30 
September 
2024 
Use of REDCap survey distribution 
for questionnaires 
Due to the volume of 
questionnaires in the study, 
offering participants the option 
of completing the questionnaires 
online  
 
 
 
 
 
 
 
 

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