Effect of Ivabradine on Patients With Postural Orthostatic Tachycardia Syndrome (a Double-blind Placebo-parallel Group Trial)
Phase: PHASE3
Conditions: Postural Orthostatic Tachycardia Syndrome
Sponsor: University of California, San Diego

Research Plan 
Effect of Ivabradine on Patients With Postural Orthostatic Tachycardia Syndrome 
NCT #: NCT03182725 
Document Date: March 7, 2020 
 

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UCSD Human Research Protections Program 
New Biomedical Application 
RESEARCH PLAN INSTRUCTIONS 
These are instructions are for completing the Research Plan that is available in MS Word format from the HRPP website. 
The headings on this set of instructions correspond to the headings of the Research Plan. 
General Instructions: Enter a response in for all topic headings.  
Enter “Not Applicable” rather than leaving an item blank if the item does not apply to this project. 
Version date: 05/11/2011 
1.    PROJECT TITLE 
Effect of Ivabradine on Patients with Postural orthostatic tachycardia syndrome (a double-blind placebo-
parallel group trial) 
2. 
PRINCIPAL INVESTIGATOR  
Pam Taub, MD, Assistant Professor of Medicine, Division of Cardiology UCSD 
Jonathan Hsu, MD PhD, Assistant Professor of Medicine, Division of Cardiology, UCSD (Co-Investigator) 
3. 
FACILITIES 
UCSD Altman Clinical and Translational Research Institution (ACTRI) 
UCSD Health System 
UCSD School of Medicine 
4. 
ESTIMATED DURATION OF THE STUDY 
 1 year 
5. 
LAY LANGUAGE SUMMARY OR SYNOPSIS (no more than one paragraph) 
Postural orthostatic tachycardia syndrome (POTS) occurs in approximately 500,000 Americans, but 
predominates in women with a 5:1 ratio.1 Patients with POTS experience debilitating tachycardia upon 
postural changes such as standing that impairs their quality of life. Tachycardia is clinically defined as a heart 
rate greater than 100 beats/min; and in POTS patients, the prolonged heart rate increase is greater than 30 
beats/min or increases to 120 beats/min within the first ten minutes of a diagnostic tilt table test without 
postural hypotension1. There are currently no effective treatment methods for POTS. However, several studies 
suggest Ivabradine could be a main treatment option for POTS because Ivabradine specifically inhibits the f-
channels (If) within the sinoatrial (SA) node, which slows the heart rate2. Currently in the US, Ivabradine is 
mainly prescribed to treat chronic heart failure. It is well tolerated in patients, but it is not commonly 
prescribed for POTS.  It has been also used for treatment of inappropriate sinus tachycardia with good benefit. 
We hypothesize that Ivabradine will reduce tachycardia and improve functional status in patients with POTS.  
6. 
SPECIFIC AIMS 
The major objective of this proof-of-concept study is to gain clinical evidence to utilize Ivabradine as a 
treatment option for POTS. Preliminary data indicates that such an expectation is possible given the fact that 
Ivabradine has been proven to decrease heart rate.  
  
We will conduct a randomized double-blind placebo controlled clinical trial with a double cross over design. 
20 patients with POTS will receive Ivabradine treatment vs placebo for one month. Then there will be a one-
week wash out period prior to the cross over in which patients who received Ivabradine will receive the 
placebo, and patients who initially were on placebo will now receive Ivabradine. We will compare heart rates 
in both groups after one-month of intervention. We will assess if Ivabradine mitigates patient symptoms and 
increases patient adherence. This work will help translate our research on beneficial effects of Ivabradine into 
a clinically relevant patient population. 
 
We will test this hypothesis by pursuing the following aim: 

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Specific Aim 1: Evaluate the change in heart rate 
Hypothesis:  Ivabradine will reduce tachycardia and improve functional status in patients with POTS. 
We propose to test this hypothesis in a randomized double-blind placebo-controlled with a cross over clinical 
trial in which otherwise healthy patients diagnosed with POTS will be randomized into Ivabradine or placebo 
group treatment for one month then crossed over to the other group for another month (one week wash-out 
period before cross over). Patients will undergo a baseline tilt table test, norepinephrine bloodwork, and 
quality of life (QOL) questionnaires.  
➢ Primary endpoint: 
o Change in heart rate after one month of Ivabradine intervention compared to baseline. 
➢ Secondary endpoint: 
o Quality of life measured with questionnaires after one month of Ivabradine intervention 
compared to baseline. 
  
We will assess: 
➢ Effects on tachycardia (table tilt test) 
➢ Orthostatic heart rate monitoring  
➢ Symptomatic changes (QOL questionnaire)  
 
Results will provide significant understanding of mechanisms that underlie sympathetic hyperactivation and 
provide a potential avenue for an effective and safe treatment with Ivabradine with the ultimate goal of 
increasing patient adherence and reducing debilitating patient symptoms.  
 
7. 
BACKGROUND AND SIGNIFICANCE 
Given that the etiology of POTS is complex, there are currently no Class I recommendations for its treatment. 
POTS has five pathophysiological subtypes 1) hyperadrenergic, 2) peripheral autonomic denervation, 3) 
hypovolemic 4) deconditioning, 5) anxiety, and hypervigilance.  Among the clinical subtypes, the most 
common form of POTS is hyperadrenergic (comprising up to 50% of POTS patients)1.  At the cellular level 
hyperadrenergic POTS is thought be associated with an increase in hyperpolarization-activated cyclic 
nucleotide-gated (HCN) channel expression in the sinus node due to an increase in sympathetic activation2 . 
The increased sympathetic activity is also associated with elevated norepinephrine levels from a 
norepinephrine transporter defect, which may have a genetic component1 . Ivabradine selectively blocks the 
HCN channel within the SA node resulting in lower heart rate and we hypothesize that it will be beneficial in 
lower heart rate in patients with POTS that have upregulation in HCN channel expression. 
The current standard of care in establishing the diagnosis of POTS is assessing if there is a significant 
increase in heart rate upon standing or with a tilt table test. The criteria for an augmented heart rate increase is 
prolonged heart rate increase of greater than 30 beats/min or an increase to 120 beats/min within the first ten 
minutes of a tilt table test without postural hypotension.1   Prior to diagnosis of POTS autonomic neuropathies, 
central dysautonomias, bedrest deconditioning, and dehydration need to be ruled out.1.   
Currently, there are no Class I recommendations for the treatment of POTS.  Class II recommendations 
include: exercise (level B-R), IV saline for acute decompensation (level E), fludrocortisone and 
pyridostogmine (level C), increased salt and fluid intake,) Midodrine or low dose-beta-blocker (level B), and 
clonidine or methyldopa (level E) for central hyperadreneric POTS. Florinef and midodrine are most 
commonly prescribed for these patients but most do not tolerate the side effects. Florinef increases blood 
volume by increasing the sensitivity of blood vessels to catecholamines; side effects include but are not 
limited to supine hypertension, hypokalemia, ankle edema, and congestive heart failure.4  Midodrine works as 
an alpha-1 adrenergic agonist that does not cross the blood brain barrier; its side effects include pilomotor 
reactions, supine hypertension, gastrointestinal issues, and urinary retention.4  There is a great unmet clinical 
need for an effective intervention in these patients.  

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Several case reports have shown that Ivabradine is effective in dramatically lowering heart rate in 
POTS patients, but none have been performed in a randomized clinical trial setting with a placebo group.  For 
example, Ewan et al documented the significant reduction in heart rate in a 15 year old female patient with 
POTS as a result of Ivabradine consumption that was accompanied by improvements in fatigue5 and blood 
pressure remained stable.  
 
Also, Hersi was able to demonstrate that Ivabradine (5mg twice daily) completely alleviated the 
symptoms (weakness, palpitations, tingling/coldness in feet) of a 25 year old female patient with POTS.6  It is 
noteworthy to mention that when she ran out of the medication, her symptoms returned, but were quickly 
mitigated when Ivabradine was reinstated. Such reports validate that Ivabradine poses as an effective treatment 
option for POTS patients.  
Additionally, the retro-perspective study conducted by McDonald et al identified and analyzed twenty 
patients who were prescribed Ivabradine (2.5mg once daily) specifically for POTS; this provided valuable 
insight for utilizing Ivabradine as a treatment option for POTS.3 McDonald et al concluded that 55% of 
patients who continued to take Ivabradine reported a decrease in palpitations and tachycardia episodes and 
44% of those patients reported a decrease in fatigue3 . These improvements in fatigue symptoms are consistent 
with the findings of Ewan et al. However, 20% of these patients were also taking florinef or midodrine in 
conjunction with Ivabradine, which may have confounded the true efficacy of Ivabradine. Nonetheless, they 
were able to show that Ivabradine was well-tolerated in patients with POTS and the adverse side effects were 
minimal.  
Similarly, Sutton et al prescribed Ivabradine (5mg twice daily) to twenty POTS patients and concluded 
that there were notable benefits in terms of reducing palpitations and vasovagal syncope over the course of 
eighteen months for eighteen patients; two patients discontinued due to lack of benefit.2 
Moreover, Barzilai et al performed an open-label trial without a placebo group in which they 
concluded that a single dose of 7.5mg Ivabradine significantly lowered the heart rate of POTS patients without 
any adverse side-effects.7 They also noted that Ivabradine maintained the sympathovagal balance despite the 
significant difference in heart rates between baseline and treatment; they postulate the dosing may be a 
contributing factor.  
Furthermore, many of these prior studies strongly recommend the need for a randomized double-blind 
placebo-controlled clinical trial in order to measure the efficacy and effectiveness of only prescribing 
Ivabradine to patients with POTS. Thus, based on prior studies, the goal of this proposal is to evaluate a 
potentially effective treatment method for POTS with Ivabradine. 
8. 
PROGRESS REPORT 
None.  
9. 
RESEARCH DESIGN AND METHODS 
Overall Study Design.  The clinical trial will be registered under www.clinicaltrials.gov. Subjects between 
the ages of 18-65 who have a POTS diagnosis will be enrolled. Specifically, we will enroll patients who have 
hyperadrenergic POTS as confirmed by norepinephrine (NE) levels > 600 pg/ml.  This is a 3-month study with 
a randomized double-blind placebo controlled cross over design.  Subjects will be randomized into one of two 
groups (Ivabradine or placebo for one-month) then crossed over after a one-week washout period to the other 
group for one-month. Refer to Figure 1 below for details.  

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Figure 1. Randomized double-blind placebo-parallel group crossover trial with Ivabradine for patients with 
POTS. 
 
Study Visits. There will be seven visits at the ACTRI and UCSD Cardiology clinics.  
-Visit 1 is the pre-screening visit during which norepinephrine (NE) blood results will be obtained to confirm 
hyperadrenergic POTS diagnosis (NE> 600pg/ml). Orthostatic heart rate will be monitored. A urine pregnancy 
test will also be administered at this time. Post-menopausal women and women who are infertile will not be 
asked to take pregnancy test per PI discretion.  
-At Visit 2, baseline lab work will be obtained to assess cardiometabolic health (CBC, CMP, TSH, T4, BNP). 
A tilt table test will be performed to determine baseline heart rate and QOL questionnaire (ShortForm36, 
SF36) will be completed. Orthostatic heart rate will be monitored. At this point, the patient will be randomized 
into the Ivabradine or placebo group for one month.  
-At Visit 3, two-weeks into treatment, the patient will return to ACTRI for drug titration. Orthostatic heart rate 
will be monitored. If the patient fulfills criteria (see Ivabradine Dosing below), they will either increase, 
decrease, stop, or not change their Ivabradine dose. 
-At Visit 4, one month after starting the current treatment, orthostatic heart rate monitoring, NE bloodwork, 
and QOL questionnaires will be completed. There will be a one-week wash-out period before the patient 
crosses over to the other group for one month.  
-At Visit 5, the patient will return for orthostatic heart rate monitoring, NE bloodwork, and QOL 
questionnaires. A urine pregnancy test will be administered at this time. Post-menopausal women and women 

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who are infertile will not be asked to take pregnancy test per PI discretion. The patient will be instructed to 
begin the secondary treatment (placebo or Ivabradine) for one month. 
-At Visit 6, two-weeks into this treatment, the patient will return to ACTRI for drug titration. Orthostatic heart 
rate will be monitored. If the patient fulfills criteria (see Ivabradine Dosing below), they will either increase, 
decrease, stop, or not change their Ivabradine dose. 
-At Visit 7, one month after starting the secondary treatment, the patient will return for orthostatic heart rate 
monitoring, NE bloodwork, and QOL questionnaires.  
 
Blood samples will be saved and securely stored with the PI for future research analysis and purposes.  
 
Randomization. Randomization refers to the order in which patients receive placebo or Ivabradine. If a 
patient receives Ivabradine first for one month, then he/she will be switched over to placebo for one month. If 
a patient receives placebo first for one month, then he/she will be switched over to Ivabradine for one month. 
There will be a one-week washout period prior to the cross-over. There will be 10 patients in each group.  
 
Ivabradine Dosing. Ivabradine dose will initiate at 5mg twice daily (bid) and be increased to 7.5mg twice 
daily (bid) after 2 weeks7 if the heart rate is greater than 70 beats/min.  If the heart rate is less than 70 
beats/min there will no increase in dose.  If the heart rate is less than 50 beats/min, or if the patient has 
symptoms of dizziness of lightheadedness, then Ivabradine will be stopped.  
If patients have side effects and feel that cannot continue with Ivabradine we will decrease the dose 
from 7.5mg bid to 5mg bid (or if they are on 5mg bid to 2.5mg bid).   After this dose reduction if the patient is 
still unable to tolerate Ivabradine, we will stop Ivabradine and withdraw patient from the study.  If a patient is 
unable to tolerate Ivabradine (particularly prior to crossover period), he/she will be withdrawn.  The starting 
dose and titration model is the same for the crossover treatment period as the initial month.  
In our clinical experience using Ivabradine in patients with inappropriate sinus tachycardia (which are 
very similar to POTS patients in age and co-morbidities) we have not seen significant side effects that have 
caused patients to stop the drug. Refer to the uploaded Ivabradine Drug Information document for more 
details.  
 
Specific Protocols. Brief synopsis of methods currently used is provided below.  
Tilt Table Test: Only the physician PIs will perform the tilt table test with assistance from the medical staff of 
the UCSD Medical Center.  
Orthostatic Heart Rate Monitoring: First, the patient’s heart rate will be measured at rest after lying down for 3 
minutes. Then, the patient will be asked to stand and the standing heart rate will be measured after 3 minutes. 
The changes in position with 3 minute intervals will establish the orthostatic heart rate.  
Quality of Life (QOL) Questionnaire: Patients will complete the Short Form-36 (SF36) subjective 
questionnaire to aid in analysis of patient symptoms before/after each treatment period. 
Blood Tests: The following blood tests will be processed at UCSD Clinical Laboratories: 1) Cardiometabolic 
parameters: (CBC, CMP, TSH, T4, BNP) and 2) norepinephrine levels (NE).  
The 2-3-month time period will be used as prior literature suggests that this length of therapy is needed to 
trigger pharmaceutical changes to translate into functional endpoints. 
 
Assessments. We will assess for patient improvement with tilt table testing, orthostatic heart rate monitoring, 
labs, and quality of life (QOL) questionnaires before and after treatment. The patient will undergo a baseline 
norepinephrine workup and a baseline tilt table test; if the patient is on Midodrine, Florinef, or Ivabradine, 
there will be a one week washout period. The patient will then be randomized into the Ivabradine or the 
placebo group for one month. After this one month, they will undergo orthostatic heart rate monitoring, blood 
work for norepinephrine levels, and QOL questionnaires. There will be a one week washout period before they 
are crossed over to the other therapy (placebo vs Ivabradine) for one month. The washout period protocol 

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includes maintaining a stable salt and fluid intake. Once crossed over, they will repeat an orthostatic heart rate 
monitoring, blood work for norepinephrine levels, and QOL questionnaires.  
We will continuously assess for all adverse events throughout the study. Some of these labeled adverse 
reactions may include bradycardia, hypertension, atrial fibrillation, and visual distortions (visual brightness, 
diplopia, visual impairment, phosphenes).  
          
Statistical Analysis. Continuous variables including mean heart rate, maximum heart rate, and quality of life 
scores will be summarized using descriptive statistics, including the number of observation (n) mean, standard 
deviation (SD), standard error (SE), median, the 1st (Q1) and 3rd (Q3) quartiles, minimum, and maximum 
values. The change in heart rate at one month from baseline will be compared by T-tests based on treatment 
status with placebo versus Ivabradine. Categorical variables will be compared by McNemar’s test based on 
treatment status with placebo versus Ivabradine.  
The study design will be adaptive and data analysis will be done in batches. The PI and others involved in data 
analysis will be blinded to who is the Ivabradine group and who is in the placebo group.    
 
Power Analysis. Assuming a decrease in average heart rate of 10 beats/min is clinically significant (e.g. 
Decrease from 100 to 90; magnitude of effect 10%) with power 0.8 and standard deviation in heart rate is 7.5 
beats/min, the estimated sample size is 18 patients. We will enroll 10 patients in each group to account for the 
10% drop-out rate and to ensure the study is adequately powered. For sample size calculation, two-sided alpha 
level = 0.05 and two sample t-test are used.  
 
Drop-outs. If any patient decides to withdraw from the study due to the intolerance of side-effects, we will try 
to obtain a tilt table test, orthostatic heart rate, QOL questionnaire, and blood tests at the time of drop-out.  
 
Documentation. All patient related documentation will be stored at UCSD for future analysis as funding 
becomes available. To minimize the potential loss of confidentiality, patients will be assigned a unique number 
as their subject identifier code. The unique subject code will be used to label all study documents. The key that 
relates the code numbers to the individuals will be kept in a locked cabinet in the PI’s office at the ACTRI.  
 
All procedures mentioned above are research procedures and are not part of standard care. 
 
Results may be used for diagnosis, treatment, and prevention of disease in patients.  
 
Incidental findings that result from the conduct of this study that require medical intervention for the 
subject will be noted by the PI or her project’s medical research staff.  They will refer the subject to his 
primary care physician. If the subject does not have a primary care physician one will be appointed for 
him or her.  
 
 
10. HUMAN SUBJECTS 
The study aims for 20 adult volunteers (18-65 years) to complete the study. Given the NE inclusion criteria, 
we will need to enroll at least 60 participants to have 20 participants pass the study screening  criteria. With an 
expected drop-out of 10% after enrollment, this will provide 18 subjects for final analysis, which provides 
adequate power to detect a significant improvement in decreasing average heart rate at the 0.05 level (see 
power analysis, above). Participants will be screened and must meet inclusion and exclusion criteria before 
they are enrolled into the study. We will recruit patients from the cardiology and internal medicine clinics at 
UCSD Medical Center; in addition, we will utilize the bioinformatics report generated from EPIC and 
ResearchMatch to assist in recruitment. The main sites of the clinical testing will be conducted at the ACTRI 
and UCSD Cardiology clinics.   

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Inclusion/exclusion criteria are below: 
1) Inclusion:  
a. Subjects aged 18-65  
b. Subjects must have POTS diagnosis (Hyperadrenergic Subtype with NE> 600pg/ml)) 
c. Subjects with norepinephrine levels greater than 600 pg/ml 
d. Subjects with normal CBC, metabolic, and thyroid levels 
 
2) Exclusion:  
a. Uncontrolled arrhythmias 
b. History of thyroid disease requiring dose titration of thyroid replacement medication(s) within 
the past 3 months (i.e. hypothyroidism on a stable dose of thyroid replacement therapy is not an 
exclusion) 
c. Drugs that interfere with Ivabradine (example: Cytochrome P450 drugs). 
d. Presentation of peripheral edema and discolored toes with peripheral autonomic neuropathy. 
Symptoms include: legs (reduced hair growth, cramps), toes (blue color), legs/feet (wounds, 
ulcers that do not heal), and muscles (numbness, heaviness). 
e. Subjects who have had a history of systemic illnesses (acute or chronic infectious); active 
and/or uncontrolled autoimmune/inflammatory disease, COPD, anemia, or diabetes. 
f. History of malignancy undergoing active treatment, except non-melanoma skin cancer. 
g. Uncontrolled psychiatric disorder (including history of hospitalization for psychiatric illness). 
h. Subjects with resting heart rate <60beats/min, atrial fibrillation, advanced AV blocks, sinus 
disease, and acute decompensated heart failure and severe hepatic impairment. 
i. Smokers or alcohol abuse. 
j. Pregnant or breastfeeding mothers. 
k. Woman of childbearing potential who are unwilling to use highly effective contraception during 
treatment and for an additional one month after discontinuing the study drug. 
 
Highly effective contraceptive method (methods that can achieve a failure rate of less than 1% per year when 
used consistently and correctly) include: 
• Combined hormonal (estrogen and progestogen) contraception associated with inhibition of ovulation 
(oral, intravaginal, transdermal) 
• Progestogen - only hormonal contraception associated with inhibition of ovulation (oral, injectable, 
implantable) 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner 
• Sexual abstinence 
• Infertility 
 
If the patient or patient’s significant other is infertile, the PI may not require the patient to start other highly 
effective contraceptive methods in this case as they deem appropriate. The PI shall discuss with the patient and 
document the decision. The research team will document this in the patient’s study file. 
 
For female participants, the PI will administer a pregnancy test at the first visit to determine if patient will be 
excluded. Another pregnancy test will be administered prior to starting the crossover treatment. 
 
11. 
RECRUITMENT 

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We aim for 20 adult volunteers with confirmed hyperadrenergic POTS (NE> 600pg/ml) to complete the study. 
We will screen at least 60 patients in order to have 20 pass the screening phase and complete the study. With 
an expected drop-out of 10% after enrollment, this will provide 18 subjects for final analysis, which provides 
adequate power to detect a significant improvement in decreasing average heart rate at the 0.05 level (see 
power analysis, above). Participants will be screened and must meet inclusion and exclusion criteria before 
they are enrolled into the study. Additionally, the PI may ask a patient to return for a reevaluation of the 
baseline screening norepinephrine levels with a blood draw if she has reason to believe that the blood draw 
was done incorrectly or the results are inaccurate. This would be an additional in-person visit, but it does not 
increase the risk of the study.  
 
We will recruit from the UCSD Medical Center cardiology and internal medicine clinics. Also, we will be 
utilizing ResearchMatch and the bioinformatics report from EPIC to help recruit patients who may qualify for 
our inclusion criteria. Each of these patients will be randomized into one of the two groups mentioned 
(Ivabradine or placebo).   
 
We will be screening and recruiting patients through UCSD Medical Center clinics. We will also use 
ResearchMatch, which enables researchers to search for appropriate matches in non-identifiable volunteer 
profiles. We will be screening patients through EPIC, with the help of their bioinformatics department, 
for research subjects who might qualify for our criteria. EPIC Bioinformatics will help search for the 
following to generate a list of potential research subjects:  
 
1. Patient’s name, date of birth (DOB), and Medical Record Number (MRN) 
2. Patient’s primary care provider (PCP) name and contact information 
3. POTS diagnosis  
4. NE levels >600pg/dl 
5. Ages 18-65  
6. Exclusion:  
a. History of thyroid disease requiring dose titration of thyroid replacement medication(s) within 
the past 3 months (i.e. hypothyroidism on a stable dose of thyroid replacement therapy is not an 
exclusion) 
b. Drugs that interfere with Ivabradine (example: Cytochrome P450 drugs) 
c. Presentation of peripheral edema and discolored toes with peripheral autonomic neuropathy. 
Symptoms include: legs (reduced hair growth, cramps), toes (blue color), legs/feet (wounds, 
ulcers that do not heal), and muscles (numbness, heaviness) 
d. Subjects who have had a history of systemic illnesses (acute or chronic infectious); active 
and/or uncontrolled autoimmune/inflammatory disease, COPD, anemia, or diabetes. 
e. History of malignancy undergoing active treatment, except non-melanoma skin cancer. 
f. Uncontrolled psychiatric disorder (including history of hospitalization for psychiatric illness). 
g. Subjects with resting heart rate <60beats/min, atrial fibrillation, advanced AV blocks, sinus 
disease, and acute decompensated heart failure and severe hepatic impairment. 
h. Smokers or alcohol abuse 
i. Pregnant women or breastfeeding mothers 
j. Woman of childbearing potential who are unwilling to use highly effective contraception during 
treatment and for an additional one month after discontinuing the study drug 
 
After we identify patients of interest for the study, we will contact their primary care provider and get their 
approval to contact the patient. We will inform clinicians in the department of endocrinology, cardiology 
family medicine and internal medicine of our study.  We will ask these clinicians to ask their patients if they 
are interested in our study. We will also ask the clinicians to specifically ask the interested patients if it is 

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acceptable if our research team contacts them.  If the patients are interested and give their consent then our 
study coordinator will either contact them by phone or after their clinic visit.  
 
We will be screening patients prior to informed consent. The following are justifications for partially waiving 
the HIPAA for screening purposes:  
 
7. It allows the timely review of PHI for patients who are visiting the UCSD clinics, which will allow a 
greater chance of finding eligible patients. It is imperative that we consent the right patients for the 
study in order to:  
 
a. Reduce the probability of screen failures, and minimize the waste of resources, time and funds. 
b. Conduct research more smoothly and efficiently, without having to unnecessarily disturb 
patients who do not qualify for our study. 
 
8. We will be using the partial HIPAA waiver only for the purposes of determining the eligibility of 
patients, and nothing more. This information can only be determined by screening the patients’ medical 
records on Epic.  
 
9. Screening cannot be practicably conducted without the use of PHI because subject eligibility depends 
on inclusion and exclusions factors that can only be found in their medical records. The PHI we will be 
using during the screening process are the patient's age, sex, past medical history, active problems, 
procedures, images, and medications. Only the PI and the research team will have access to this 
information.  
 
10. There will be no disclosure of data to anyone outside this research group. PHI will be protected from 
improper use/disclosure. This will be done by securing the PHI in a locked cabinet in the PI’s locked 
office at the Altman Clinical Translational Research Institute (ACTRI). Only the PI and the research 
team will have the keys to the office and the cabinet so that only they can review the documents. The 
PHI will never leave the office or the building.    
 
11. The use of PHI by our research team does not involve more than minimal risk since there are no 
routine physical or psychological examinations or tests for screening.  
 
12. The research could not be practicably conducted without the waiver since we have to screen the subject 
prior to recruiting them into the study.  
 
13. The privacy risks are reasonable relative to the anticipated benefits of the research, since the results of 
the study may improve patient compliance in taking statins, an important drug for cardiovascular 
disease.  
 
14. If the patient does not qualify, or does not agree to participate in the study, his/her PHI will not be re-
used and will be destroyed at the earliest opportunity. 
 
12. INFORMED CONSENT 
See attached consent. 
 
Informed consent will be obtained by the study coordinators or research assistants associated with this 
protocol. Informed consent procedures will be supervised either by the study coordinator, supervising 
physicians, or the principal investigator. All research personnel giving informed consent will have undergone 

11 
 
proper training and obtained the required certificates. 
 
The following are justifications for partially waiving informed consent for screening purposes:  
 
1. It allows the timely review of PHI for patients who are visiting the UCSD clinics, which will allow a 
greater chance of finding eligible patients. It is imperative that we consent the right patients for the study 
in order to:  
 
a. Reduce the probability of screen failures, and minimize the waste of resources, time and funds. 
b. Conduct research more smoothly and efficiently, without having to unnecessarily disturb patients who 
do not qualify for our study. 
 
2. Minimal Risk: The screening procedures are considered minimal risk to the potential subjects because we 
will be using the partial consent waiver only for the purposes of determining the eligibility of patients, and 
nothing more. This information can only be determined by screening the patients’ medical records on Epic.  
Screening cannot be practicably conducted without the use of PHI because subject eligibility depends 
on inclusion and exclusions factors that can only be found in their medical records. The PHI we will be 
using during the screening process are the patient's age, sex, past medical history, active problems, 
procedures, images, and medications. Only the PI and the research team will have access to this 
information. There will be no disclosure of data to anyone outside this research group. PHI will be 
protected from improper use/disclosure. This will be done by securing the PHI in a locked cabinet in the 
PI’s locked office at the Altman Clinical Translational Research Institute (ACTRI). Only the PI and the 
research team will have the keys to the office and the cabinet so that only they can review the documents. 
The PHI will never leave the office or the building. The use of PHI by our research team also does not 
involve more than minimal risk since there are no routine physical or psychological examinations or tests 
for screening. If the patient does not qualify, or does not agree to participate in the study, his/her PHI will 
not be re-used and will be destroyed at the earliest opportunity. 
 
3. Rights and Welfare of Subjects: The waiver of consent would not adversely affect the rights and welfare 
of the potential subjects. Their standard of care in the hospital will remain the same regardless of the 
partial waiver of consent.  
 
4. The potential subject will be informed about the purpose of the study, the duration of the study, the 
activities they will be doing in the study, the risks and benefits, expenses, compensation, alternatives to 
participating, privacy, their rights as research subjects and study contact information.  
 
5. The privacy risks are reasonable relative to the anticipated benefits of the research, since the results of the 
study may improve patient’s symptoms and be a potential treatment for POTS.  
 
Reconsenting 
In the event that the consent is amended, participants who are active and have not yet completed the study will 
be informed of these changes and be asked to sign the updated consent form. The updated consent form will 
be provided to them at an upcoming visit, or through mail, email or fax. They will be given time to review 
these changes and provide their written consent. They may sign and return it to the research team at the 
upcoming visit, or through mail, email or fax.  
 
Participants who have completed the study and are no longer active in the study will be made aware of the 
changes through mail, email or fax. However, these participants will not be asked to acknowledge or confirm 
the receipt of the updated consent or to sign and return it. 

12 
 
 
 
13. ALTERNATIVES TO STUDY PARTICIPATION 
Subjects have the right to refuse participation in the study. Patients will have no changes to their current 
medical regimen.  They can choose to withdraw at any time. 
 
14. POTENTIAL RISKS 
 
1. Ivabradine: Labeled side effects include: bradycardia, hypertension, atrial fibrillation, and visual 
distortions (visual brightness, diplopia, visual impairment, phosphenes). 
2. Venipuncture: pain, a bruise at the point where the blood is taken, discoloration, redness and 
swelling of the vein and infection.  
3. Tilt table test: Patient will lie flat on a table and straps will be secured. After 15 minutes, the table 
will be quickly tilted to raise the body to stimulate a change in position like standing. Patient will 
remain secured and in “standing” position for up to 45 minutes, while being monitored 
continuously. Only qualified medical professionals will perform this test. There may be an 
increased risk of prolonged hypotension or tachycardia when in “standing” position. These minor 
complications improve once the table is returned to the horizontal position.  
4. Orthostatic heart rate monitoring: Only qualified medical professionals will perform this test. There 
may be an increased risk of hypotension or tachycardia upon changing positions from laying down 
to sitting to standing. Patient will be monitored to avoid such risks and treatment will be provided 
if necessary to return patient to resting heart rate.  
5. Quality of life (QOL) questionnaire: Although there are no known adverse risks, some patients may 
experience frustration, stress, discomfort, fatigue and boredom. These risks will be addressed by 
informing participants in advance and allowing them to stop or pause the questionnaire at any time 
if they wish, and resume when they are ready.  
6. Washout Period: The washout period may increase risks of cardiovascular events, such as 
tachycardia.   
7. A potential loss of confidentiality: The UCSD Institutional Review Board (IRB), the FDA, and 
other government agencies may inspect the study records.  To minimize the risk of a potential loss 
of confidentiality, subjects will be assigned a unique subject code and their blood samples will be 
assigned a different unique specimen code.  A separate paper document will link patient identifiers 
with subject codes and specimen codes.  This document will be kept in a secure location in a 
locked cabinet.  Only the PI and study coordinator will have the key to the cabinet.  No research 
documents will have any patient identifiers and will only be labeled with the unique assigned 
subject codes. 
8. Unscheduled visits: There may be the possibility of having patients return for unscheduled visits in 
between the scheduled visits. This would be based on PI discretion and/or if the bloodwork needs 
to be redrawn due to lab or processing errors.  
.  
15. RISK MANAGEMENT PROCEDURES AND ADEQUACY OF RESOURCES 
All subjects are screened with a medical history and physical exam to ensure none has health problems that 
put them at risk. Subjects will be thoroughly informed as to these potential problems. 
 
Because this is a low risk study, a Data Safety Monitoring Board (DSMB) is not necessary. Instead, a Data 
Safety Monitoring Plan (DSMP) is provided.   
 
A DSMB is not needed for this study for various reasons: 

13 
 
• The study meets the following IND exemption criteria: The drug product is lawfully marketed in 
the United States, and the intent was to provide some latitude to modify the marketed version of 
the drug product for use in the clinical investigation (see attached Supplement to Biomedical 
Application Research Plan IND Exemption).  
• This is a low risk study assessing the impact of the drug on lowering heart rate in a specific patient 
population.  
• The study does not involve a high-risk intervention or a vulnerable population, so DSMB should not be 
needed.  
• This is a single site study that is not intended to evaluate treatments intended to prolong life or reduce 
risk of a major adverse health outcome.  
• This study is not intended to compare rates of mortality or major morbidity.  
• This study is addressing lesser outcomes, such as improving patient adherence  
• The study population is not at an elevated risk of more severe outcomes.  
 
DATA SAFETY MONITORING PLAN (DSMP) 
 
Oversight responsibilities 
Oversight of the trial is provided by the Principal Investigator (PI), Dr. Taub. 
 
Monitoring procedures 
Dr. Taub assures that informed consent is obtained prior to performing any research procedures, that all 
subjects meet eligibility criteria, and that the study is conducted according to the IRB-approved research plan.   
Study data are accessible at all times for the PI to review. The PI reviews study conduct such as accrual, drop-
outs, protocol deviations on a monthly basis.  The PI reviews AEs individually real-time and in aggregate on a 
weekly basis.  The PI reviews serious adverse events (SAEs) in real-time. The PI ensures all protocol 
deviations, AEs, and SAEs are reported to the IRB according to the applicable regulatory requirements. 
 
Collection and reporting of SAEs and AEs 
For this study, the following standard AE definitions are used: 
Adverse event:  Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom or disease temporally associated with the use of a medical treatment or procedure, regardless of 
whether it is considered related to the medical treatment or procedure. 
Serious Adverse Event:  Any AE that results in any of the following outcomes: 
• Death 
• Life-threatening  
• Event requiring inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity 
 
AEs are graded according to the following scale: 
Mild:  An experience that is transient, & requires no special treatment or intervention.  The experience 
does not generally interfere with usual daily activities.  This includes transient laboratory test 
alterations. 
Moderate:  An experience that is alleviated with simple therapeutic treatments.  The experience 
impacts usual daily activities.  Includes laboratory test alterations indicating injury, but without long-
term risk. 
Severe:  An experience that requires therapeutic intervention.  The experience interrupts usual daily 
activities. If hospitalization (or prolongation of hospitalization) is required for treatment it becomes an 
SAE. 
 

14 
 
The study uses the following AE attribution scale: 
Not related:  The AE is clearly not related to the study procedures (i.e., another cause of the event is 
most plausible and/or a clinically plausible temporal sequence is inconsistent with the onset of the 
event).   
Possibly related:  An event that follows a reasonable temporal sequence from the initiation of study 
procedures, but that could readily have been produced by a number of other factors. 
 
Related:  The AE is clearly related to the study procedures.   
 
AEs are identified immediately after the study procedure. We will have the patient rest for 30 minutes to an 
hour after the procedure or activity to observe him or her for any AEs. We will follow up with patient the next 
day and once a week for the following weeks leading up to their next appointment with us. Dr. Taub who is a 
cardiologist and a team of nurses will always be nearby the patient at the appointment in case an event occurs.  
 
SAEs and specific procedure-associated AEs are reported to the PI, IRB, and Amgen within 24 hours; PI will 
report to the FDA in a timely manner.  In addition, all AEs are reported according to the IRB AE reporting 
guidelines.  
 
If a patient becomes pregnant during the study or within a month after the study has ended, patient will be 
advised to inform the PI immediately and to inform her pregnancy doctor. Patient may be withdrawn from 
study if she becomes pregnant and the use of the drug will be discontinued. For pregnancies and lactation 
cases, the PI is responsible for asking the patient if they are willing to allow Amgen to collect pregnancy/birth 
outcome and/or breastfeeding information and the PI will provide patient’s response to Amgen. The PI will be 
held responsible for reporting SAEs in a timely manner. The PI will attempt to assess any relationship between 
the procedures and adverse events to prevent future incidences. 
 
Management of risks to subjects 
 
Expected AEs 
 
1. Blood draw 
a. Hematoma 
b. Arterial puncture 
c. Pain 
d. Nerve damage 
e. Re-bleeding 
f. Allergy 
g. Phlebitis 
h. Vasovagal reaction 
i. Anxiety/fear 
2. Tilt table test 
a. Prolonged hypotension 
b. Increased tachycardia  
3. Orthostatic heart rate monitoring 
a. Acute hypotension 
b. Increased tachycardia  
4. Consuming Ivabradine 
a. Bradycardia 

15 
 
b. Hypertension 
c. Atrial fibrillation 
d. Luminous phenomena (phosphenes) 
5. Washout period 
a. Increased risk for cardiovascular events such as tachycardia  
 
AE Management 
 
1. Blood Draw: 
a. Prior to enrollment into the study, the patient will be educated on the risks of the blood draw. 
The phlebotomist will calm the patient beforehand to reduce anxiety/fear and minimize the 
probability of vasovagal response. Only sterile needles and gauze will be used to prevent 
allergic reactions and infection. The area of the blood draw will be thoroughly sanitized with an 
alcohol wipe prior to the needle stick. Care will be used when penetrating the skin with the 
needle so that there is a minimized risk of punctured artery and damaged nerve. The needle 
stick will be done swiftly and securely by an experienced phlebotomist in order to reduce pain. 
Pressure will be applied on the area immediately after the needle stick to minimize the risk of 
hematoma. The phlebotomist will inform the patient on when and how to undress their 
puncture site. Dr. Taub, who is a cardiologist, will be overseeing the procedure to check for the 
patient’s vital signs. Dr. Taub’s phone number will be given to the patient for any questions or 
concerns that may arise in the future.    
b. In the event of an AE that occurs during the appointment, the facility is equipped with trained 
medical staff (physicians and nurses) who can respond quickly. Should an event occur, Dr. 
Taub and the nurses will be nearby to administer immediate medical care and send the patient 
to the nearest hospital. If the AE occurs after the appointment, the patient will be referred for 
prompt medical attention. The patient will be withdrawn from the study. Dr. Taub will monitor 
the patient until the problem has been resolved or has stabilized.  
2. Tilt table test: 
a. Prior to enrollment into the study, the patient will be educated on the risks of the tilt table test. 
The physician will calm the patient beforehand to reduce anxiety/fear and minimize the 
probability of vasovagal response. Dr. Taub, who is a cardiologist, will be conducting and 
overseeing the procedure to check for the patient’s vital signs. Dr. Taub’s phone number will 
be given to the patient for any questions or concerns that may arise in the future.    
b. In the event of an AE that occurs during the appointment, the facility is equipped with trained 
medical staff (physicians and nurses) who can respond quickly. Should an event occur, Dr. 
Taub and the nurses will be nearby to administer immediate medical care and send the patient 
to the nearest hospital. If the AE occurs after the appointment, the patient will be referred for 
prompt medical attention. The patient will be withdrawn from the study. Dr. Taub will monitor 
the patient until the problem has been resolved or has stabilized.  
3. Orthostatic heart rate monitoring: 

16 
 
a. Prior to enrollment, the patient will be informed about the risks of orthostatic heart rate 
monitoring. The physician will comfort the patient to reduce anxiety/fear in order to minimize 
the probability of a vasovagal response. Dr. Taub will continuously monitor and oversee the 
procedure by checking vital signs. The patient may contact Dr. Taub for further 
questions/concerns.  
b. In the event of an AE that occurs during the appointment, the facility is equipped with trained 
medical staff (physicians and nurses) who can respond quickly. Should an event occur, Dr. 
Taub and the nurses will be nearby to administer immediate medical care and send the patient 
to the nearest hospital. If the AE occurs after the appointment, the patient will be referred for 
prompt medical attention. The patient will be withdrawn from the study. Dr. Taub will monitor 
the patient until the problem has been resolved or has stabilized.  
4. Consuming Ivabradine  
a. Dr. Taub, a cardiologist, will give the patients specific instructions on the amount of ivabradine 
capsules they would need to consume each day. A research person will follow up with the 
patient the next day and once a week for the next 90 days to assess the patient’s condition. The 
patient’s conditions will be reported back to the PI. If the patients have reasons to believe that 
Ivabradine is causing any discomfort, consumption of the capsule will be stopped.  
b. In the event of an AE that occurs during the appointment, the facility is equipped with trained 
medical staff (physicians and nurses) who can respond quickly. Should an event occur, Dr. 
Taub and the nurses will be nearby to administer immediate medical care and send the patient 
to the nearest hospital. If the AE occurs after the appointment, the patient will be referred for 
prompt medical attention. The patient will be withdrawn from the study. Dr. Taub will monitor 
the patient until the problem has been resolved or has stabilized.  
5. Washout Period 
a. Dr. Taub will monitor the patients closely during this washout period. Dr. Taub will remove 
patients from the study if it is in their best medical interest. A research person will follow up 
with the patient once a week during this period to assess the patient’s condition. The patient’s 
conditions will be reported back to the PI. 
b. If an AE occurs, the patient will be referred for prompt medical attention. The patient will be 
withdrawn from the study. Dr. Taub will monitor the patient until the problem has been 
resolved or has stabilized. 
In the event that a patient either withdraws from the study or the investigator decides to discontinue a patient 
due to SAE, the patient will have appropriate follow-up medical monitoring. Monitoring will continue until 
the problem requiring hospitalization has resolved or stabilized with no further change expected, is clearly 
unrelated to study medication, or results in death.  
 
Plan for data management  
 
Data will be collected using standardized paper forms and will only be identified with the study’s ID of the 
participant. The codes that link the name of the participant and the study ID will be kept confidential by the 

17 
 
Principal Investigator in a secured cabinet. Data will be entered in the computer independently by UCSD 
certificated and trained data entry staff, and discrepancies corrected by a supervisor based on source 
documents. 
 
Data quality will be monitored by random inspection of the completed forms by the PI. If necessary, re-
training of data collectors will be conducted. 
 
16. PRIVACY AND CONFIDENTIALITY CONSIDERATIONS INCLUDING DATA ACCESS AND 
MANAGEMENT 
All study forms including consents, HIPAAs, and case report forms (CRFs), which will include elements from 
the present and past history, patient demographics, including age, current medications and lab draws, will be 
stored in in a locked cabinet in Dr. Taub's office in the ACTRI. Only approved study personnel will have access 
to this information. To minimize the potential loss of confidentiality, patients will be assigned a unique number 
as their subject identifier code. The unique subject code will be used to label all study documents.  
 
Collected samples will be saved and securely stored for future analysis.  All samples will be labeled with a 
unique specimen code and the only way to link the specimens with the subject code and any personal health 
identifiers will be on a physical sheet of paper locked in a cabinet in Dr. Taub's office. 
 
Medical record numbers and social security numbers will be collected only for purposes of subject payment. 
This information will only be available to study personnel and will be secured in the same manner mentioned 
above. 
17. POTENTIAL BENEFITS 
Subjects may or may not benefit directly from participating in the study. The potential benefits to society in 
general includes an improved understanding of POTS in patients. The increased knowledge may lead to the 
design of more effective therapeutic regimens for POTS.  
18. RISK/BENEFIT RATIO 
Ivabradine is an FDA approved drug that has shown many benefits. We expect the benefit to be greater than 
the potential risks. We believe that risks are minimal in this study. 
19. EXPENSE TO PARTICIPANT 
There will be no expense to participants. The study drug (Ivabradine) will be provided to enrolled patients at no 
charge. 
20. COMPENSATION FOR PARTICIPATION 
Patients will be compensated up to $180 for fully participating in the study. $45 will be dispensed at the end of 
visits 1, 4, 5, and 7 for a total of $180 upon successful completion of the entire study.  
 
21. PRIVILEGES/CERTIFICATIONS/LICENSES AND RESEARCH TEAM RESPONSIBILITIES 
Dr. Pam Taub is an Associate Professor of Medicine at UCSD and is board certified in internal medicine and 
cardiology. She has clinical privileges at the VA Medical Center and UCSD Medical Center. 
 
Dr. Jonathan Hsu is an Assistant Professor of Medicine at UCSD and is board certified in internal medicine 
and cardiology. He has clinical privileges at the UCSD Medical Center. 
 
Michael Wilkinson, MD is a cardiology fellow and will be involved with consenting subjects, as well as 
participating in data collection and analysis. He is board certified internal medicine and has privileges at 
UCSD Medical Center. 
 

18 
 
Jia Shen, MD (Co-Investigator) is an Assistant Professor of Medicine at UCSD and is a board-certified 
cardiologist. She will assist with the following: patient recruitment, data analysis and manuscript writing.  
 
Iwona Swiatkiewicz, MD, PhD (Co-Investigator) is an Associate Professor of Medicine at Nicolaus 
Copernicus University and a board-certified cardiologist. She is a visiting scholar who will assist with the 
following: patient recruitment, data analysis, and manuscript writing.  
 
Adena Zadourian, BS is a research coordinator who will be involved with screening/recruiting/consenting 
participants, patient visits, administrative support, as well as participating in data collection and analysis. She 
has undergone proper training and obtained the certificates necessary to work with human subjects. 
 
Hannah Lo, BS is a research coordinator who will be involved with screening/recruiting/consenting 
participants, patient visits, administrative support, as well as participating in data collection and analysis. She 
has undergone proper training and obtained the certificates necessary to work with human subjects. 
 
Tiffany Gee, BS is a research assistant who will help with screening/recruiting/ consenting patients, patient 
visits, and administrative tasks. She has undergone proper training and obtained the certificates necessary to 
work with human subjects. 
 
Alma Fregoso, BS is a research assistant who will help with screening/recruiting/ consenting patients, patient 
visits, and administrative tasks. She has undergone proper training and obtained the certificates necessary to 
work with human subjects. 
 
Christiana Stark, BS is a research assistant who will help with screening/recruiting/scheduling and consenting 
patients. She will assist with administrative tasks as well. She has undergone proper training and obtained the 
necessary certificates to work with human subjects.  
 
22. BIBLIOGRAPHY 
1. Kaufmann, H and Freeman, R. Postural tachycardia syndrome. UpToDate:2016. 
2. Sutton, R and Salukhe, T. Ivabradine in the treatment of orthostatic intolerance. Eurospace:2011; 13, 
306-307.  
3. McDonald, C, Frith J, and Newton, J. Single Centre experience of ivabradine in postural orthostatic 
tachycardia syndrome. Eurospace: 2011, 13; 427-430.  
4. Kaufmann, H and Freeman, R. Treatment of orthostatic and postprandial hypotension. 
UpToDate:2016. 
5. Ewan, V, Norton M, and Newton J. Symptom improvement in postural orthostatic tachycardia 
syndrome with the sinus node blocker Ivabradine. Eurospace: 2007; 9.1202. 
6. Hersi, Ahmad S. Case Report: Potential New Indication of Ivabradine for Treatment of Patient with 
Postural Orthostatic Tachycardia Syndrome. Open Cardiovascular Medicine Journal, 2010; 4, 166-
167. 
7. Barzilai, M and Jacob G. The Effect of Ivabradine on the Heart Rate and Sympathovagal Balance in 
Tachycardia Syndrome Patients. Rambam Maimonides Medical Journal:2015,6; 1-7.  
23. FUNDING SUPPORT FOR THIS STUDY 
This study is fully funded by Amgen; Amgen will indemnify. 
24. BIOLOGICAL MATERIALS TRANSFER AGREEMENT 
None 
25. INVESTIGATIONAL DRUG FACT SHEET AND IND/IDE HOLDER 

19 
 
See uploaded documents.  
26. IMPACT ON STAFF 
None 
27. CONFLICT OF INTEREST 
None 
28. SUPPLEMENTAL INSTRUCTIONS FOR CANCER-RELATED STUDIES 
None 
29. OTHER APPROVALS/REGULATED MATERIALS 
None 
30. PROCEDURES FOR SURROGATE CONSENT AND/OR DECISIONAL CAPACITY 
ASSESSMENT 
Only patients who are competent to provide consent will be enrolled in the study.