Standing Cognition and Co-morbidities of POTS Evaluation
Phase: NA
Conditions: Postural Tachycardia Syndrome, Ehlers-Danlos Syndrome
Sponsor: Milton S. Hershey Medical Center

Page 1 of 12 (V.04/27/2017)  
                                                                                        
 
 
HRP-591 - Protocol for  
Human Subject Research 
 
Protocol Title: STUDY00009606: Standing Cognition and Co-morbidities of POTS Evaluation (SCOPE) 
 
Principal Investigator: 
Name: Amanda J. Miller  
Department: Neural and Behavioral Sciences 
Telephone: 717-531-0003 ext. 286490 
E-mail Address: aross1@pennstatehealth.psu.edu 
 
Version Date:  4/24/19  
 
Clinicaltrials.gov Registration #: in progress 
 
Important Instructions for Using This Protocol Template: 
1. 
Add this completed protocol template to your study in CATS IRB (http://irb.psu.edu) on the “Basic Information” 
page, item 7.  
2. 
This template is provided to help investigators prepare a protocol that includes the necessary information needed 
by the IRB to determine whether a study meets all applicable criteria for approval.  
3. 
Type your protocol responses below the gray instructional boxes of guidance language.  If the section or item is 
not applicable, indicate not applicable. 
4. 
For research being conducted at Penn State Hershey or by Penn State Hershey researchers only, delete the 
instructional boxes from the final version of the protocol prior to upload to CATS IRB (http://irb.psu.edu).  For all 
other research, do not delete the instructional boxes from the final version of the protocol. 
5. 
When making revisions to this protocol as requested by the IRB, please follow the instructions outlined in the Study 
Submission Guide available in the Help Center in CATS IRB (http://irb.psu.edu) for using track changes.  
 
If you need help… 
University Park and other campuses: 
Office for Research Protections Human Research Protection Program 
The 330 Building, Suite 205 
University Park, PA 16802-7014 
Phone: 814-865-1775 
Fax: 814-863-8699 
Email: irb-orp@psu.edu 
College of Medicine and Hershey Medical Center: 
Human Subjects Protection Office 
90 Hope Drive, Mail Code A115, P.O. Box 855 
Hershey, PA 17033 
(Physical Office Location: Academic Support Building Room 1140) 
Phone: 717-531-5687 
Fax number: 717-531-3937 
Email: irb-hspo@psu.edu 
 
Table of Contents 
1.0 
Objectives 
2.0 
Background 
3.0 
Inclusion and Exclusion Criteria 
4.0 
Recruitment Methods 

Page 2 of 12 (V.04/27/2017)  
5.0 
Consent Process and Documentation 
6.0 
HIPAA Research Authorization and/or Waiver or Alteration of Authorization 
7.0 
Study Design and Procedures 
8.0 
Subject Numbers and Statistical Plan 
9.0 
Confidentiality, Privacy and Data Management 
10.0 
Data and Safety Monitoring Plan 
11.0 
Risks 
12.0 
Potential Benefits to Subjects and Others 
13.0 
Sharing Results with Subjects 
14.0 
Subject Stipend (Compensation) and/or Travel Reimbursements 
15.0 
Economic Burden to Subjects 
16.0 
Resources Available 
17.0 
Other Approvals 
18.0 
Multi-Site Research 
19.0 
Adverse Event Reporting 
20.0 
Study Monitoring, Auditing and Inspecting 
21.0 
Future Undetermined Research: Data and Specimen Banking 
22.0 
References 
 
 

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1.0 
Objectives 
 
1.1 
Study Objectives 
The overall goal of this study is to investigate the impact of orthostatic stress on cognitive function in postural 
tachycardia syndrome (POTS), and to assess the prevalence of Hypermobile Ehlers-Danlos Syndrome (hEDS) and 
Hypermobility spectrum disorders (HSD) in patients with POTS. This study will be performed in a large cohort 
(100 POTS patients) at the Dysautonomia International Conference in Nashville, TN June 22-24, 2018. Healthy 
control subjects will be enrolled at Penn State Hershey Medical Center. The central hypothesis is that active 
standing in POTS worsens cognitive function and related to joint hypermobility. We will test this hypothesis in the 
following two specific aims:  
 
Aim 1: Determine impact of orthostatic stress on cognition in POTS. Hypothesis 1: Active standing in POTS worsens 
cognitive function. Cognitive function will be assessed in the supine and standing postures using a short battery 
of cognitive tests. These tests examine aspects of cognition known to be impaired in POTS patients including 
executive function (Stroop word color test), attention (CogState Identification test), and working memory 
(CogState two-back test). Aim 1 will be performed in POTS patients and in healthy subjects. 
 
Aim 2: Determine the prevalence hEDS and HSD in POTS. We will assess patients for hEDS and HSD using a 
questionnaire and physical exam based on the new guidelines. Aim 2 will only be performed in POTS patients. 
 
1.2 
Primary Study Endpoints 
Our primary endpoints are the scores on the cognitive tests and the Beighton score. 
 
1.3 
Secondary Study Endpoints 
Our secondary study endpoints are questionnaire answers and blood pressure and heart rate during 
standing. 
2.0 
Background  
 
2.1 
Scientific Background and Gaps  
2.2 
Previous Data 
 
POTS is a form of chronic orthostatic intolerance that produces daily symptoms such as fatigue, 
lightheadedness, palpitations, dyspnea, and nausea. POTS is defined by the presence of these symptoms along 
with an increase in heart rate of at least 30 beats/minute in adults within 10 minutes of standing.1 It is estimated 
that 1 to 3 million Americans have POTS and it predominantly effects women of childbearing age.  
 
Cognition in POTS 
Cognitive impairment or “brain fog” is experienced by almost all POTS patients and affects daily life 
including school and work performance.2 While most symptoms of POTS have an onset with orthostasis, it is 
unclear whether “brain fog” is posturally related. In my previous study, over 95% of POTS patients reported 
cognitive impairment, with many experiencing symptoms on a daily basis and even while supine.2 However, there 
is limited objective data to support this claim, with few studies evaluating cognitive function in POTS. To date, 
only five studies have objectively measured cognition in POTS.3-7 Working memory is the only cognitive domain 
that has been evaluated in the supine posture in POTS, and these studies found no impairments in working 
memory in POTS patients while supine.4, 5, 7 Multiple domains of cognitive function have been evaluated in POTS 
patients while seated and during head-up tilt (HUT). While seated, one study showed that POTS patients have 
clinically meaningful impairment in selective attention, cognitive processing speed, and executive function with 
no differences in psychomotor speed, memory function, or verbal fluency compared to age-matched healthy 
participants.3 During graded HUT, studies have demonstrated impaired attention, processing, and working 
memory in POTS patients compared to healthy participants.4-7 Therefore, evidence suggests that POTS patients 

Page 4 of 12 (V.04/27/2017)  
have impaired cognition even while seated, when tachycardia and orthostatic symptoms are minimized, perhaps 
indicating that this phenomenon is not solely related to posture. However, no studies have evaluated cognitive 
function in POTS during active standing. There are marked physiological differences between active standing and 
passive HUT. For example, during active standing the body engages the skeletal muscle pump to improve venous 
return to the heart. Furthermore, passive HUT can elicit exaggerated hemodynamic responses and vasovagal 
episodes even in health participants with no prior experience of clinical faints (false positives). Since active 
standing is more physiologically relevant in terms of daily life, it is critical to better understand how standing 
impacts cognitive function in POTS. 
 
 
Joint Hypermobility in POTS 
 
 
The high prevalence of hEDS in POTS was first recognized by Dr. Peter Rowe, et al. in 1999.8 He found  that 
about 60% of patients with chronic fatigue syndrome and orthostatic intolerance had joint hypermobility but this 
study was only conducted in 12 subjects. One small study found that 29% of pediatric POTS patients have joint 
hypermobility.9 Larger, questionnaire based studies have estimated that 30-40% of POTS patients have been 
diagnosed with EDS.10 But because there are very few geneticists that specialize in EDS and most physicians who 
evaluate POTS patients do not evaluate for EDS. The true prevalence of hEDS in POTS has not been evaluated. 
Furthermore, HSD is a new diagnosis defined in 2017, and no study to date has attempted to determine 
the rate of HSD in POTS. 
 
 
2.3 
Study Rationale 
 
POTS patients have impaired cognitive function that impacts their daily life including school and work 
performance. 2 hEDS and HSD contribute to functional disability and pain in POTS but are often undiagnosed 
because the prevalence is unknown and most POTS patients are not evaluated. The current study will determine 
the impact of standing on cognitive function in POTS and investigate the prevalence of hEDS and HSD in POTS. 
The findings from this study will provide the foundation to explore mechanisms of cognitive function in POTS 
and improve physician awareness of the importance of evaluating EDS in POTS patients.  We will perform this 
study at the 2018 Dysautonomia Patient Conference in Nashville, TN June 22-24, 2018. Performing this study at 
the conference will provide a convenience sample in which we can examine cognitive function and hEDS and 
HSD prevalence in a larger and more diverse cohort of POTS participants than could be accomplished at our 
institution. The mechanisms underlying cognitive dysfunction in POTS will be investigated more thoroughly at 
our institution under a separate IRB protocol (study STUDY00009333: Cognition in Postural Tachycardia 
Syndrome-submission in progress). 
3.0 
Inclusion and Exclusion Criteria 
3.1 
Inclusion Criteria 
 
Postural Tachycardia Syndrome or healthy control 
o Previously diagnosed with POTS 
 
Age between 13-60 years 
 
Participants may be any race, ethnicity, sex, or gender 
 
Able and willing to provide informed consent 
 
3.2 
Exclusion Criteria 
 
Inability to give, or withdrawal of, informed consent  
 
Age ≤ 13 or ≥ 61 years 
 
Prisoners 
 
Unable to stand 
 
Healthy controls must be free of chronic and systemic illness and not have a history of recurrent syncope 
 
3.3 
Early Withdrawal of Subjects 
 

Page 5 of 12 (V.04/27/2017)  
3.3.1 Criteria for removal from study 
The subject may withdraw from the study at any time for any reason. 
 
3.3.2 
Follow-up for withdrawn subjects 
No follow-up is required. 
4.0 
Recruitment Methods 
We will conduct this study at the 2018 Dysautonomia International Patient conference if our proposal is selected 
for the conference by Dysautonomia International’s Board of Directors. Healthy control subjects will be 
recruited using Penn State study finder and a paper flyer. 
 
4.1 
Identification of subjects 
 POTS patients will be recruited from attendees at the 2018 Dysautonomia International Patient 
Conference in Nashville, TN June 22-24, 2018. Announcements calling for participation will be 
made during the conference. 
 Healthy control subjects will be recruited using Penn State Study Finder and a paper flyer. 
4.2 
Recruitment process 
We will perform this study at the 2018 Dysautonomia Patient Conference in Nashville, TN. Interested 
participants will report to the study room. Study personal will obtain informed consent in all subjects. We will 
contact eligible healthy subjects through email when they respond to STUDYfinder or the paper flyer. 
 
4.3 
Recruitment materials 
Paper flyer 
 
4.4 
Eligibility/screening of subjects 
The study team will go over the inclusion and exclusion criteria with subjects prior to consent. 
5.0 
Consent Process and Documentation  
5.1 
Consent Process  
  
5.1.1 Obtaining Informed Consent 
 
5.1.1.1 Timing and Location of Consent 
Interested participants will report to the study room at the conference or at Penn State 
Hershey Medical Center CRC. They will be asked the screening questions. If eligible, study 
personal will obtain informed consent in all subjects. All subjects will be given sufficient time 
to read the consent, all procedures will be explain in layman’s terms and they will be given a 
copy of the signed consent form. 
 
5.1.1.2 Coercion or Undue Influence during Consent 
The subject will be provided with ample opportunity to have questions answered before 
participating in the study. All procedures will be explained to them in layman’s terms and 
they will be given a copy of their signed consent form. Subjects will have the right to 
withdraw for the study at any time. 
 
5.1.2 Waiver or alteration of the informed consent requirement 
Not applicable 
 

Page 6 of 12 (V.04/27/2017)  
5.2 
Consent Documentation 
 
5.2.1 
Written Documentation of Consent 
Subjects will sign the IRB-approved consent form. 
 
5.2.2 
Waiver of Documentation of Consent (Implied consent, Verbal consent, etc.) 
Not applicable 
5.3 
Consent – Other Considerations  
 
5.3.1 
Non-English Speaking Subjects 
Not applicable 
5.3.2 
Cognitively Impaired Adults 
 
 
Not applicable 
5.3.3 
Subjects who are not yet adults (infants, children, teenagers)  
5.3.3.1 Parental Permission 
Parents will sign the IRB-approved consent form.  
5.3.3.2 Assent of subjects who are not yet adults 
All subjects age 13-17 will sign the IRB-approved assent form. 
 
6.0 
HIPAA Research Authorization and/or Waiver or Alteration of Authorization 
 
6.1 
Authorization and/or Waiver or Alteration of Authorization for the Uses and Disclosures of PHI 
 
Check all that apply: 
  
Not applicable, no identifiable protected health information (PHI) is accessed, used or 
disclosed in this study. [Mark all parts of sections 6.2 and 6.3 as not applicable] 
 
 
Authorization will be obtained and documented as part of the consent process. [If this is the 
only box checked, mark sections 6.2 and 6.3 as not applicable] 
 
 
Partial waiver is requested for recruitment purposes only (Check this box if patients’ medical 
records will be accessed to determine eligibility before consent/authorization has been 
obtained). [Complete all parts of sections 6.2 and 6.3] 
 
 
Full waiver is requested for entire research study (e.g., medical record review studies). 
[Complete all parts of sections 6.2 and 6.3] 
 
 
Alteration is requested to waive requirement for written documentation of authorization 
(verbal authorization will be obtained). [Complete all parts of sections 6.2 and 6.3] 
 
6.2 
Waiver or Alteration of Authorization for the Uses and Disclosures of PHI 
Not Applicable 
 
6.3 
Waiver or alteration of authorization statements of agreement 
Not Applicable 
 
7.0 
Study Design and Procedures 
 

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7.1 
Study Design 
For Aim 1, this study will utilize a repeated measures design in which test scores and physiological 
parameters will be measured at 2 different postures (supine, standing). For Aim 2, questionnaire and 
exam data will be reported as percentages. 
 
7.2 
Study Procedures 
Step 1- Questionnaires (15 mins) 
Subjects will answer questions about their POTS diagnosis, co-morbid conditions (including hEDS), and 
current medications, and family history. Participants will also complete standardized questionnaires 
including the Orthostatic grading scale, Compass 31, RAND-36, and Fatigue-VAS. All questions will be 
answered on tablets and data will be entered directly into REDCap. Participants will have the option to 
complete the questionnaires during the study visit on a tablet or after their study visit by providing 
their email address. A link to the questionnaires in REDCap will be emailed to participants to complete 
after the study visit. 
 
Step 3- Orthostatic Cognitive Testing (30 minutes) 
Subjects will lie down on a bed for 5 minutes. Their blood pressure will be taken in triplicate while 
supine. Half the subjects will perform cognitive tests (stroop word color test and identification test) 
before standing up. The testing will take 6 minutes (3 minutes each) and the order of the tests will be 
randomized. Subjects will then stand up. Blood pressure and heart rate will be taken using a brachial 
artery oscillometric cuff every 2 minutes. While standing, the blood pressure cuff will inflate at minutes 
1, 3, 5, 7, and 9 since it takes approximately 1 minute to get the recording. After 4 minutes standing, 
subjects will perform cognitive tests again while standing. Subjects will remain standing for up to 10 
minutes. Subjects may choose to sit down and stand again to complete testing or choose to end testing 
at anytime. Subjects will then lie supine for 5 minutes to recover. Half of the subjects will perform 
cognitive testing following recovery. 
 
The Stroop word color test is a paper-based test and correct answers recorded by a member of the 
research team. This test takes approximately 3 minutes to complete. The Stroop word color test 
evaluates executive function. Participants will be asked to name the color of ink a word is printed in, 
when the word itself is a different color name.11 For example, subjects will be shown card with a word 
like “yellow” but will need to say “green” not “yellow” to answer correctly. This is difficult since we 
read faster than we can recognize color. This is primarily an assessment of concentration ability, but 
also involves executive function. In a previous study by Arnold, et al. the stroop word color test was 
most impaired in POTS while seated (cite the prior study). However, cognitive dysfunction in POTS 
linked to posture is poorly understood. It is important to assess cognitive function supine and during 
active standing in a large sample of POTS patients. The Identification test evaluates attention based on 
reaction time to correct responses to “yes or no” questions. In this study, participants will be asked “is 
this card red?” and then will be shown a random playing card on the tablet and press the “yes” or “no” 
button as quickly as possible. This test will be performed using Cogstate software on a tablet and takes 
approximately 3 minutes to complete. 
 
Step 4- EDS evaluation (20 mins) 
Subjects will be evaluated for hypermobile EDS (hEDS) and hypermobility spectrum disorders (HSD) by 
Dr. Clair Francomano or a colleague trained to diagnose EDS using a standardized form.  
 
7.3 
Duration of Participation 
Study participation will take approximately 1 hour per subject. Subjects may opt to complete 
questionnaires up to 1 month after their study visit. Only POTS patients will complete questionnaires. 

Page 8 of 12 (V.04/27/2017)  
8.0 
Subject Numbers and Statistical Plan 
 
8.1 
Number of Subjects 
We will enroll up to 100 participants with Postural Tachycardia Syndrome and 50 healthy controls for this 
study. Subjects will participate in both aims.  
 
8.2 
Sample size determination 
We propose to enroll up to 100 POTS patients and 50 healthy controls. We expect that this convenience 
sample, based on meeting attendance and recruitment feasibility, will allow for sufficient data on the 
prevalence of hEDS and HSD in POTS and whether cognition is affected by orthostasis in this patient 
population. 
 
8.3 
Statistical methods 
We will compare cognitive testing results by position using Wilcoxon signed-rank tests. Results will be 
compared between groups (POTS, controls) using Mann-Whitney U test. 
 
9.0 
Confidentiality, Privacy and Data Management  
See the Research Data Plan Review Form. 
10.0 Data and Safety Monitoring Plan 
10.1 
Periodic evaluation of data 
Safety is constantly monitored during a study because our studies involve continuous monitoring of physiological 
variables. The PI immediately reviews any concerns. Adverse events are not anticipated, but any occurring will be 
documented and reported according to HSPO policies and procedures. The PI will be solely responsible for data 
collection and verification, and review of cumulative adverse events. 
 
10.2 
Data that are reviewed 
Physiological variables will be reviewed continuously during the study for safety purposes. Any concerns will 
immediately be brought to the attention of the PI.  
 
10.3 
Method of collection of safety information 
Physiologic variables and general well being of the subject will be monitored continuously during study visits and 
reported on paper worksheets. 
 
10.4 
Frequency of data collection 
Data collection will start on the first study visit and continue until the subject leaves the study. Safety will be 
continuously monitored.  
 
10.5 
Individuals reviewing the data 
The PI and research team will review data in real-time throughout the study. A data safety monitor will also 
provide an objective review of treatment results as they relate to subject safety and data quality. The data safety 
monitor for this study will be Dr. Urs Leuenberger. Dr. Leuenberger has over 30 years of clinical research 
experience in various patient populations and the methods in this protocol, and does not have any significant 
conflict of interest with the PI or the study.  
 
10.6 
Frequency of review of cumulative data 
Safety is constantly monitored during the studies and any concerns are brought to the attention of the PI 
immediately. The PI will analyze subject data within one week of the experimental visit. Adverse events will be 
documented and reported appropriately according to HSPO policies and procedures.  
 

Page 9 of 12 (V.04/27/2017)  
The data safety monitor will meet every 6 months with the PI, or more often if needed. In preparation for these 
meetings, the PI will provide information by email regarding enrollment, protocol adherence, and data quality. 
The data safety monitor will also assess safety data including common and serious adverse events. In the case of 
an unanticipated or serious adverse event, the data safety monitor will be notified within 24 hours of the PI’s 
notification of the event. The PI will provide the data safety monitor with a list of non-serious adverse events 
during regularly scheduled meetings. 
 
10.7 
Statistical tests 
Any occurrences will be evaluated immediately on a case-by-case basis. 
 
10.8 
Suspension of research 
If a serious adverse event occurred, we would assess the need to suspend the research with the data safety 
monitor.   
 
11.0 Risks 
Confidentiality: There is a risk of loss of confidentiality if medical information or identity are obtained by someone 
other than the investigators, but precautions will be taken to prevent this from happening.  
 
Blood Pressure and Heart Rate Measurement: Frequent blood pressure measurements with the cuff around the 
arm may be inconvenient and may produce some discomfort and occasional bruising of the upper arm.  
 
Questionnaires: No risk 
 
Physical Exam: No risk 
 
Cognitive Tests: No risk 
 
12.0 Potential Benefits to Subjects and Others 
 
12.1 
Potential Benefits to Subjects 
There will be no direct benefit to subjects in this study. 
 
 
12.2 
Potential Benefits to Others 
This study may provide new insight for research scientists on cognitive function and the prevalence of hEDS and 
HSD in POTS.  
 
13.0 Sharing Results with Subjects 
Subjects with POTS will receive a copy of their hEDS evaluation form to discuss with their physician. 
 
14.0 Subject Stipend (Compensation) and/or Travel Reimbursements 
 Subjects will receive a $20 giftcard for participation in the study. 
15.0 Economic Burden to Subjects 
 

Page 10 of 12 (V.04/27/2017)  
15.1 
Costs  
There is no cost to the subject for taking part in this study. 
 
15.2 
Compensation for research-related injury 
It is the policy of the institution to provide neither financial compensation nor free medical treatment for research-
related injury. In the event of injury resulting from this research, medical treatment is available but will be 
provided at the usual charge. Costs for the treatment of research-related injuries will be charged to subjects or 
their insurance carriers.  
 
16.0 Resources Available 
 
16.1 
Facilities and locations 
Studies will be conducted at the 2018 Dysautonomia International Patient Conference. Subjects will be 
recruited from participants at the 2018 Dysautonomia International Patient Conference. Studies at Penn 
State Hershey Medical Center will occur in the General Clinical Research Center. 
 
16.2 
Feasibility of recruiting the required number of subjects 
The Dysautonomia International Patient conference has 500 attendees which are mostly POTS patients 
and caregivers. In past years, over 100 participants have volunteered for the research study conducted 
at the conference. We expect to recruit and approximately 100 POTS patients at the conference. We 
expect to recruit 5-10 healthy subjects per month. 
 
16.3 
PI Time devoted to conducting the research 
The PI will devote 10% effort to this project. 
 
16.4 
Availability of medical or psychological resources 
Physicians will be present during the study if any concerns arise. 
 
16.5 
Process for informing Study Team 
All members of the study team have access to approved documentation for this study. The PI will review 
the protocol with all members of the study team and will communicate with them regularly in person and 
through email. The PI is responsible for direct communication related to any changes in the protocol and 
the individual duties of each study member.  
 
17.0 Other Approvals 
17.1 
Other Approvals from External Entities 
Not applicable 
 
17.2 
Internal PSU Committee Approvals 
 
Check all that apply: 
  Anatomic Pathology – Hershey only – Research involves the collection of tissues or use of pathologic 
specimens. Upload a copy of HRP-902 - Human Tissue For Research Form on the “Supporting 
Documents” page in CATS IRB. This form is available in the CATS IRB Library.   
 
  Animal Care and Use – All campuses – Human research involves animals and humans or the use of 
human tissues in animals 
 

Page 11 of 12 (V.04/27/2017)  
  Biosafety – All campuses – Research involves biohazardous materials (human biological specimens 
in a PSU research lab, biological toxins, carcinogens, infectious agents, recombinant viruses or DNA 
or gene therapy). 
 
  Clinical Laboratories – Hershey only – Collection, processing and/or storage of extra tubes of body 
fluid specimens for research purposes by the Clinical Laboratories; and/or use of body fluids that 
had been collected for clinical purposes, but are no longer needed for clinical use. Upload a copy of 
HRP-901 - Human Body Fluids for Research Form on the “Supporting Documents” page in CATS IRB. 
This form is available in the CATS IRB Library.  
 
  Clinical Research Center (CRC) Advisory Committee – All campuses – Research involves the use of 
CRC services in any way. 
 
  Conflict of Interest Review – All campuses – Research has one or more of study team members 
indicated as having a financial interest. 
 
  Radiation Safety – Hershey only – Research involves research-related radiation procedures. All 
research involving radiation procedures (standard of care and/or research-related) must upload a 
copy of HRP-903 - Radiation Review Form on the “Supporting Documents” page in CATS IRB. This 
form is available in the CATS IRB Library. 
 
  IND/IDE Audit – All campuses – Research in which the PSU researcher holds the IND or IDE or 
intends to hold the IND or IDE. 
 
  Scientific Review – Hershey only – All investigator-written research studies requiring review by the 
convened IRB must provide documentation of scientific review with the IRB submission. The 
scientific review requirement may be fulfilled by one of the following: (1) external peer-review 
process; (2) department/institute scientific review committee; or (3) scientific review by the Clinical 
Research Center Advisory committee.  NOTE: Review by the Penn State Hershey Cancer Institute 
Scientific Review Committee is required if the study involves cancer prevention studies or cancer 
patients, records and/or tissues. For more information about this requirement see the IRB website 
at: http://www.pennstatehershey.org/web/irb/home/resources/investigator  
 
17.0 Multi-Site Research 
Not applicable.  
19.0 Adverse Event Reporting 
 
19.1 
Reporting Adverse Reactions and Unanticipated Problems to the Responsible IRB 
In accordance with applicable policies of The Pennsylvania State University Institutional Review Board 
(IRB), the investigator will report, to the IRB, any observed or reported harm (adverse event) 
experienced by a subject or other individual, which in the opinion of the investigator is determined to be 
(1) unexpected; and (2) probably related to the research procedures. Harms (adverse events) will be 
submitted to the IRB in accordance with the IRB policies and procedures. 
 

Page 12 of 12 (V.04/27/2017)  
20.0 Study Monitoring, Auditing and Inspecting 
 
20.1 
Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the Penn State quality 
assurance program office(s), IRB, the sponsor, and government regulatory bodies, of all study related 
documents (e.g., source documents, regulatory documents, data collection instruments, study data 
etc.).  The investigator will ensure the capability for inspections of applicable study-related facilities 
(e.g., pharmacy, diagnostic laboratory, etc.). 
 
21.0 Future Undetermined Research: Data and Specimen Banking 
 
Not Applicable 
 
22.0 References 
 
References 
 
1. 
Sheldon RS, Grubb BP, 2nd, Olshansky B, Shen WK, Calkins H, Brignole M, Raj SR, Krahn AD, 
Morillo CA, Stewart JM, Sutton R, Sandroni P, Friday KJ, Hachul DT, Cohen MI, Lau DH, Mayuga KA, Moak 
JP, Sandhu RK and Kanjwal K. 2015 heart rhythm society expert consensus statement on the diagnosis and 
treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart 
Rhythm. 2015;12:e41-63. 
2. 
Ross AJ, Medow MS, Rowe PC and Stewart JM. What is brain fog? An evaluation of the symptom in 
postural tachycardia syndrome. Clin Auton Res. 2013;23:305-11. 
3. 
Arnold AC, Haman K, Garland EM, Raj V, Dupont WD, Biaggioni I, Robertson D and Raj SR. 
Cognitive dysfunction in postural tachycardia syndrome. Clin Sci (Lond). 2015;128:39-45. 
4. 
Ocon AJ, Messer ZR, Medow MS and Stewart JM. Increasing orthostatic stress impairs neurocognitive 
functioning in chronic fatigue syndrome with postural tachycardia syndrome. Clin Sci (Lond). 2012;122:227-38. 
5. 
Stewart JM, Medow MS, Messer ZR, Baugham IL, Terilli C and Ocon AJ. Postural neurocognitive and 
neuronal activated cerebral blood flow deficits in young chronic fatigue syndrome patients with postural 
tachycardia syndrome. Am J Physiol Heart Circ Physiol. 2012;302:H1185-94. 
6. 
Anderson JW, Lambert EA, Sari CI, Dawood T, Esler MD, Vaddadi G and Lambert GW. Cognitive 
function, health-related quality of life, and symptoms of depression and anxiety sensitivity are impaired in 
patients with the postural orthostatic tachycardia syndrome (POTS). Front Physiol. 2014;5:230. 
7. 
Stewart JM, Del Pozzi AT, Pandey A, Messer ZR, Terilli C and Medow MS. Oscillatory cerebral blood 
flow is associated with impaired neurocognition and functional hyperemia in postural tachycardia syndrome 
during graded tilt. Hypertension. 2015;65:636-43. 
8. 
Rowe PC, Barron DF, Calkins H, Maumenee IH, Tong PY and Geraghty MT. Orthostatic intolerance 
and chronic fatigue syndrome associated with Ehlers-Danlos syndrome. J Pediatr. 1999;135:494-9. 
9. 
Kovacic K,  TCC,  AR,  MS, Simpson P,  MN and  GC. The co-morbidities of pediatric POTS: will the 
real 
‘‘POTS’’ please stand up? Clin Auton Res. 2013;23:1. 
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