Precision Approach to PPI Therapy in Gastroesophageal Reflux Disease
Phase: NA
Conditions: Gastroesophageal Reflux, Laryngopharyngeal Reflux
Sponsor: University of California, San Diego

   
 
 
Precision Approach to PPI Therapy in Gastroesophageal reflux disease. 
 
NCT03619811 
 
Document Date: 9/30/2019  
 

 
 
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UCSD Human Research Protections Program 
New Biomedical Application 
RESEARCH PLAN 
Instructions for completing the Research Plan are available on the HRPP website. 
The headings on this set of instructions correspond to the headings of the Research Plan. 
General Instructions: Enter a response for all topic headings.  
Enter “Not Applicable” rather than leaving an item blank if the item does not apply to this project. 
Version date: 9/30/2019 
1. 
PROJECT TITLE 
Precision Approach to PPI Therapy in Gastroesophageal reflux disease. 
 
2. 
PRINCIPAL INVESTIGATOR  
Dr. Rena Yadlapati, Associate Professor of Clinical Medicine, Department of Medicine, Division of 
Gastroenterology & Hepatology 
 
3. 
FACILITIES 
University of California San Diego    
 
4. 
ESTIMATED DURATION OF THE STUDY 
5 years. 
 
5. 
LAY LANGUAGE SUMMARY OR SYNOPSIS (no more than one paragraph) 
The clinical and financial burden of patients with suspected reflux associated laryngeal symptoms 
(RALS) is substantial. RALS is the process where gastro-esophago-pharyngeal reflux contributes to 
chronic laryngeal symptoms such as sore throat and dysphonia. The objectives of this proposal are 
to understand the performance of standard of care diagnostic tools and treatment options among 
suspected RALS. 
 
6. 
SPECIFIC AIMS 
Aim 1: To determine the ability of novel diagnostic tools to predict symptom-based treatment response 
in suspected RALS. 
Hypothesis: Salivary pepsin will have high sensitivity for response to proton pump inhibitor (PPI); pH-
impedance (Z2pH) and esophageal manometry (HRIM) will have high specificity for response to Upper 
esophageal sphincter assist device (UESAD) in adjunct to PPI. 
 
Aim 2: To examine the therapeutic efficacy of UES augmentation in suspected RALS. 
Hypothesis: UESAD in adjunct to PPI will result in greater symptom response versus PPI alone. 
 
Approach:  We will perform an 8 week clinical trial. Patients with suspected RALS will undergo 
baseline standard of care diagnostic tests (esophageal manometry (HRIM), pH-impedance (Z2pH)) 
and research diagnostic test (salivary pepsin) followed by two standard of care therapies (PPI x 4 
weeks followed by UESAD in adjunct to PPI x 4 weeks). 
7. 
BACKGROUND AND SIGNIFICANCE 
Reflux associated laryngeal symptoms (RALS), coined “laryngopharyngeal reflux”, occurs when 
gastro-esophago-pharyngeal reflux contributes to chronic laryngeal symptoms such as throat 
clearing, sore throat and dysphonia.1, 2, 23 Over the past 25 years, RALS has been increasingly, and 
often incorrectly, diagnosed and has emerged as a point of controversy and confusion.  
 
Critical Healthcare Burden RALS is prevalent, costly, and impairs quality of life Fifty percent of 

 
 
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patients with laryngeal symptoms are considered to have RALS, although 60% of cases are likely 
misdiagnosed.5, 12, 18 The evaluation of suspected RALS entails an average of 10 specialist office 
visits and 6 diagnostic tests, often without clarity or improved health-related quality of life.12, 24-26 This 
redundant and ineffective clinical paradigm contributes to health care costs of $5,438 per patient, 
equating to over $50 billion annually.12 Thus, there is a critical need for cost-effective and patient-
centered approaches to suspected RALS.   
 
Clinical Barrier Treatment strategies for suspected RALS are inappropriately generalized 
Patients presenting with laryngeal complaints are heterogeneous in terms of symptom presentation, 
underlying physiology, and response to treatment. For instance, non-reflux mechanisms commonly 
generate laryngeal irritation; in these cases acid suppression and anti-reflux therapy is 
unwarranted.27 Nonetheless, the majority of patients with suspected RALS are trialed on empiric PPIs 
over long and oftentimes indefinite intervals. However, fewer than 50% of patients will derive 
symptom relief with PPI therapy.13, 14 The low response to PPI therapy relates to the dilutional effect 
of patients incorrectly considered to have RALS.28 Furthermore, anti-reflux surgery is often 
considered, even though anti-reflux surgery is invasive, morbid and costly, and not shown to improve 
outcomes.15-17  Thus, effective, safe, and personalized treatment options are needed.   
 
Diagnostic Challenges Current diagnostic tools are unable to reliably identify RALS A major 
barrier to identifying true RALS is that traditional diagnostic tools assess anatomic or physiologic 
properties in isolation, resulting in poor specificity, sensitivity, and prognostic ability 
8. 
PROGRESS REPORT 
Start Date: July 1, 2018 (University of Colorado) 
Total enrolled: 17. 
Total completed phase 1 (PPI trial):15 
Total completed phase 1 and 2 (PPI trial & UESAD): 8 
Currently enrolled: 2 
Dropped out or lost to follow-up: 1 
 
9. 
RESEARCH DESIGN AND METHODS 
Study Design: This is a prospective multicenter single-arm non-randomized non-controlled clinical 
trial registered with clinicaltrials.gov. This study will be performed at the UCSD Medical Campus and 
the University of Colorado (CU) Medical Campus. With regards to IRB the plan is that University of 
Colorado will have IRB oversight of the study activities at University of Colorado and UCSD will have 
IRB oversight of study activities at UCSD. The study has already been active and IRB approved at 
University of Colorado. (IRB Approval letter from University of Colorado included) 
Setting at UCSD: Patients will be enrolled from clinics of study investigators that are also the treating 
provider for the patient. Therefore, the patients are known to the investigator and have a treatment 
relationship. Inclusion and exclusion criteria are below. The clinics are clinics of Dr. Yadlapati, Dr. 
Mittal, Dr. Kunkel, Dr. Weissbrod, Dr. Vahabzadeh.  
Study Protocol:  
Screening: Upcoming clinics staffed by study investigators will be screened by Research Assistant 
(RA) to identify potential participants. The PI/RA will notify the study investigator MD of patient’s 
eligibility. Once investigator approves, the RA will contact the potential research participant by phone 
to provide information about the study, determine eligibility, and answer any questions.  

 
 
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Standard of care Clinic Visit (Visit 1): At the already scheduled standard of care clinic visit the 
treating physician will provide the potential participant with information regarding the study. If the 
patient is interested in participating in the study, the RA will review the study in detail and obtain 
informed consent. At this time requests for procedures, office visits, and PPI therapy will be placed to 
the insurance company during this standard of care visit so that the participant understands expense 
coverage at the onset of study participation. 
 
Standard of Care Diagnostic Evaluation (Visit 2): Participants will present for standard of care 
(SOC) diagnostic evaluation.  
• Esophageal manometry (will not be repeated if performed within 3 months of study) 
• 24 hour pH impedance monitoring (will not be repeated if performed within 3 months of study) 
• Patient reported outcome questionnaires: the Gerd questionnaire (GerdQ) and the Reflux Symptom 
Index. These are validated patient reported outcome instruments, available in English and Spanish. 
• Saliva sample collection. Participants will self-induce (non-invasive) 2cc of saliva. Saliva will be 
collected in a testtube and immediately processed using the Peptest technique to measure pepsin 
concentration in the saliva. Saliva will not be stored. 
Per national guidelines and recommendations, it is SOC to evaluate patients with suspected RALS 
with esophageal manometry and pH impedance in the motility laboratory. This practice is SOC at 
UCSD. Therefore, esophageal manometry and pH impedance procedures are expenses that 
insurance typically covers. Patient reported outcome questionnaires are SOC nationwide and are 
SOC at our motility lab at UCSD. The time for these SOC procedures combined is 90 minutes. * in 
the table indicates that the costs for these SOC procedures are expected to be covered by insurance 
however there is always a risk that for a certain subject insurance may cover the costs. Therefore, 
orders for tests will be placed at the first SOC clinic visit and potential costs not covered by insurance 
will be disclosed to the patient.  
Table 1. 
 
Standard 
of Care 
Coverage 
Visit Time 
(mins) 
Costs to Manage Side Effects 
Esophageal 
manometry 
Yes 
*Insurance 
45 
Not anticipated, but would be 
covered as standard of care by 
Insurance 
pH impedance 
Yes 
*Insurance 
45 
Not anticipated, but would be 
covered as standard of care by 
Insurance 
Questionnaires 
Yes 
No coverage 
needed 
10 
None 
Salivary peptest 
No 
Research 
costs 
2 
None 
4 week PPI 
therapy 
Yes 
*Insurance  
Not 
applicable 
Covered as standard of care by 
Insurance 
UES Assist 
Device 
Yes 
Typically self-
pay; In this 
study will be a 
research cost 
30 min visit 
to receive 
device 
Not anticipated, but would be 
covered as standard of care by 
insurance 

 
 
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Saliva samples will be collected non-invasively via the method described below and analyzed for 
pepsin concentration. Saliva sample collection will be performed in the motility lab and will add two 
minutes to the visit time. Salivary peptest is FDA approved though not a SOC procedure at UCSD 
and therefore the supplies will be covered through research costs and analyses will be performed by 
the research team. There are no expected costs to manage side effects.  
Standard of Care Drop off of Ph Impedance Catheter (Visit 3): Participants will return the pH 
impedance catheter to the motility lab as per SOC. There are no costs associated with this visit.  
 
PPI Therapy (Weeks 0 to 4): Following the diagnostic evaluation (visit 2 & 3) the participants will 
start their 4 week course of PPI therapy. PPI therapy is an FDA approved standard treatment per 
national guidelines and recommendations, and is the SOC practice at UCSD covered by insurance. 
The 4 week course of PPI therapy is not an intervention. Per SOC the PPI will be Omeprazole 40mg 
BID or equivalent;  4 weeks is chosen given reports of esophagitis healing within 2 weeks of PPI.52 
The PPI will be obtained through the participant’s pharmacy. The RA will call the participant at week 
2 and week 3 of PPI therapy per phone script attached to review appropriate PPI use, adherence, 
and remind the participant of the mid-treatment visit.  
Mid-Treatment Visit (Visit 4): After 4 weeks of PPI therapy, the participant will present to a clinic 
room at Clinical Trial Research Institute for a mid-treatment visit. During this visit the PI/RA will collect 
a saliva sample non-invasively via the method described below and analyzed for pepsin 
concentration (2 minutes). The participant will complete a SOC questionnaire to assess clinical 
outcomes following the PPI therapy. The participant will be given an UES assist device. The PI/RA 
will fit the UES assist device during this visit and educate the participant on use of the UES assist 
device. The UES assist device is an FDA approved non-invasive device that is available over the 
counter for this proposed participant population, and is not considered a research intervention. For 
this study the research team will provide the UES assist device free of cost to the participant. 
Therefore, the participant will not incur any costs related to the UES assist device.  The visit duration 
will be 30 minutes.  
UES Assist Device & PPI Therapy (Weeks 5 to 8): The participant will use the UES assist device 
and continue their PPI therapy for 4 weeks.  The RA will call the participant at week 5 and 7 therapy 
per phone script attached to review appropriate use, adherence, and remind the participant of the 
mid-treatment visit.  
Post-Treatment Clinic Visit (Visit 5): Participants will return to the treating MD’s clinic at the end of 
the 8 week treatment to review test results, symptom response, and discuss next steps as per 
standard of care. For patients without signs of esophagopharyngeal reflux or GERD, MD will 
recommend further evaluation by either laryngology, asthma, allergy, and/or behavioral psychology 
as indicated by standard practice. During this visit, the PI/RA will collect a saliva sample non-
invasively via the method described below and analyzed for pepsin concentration (2 minutes). The 
participant will complete a SOC questionnaire to assess clinical outcomes following the PPI + UES 
assist device therapy. Participants are permitted to keep the UES assist device if they intend to 
continue to use it, free of cost.  
Phone Call: The PI/RA will call the participant at week 20 with basic questions about their progress 
after the completion of the trial, whether they have continued using the reflux band, and their current 

 
 
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medications to understand long-term outcomes and adherence.  
Typically, patients with suspected RALS will see 10 consultants, undergo 6 diagnostic tests, and 
receive treatment with PPI therapy and a trial of the UES assist device. In this research protocol, 
patients will present for 2 clinic visits, have diagnostic testing expedited and scheduled all within one 
setting, and undergo a streamlined therapeutic flow of PPI therapy, and UES assist device within 2 
months. This study protocol was specifically designed to entail minimal perturbation to participants, 
including time and cost, and provide a streamlined and efficient evaluation.   
 
 
 
SPECIFIC AIMS & DATA ANALYSIS 
 
Aim 1: To determine the ability of novel diagnostic tools to predict symptom-based treatment response 
in suspected RALS. 
Data Analysis for Aim 1 
Aim 1 analysis will employ a series of receiver operating characteristic (ROC) curves to assess and 
compare baseline diagnostic tool ability to predict patient-reported symptom response to treatment 
(positive or negative) at time points B (post-PPI) and C (post-UESAD+PPI). The areas under the 
ROC curves (AUCs) will be  
 
Sample Size & Power Calculation: At UCSD we plan to enroll 100 participants with an 
expected <15% dropout, with an overall analytic sample size of ≥80. Assuming a minimal response 
rate of 50% to PPI and 67% to UESAD+PPI, a sample size of 80 and alpha level of 0.05 allows for 
90% power to detect an AUC ≥0.70. The UESAD+PPI response rate is an extrapolated combined 
estimate of UESAD alone and PPI alone from our prior data.  
 
Aim 2: To examine the therapeutic efficacy of UES augmentation in suspected RALS. 
Data Analysis for Aim 2 
Aim 2 analysis will employ a longitudinal mixed model to assess the association between intervention 
(PPI or UESAD+PPI) and outcome (patient reported symptom response). Longitudinal data will be 
clustered by participant measured in per month units, and analyzed at 3 study time points: A 
(baseline), B (post-PPI), and C (post-UESAD+PPI) to specifically compare change from A to B and B 
to C. Salivary pepsin at time points B and C will also serve as an objectively measured response 
variable. 
 
Sample Size & Power Calculation: The participants in Aim 1 will be included in Aim 2. With 80 
participants, if we conservatively assume that the correlations among the repeated measures is ≥0.5, 
we have 90% power to detect an effect of 0.37SD as measured by the change from A to B and B to 
C (the effects measured in pilot data exceeds 0.1SD). It is likely that we would also want to estimate 
change from BtoC in the subset of PPI responder and non-responders; we have 90% power to detect 
a change of 0.37SD (30 participants) or 0.53SD (40 participants). 
 
Inclusion of Women & Minorities: Approximately 25% of women and minorities have RALS. We 
anticipate that approximately 60% of participants will be women and at least 10% will be minorities.  
 

 
 
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UCSD as Prime Grant Holder: UCSD will be the prime grant holder and University of Colorado will 
be a second site for participant enrollment and data collection. Data will be collected in REDCap 
database developed by UCSD REDCap. University of Colorado will be able to enter de-identified 
data into the REDCap database.   
 
 
10. 
HUMAN PARTICIPANTS 
Total number of participants to be enrolled at: UCSD (100), University of Colorado Aurora CO 
(100). The study has already been active at CU since 2018 and actively enrolling as described in the 
progress report.  
 
A. Inclusion: Age 18-89 years male and female, >8 weeks of symptoms of sore throat, throat 
clearing, and/or voice hoarseness, naïve to PPI or able to stop for 8 weeks, any ethnic 
background  
B. Exclusion criteria: Laryngeal mass lesion on laryngoscopy (if performed); Pregnant; 
Breastfeeding; Unable to consent in English or Spanish as questionnaires are only validated in 
English and Spanish; Imprisoned; PPI intolerance; Contraindication to UESAD use per 
manufacturer guidelines which include:  
• 
Patients with implants or implant parts that reside in the area where UESAD is applied. 
• 
Patients with an implanted pacemaker, implanted cardioverter defibrillator (ICD), vagus nerve 
stimulator, or other such similar devices implanted in the neck. 
• 
Patients diagnosed with glaucoma. 
• 
Patients who had a malignancy of the neck, including neck surgery. 
• 
Patients that may have an altered mental status including due to the use of sedative drugs or 
narcotics. 
• 
Patients with carotid artery disease, thyroid disease, a history of cerebrovascular disease, or any 
disorder of connective tissues (e.g., Marfan’s Syndrome or Ehlers-Danlos Syndrome). 
• Patients who use nocturnal NIV machines such as CPAP or BiPAP.  
 
11. 
RECRUITMENT AND PROCEDURES PREPARATORY TO RESEARCH 
How will participants be identified for recruitment? The research assistant (RA)/PI will screen 
eligible patients coming in for evaluation in the clinic, endoscopy unit and motility lab that are patients 
of study investigators. The RA/PI will notify study investigators/treating MDs if eligible participant 
meeting inclusion criteria is identified. RA will keep a password protected screening list stored in a 
secure server separate from research data. This will protect identifiers from improper use and 
disclosure. A partial HIPAA waiver will be used for the minimal risk record review because identifying 
and contacting thousands of potential subjects would not be feasible for a medical record review where 
results would not change care the individuals already would have received, and waiver will not adversely 
affect the rights of welfare of the subjects.  
1. What PHI will be accessed to identify participants? Participants name, DOB, MRN, current 
medications, disease diagnosis, and relevant medical records (gastroenterology and laryngology 
records) will be accessed to identify if a patient meets inclusion criteria. No PHI will be stored in 
the screening log if the patient does not meet the inclusion criteria. This will protect identifiers 
from improper use and disclosure. 
 
2. When will participants be approached for recruitment? If treating MD/study investigator 
approves, the RA will call the potential research participant using the pre-screening phone script 
to notify the participant about the study, review eligibility and answer any questions and/or will 
contact the potential research participant in person in clinic. They will be given the consent form 

 
 
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and sufficient time to read it and ask any questions they may have. They will be given the 
opportunity to speak to the PI about any questions they have that cannot be answered by the RA. 
 
3. Who can refer patients to the study? Patients may be referred to the study by study 
investigators, and are participant to the same screening process to determine if they are eligible. 
Patients will not be obtained from any recruitment database. 
 
4. Who will not be considered for recruitment? Participant must be able to consent to the study. 
This protocol involves minimal risk, and/or targets only populations wherein impaired decision-
making capacity is unlikely. Based upon past experience, we expect that the population of 
patients we will be including in this protocol will be competent to give informed consent. If there is 
any concern by an investigator that a potential research participant has a condition or 
circumstance that is associated with a possible decrease in decision making capacity, that 
participant will not be included in the study.  
 
At risk populations including but not limited to prisoners, pregnant women, breastfeeding women, 
the mentally disabled, cognitively impaired, those requiring legal adult representation, and 
individuals under the age of 18 will not be approached. Pregnant women are excluded from our 
protocols, to make that distinction clear, we will ask if the potential research participant is 
pregnant at when determining eligibility. Breastfeeding women are excluded from our protocols. 
To make that distinction clear, the we will ask about breastfeeding when determining eligibility. 
 
If potential research participants are not interested in participating in the study then their identifying 
information in the screening log will be destroyed at the earliest opportunity consistent with conduct 
of research.  
 
12. 
INFORMED CONSENT 
This study has a consent process. The RA/PI will obtain informed consent.  Participants will be 
screened prior to consent by reviewing medical records. Only patients under a treating relationship 
by one of the study investigators will be screened and consented. No research procedures will be 
done prior to obtaining consent (including fasting). Participants will not provide information about 
other identifiable persons, such as relatives or friends (secondary participants) that will be used for 
data analysis. Participants will receive a signed and dated copy of the consent form to be kept in their 
electronic medical record, and can ask for a paper copy in clinic. There is no deception involved in 
this study. 
 
1. How will consent be obtained? Consent will be obtained face-to-face and/or via email. The 
consent will be obtained by the RA/PI. If consent is obtained face-to-face it will take place in a 
private clinic setting. The participant will be given time to read the consent and ask questions 
before they decide to participate. Comprehension and autonomy will be assessed by asking 
questions about the study and assessing their responses. Only the participant may provide 
consent or permission. 
2. Who will obtain consent? The RA/PI will obtain consent for all participants. The PI will be 
responsible for ensuring the RA is completely trained on the study and the consent process. 
3. Who will be excluded from the study and why? Participants unable to consent and complete 
questionnaires in English or Spanish will be excluded. This study requires participant’s patients to 
answer their own questionnaires. The questionnaires used in this study are verified in English and 
Spanish. Participants who are blind, illiterate or have similar reading limitations will be excluded. A 

 
 
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self-reporting questionnaire will be used in this study. It may alter the answers if the questionnaire 
is read to them. If English is not the participant’s primary language then an official health 
translator will be used. A Spanish version of the informed consent form will also be developed 
after the current informed consent version is approved by the IRB.  
4. How will consent be documented? A copy of the signed informed consent and HIPAA 
authorization will be placed in the participant’s medical record. The patient will also receive a 
signed and dated copy of the consent form electronically, and may request a paper copy in clinic 
if this is not accessible to them. The original consent form and HIPAA authorization will be kept in 
a secure office until completion of the study. 
 
 
13. 
ALTERNATIVES TO STUDY PARTICIPATION 
Patients may elect to not participate in the study and continue with a standard course of treatment for 
their GERD and RALS as discussed with their physician. 
 
14. 
POTENTIAL RISKS 
Completion of questionnaire (Standard of Care):  There exists a small risk of emotional upset 
when filling out questionnaires. Participants may experience some anxiety as they are asked to 
answer personal questions or are reminded of unpleasant thoughts or experiences during the 
questionnaire process. The participant, as always, has the right to refuse to answer any question 
they are asked. However the study team shall determine if the extent of refusal may warrant the 
removal of the participant from the research study so as to ensure complete and accurate data 
collection.   
 
Pepsin analysis (Research): The Peptest requires non-invasive (participant induced) collection of 
saliva.  There is no diagnostic or therapeutic procedure performed. There may be a small amount of 
discomfort when the participant is bringing up saliva for collection. There is also a risk that the 
Peptest result will be incorrect (false negative or false positive).  However, no decisions regarding 
management of a patient’s disease will be made based on the results of this test.   
 
Esophageal Manometry (HRIM) (Standard of Care) 
The manometry test measures the strength of the esophagus muscle and the direction of movement 
of the muscular contractions.  Impedance can also detect the direction and speed of fluid and airflow 
through the esophagus. This procedure takes approximately 45 minutes.  It involves passing a 
recording tube (less than 1/4 inch across) through the nose into the esophagus.  The tube is 
designed to measure pressures in the pharynx, esophagus and stomach.  A lubricant will be put on 
the end of the tube to make the placement more comfortable. An anesthetic (numbing) jelly 
(Lidocaine®) is also available if you choose. Once the manometry tube is in place, the participant will 
be asked to swallow 5 ml (1 teaspoon) of water or a salt solution several times throughout the 
measurement. 
 
pH impedance (Standard of Care) (Z2pH): 
A pH-impedance catheter will then be placed in a similar manner through the nose and into the 
esophagus.  This catheter measures how acidic the environment in your esophagus is.  Impedance 
can also detect the direction and speed of fluid and airflow through the esophagus.  These 
measurements allow the physician to determine if gastro-esophageal reflux is contributing to your 
symptoms. This procedure takes approximately 45 minutes. 
 

 
 
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The catheter will be attached to a portable receiver that you will wear for 24 hours.  You will be given 
instructions as to how to note meals, sleep, and symptoms throughout the 24 hour period. 
 
The risks of manometry (HRIM) and pH impedance (Z2pH): Placement of the manometry and pH-
Impedance catheters through the nose can cause gagging or mild pain in the nose and throat, skin 
irritation. Nosebleeds can also rarely occur. These tests are standard of care and care will be taken 
to reduce these risks as much as possible. All procedures will be performed by experienced 
personnel who specialize in these procedures.  
 
Upper esophageal sphincter assist device (Standard of Care): 
The upper esophageal sphincter assist device (UESAD) is a band that is worn externally around the 
neck, and provide increased pressure at the upper esophageal sphincter. It is recommended to be 
worn at nighttime.  
 
The safety of the UESAD (Reflux Band) has been assessed in previous studies. Adverse events that 
were reported during these studies were generally mild, short in duration, and the majority of these 
events were not related to the device. Those events that were related to the device were also 
generally mild and short in duration. Potential risks include discomfort, difficulty sleeping, skin 
irritation, risk of over compression, misuse, incorrect fitting, and malfunctions.  
 
Device-related adverse events did not result in reduced outcomes in relation to the change of the RSI 
score from baseline to the score measured after 4 weeks of use. There were no deaths in these 
studies and there were no unexpected adverse events, and none of the participants withdrew from 
the studies due to an adverse event. These studies also showed that there was no effect on heart 
rate, blood pressure, cardiac rhythm, or intraocular pressure when the UESAD was worn as intended 
as well as when it was intentionally displaced laterally, as compared to the baseline. This device has 
been approved for sale and marketing by the FDA for the proposed participant population, and is 
available as an over the counter device.  
 
Proton pump inhibitor (PPI) Therapy: Short-term use of PPI therapy may be associated with the 
following side effects: headache, diarrhea, constipation, abdominal pain, flatulence, nausea, 
vomiting, and rash. Short-term PPI use may increase the risk of Clostridium difficile infection of the 
colon. The FDA has determined that short-term use of PPI therapy has an unlikely risk of fracture.  
 
 
Potential loss of confidentiality: Finally, there is a risk that confidentiality of participant information 
will be breached.  However, all participant data will be kept confidential, following HIPAA regulations.  
Participant data will be stored on encrypted files.     
 
Data safety and compliance monitoring: Compliance to UESAD use will be monitored via patient-
reported outcomes during telephone follow-up by the research assistant. In addition, research 
assistant will assess for adverse events to the UESAD during telephone follow-up. A designated 
physician in gastroenterology team will serve as the safety monitor will to assess adverse events and 
safety concerns.  
 
 
15. RISK MANAGEMENT PROCEDURES AND ADEQUACY OF RESOURCES 

 
 
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Questionnaires- The participant, as always, has the right to refuse to answer any question they are 
asked.  However the study team shall determine if the extent of refusal may warrant the removal of 
the participant from the research study so as to ensure complete and accurate data collection.    
 
Manometry & pH impedance – 
-Gagging or mild pain in the nose and throat. In this event, the nurse/technician will stop catheter 
advancement and will use a light to inspect the oral cavity and nares. If the catheter is in an 
appropriate configuration, the patient will be asked to take deep breaths and promote relaxation. 
Once the patient is comfortable the patient will be advised to drink sips of water as catheter 
advancement is attempted. If symptoms do not improve catheter placement will be aborted and the 
ordering provider notified.  
-Skin irritation. The catheter is transnasally placed and the proximal end of the catheter will sit gently 
across the patient’s cheek and loop around the ear lobe. To ensure adequate placement of the pH 
impedance catheter over the 24 hour period, a non-abrasive anti-slip tape will be used to secure the 
catheter to the cheek. There is risk of skin irritation. The motility nurse/technician and 
gastroenterology team are on call 24 hours a day, and in the event of skin irritation the patient will be 
advised by the team to remove the adhesive and permit a finger width space between the catheter 
and the cheek. The skin will be evaluated the following day when the patient drops the catheter off by 
the nurse. However, if the skin remains irritated the patient will be educated on catheter removal over 
the phone.     
-Nosebleeds can also rarely occur. In this rare event, pressure will be applied by the nurse.  An 
epistaxis kit is also available to nurses in the motility lab inclusive of gauze and decongestant nose 
drops.   
 
Reflux band Band (UESAD)- the device, and how it works will be fully explained to the participant, 
any questions they have will be answered. If the device is worn the correct way, there have been no 
risks found. Participants will have the phone number of the PI and research assistant, and will be 
advised to contact the research team if they experience symptoms related to the device or any 
issues. The PI will evaluate the symptoms over the phone or in person without added cost to the 
participant, and will discuss how they will move forward which may include re-education about device 
use, re-fitting of the device, or stopping device use.   
  
Peptest- very little risk to begin with, other than the participant being slightly uncomfortable during 
saliva production. The procedure will be explained to the participant so they know what to expect. If 
there is  false negative or false positive result, no decisions regarding management of a patient's 
disease will be made based on the results of this test.   
  
To protect confidentiality, all participant data will be kept confidential, following HIPAA regulations.  
Participant data will be stored on encrypted files on a password protected data base that only the 
study team will have access to.  
  
RALS participants will be called every 2 weeks by the coordinator. This will assess their symptoms 
and if they are having any issues with the device or treatment.  
16. PRIVACY AND CONFIDENTIALITY CONSIDERATIONS INCLUDING DATA ACCESS AND MANAGEMENT 
Data will be stored in REDCap and accessible only by authorized research personnel who have 
undergone appropriate training. All research data will be stored in REDCap.  When the study closes 
the data will be stored in REDCap for 7 years until destruction per REDCap policies. As for paper 
document, all records will be retained for 7 years after study closes before being destroyed. The 
records will be retained 1 year in the GI record storage room and transported to Iron Mountain for 7 

 
 
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year storage. We will store the pre-screening list on the GI Division secure server. The excel list will 
be password protected. In the event that confidentiality is lost, this event will be reported to the UCSD 
IRB HRPP within 10 days.  
17. POTENTIAL BENEFITS 
Benefits of this study include assisting doctors in having a better diagnostic and therapeutic plan for 
RALS to be more accurate and efficient, and offering an improved diagnostic and therapeutic plan to 
society. 
 
18. RISK/BENEFIT RATIO 
The risks in this research study are minimal. UESAD has very little found side-effects, and has been 
proven to help symptoms. This device is non-medication and non-surgical. It is not invasive.  
The pepsin test also has minimal risk, but it could help the doctor better diagnose and assess the 
participant to find the best course of treatment. The pepsin test is much less invasive than all the 
other diagnostic tests that are being used for RALS, hopefully this will be a much easier way to 
diagnose RALS and more comfortable for the participant.  
  
The benefits to this study could entail much more affordable and more effective treatments for the 
patient suffering from RALS, which outweighs the minimal risks listed. 
 
The ineffective and circuitous care for suspected RALS contributes to an estimated $50 billion in 
health care costs.  
This study will allow for not only a more efficient way to diagnose RALS, but also to decrease the 
symptoms. This can minimize the cost that all the current procedures and misdiagnoses regarding 
 
 
 
19. EXPENSE TO PARTICIPANT 
The study protocol is designed so that participants will not incur any expenses outside of standard of 
care, and so that participants will receive compensation for participation.  
 
The following procedures are standard of care for this patient population at UCSD and the procedure 
and related side effects will be covered by insurance: esophageal manometry, pH impedance, and PPI 
therapy.  
 
Questionnaires are standard of care for this patient population at UCSD and there are no costs related 
to questionnaires.  
 
Salivary peptest is not standard of care, and the costs (equipment and processing) will be covered by 
the PI as a research expense.  
 
The UES assist device is standard of care, and typically obtained over the counter ($199) by the 
patient. In this study the UES assist device will be covered by the PI as a research expense and 
provided to the participant free of cost.  
 

 
 
Biomedical IRB Application Instructions 
Page 13 
 
  
 
 
Standard 
of Care 
Coverage 
Visit Time 
(mins) 
Costs to Manage Side Effects 
Esophageal 
manometry 
Yes 
Insurance 
45 
Not anticipated, but would be 
covered as standard of care by 
Insurance 
pH impedance 
Yes 
Insurance 
45 
Not anticipated, but would be 
covered as standard of care by 
Insurance 
Questionnaires 
Yes 
No coverage 
needed 
10 
None 
Salivary peptest 
No 
Research 
costs 
2 
None 
4 week PPI 
therapy 
Yes 
Insurance  
Not 
applicable 
Covered as standard of care by 
Insurance 
UES Assist 
Device 
Yes 
Typically self-
pay; In this 
study will be a 
research cost 
30 min visit 
to receive 
device 
Not anticipated, but would be 
covered as standard of care by 
insurance 
20. COMPENSATION FOR PARTICIPATION 
Participants will receive $100 pro-rated for their time: $25 for completing visit 3, $25 for completing 
visit 4, and $50 for completing visit 5. Participants will also receive the Reflux band (commercial cost 
$199.00) free of cost. 
 
21. PRIVILEGES/CERTIFICATIONS/LICENSES AND RESEARCH TEAM RESPONSIBILITIES 
Rena Yadlapati MD, MSHS is a licensed gastroenterologist at UCSD with expertise in esophageal 
reflux. David Kunkel MD is a licensed gastroenterologist at UCSD with expertise in esophageal reflux. 
Ravi Mittal MD is a licensed gastroenterologist at UCSD with expertise in esophageal reflux.  Andrew 
Vahabzadeh MD is a licensed otolaryngologist at UCSD with expertise in laryngeal symptoms. Philip 
Weissbrod MD is a licensed otolaryngologist at UCSD with expertise in laryngeal symptoms. Madeline 
Greytak is the research assistant to this protocol.  
 
 
Table 2.  
 
 
Responsibilities 
Role 
Name 
Admin-
ister 
Consent 
Screen 
particip
ants 
Obtain 
medical 
history 
Deter-
mine 
elig-
ibility 
Assess 
adverse 
events 
Complet
e source 
docu-
ments 
Complet
e study 
forms 
Make 
follow-
up 
phone 
calls 
Principal 
Investigator 
Rena 
Yadlapati  
 x 
x 
X 
x 
x 
x 
x 
x 
Research 
Assistant 
Madeline 
Greytak 
x 
X 
 
 
 
X 
X 
x 
Co-
Investigator 
David 
Kunkel 
 
 
X 
 
 
 
 
 
Co-
Investigator 
Ravi Mittal 
 
 
X 
 
 
 
 
 

 
 
Biomedical IRB Application Instructions 
Page 14 
Co-
Investigator 
Andrew 
Vahabzadeh 
 
 
X 
 
 
 
 
 
Co-
Investigator 
Philip 
Weissbrod 
 
 
X 
 
 
 
 
 
 
 
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23. FUNDING SUPPORT FOR THIS STUDY 
This study is being supported by the American College of Gastroenterology 2018 ACG Junior Faculty 
Development Grant. This grant is for $100,000 for 3 years, from 7/01/2019 until 6/30/2021. 
 
24. BIOLOGICAL MATERIALS TRANSFER AGREEMENT 
There will be no shipping or transport of biological materials during this study. 
25. INVESTIGATIONAL DRUG FACT SHEET AND IND/IDE HOLDER 
There are no investigational drugs being used in this study. 
 
26. IMPACT ON NURSING STAFF 
This study will involve the nursing staff from UCSD in endoscopy. The time for study participants will 
fall within normal scheduling of patients for HRIM and pH-impedance. Research patients will only be 
scheduled during normal hours within the schedule for these procedures. There is no additional 

 
 
Biomedical IRB Application Instructions 
Page 18 
budget provided for nursing staff training and participation in this study. This study will be done within 
the outpatient setting and attached is the affirmative statement that the study plan has been 
discussed with the appropriate nursing supervisor and that they have approved of these services. 
 
27. CONFLICT OF INTEREST 
All investigators and coordinators listed on this application have completed and submitted a UCSD 
COI disclosure form to the UCSD COI office. 
There are no conflicts of interest issues to be disclosed for the investigators or key personnel that 
relate to this study. 
 
28. SUPPLEMENTAL INSTRUCTIONS FOR CANCER-RELATED STUDIES 
This is not a cancer-related study and does not qualify under the California Clinical Trial Law (Section 
1370.6 of the Health and Safety Code; Section 10145.4 of the Insurance Code; and Sections 
14087.11, 14132.98, and 14132.99 of the Welfare and Institutions Code). 
 
29. OTHER APPROVALS/REGULATED MATERIALS 
Attached is the FDA approval of the Reflux Band (UESAD). 
 
30. PROCEDURES FOR SURROGATE CONSENT AND/OR DECISIONAL CAPACITY ASSESSMENT 
Surrogate consent and/or decisional capacity assessment will not be sought for this study.