Physiologic and Behavioral Correlates of GERD Symptom Severity
Conditions: GERD
Sponsor: Massachusetts General Hospital

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Physiologic and Behavioral Correlates of GERD Symptom Severity 
 
 
 
Principal Investigator: 
Michelle L. Dossett, MD, PhD, MPH 
Research Staff, 
 
Benson-Henry Institute for Mind Body Medicine 
and Division of General Medicine, 
Massachusetts General Hospital, 
Assistant Professor in Residence, University of California, Davis 
 
 
 
Supported by: 
The National Center for Complementary and Integrative Health 
K23 AT009218-01 
MGH Site PI: John W. Denninger, MD, PhD 

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Tool Revision History 
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Version Date:  5.8.2020 

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TABLE OF CONTENTS  
 
Page 
 
FULL PROTOCOL TITLE ......................................................................................................... 1 
Tool Revision History ................................................................................................................. 2 
TABLE OF CONTENTS .............................................................................................................. 3 
STUDY TEAM ROSTER ........................................................................................................... 6 
PRÉCIS ....................................................................................................................................... 6 
1. STUDY OBJECTIVES ............................................................................................................. 7 
1.1 
Primary Objective ........................................................................................................... 7 
1.2 
Secondary Objectives ...................................................................................................... 7 
2. BACKGROUND AND RATIONALE ..................................................................................... 7 
2.1 
Background on Condition, Disease, or Other Primary Study Focus ............................... 7 
2.2 
Study Rationale ............................................................................................................... 8 
3. STUDY DESIGN ..................................................................................................................... 10 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS ............................................... 11 
4.1 
Inclusion Criteria ........................................................................................................... 11 
4.2 
Exclusion Criteria ......................................................................................................... 11 
4.3 
Study Enrollment Procedures ........................................................................................ 12 
5. STUDY INTERVENTIONS ................................................................................................... 14 
5.1 
Interventions, Administration, and Duration ................................................................. 14 
5.2 
Handling of Study Interventions ................................................................................... 15 
5.3 
Concomitant Interventions ............................................................................................ 16 
5.3.1 Allowed Interventions ............................................................................................... 16 
5.3.2 Required Interventions .............................................................................................. 16 
5.3.3 Prohibited Interventions ............................................................................................ 16 
5.4 
Adherence Assessment ................................................................................................. 16 
6. STUDY PROCEDURES ......................................................................................................... 17 
6.1 
Schedule of Evaluations ................................................................................................ 18 
6.2 
Description of Evaluations ............................................................................................ 19 
6.2.1 Telephone Screening .................................................................................................. 19 
6.2.2 Enrollment, Baseline, and/or Randomization ........................................................... 19 
6.2.3 Blinding ..................................................................................................................... 20 

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6.2.4 Post Intervention Measures ....................................................................................... 21 
6.2.5 Telephone Check-In .................................................................................................. 22 
6.2.6 Completion/Final Evaluation. .................................................................................... 22 
7. SAFETY ASSESSMENTS ..................................................................................................... 23 
7.1 
Specification of Safety Parameters ............................................................................... 23 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters ..... 23 
7.3 
Adverse Events and Serious Adverse Events ................................................................ 24 
7.4 
Reporting Procedures .................................................................................................... 24 
7.5 
Followup for Adverse Events ........................................................................................ 24 
7.6 
Safety Monitoring ......................................................................................................... 25 
8. INTERVENTION DISCONTINUATION ............................................................................ 25 
9. STATISTICAL CONSIDERATIONS ................................................................................... 25 
9.1 
General Design Issues ................................................................................................... 25 
9.2 
Sample Size and Randomization ................................................................................... 26 
Treatment Assignment Procedures ............................................................................... 26 
9.3 
Definition of Populations .............................................................................................. 26 
9.4 
Interim Analyses and Stopping Rules ........................................................................... 26 
9.5 
Outcomes ............................................................................................................................. 28 
9.5.1 Primary Outcome ...................................................................................................... 29 
9.5.2 Secondary Outcomes ................................................................................................ 29 
9.6 
Data Analyses................................................................................................................ 30 
10. DATA COLLECTION AND QUALITY ASSURANCE ................................................... 30 
10.1 
Data Collection Forms .................................................................................................. 30 
10.2 
Data Management ......................................................................................................... 31 
10.3 
Quality Assurance ......................................................................................................... 31 
10.3.1 Training ................................................................................................................. 31 
10.3.2 Protocol Deviations ............................................................................................... 31 
10.3.3 Monitoring................................................................................................................... 31 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY .................................................... 32 
11.1 
Institutional Review Board (IRB) Review .................................................................... 32 
11.2 
Informed Consent Forms .............................................................................................. 33 
11.3 
Participant Confidentiality ............................................................................................ 33 
11.4 
Study Discontinuation ................................................................................................... 34 

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12. POTENTIAL BENEFITS .................................................................................................... 34 
12.1 
Potential Benefits to Participating Individuals .............................................................. 33 
12.2 
Potential Benefits to Society ......................................................................................... 33 
13. REFERENCES ...................................................................................................................... 33 
14. SUPPLEMENTS/APPENDICES ......................................................................................... 40 

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STUDY TEAM ROSTER – key personnel 
Michelle L. Dossett, MD, PhD, MPH, Principal investigator 
John W. Denninger, MD, PhD, Co-investigator, MGH site PI 
Maurizio Fava, MD, Co-investigator  
Emma Needles, Research coordinator 
PRÉCIS 
Study Title 
Physiologic and Behavioral Correlates of GERD Symptom Severity 
Objectives 
Primary Aim: To identify the physiologic responses associated with improvement in 
gastroesophageal reflux disease (GERD) symptom severity in response to two different types 
of patient-provider interactions. 
Secondary Aim: To determine whether an expanded patient-provider visit modeled after an 
integrative medicine consultation leads to more supportive provider behaviors and improved 
rapport, engagement, and reciprocity in the patient-provider interaction. 
Design and Outcomes 
This is a pilot, proof-of-concept randomized controlled trial to assess the physiologic and 
behavioral mechanisms associated with improved symptom severity in adult patients with 
GERD-related symptoms in response to enhanced patient-provider interactions. 
Subjects will be randomized to receive one of two different semi-scripted visit types – either 
a “standard visit” modeled after an empathic, conventional primary care evaluation or an 
“expanded visit” modeled after an integrative medicine consultation. During the visit we will 
measure heart rate variability (HRV) and galvanic skin response (GSR) in the patient- 
provider dyads; in addition, we will video record the interactions for later analysis of 
behavioral responses. Subjects will also complete a daily GERD symptom diary and 
questionnaires about GERD symptoms before their visit with a study provider and two weeks 
later. Blood will also be drawn and frozen for later omics-based analyses. 
Interventions and Duration 
Subjects will have a single visit with a “study provider,” a physician or nurse practitioner 
who they have never previously met. Subjects will complete a daily symptom diary for 2 
weeks following this visit and return for a second study-related visit in which they will 
complete questionnaires and be debriefed by a physician on the study team (not the 
individual who conducted the study intervention visit). 
Sample Size and Population 
We plan to enroll to obtain 24 completing subjects with GERD, age 21-70 with heartburn 
symptoms 3 or more days per week.  To permit a spread of physiologic, behavioral, and 
symptom responses, 16 subjects will be randomized to the expanded visit intervention and 8 
subjects will be randomized to the standard visit intervention (2:1 expanded:standard 

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randomization).  We will stratify randomization by study provider such that each provider 
will see 6 subjects (4 expanded visits and 2 standard visits). 
 
1. STUDY OBJECTIVES 
The patient-provider relationship is central to the art of medicine and affects a range of health 
outcomes. However, the specific benefits, and exact mechanisms, by which this relationship 
supports the healing process is poorly understood. Emerging data suggests that physiologic 
biomarkers such as galvanic skin response (GSR) and heart rate variability (HRV) are 
associated with empathy and correlated with the complex verbal and non-verbal behaviors of 
patients and providers during an encounter. Physiologic synchrony in patient-provider dyads 
and supportive non-verbal behaviors may be associated with subsequent health outcomes. This 
pilot study will test these hypotheses using GERD as a model condition. 
 
1.1 Primary Objective 
To identify the physiologic responses associated with improvement in GERD symptom 
severity in response to two different types of patient-provider interactions. 
 
1.2 Secondary Objective 
To determine whether an expanded patient-provider visit modeled after an integrative 
medicine consultation leads to more supportive provider behaviors and improved rapport, 
engagement, and reciprocity in the patient-provider interaction. 
 
2. BACKGROUND AND RATIONALE 
2.1 Background on Condition, Disease, or Other Primary Study Focus 
The patient-physician relationship is central to the art of medicine [1,2]. The quality of 
this relationship affects a range of health outcomes, from irritable bowel [3] and cold 
symptoms [4] to blood pressure, pain levels, and diabetes outcomes [5–8]. However, the 
specific benefits, and exact mechanisms, by which this relationship supports healing 
remain poorly understood. Previous work has demonstrated that when providers maintain 
eye contact, actively listen, and express empathy, their patients improve more after 
receiving a placebo than patients receiving care from apparently more detached providers 
[3,4]. Though studies have suggested a role for communication skills and both cognitive 
and emotional components of empathy, the variety of measures used and lack of clarity in 
definitions have limited the interpretation of this work [5,6,9,10]. 
In most conventional medical settings, practice demands have resulted in reduced time to 
focus on relational aspects of care. Concomitantly, medical educators and professional 
societies have called for greater emphasis on humanism, patient-centered care, and 
improved patient-provider communication [11,12]. Indeed, patients are frequently 
stressed/in distress when they visit a physician [13]. Perceived lack of time and anxiety 
about the visit likely contributes to this stress, one manifestation of which is white coat 
hypertension [14]. 

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The public has become increasingly interested in complementary and integrative 
medicine (IM) healing approaches in which patient-provider dynamics often differ 
substantially from most conventional medical visits [15–19]. IM providers frequently 
spend more time with patients and ask questions that are quite different from those asked 
during conventional visits. The IM consultation process may produce enhanced placebo 
effects [19]. It is unclear whether these effects represent a form of interpersonal healing 
[20], an enhanced patient-provider relationship (e.g., increased perceived empathy or 
trust), or simply provide patients with the opportunity to reflect on their symptoms in a 
safe and non-judgmental space (a form of therapeutic narrative medicine [21]) creating an 
openness to perceiving symptoms differently and enhancing coping [22]. Some patients 
feel “more heard” by IM providers [23]. IM providers may make patients feel more “at 
ease” and relaxed, promoting a physiologic response (e.g., reduced heart rate and blood 
pressure) similar to that elicited by meditation and other mind body techniques [24]. 
Feeling less stressed during a medical visit may create an openness to change and 
improved memory of, and follow-through with, the provider’s recommendations [25]. 
Yet there are few studies of these interactions and they largely rely upon patient 
interviews or responses to surveys [15–18]. 
Gastroesphageal reflux disease (GERD) is one of the most prevalent health-related 
conditions in the Western world with prevalence estimates ranging from 20-40% [26,27]. 
GERD is primarily a clinical diagnosis, characterized by symptoms of heartburn and acid 
reflux. It is associated with decreased health-related quality of life and significant 
healthcare costs and lost productivity [28,29]. Standard treatment includes antacids, H2 
receptor blockers, and proton pump inhibitors (PPIs), with the latter generally regarded as 
the most effective of these therapies. Nonetheless, many patients experience continued 
symptoms despite taking PPIs [30]. Many patients who do not find relief with PPIs have 
functional heartburn symptoms and/or co-occurring dyspepsia symptoms (e.g., upper 
abdominal discomfort, bloating, and gas) that do not respond well to this class of 
medication [31,32]. Moreover, awareness of the interconnections between the central 
nervous and gastrointestinal systems has led to the recognition that stress can profoundly 
affect gastrointestinal (GI) symptoms, such as GERD [33], suggesting that interventions 
targeting these pathways may improve symptoms [34]. Notably, the placebo response 
rate in trials of GERD medications can be as high as 40% [35]. 
 
2.2 Study Rationale 
Recent studies are beginning to reveal the neural 
correlates of empathy, both in general [36] and in 
patient-provider relationships [37,38]. Activation 
of specific neural pathways drives changes in 
autonomic nervous system regulation [39], 
resulting in downstream changes in physiologic 
 
 
 
Figure 1: Proposed model for mechanisms 
underlying the patient-provider relationship 
 
Provider 
Patient 
biomarkers such as galvanic skin response (GSR) 
and heart rate variability (HRV) [40,41]. A 
growing body of research has identified 
concordance in physiologic biomarkers between 
individuals. An excellent review of this topic, 
also known as “interpersonal autonomic 
1. Provider statement 
or behavior 
 
6. Change in autonomic 
activity 
5. Provider’s neural 
response 
2. Patient’s neural 
response 
 
3. Change in autonomic 
activity 
4. Patient  statement 
or behavior 

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physiology” or “physiologic synchrony,” has recently been published [42]. The authors 
reviewed 61 studies covering relationships between therapist and client, couples, mother 
and child, teammates, and other relationships. There were 8 studies of the therapist-client 
relationship which examined either heart rate (HR) or skin conductance/galvanic skin 
response (GSR). Multiple studies found positive correlations between empathy ratings 
and physiologic synchrony. The study I have proposed would be the first to examine 
physiologic biomarkers in the context of physician-patient interactions in a medical 
setting. 
As illustrated in Figure 1 above, we hypothesize that moment-to-moment autonomic 
changes in patients and providers over the course of a visit collectively influence 
perceptions of the encounter (part of the “neural response”) and response to treatment and 
that improved treatment response is associated with increased concordance in these 
autonomic changes. 
GSR and HRV can also be used to assess relative physiologic stress vs. relaxation [43]. 
Typically GSR and HR decrease and high frequency HRV increases in the relaxed state 
[24,44,45]. While empathic visits may theoretically reduce patients’ allostatic load and 
distress [46], this hypothesis has not been studied rigorously. Newer computational 
approaches incorporating complexity theory to the analysis of physiologic data [47] have 
yielded valuable insights to the study of human disease (e.g., decreased HRV is 
associated with increased cardiovascular mortality [48,49]) and the effects of integrative 
modalities such as tai chi [50,51]. There is limited data using these approaches to study 
client-therapist interactions [52–54]. 
Social psychologists have developed and validated a variety of coding schemes to  
analyze providers’ verbal and non-verbal behaviors and to link these behaviors with 
patient satisfaction, understanding, trust, rapport, empathy, and a variety of related factors 
[9,55–60]. This rich literature has yielded many insights and a variety of tools used in 
studies of physician-patient communication, but rarely have these tools been linked with 
physiology or health outcomes [7]. 
I recently found that an “expanded” provider visit modeled after a visit to an IM provider 
was more effective in decreasing heartburn and dyspepsia symptoms in patients with 
GERD than a “standard” provider visit modeled after an empathic conventional medical 
visit [61]. I used a script of pre-determined questions for each visit type. The standard 
visit script included questions about GERD history, symptoms, prior evaluation and 
treatments, and past medical history. The expanded visit script included the same 
questions plus additional questions that inquired about their GI symptoms, non-GI 
symptoms, and overall temperament. Thus, the main differences between the visits were 
the length of time spent with the subject and the additional questions that were asked. 
Many of the subjects in this study were already taking pharmaceutical medications for 
GERD, suggesting that symptom improvement resulting from the expanded provider visit 
may enhance the efficacy of some medications in providing adequate symptom relief. 
While some may argue that increasing visit length is impractical in conventional 
healthcare settings, one reason why payers will not adequately reimburse for increased 
visit lengths is the lack of data linking visit length with health outcomes. Increased visit 
length has been associated in clinical practice with reduced number of prescriptions and 

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increased patient satisfaction, engagement, and quality of care [62–64]. Other studies 
suggest mechanisms by which provider communication (verbal & non-verbal) may affect 
health outcomes [65]. Yet we really do not know what makes longer visits more 
effective. By first better understanding the mechanisms that make the expanded visit 
intervention effective, I will be able to make informed decisions regarding future changes 
to this intervention and adaptations that may make it more feasible in today’s healthcare 
environment. 
 
3. STUDY DESIGN 
Study design: Single-center, single-blind, pilot randomized controlled trial 
Primary outcomes: 
1) Correlation between physiologic synchrony in patient-provider dyads (GSR or HRV) 
and improvement in GERD symptom severity. 
2) Correlation between absolute changes in GSR within subjects over the course of the 
study visit and subsequent changes in GERD symptom severity. 
3) Correlation between absolute changes in high frequency HRV within subjects over 
the course of the study visit and subsequent changes in GERD symptom severity. 
 
Secondary outcomes: 
1) The difference in the frequency of supportive provider behaviors between the 
standard and expanded visit groups. 
2) The difference in the ratings of rapport, engagement, and reciprocity between the 
standard and expanded visit groups. 
Study population: 
Men and women age 21-70 with heartburn symptoms 3 or more days per week. We will 
enroll until we reach 24 completing subjects. 
Study location: 
The Clinical Research Center (CRC) at Massachusetts General Hospital (MGH), the 
Benson-Henry Institute (BHI) for Mind Body Medicine, or another MGH location. 
Length of subject participation: 2 weeks 
Length of study enrollment: 12-14 months 
Groups: 
1) Standard visit (n=8), modeled after an empathic, high quality conventional primary 
care visit. 
2) Expanded visit (n=16), modeled after a visit with an integrative medicine provider 
Randomization: 
The randomization code will be generated by the study statistician as described below 
(section 4.3). The study will be single-blinded (study providers and the research team will 
know what the subject is receiving but the subject will not). Randomization will be 

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stratified based on study provider. We anticipate 4 providers each seeing 6 subjects (2 
standard visits, 4 expanded visits). 
 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS 
4.1 Inclusion Criteria 
Research subjects must meet all of the following inclusion criteria to participate in the 
study: 
• Adults ages 21-70 years old (rationale: population of interest, GERD frequency 
increases with age; adults 70+ are more likely to have complicated disease and/or 
meet one or more exclusion criteria) 
• Heartburn symptoms 3 or more days per week with an average daily symptom 
severity of 3 or more on a 7 day baseline symptom diary (see section 6.2.2 for 
description of instrument; rationale: subjects must be symptomatic enough that 
improvement in symptoms is detectable. This threshold is similar to that seen in 
my pilot study [61].) 
• English language proficiency (rationale: feasibility) 
• Willingness to be videotaped and connected to physiologic monitoring devices 
during the visit (rationale: feasibility/study procedures) 
 
4.2 Exclusion Criteria 
Any candidates meeting any of the following exclusion criteria at baseline will be 
excluded from study participation. 
• Diagnosis of Crohn’s disease, systemic sclerosis, known active ulcer disease, 
gastric cancer, or untreated/active Barrett’s esophagitis based on subject self-report 
and/or medical record review (rationale: heartburn symptoms may be due to 
another, more serious medical illness) 
• Heavy alcohol use (> 6 drinks/week for women and > 13 drinks/week for men) 
based on subject self-report (rationale: can exacerbate heartburn symptoms) 
• Pregnant women. Due to the short nature of the study and lack of interventions that 
will interfere with pregnancy, we will not screen for pregnancy or request female 
participants to use contraception (rationale: feasibility/physiology of heartburn is 
different in pregnant women). 
• Dementia or significant memory difficulties as determined by the study team and 
medical record review (rationale: feasibility and human subjects concerns) 
• Severe, unstable psychiatric disease based on subject self-report, study team 
determination, and/or medical record review (rationale: feasibility and human 
subjects concerns) 
• Greater than 15 doses of nonsteroidal anti-inflammatory drugs (NSAIDS) within 
the prior 30 days (aspirin ≤ 325 mg daily permitted) or ongoing NSAID use at a 

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level deemed likely to interfere with the study (rationale: NSAIDS can exacerbate 
GERD and cause peptic ulcers) 
• Failure to complete the baseline symptom diary for at least 6 of 7 days (rationale: 
feasibility) 
• Change in GERD treatment regimen within the last 2 weeks (subjects may use 
antacids, H2 receptor blockers, and/or proton pump inhibitors as long as they are 
symptomatic on a stable regimen; rationale: feasibility, need a stable symptom 
baseline) 
• Allergy to adhesives (rationale: feasibility/study procedures) 
• Inability to provide informed consent (rationale: human subjects concerns) 
• In the opinion of the investigator, unable to comply with the study protocol or has a 
condition that would likely interfere with the study (rationale: feasibility) 
 
 
4.3 Study Enrollment Procedures 
Patient Recruitment: 
Initial recruitment efforts will start with the MGH Internal Medicine Associates (IMA) 
primary care practice and the Benson-Henry Institute (BHI; clinician referral, flyers in 
clinic, and posting on the BHI website), but may expand to include a) other MGH 
primary care practices, b) the MGH gastroenterology clinic, c) Research Study 
Volunteer Program (RSVP) for Health (an online registry of Partner’s affiliated clinical 
trials), d) the Partners’ clinical trials website, e) MGH Broadcast weekly research studies 
seeking volunteers email, f) clinician referral, g) the Research Opportunities Direct to 
You (RODY) program, and/or h) flyers posted in clinics and hospital-approved bulletin 
boards if we are not meeting our recruitment goal of 3-5 subjects/month. 
 
We will begin by identifying potential subjects from the MGH primary care practice- 
based research network (PBRN) cohort. Potential subjects identified through the PBRN 
cohort will receive a letter from the study PI informing them of the study and inviting 
them to participate along with contact information for a study coordinator and a postcard 
they can mail in if they wish to opt-out and not be contacted. Patients who do not mail 
back the opt-out card will receive a telephone call from a study team member at least 2 
weeks after the letter was mailed. We will seek permission from patients’ primary care 
physicians prior to sending any letters. Letters sent to potential participants that are part 
of the RODY program will not include an opt-out card, but the study coordinator’s 
number and email with instructions to call or email if they do not wish to be contacted 
about the study.  
 
Study flyers will be posted in the BHI waiting room to recruit participants. If a patient is 
interested in learning more about the study, they may request additional information 
during their appointment or may call the phone number on the flyer. Alternatively, if the 
investigator sees a patient who may be eligible, she may mention that the BHI is 
conducting a study for patients with GERD and ask if they would like to receive more 
information from a study research coordinator.  In all cases, prospective subjects will be 
informed that their decision whether to participate will have no effect on the care they 

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receive at the Institute. The Investigator will address any immediate questions the 
prospective subject may have and obtain verbal permission to give their contact 
information to a study staff member who can provide further details. 
Patient Screening: 
Potential subjects will undergo a telephone prescreen by study staff and have the 
opportunity to ask questions about the study (see telephone script). Potential subjects 
will be told that they will not receive specific treatment recommendations for their 
GERD as part of the study. They will also be informed that the study involves optional 
blood draws at each visit. If the potential subject receives care at a Partner’s Healthcare 
affiliated institution, their medical record will be reviewed as part of the eligibility 
assessment. A standardized form (see attached) will be used to ascertain potential 
eligibility and an electronic screening log will be kept to keep track of reasons for 
ineligibility. Those who are deemed potentially eligible and are interested in 
participating will be sent a 7 day baseline symptom diary (by email or via the post 
office) and scheduled for an intake visit and two week follow-up visit. Potential subjects 
will be mailed a copy of their medication list (if they are a Partner’s patient) and asked to 
update it or bring a complete list of medications, vitamins, herbs, and supplements that 
they are taking to the baseline visit. Potential subjects will be called several days after the 
diary is mailed to ensure that they received it and that the instructions for completing the 
diary are clear. 
Intake Visit and Consent: 
Subjects will present to the BHI, the CRC at MGH, or another pre-determined MGH 
location. The baseline symptom diary will be reviewed by a study team physician (one 
of the study investigators, not a provider delivering the study visit intervention) and 
potential subjects will be rescreened. If they are deemed eligible, they will have an 
opportunity to review the written informed consent document, ask any questions, and 
will be consented by a study team physician. 
To avoid alerting subjects to the fact that we are directly studying the effect of the 
patient-provider relationship on health outcomes (which could influence study results 
[66,67]), the study team physician will inform subjects during the consent process that 1) 
talking about their symptoms with a physician may result in improved autonomic 
nervous system regulation and improvement in GERD symptoms (to set an expectation 
for possible symptom improvement and explain why GSR and HRV are being 
monitored) and 2) we are studying whether physicians mirror patients’ physiology as has 
been suggested by some neuroimaging studies [37,68] (to explain why providers are 
being similarly monitored). While it is challenging to study patient-provider interactions 
without subjects’ direct knowledge, particularly since both are being monitored in this 
study, we believe that framing the study in this way is the most sensible way to proceed 
and the least likely to substantively affect the study’s results. As the intervention is 
minimal risk, we believe it meets the federal criteria for modification of informed consent 
[69], to allow us to conceal from participants that we are studying the patient-provider 
interaction. 
Subjects will also be informed during the consent process that the healthcare provider who 
will be asking them about their GERD symptoms has been instructed not to provide any 
specific GERD treatment advice since they will not have the opportunity to follow-up and 

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because their primary care physician may have a preferred treatment plan for their GERD. 
We will provide study participants with an informational handout on GERD and possible 
treatment approaches at the end of the study. 
Individuals who sign the informed consent document and elect to participate in the study 
will be considered enrolled. Only individuals who can provide informed consent will be 
eligible to participate. 
Randomization: 
Once enrolled, subjects will be randomized to receive either the standard visit 
intervention (n=8) or the expanded visit intervention (n=16; section 9.2). They will not 
know that there are two possible visit choices. This aspect will be revealed to subjects 
during a debriefing at the follow-up visit. We will stratify by provider and create 
permuted block sizes of 3 and 6 (2 expanded, 1 standard; 4 expanded, 2 standard) with 
the intent to enroll 4 providers who will each see 6 subjects. If we can only enroll 3 
providers or one provider cannot see 6 subjects then the remaining slots will be divided 
among the remaining providers. 
Provider Recruitment and Screening: 
We will approach pre-identified MGH internal medicine physicians and ask whether 
they are interested in participating in the study as providers. If we cannot identify 
enough interested physicians internally, we may approach colleagues at other Partners- 
affiliated institutions and/or send an email describing the study to internists within the 
MGH Division of General Internal Medicine. We may also present the study at practice 
meetings or division conferences. Providers must be willing to adhere to the study 
protocol and not provide specific treatment recommendations (pharmacologic or non- 
pharmacologic) as this is outside the scope of the study and subjects must remain on a 
stable regimen during the course of the study. Providers must also be willing to receive a 
brief training to understand how to deliver the standard and expanded visit interventions. 
Provider Consent: 
Participating providers will be consented by the study PI. As study providers will deliver 
both visit interventions, they will not be blinded as to the study’s hypotheses or the 
group to which a given subject is assigned. They will be notified of which intervention 
they are delivering immediately before walking into the room to conduct the study visit. 
 
 
 
5. STUDY INTERVENTIONS 
5.1 Interventions, Administration, and Duration 
Standard and Expanded Visit Groups 
Subjects will be randomized to receive either a “standard visit” or an “expanded visit” 
with a study provider. The standard visit is based on a high quality, empathic, 
conventional primary care encounter. The expanded visit is based on an integrative 
medicine consultation. Both visits are based on a script of questions and statements to the 

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patient/subject (see Appendix E). The standard visit script includes questions about 
GERD history, symptoms, prior evaluation and treatments, and past medical history as 
well as a brief physical exam. The expanded visit script includes the same questions as 
the standard visit script plus additional questions that inquire about the modalities of their 
GI symptoms (e.g., nature of the reflux taste, sensation of heartburn pain and/or 
abdominal fullness, time of day better/worse), details about non-GI symptoms, quality of 
sleep, the effect of the weather on symptoms, food cravings and aversions, menstrual 
flow, fears/phobias, and overall temperament. In this way, the expanded visit tries to 
understand the patient’s/subject’s constitution in a way that many systems of integrative 
medicine attempt to do. To reduce the potential for introducing bias by using the words 
“standard” and “expanded”, the visit templates that they study providers will follow will 
simply refer to the number of questions to be asked on the template (e.g., 6 Question 
Template). 
In our pilot study [61] we did not limit the amount of time spent with the study subject. 
On average, the standard visit lasted 18 minutes (range 11-32 minutes) and the expanded 
visit lasted 42 minutes (range 23-74 minutes). The study providers will be instructed to 
maintain equal empathy in both groups (e.g., kind and friendly manner, maintained eye 
contact, active listening and repeating back the patient’s words, expressions of empathy). 
Thus, the main differences between the visits will be the length of time spent with the 
subject and the additional questions that are asked. 
Each study provider will participate in an orientation session to learn how to deliver the 
standard and expanded visit interventions. Providers will be explicitly instructed not to 
offer specific GERD treatment advice – either pharmacologic or non-pharmacologic. The 
study PI will review video recordings of the interactions to offer feedback to study 
providers and ensure protocol fidelity. As each study provider finishes his/her portion of 
the study, the PI will interview them to understand their experiences of the study, the two 
visit types, and their views on the doctor-patient relationship. 
We do not anticipate any adverse effects as a result of this intervention. 
 
5.2 Handling of Study Interventions 
To minimize potential bias that could affect study staff interactions with subjects, the 
study provider will open an envelope indicating which visit type he or she is to deliver 
immediately before conducting the study visit and will receive the appropriate study visit 
script. At the time of consent, study subjects will not be informed about the two different 
interview types or that part of the study involves testing the effect of the doctor-patient 
interaction on response to treatment. Concealment of these aspects of the study protocol 
is essential to maintaining the validity of the study as data suggests that patients 
responses change when they know that the doctor-patient interaction is being studied 
[66,67]. The study PI, or another study team physician, will notify subjects at their 
follow-up study visit, after the exit interview, that there were two possible types of 
physician visits, that this aspect of the study was concealed from them initially, and of 
the rationale for doing so.  A script outlining this planned debriefing is present in 
Appendix G.  We believe that this intervention is minimal risk and that our plan meets 
the federal criteria for permitting alteration of some elements of informed consent [69]. 

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5.3 Concomitant Interventions 
5.3.1 Allowed Interventions 
Subjects are permitted to remain on all baseline medications, over-the-counter products, 
and dietary supplements, including those used to treat GERD symptoms (e.g., antacids, 
H2 receptor blockers, and proton pump inhibitors) during the study. We will request that 
they not change doses of medications used to treat GERD symptoms during the two 
weeks that they are enrolled in the study. 
5.3.2 Required Interventions 
None. 
5.3.3 Prohibited Interventions 
Subjects may not have consumed more than 15 doses of NSAIDS within the prior 30 
days (or more than 8 doses during the 2 week study period. Aspirin at doses of 325 mg or 
less daily is permitted. 
We will ask subjects not to change their GERD treatment regimen during the study. This 
will be monitored via the daily symptom diary. 
 
5.4 Adherence Assessment 
Subject adherence is defined by subjects completing at least 12 out of 14 days of their 
daily symptom diary during the two week study period. Adherence will be assessed when 
subjects return their symptom diaries at their follow-up visit. For subjects who return 
incomplete symptom diaries, average daily symptom severity for the days completed will 
be calculated. If there is insufficient data to make this calculation, we will assume that 
symptoms are unchanged from baseline. 
 

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6. STUDY PROCEDURE 
 
6.1 Schedule of Evaluations for Subjects/Patients 
 
Assessment 
Telephone 
Screening: 
(Day 
-30 to -7) 
Baseline, 
Enrollment, 
Randomization: 
Visit 1 (Day 0) 
Post Intervention: 
Visit 1 
(Day 0) 
Follow-up: Visit 2 
(Day 13-18) 
Prescreen Form 
X 
X 
GERD Daily Symptom Diary 
Reviewed 
X 
X 
Informed Consent Form 
X 
Current Medication List 
X 
X 
Height and weight 
X 
Blood draw 
X 
X 
X 
Demographics & Health Behaviors 
X 
GERD-Health Related Quality of Life 
Questionnaire (GERD-HRQL) 
X 
X 
NIH Patient Reported Outcomes 
Measurement Information System 
(PROMIS) GERD 
X 
X 
Gastrointestinal Symptom Rating 
Scale (GSRS) 
X 
X 
Perceived Stress Scale-10 (PSS-10) 
X 
X 
Current Stress Question 
X 
X 
X 
NEO Five Factor Inventory (NEO- 
FFI) 
X 
Randomization 
X 
HRV, respiratory rate, skin 
temperature, and GSR 
X 
Video recording 
X 
Study visit 
X 
Consultation And Relational Empathy 
questionnaire (CARE) 
X 
HEAL Patient-Provider Connection 
X 
Adverse Events 
X 
Qualitative Interview 
X 
Debriefing 
X 

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Schedule of Evaluations for Providers 
 
Assessment 
Enrollment 
Prior to each 
subject/patient 
encounter 
Informed Consent Form 
X 
Interpersonal Reactivity Index (IRI) 
X 
NEO-FFI 
X 
Demographics 
X 
Intervention Training 
X 
PSS-10 
X 
Current Stress Question 
X 
Fatigue Scale 
X 
Interview at completion of study 

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6.2 Description of Evaluations 
6.2.1 Telephone Screening (Day -30 to -7) 
A standardized form will be used to assess the potential subject’s eligibility for the study. 
See Appendix B. 
6.2.2 Enrollment, Baseline, and Randomization (Visit 1, Day 0) 
Potential subjects will be rescreened using the pre-screen form by a study physician. The 
study physician will also review the baseline symptom dairy to ensure that the individual 
is symptomatic enough to enroll. If the individual is eligible to participate in the study, 
they will be given a copy of the consent form to review. 
 
Consenting Procedure 
Written informed consent will be obtained by a study team physician (see also section 
4.3). The subject will be given adequate time to read the consent form, and any 
questions the subject has will be answered. The study team physician will confirm 
that the subject understands that he/she will be connected to physiologic monitors 
during the visit and that the visit will be video recorded. The subject will also have 
the opportunity to choose whether or not to consent to blood draws as part of the 
study which will involve two blood draws at the first visit and one blood draw at the 
second visit. The subject will receive a copy of the consent form and the original 
signed copy will be kept in a study binder. If the subject agrees to participate and 
signs the informed consent form, they will be considered “enrolled”. 
Study providers will be consented by the study PI, following a similar process, using 
a different written informed consent form. 
 
Baseline Assessments 
Evaluations for Study participants/patients: 
• Current medication List – will be pulled from Epic and verified with the 
patient by a study team physician. 
• Height and weight – will be obtained by a CRC nurse or study team member. 
• Blood draw (optional) – 10 mL of blood will be obtained by a research nurse 
in the CRC or other appropriate clinician. Blood will be processed to obtain 
RNA, DNA, and plasma then frozen at -80oC for later omics analyses. 
• Demographics and health behaviors – will assess things such as age, gender, 
race/ethnicity, smoking status, alcohol & caffeine use (see Appendix D) 
• Baseline Symptom Diary – 7 day diary indicating the frequency and severity 
of 9 different GERD and dyspepsia-related symptoms on a 5 point scale as 
well as any medications, supplements, or other products used to help manage 
symptoms. The first 3 symptoms (daytime heartburn, nighttime heartburn, and 
acid reflux) will be used to assess severity of GERD symptoms. 

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• GERD-HRQL - a validated 11 item scale for assessing the impact of GERD 
symptoms on health-related quality of life [70]. 
• NIH PROMIS GERD scale – a validated 13 item instrument assessing 
frequency and severity of GERD symptoms over a 7 day recall period [26]. 
• GSRS: The Gastrointestinal Symptom Rating Scale is a validated 15 item 
instrument for measuring the severity of gastrointestinal symptoms [71]. It 
contains 5 subscales: abdominal pain, reflux syndrome, diarrhea syndrome, 
indigestion syndrome, and constipation syndrome. 
• Current Stress Question – 1 item self-report measure of current stress level on 
a scale of 0 (no stress) to 10 (extreme stress). 
• Perceived Stress Scale (PSS) – a widely used 10 item measure of perceived 
stress that has been shown to correlate with a variety of different health 
outcomes [72]. We have adapted the originally validated measure to ask about 
stress over the past week (7 days), rather than the past month, to better fit the 
timeframe of the study. We have used this timeframe in other studies. 
• NEO Five Factor Inventory (NEO-FFI) – a validated 60-item instrument that 
measures five major dimensions of personality: extraversion, neuroticism, 
agreeableness, conscientiousness, and openness to experience [73]. Some 
dimensions have been associated with response to enhanced patient-provider 
interactions in others studies [74]. 
• Physiologic Measures and Video Recording: During the intervention we will 
measure HRV, respiratory rate, skin temperature, and GSR in both study 
patients and study providers.  The study visit will also be video recorded. 
 
Evaluations for Study providers: 
• Interpersonal Reactivity Index ( IRI) –– a validated 28 item self-assessment of 
cognitive and affective components of empathy [75]. 
• NEO Five Factor Inventory (NEO-FFI) – a validated 60-item instrument that 
measures five major dimensions of personality: extraversion, neuroticism, 
agreeableness, conscientiousness, and openness to experience [73]. Some 
dimensions have been associated with response to enhanced patient-provider 
interactions in others studies [74]. 
• Demographics and practice– will assess things such as age, gender, 
race/ethnicity, and clinical experience (see Appendix D) 
• Current Stress Question – 1 item self-report measure of current stress level on 
a scale of 0 (no stress) to 10 (extreme stress).  Study providers will complete 
this question immediately prior to each study subject visit. 
• Perceived Stress Scale (PSS) – a widely used 10 item measure of perceived 
stress that has been shown to correlate with a variety of different health 
outcomes [72].Study providers will complete this questionnaire immediately 
prior to each study subject visit. 

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• Fatigue Scale – 1 item self-report measure of the current fatigue level on a 
scale of 0 (no fatigue) to 10 (extreme fatigue). Study providers will complete 
this question immediately prior to each study subject visit. 
 
Randomization 
Subjects will be randomized on the day of their baseline visit (Visit 1), following consent, 
to receive either the standard or expanded visit with the particular provided that they are 
scheduled to see that day. We will stratify randomization by provider so that each 
provider does the same proportion of standard and expanded visits. Randomization will 
occur after subjects have completed their optional first blood draw and baseline 
questionnaires, immediately prior to the study visit. Study providers will open an 
envelope instructing them which study visit intervention to deliver. 
6.2.3 Blinding 
This is a single-blinded study. Subjects will be unaware of the possibility for two 
different types of study visits. Study providers and staff will be aware of the study 
intervention delivered, but only immediately prior to the study visit to decrease the 
potential for introducing bias in how study staff interact with subjects during recruitment 
and consent. Subjects will be debriefed at the end of the Visit 2 regarding the nature of 
the study and the intervention that they received. Data will be analyzed in a blinded 
fashion, also to avoid introducing bias. Given the low-risk nature of the study, we do not 
anticipate a need to break the blind while a subject is enrolled. 
6.2.4 Post Intervention Measures (Day 0) 
Immediately following the study physician visit, subjects who consented to blood draws 
will be asked to have another 7.5mL sample of blood taken (to obtain RNA and plasma) 
and all subjects will be asked to complete the following questionnaires: 
• CARE – Consultation And Relational Empathy questionnaire, a validated and 
commonly used 10 item measure for assessing the quality of the patient encounter 
and perceptions of empathy from the treatment provider [76]. I used it in my pilot 
study. 
• HEAL Patient-Provider Connection – a subset of the Healing Encounters and 
Attitudes List, a recently validated 7-item measure of the patient-provider connection. 
This is a patient-reported outcome developed as part of a set of tools to measure non- 
specific factors in treatment using the NIH PROMIS methodology [77]. 
• Current Stress Question – 1 item self-report measure of current stress level on a scale 
of 0 (no stress) to 10 (extreme stress). 
6.2.5 Telephone check-in 
Study coordinators will call enrolled subjects who have completed study visit 1 
approximately half-way between the first and second study visits. These telephone check- 
ins will a) serve as a reminder to participants to complete their daily symptom diary, b) 
address any participant questions or concerns, and c) remind/confirm participants’ second 
study visit appointment. 

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6.2.6 Completion/Final Evaluation 
We will attempt to schedule subjects’ Visit 2 appointments as close to the 2 week 
window as possible, but will allow a window of 13-18 days. Visit 2 will be scheduled 
simultaneously with Visit 1 to help promote adherence to this timeline. 
• Current medication List – will be pulled from Epic or the prior visit and verified with 
the subject by a study team physician. 
• Blood draw (optional) – 7.5mL of blood will be obtained by a research nurse in the 
CRC or other appropriate clinician. Blood will be processed to obtain RNA, and 
plasma then frozen at -80oC for later omics analyses 
• GERD-HRQL - a validated 11 item scale for assessing the impact of GERD 
symptoms on health-related quality of life [70]. 
• NIH PROMIS GERD scale – a validated 13 item instrument assessing frequency and 
severity of GERD symptoms over a 7 day recall period [26]. 
• GSRS: The Gastrointestinal Symptom Rating Scale is a validated 15 item instrument 
for measuring the severity of gastrointestinal symptoms [71]. It contains 5 subscales: 
abdominal pain, reflux syndrome, diarrhea syndrome, indigestion syndrome, and 
constipation syndrome. 
• Current Stress Question – 1 item self-report measure of current stress level on a scale 
of 0 (no stress) to 10 (extreme stress). 
• Perceived Stress Scale (PSS) – a widely used 10 item measure of perceived stress that 
has been shown to correlate with a variety of different health outcomes [72]. 
• Adverse events – study staff will ask subjects if they experienced any adverse events 
and ask about any hospital or emergency room visits since enrollment. 
• Daily symptom diary – Identical in content to the baseline symptom diary, this 14 day 
diary allows subjects to track the frequency and severity of 9 different GERD and 
dyspepsia-related symptoms on a 5 point scale as well as any medications, 
supplements, or other products used to help manage symptoms. 
• Qualitative interview – a study team member will conduct a semi-structured 
qualitative interview (see Appendix F) with each subject after the subject has 
completed questionnaires and prior to the debriefing. These interviews will be audio 
recorded and will include questions about their perceptions of their interaction with 
the study provider and with healthcare providers in general and their experience 
participating in the study. 
• GERD handout – an informational handout on GERD and possible treatment 
approaches will be provided to subjects.  See Appendix I. 
• Debriefing – a study team physician will debrief with each subject regarding the 
actual nature of the study. See Appendix G for a debriefing script. 

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7. SAFETY  ASSESSMENTS 
Expected risks to subjects are as follows: 
• Study questionnaires: Symptom and behavioral data collection involves virtually no risk; 
however, psychosocial tests or questions about symptom intensity may cause minor 
emotional distress. Because participants are free to stop at any time and will be reminded 
of this throughout the assessment process, the risk of distress is low. In our experience, 
such questionnaires are well tolerated and complications are extremely rare. 
• Discomfort from ECG/GSR leads and physiologic monitoring: Some participants may 
experience minor skin irritation due to the adhesive used to apply leads for physiologic 
monitoring. Subjects with known adhesive allergies will not be eligible to participate in 
the study. Some participants may experience psychological distress knowing that their 
physiology is being monitored. The physiologic monitoring will be described in the 
consent document and care will be taken to minimize such distress. Participants will be 
free to stop at any time. In general, such monitoring is well-tolerated. 
• Discomfort from blood draws: some participants may have an aversion to needles, blood, 
and/or the drawing of blood. Blood will be drawn by experienced nurses at the MGH 
CRC and care will be taken to minimize discomfort to participants. Blood draws are 
generally well-tolerated, although occasionally there may be bruising or discomfort at the 
site. Rarely an infection can occur. The blood draw will be an optional component of the 
study, and if an enrolled subject consents to the blood draw and is particularly 
challenging to draw blood from, we will not require a successful blood draw to be a 
condition of continued enrollment in the study. 
• Videotaping: Some participants may experience psychological distress knowing that they 
are being videotaped. Participants will be free to stop at any time. In general, videotaping 
is generally well-tolerated. 
• Deception: Subjects may experience minor psychological distress at study visit 2 when 
they learn that some information was withheld from them at enrollment. Based upon our 
experience with our prior study, we feel this is unlikely to happen or to be problematic as 
we have experience conducting such debriefings and subjects generally understand why 
such information was withheld initially. 
 
7.1 Specification of Safety Parameters 
Blood will be drawn by experienced nursing staff and samples will be processed then 
frozen for later analysis. There will be no immediate laboratory analysis of the samples 
collected. 
 
7.2 Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
When subjects return for their follow-up visit, a study team member will inquire about 
any changes to their health or medical visits (including emergency room visits or 
hospitalizations) since their initial study visit. We do not anticipate any issues that will be 
causally related to the study. If a subject reports a new or worsening symptom that is 
medically concerning (e.g., bright red blood per rectum), they will be referred to their 

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usual healthcare provider for further evaluation. 
 
7.3 Adverse Events and Serious Adverse Events 
An adverse event (AE) is any unfavorable or unintended diagnosis, symptom, sign, 
syndrome or disease which either occurs during the study (having been absent at 
baseline), or if present at baseline, appears to worsen. 
A serious adverse event (SAE) is any untoward medical occurrence that results in death, 
is life threatening, requires inpatient hospitalization or prolongation of existing 
hospitalization, results in persistent or significant disability/incapacity, or is a congenital 
anomaly. 
During the follow-up visit, the study team member will specifically ask about any new or 
worsening symptoms in the last 2 weeks, unanticipated medical appointments, emergency 
room, or hospital visits. 
In addition, during telephone check-ins, the study research coordinator will record any 
health concerns reported by subjects (not specifically solicited) and report these to the 
study PI. If there are any signs or symptoms of concern or that require further 
clarification, the study PI will contact the subject. 
• Unexpected fatal or life-threatening AEs related to the intervention will be 
reported to the National Center for Complementary and Integrative Health 
(NCCIH) Program Officer, Independent Safety Monitor(s), and Partner’s IRB 
within 3 business days of the investigator becoming aware of the event. Other 
serious and unexpected AEs related to the intervention will be reported within 5 
business days. 
• Anticipated or unrelated SAEs will be handled in a less urgent manner but will be 
reported to the Independent Safety Monitor(s), IRB, and other oversight 
organizations in accordance with their requirements and will be reported to 
NCCIH on an annual basis. 
• All other AEs documented during the course of the trial will be reported to 
NCCIH and the Partner’s IRB on an annual basis by way of inclusion in the 
annual report and in the annual AE summary which will be provided to NCCIH 
and to the Independent Monitors. The Independent Safety Monitor(s) Report will 
state that all AEs have been reviewed (see Data Safety and Monitoring Plan). 
 
7.4 Reporting Procedures 
Study staff and visit intervention providers will be instructed to report all adverse events 
(or potential AEs) to the study PI (Dr. Dossett). Determination of relatedness will be 
made in conjunction with Dr. Denninger and/or Dr. Hur. An electronic log of various 
types of AEs will be kept and updated by study staff, including the PI. 
 
7.5 Follow-up for Adverse Events 
AEs will be followed-up by the study PI by phone calls to the subject and/or monitoring 
of the medical record until they are resolved or considered stable. Formal AE follow-up 
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an event after completing the study. 
 
7.6 Safety Monitoring 
Please see the separate data safety and monitoring plan for this study, found in Appendix 
H. 
 
8. INTERVENTION    DISCONTINUATION 
We will discontinue the intervention for any subject who declines or is unable to complete the 
study questionnaires, physiologic monitoring, and/or video recording. Any subjects who are 
disruptive or felt to pose a threat to study staff will also be discontinued. Given the nature of the 
study intervention and outcomes, we will not continue to follow subjects who discontinue the 
study, unless it is for a health-related reason to monitor an adverse event. 
 
9. STATISTICAL   CONSIDERATIONS 
9.1 General Design Issues 
Design: This is a pilot, proof-of-concept, single-blinded randomized controlled trial in 
which subjects will be randomized in a 2:1 fashion to receive either an expanded or 
standard visit intervention. We are including both types of visit interventions and 
randomizing subjects in this way to maximize our potential to measure a wide range in 
physiologic concordance within the patient-provider dyads so we can best assess our 
hypotheses. 
Primary hypotheses: 
1. Subjects in patient-provider dyads with higher levels of concordance in GSR or 
HRV (i.e., where patient and provider GSR or HRV change in concert) will 
demonstrate greater improvement in GERD symptom severity than subjects in 
patient-provider dyads with lower levels of concordance in these measures. 
2. Subjects who experience physiologic changes similar to those elicited by mind-body 
techniques (i.e., decreased GSR and increased high frequency HRV) over the course 
of their visit will demonstrate greater improvements in GERD symptom severity 
than subjects who do not. 
Secondary hypothesis: 
1.   As the expanded visit unfolds, providers will demonstrate significantly more 
patient-centered, nonverbally supportive behaviors and have higher global 
impression ratings of rapport, engagement, and reciprocity compared to early in 
the expanded visit and both early and late in the standard visit. 
Primary outcomes: 
1. Correlation between physiologic synchrony in patient-provider dyads (GSR or 
HRV) and subsequent improvement in GERD symptom severity. 
2. Correlation between absolute changes in GSR within subjects over the course of 
the study visit and subsequent changes in GERD symptom severity. 

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3. Correlation between absolute changes in high frequency HRV within subjects over 
the course of the study visit and subsequent changes in GERD symptom severity. 
Secondary outcomes: 
1. The difference in the frequency of supportive provider behaviors between the 
standard and expanded visit groups. 
2. The difference in the ratings of rapport, engagement, and reciprocity between the 
standard and expanded visit groups. 
Validity and reliability of outcome measures: 
1. Assessment of physiologic concordance has been described by a number of groups 
and we will be using similar methodology [42,78]. 
2. GERD symptom severity will be assessed by a daily symptom diary used by a 
number of other groups in medication trials and in our previous study [61,79,80]. 
The average daily GERD symptom severity is based on the daily sum of scores 
from the first three questions assessing severity of daytime heartburn, nighttime 
heartburn, and acid reflux averaged over a 7 day period. The change in GERD 
symptom severity is calculated by subtracting the average daily GERD symptom 
severity score during the last 7 days of the study from the average daily GERD 
symptom severity score at study enrollment. The other GERD symptom 
questionnaires we are using have also been validated [26,70,71]. 
3. Social psychologists have developed and validated a variety of coding schemes to 
analyze providers’ verbal and non-verbal behaviors and to link these behaviors 
with patient satisfaction, understanding, trust, rapport, empathy, and a variety of 
related factors [9,55–60]. We will use a subset of these validated coding schemes. 
Thin slices have shown high reliability and validity for behaviors such as gaze, nods, 
and smiles [81]. 
 
 
9.2 Sample Size and Randomization 
This is a pilot study whose aim is to identify features on which to focus in subsequent 
studies. For the primary outcome, we would consider an observed correlation greater than 
r = 0.20 adequate evidence of a positive association worthy of further investigation. With 
a sample size of 24 patient-provider dyads, the study will have an 80% probability of 
obtaining an estimated correlation between physiologic concordance and changes in 
GERD symptoms (our primary outcome) greater than r = 0.20 if the true correlation is at 
least rho = 0.36. The study will have 80% power to declare the correlation significantly 
greater than zero based on a two-sided alpha = 0.05 if the true correlation is at least rho = 
0.54. 
Treatment Assignment Procedures 
A randomization scheme will be devised before the start of the study by the study 
biostatistician who will retain the code and will be responsible for breaking the blind at the 
end of the study. We do not anticipate a need to break the blind during the study because 

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we are not expecting serious adverse events to occur more frequently in one visit group 
than another. Randomization will be stratified by provider, with a goal to have 4 
providers each see 6 subjects (4 expanded and 2 standard visits each). If a provider 
cannot commit to this many visits, the study biostatistician may need to adjust the 
randomization scheme. 
The study biostatistician will create numbered envelopes that will indicate which 
intervention is to be delivered. After a subject has consented to participate in the 
study, while he or she is completing the baseline questionnaires, immediately prior to 
the actual visit intervention, the envelope corresponding to the enrolled subject will 
be opened to reveal which intervention is to be delivered. 
If a subject drops or is unable to complete the study, the statistician may need to 
rebalance the randomization scheme within a stratum. 
Subjects will be informed of their “treatment” assignment during a debriefing at the 
end of the second study visit. 
 
9.3 Definition of Populations 
For analyses including intervention group, we will analyze our data according to 
which visit intervention subjects received (standard or expanded). We do not 
anticipate any discrepancies between what subjects were assigned to receive by 
randomization and what they actually received. Study visit type will be guided by a 
written script that the providers will follow during the visit. The actual intervention 
received will also be verified by reviewing study video recordings. 
 
9.4 Interim Analyses and Stopping Rules 
As this is a pilot study, the study PI will review video recordings of visit 
interventions as the study progresses to offer feedback to the study intervention 
providers. To ensure that we will have an adequate response rate to analyze our 
outcomes of interest, we will analyze changes in GERD symptom improvement after 
6 subjects have completed the expanded visit intervention (we will not break the 
blind for unenrolled subjects). If there are not at least 2 subjects with a 50% or 
greater improvement in GERD symptoms and it is deemed that the study providers 
are delivering the standard and expanded interventions appropriately, we may 
consider protocol amendments to improve subject expectancy for symptom 
improvement. 
 
 
9.5 
Outcomes 

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Assessment 
Time Points Collected 
Analysis Plan 
Section 
Demographics, health 
behaviors, height & 
weight 
Visit 1 
Descriptive statistics 
9.6 
Daily GERD Symptom 
Diary 
Visit 1 & Visit 2 
Primary Outcome - Pearson correlation between change 
in GERD symptom severity and physiologic 
concordance in patient-provider dyads 
9.5.1 
GERD-HRQL 
Visit 1 & Visit 2 
Descriptive statistics and secondary measures of GERD 
symptom severity 
9.6 
NIH PROMIS GERD 
GSRS 
Current Stress 
Visit 1 (both before & 
after provider visit) 
&Visit 2 
9.6 
PSS-10 
Visit 1 (before provider 
visit) &Visit 2 
Generalized linear model to determine whether perceived 
stress is a modifying factor for change in GSR and HRV 
in the context of the visit intervention 
9.6 
FFI 
Visit 1 
Generalized linear model to determine whether 
personality is a modifying factor for change in GERD 
symptoms in the context of the visit intervention 
9.6 
GSR & HRV 
Visit 1 
Primary Outcome - Pearson correlation between change 
in GERD symptom severity and physiologic 
concordance in patient-provider dyads 
9.5.1 
Video Recording 
Visit 1 
Secondary Outcomes - generalized linear mixed models 
to compare the frequency of supportive provider 
behaviors and ratings of rapport, engagement, and 
reciprocity between the standard and expanded visit 
groups. 
9.5.2 
CARE 
Visit 1, post- 
intervention 
Generalized linear model to determine whether empathy 
and the patient-provider connection modify change in 
GERD symptoms in the context of the visit intervention 
9.6 
HEAL Patient-Provider 
Connection 
Qualitative Interview 
Visit 2 
Qualitative analysis to understand subjects’ experiences 
of the study and with healthcare providers generally 
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9.5.1 Primary Outcomes 
1. Pearson correlation between concordance in GSR or HRV within patient-provider 
dyads and improvement in GERD symptom severity in the patient. Changes in 
GERD symptom severity will be calculated from the GERD symptom diaries 
collected at the first and second study visits. HRV and GSR will be measured 
during the visit intervention (first study visit). 
We will calculate Pearson correlations between the slopes of time-locked patient 
and provider GSR data in 15 second intervals after smoothing. An index of 
concordance in GSR responses for each patient-provider dyad will be calculated as 
the natural logarithm of the sum of the positive correlations from the entire 
session minus the natural logarithm of the sum of the absolute value of negative 
correlations across the session [78]. Dyads with a more positive index 
demonstrate greater concordance, and the subjects in these dyads would be 
expected to demonstrate greater improvement in GERD symptom severity. 
I will also perform an analysis using a similar approach to analyze the HRV data – 
comparing variation in the beat-to-beat intervals over short segments of time and 
calculating Pearson correlation coefficients for time-locked patient and provider 
data for these intervals. 
2. Correlation between change in GSR (or high frequency HRV) and subsequent 
changes in GERD symptoms. We will calculate absolute changes in GSR, and also 
for high frequency HRV, within study subjects from the beginning to the end of the 
study visit and determine the Pearson correlation between these changes and 
reported changes in GERD symptom severity. As a secondary analysis, I will test 
whether changes in GSR and HRV are a function of baseline perceived stress and if 
that relationship differs between the standard and expanded visit interventions. 
The average daily GERD symptom severity score is derived from the daily 
symptom diaries (sections 6.2.2 and 6.2.5) that subjects complete. The average 
daily GERD symptom severity is based on the daily sum of scores from the first 
three questions assessing severity of daytime heartburn, nighttime heartburn, and 
acid reflux averaged over a 7 day period. The change in GERD symptom severity 
is calculated by subtracting the average daily GERD symptom severity score 
during the last 7 days of the study from the average daily GERD symptom 
severity score at study enrollment. The GERD symptom severity score has been 
used in many GERD medication studies and was the primary outcome measure in 
my pilot study [61]. 
 
9.5.2 Secondary Outcomes 
1. The difference in the frequency of supportive provider behaviors between the 
standard and expanded visit groups. 
2. The difference in the ratings of rapport, engagement, and reciprocity between the 
standard and expanded visit groups. 

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The number of nonverbally supportive behaviors and impression ratings of the patient- 
provider interaction will come from coding of video recordings of the patient provider 
interactions (study visit 1). 
We hypothesize that the frequency/intensity of supportive provider behaviors 
increases as the expanded visit unfolds, compared to the standard visit, as rapport, 
engagement, and reciprocity between patient and provider increase. Briefly, thin 
slices (1.5 minutes) of video occurring near the beginning and end of the standard 
visit (and also a time point in the middle of the expanded visit roughly equivalent to 
the end of the standard visit) will be analyzed by trained coders, blinded to the study 
hypotheses, for the presence of 1) micro-level nonverbally supportive behaviors (e.g., 
friendly voice quality, leaning forward, open body posture, eye contact, nod, smile, 
and gestures) as well as 2) macro-level impression ratings of the interaction (e.g., 
rapport, engagement, reciprocity). 
The PI will meet weekly with the coders to review findings and resolve areas of 
disagreement until greater than 80% concordance is achieved between coders. 
Frequency of supportive behaviors and ratings of interactions will be compared using 
generalized linear mixed models as appropriate for each outcome (e.g., occurrence of 
binary events, counts of discrete events, ordinal ratings of rapport or engagement). The 
models will include terms for time-point, visit group assignment, and their interaction. 
 
9.6  Data Analyses 
We will perform descriptive statistics on the sample demographics similar to our prior 
paper [61] including age, gender, race, ethnicity, body mass index (BMI), smoking status, 
and current medication use for GERD symptoms. We will also assess whether perceived 
stress, perceived empathy (both patient and provider), or personality type (five factor 
inventory) modify improvement in GERD symptoms using generalized linear models. 
We will use the GERD-HRQL, NIH PROMIS GERD, and GSRS as 
adjunct/corroborating measures of GERD symptom severity. We will also assess whether 
subject gender or race modifies our results. For all of these analyses, there is a risk that 
we will be underpowered for detecting significant effects. Qualitative interviews will be 
audio recorded, transcribed, and coded using standard qualitative methodologies and a 
grounded theory-based approach [82].  Blood samples will be processed and stored at - 
80oC for later omics-based analyses that will be the subject of a future grant/study. 
 
As Dr. Dossett has moved and now has a faculty appointment at the University of 
California, Davis (UC Davis), some data analysis will occur there under her supervision 
at that location.  Dr. Dossett and her team at UC Davis will continue to collaborate with 
her mentor, Dr. Denninger who serves as the site PI at MGH, on this project.   
 
 
10. DATA COLLECTION AND QUALITY ASSURANCE 
10.1 Data Collection Forms 
Blood samples will collected at the MGH CRC. Questionnaire data will be collected on 
iPads at the MGH CRC or Benson-Henry Institute using Research Electronic Data 
Capture (REDCap; http://project-redcap.org/) forms, with the exception of GERD 

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symptom dairies which subjects will complete either online (REDCap) or in paper 
format daily. Paper data will be doubled entered into a REDCap database by study 
personal and checked for consistency. REDCap is a secure, web-based application 
developed by Vanderbilt University for electronic collection and management of clinical 
research study data. In collaboration with Harvard Catalyst, Partners Research 
Computing locally hosts REDCap. 
Study staff will maintain an electronic screening file and enrollment log file and paper 
files of consent forms. 
Study participant confidentiality will be maintained by a unique identifier. An electronic 
file linking participants’ personally identifying information and study ID will be 
password protected. All paper data will be stored in a locked filing cabinet. Only study 
affiliated personal will have access to the study database and associated files. Electronic 
communication with collaborators will only involve deidentified information. All 
published data will be presented in aggregate format and deidentified. 
 
10.2 Data Management 
All paper symptom diaries will be reviewed in real time with subjects to ensure that data 
can be transferred completely and accurately to electronic form. Such data will be 
double entered and cross checked as described above. All data (questionnaire, 
physiologic, video) will be cleaned by study staff and reviewed every 1-2 months by the 
study PI to ensure accuracy, completeness, and timeliness of subsequent analyses. All 
biological samples will be labeled with PIDs, logged, tracked, and stored in a securely 
locked specimen freezer at the BHI. 
 
10.3 Quality Assurance 
10.3.1 Training 
The study PI will personally train and supervise all research coordinators and interns 
working on the study in collaboration with relevant consultants to ensure that study 
measures are collected appropriately. All research coordinators/interns will have 
completed the appropriate human subjects and Partners’ research training programs and 
may complete additional training depending upon the capacity in which they will serve 
in the study. 
10.3.2 Protocol Deviations 
Protocol deviations will be documented and reported using Partners’ Insight/Institutional 
Review Board (IRB) service as an Other Event. Unapproved major protocol deviations 
will be reported to the IRB and NCCIH within 5 business days of discovery. 
Unapproved minor protocol deviations will be reported to the IRB at the time of the 
annual continuing review and to NCCIH annually as well. Should a protocol deviation 
become repetitive and/or problematic, the investigational team may consider submitting a 
protocol amendment to adjust study procedures. 
10.3.3 Monitoring 
The study PI will regularly review study questionnaires, HRV and GSR data, video 
recordings, and logs for completeness and quality. Such review will follow each subject 
initially but will occur at least every 1-2 months for the duration of the study. 

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11. PARTICIPANT RIGHTS AND CONFIDENTIALITY 
11.1 Institutional Review Board (IRB) Review 
This protocol and the informed consent documents and any subsequent modifications 
will be reviewed and approved by the Partner’s IRB. 
 
11.2 Informed Consent Forms 
Written informed consent will be obtained by a study team physician at the initial study 
visit after reviewing inclusion and exclusion criteria, the participant’s symptom diary, 
and the electronic medical record if the participant is a patient at a Partner’s affiliated 
hospital. The consent form will describe the purpose of the study, the procedures to be 
followed, and the risks and benefits of participation. Participants will have the 
opportunity to ask questions. A copy will be given to each participant and this fact will 
be documented in the participant’s record. Participants who cannot consent for 
themselves or who are not fluent in English will not be eligible to participate due to the 
nature of the study. 
 
11.3 Participant Confidentiality 
Study visits will be conducted in a private setting. Whenever possible, questionnaire 
data will be collected electronically using REDCap. REDCap is a secure, web-based 
application developed by Vanderbilt University for electronic collection and 
management of clinical research study data. In collaboration with Harvard Catalyst, 
Partners Research Computing locally hosts REDCap. All electronic data not gathered 
using REDCap (symptoms diaries, physiologic data, video recordings) will be stored on 
a Partners Research Computing shared drive which is backed up nightly to protect 
against data loss and is behind the Partner’s firewall. Any data that cannot be collected 
directly onto a shared drive (i.e., must be saved on a local hard disk during data 
collection) will be collected on an encrypted laptop, transferred to a Partner’s-affiliated 
server shortly after collection, and then removed from the laptop. Any paper 
questionnaire data will be stored in a locked filing cabinet at BHI. 
Only those researchers involved in the study will have access to electronic and paper 
data. The file linking participants’ personally identifiable information with their 
participant identification number (PID) will be password protected and access will be 
restricted to the fewest number of staff required but will include at least the PI and a 
research coordinator. Electronic access to videos will also be password protected. All 
paper records will be kept in a locked file cabinet. All computer entry and analysis will 
be done using PIDs only. Any data, forms, reports, video recordings, and other records 
that leave the site will be identified only by a PID to maintain confidentiality.  Digital 
video files may be stored for up to 12 years but may be destroyed sooner. 
 
For analysis of video-recorded data, we will be collaborating with Dr. Judy Hall at 
Northeastern University. Video file names will be coded with participant ID numbers. 
We may share video data with Dr. Hall and her team using an application supported by 
Partners Research Computing that is similar to Dropbox but HIPAA compliant. The only 
personally identifiable information that will be available will be subjects’ images in the 

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videos. All individuals who will be accessing this data will be added to the protocol and 
educated in the importance of subject privacy and confidentiality. 
 
Information will not be released without written permission of the participant, except as 
necessary for monitoring by IRB, the NCCIH, and the OHRP. 
 
11.4 Study Discontinuation 
The study may be discontinued at any time by the IRB, the NCCIH, the Office of 
Human Research Protections (OHRP, or other government agencies as part of their 
duties to ensure that research participants are protected. 
 
12. POTENTIAL BENEFITS 
12.1 Potential Benefits to Participating Individuals 
Study subjects (“patients”) may experience improvement in their GERD symptoms by 
participating in this study. The placebo response in GERD-related trials may be as high as 
40% [35] and our prior data suggests that a therapeutic encounter such as the expanded 
visit can result in at least temporary symptom improvement for some individuals [61]. It is 
also possible that subjects may not experience any direct benefit from participating in this 
study. Participants will be remunerated for their time ($50 per visit) and receive a parking 
voucher. 
Participating study providers will also be remunerated for their time ($80 per visit) and 
may benefit by learning skills for relating to patients more effectively. 
 
12.2 Potential Benefits to Society 
This study will provide insights on the physiologic and behavioral mechanisms that result 
in improved health outcomes from enhanced patient-provider relationships that may be 
applicable to a range of different medical conditions. 
 
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14. LIST OF SUPPLEMENTS/APPENDICES 
 
Appendix A: Recruitment Materials 
A.1 Study invitation letter to prospective participants 
A.2 Study flyer 
A.3 Study invitation letter to prospective participants who have agreed to direct contact 
A.4 Partners Clinical Trials website posting 
A.5 Provider Study Flyer 
 
Appendix B: Screening Documents 
B.1 Telephone script for pre-screening 
B.2 Screening form 
 
Appendix C: GERD Daily Symptom Diary 
Appendix D: Study Questionnaires 
Appendix E: Standard and Expanded Visit scripts 
E.1 Standard Visit Script 
E.2 Expanded Visit Script 
 
Appendix F: Semi-Structured Qualitative Interview 
F2: Semi-Structured Interview of Study Providers 
Appendix G: Debriefing Script 

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Appendix H: Data Safety and Monitoring Plan 
Appendix I: GERD Information Handout 
Appendix J: Provider recruitment emails 
Appendix K: Opt-out post card