Clinical trial NCT03535272
Conditions: Diarrhea Travelers Antibiotic Resistant Infection
Sponsor: Centers for Disease Control and Prevention
Start date: 2018-05-20; Completion date: 2023-12-31
Enrollment: 482 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if the use of prophylactic bismuth subsalicylate (BSS) has an effect on the acquisition of travelers' diarrhea (TD) or antimicrobial resistance (AMR) genes in fecal samples among international travelers who departed from the United States to South East Asia, South Central Asia, or Africa. Our hypotheses will be tested using a double-blinded, placebo controlled randomized clinical trial with participants from a pre-travel health clinic in the United States.

Detailed description:

Arms: arm 1: Bismuth subsalicylate 4 tablets po bid (2.1 grams total of BSS) arm 2: Placebo oral tablet 4 bid
Interventions: intervention 1: Bismuth subsalicylate intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: We aim to determine if there is a biologic benefit to an intervention (BSS administration) in the acquisition of travelers diarrhea and the acquisition of antimicrobial resistance genes. intervention 2: Placebo manufactured to mimic pepto bismol

Protocol documents:
Prot_SAP_001.pdf: 
1 
 
 
 
 
 
 
Bismuth Subsalicylate’s Role in the Prevention of Travelers’ Diarrhea and Impact on 
Acquisition of Gut Antimicrobial Resistance Genes  
____________________________________________________________________ 
NCT: NCT03535272 
Date: 12/20/23 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
 
 
Table of Contents 
 
Project Overview______________________________________________________________ 5–9 
 
 
Protocol Summary  
 
 
Accelerated Protocol Review 
 
 
Investigators/Collaborators and Funding Mechanism 
 
 
Conflicts of Interest 
 
Introduction__________________________________________________________________9–13 
 
 
Current State of Knowledge 
 
Justification for Study 
 
Intended Potential Use of Study Findings 
 
Study Design and Location(s) 
 
 
Objectives 
 
 
Hypotheses 
 
General Approach 
 
Procedures and Methods________________________________________________________13–39 
 
 
Design 
 
 
 
Statement of Purpose 
 
 
 
Study Medications 
 
 
 
Procedures 
 
 
 
Duration of Subject Involvement 
 
How the Study Design Addresses the Objectives and Hypotheses 
 
 
 
Stakeholder Participation 
 
 
 
Cost Benefit/Prevention Effectiveness 
 
 
 
Description of Risks to the Participant 
 
 
 
Description of Anticipated Benefits to the Participant 
 
 
 
Description of the Potential Risks to Anticipated Benefit Ratio 
 
 
 
Emergency Care 
 
 
 
Study Timeline 
 
 
Study Population 
 
 
 
Description and Source of the Study Population 
 
 
 
Definitions 


3 
 
 
 
 
Participant Inclusion Criteria 
 
 
 
Participant Exclusion Criteria 
 
 
 
Estimated Number of Participants 
 
 
 
Sample Size and Power Calculation 
 
 
 
Recruitment and Enrollment 
 
 
 
Description and Justification of Compensation 
 
Statement of Extra Costs to Participants Due to their Involvement in the Study 
 
Procedures for Implementing and Documenting Informed Consent 
 
Plan for Monitoring the Informed Consent Process 
 
 
Variables and Interventions 
 
 
 
Variables 
 
 
 
Study Instruments 
 
 
 
 
Questionnaires 
 
 
 
 
 
Pre-travel 
 
 
 
 
 
During travel 
 
 
 
 
 
Post-travel 
 
 
 
 
Laboratory Instruments 
 
 
 
 
Analytic Tests 
 
 
 
Intervention 
 
 
 
Outcomes 
 
 
 
Criteria for Removal from the Study 
 
 
 
Training for Study Personnel  
 
 
Data Handling and Analysis 
 
 
 
Data Analysis Plan 
 
 
 
Data Collection 
 
 
 
Biologic (stool) Specimen Collection and Testing 
 
 
 
Provision for Protecting/Privacy/Confidentiality 
 
 
 
Information Management and Analysis Software 
 
 
 
Data Entry, Editing and Management, and Data Storage 
 
 
 
Quality Control and Assurance 
 
 
 
Bias in Data Collection, Measurement, and Analysis 
 
 
 
Study Limitations 
 
 
Response to New or Unexpected Findings and Changes in the Study Environment 


4 
 
 
 
Identifying, Managing, and Reporting Adverse Events 
 
 
Notifying Participants of their Individual Results 
 
 
Disseminating Information to the Public 
 
Budget Estimates_______________________________________________________________40–41 
 
References____________________________________________________________________42–44 
 
Appendices____________________________________________________________________45–75 
 
 
APPENDIX A: Screener 
 
 
APPENDIX B: Country Listing for Inclusion 
 
APPENDIX C: Pre-travel Questionnaire 
APPENDIX D: During-travel Questionnaire 
APPENDIX E: Post-travel Questionnaire 
APPENDIX F: Informed Consent Form 
APPENDIX G: Follow-up Phone Call Schedule 
APPENDIX H: Recruitment Materials 
APPENDIX I: Data Analysis Table Shells 
APPENDIX J: Auto-Generated Email for Questionnaires 
APPENDIX K: Handout: Participant Instructions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


5 
 
 
 
 
Project Overview 
 
Protocol Summary 
The purpose of this study is to determine if the use of prophylactic bismuth subsalicylate (BSS) 
has an effect on the acquisition of travelers’ diarrhea (TD) or antimicrobial resistance (AMR) 
genes in fecal samples among international travelers who departed from the United States to 
South East Asia, South Central Asia, or Africa. Our hypotheses will be tested using a double-
blinded, placebo controlled randomized clinical trial with participants from a pre-travel health 
clinic in the United States (see Study Design and Location). To be eligible to participate, travelers 
must be at least 18 years and no older than 70 years of age, travel internationally to South East 
Asia, South Central Asia, North Africa, or Sub-Saharan Africa for 7 to 21 days, be non-pregnant 
and non-nursing, and be willing to participate. We expect, based upon prior studies (see Current 
State of Knowledge), to see a decreased incidence of TD among participants in the intervention 
group. We also believe, based upon known properties and actions of BSS, that there will be 
reduced acquisition of gut AMR genes in the intervention group. We hope findings from this 
study will be used to help international travelers prevent TD and changes to their intestinal 
resistome, thereby decreasing the spread of AMR genes across international borders.  
 
 
Accelerated Protocol Review 
 
 
None needed. 
 
 
Funding Mechanism 
This will be funded under the 28th Amendment to a Cooperative Research and Development 
Agreement (CRADA) between CDC and P&G (expiration: June 30, 2018). A new Amendment will 
be instated to allow continuation beyond the expiration date. The New York Center for Travel 
and Tropical Medicine clinic will be the lead of the project. Funds will also be provided directly 
to the New York Center for Travel and Tropical Medicine for clinic activities. 
  
Investigators/Collaborators 
Principal Investigators: 


6 
 
The New York Center for Travel and Tropical Medicine clinic director Bradley A. Connor, 
MD will serve as a co-Principal Investigator(s) (co-PI) with the CDC’s Kristina M. Angelo, 
DO, MPH&TM (co-PI).  
 
The New York Center for Travel and Tropical Medicine:  
Bradley A. Connor, MD  
 
Clinic Director, New York Center for Travel and Tropical Medicine clinic 
 
Co-Principal Investigator 
 
Olga Whyte, R.N. 
 
 
Nurse and study personnel 
 
Marina Rogova, R.N. 
 
 
Nurse and study personnel 
 
 
 
 
Centers for Disease Control and Prevention:  
Kristina M. Angelo, DO, MPH&TM 
Division of Global Migration and Quarantine 
Travelers’ Health Branch 
Co-Principal Investigator 
Erin Breaker  
Division of Healthcare Quality Promotion 
Clinical and Environmental Microbiology Branch  
Jonathan Daniels, MS 
Division of Healthcare Quality Promotion 
Clinical and Environmental Microbiology Branch  
Tom de Man, MS 
Division of Healthcare Quality Promotion 
Clinical and Environmental Microbiology Branch  
Douglas H. Esposito, MD, MPH  
Division of Global Migration and Quarantine 
Travelers’ Health Branch 
Kirsten P. Fagerli 
Division of Foodborne, Waterborne, and Environmental Diseases 
Waterborne Diseases Prevention Branch 


7 
 
Cindy Friedman, MD 
Division of Foodborne, Waterborne, and Environmental Diseases 
Enteric Diseases Epidemiology Branch 
Alison Halpin, BS, PhD 
Division of Healthcare Quality Promotion 
Clinical and Environmental Microbiology Branch  
Sunkyung Kim, PhD 
Division of Foodborne, Waterborne, and Environmental Diseases 
Waterborne Diseases Prevention Branch 
Adrian Lawsin 
Division of Healthcare Quality Promotion 
Clinical and Environmental Microbiology Branch  
Gillian McAllister 
Division of Healthcare Quality Promotion 
Clinical and Environmental Microbiology Branch  
Eric Mintz, MD  
Division of Foodborne, Waterborne, and Environmental Diseases 
Waterborne Diseases Prevention Branch 
K. Allison Perry, MS 
Division of Healthcare Quality Promotion 
Clinical and Environmental Microbiology Branch  
Ian Plumb, MBBS, MSc  
Division of Foodborne, Waterborne, and Environmental Diseases 
Enteric Diseases Epidemiology Branch 
Mark Sotir, PhD  
Division of Global Migration and Quarantine 
Travelers’ Health Branch 
Allison Taylor Walker, PhD 
Division of Global Migration and Quarantine 
Travelers’ Health Branch 
Nicholas Vlachos 
Division of Healthcare Quality Promotion 
Clinical and Environmental Microbiology Branch  


8 
 
 
 
Dr. Connor’s team at The New York Center for Travel and Tropical Medicine will lead this study. 
They will perform study subject consent, enrollment, double-blinded assignment of study 
subjects to intervention and placebo groups, data (both questionnaires and biologic [stool] 
sample) collection, and response to traveler questions during travel as required. They will also 
manage the IRB submission. 
 
Dr. Angelo’s team in the Travelers’ Health Branch at CDC will assist with the study design and 
protocol development, conduct the blinding of placebo and intervention medications, perform 
data analysis of both questionnaire and biologic (stool) specimen data including data 
interpretation (with coded data), and provide epidemiologic and travelers’ health subject matter 
expertise and support to Dr. Connor’s team.  
 
Any publications using this data will require with the New York Center for Travel and Tropical 
Medicine clinic’s involvement and oversight. CDC will not interact with any research subjects or 
have access to or handle any personally identifiable information, with the exception of a limited 
number of information technology personnel responsible for REDCap software maintenance, 
who are not participating in the study or protocol. CDC will not retain or claim ownership of the 
resulting data. CDC will be providing a secure data management platform (REDCap) to the New 
York Center for Travel and Tropical Medicine; CDC will have access to de-identified data only 
with the approval of Dr. Connor and his team. A nondisclosure agreement with The New York 
Center for Travel and Tropical Medicine will be signed; the clinic will not provide any PII (or the 
key to the coded PII) to any CDC staff.  
 
The Clinical and Environmental Microbiology Branch at CDC will assist with study design, receive 
all biologic (stool) specimens for testing (coded; no PII will be sent with the specimens), and 
perform all laboratory analyses as indicated per the protocol. They will also store biologic (stool) 
specimens for further analysis.  
 
The Enteric Diseases Epidemiology Branch at CDC will assist with study design and protocol 
development, data interpretation, and will provide epidemiological, statistical, and enteric 
diseases subject matter expertise and support. 


9 
 
 
P&G will not be involved with execution of the protocol. They will provide all intervention and 
placebo group medications and funding for the study.  
 
 
Conflicts of Interest 
P&G states that their purpose is to improve the lives of the world’s consumers, and are 
interested in knowing whether their products and services are effective in this capacity. Because 
it is a publicly-traded private, for-profit corporation, P&G must develop products that 
consumers find useful enough to purchase regularly. This study will help the company 
understand more fully how its products further their mission to improve lives, may help the 
company develop new marketing strategies for their products, or modify existing formulations 
of their products to be more effective at preventing intestinal colonization with potentially 
harmful microorganisms.  
 
 
Introduction 
 
Current State of Knowledge 
Travelers’ diarrhea (TD) is the most common travel-related illness reported by international 
travelers, affecting between 30–70% of all travelers (1). The incidence of TD varies by travel 
destination, duration of travel, season, travel activities, and personal traveler attributes. Some 
areas of the world are considered high-risk, including Asia and Africa, but also the Middle East, 
Mexico, and Central and South America (1). Previous placebo-controlled clinical trials with the 
prophylactic use of bismuth subsalicylate (BSS) demonstrated a significant reduction in the 
incidence of TD among those receiving the drug. A recent unpublished meta-analysis on the 
subject of BSS prophylaxis found that persons who took BSS while traveling internationally 
before the onset of gastrointestinal symptoms had a 3.5 times greater odds of remaining free of 
TD in comparison to those who received placebo (2). BSS is available in both liquid and tablet 
formulations; both formulations reduced TD at doses of either 60mL four times daily (4.2g/d) for 
the liquid formulation (3) or 2 tablets, four times daily (2.1 g/day) for a maximum of 3 weeks (3, 
4, 5). BSS at 2.1 g/day protected 41–65% of participants (3, 5), while the liquid formulation 
protected 62% of participants (3). Studies suggest the lowest minimum dose for protection may 
be 1g daily taken in 2 doses, which provided 35% protection in one analysis (5) and 40% 
protection in others (3, 4). BSS had minimal side effects, but these may include nausea, 


10 
 
constipation, tinnitus, and blackening of the tongue and stool (5, 6). BSS may cause 
encephalopathy if taken in high doses for prolonged periods, but this is exceedingly rare and 
above the recommended dose (7, 8).   
 
The active component of BSS with antimicrobial effects is bismuth, which is poorly absorbed and 
mostly remains in the GI tract while salicylate is systemically absorbed in the stomach (9). The 
mechanism of action of BSS in the prevention of TD is thought to be due to bismuth’s 
intraluminal antimicrobial properties and a reduction in the number of bacteria (4, 6, 9, 10). In-
vitro studies suggest that bismuth’s action is bactericidal (6, 11), even at various levels of 
intestinal pH and against a wide range of organisms (11). The precise mechanisms of action 
include the binding of ingested bacteria and subsequent marking of these organisms to be killed 
by host defenses, rendering the bacteria unable to attach to receptor sites that are important 
for colonization and infection (11), degrading the bacterial cell wall, inhibiting ATP synthesis, and 
inhibiting the function of the plasma membrane (9). This inhibition may occur in as little as 0.5–
24 hours (9). BSS may also inactivate bacterial toxins before attachment to the intestinal mucosa 
(12). Viruses may be inhibited by BSS; it may prevent viral invasion and deter replication through 
unknown mechanisms (4).  
 
There is a current domestic and international focus on preventing the acquisition of drug-
resistant enteric bacteria by high-risk groups, including travelers (13). International travelers are 
at increased risk for acquiring gut organisms containing AMR genes (especially after travel to 
Asia), developing TD, taking antibiotics, and requiring hospitalization (14, 15, 16, 17). Although 
carriage of organisms containing gut AMR genes may be transient in most travelers (15), it can 
persist for ≥1 year in over 10% of travelers, increasing the risk of transmission to household 
members and others (18). Avoiding the use of antibiotics while abroad is one way to lessen 
acquisition of antibiotic-resistant organisms (19). BSS treatment of adult outpatients with acute 
diarrhea has been found to reduce antimicrobial medication use in a high prevalence area (20). 
It is currently unknown whether BSS affects the acquisition of gut AMR genes while traveling 
abroad; however, given BSS’ antimicrobial properties, stability in acidic conditions, and blockage 
of receptor sites to prevent colonization, it is possible that prophylactic BSS may indirectly 
prevent acquisition of AMR genes in international travelers by preventing intestinal colonization 
of ingested microbes. More research must be done to address this uncertainty.  
 


11 
 
Justification for Study 
International travel has expanded over the past 50 years. Worldwide annual tourist arrivals are 
expected to reach 1.8 billion by 2030 (21). Travel destinations continue to diversify, including 
increasing numbers of travelers visiting countries with emerging economies, such as Asia and 
Africa. These trends may place international travelers into closer contact with infectious 
pathogens, including those that cause TD and have AMR genes (21, 22). This may contribute to 
infectious disease spread across international borders. International travel, particularly to 
countries with emerging economies, is a well-documented risk factor for acquisition of gut AMR 
genes (23, 24). Also, acquisition of TD during travel has been associated with persistent infection 
or post-infectious irritable bowel syndrome (PI-IBS). PI-IBS is the onset of irritable bowel 
symptoms after an enteric infection, and may lead to a permanent change in bowel function 
(25).  
 
Given the burden of TD and the possibility of acquiring AMR genes while abroad, there is ample 
justification for studying simple, cost-effective, and safe actions that could be taken by 
international travelers to reduce these risks.  
 
Intended Potential Use of Study Findings 
Healthcare providers and public health officials may use the findings from this study to enhance 
or change recommendations made to international travelers when offering pre-travel advice. 
Healthcare providers may advise travelers on improved best practices to decrease their risk of 
TD and acquisition of AMR genes. Public health officials may use information from this study to 
develop guidelines and advise on best practices to ensure that the impact of TD and drug-
resistant organisms is minimized in international travelers. By minimizing acquisition of AMR 
genes in international travelers, we would also be helping protect the general, non-traveling 
public from exposure to imported antimicrobial resistant organisms. This study may also 
generate hypotheses that could help guide future study of possible mechanisms of action and 
uses of BSS in reducing the development of and treating TD.  
 
The results will be made public through publication(s) within 18 months of the termination of 
data collection. This/these publication(s) will be in a peer-reviewed journal; however, the initial 
release may be in the form of an abstract and presentation at a scientific meeting (see 
Disseminating Information to the Public).  


12 
 
 
Study Design and Location(s) 
This study will be conducted as a double-blinded, placebo-controlled randomized clinical trial.  
We propose two arms to test BSS against placebo: 
 
1. BSS 4 tablets po bid (2.1 grams total of BSS)   
2. Placebo 4 tablets po bid 
 
Study participants will be recruited from The New York Center for Travel and Tropical Medicine 
Clinic in New York, New York, USA (see Procedures) (http://www.travelhealth.net/). Throughout 
the study period, the recruiting site will maintain adequate personnel trained in the study 
protocol and procedures (see Training for Study Personnel). Study personnel will be available to 
communicate with the co-PIs as necessary and to address issues with the study protocol and 
concerns of the study participants. This site will be able to consent and enroll participants (see 
Procedures for Implementing and Documenting Informed Consent), store and distribute the 
study drug and placebo, and collect and safely store questionnaire data (see Data Handling and 
Analysis) and biologic samples (stool) data (see Biologic [stool] Specimen Collection and Testing), 
in accordance with the study protocol.  
 
Objectives 
1. (Hereafter, “primary objective”) Test the efficacy of BSS in the prevention of TD among 
international travelers.  
2. (Hereafter, “secondary objective”) Determine the impact BSS has in the acquisition of gut AMR 
genes among international travelers.   
 
Hypotheses 
 
The following hypotheses follow the objectives above: 
1. NULL HYPOTHESIS: BSS does not prevent TD among international travelers.  
a. Does BSS prevent TD among international travelers? 
b. Does BSS reduce severity/frequency of TD among international travelers? 
2. NULL HYPOTHESIS: BSS does not alter the acquisition of gut AMR genes among international 
travelers. 
a. Does BSS affect the acquisition of gut AMR genes among international travelers? 


13 
 
b. Does BSS affect the acquisition of gut AMR genes among international travelers that 
develop TD? 
i. Does BSS alter the acquisition of gut AMR genes if an international traveler with 
TD takes an antimicrobial while taking BSS?  
c. Does BSS affect the acquisition of gut AMR genes among international travelers that do 
not develop TD? 
 
General Approach 
 
The approach of this study will be hypothesis-testing.  
 
Procedures and Methods 
 
Design 
Statement of Purpose 
The purpose of this study is to investigate the impact of BSS on the acquisition of TD and 
acquisition of gut AMR genes among international travelers.  
 
 
 
Study Medications 
The placebo, produced by P&G, will be comprised of the following components: 
microcrystal cellulose, calcium carbonate, D&C red No. 27 aluminum lake, flavor, 
magnesium stearate, mannitol, povidone, saccharin sodium, and talc. It will be 
formulated to have an appearance (size, shape, color, and packaging), texture, and taste 
similar to BSS.  
 
Each bottle to be used in the study will be blinded by CDC personnel (but not the co-PI). 
Each bottle will include an internal study ID#, owner name, batch number, start date, 
and expiration date. The blinding label will additionally include a study ID for 
identification. Bottles of study medications will be sent to The New York Center for 
Travel and Tropical Medicine clinic for distribution to participants at their pre-travel 
consultation/enrollment visit.  
 
Procedures 
This study will be in the form of a double-blinded, placebo-controlled randomized 
clinical trial, conducted at The New York Center for Travel and Tropical Medicine clinic in 


14 
 
New York (see Description and Source of the Study Population). This clinic offers pre-
travel specialty medical services to persons planning international travel and has the 
necessary resources, skills, and expertise to evaluate and treat travelers who acquire 
travel-related illness, and offer advice to travelers when questions or problems arise 
during their trips.  
 
All travelers who are seen for a pre-travel consultation at The New York Center for 
Travel and Tropical Medicine will be administered the screening questionnaire by study 
personnel upon arrival to their consultation to determine their eligibility. Eligible 
travelers will be invited to participate in the study (see Participant Inclusion / Exclusion 
Criteria). All participants will be consented as per the protocol (see Procedures for 
Implementing and Documenting Informed Consent). Randomization of participants will 
be double-blinded and conducted via block randomization to ensure groups of equal 
sample sizes using a computer generated distribution. Study medications for both the 
intervention and placebo group will be provided by P&G, blinded by CDC (using a unique 
identifier), and distributed to participants at the clinic site during the pre-travel 
consultation/enrollment visit per the randomization mentioned above (see Study 
Medications). Study personnel at The New York Center for Travel and Tropical Medicine 
will not be aware of which medications are BSS or placebo. The code number of the 
medication (intervention or placebo) administered to a particular participant will be 
recorded. All code numbers and corresponding arms will be kept secret until the end of 
the trial.   
 
Web-based questionnaires will be administered during and post-travel (see Study 
Instruments). Pre-travel data will be collected via telephone with study personnel. Pre-
travel data will include information on the participant’s medical history and travel plans, 
and post-travel data will include information on the TD symptoms, medication use, 
medical care received, and adverse events. During travel, the participant will complete a 
daily questionnaire that will include data on compliance with taking the study tablets, 
presence of symptoms of TD, onset of adverse reactions, any medical care received, and 
trip specifics. The during-travel questionnaire will be made available in both a web-
based electronic form and a paper form in the event that the participant does not have 
reliable internet access. Any paper forms that were completed will be returned by mail 


15 
 
after they return from travel via a pre-paid envelope addressed to the study clinic that 
was given to the participant when enrolled. 
 
To address the secondary objective, participants will also be asked to provide pre- and 
post-travel biologic (stool) samples for laboratory testing for the presence of gut AMR 
genes (see Laboratory instruments). Timing of the pre- and post-travel data and stool 
sample collections will be within 7 days before departure and 10 days after return from 
travel, respectively. Both biologic (stool) samples will be self-collected and submitted by 
mail to the clinic (the collection kit, and all necessary packaging and postage will be 
provided to the traveler). The participant will not be seen by a healthcare provider 
involved with the study post-travel unless they are ill and seek an evaluation.  
 
As part of standard pre-travel consultation practices, if indicated, travelers will be 
prescribed anti-diarrheal medications and/or antibiotics for self-treatment of TD. These 
medications may include loperamide (Imodium), diphenoxylate and atropine (Lomotil), 
BSS (Pepto bismol), ciprofloxacin, azithromycin, or rifaximin. If these medications are 
taken while abroad, the travelers will be asked to note this on the during travel or post-
travel questionnaires.  
 
No difference in pre-travel advice, provision of anti-diarrheal medications, or during- or 
after-travel medical evaluation or advice will occur based on the traveler’s assigned 
study arm. 
 
 
 
Duration of Subject Involvement 
The duration of each participant’s involvement in the study is expected to be a 
maximum of 6 weeks. This will account for time to complete the pre-travel 
consultation/enrollment visit, 21 days (or less) of travel, and post-travel follow-up.  
 
How the Study Design Addresses the Objectives and Hypotheses 
A double-blinded, placebo-controlled randomized clinical trial is the best study design to 
address the study objectives and hypotheses. We aim to determine if there is a biologic 
benefit to an intervention (BSS administration), and a placebo-controlled methodology 
is required to determine if there is a statistically significant benefit of the intervention 


16 
 
regarding incidence of TD and acquisition of gut AMR genes. It is imperative to blind 
both healthcare providers and participants to ensure that biases, including selection and 
observer bias, are minimized.   
  
Stakeholder Participation 
The primary stakeholders for the project are international travelers, healthcare 
providers, and public health officials.  
 
P&G cannot participate in the study procedures (i.e., data collection or analysis) to 
minimize the potential for any commercial influences or the appearance thereof. They 
will not be able to prevent the publication of negative results, nor influence the 
interpretation of the results. They will be responsible for providing both intervention 
medication and placebo.  
 
CDC and P&G will operate under the terms of the CRADA regarding cooperative 
research, reports, financial and staffing obligations, patent applications, licensing, 
proprietary rights and publication, representations and warranties, disputes, and 
liability.  
 
Cost Benefit/Prevention Effectiveness 
A single 262mg tablet of BSS costs approximately $0.26 when purchased over-the-
counter ($10.49 for 40 tablets). The cost of antibiotic treatment of TD or potential 
hospitalization from complications, or for diagnostic procedures or other treatment 
interventions, far surpasses the cost of BSS for possible TD prevention. 
 
The cost benefit regarding the secondary objective is unable to be defined, however, 
the potential costs for spread of gut AMR genes from colonized international travelers 
are presumed to be large compared to the minimal cost of BSS prophylaxis. Further, 
there is no evidence currently that any microbial resistance to BSS exists, inducible or 
otherwise. Finally, any reductions in TD incidence among travelers that is related to 
prophylactic BSS use could result in a reduced need for and use of antibiotics by 
travelers, with a concomitant reduction in the selective pressures for antimicrobial 
resistance genes. 


17 
 
 
 
 
Description of Risks to the Participant 
There are minimal risks to participants in this study. BSS has been marketed in the 
United States for over 100 years, and is widely available without a prescription. It has a 
good safety profile at the recommended dose and duration of use. We will not exceed 
these safe dosing ranges in this study. The maximum daily dose (4.2g per day) of BSS 
results in peak serum concentrations of salicylate considerably below toxicity levels. This 
dose has been documented to be safely used for up to 3–4 weeks (26). We will include 
only adult participants and exclude children <18 years of age or elderly adults 70 years 
of age or older, pregnant or breastfeeding women, participants with a known 
contraindication to BSS use, or anyone taking medications known to interact with BSS, 
including other salicylate-containing compounds. Participants will be asked to refrain 
from taking aspirin or aspirin-containing compounds. The duration of BSS administration 
in this study will be limited to a maximum of 21 days. 
 
BSS lists possible side effects on its packaging (including, but not limited to, constipation 
and tinnitus) that will all be discussed with the participant before informed consent and 
enrollment.  
 
Participants will be provided contact information for study personnel at The New York 
Center for Travel and Tropical Medicine in the event that they have questions regarding 
the study or the medications before, during, or after travel. They will be notified to 
contact study personnel at The New York Center for Travel and Tropical Medicine in the 
event that they experience any adverse events of BSS or symptoms of TD. 
 
In addition to the study preparations (BSS or placebo tablets), participants may also be 
provided with an appropriate medication for TD self-treatment (at the discretion of the 
healthcare provider) to carry with them in the event they develop TD while abroad. If 
they experience an episode of TD, they will be instructed to continue their study 
medication. Participants will also be counseled on hydration, the indications for 
antibiotic use (i.e., in the event of severe diarrhea, but not mild or moderate diarrhea), 
and when to seek healthcare.  
 


18 
 
Each participant’s confidentiality will be rigorously maintained (see Procedures for 
Implementing and Documenting Informed Consent). If a breech occurs, the IRB will be 
notified immediately and standard procedures will be followed.  
 
 
 
Description of Anticipated Benefits to the Participant 
Based upon published reports, we anticipate that participants in the intervention arm of 
the study will experience a health benefit; they will be less likely to acquire TD while 
abroad. They also may benefit, in the event that they do acquire TD, by having a shorter 
duration and lesser severity of TD symptoms in comparison to those in the placebo 
group. 
 
 
 
Description of the Potential Risks to Anticipated Benefit Ratio 
 
 
 
The potential benefits of participating in this study outweigh the minimal risks.  
 
 
 
Emergency Care 
We do not anticipate participants needing emergency care as a part of this study. 
Participants will be provided phone and email contact information for study personnel 
in the event questions or concerns arise that may relate to their participation in the 
study.  
 
 
 
Study Timeline 
 
 
Table 1. Study Timeline, 2017–2020 
Study Component
Date of Anticipated Start
Date of Anticipated End
Protocol Writing and Coordination
March 2017
October 2017
Submission of protocol/consent forms 
for IRB approval 
November 2017
Late December 2017
Training of study personnel
January 2018
January 2018
Enrollment of participants
February 2018 
July 2019
Laboratory analysis of stool specimens
February 2018
October 2019
Data entry
February 2018
October 2019
Data analysis (every 3 months)
April 2018
November 2019
Manuscript writing and clearance
November 2019
March 2020
Dissemination of findings
March 2020


19 
 
 
 
Study Population 
Description and Source of the Study Population 
Participants will be selected from persons seeking a pre-travel consultation at The New 
York Center for Travel and Tropical Medicine, New York, United States. This clinic serves 
travelers by providing pre-travel consultative services, in addition to post-travel 
screening, assessment, diagnostic, and treatment services. Centrally located in 
Manhattan, this clinic serves a large variety of international travelers, including tourists, 
immigrants or their relatives, and business travelers, among others. Travelers’ 
destinations are equally varied, reflecting the ethnic and cultural diversity of New York 
City.  
 
Definitions 
Diarrhea: 
≥ 3 unformed stools in 24 hours, with or without associated symptoms such as 
fever, cramping, or abdominal pain  
 
Travelers’ diarrhea: 
Diarrhea that begins while traveling (after arrival in a country) or within 10 days 
after return 
 
 
 
 
Study period:  
Includes the 7 days prior to departure in which the pre-travel questionnaire and 
a biologic (stool) specimen is collected, the full duration of travel, and through 
10 days maximum post-return from travel, or until both the post-travel 
questionnaire and submission of the post-travel biologic (stool) specimen is 
complete (a maximum of 17 days post-travel) 
 
Travel companion (group):  
Two or more study participants with a common relation (friends, colleagues, or 
relatives) with the same itinerary, who anticipate performing the same activities 
during travel 
 


20 
 
 
 
 
Trip duration: 
 
 
 
 
The number of days spent in country; excludes air travel time 
 
 
 
 
 
 
 
Severe TD: 
 
 
 
 
Hospitalization to an inpatient ward either during travel or after travel with a  
diagnosis of diarrhea 
 
Acquisition of AMR gene(s): 
The presence in a post-travel biologic (stool) specimen of one or more 
antimicrobial resistance gene(s) that were not present in a pre-travel biologic 
(stool) specimen from the same person, and which is known to confer 
antimicrobial resistance to one or more antimicrobial agents (“resistome”) 
 
 
 
 
Medication compliance: 
Full = participant takes all scheduled doses according to directions 
Good = If <15% of BSS or placebo doses were missed during travel 
Fair = If 15–30% of BSS or placebo doses were missed during travel 
Poor = If >30% of doses were missed during travel  
 
 
 
 
Questionnaire compliance: 
 
 
 
 
Full = participant completes all questionnaires 
 
 
 
 
Good = participant completes >80% of all during travel questionnaires, AND 
both the pre- and post-travel questionnaires 
Fair = participant completes between 30–80% of all during travel  
questionnaires, including AT LEAST the pre-travel questionnaire 
Poor = participant completes <40% of all during travel questionnaires, and AT 
LEAST the pre-travel questionnaire 
 
 
 
 
 
Biologic (stool) specimen compliance: 
 
 
 
 
Full = BOTH specimens collected and sent  
 
 
 
 
Fair = ONLY one specimen collected and sent 
 
 
 
 
Poor = No specimens collected and sent 
 


21 
 
 
 
 
Loss to follow-up: 
Failure to complete the post-travel questionnaire after three attempts to 
contact the participant or if submission of the post-travel biologic specimen 
(stool) occurs more than 10 days after return from travel or is not submitted 
 
 
 
Participant Inclusion Criteria 
Willing participants must meet the inclusion criteria as outlined here: 
1. Be ≥ 18 and <70 years of age at the time of enrollment 
2. Sign an informed consent (see Procedures for Implementing and Documenting 
Informed Consent) stating willingness to participate and comply with the study 
protocol 
3. Plan on leaving for an international trip ≥7 days after their pre-travel consultation 
4. Plan on traveling in country for ≥7 days but ≤21 days (21 day limit due to BSS 
duration recommendations and a lack of data on longer-term BSS use) (see 
Definitions) 
5. Traveling to either South East Asia, South Central Asia, North Africa, or Sub-Saharan 
Africa for at least 7 days of their itinerary (see APPENDIX B for list of countries 
classified to each region) 
6. Be willing to complete an initial eligibility screening (see Recruitment and 
Enrollment) 
7. Be willing to complete questionnaires and provide biologic specimens (stool) within 
7 days of departure and within 10 days after return 
8. Be willing to refrain from taking any pre-biotics, probiotics, synbiotics and/or herbal 
supplements throughout their study period 
 
Participant Exclusion Criteria 
Willing participants must not meet any exclusion criteria as outlined here: 
1. Are <18 years of age or >69 years of age 
2. Are traveling in country for <7 or >21 days (see Definitions) 
3. Have known or suspected contraindications to taking BSS (including, but not limited 
to, travelers with kidney disease, diabetes, gout, a clotting disorder, or an allergy to 
any component of BSS) 


22 
 
4. Are pregnant (via self-report), are planning to become pregnant, or may become 
pregnant during travel (not actively using contraception and are sexually active), or 
are breastfeeding 
5. Routinely take a medication known to interact with BSS (including, but not limited 
to, insulin, methotrexate, valproic acid, ACE inhibitors, anticoagulants, or other 
salicylates) (see APPENDIX A for complete list) 
6. Have taken an antibiotic in the 30 days before departure 
7. Have taken any medications that may lower one’s ability to fight infection (e.g., 
steroids, monoclonal antibodies, etc.) 
8. Have previous diagnoses of immunocompromising conditions such as HIV/AIDS, 
complement deficiency, immunoglobulin deficiency, or undergoing active 
chemotherapy or participants with chronic gastrointestinal disorders, such as 
chronic diarrhea, irritable bowel syndrome (IBS), inflammatory bowel disease (i.e., 
Crohn’s disease, ulcerative colitis), celiac disease, malabsorption syndromes, 
pancreatic insufficiency, gallbladder disease, or current gastrointestinal cancer  
9. Have had diarrhea (see Definitions) anytime in the previous 30 days, have diarrhea 
at the pre-travel consultation, or develop diarrhea before departure 
10. Have been given doxycycline for malaria prophylaxis for the current trip (due to 
possible drug-drug interactions and decreased absorption of the doxycycline) (27) 
11. Have an allergy to any component of the placebo tablets 
 
Estimated Number of Participants 
We anticipate enrolling approximately 500 participants (see Sample Size and Power 
Calculation). 
 
Sample Size and Power Calculation 
A sample size of 488 participants with full compliance to medications and 
questionnaires (244 participants in each arm) is needed to fulfill the objectives 
[anticipated incidence of the endpoint as 40% incidence of TD with a 30% minimum 
intervention protection (0.40-[0.4x0.30]= 0.28) with an alpha of 0.05, and 80% power].  
 
Recruitment and Enrollment 


23 
 
All international travelers undergo a screening questionnaire at their pre-travel 
consultation to determine eligibility. This short questionnaire includes questions 
regarding the travelers’ [see APPENDIX A]: 
1. Age 
2. Travel destination(s) 
3. Trip duration 
4. Acute and chronic medical conditions, including diarrhea  
5. Contraindications to BSS administration 
6. All current medications, including antibiotic use within the 30 days before 
screening 
7. Willingness to participate in the trial and comply with the data collection 
requirements 
 
This screening questionnaire will be administered to the traveler by study personnel at 
The New York Center for Travel and Tropical Medicine. The purpose will be to exclude 
those travelers who do not meet all inclusion criteria and those who meet any exclusion 
criteria (see Participant Inclusion / Exclusion Criteria). Travelers who meet the inclusion 
criteria and do not meet any exclusion criteria will be introduced to the project 
objectives and procedures, including the procedures for biologic (stool) specimen 
collection (see Laboratory instruments).  
 
Once recruited and consented, eligible participants will be registered in the study at the 
clinic site and receive a one-page instructional handout regarding stool specimen 
collection and questionnaire completion [APPENDIX K]. All primary participant 
information will be kept at the clinic. Travelers will agree to inform the study personnel 
at their clinic site if they have a change in travel plans, begin a course of antibiotics, 
become pregnant before or during travel, or develop diarrhea before departure, to 
determine if they are still eligible to participate. In the event that a participant 
withdraws from the study at any time, the clinic must note this in the study database. 
 
 
 
Description and Justification of Compensation 
Gift card compensation will be provided to the participants for the time spent on this 
project.  


24 
 
 
The participant will receive $100 for completion of the pre-travel questionnaire and the 
submission of a pre-travel biologic (stool) specimen. For each daily questionnaire that 
the participant completes while traveling, they will receive an additional $5 (maximum 
additional $100). The participant will receive an additional $50 for completion of the 
web-based post-travel questionnaire and an additional $50 for the submission of a 
biologic (stool) specimen post-travel. The maximum compensation will be $300 total. 
The minimum participation to receive compensation is good medication compliance, 
good questionnaire compliance, and good biologic (stool) specimen compliance (see 
Definitions).    
 
Compensation will be mailed to participants upon completion of their study period.  
 
Statement of Extra Costs to Participants Due to their Involvement in the Study 
 
We do not anticipate any extra costs to the participants due to their involvement.  
 
Procedures for Implementing and Documenting Informed Consent 
The New York Center for Travel and Tropical Medicine clinic must obtain and ensure 
scientific and ethical permission, in accordance with state and national regulations. All 
collaborators must adhere to strict guidelines to ensure participant confidentiality, 
following the Privacy Act. Biological specimens (stool) must be processed per 
established safety protocols.  
 
Each participant will provide written informed consent for the project at their initial pre-
travel consultation when they are enrolled by study personnel (see APPENDIX F). This 
will include (but is not limited to) information regarding the study objectives and 
rationale, the study procedures, how each participant’s confidentiality will be protected, 
their rights as participants, and compensation for participation. It will also include 
information on how their biologic specimens will and will not be used. Study personnel 
will answer the travelers’ questions pertaining to study logistics and BSS as necessary. 
 
Participants may withdraw from the study at any time. Participants will self-monitor for 
BSS side effects and the study will be suspended in the event of safety concerns.  


25 
 
 
Plan for Monitoring the Informed Consent Process 
Each informed consent will be signed in the presence of a witness to ensure all risks and 
benefits, in addition to an explanation of confidentiality, were described to the 
participant.  
 
 
Variables and Interventions 
 
 
Variables 
Variables collected on participants are available in the APPENDICES. They are also 
described in further detail below. 
 
 
 
Study Instruments 
 
 
 
Questionnaires (see APPENDICES) 
Any revisions to study procedures or instruments will be submitted to 
the IRB as an amendment for approval before changes are 
implemented. 
 
 
 
 
 
Screening (see APPENDIX A) 
 
 
 
 
 
Pre-travel (see APPENDIX C) 
Contact information (phone and email) for each participant who consented 
at the pre-travel consultation/enrollment visit will be given to the study 
personnel who will administer the screening questionnaire. Each participant 
will be contacted via telephone 7 days before departure, and study 
personnel will review the participant’s responses to each question on the 
screening questionnaire to ensure they are still eligible to participate. At this 
time, they will complete the pre-travel questionnaire with the participant on 
the phone and answer any questions they may have. The participant will 
also be reminded to submit their pre-travel biologic (stool) specimen. 
 
Study personnel will make follow-up telephone calls on pre-departure days 
7, 5, 3, and 1 as needed to ensure the questionnaire is completed.   
 


26 
 
This questionnaire will include information from the eligibility screening, in 
addition to the following information: 
1. Demographics (e.g., age, sex, and ethnicity) 
2. Medical history 
3. Current medications (including use of probiotics, over-the-counter 
medications, or herbal supplements) 
4. Previous international travel in the past 90 days 
5. Travel plans including destination(s) and duration 
6. Reason(s) for travel 
 
During Travel (see APPENDIX D) 
During travel, participants complete a daily questionnaire that will include 
the following information: 
1. Date, time, and number of study tablets taken (to provide 
information on the number of missed doses) 
2. Presence of gastrointestinal symptoms (e.g., abdominal cramping, 
fever, nausea, vomiting, tenesmus)  
3. Duration of GI symptoms 
4. Possible medication adverse reactions (e.g., tinnitus, black stool, 
etc.) 
5. Other illnesses acquired (e.g., upper respiratory infection) 
6. Hospital admission or contact with a healthcare facilities or 
providers or taking any non-routine medications for illness while 
abroad 
7. Countries visited 
8. Foods eaten (fermented foods or yogurt) 
 
Details on the participant’s trip (number 7 above) are necessary to 
determine risk factors for the acquisition of gut AMR genes among 
those participants in the placebo group vs the intervention group. 
 
Web-based data collection will be used to facilitate data collection 
during travel. Each participant will receive a unique URL to input their 


27 
 
daily information using their unique Study ID and Group ID. A paper 
copy of the daily travel questionnaire will be provided as a back-up 
mechanism for data capture where internet access is limited or 
unavailable. If a participant does not think that they will have reliable 
internet access while abroad, they will be encouraged to use the paper 
copies to ensure real-time data collection. Labels will be provided to 
ensure that the paper copies are de-identified. Any paper forms that 
were completed will be returned by mail after they return from travel 
via a pre-paid envelope addressed to the study clinic that was given to 
the participant when enrolled (see Procedures).  
 
Participants will take either BSS or placebo for the duration of travel, 
unless they reach a study outcome or criteria for removal (see 
Outcomes and Criteria for Removal from the Study).  
 
Post-travel (see APPENDIX E) 
Participants will be asked to submit a web-based post-travel 
questionnaire within 10 days after return from travel, submit a biologic 
(stool) specimen, and provide all daily questionnaires that were 
completed during travel. This will be submitted via a pre-paid envelope 
addressed to the study clinic that was given to the participant when 
enrolled. 
 
Study personnel will make follow-up telephone calls on days 3, 5, 7, and 
10 after return as needed to encourage that the post-travel 
questionnaire, paper questionnaires from during-travel, and biologic 
(stool) specimens are all submitted. 
 
The web-based post-travel questionnaire will include questions on: 
1. The development of symptoms of TD since returning from 
abroad, including duration of symptoms 
2. New antibiotic or other medication use 
3. Adverse events 


28 
 
4. Contact with healthcare facilities or providers 
5. Changes to travel itinerary during travel  
 
       Table 2. Schedule of CLINIC events (primary and secondary objectives): 
                                     Stages
Pre-travel 
consultation 
(baseline) 
Pre-travel
(≤7 days 
before 
departure)
During 
travel 
Post-travel 
(≤10 days 
after return) 
Screening Questionnaire
X
Informed Consent
X
Pre-travel
Questionnaire* 
X
Follow-up call(s)
X
X†
During travel 
Questionnaires 
X
Post-travel 
Questionnaire 
X
Adverse Events Reporting
X
X
*Study personnel will call the participant to complete a pre-travel questionnaire 
7 days before departure and to ensure that answers to the questions on the 
screening questionnaire have not changed. Reminder calls will occur as per 
APPENDIX G. If the traveler is leaving exactly 7 days after the pre-travel 
consultation/enrollment visit, this questionnaire can be performed at the pre-
travel consultation/enrollment visit.  
†Study personnel will call the participant within 3 days of return from travel to 
remind participants to complete their web-based post-travel questionnaire, 
submit any paper during travel questionnaires, and collect and submit the post-
travel biologic (stool) sample. Reminder calls will occur as per APPENDIX G. 
   
 
 
 
Laboratory Instruments 
All participants will collect and submit a fresh biologic (stool) sample in the 7 
days before departure and within 10 days after return. Participants will be 


29 
 
provided all instructions and materials necessary to collect and submit these 
samples at enrollment. All biologic (stool) specimens will be submitted by mail, 
and participants will be given pre-paid shipping materials. 
 
Participants will be provided two OMNIgene gut kits at their pre-travel 
consultation/enrollment visit once enrolled (see Biologic [Stool] Specimen Data 
Collection and Testing). These kits will come with instructions on use, handling, 
and shipment. 
 
In the event that participants are able to provide a stool sample while in clinic 
for their pre-travel consultation/enrollment visit or during a non-study post-
travel follow-up sick visit within 10 days of return, these samples will be 
aliquoted by study personnel at The New York Center for Travel and Tropical 
Medicine in the following manner: 
*First, the required quantity will be placed in the participant’s 
OMNIgene gut kit (per manufacturer directions) to be sent to CDC’s 
Clinical and Environmental Microbiology Branch for resistome testing. 
The remainder will be frozen, and sent to CDC for analysis at a later date 
(note: OMNIgene gut kit does not allow for culture - a see Biologic 
[Stool] Specimen Collection and Testing). Only those participants who 
happen to have a biologic (stool) specimen collection completed at the 
clinic will have their stool analyzed by culture; this is not a requirement 
for participation and no additional compensation above that previously 
described will be offered. 
 
                                                  Table 3. Schedule of LABORATORY events (secondary objective)  
 
 
 
                     (Events from Table 2 still apply to these participants) 
                                   Stages
Pre-travel
During travel
Post-travel
Biologic (stool) sample 
X
X
Laboratory testing of stool
X
X
 
Analytic tests 


30 
 
Questionnaires: Data from the questionnaires will be analyzed for statistical 
significance comparing intervention vs placebo groups.  
 
Biologic (stool) specimens: A highly multiplexed PCR assay detecting over 500 
different AMR genes will be used to test the DNA extracted from all biologic 
(stool) specimens that were placed in the OMNIgene gut kit (see Biologic (Stool) 
Specimen Collection and Testing). Results will be analyzed to determine if the 
participants acquire gut AMR genes (changes to the “resistome”) as a result of 
travel and whether or not that change varied with the bismuth subsalicylate 
treatment received. Additionally, stool bacteriologic culture will be performed 
on those specimens submitted in clinic. 
 
Intervention 
We propose the inclusion of two arms to test BSS against placebo: 
1. BSS 4 tablets po bid (2.1 grams total)    
2. Placebo 4 tablets po bid 
 
Dosing will begin on the flight prior to arrival in the destination and will cease once they 
return home. The study medications must be taken twice daily (a morning and an 
evening dose); with time zone changes, the first dose should be taken to ensure that no 
longer than 12 hours passes before a subsequent dose.   
 
Before departure, participants will be provided, free of charge, all needed study 
medication for the duration of their trip. Participants will be encouraged to take all 
doses of their medication and appropriately document on their daily during travel 
questionnaires if a dose was missed or taken off schedule.    
 
 
 
Outcomes 
 
 
 
The outcomes of this study will include:  
Favorable Outcome
Non-favorable Outcome
Hypothesis 1: 
Prevention of TD 
Prevention of TD in the 
intervention group 
TD in the intervention group at a 
rate similar to placebo; intervention 
drug side effects; adverse events 


31 
 
Hypothesis 2: 
Acquisition of AMR 
genes 
Reduced or no presence of 
travel-associated gut AMR 
genes in the intervention 
group 
No reduction in the presence of 
travel-associated gut AMR genes in 
the intervention group 
 
The participant’s study period will end in the following circumstances: 
1. The traveler meets criteria for removal (see Criteria for Removal from the Study) 
2. The participant voluntarily withdraws from the study (see Procedures for 
Implementing and Documenting Informed Consent) 
3. The participant completes all study activities and submits all study 
questionnaires and biologic (stool) specimens 
4. The participant is lost to follow-up 
 
The participants will be instructed at enrollment to stop the study medication for any of 
the following reasons (although they will still be instructed to answer their 
questionnaires and submit biologic [stool] specimens as scheduled): 
1. Antibiotics or BSS (either provided by the study personnel for TD treatment, or 
taken as an over-the-counter remedy) are taken for TD or for another medical 
condition 
2. Any severe adverse events as described, such as signs and symptoms of 
salicylism or neurotoxicity, occur 
3. Hospitalization for any reason 
 
Barring the reasons listed above, the study medication should be taken throughout the 
trip duration, even if diarrhea occurs, if possible. 
 
 
 
Criteria for Removal from the Study 
 
Participants will be removed from the study when any of the following criteria apply: 
1. Do not complete the pre-travel questionnaire (see Definitions for compliance) 
2. Loss to follow-up (see Definitions) 
3. Voluntary withdrawal of consent by the participant for any purpose at any time 
4. Pregnancy 
5. Death 


32 
 
6. Co-PIs decide to remove a participant because of safety or integrity of the study 
 
In the event of removal for reason #6 above, participants will still be compensated for 
their participation in the study (see Description and Justification of Compensation).  
 
The date and reason for removal will be documented in the study records.  
 
 
 
Training for Study Personnel  
All study personnel at the The New York Center for Travel and Tropical Medicine clinic 
will be trained in screening potential participants, questionnaire administration, and 
data collection. They will also be trained in appropriate informed consent practices. 
Laboratory study personnel at CDC’s Clinical and Environmental Microbiology Branch 
will also be trained in the handling, preparation, storage, and testing of biologic (stool) 
specimens.  
 
We do not anticipate inter-observer differences due to the structured and closed-ended 
format of the questionnaires and the standardization of biologic (stool) specimen 
collection and testing. 
 
 
Data Handling and Analysis 
 
 
 
Data Collection  
Data from the screening questionnaire and pre-travel questionnaire will be collected on 
paper and put into REDCap by Dr. Connor’s team. Data from the during travel and post-
travel questionnaires will be collected electronically (web-based). Red Cap’s electronic 
app (web-based) will be used to collect daily questionnaire data during travel, with an 
option to have a paper-based form if the participant prefers. Participants will be notified 
during consent that they should only agree to use web-based data collection during 
travel if they can reasonably assume that they will have reliable daily internet access; if 
not, they will be offered paper copies with coded labels. All data collected (either web-
based or paper based) will be coded and will be entered and maintained in an electronic 
database and stored on a secure server by study personnel at The New York Center for 
Travel and Tropical Medicine clinic. 


33 
 
 
 
 
Biologic (Stool) Specimen Collection and Testing 
Most biologic (stool) specimens will be self-collected by the participant using the DNA 
Genotek OMNIgene gut kit that will be provided to them at their pre-travel 
consultation/enrollment visit (each participant will receive 2 kits; one for a pre-travel 
biologic (stool) specimen and the other for the post-travel biologic [stool] specimen). 
Each kit includes detailed instructions on collection. All biologic [stool] specimens 
collected at home will be submitted by mail (postage pre-paid) to the travel clinic. The 
OMNIgene kits are stable at ambient temperatures for long periods of time and 
designed for home collection and postal return. Specimens will be mailed from the 
travel clinic to the CDC’s Clinical and Environmental Microbiology Branch in batches. 
Biologic (stool) specimens will be stored at ambient temperature until DNA extraction.  
 
For those participants able to provide a biologic (stool) sample during their pre-travel 
clinic consultation/enrollment visit or during a non-study post-travel follow-up sick visit 
within 10 days of return, study personnel at The New York Center for Travel and Tropical 
Medicine will aliquot the specimens (see Laboratory Instruments).  
 
All biologic (stool) specimen results will be securely shared through password protected, 
coded data files. The Clinical and Environmental Microbiology Branch Branch will receive 
and share only coded information with the co-PIs (see Provision for Protecting 
Privacy/Confidentiality).  
 
The following analyses will be performed on biologic (stool) specimens collected using 
the OMNIgene gut kit.  
1. DNA extraction from single aliquots of stool 
2. Highly multiplexed PCR assay detecting over 500 different antimicrobial 
resistance (AMR) genes will be used to test the extracted DNA  
3. Amplicons produced by the panel will be sequenced on an Illumina MiSeq 
 
Remaining biologic (stool) specimens and extracted DNA will be stored at CDC in the 
Clinical and Environmental Microbiology Branch indefinitely for potential further use. 
Stools collected at the clinic and aliquoted for freezing will be stored for potential 


34 
 
further use in analyses that are yet to be determined. Consent for storage of specimens 
for future research use will be obtained from participants. 
 
 
 
Provision for Protecting Privacy/Confidentiality 
The identity of all study participants will be protected. All questionnaires will be coded 
using study and group IDs and participants will each be given a unique study ID and 
group ID. The unique study ID will include a site letter designation of “T”, year, and 
participant number (provided numerically from 1 to 10,000). For example, the unique 
identifier for the first participant would be: T2017-00001. The group ID will begin with 
“G” and group number (provided numerically from 1 to 10,000). Those participants who 
are travel companions and have identical itineraries to other participants in the study 
and anticipate performing the same activities, (including family and friends), are given 
the same group number. For example, the group ID for the first participant would be G-
00001. If they have a companion traveling with them, that participant would also be G-
00001.  
 
The original completed screening questionnaires and any original completed paper daily 
travel forms will be housed at the clinic in a secure location and destroyed per 
institutional guidelines.  
 
Biologic (stool) specimens submitted by the participant will be coded. Labels will be 
provided to the participants for labeling the specimens and will include the participant’s 
unique study ID and group ID. Specimens will be sent to the CDC Clinical and 
Environmental Microbiology Branch by the Center for Travel and Tropical Medicine for 
testing and storage.  
 
Labels will also be provided to participants for the paper copies of the during travel 
questionnaire to ensure confidentiality and to avoid mislabeling.  
 
The database will be password-protected and only study personnel at New York Center 
for Travel and Tropical Medicine clinic will have access to the password (and thus 
patient identifiers). No study personnel from CDC will have access to participant 
identifying information. Identifying information will be stored in a secure, passcode 


35 
 
protected file on a password protected computer and server. This file will be destroyed 
upon completion of the study.   
 
 
 
Information Management and Analysis Software 
 
 
 
Data will be managed securely in REDCap.  
SAS v9.4 will be used for analysis.  
 
 
 
Data Entry, Editing and Management, and Data Storage 
The New York Center for Travel and Tropical Medicine clinic will be responsible for 
managing the questionnaire data in REDCap. The data will belong to The New York 
Center for Travel and Tropical Medicine, will be responsible, in collaboration with 
partners, for the reporting of findings. Data (questionnaires) done on paper will be 
stored confidentially at the clinic site and electronic data will be stored confidentially on 
the REDCap server (see Provision for Protecting Privacy/Confidentiality). The New York 
Center for Travel and Tropical Medicine clinic will have full access rights and CDC will 
have access to data (all de-identified) only with the approval of Dr. Connor and his team. 
 
Coded laboratory data in a password-protected database, using the participant’s unique 
ID, will be sent from the laboratory to the New York Center for Travel and Tropical 
Medicine for input into REDCap.  
 
 
 
Quality Control and Assurance 
Data quality will be controlled by input of data from screening questionnaires and paper 
copies of the during travel questionnaires into REDCap by one or two trained personnel 
at The New York Center for Travel and Tropical Medicine. We will place all data, exactly 
as received into the database. Data from the web-based questionnaires will be input 
directly into the REDCap database. Data will not be altered in any way.  
 
Laboratory quality control will be performed by the study laboratorians to ensure that 
all specimens are tested with appropriate controls as necessary and applicable. 
 


36 
 
Every 3 months, data entered into REDCap will be checked for completeness and 
accuracy by the co-PIs (CDC would only access coded data) and/or study personnel; 
interim data analysis will be performed every 3 months as desired.   
 
 
 
Bias in Data Collection, Measurement, and Analysis 
Double-blinded randomization will control for the introduction of selection bias or 
observer bias in the study; the participants and the healthcare providers will not know 
which arm of the study the participant is assigned to. However, our inclusion criteria 
necessitate the exclusion of travelers with chronic gastrointestinal diseases or travelers 
on certain medications, possibly creating an exclusion bias. These biases will be 
addressed in the limitations section of the manuscript. Participants may also introduce 
recall bias during the pre- and post-travel questionnaires. Reporting bias will be 
minimized by limiting P&G’s involvement with any aspects of the study design, 
implementation, or analysis.   
 
 
 
Study Limitations 
As mentioned, a study limitation is the possible incorporation of exclusion bias by 
excluding travelers with certain chronic medical conditions and those who take certain 
medications. This will lead to a need to caveat the results of our study to a particular 
population if the intervention disproves the null hypotheses.  
 
An additional limitation is the inability to collect biologic (stool) samples from 
participants while abroad in the event that they acquire TD. The collection and sending 
of biologic (stool) specimens over country borders is complicated and impedes us from 
collecting real-time potentially infectious specimens to assess the secondary objective 
— the direct relation between an episode of TD and the acquisition of gut AMR genes.   
 
Participants in the intervention arm of the study may experience side effects of BSS 
(dark stool and dark discoloration of the mouth) due to oxidization of the bismuth 
component of the drug. Those in the placebo arm will likely not experience such effects, 
and the appearance of these effects may cause participants to suspect they were 
randomized into the intervention arm. Knowledge or suspicion of a participant’s own 
study arm could influence responses to the questionnaire questions. 


37 
 
 
The results from this study may not be generalizable to all international travelers. This is 
due to various host factors beyond the study’s control and also due to the exclusion of 
travelers going to regions outside of Asia and Africa. Participants are being recruited 
from those who are seeking specialized pre-travel medical advice. Not all travelers to 
the targeted regions seek this care, and travelers who seek pre-travel care may be more 
likely to comply with safe food/water recommendations. However, by focusing the 
study on a population of travelers that are visiting places with a high prevalence of TD, 
the study objectives are likely to be met quickly.  
 
 
The laboratory assays also have limitations. The multiplex PCR assay detecting AMR 
genes will not provide any information regarding the organism of origin for the genes 
detected, including whether or not two or more genes originated from the same 
organism or if multiple organisms harbor the same resistance gene. This assay is only 
capable of detecting genes for which primers are included in the assay. However, the 
assay currently includes more than 500 targets and can be expanded to include 
additional targets of interest to study stakeholders. Also, many of the primers on this 
panel will readily amplify closely related gene variants even if a specific primer pair is 
not present, e.g. a tetX primer pair may amplify a tetA gene. Finally, the presence of a 
specific gene product does not guarantee the gene itself is expressed as functional 
antimicrobial resistance. 
 
An additional limitation is that culture cannot be obtained from most biologic (stool) 
samples, making it difficult to answer future questions that involve assigning AMRs to 
particular organisms, unless there are further advances in sequencing/bioinformatic 
technology. Without a pre-screening step like the highly multiplexed PCR assay 
suggested, the scope of the study will have to be significantly limited to a few AMR gene 
groups because the real time isolation and testing of samples as they are collected is 
labor intensive and cannot include the breadth of targets possible with molecular 
testing. 
 
 
 
Response to New or Unexpected Findings and Changes in the Study Environment 


38 
 
If a new or unexpected finding is identified, the co-PIs and collaborating partners will be 
alerted immediately. Depending on the scope and potential morbidity associated with 
this finding, appropriate action will be taken.   
 
Additionally, an incident report will be filed as required by the reviewing IRB if there is 
an unexpected violation of study procedures or expectations or if unanticipated 
problems or adverse events are identified.  
 
If deemed necessary by the IRB, we would consider using a Study Data Safety 
Monitoring Board to analyze the data and stop the study early in the event there are 
serious adverse outcomes that are significantly higher in the placebo or intervention 
arm. However, due to the relative safety of BSS, we do not anticipate this will be 
necessary. 
 
Due to the number of participants that will need to be enrolled in this study to achieve 
adequate power, there is the possibility that this study may extend beyond the current 
study timeline. Although we do not anticipate difficulty enrolling participants, we want 
be prepared for any unanticipated issues with enrollment. In the event that 488 
participants are not enrolled at two years, an interim analysis will be performed and 
additional funding will be requested to continue the project until adequate power is 
achieved.  
 
 
 
Identifying, Managing, and Reporting Adverse Events 
 
 
 
Adverse events in this study may include, but are not limited to, the following: 
1. Medication side effects, such as constipation, tinnitus, or dizziness  
2. Medication adverse events, such as neurologic findings from salicylate 
toxicity (confusion, slurred speech, drowsiness, muscle weakness, 
headache, mental depression) or severe stomach pain, increased sweating, 
or increased thirst 
 
All participants will be asked about adverse events on each of the study questionnaires, 
including the daily questionnaire while traveling. If the participant experiences an 


39 
 
adverse event while abroad, they are to stop the study medication and contact the 
study personnel to report the symptoms and obtain advice.  
 
  
 
Notifying Participants of their Individual Results 
Participants will not be notified of their study results, since the results will not impact 
their healthcare.  
  
 
 
Disseminating Information to the Public 
The results from this study will be published in a peer-reviewed journal, however, the 
initial release may be in the form of an abstract for a scientific meeting.  
 
Preliminary study findings will be shared with P&G after the data analysis phase is 
complete.  
 
 
 
 
 


40 
 
Budget Estimates  
Table 4. CLINIC events with estimated costs (primary objective) 
NOTE: Table 4 costs are for 500 participants 
                                                    Stages
Pre-travel consultation/
enrollment visit 
(baseline) 
During travel
Post-travel
TOTAL 
Recruitment materials
$200
N/A
N/A
$200
Printing costs (screening 
questionnaire, daily travel 
logs, labels)  
$50
$150
N/Aa
$200
Participant compensation
$100 per participant
 
up to $100 per 
participant 
($5 per entry) 
$100 per 
participant 
 
$150,000
Advertising 
$1,500
N/A
N/A
$1,500
IRB Costs  
$3,000
N/A
N/A
$3,000
Prepaid envelopes for 
during-travel 
questionnaires 
N/A
$1,000 ($2.00 stamp)
N/A
$1,000
Shipment of study 
medications from CDC to 
clinic 
$10,000
N/A
N/A
$10,000
Administrative 
Personnel Costs: Physician 
PI (5%) plus study 
coordinator (40%) 
Recruitment/enrollment, 
documentation and 
completion of study forms 
and participant and data 
follow up 
$110,000
 
N/A
N/A
$110,000
 
Travel (conferences)
N/A
N/A
$20,000
$20,000


41 
 
TOTAL
$295,900
aNot applicable 
 
Table 5. LABORATORY events with estimated costs  
                                                    Stages
Pre-travel 
consultation/enrollment 
visit (baseline) 
During travel
Post-travel 
TOTAL
 
Supplies for stool sample 
(OMNIgene gut kit)  
(n=1,000 stools or 500 participants) 
$25
N/A
$25
$25,000
Shipping stool sample to the clinic 
(n=1,000 stools or 500 participants) 
$10 per sample
N/A
$10 per 
sample 
$10,000
Shipping stool samples to CDC lab 
from clinic 
 (n=1,000 stools or 500 participants) 
$15 per sample
N/A
$15 per 
sample 
$15,000
Diagnostic testing of stool 
(n=500 stools or 250 participants) 
             DNA extraction 
             PCR (AMR gene assay) 
             Amplicon sequencing 
 
$15 
$35 
$25 
 
N/A 
N/A 
N/A 
 
$15 
$35 
$25 
 
$7,500 
$17,500 
$12,500 
Laboratorian (ORISE)
$28,000
N/A
N/A
$28,000
Bioinformatics (ORISE)
$66,000
N/A
N/A
$66,000
TOTAL
$181,500
 
Table 6. Cumulative costs of both CLINIC and LABORATORY events from Table 4 and Table 5 
Cumulative totals 
Total
Clinic Events 
$295,900
Laboratory Events
$181,500
$477,400 
 
 


42 
 
References 
1. Connor B. Travelers’ diarrhea. In Yellow Book (pp. 60–64). New York, NY: Oxford University Press; 2016.    
2. Brum J, Gibb R, Ramsey D, Balan G, Yacyshyn B. Meta-analyses assessment of the clinical efficacy of 
bismuth subsalicylate for prevention and treatment of infectious diarrhea. [not yet published] 
3. DuPont HL, Ericsson CD, Johnson PC, de la Calabra. Use of bismuth subsalicylate for the prevention of 
travelers’ diarrhea. Rev Infect Dis, 1990; Suppl 1:S67–67. 
4. DuPont HL, Ericsson CD, Johnson PC, Bitsura JM, DuPont MW, de la Cabada FJ. Prevention of travelers’ 
diarrhea by tablet formulation of bismuth subsalicylate. JAMA, 1987; 257(10):1347–1350. 
5. Steffen R, DuPont HL, Huesser R, Helminger A, Witassek F, Manhart MD, Schär M. Prevention of 
travelers’ diarrhea by the tablet form of bismuth subsalicylate. Antimicrob Agents Chemother, 1986; 
29:625–629. 
6. Graham DY, Estes MK, Gentry LO. Double-blind comparison of bismuth subsalicylate and placebo in the 
prevention and treatment of enterotoxigenic Escherichia coli-induced diarrhea in volunteers. 
Gastroenterology, 1983; 85(5):1017–1022. 
7. Reynolds PT, Abalos KC, Hopp J, Williams ME. Bismuth toxicity: a rare cause of neurologic dysfunction. 
Int J Clin Med, 2012; 3:46–48. 
8. Gordon MF, Abrams RI, Rubin DB, Barr WB, Correa DD. Bismuth subsalicylate toxicity as a cause of 
prolonged encephalopathy with myoclonus. Mov Disord, 1995; 10(2):220–222. 
9. Pitz AM, Park GW, Lee D, Boissy YL, Vinjé J. Antimicrobial activity of bismuth subsalicylate on Clostridium 
difficile, Escherichia coli O157:H7, norovirus, and other common enteric pathogens. Gut Microbes, 2015; 
6(2):93–100. 
10. Manhart MD. In vitro antimicrobial activity of bismuth subsalicylate and other bismuth salts. Rev Infect 
Dis, 1990; 21 Suppl 1, S11–15. 
11. Sox TE, Olson CA. Binding and killing of bacteria by bismuth subsalicylate. Antimicrob Agents Chemother, 
1989; 33(12):2075–2082. 
12. Ericsson CD, Evans DG, DuPont HL, Evans DJ Jr, Pickering LK. Bismuth subsalicylate inhibits activity of 
crude toxins of Escherichia coli and Vibrio cholerae. J Infect Dis, 1977; 136(5):693–696. 
13. Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States, 2013. 
Available at: https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf  Accessed 22 March 
2017. 
14. Hassing RJ, Alsma J, Arcilla MS, van Genderen PJ, Stricker BH, Verbon A. International travel and 
acquisition of multidrug-resistant Enterobacteriaceae: a systematic review. Euro Surveill, 2015; 20(47).   


43 
 
15. Ruppé E, Armand-Lefevre L, Estellat C, Consigny PH, El Mniai A, Boussadia Y, Goujon C, Ralaimazava P, 
Campa P, Girard PM, Wyplosz B, Vittecog D, Bouchard O, Le Loup G, Pialoux G, Perrier M, Wieder I, 
Moussa N, Esposito-Farèse M, Hoffmann I, Coignard B, Lucet JC, Andremont A, Matheron S. High rate of 
acquisition but short duration of carriage of multidrug-resistant Enterobacteriacae after travel to the 
tropics. Clin Infect Dis, 2015; 61(4):593–600. 
16. Angue M, Allou N, Belmonte O, Lefort Y, Lugagne N, Vandroux D, Montravers P, Allyn J. Risk factors for 
colonization with multidrug-resistant bacteria among patients admitted to the intensive care unit after 
returning from abroad. J Travel Med, 2015; 22(5): 300–305. 
17. Epelboin L, Robert J, Tsyrina-Kouyoumdjian E, Laouira S, Meyssonnier V, caumes E. High rate of 
multidrug-resistant gram-negative bacilli carriage and infection in hospitalized returning travelers: a 
cross-sectional cohort study. J Travel Med, 2015; 22(5): 292–299. 
18. Arcilla MS, van Hattem JM, Haverkate MR, et al. Import and spread of extended-spectrum β-lactamase-
producing Enterobacteriaceae by international travellers (COMBAT study): a prospective, multicentre 
cohort study. Lancet Infect Dis, 2017; 17(1): 78-85. 
19. Kantele A. A call to restrict prescribing antibiotics for travellers' diarrhea — Travel medicine practitioners 
can play an active role in preventing the spread of antimicrobial resistance. Trav Med Infect Dis, 2015; 
13(3): 213. 
20. Bowen A, Agboatwalla M, Pitz AM, Brum J, Plikaytis B. Bismuth subsalicylate reduces antimicrobial 
medication use among adult diarrhea outpatients in Pakistan: a randomized, placebo-controlled, triple-
masked clinical trial. ASTMH 65th Annual Meeting. Atlanta, Georgia, 2016.  
21. World Tourism Organization. UNWTO tourism highlights: 2014 edition. Available at: 
http://mkt.unwto.org/publication/unwto-tourism-highlights-2014-edition. Accessed 9 March 2017. 
22. World Health Organization. Antimicrobial Resistance Global Report on Surveillance. 2014. Available at: 
http://apps.who.int/iris/bitstream/10665/112642/1/9789241564748_eng.pdf. Accessed 15 March 
2017.  
23. Hassing RJ, Alsma J, Arcilla MS, van Genderen PJ, Stricker BH, Verbon A. International travel and 
acquisition of multidrug-resistant Enterobacteriaceae: a systematic review. Euro Surv, 2015; 20(47).  
24. Von Wintersdorff CJH, Penders J, Stobberingh EE, et al. High rates of antimicrobial drug resistance gene 
acquisition after international travel, the Netherlands. Emerg Infect Dis, 2014; 20(4):649–657. 
25. Connor BA. Sequelae of traveler’s diarrhea: focus on post-infectious irritable bowel syndrome. Clin Infect 
Dis, 2005; 41(8): S577–586.             
26. Bierer DW, Bismuth subsalicylate: history, chemistry, and safety. Rev Infect Dis, 1990; 12(1):3–8. 


44 
 
27. Ericsson CD, Feldman S, Pickering LK, Cleary TG. Influence of subsalicylate bismuth on absorption of 
doxycycline. JAMA, 1982; 247(16):2266–2267. 
 
 
 
 
 
 
 
 


45 
 
Appendices 
APPENDIX A: Screening Questionnaire 
 
Screening Questionnaire 
Script [read to all travelers]: Hello, my name is [name] and I am a [role in the clinic] at The New York 
Center for Travel and Tropical Medicine. We are conducting a study of international travelers to see if 
bismuth subsalicylate (or BSS) can help to prevent travelers’ diarrhea. Participation in this 
questionnaire to see if you are eligible is voluntary, and it will only take a moment of your time. We will 
be collecting your email address, so in the event that you are eligible to participate, we can send you 
the study questionnaires and reminder emails; your email will only be used for study purposes. Are you 
interested in seeing if you are eligible to participate?    
 
 
 
  □ YES       □ NO   
[If “yes”, please complete the following with the traveler]:  
Participant’s Initials 
 
Date  
 
Age 
 
 
 Participant Email (REQUIRED): ________________________________________________________________ 
 Participant Phone #1 (OPTIONAL): _______________ Participant Phone #2 (OPTIONAL):________________ 
 
1. Are you ≥ 18 years of age and <70 years of age? 
 
 
 Yes*  
 
 
 No  
  
 
 Don’t know 
 
2. Are you traveling to either South East Asia, South Central Asia, North Africa, or Sub-Saharan Africa? 
 
 
 Yes*  
 
 
 No  
  
 
 Don’t know 
 
3. Are you spending at least 7 days and no more than 21 days in these regions? 
 
 Yes*  
 
 
 No  
  
 
 Don’t know 
4. Are you leaving for your trip in at least 7 days? 
 
 
 Yes*  
 
 
 No  
  
 
 Don’t know 
 
5. Are you now pregnant or nursing or do you plan to get pregnant before the end of your trip? 
 
 
 Yes  
 
 
 No*  
  
 
 Don’t know 


46 
 
6. Do you have known or suspected allergy to bismuth, salicylate, or aspirin? 
 
 
 Yes  
 
 
 No*  
  
 
 Don’t know 
 
7. Do you have known or suspected allergy to microcrystal cellulose, calcium carbonate, artificial coloring, 
magnesium, mannitol, povidone, saccharin, or talc? 
 
 
 Yes  
 
 
 No*  
  
 
 Don’t know 
 
8. Do you have kidney disease, diabetes, gout, or a clotting disorder? 
 
 
 Yes  
 
 
 No*  
  
 
 Don’t know 
 
9. Have you taken an antibiotic in the past 30 days? For example: 
• 
Doxycycline or minocycline 
• 
Flagyl, cotrimoxazole (e.g., Bactrim, Septra) 
• 
Penicillins (e.g., amoxicillin, Augmentin) 
• 
Cephalosporins (e.g., Keflex)  
• 
Fluoroquinolones (e.g., ciprofloxacin) 
• 
Macrolides (e.g., azithromycin [Zithromax], erythromycin) 
 
 
 
 Yes  
 
 
 No*  
  
 
 Don’t know 
 
10. Do you take any of the following medications or therapies?  
• 
Chronic oral or intravenous IV steroids (e.g., hydrocortisone or prednisone); not inhaled 
steroids 
• 
Alkylating agents (e.g., cyclophosphamide [Cytoxan]) 
• 
Antimetabolites (e.g., azathioprine [Imuran], 6-mercaptopurine [Purinethol]) 
• 
Chemotherapeutic agents (e.g., including methotrexate [Trexall]) 
• 
Tumor necrosis factor (TNF) blockers (e.g., etanercept [Enbrel], adalimumab [Humira], 
certolizumabpegol [Entyvio], golimumab [Simponi], and infliximab [Remicade]) 
• 
Monoclonal antibodies (e.g., rituximab [Rituxan] or alemtuzumab [Lemtrada]) 
• 
Insulin (e.g., Humalog, NPH, Lantus, Levemir) 
• 
Valproic acid (e.g., divalproex, Depakote, Depacon) 
• 
ACE-inhibitors (e.g., lisinopril [Zestril], enalapril [Vasotec], captopril [Capoten], ramipril 
[Altase], benazepril [Lotensin]) 
• 
Anticoagulants (e.g., warfarin [Coumadin], aspirin, clopidogrel [Plavix], argatroban 
[Acova], bivalirudin [Angiomax], dabigatran [Pradaxa]) 
 
 
 Yes  
 
 
 No*  
  
 
 Don’t know 
 
11. Do you have any of the following chronic stomach or intestinal illnesses? 
• 
Irritable bowel syndrome (IBS) 
• 
Inflammatory bowel disease (including ulcerative colitis and Crohn’s disease) 
• 
Celiac disease; any form of chronic diarrhea or chronic abdominal pain; 
• 
Pancreatic insufficiency 
• 
Gallbladder disease 
• 
Malabsorption syndromes 
• 
Gastrointestinal malignancy/cancer currently receiving chemo; radio, or immunotherapy 
• 
Chronic diarrhea from another cause 


47 
 
 
 
 Yes  
 
 
 No*  
  
 
 Don’t know 
12. Do you have any illnesses that you have been told lowers your body’s ability to fight infection? 
• 
Missing or non-functioning spleen 
• 
Insulin-dependent diabetes mellitus 
• 
Diabetes mellitus receiving oral hypoglycemic medications (e.g. metformin, glyburide) 
• 
HIV/AIDS 
• 
Other immunodeficiency syndrome (e.g. complement deficiency, antibody or immunoglobulin 
deficiency) 
• 
Malignancy or cancer under active chemo, radio, or immunotherapy; or any other 
immunocompromising condition? 
 
 
 Yes  
 
 
 No*  
  
 
 Don’t know 
13. Have you ever received a solid organ transplant? 
 
 
 Yes  
 
 
 No*  
  
 
 Don’t know 
 
14. Have you had diarrhea (3 or more unformed stools in 24 hours) in the 30 days before enrollment or do 
you currently have diarrhea?  
 
 
 Yes  
 
 
 No*  
  
 
 Don’t know 
*Must answer “Yes” to questions 1, 2, 3, AND 4 and “No” to all subsequent to be eligible for enrollment. 
 Eligible per Appx A 
 Not Eligible per Appx A 
Comments: 
By signing below, I confirm that I conducted the verbal screening and have reviewed the answers before 
proceeding with additional study activities: 
Name of Interviewer
Signature
Date
If eligible, collect the following: 
Participant First Name: ________________________ 
Participant Last Name: ____________________ 
State of Residence: _____________ County of Residence: _____________________ 
Residence Zip Code: ____________ 
 
 
Generation of Study ID and Group ID: 
UNIQUE STUDY ID: 
The unique study ID will include a site letter designation of “T”, year, and participant number (provided 
numerically from 1 to 10,000).  
*For example, the unique identifier for the first participant would be: T2017-00001.  
GROUP ID: 
The group ID will begin with “G” and a group number (provided numerically from 1 to 10,000). Those 
participants who are travel companions and have identical itineraries to other participants in the study 


48 
 
and anticipate performing the same activities, (including family and friends), are given the same 
number. 
*For example, the group ID for the first participant would be G-00001. Their mother, traveling 
with them, would also be G-00001.  
Study ID Number 
 
 
 
 


49 
 
APPENDIX B: Country Listing for Inclusion 
South East Asia 
Cambodia 
Laos
West Malaysia (excluding Malaysian Borneo)
Myanmar (Burma)
Thailand
Vietnam
 
South Central Asia 
Afghanistan 
Bangladesh 
Bhutan
India
Maldives
Nepal
Pakistan
Sri Lanka
 
North Africa 
Algeria
Egypt
Libya
Morocco
Sudan
Tunisia
 
Sub-Saharan Africa (Does NOT include the country of SOUTH AFRICA) 
Angola
Congo
Guinea-Bissou
Mozambique
Sierra Leone
Benin
Democratic Republic 
of the Congo 
Kenya
Namibia
Somalia
Botswana 
Côte d’ Ivoire
Lesotho
Niger
South Sudan
Burkina Faso 
Djibouti
Liberia
Nigeria
Swaziland
Burundi
Equatorial Guinea
Madagascar
Reunion
United Republic of 
Tanzania 
Cameroon 
Eritrea
Malawi
Rwanda
The Gambia
Cabo (Cape) Verde
Ethiopia
Mali
Saint Helena
Togo
Central African 
Republic 
Gabon
Mauritania
São Tomé and 
Príncipe 
Uganda
Chad
Ghana
Mauritius
Senegal
Zambia
Comoros
Guinea
Mayotte
Seychelles
Zimbabwe


50 
 
APPENDIX C: Pre-travel Questionnaire 
 
Pre-travel Questionnaire  
 
     
 
 
 
 
 
             PARTICIPANT UNIQUE ID:_________________ 
 
 
 
 
 
 
 
GROUP ID: _____________________________ 
 
[Please review the screening questionnaire with the participant.] 
Have there been any changes to the screening questionnaire making the participant ineligible to participate? 
a. Yes 
b. No 
 
If yes, please describe: 
___________________________________________________________________________________________ 
 
Demographics 
Age (in years): ________________ 
Sex (M/F): _____________                                                       
Race:       
a. White or Caucasian 
b. Black or African American 
c. American Indian or Alaskan native 
d. Asian or Pacific Islander 
e. Other (please specify) ______________________________ 
f. Don’t know 
g. I would rather not answer 
 
Ethnicity: 
a. Hispanic  
b. Non-Hispanic  
 
Medical History 
2. Do you have any medical conditions or illnesses? 
a. Yes 
b. No 
c. Don’t know 
d. I would rather not answer 
 
If yes to question 1, please list them all.  
 
___________________________________________________________________________________________ 
 


51 
 
___________________________________________________________________________________________ 
 
3. Do you have recurrent or persistent tinnitus (ringing in the ears)? 
a. Yes 
b. No 
c. Don’t know 
d. I would rather not answer 
 
4. Do you take any medications on a regular basis? 
a. Yes 
b. No 
c. Don’t know 
d. I would rather not answer 
 
If Yes to question 3, please list them all:  
1.
4.
2.
5.
3.
6.
 
5. Have you taken any oral or intravenous (IV) antibiotics in the past 90 days for any reason (e.g., 
azithromycin [Zithro-max], ciprofloxacin [Cipro], rifaximin [Xifaxan], doxycycline or minocycline, 
metronidazole [Flagyl], cotrimoxazole [Bactrim or Septra], penicillins [e.g., amoxicillin or Augmentin], or 
cephalosporins [e.g., Keflex])? 
a. Yes 
b. No  
c. Don’t know 
d. I would rather not answer 
 
If yes to question 4, please give the antibiotic name, start date, duration, and illness taken for: 
No. 
Antibiotic Name
Start Date
(MM/DD/YYYY) 
Duration 
(Days) 
Illness taken for
1
2
3
4
5
6
 
6. In the past 30 days, have you taken a probiotic? - 
Probiotics are live microorganisms (such as certain types of bacteria) that may benefit the health of the 
person consuming them. Yogurts and other fermented dairy products are probiotics. Probiotics can also take 
the form of capsules, pills, or powders. Probiotics also include any foods or drinks labeled as containing “live 
and active cultures” or “probiotics.” 
a. Yes 


52 
 
b. No 
c. Don’t know 
d. I would rather not answer 
 
Travel History 
7. Have you traveled internationally in the past 90 days?  
a. Yes 
b. No 
c. Don’t know 
d. I would rather not answer 
 
If yes to question 6, which countries did you travel to and what were your dates of travel? If the exact 
dates of travel are unknown, please list the month and year only. 
Country name 
Dates of travel 
(MM/DD/YY to 
MM/DD/YY) 
1.
__/__/__ to __/__/__
 Unknown 
2.
__/__/__ to __/__/__
 Unknown 
3.
__/__/__ to __/__/__
 Unknown 
4.
__/__/__ to __/__/__
 Unknown 
5.
__/__/__ to __/__/__
 Unknown 
6.
__/__/__ to __/__/__
 Unknown 
 
  
8. Where are you planning to travel? Please specify each country name, the specific locations you plan to 
visit, and the number of days you plan to spend in each country.  
Country name 
Specific location(s) to be visited
(e.g., city/town, attraction) 
Number of days in 
this country 
1.
            
2.
3.


53 
 
4.
5.
6.
 
9. What is the total duration of your trip (in days)? 
__________________________________ 
 
10. What is your main reason for travel (circle only one)? 
a. Education or research (includes medical or veterinary-type education) 
b. Adoption 
c. Business 
d. Leisure/tourism 
e. Immigrant traveling back to visit friends or relatives 
f. Providing medical care as a health professional (including paid or unpaid/volunteer) 
g. Receiving medical care (as a patient) 
h. Non-medical service or volunteer work 
i. 
Missionary work 
j. 
Military service 
k. Attending large gathering or event (e.g., large sporting event, large conference, Hajj) 
l. 
Adventuring (extreme mountaineering, water sports, outdoor activities, etc.) 
m. Other: 
_____________________________________________________________________ 
n. I would rather not answer 
 
11. What are the secondary reasons for travel (circle all that apply)? 
a. Education or research (includes medical or veterinary-type education) 
b. Adoption 
c. Business 
d. Leisure/tourism 
e. Returning to region of origin of self or family to visit friends and relatives 
f. Providing medical care as a health professional (including paid or unpaid/volunteer) 
g. Receiving medical care (as a patient) 
h. Non-medical service or volunteer work 
i. 
Missionary work 
j. 
Military service 
k. Attending large gathering or event (e.g., large sporting event, large conference, Hajj) 
l. 
Adventuring (extreme mountaineering, water sports, outdoor activities, etc.) 
m. Other:  
_____________________________________________________________________ 
n. I would rather not answer 
 
 
This survey is now completed.  


54 
 
Thank you very much for your time.  
 


55 
 
APPENDIX D: During-travel Questionnaire 
During Travel Questionnaire 
PARTICIPANT UNIQUE ID:_________________ 
GROUP ID: _____________________________ 
Day 1
Day 2
Day 3
Day 4
Day 5
Please write the calendar date that corresponds to each day of your trip. 
Day 1 is your first day of arrival in the country. 
Number of tablets taken in the morning (maximum 4)
Number of tablets taken in the afternoon/evening (maximum 4)
Symptoms in the prior 24 hours (check off all that apply)
. . .
. . .
. . .
. . .
. . .
    Fever





    Nausea





    Vomiting





    Loose stools (less than three in a 24 hour period)





    Diarrhea (three or more loose stools in 24 hours)





    Bloody diarrhea





    Constipation





    Dark or black stool 





    Dark or black tongue 





    Abdominal pain





    Abdominal cramps 





    Urgency to relieve oneself (in reference to stool)





    Bloating





    Flatulence/gas





    Congestion/runny nose





    Sore throat





    Cough





    Rash





    Headache





    Dizziness 





    Ringing in your ears 





    Muscle pain/soreness 





    Joint pain/swelling/redness







56 
 
    Drowsiness (severe) 





    Confusion





    Depression





    Other (list/describe): 





Medical care
. . .
. . .
. . .
. . .
. . .
Did you seek medical care for one or more of these symptoms?    
(Yes/No/Don’t Know) 
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Y   N   D
 If yes, where? (check the corresponding box(es))
. . .
. . .
. . .
. . .
. . .
                                                   A doctor’s office
                                                   Urgent care clinic (outpatient)
                                                   Emergency room
                                                  Hospital outpatient clinic setting
                                                   Hospital inpatient ward – hospitalized
                                                   Other (specify)
 Was your diagnosis travelers’ diarrhea? 
(Yes/No/Don’t Know) 
Y   N   D
Y   N   D
Y   N   D
Y  N   D
Y   N   D
Have you started any medications in the past 24 hours?
(Yes/No/Don’t Know) 
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Y   N   D
 If yes, what medication(s)?
 Please circle those that were provided for you at 
your pre-travel consultation with the study clinic. 
. . .
. . .
. . .
. . .
. . .
What city(ies) and country(ies) have you been in during the past 24 hours?
Please write answers to all questions in the corresponding box. 
Have you eaten any of the following in the past 24 hours?
(Yes/No/Don’t Know) 
. . .
. . .
. . .
. . .
. . .
 Fermented or pickled foods (e.g., bean paste, fish 
kimchi, etc.)  
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Y   N   D
 Yogurt
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Did you have any diarrhea between completing the pre-travel 
questionnaire and arriving in the country? (Yes/No/Don’t Know) 
Y   N   D
. . .
. . .
. . .
. . .
Comments:


57 
 
PARTICIPANT UNIQUE ID:_________________ 
GROUP ID: _____________________________ 
Day 6
Day 7
Day 8
Day 9
Day 10
Please write the calendar date that corresponds to each day of your trip. 
Day 1 is your first day of arrival in the country. 
Number of tablets taken in the morning (maximum 4)
Number of tablets taken in the afternoon/evening (maximum 4)
Symptoms in the prior 24 hours (check off all that apply)
. . .
. . .
. . .
. . .
. . .
    Fever





    Nausea





    Vomiting





    Loose stools (less than three in a 24 hour period)





    Diarrhea (three or more loose stools in 24 hours)





    Bloody diarrhea





    Constipation





    Dark or black stool 





    Dark or black tongue 





    Abdominal pain





    Abdominal cramps 





    Urgency to relieve oneself (in reference to stool)





    Bloating





    Flatulence/gas





    Congestion/runny nose





    Sore throat





    Cough





    Rash





    Headache





    Dizziness 





    Ringing in your ears 





    Muscle pain/soreness 





    Joint pain/swelling/redness





    Drowsiness (severe) 





    Confusion





    Depression







58 
 
    Other (list/describe): 





Medical care
. . .
. . .
. . .
. . .
. . .
Did you seek medical care for one or more of these symptoms?   
(Yes/No/Don’t Know) 
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Y   N   D
 If yes, where? (check the corresponding box(es))
. . .
. . .
. . .
. . .
. . .
                                                   A doctor’s office
                                                   Urgent care clinic (outpatient)
                                                   Emergency room
                                                  Hospital outpatient clinic setting
                                                   Hospital inpatient ward – hospitalized
                                                   Other (specify)
 Was your diagnosis travelers’ diarrhea? 
(Yes/No/Don’t Know) 
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Have you started any medications in the past 24 hours?
(Yes/No/Don’t Know) 
Y  N   D
Y   N   D
Y   N   D
Y   N   D
Y   N   D
 If yes, what medication(s)?
 Please circle those that were provided for you at 
your pre-travel consultation with the study clinic. 
. . .
. . .
. . .
. . .
. . .
What city(ies) and country(ies) have you been in during the past 24 hours?
Please write answers to all questions in the corresponding box. 
 
 
 
Have you eaten any of the following in the past 24 hours?
(Yes/No/Don’t Know) 
. . .
. . .
. . .
. . .
. . .
 Fermented or pickled foods (e.g., bean paste, fish 
kimchi, etc.)  
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Y   N   D
 Yogurt
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Comments:


59 
 
PARTICIPANT UNIQUE ID:_________________ 
GROUP ID: _____________________________ 
Day 11
Day 12
Day 13
Day 14
Day 15
Please write the calendar date that corresponds to each day of your trip. 
Day 1 is your first day of arrival in the country. 
Number of tablets taken in the morning (maximum 4)
Number of tablets taken in the afternoon/evening (maximum 4)
Symptoms in the prior 24 hours (check off all that apply)
. . .
. . .
. . .
. . .
. . .
    Fever





    Nausea





    Vomiting





    Loose stools (less than three in a 24 hour period)





    Diarrhea (three or more loose stools in 24 hours)





    Bloody diarrhea





    Constipation





    Dark or black stool 





    Dark or black tongue 





    Abdominal pain





    Abdominal cramps 





    Urgency to relieve oneself (in reference to stool)





    Bloating





    Flatulence/gas





    Congestion/runny nose





    Sore throat





    Cough





    Rash





    Headache





    Dizziness 





    Ringing in your ears 





    Muscle pain/soreness 





    Joint pain/swelling/redness





    Drowsiness (severe) 





    Confusion





    Depression







60 
 
    Other (list/describe): 





Medical care
. . .
. . .
. . .
. . .
. . .
Did you seek medical care for one or more of these symptoms?       
(Yes/No/Don’t Know) 
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Y   N   D
 If yes, where? (check the corresponding box(es))
. . .
. . .
. . .
. . .
. . .
                                                   A doctor’s office
                                                   Urgent care clinic (outpatient)
                                                   Emergency room
                                                  Hospital outpatient clinic setting
                                                   Hospital inpatient ward – hospitalized
                                                   Other (specify)
 Was your diagnosis travelers’ diarrhea? 
(Yes/No/Don’t Know) 
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Have you started any medications in the past 24 hours?
(Yes/No/Don’t Know) 
Y  N   D
Y   N   D
Y   N   D
Y   N   D
Y   N   D
 If yes, what medication(s)?
 Please circle those that were provided for you at 
your pre-travel consultation with the study clinic. 
. . .
. . .
. . .
. . .
. . .
What city(ies) and country(ies) have you been in during the past 24 hours?
Please write answers to all questions in the corresponding box. 
 
 
 
Have you eaten any of the following in the past 24 hours?
(Yes/No/Don’t Know) 
. . .
. . .
. . .
. . .
. . .
 Fermented or pickled foods (e.g., bean paste, fish 
kimchi, etc.)  
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Y   N   D
 Yogurt
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Comments:


61 
 
PARTICIPANT UNIQUE ID:_________________ 
GROUP ID: _____________________________ 
Day 16
Day 17
Day 18
Day 19
Day 20
Please write the calendar date that corresponds to each day of your trip. 
Day 1 is your first day of arrival in the country. 
Number of tablets taken in the morning (maximum 4)
Number of tablets taken in the afternoon/evening (maximum 4)
Symptoms in the prior 24 hours (check off all that apply)
. . .
. . .
. . .
. . .
. . .
    Fever





    Nausea





    Vomiting





    Loose stools (less than three in a 24 hour period)





    Diarrhea (three or more loose stools in 24 hours)





    Bloody diarrhea





    Constipation





    Dark or black stool 





    Dark or black tongue 





    Abdominal pain





    Abdominal cramps 





    Urgency to relieve oneself (in reference to stool)





    Bloating





    Flatulence/gas





    Congestion/runny nose





    Sore throat





    Cough





    Rash





    Headache





    Dizziness 





    Ringing in your ears 





    Muscle pain/soreness 





    Joint pain/swelling/redness





    Drowsiness (severe) 





    Confusion





    Depression







62 
 
    Other (list/describe): 





Medical care
. . .
. . .
. . .
. . .
. . .
Did you seek medical care for one or more of these symptoms?   
(Yes/No/Don’t Know) 
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Y   N   D
 If yes, where? (check the corresponding box(es))
. . .
. . .
. . .
. . .
. . .
                                                   A doctor’s office
                                                   Urgent care clinic (outpatient)
                                                   Emergency room
                                                  Hospital outpatient clinic setting
                                                   Hospital inpatient ward – hospitalized
                                                   Other (specify)
 Was your diagnosis travelers’ diarrhea? 
(Yes/No/Don’t Know) 
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Have you started any medications in the past 24 hours?
(Yes/No/Don’t Know) 
Y  N   D
Y   N   D
Y   N   D
Y   N   D
Y   N   D
 If yes, what medication(s)?
 Please circle those that were provided for you at 
your pre-travel consultation with the study clinic. 
. . .
. . .
. . .
. . .
. . .
What city(ies) and country(ies) have you been in during the past 24 hours?
Please write answers to all questions in the corresponding box. 
 
 
 
Have you eaten any of the following in the past 24 hours?
(Yes/No/Don’t Know) 
. . .
. . .
. . .
. . .
. . .
 Fermented or pickled foods (e.g., bean paste, fish 
kimchi, etc.)  
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Y   N   D
 Yogurt
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Y   N   D
Comments:
 


63 
 
 
PARTICIPANT UNIQUE ID:_________________ 
GROUP ID: _____________________________ 
 
Day 21
Please write the calendar date that corresponds to each day of your trip. 
Day 1 is your first day of arrival in the country. 
Number of tablets taken in the morning (maximum 4)
Number of tablets taken in the afternoon/evening (maximum 4)
Symptoms in the prior 24 hours (check off all that apply)
. . .
    Fever

    Nausea

    Vomiting

    Loose stools (less than three in a 24 hour period)

    Diarrhea (three or more loose stools in 24 hours)

    Bloody diarrhea

    Constipation

    Dark or black stool 

    Dark or black tongue 

    Abdominal pain

    Abdominal cramps 

    Urgency to relieve oneself (in reference to stool)

    Bloating

    Flatulence/gas

    Congestion/runny nose

    Sore throat

    Cough

    Rash

    Headache

    Dizziness 

    Ringing in your ears 

    Muscle pain/soreness 

    Joint pain/swelling/redness



64 
 
    Drowsiness (severe) 

    Confusion

    Depression

    Other (list/describe): 

Medical care
. . .
Did you seek medical care for one or more of these symptoms?   
(Yes/No/Don’t Know) 
Y   N   D
 If yes, where? (check the corresponding box(es))
. . .
                                                   A doctor’s office
                                                   Urgent care clinic (outpatient)
                                                   Emergency room
                                                  Hospital outpatient clinic setting
                                                   Hospital inpatient ward – hospitalized
                                                   Other (specify)
 Was your diagnosis travelers’ diarrhea? 
(Yes/No/Don’t Know) 
Y   N   D
Have you started any medications in the past 24 hours?
(Yes/No/Don’t Know) 
Y   N   D
 If yes, what medication(s)?
 Please circle those that were provided for you at 
your pre-travel consultation with the study clinic. 
. . .
What city(ies) and country(ies) have you been in during the past 24 hours?
Please write answers to all questions in the corresponding box. 
 
 
Have you eaten any of the following in the past 24 hours?
(Yes/No/Don’t Know) 
. . .
 Fermented or pickled foods (e.g., bean paste, fish 
kimchi, etc.)  
Y   N   D
 Yogurt
Y   N   D
Comments:


65 
 
APPENDIX E: Post-travel Questionnaire 
 
Post-travel Questionnaire 
 
 
 
 
 
 
 
 
PARTICIPANT UNIQUE ID:_________________ 
GROUP ID: _____________________________ 
 
1. Have you had any of the following symptoms since returning home from your trip (circle all that 
apply)? 
 
Symptom
Duration (in days)
    Fever
    Nausea
    Vomiting
    Loose stools (less than three in a 24 hour period)
    Diarrhea (three or more loose stools in 24 hours)
    Bloody diarrhea
    Constipation
    Dark or black stool
    Dark or black tongue
    Abdominal pain
    Abdominal cramps
    Fecal urgency
    Bloating
    Flatulence/gas
    Congestion/runny nose
    Sore throat
    Cough
    Rash
    Headache
    Dizziness 
    Ringing in your ears
    Muscle pain/soreness
    Joint pain/swelling/redness
    Drowsiness (severe)
    Confusion
    Depression
    Other (list/describe):
    Don’t know
. . .
    I would rather not answer
. . .
 


66 
 
2. Did you start taking any of the following medications since you arrived home (circle all that apply)?  
 
a. Oral or intravenous (IV) antibiotics (e.g., azithromycin [Zithromax], ciprofloxacin [Cipro], 
rifaximin [Xifaxan], doxycycline or minocycline, metronidazole [Flagyl], cotrimoxazole [Bactrim or 
Septra], penicillins [e.g., amoxicillin, Augmentin], or cephalosporins [e.g., Keflex]) 
b. Antidiarrheals (e.g., bismuth subsalicylate [Pepto Bismol/Kaopectate]) 
c. Antimotility agents (e.g., loperamide [Imodium]) 
d. H2 blocker (e.g., ranitidine [Zantac], cimetidine [Tagamet], famotidine [Pepcid]) 
e. Proton pump inhibitor (e.g., omeprazole [Prilosec], pantoprazole [Protonix], lansoprazole 
[Prevacid], esomeprazole [Nexium]) 
f. Other antacids (e.g., calcium carbonate [Tums/Rolaids], Maalox/Mylanta) 
g. Probiotics (Yogurts and other fermented dairy products are probiotics. Probiotics can also take 
the form of capsules, pills, or powders. Probiotics also include any foods or drinks labeled as 
containing “live and active cultures” or “probiotics”) 
h. Oral or intravenous steroids (e.g., prednisone, hydrocortisone) 
i. 
Local/natural or herbal remedies (herbs, etc.) 
j. 
Other:  
_______________________________________________________________________________ 
 
 
3. Did you experience any of the following at any point during your travels? 
Symptom
(Yes/No/Don’t Know)
If yes, what was the 
duration (in days)? 
    Ringing in your ears
Y   N   D
    Constipation
Y   N   D
    Dark or black stool
Y   N   D
    Dark or black tongue
Y   N   D
    Drowsiness
Y   N   D
    Nausea
Y   N   D
    Vomiting
Y   N   D
    Rash
Y   N   D
    Other (list/describe):
 
4. Did you seek medical care for an illness since returning to the United States after your trip? 
a. Yes 
b. No 
c. Don’t know 
d. I would rather not answer  
 
If yes to question 4, where did you seek and receive care? 
a. A doctor’s office 
b. Urgent care clinic (outpatient) 
c. Emergency room 
d. Hospital outpatient clinical setting 
e. Hospital inpatient ward – hospitalized 
f. Other (please specify) 
______________________________________________________________________________ 
 
 
If yes to question 4, what was/were your diagnosis/es? 


67 
 
             
_____________________________________________________________________________________
_____________________________________________________________________________________ 
 
 
 
If yes to question 4, were you told that your illness was related to travel? 
a. Yes 
b. No 
c. Don’t know 
d. I would rather not answer  
 
If yes to question 4, were you told that you had travelers’ diarrhea? 
a. Yes 
b. No 
c. Don’t know 
d. I would rather not answer  
 
If yes to question 4, were you told that you had a bacteria that was resistant to antibiotics? 
a. Yes 
b. No 
c. Don’t know 
d. I would rather not answer  
 
5. Did you travel to any countries not discussed during your pre-travel visit? 
a. Yes 
b. No 
c. Don’t know 
d. I would rather not answer 
 
If yes to question 5, please list the new countries you visited, the location(s) visited, and the number 
of days in each country: 
Country name 
Specific location(s) to be visited
(e.g., city/town, attraction) 
Number of days in 
this country 
1.
            
2.
3.
4.
5.
  
6. Did you not travel to a country you discussed at your pre-travel visit? 
a. Yes 


68 
 
b. No 
c. Don’t know 
d. I would rather not answer 
 
If yes to question 6, please list the countries you did not visit. 
Country name
 
1.
2.
3.
4.
5.
 
7. Did the time you spent in each country change from what you reported at your pre-travel visit? 
a. Yes 
b. No 
c. Don’t know 
d. I would rather not answer 
 
If yes to question 7, please list the countries in which the amount of time spent changed, including the 
number of days actually spent in each country: 
Country name 
Number of days in 
this country 
1.
            
2.
3.
4.
5.
 


69 
 
This survey is now completed.  
Thank you very much for your time.  
 
 
 
 
 


70 
 
APPENDIX F: Informed Consent Form 
[PLEASE SEE SEPARATE DOCUMENT] 
 
 
 
 
 
 
 


71 
 
APPENDIX G: Follow-up Phone Call Schedule 
7 days before 
travel 
5 days before 
travel 
3 days before 
travel 
1 day before 
travel 
Review all screening 
questionnaire answers with 
the participant, perform the 
pre-travel questionnaire, and 
provide a reminder for stool 
sample submission 
X 
X 
X 
X 
3 days after 
travel 
5 days after 
travel 
7 days after travel
10 days after 
travel 
Reminder for post-travel 
questionnaire and stool 
sample submission 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


72 
 
APPENDIX H: Promotion Materials 
Facebook: 
 
Traveling overseas? Our clinic is offering an opportunity to enroll in a study regarding travelers diarrhea. 
You’ll be compensated for your participation. Check out our website at www.travelhealth.net for more 
information! 
 
Traveling abroad? Consider enrolling in our study regarding travelers’ diarrhea. Visit our website at 
www.travelhealth.net or schedule an appointment by calling 646-374-4132 to learn more! 
Participate in our study regarding travelers’ diarrhea! If you’re interested and have international travel 
plans, check out our website at www.travelhealth.net for more information. 
Twitter (@nyctravelmed): 
 
Traveling abroad? Enroll in our study regarding travelers’ diarrhea. More info at www.travelhealth.net!   
[102 characters] 
 
Make $ during travel & help us learn more - enroll in a study regarding travelers’ diarrhea. Visit 
www.travelhealth.net! [121 characters] 
 
Our clinic is now enrolling for a study regarding travelers’ diarrhea. Make $ and learn more at 
www.travelhealth.net! [117 characters] 
Instagram: 
 
[stock image from public health image library] 
Participate in a study regarding travelers’ diarrhea! Visit our website at www.travelhealth.net for more info on 
how to participate!     


73 
 
 
 [stock image from public health image library] 
Traveling internationally? Participate in a study regarding travelers’ diarrhea and receive compensation for your 
time! Visit our website at www.travelhealth.net for more info!     
Clinic website: 
Participate in a Study to Prevent Travelers’ Diarrhea 
The New York Travel and Tropical Medicine Clinic is now enrolling international travelers in a study of a 
medication to prevent travelers’ diarrhea. Participants will be compensated for their time. If you or someone 
you know is 18 or older, is traveling internationally in the upcoming months, and is interested in learning more, 
give us a call or schedule an appointment with a provider.   
Newspaper (Manhattan and/or Brooklyn): 
Traveling internationally soon? 
The New York Travel and Tropical Medicine Clinic is now enrolling international travelers in a study of a 
medication to prevent travelers’ diarrhea. Participants will be compensated for their time! If you or someone 
you know is 18 or older, is traveling internationally in the upcoming months, and is interested in learning more, 
give us a call at 646-374-4132 to schedule an appointment. Visit us at www.travelhealth.net.  
 
 
Social media management plan: 
1. User comments will be monitored for accuracy weekly 
2. For any technical issues regarding posts on Facebook, Twitter, and Instagram, those platforms will be 
notified of issues. A web management organization assists with the clinic website.  
3. Inappropriate or misleading comments will be addressed immediately. Depending on the nature of the 
comment, it will be addressed in public forum or removed and addressed specifically with the individual 
who posted the comment.  
 


74 
 
APPENDIX I: Data Analysis Table Shells 
Table 1. Baseline Characteristics of Participants 
BSS
Placebo
P-value
Demographics
Age
Sex
Race 
Ethnicity
Medical History
Chronic medical conditions
     Tinnitis 
Antibiotics between 30 to 
90 days prior to travel 
Probiotics within 30 days
Travel
Duration of travel
Primary reason for travel
Secondary reasons for 
travel 
Exposures during travel
Fermented or pickled foods
Yogurt
Attended provider (by type)
 
Table 2. Odds ratios (OR) of TD associated with BSS among international travelers, adjusting for select factors 
 
Total, 
N  
TD, 
% 
OR (95% CI) 
Tablets
BSS
Placebo
Ref
Age groups, years
≥18 
Sex
Male
Female
Ref
Race/ethnicity
. 
.
Travel region 
Travel duration
 


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Table 3. The proportion of participants having resistance genes before and after travel; acquiring, losing, or 
maintaining genes after travel 
All participants
BSS
Placebo
P-value
Pre-travel 
Gene 1
Gene 2
Gene 3
Gene 4
…
Post-travel 
Gene 1
Gene 2
Gene 3
Gene 4
…
Acquisition of gene
Gene 1
Gene 2
Gene 3
Gene 4
…
Loss of gene 
Gene 1
Gene 2
Gene 3
Gene 4
…
Maintenance of 
gene 
Gene 1
Gene 2
Gene 3
Gene 4
…
 
 
 
 


76 
 
APPENDIX J: Auto-Generate Email for Questionnaires 
Greetings, 
 
It's time to complete your "Day X" survey!  
 
If your travel plans change or you need to contact us regarding the study, please contact us at: 
NYTravelStudy@gmail.com. 
 
Thank you,  
The New York Center for Travel and Tropical Medicine 
 
You may open the survey in your web browser by clicking the link below: 
Bismuth subsalicylate's Role in the Prevention of Travelers' Diarrhea: Daily Questionnaire 
 
If the link above does not work, try copying the link below into your web browser: 
https://rdcp.cdc.gov/surveys/?s=QbH5omcTYB 
 
This link is unique to you and should not be forwarded to others.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


77 
 
APPENDIX K: Handout: Participant Instructions 
 
Thank you for your participation in this study to see if bismuth subsalicylate (BSS) prevents travelers’ diarrhea or 
prevents you from being colonized with drug-resistant bacteria in your gut. 
Summary of Procedures for Participants:  
 Approximately 7 days prior to your departure, you will receive a call from clinic personnel.  They will 
verify that the responses you provided to the brief questionnaire at your enrollment visit are still 
accurate. They will also administer a Pre-Travel Questionnaire over the phone and remind you to 
submit your first stool sample. 
 After this call, you will receive an email containing your Study ID, Group ID, and a link for you to 
fill out some addition information about your upcoming trip.   
 You MUST complete this questionnaire prior to departing for your trip. If you do not complete 
it, you will be excluded from the study.   
 If you do not receive an email within 24 hours of completing the enrollment form, please 
contact the travel clinic. 
 Stool sample mailing materials will be provided to you at your pre-travel visit. If they were not 
received or if they were misplaced, please contact the travel clinic. 
 You will receive your first Daily Travel Log via email on your first day of travel in Africa (excluding South 
Africa) and/or South East or South Central Asia.  You will continue to receive these emails daily for the 
duration of your travels in these regions.   
 Complete the Daily Travel Log after taking your second dose of tablets (e.g., evening). 
 You will have 48 hours to complete each Daily Travel Log entry.  You will receive an email 
reminder every 12 hours until each questionnaire has been completed or expires. 
 If you have limited internet access or are unable to access the link, please complete the Daily 
Travel Log on the paper form provided instead. 
 If you are filling out the Daily Travel Log on the paper copies provided and are unable to 
complete a daily entry within 48 hours, please leave that day blank. 
 On the day you return to the US, you will receive an additional email asking you to complete the Post-
Travel Questionnaire.   
 You have 10 days to complete this questionnaire. You will receive an email reminder every 48 
hours until the post-travel questionnaire has been completed or expires.   
 You will also need to submit your second stool sample and any paper Travel Log Forms that 
were completed in lieu of the web-based form. Materials to mail the stool sample and the 
questionnaires should have been provided to you at your pre-travel visit. If they were not 
recieved or if they were misplaced, please contact the travel clinic. 


78 
 
 If you do not receive an email within 24 hours of returning from your trip, please contact the 
travel clinic. 
If your travel plans change or if you have any questions regarding the study, 
please contact The New York Center for Travel and Tropical Medicine: 
 
Phone: +1 (646) 461-1125 
E-mail: NYTravelStudy@gmail.com