Trial Evaluating Chemoprophylaxis Against Travelers' Diarrhea - Prevent TD
Trial Evaluating Chemoprophylaxis Against Travelers' Diarrhea - Prevent TD
The purpose of this study is to develop evidence on the relative efficacy of 2 rifaximin
 chemoprophylaxis regimens for the prevention of Travelers' Diarrhea (TD) in a deployed
 setting. An additional purpose is to explore the effect of chemoprophylaxis on microbial
 flora and antimicrobial resistance, and obtain parameter estimates to inform a
 cost-effectiveness model of chemoprophylaxis in prevention of TD. Information from this study
 will be used to develop management guidelines for the prevention of TD among deployed (United
 States (US) and United Kingdom (UK) military personnel.

 The study will be a multi-site, randomized, placebo-controlled, double-blind, clinical trial
 among deployed military personnel. The study will test 2 TD chemoprophylaxis regimens (once
 daily versus twice daily) of the same antibiotic, rifaximin, compared to a placebo.

 For the proposed chemoprophylaxis study described herein, cohorts of military personnel (US
 and UK) deploying/traveling overseas will be recruited prior to travel to participate and
 will undergo enrollment procedures as outlined in study appendices. Subjects who are eligible
 and agree to participate will be randomized to receive one of 3 regimens: (1) rifaximin 550
 mg daily; (2) rifaximin 550 mg twice a day; or (3) placebo, to be taken while deployed.
 Chemoprophylaxis will be maintained for duration of travel or a predetermined period of up to
 6 weeks and at least 2 weeks, which may include a period of up to 5 days of use after return
 to COO for deployments less than 6 weeks in duration. Clinical and laboratory data will be
 obtained before, during if available and after deployment/chemoprophylaxis.
The primary efficacy outcome will be assessed by review of the symptom memory aid (TravMil
 diary). Subjects will follow a symptom memory aid from the onset of a disease episode and
 record relevant symptomatology (date/time and number of diarrheal episodes, associated
 symptoms such as fever, vomiting, nausea, bloody stools and cramps, severity of symptoms,
 functional activity). Use of antibiotics and/or Imodium (loperamide) for each episode will
 also be recorded). An additional memory aid to capture occurrence of solicited adverse
 events, use of new prescription medications, as well as adherence to study medication regimen
 will be utilized by subjects during deployment and returned (or re-created with study
 personnel if lost or incomplete) at follow-up Memory aid data will be actively sought from
 all subjects via required in-person follow-up.

 Secondary efficacy outcomes will also largely be derived from the self-report of subjects via
 use of the memory aid data. Secondary safety evaluation will be performed at the end of study
 visit based on history obtained from the subject regarding medical treatment requiring events
 while deployed.

 Individuals will be enrolled prior to travel/deployment. At the time of enrollment they will
 undergo eligibility criteria review, informed consent process, baseline assessment
 (demographics, medical history, others), sample collection (blood and stool), and blinded
 randomization into a study arm.

 Episodes of diarrhea are expected to occur while on study drug. Subjects will be instructed
 and expected to seek care for these episodes from medical assets available to them at COD.

 Subjects will be instructed to discontinue study drug if they develop diarrhea and are given
 antibiotic therapy. It is not expected that study drug will impact the choice or
 effectiveness of antibiotics used to treat travelers' diarrhea. Some subjects will be
 eligible to restart (only once restart) study drug once they are cured of a travelers'
 diarrhea episode. See US and UK addenda for details.

 The end of prophylaxis is defined as the +/- 96hr period from cessation of prophylaxis due to
 (A) the subject completing maximal period of prophylaxis but remains deployed, or (B) being
 re-deployed and returns to mainland/COO. During this end of prophylaxis period, subjects may
 be seen by study personnel and perform an end of prophylaxis visit.

 The post-deployment period is defined as the return to COO through 8 weeks from return. A
 post-deployment visit, in the COO will be planned for all subjects enrolled in the study and
 will occur as soon as it can be scheduled.

 All subjects will be asked to complete a baseline questionnaire on day of enrollment and
 complete web-based surveys during the follow-up period. Subjects will be emailed the survey
 link at 3 and 6 months post-return to COO. The survey will assess for several types of
 functional bowel disorders and symptoms of ReA using standardized questions and definitions
 and questions and will use disease activity scales to assess impact on daily life.

 A sample of blood will be collected up to 2 times as part of participation in this study. The
 samples will be collected, processed and stored until transported at a later date to central
 lab for testing of acute and convalescent titers directed against bacterial and viral
 enteropathogens. Samples will also be used for biomarker evaluation and support of
 exploratory objectives.

 Stool samples will be used for exploratory microbiological analyses to assess etiology of
 diarrhea by pathogen, antibiotic susceptibility of enteropathogens, and evaluation of impact
 of rifaximin on the microbiome. Serum will be utilized to attempt to determine seroconversion
 status for pathogens not identified during stool analysis.
Inclusion Criteria:

 1. An Institutional Review Board (IRB) / Ethics Committee (EC)-approved informed consent
 form is signed and dated.

 2. Subject is at least 18 years of age

 3. Subject's duration of prophylaxis will be least 2 weeks.

 4. Subject is capable of and willing to comply with all study procedures and available
 for the end of study visits and sample collection at COO (within 6 months from start
 of prophylaxis).

 5. Women: Non-nursing and negative urine/serum pregnancy test with understanding (through
 informed consent process) to avoid pregnancy while on study drug. Sole reliance on
 oral contraceptives (OCPs) for birth control will not be recommended (see section
 6.3.2.1.) Should an individual have a documented surgical sterilization in her medical
 record, a pregnancy test will not be required. If a volunteer becomes pregnant during
 the study, the principal investigator will notify the study research monitor and the
 IRBs. The pregnancy outcome will be followed per IRB and other regulatory requirements
 for US and UK personnel.

 6. (For US Personnel Only). Have consented to participate in TravMil protocol.

 Exclusion Criteria:

 1. Subject received any systemic or gastrointestinal antibiotic in the 7 days prior to
 enrollment (except anti-malarial prophylaxis agents).

 2. Subject has hypersensitivity or allergy to rifaximin or rifampicin.

 3. Subject has acute diarrhea within 7 days prior to enrollment

 4. Subject has a concomitant disease or condition that could interfere with, or for which
 treatment could interfere with, the conduct of the study, or could in the opinion of
 the investigator increase the risk of AEs during the subject's participation in the
 study

 5. Subject is currently taking or plans to take during deployment at least one of the
 following medications: theophylline or warfarin (Coumadin).