Trial Evaluating Ambulatory Treatment of Travelers' Diarrhea

Study Overview
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Brief Summary
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The purpose of the trial is to develop the evidence on relative efficacy of 3 available single-dose loperamide adjuncted regimens for watery diarrhea and a single-dose regimen, with and without loperamide, for dysentery/febrile diarrhea required for informing decisions among these regimens. Information from this study will be used to develop management guidelines for the diagnosis and management of travelers' diarrhea (TD) among deployed United States and United Kingdom military personnel.

Detailed Description
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The study will be a multi-site, randomized, double-blind, controlled clinical trial among ambulatory deployed personnel. Patients presenting for care will be clinically assessed and a determination made as to whether they have acute watery diarrhea (AWD) or acute dysentery/febrile diarrhea (ADF). For the AWD arm, patients will be randomized to receive 1 of 3 regimens: (1) rifaximin 1650 mg as a single dose plus loperamide 4 mg initially followed by 2 mg after each unformed stool, not to exceed 16 mg/day for 2 days (120 subjects); (2) azithromycin 500 mg as a single dose plus loperamide 4 mg initially followed by 2 mg after each unformed stool, not to exceed 16 mg/day for 2 days (120 subjects); or (3) levofloxacin 500 mg as a single dose plus loperamide 4 mg initially followed by 2 mg after each unformed stool, not to exceed 16 mg/day for 2 days (120 subjects). For the ADF arm, patients will be randomized to receive 1 of 2 regimens: (1) azithromycin 1000 mg as a single dose plus loperamide 4 mg initially followed by 2 mg after each unformed stool, not to exceed 16 mg/day for 2 days (75 subjects); or (2) azithromycin 1000 mg as a single dose without loperamide (75 subjects). Study Procedures (Brief): Baseline exam as well as blood and stool samples will be collected at initial clinic visit. Clinical assessments will be performed at 24 hours, 72 hours, and 7 days. In addition, microbiological cure will be evaluated at 7-d post initiation of treatment. Subjects will have blood drawn to assess for serological conversion to common enteric pathogens, and stool collected at 7- and 21-d . Subjects may also opt in for long-term follow-up at time of enrollment, which will assess for development of post-infectious functional bowel disorders. All subjects will complete a baseline assessment at 7-d visit, and those who opt for the additional follow-up will complete a series of web-based surveys at 3-, 6-, 9-, and 12-m post enrollment.

Official Title
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A Randomized, Double-Blind, Clinical Trial Evaluating Three Single Dose Regimens With Loperamide for Treatment of Ambulatory Watery Travelers' Diarrhea, and Azithromycin With and Without Loperamide for Treatment of Ambulatory Dysentery/Febrile Diarrhea

Conditions
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Acute Watery Diarrhea, Dysentery/Febrile Diarrhea

Intervention / Treatment
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* Drug: Single dose rifaximin 1650 mg
* Drug: Single dose azithromycin 500 mg
* Drug: Single dose levofloxacin 500 mg
* Drug: Single dose azithromycin 1000 mg plus loperamide
* Drug: Single dose azithromycin 1000 mg plus placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Active duty military or military beneficiary, 18 years-old or older. Presence of acute diarrhea (3 or more stools in 24 hours or 2 or more stools in 24 hours and associated symptoms such as nausea, vomiting, abdominal cramps or tenesmus) and <96 hours duration. Eligible for ambulatory management. Able to comply with follow-up procedures. Will remain in country for at least 7 days Exclusion Criteria: Allergy to rifamycins, quinolones, macrolides, or loperamide (not including mild gastrointestinal upset). Antibiotic therapy in the 72 hours prior to presentation (excluding malaria prophylaxis with mefloquine, malarone, chloroquine/proguanil, or doxycycline). Concomitant medications with known drug-drug interactions with any of the study drugs (includes theophylline, digoxin, and warfarin). History of seizures (relative contraindication to quinolones) Positive pregnancy test at presentation (contraindicated with fluoroquinolone therapy). All female subjects will be administered a urine pregnancy test prior to enrollment. Presence of symptoms >96 hours prior to initiating treatment. Use of >4 mg loperamide or use of any amount of loperamide for greater than 24 hours prior to enrollment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acute Watery Diarrhea<br> | Drug: Single dose rifaximin 1650 mg<br>* Rifaximin 1650 mg as a single dose plus loperamide 4 mg initially followed by 2 mg after each unformed stool, not to exceed 16 mg/day for 2 days<br>Drug: Single dose azithromycin 500 mg<br>* Azithromycin 500 mg as a single dose plus loperamide 4 mg initially followed by 2 mg after each unformed stool, not to exceed 16 mg/day for 2 days<br>Drug: Single dose levofloxacin 500 mg<br>* Levofloxacin 500 mg as a single dose plus loperamide 4 mg initially followed by 2 mg after each unformed stool, not to exceed 16 mg/day for 2 days<br>|
| Experimental: Acute Dysentery/Febrile<br> | Drug: Single dose azithromycin 1000 mg plus loperamide<br>* Azithromycin 1000 mg as a single dose plus loperamide 4 mg initially followed by 2 mg after each unformed stool, not to exceed 16 mg/day for 2 days<br>Drug: Single dose azithromycin 1000 mg plus placebo<br>* Azithromycin 1000 mg as a single dose and placebo in lieu of loperamide<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Cure - Acute Watery Diarrhea group | No grade 3-5 stools beyond 24 hours after initiation of therapy meeting diarrhea definition (≥3 loose or liquid stools in 24 hour period). All diarrhea associated symptoms present must be no greater than mild in severity and have no impact on activity. AND, no treatment failure events to include the following: Recurrence of diarrheal illness meeting case definition of TD occurring within 72 hours after clinical cure Worsening of, or failure to improve, clinical symptoms after 24 hours of therapy Illness continuing after 72 hours | 24 hours | 
| Clinical Cure - Acute Dysentery/Febrile Diarrhea group | No grade 3-5 stools beyond 48 hours after initiation of therapy meeting diarrhea definition (≥3 loose or liquid stools in 24 hour period) and resolution of acute dysentery/febrile diarrhea-associated signs/symptoms to include fever and gross blood in stool, as well as report of no impact on activity AND, no treatment failure events to include the following: Recurrence of diarrheal illness meeting case definition of TD occurring within 72 hours after clinical cure Worsening of, or failure to improve after 24 hours of therapy Illness continuing after 72 hours | 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Last Unformed Stool | Calculated as the time from taking the first dose of study medication until passage of the last unformed stool that meets diarrhea definition (grade 3-5 stool associated with 2 other loose stools in 24 hours or 1 other loose stool and associated symptoms in that same 24 hour block) after which subjects are declared well. Where, last unformed stool = last grade 3-5 stool occurring in a 24-hr period meeting the diarrhea definition. | 24, 48, 72 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diarrhea, travelers' diarrhea, watery diarrhea, enteric illness, dysentery, gastrointestinal