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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
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
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
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
UK Role 3 Joint Force Hospital
Camp Bastion Air Base, Afghanistan
U.S. Naval Expeditionary Base
Camp Lemonnier, Djibouti
Joint Task Force - Bravo
Soto Cano Air Base, Honduras
British Army Training Unit Kenya
Nanyuki, Kenya
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
Time frame: 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
Time frame: 48 hours
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.
Time frame: 24, 48, 72 hours
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Purpose
TREATMENT
Masking
TRIPLE
Enrollment
384
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
Azithromycin 1000 mg as a single dose and placebo in lieu of loperamide
Armed Forces Research Institute of Medical Sciences
Bangkok, Thailand