Traveler's Diarrhea
Conditions
Keywords
traveler's, diarrhea, Rifamycin SV MMX, Rifamycin, MMX, Traveler's Diarrhea
Brief summary
The purpose of this study is to determine whether Rifamycin SV MMX is a safe and effective treatment for Traveler's Diarrhea.
Detailed description
This is a multicenter, randomized, double-blind, placebo-controlled efficacy and safety study conducted in patients traveling to developing regions with a known high incidence of TD. Eligibility will be based on a symptom complex that is highly indicative of enteric acute bacterial infection without indication of systemic infection. Approximately 262 patients will be enrolled in the study and randomized at a 3:1 ratio to receive Rifamycin SV MMX® 400 mg or placebo orally twice daily for 3 days (72 hours). Treatment will be initiated on the day of Screening (Visit 1, Day 1), within 72 hours of onset of diarrhea. Daily doses of study drug will be taken at breakfast time and dinner time with a glass of liquid. Safety and efficacy will be assessed. Blood samples for routine safety tests (chemistry and hematology) will be collected at Visit 1 and at Visit 3 and sent to a local laboratory for analysis and reporting to the Investigator for safety monitoring. Urine samples for routine urinalysis (dipstick only) will be collected at Visits 1 and 3, and the results will be used by the Investigator for safety monitoring. If a patient's diarrhea and/or signs or symptoms of enteric infection worsen in a 24 hour interval of time during the treatment period or if the enteric illness fails to improve after 24 hours or more of therapy, the patient may receive Rescue Therapy. Rescue Therapy will be prescribed by the Investigator using local standard empiric therapy and/or guided by pathogen identification.
Interventions
DRUGPlacebo
Placebo (two matching tablets) orally twice daily for 3 days (72 hours).
DRUGRifamycin SV MMX
Rifamycin SV MMX® 400 mg (two 200 mg tablets) orally twice daily for 3 days (72 hours).
Sponsors
Bausch Health Americas, Inc.
Cosmo Technologies Ltd
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients were enrolled in the study only if they met all of the following criteria: 1. Male and female patients 18 years of age or older 2. Female and male patients of childbearing potential must have agreed to use an effective method of birth control (this method must have been approved by the investigator and may have included total abstinence from sexual intercourse) during the treatment and follow-up study periods; female patients of childbearing potential must have had a negative pregnancy test in the 72 hours before randomization; female patients who abstained totally from sexual intercourse were not required to take the pregnancy test 3. Recent travel (i.e., must be within 30 days of randomization) from an industrialized country 4. Experiencing signs or symptoms indicative of acute bacterial diarrhea (TD), defined as at least three unformed, watery or soft, stools within the 24 hours preceding randomization and the duration of illness 72 hours before randomization, and able to provide an unformed stool sample during Screening (the latter can be the third unformed stool passed by the patient within the 24 hours preceding randomization); the bacterial cause of diarrhea was confirmed by microbiology analysis of the stool sample 5. Experiencing one or more signs or symptoms of enteric infection (moderate to severe gas/flatulence, nausea, vomiting, abdominal cramps or pain, rectal tenesmus, or defecation urgency) 6. Capable of and willing to give informed consent
Exclusion criteria
Patients were excluded from the study if they met any of the following criteria: 1. Fever (\> 100.4F or 38C) or presence of signs and symptoms of systemic infection Note: antipyretic medication should not have been administered in the 6 hours before this assessment 2. Known or suspected infection with non-bacterial pathogen before randomization 3. Presence of diarrhea for \> 72 hours duration 4. Presence of grossly bloody stool 5. Presence of moderate to severe dehydration (i.e., presence of orthostatic hypotension and/or dehydration requiring treatment with intravenous fluids) 6. History of ulcerative colitis, diarrhea-predominant irritable bowel syndrome, Crohn's disease, celiac sprue (gluten-enteropathy), chronic pancreatitis, malabsorption, or any other gastrointestinal disease associated with diarrhea. Note: lactose intolerance treated with lactase supplements or a lactose-free diet were not excluded if these regimens were maintained during the study. 7. Receiving more than two doses of an antidiarrheal medication (e.g., antimotility, absorbent, adsorbent, antisecretory, or probiotics) within 24 hours before randomization 8. Receiving one or more of the following antibiotics, which are active against gram negative bacteria TMP-SMX, fluorquinolone, azithromycin or rifaximin within 7 days before randomization 9. Females pregnant or breast feeding or not using adequate birth control 10. Known intolerance/hypersensitivity/resistance to rifamycin or rifamycin-related antibiotics or to any excipient included in the study medications 11. Patients unable or unwilling to comply with study protocol (e.g., alcoholism, mental illness, travel schedule) 12. Participation in a clinical study with another investigational drug in the 30 days prior to randomization or while participating in this study 13. Previous participation in this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Last Unformed Stool (TLUS) | 24 hours | The primary endpoint is TLUS defined as the interval in hours between the first dose of study drug and the last unformed stool passed just before the start of Clinical Cure. An unformed stool is defined as either a soft or watery stool. TLUS will be calculated for each patient in the following manner: Step 1: Identify when the patient achieves Clinical Cure. Step 2: Moving backwards from this time, identify the time of the last unformed stool. Step 3: The TLUS equals the time from the first dose of study drug to the time of the last unformed stool identified in Step 2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Cure | 24 hours | Clinical Cure is defined as either of the following: * Passage of two or fewer soft stools and no watery stools, no fever (\>100.4 ºF or 38 ºC), and no signs or symptoms of enteric infection (other than mild excess gas/flatulence) during a 24 hour interval in the 120-hr data collection period after the first dose of study drug * Passage of no stools or only formed stools and no fever during a 48-hour interval in the 120-hr data collection period after the first dose of study drug, with or without other signs or symptoms of enteric infection |
Countries
Guatemala, Mexico
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo (two matching tablets) orally twice daily for 3 days (72 hours)
Placebo: Placebo (two matching tablets) orally twice daily for 3 days (72 hours).
Intent To Treat (ITT) | 65 |
| Rifamycin SV MMX Rifamycin SV MMX® 400 mg (two 200 mg tablets) orally twice daily for 3 days (72 hours).
Rifamycin SV MMX: Rifamycin SV MMX® 400 mg (two 200 mg tablets) orally twice daily for 3 days (72 hours).
Intent To Treat (ITT) | 199 |
| Total | 264 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Noncompliance with study procedures | 2 | 1 |
| Overall Study | Patient required rescue medication | 8 | 17 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Use of prohibited medications | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo | Rifamycin SV MMX | Total |
|---|---|---|---|
| Age, Continuous | 28.9 years STANDARD_DEVIATION 12.72 | 28 years STANDARD_DEVIATION 11.43 | 28.3 years STANDARD_DEVIATION 11.74 |
| Baseline Pathogen Identified No | 17 Participants | 66 Participants | 83 Participants |
| Baseline Pathogen Identified Yes | 48 Participants | 133 Participants | 181 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 9 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 10 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 5 Participants | 8 Participants |
| Race (NIH/OMB) White | 56 Participants | 175 Participants | 231 Participants |
| Sex: Female, Male Female | 33 Participants | 100 Participants | 133 Participants |
| Sex: Female, Male Male | 32 Participants | 99 Participants | 131 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 65 | 0 / 199 |
| other Total, other adverse events | 25 / 65 | 58 / 199 |
| serious Total, serious adverse events | 1 / 65 | 2 / 199 |
Outcome results
Primary
Time to Last Unformed Stool (TLUS)
The primary endpoint is TLUS defined as the interval in hours between the first dose of study drug and the last unformed stool passed just before the start of Clinical Cure. An unformed stool is defined as either a soft or watery stool. TLUS will be calculated for each patient in the following manner: Step 1: Identify when the patient achieves Clinical Cure. Step 2: Moving backwards from this time, identify the time of the last unformed stool. Step 3: The TLUS equals the time from the first dose of study drug to the time of the last unformed stool identified in Step 2.
Time frame: 24 hours
Population: Intent To Treat (ITT). Please note that the 75th percentile was not observed during the 120-hour study period for placebo patients.~The percentile groups indicate the hour at which the appropriate percentage of the patient group had met the primary endpoint i.e. by 72 hours, 75% of Rifamycin SV MMX patients had met the endpoint.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Time to Last Unformed Stool (TLUS) | 25th percentile | 37.4 TLUS (hours) |
| Placebo | Time to Last Unformed Stool (TLUS) | 50th percentile | 68 TLUS (hours) |
| Placebo | Time to Last Unformed Stool (TLUS) | 75th percentile | NA TLUS (hours) |
| Rifamycin SV MMX | Time to Last Unformed Stool (TLUS) | 25th percentile | 21. TLUS (hours) |
| Rifamycin SV MMX | Time to Last Unformed Stool (TLUS) | 50th percentile | 46 TLUS (hours) |
| Rifamycin SV MMX | Time to Last Unformed Stool (TLUS) | 75th percentile | 72.2 TLUS (hours) |
Secondary
Clinical Cure
Clinical Cure is defined as either of the following: * Passage of two or fewer soft stools and no watery stools, no fever (\>100.4 ºF or 38 ºC), and no signs or symptoms of enteric infection (other than mild excess gas/flatulence) during a 24 hour interval in the 120-hr data collection period after the first dose of study drug * Passage of no stools or only formed stools and no fever during a 48-hour interval in the 120-hr data collection period after the first dose of study drug, with or without other signs or symptoms of enteric infection
Time frame: 24 hours
Population: Intent to treat (ITT)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Clinical Cure | 35 Participants |
| Rifamycin SV MMX | Clinical Cure | 162 Participants |