Diarrhea
Conditions
Brief summary
The primary objective is to demonstrate rifaximin 200 milligrams (mg) tablets (test) and Xifaxan® 200 mg tablets (reference) are clinically bioequivalent with respect to the clinical cure rates when administered 3 times a day (TID) for 3 days in participants with travelers' diarrhea.
Detailed description
This is a randomized, placebo-controlled bioequivalent study with a clinical endpoint in the treatment of travelers' diarrhea. After 3 unformed stools are recorded within the 24 hours immediately preceding randomization, participants are to be randomized to receive the generic rifaximin 200 mg oral tablet, Xifaxan (the reference listed drug)200 mg oral tablet, or placebo 3 times daily for 3 days (that is; on Days 1, 2, and 3).
Interventions
DRUGRifaximin
Tablets, generic formulation of the brand product.
DRUGXifaxan®
Tablets, brand product.
DRUGPlacebo Tablet
Placebo tablets in the same image of the generic rifaximin. Has no active ingredient.
Sponsors
Actavis Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adult male or nonpregnant female aged ≥18 years non-indigenous travelers (for example; visiting students/faculty or international tourists) affected by naturally acquired acute diarrhea. Diarrhea is defined as the passage of at least 3 unformed stools in a 24-hour period. Stools are classified as formed (retains shape), soft (assumes shape of container), or watery (can be poured). When using this classification, both soft and watery stools are unformed and abnormal. 2. At least 3 unformed stools recorded within the 24 hours immediately preceding randomization. 3. At least 1 of the following signs and symptoms of enteric infection: * abdominal pain or cramps * nausea * vomiting * fecal urgency * excessive gas/flatulence * tenesmus 4. Women of child-bearing potential have a negative pregnancy test prior to beginning therapy and agree to use effective contraceptive methods during the study.
Exclusion criteria
1. Pregnant, breast feeding, or planning a pregnancy. 2. Immediately prior to randomization, acute diarrhea for \>72 hours. 3. Presence of: * fever (≥100 degrees fahrenheit \[°F\] or ≥37.8 degrees celsius \[°C\]), or * hematochezia (blood in stool), or * clinical findings suggesting moderate or severe dehydration. 4. Active, uncontrolled, or clinically significant diseases or disorders of the heart, lung, kidney, gastrointestinal (GI) tract (other than infectious diarrhea in travelers), or central nervous system. 5. Administration of any of the following: * any antimicrobial agents with an expected activity against enteric bacterial pathogens within 7 days preceding randomization * more than 2 doses of a symptomatic antidiarrheal compound such as antimotility agents, absorbent agents, and antisecretory agents within 8 hours preceding randomization 6. Use of any drug such as aspirin or ibuprofen (Advil), which can cause GI bleeding. Acetaminophen (Tylenol) or paracetamol is acceptable.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved Clinical Cure at Test of Cure (TOC) Visit (Within 24 to 72 Hours From the Time of Last Dose): Per-Protocol (PP) Population | TOC visit (Day 5, 6 or 7) | Clinical cure was defined as either of the following: No stools or only formed stools within a 48-hour period and no fever, with or without other enteric symptoms or; No watery stools or no more than 2 soft stools passed within a 24-hour period with no fever and no other enteric symptoms except for mild excess gas/flatulence. Bioequivalence evaluation between test (generic rifaximin 200 mg tablets) and reference groups (xifaxan 200 mg tablets) was conducted in this endpoint, hence placebo group was not included. Participants who were discontinued early from the study due to lack of treatment effect after completing 9 doses within 72 hours from the time of first dose were included in the PP population using Last Observation Carried Forward (LOCF) method. Additionally, participants whose condition worsened and who required alternate or supplemental therapy for the treatment of travelers' diarrhea were discontinued and included in the PP population analysis using LOCF. |
| Number of Participants Who Achieved Clinical Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose): Modified Intent-to-Treat (mITT) Population | TOC visit (Day 5, 6 ,or 7) | Clinical cure was defined as either of the following: No stools or only formed stools within a 48-hour period and no fever, with or without other enteric symptoms or; No watery stools or no more than 2 soft stools passed within a 24-hour period with no fever and no other enteric symptoms except for mild excess gas/flatulence. Participants discontinued early for reasons other than lack of treatment effect after completing 9 doses within 72 hours from the time of first dose and for participants whose condition worsened and who required alternate or supplemental therapy for the treatment of travelers' diarrhea were included in the mITT population analysis using LOCF. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Last Unformed Stool (TLUS) | Day 1 to Day 5 | TLUS was defined as the interval beginning with the first dose of study drug and ending with the last unformed stool passed within a period of 120 hours (within 48 hours from the time of last dose \[at 72 hours\]). Mathematically, TLUS was calculated as follows. TLUS (hours) = date/time of last unformed stool within 48 hours from the time of last dose - date/time of first dose. |
| Percentage of Participants Who Achieved Microbiological Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose) | TOC visit (Day 5, 6, or 7) | Participants were considered to have achieved microbiological cure if the pathogen identified at Day 1 is no longer found in the stool at the TOC visit. |
Countries
United States
Participant flow
Pre-assignment details
A total of 739 nonindigenous travelers with naturally acquired acute diarrhea were enrolled and randomized in this study.
Participants by arm
| Arm | Count |
|---|---|
| Generic Rifaximin 200 mg Tablets Participants received a generic rifaximin 200 mg tablet 3 times daily orally for 3 days. | 247 |
| Xifaxan 200 mg Tablets Participants received a xifaxan 200 mg tablet 3 times daily orally for 3 days. | 248 |
| Rifaximin Placebo Tablets Participants received a rifaximin placebo tablet 3 times daily orally for 3 days. | 244 |
| Total | 739 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lack of Efficacy | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 | 1 |
| Overall Study | Participant taken prohibited medication | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 3 |
Baseline characteristics
| Characteristic | Generic Rifaximin 200 mg Tablets | Xifaxan 200 mg Tablets | Rifaximin Placebo Tablets | Total |
|---|---|---|---|---|
| Age, Continuous | 42.5 years STANDARD_DEVIATION 15.78 | 44.3 years STANDARD_DEVIATION 16.58 | 42.0 years STANDARD_DEVIATION 15.21 | 42.9 years STANDARD_DEVIATION 15.87 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 189 Participants | 188 Participants | 188 Participants | 565 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 58 Participants | 58 Participants | 54 Participants | 170 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 2 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 23 Participants | 18 Participants | 13 Participants | 54 Participants |
| Race (NIH/OMB) More than one race | 13 Participants | 5 Participants | 9 Participants | 27 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 208 Participants | 222 Participants | 220 Participants | 650 Participants |
| Sex: Female, Male Female | 123 Participants | 130 Participants | 132 Participants | 385 Participants |
| Sex: Female, Male Male | 124 Participants | 118 Participants | 112 Participants | 354 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 246 | 0 / 247 | 0 / 244 |
| other Total, other adverse events | 17 / 246 | 17 / 247 | 24 / 244 |
| serious Total, serious adverse events | 0 / 246 | 0 / 247 | 0 / 244 |
Outcome results
Primary
Number of Participants Who Achieved Clinical Cure at Test of Cure (TOC) Visit (Within 24 to 72 Hours From the Time of Last Dose): Per-Protocol (PP) Population
Clinical cure was defined as either of the following: No stools or only formed stools within a 48-hour period and no fever, with or without other enteric symptoms or; No watery stools or no more than 2 soft stools passed within a 24-hour period with no fever and no other enteric symptoms except for mild excess gas/flatulence. Bioequivalence evaluation between test (generic rifaximin 200 mg tablets) and reference groups (xifaxan 200 mg tablets) was conducted in this endpoint, hence placebo group was not included. Participants who were discontinued early from the study due to lack of treatment effect after completing 9 doses within 72 hours from the time of first dose were included in the PP population using Last Observation Carried Forward (LOCF) method. Additionally, participants whose condition worsened and who required alternate or supplemental therapy for the treatment of travelers' diarrhea were discontinued and included in the PP population analysis using LOCF.
Time frame: TOC visit (Day 5, 6 or 7)
Population: PP population: randomized participants, met inclusion/exclusion criteria, took 3 days of study drug, were compliant with study drug dose, and completed Visit 3 within 24-72 hours from the time of last dose, with no major protocol deviations/violations that would affect treatment evaluation. LOCF method was used as applicable for this population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Generic Rifaximin 200 mg Tablets | Number of Participants Who Achieved Clinical Cure at Test of Cure (TOC) Visit (Within 24 to 72 Hours From the Time of Last Dose): Per-Protocol (PP) Population | 90 Participants |
| Xifaxan 200 mg Tablets | Number of Participants Who Achieved Clinical Cure at Test of Cure (TOC) Visit (Within 24 to 72 Hours From the Time of Last Dose): Per-Protocol (PP) Population | 93 Participants |
Comparison: Bioequivalence was evaluated based on the PP analysis set using Z-test with Yates correction.90% CI: [-0.11, 0.07]
Primary
Number of Participants Who Achieved Clinical Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose): Modified Intent-to-Treat (mITT) Population
Clinical cure was defined as either of the following: No stools or only formed stools within a 48-hour period and no fever, with or without other enteric symptoms or; No watery stools or no more than 2 soft stools passed within a 24-hour period with no fever and no other enteric symptoms except for mild excess gas/flatulence. Participants discontinued early for reasons other than lack of treatment effect after completing 9 doses within 72 hours from the time of first dose and for participants whose condition worsened and who required alternate or supplemental therapy for the treatment of travelers' diarrhea were included in the mITT population analysis using LOCF.
Time frame: TOC visit (Day 5, 6 ,or 7)
Population: mITT population included all randomized participants who met all inclusion and none of the exclusion criteria, received at least 1 dose of study drug and provided efficacy and safety data after 1 dose of study drug. LOCF method was used as applicable for this population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Generic Rifaximin 200 mg Tablets | Number of Participants Who Achieved Clinical Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose): Modified Intent-to-Treat (mITT) Population | 91 Participants |
| Xifaxan 200 mg Tablets | Number of Participants Who Achieved Clinical Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose): Modified Intent-to-Treat (mITT) Population | 95 Participants |
| Rifaximin Placebo Tablets | Number of Participants Who Achieved Clinical Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose): Modified Intent-to-Treat (mITT) Population | 86 Participants |
Comparison: 95% CIs was calculated using Z-test with Yates' correction.p-value: 0.789995% CI: [-0.09, 0.13]Z-test
Comparison: 95% CIs was calculated using Z-test with Yates' correction.p-value: 0.598795% CI: [-0.07, 0.14]Z-test
Secondary
Percentage of Participants Who Achieved Microbiological Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose)
Participants were considered to have achieved microbiological cure if the pathogen identified at Day 1 is no longer found in the stool at the TOC visit.
Time frame: TOC visit (Day 5, 6, or 7)
Population: mITT population: all randomized participants who met all inclusion and none of the exclusion criteria, received at least 1 dose of study drug and provided efficacy and safety data after 1 dose. 'Overall number of participants analyzed'=participants evaluable for this endpoint. 'Number analyzed'=participants evaluable for the specified categories.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Generic Rifaximin 200 mg Tablets | Percentage of Participants Who Achieved Microbiological Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose) | Stool microscopy for ova and parasites | 83.3 percentage of participants |
| Generic Rifaximin 200 mg Tablets | Percentage of Participants Who Achieved Microbiological Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose) | Enteroaggregative Escherichia coli (EAEC) | 32.0 percentage of participants |
| Generic Rifaximin 200 mg Tablets | Percentage of Participants Who Achieved Microbiological Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose) | Escherichia coli | 25.5 percentage of participants |
| Generic Rifaximin 200 mg Tablets | Percentage of Participants Who Achieved Microbiological Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose) | Enterotoxigenic Escherichia coli (ETEC) | 43.5 percentage of participants |
| Generic Rifaximin 200 mg Tablets | Percentage of Participants Who Achieved Microbiological Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose) | Other microorganisms | 70.6 percentage of participants |
| Xifaxan 200 mg Tablets | Percentage of Participants Who Achieved Microbiological Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose) | Enterotoxigenic Escherichia coli (ETEC) | 54.5 percentage of participants |
| Xifaxan 200 mg Tablets | Percentage of Participants Who Achieved Microbiological Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose) | Stool microscopy for ova and parasites | 100.0 percentage of participants |
| Xifaxan 200 mg Tablets | Percentage of Participants Who Achieved Microbiological Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose) | Other microorganisms | 81.8 percentage of participants |
| Xifaxan 200 mg Tablets | Percentage of Participants Who Achieved Microbiological Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose) | Enteroaggregative Escherichia coli (EAEC) | 27.3 percentage of participants |
| Xifaxan 200 mg Tablets | Percentage of Participants Who Achieved Microbiological Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose) | Escherichia coli | 31.9 percentage of participants |
| Rifaximin Placebo Tablets | Percentage of Participants Who Achieved Microbiological Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose) | Stool microscopy for ova and parasites | 100.0 percentage of participants |
| Rifaximin Placebo Tablets | Percentage of Participants Who Achieved Microbiological Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose) | Escherichia coli | 17.4 percentage of participants |
| Rifaximin Placebo Tablets | Percentage of Participants Who Achieved Microbiological Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose) | Enteroaggregative Escherichia coli (EAEC) | 26.1 percentage of participants |
| Rifaximin Placebo Tablets | Percentage of Participants Who Achieved Microbiological Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose) | Other microorganisms | 92.9 percentage of participants |
| Rifaximin Placebo Tablets | Percentage of Participants Who Achieved Microbiological Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose) | Enterotoxigenic Escherichia coli (ETEC) | 68.4 percentage of participants |
Secondary
Time to Last Unformed Stool (TLUS)
TLUS was defined as the interval beginning with the first dose of study drug and ending with the last unformed stool passed within a period of 120 hours (within 48 hours from the time of last dose \[at 72 hours\]). Mathematically, TLUS was calculated as follows. TLUS (hours) = date/time of last unformed stool within 48 hours from the time of last dose - date/time of first dose.
Time frame: Day 1 to Day 5
Population: mITT population included all randomized participants who met all inclusion and none of the exclusion criteria, received at least 1 dose of study drug and provided efficacy and safety data after 1 dose of study drug. Here, 'Overall number of participants analyzed'=participants with TLUS in the mITT population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Generic Rifaximin 200 mg Tablets | Time to Last Unformed Stool (TLUS) | 65.25 hours |
| Xifaxan 200 mg Tablets | Time to Last Unformed Stool (TLUS) | 65.75 hours |
| Rifaximin Placebo Tablets | Time to Last Unformed Stool (TLUS) | 67.01 hours |