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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.
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Generic Rifaximin 200 mg Tablets | Experimental | Participants will receive a generic rifaximin 200 mg tablet 3 times daily orally for 3 days. |
|
| Xifaxan 200 mg Tablets | Active Comparator | Participants will receive a xifaxan 200 mg tablet 3 times daily orally for 3 days. |
|
| Placebo | Placebo Comparator | Participants will receive a rifaximin placebo tablet 3 times daily orally for 3 days. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rifaximin | Drug | Tablets, generic formulation of the brand product. |
| |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | TOC visit (Day 5, 6 or 7) |
| 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. | TOC visit (Day 5, 6 ,or 7) |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
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.
At least 3 unformed stools recorded within the 24 hours immediately preceding randomization.
At least 1 of the following signs and symptoms of enteric infection:
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:
Pregnant, breast feeding, or planning a pregnancy.
Immediately prior to randomization, acute diarrhea for >72 hours.
Presence of:
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.
Administration of any of the following:
Use of any drug such as aspirin or ibuprofen (Advil), which can cause GI bleeding. Acetaminophen (Tylenol) or paracetamol is acceptable.
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| Name | Affiliation | Role |
|---|---|---|
| Study Director | Actavis Inc. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Site 1 | Coral Gables | Florida | 33134 | United States |
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A total of 739 nonindigenous travelers with naturally acquired acute diarrhea were enrolled and randomized in this study.
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| ID | Title | Description |
|---|---|---|
| FG000 | Generic Rifaximin 200 mg Tablets | Participants received a generic rifaximin 200 milligrams (mg) tablet 3 times daily orally for 3 days. |
| FG001 | Xifaxan 200 mg Tablets | Participants received a xifaxan 200 mg tablet 3 times daily orally for 3 days. |
| FG002 | Rifaximin Placebo Tablets | Participants received a rifaximin placebo tablet 3 times daily orally for 3 days. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Randomized population included all the participants who satisfied the inclusion and exclusion criteria and were randomized into the study.
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| ID | Title | Description |
|---|---|---|
| BG000 | Generic Rifaximin 200 mg Tablets | Participants received a generic rifaximin 200 mg tablet 3 times daily orally for 3 days. |
| BG001 | Xifaxan 200 mg Tablets | Participants received a xifaxan 200 mg tablet 3 times daily orally for 3 days. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Count of Participants | Participants | TOC visit (Day 5, 6 or 7) |
Day 1 up to Day 7
Safety population included all randomized participants who received at least 1 dose of study drug.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Generic Rifaximin 200 mg Tablets | Participants received a generic rifaximin 200 mg tablet 3 times daily orally for 3 days. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Lymphocytosis | Blood and lymphatic system disorders | MedDRA 18.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Director, CE Studies | Teva Pharmaceuticals Inc. USA | 1-888-483-8279 | USMedInfo@tevapharm.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| SAP | No | Yes | No | Statistical Analysis Plan | Apr 19, 2017 | Dec 3, 2019 | SAP_000.pdf |
| Prot | Yes | No | No | Study Protocol | Oct 27, 2015 | Dec 3, 2019 | Prot_001.pdf |
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| ID | Term |
|---|---|
| D003967 | Diarrhea |
| ID | Term |
|---|---|
| D012817 | Signs and Symptoms, Digestive |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000078262 | Rifaximin |
| ID | Term |
|---|---|
| D012294 | Rifamycins |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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| Xifaxan® |
| Drug |
Tablets, brand product. |
|
| Placebo Tablet | Drug | Placebo tablets in the same image of the generic rifaximin. Has no active ingredient. |
|
| Day 1 to Day 5 |
| 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. | TOC visit (Day 5, 6, or 7) |
| Lost to Follow-up |
|
| Participant taken prohibited medication |
|
| BG002 | Rifaximin Placebo Tablets | Participants received a rifaximin placebo tablet 3 times daily orally for 3 days. |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | 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. | 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. | Posted | Median | Full Range | hours | Day 1 to Day 5 |
|
|
|
| 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. | 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. | Posted | Number | percentage of participants | TOC visit (Day 5, 6, or 7) |
|
|
|
| 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. | 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. | Posted | Count of Participants | Participants | TOC visit (Day 5, 6 ,or 7) |
|
|
|
|
| 0 |
| 246 |
| 0 |
| 246 |
| 17 |
| 246 |
| EG001 | Xifaxan 200 mg Tablets | Participants received a xifaxan 200 mg tablet 3 times daily orally for 3 days. | 0 | 247 | 0 | 247 | 17 | 247 |
| EG002 | Rifaximin Placebo Tablets | Participants received a rifaximin placebo tablet 3 times daily orally for 3 days. | 0 | 244 | 0 | 244 | 24 | 244 |
| Abdominal pain | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA 18.1 | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA 18.1 | Systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | MedDRA 18.1 | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA 18.1 | Systematic Assessment |
|
| Defecation urgency | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Dry mouth | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Flatulence | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Rectal tenesmus | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Food allergy | Immune system disorders | MedDRA 18.1 | Systematic Assessment |
|
| Seasonal allergy | Immune system disorders | MedDRA 18.1 | Systematic Assessment |
|
| Blood bilirubin increased | Investigations | MedDRA 18.1 | Systematic Assessment |
|
| Protein urine present | Investigations | MedDRA 18.1 | Systematic Assessment |
|
| Urine leukocyte esterase | Investigations | MedDRA 18.1 | Systematic Assessment |
|
| Weight decreased | Investigations | MedDRA 18.1 | Systematic Assessment |
|
| White blood cells urine positive | Investigations | MedDRA 18.1 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 18.1 | Systematic Assessment |
|
The results of the study may be published or presented by the Investigator(s) after the review by, and in consultation and agreement with the Sponsor, and such that confidential or proprietary information is not disclosed.
| D047029 | Lactams, Macrocyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |
| Enterotoxigenic Escherichia coli (ETEC) |
|
|
| Enteroaggregative Escherichia coli (EAEC) |
|
|
| Other microorganisms |
|
|
| Stool microscopy for ova and parasites |
|
|
95% CIs was calculated using Z-test with Yates' correction.
| Z-test |
| 0.5987 |
Threshold for significance at 0.05 level. |
| Difference in percentage of participants |
| 0.0330 |
| 2-Sided |
| 95 |
| -0.07 |
| 0.14 |
| Superiority |