Study Comparing Rifaximin With Xifaxan 200 mg in Traveler's Diarrhea

• Sponsor: Actavis Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02498418
• Collaborator: (none)
• Enrollment: 739
• Location: 1
• Arms: 3
• Actual Duration (Months): 13.8
• Patients Per Site Per Month: 53.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Diarrhea	Drug: Rifaximin; Drug: Xifaxan®; Drug: Placebo Tablet	Phase 3

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 739 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel Design, Multicenter, Bioequivalence Study With Clinical Endpoint Comparing Rifaximin 200-mg Tablets With Xifaxan® 200-mg Tablets in the Treatment of Travelers' Diarrhea
• Actual Study Start Date: Jan 6, 2016
• Actual Primary Completion Date: Feb 28, 2017
• Actual Study Completion Date: Feb 28, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Generic Rifaximin 200 mg Tablets Participants will receive a generic rifaximin 200 mg tablet 3 times daily orally for 3 days.	Drug: Rifaximin; Tablets, generic formulation of the brand product.
Active Comparator: Xifaxan 200 mg Tablets Participants will receive a xifaxan 200 mg tablet 3 times daily orally for 3 days.	Drug: Xifaxan®; Tablets, brand product.
Placebo Comparator: Placebo Participants will receive a rifaximin placebo tablet 3 times daily orally for 3 days.	Drug: Placebo Tablet; Placebo tablets in the same image of the generic rifaximin. Has no active ingredient.

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

1. 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.

1. 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.

2. 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

1. Use of any drug such as aspirin or ibuprofen (Advil), which can cause GI bleeding. Acetaminophen (Tylenol) or paracetamol is acceptable.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Site 1	Coral Gables	Florida	United States	33134

Sponsors and Collaborators

• Actavis Inc.

Investigators

• Study Director: Study Director, Actavis Inc.

Study Documents (Full-Text)

• Statistical Analysis Plan - Apr 19, 2017
• Study Protocol - Oct 27, 2015

More Information

Publications

None provided.

• Responsible Party: Actavis Inc.
• ClinicalTrials.gov Identifier: NCT02498418
• Other Study ID Numbers: ACTA/RIFX/2015
• First Posted: Jul 15, 2015
• Last Update Posted: Dec 5, 2019
• Last Verified: Dec 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Diarrhea; Rifaximin

Study Results

Participant Flow

Pre-assignment Detail	A total of 739 nonindigenous travelers with naturally acquired acute diarrhea were enrolled and randomized in this study.

Arm/Group Title	Generic Rifaximin 200 mg Tablets	Xifaxan 200 mg Tablets	Rifaximin Placebo Tablets
Arm/Group Description	Participants received a generic rifaximin 200 milligrams (mg) tablet 3 times daily orally for 3 days.	Participants received a xifaxan 200 mg tablet 3 times daily orally for 3 days.	Participants received a rifaximin placebo tablet 3 times daily orally for 3 days.
Period Title: Overall Study
STARTED	247	248	244
Safety Population	246	247	244
Modified Intent-to-treat Population	183	186	180
Per-protocol Analysis Set	182	181	176
COMPLETED	245	246	238
NOT COMPLETED	2	2	6

Baseline Characteristics

Arm/Group Title	Generic Rifaximin 200 mg Tablets	Xifaxan 200 mg Tablets	Rifaximin Placebo Tablets	Total
Arm/Group Description	Participants received a generic rifaximin 200 mg tablet 3 times daily orally for 3 days.	Participants received a xifaxan 200 mg tablet 3 times daily orally for 3 days.	Participants received a rifaximin placebo tablet 3 times daily orally for 3 days.	Total of all reporting groups
Overall Participants	247	248	244	739
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.5 (15.78)	44.3 (16.58)	42.0 (15.21)	42.9 (15.87)
Sex: Female, Male (Count of Participants)
Female	123 49.8%	130 52.4%	132 54.1%	385 52.1%
Male	124 50.2%	118 47.6%	112 45.9%	354 47.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	189 76.5%	188 75.8%	188 77%	565 76.5%
Not Hispanic or Latino	58 23.5%	58 23.4%	54 22.1%	170 23%
Unknown or Not Reported	0 0%	2 0.8%	2 0.8%	4 0.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	3 1.2%	2 0.8%	2 0.8%	7 0.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	23 9.3%	18 7.3%	13 5.3%	54 7.3%
White	208 84.2%	222 89.5%	220 90.2%	650 88%
More than one race	13 5.3%	5 2%	9 3.7%	27 3.7%
Unknown or Not Reported	0 0%	1 0.4%	0 0%	1 0.1%

Outcome Measures

1. Primary Outcome

Title	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
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Generic Rifaximin 200 mg Tablets	Xifaxan 200 mg Tablets
Arm/Group Description	Participants received a generic rifaximin 200 mg tablet 3 times daily orally for 3 days.	Participants received a xifaxan 200 mg tablet 3 times daily orally for 3 days.
Measure Participants	182	181
Count of Participants [Participants]	90 36.4%	93 37.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Generic Rifaximin 200 mg Tablets, Xifaxan 200 mg Tablets
	Comments	Bioequivalence was evaluated based on the PP analysis set using Z-test with Yates correction.
	Type of Statistical Test	Equivalence
	Comments	Bioequivalence was demonstrated if 90% confidence interval (CI) of percentage difference between generic rifaximin 200 mg tablets and xifaxan 200 mg tablets was within the equivalence range (-20%, +20%).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in percentage of participants
	Estimated Value	-0.0193
	Confidence Interval	(2-Sided) 90%; -0.11 to 0.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Time to Last Unformed Stool (TLUS)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Generic Rifaximin 200 mg Tablets	Xifaxan 200 mg Tablets	Rifaximin Placebo Tablets
Arm/Group Description	Participants received a generic rifaximin 200 mg tablet 3 times daily orally for 3 days.	Participants received a xifaxan 200 mg tablet 3 times daily orally for 3 days.	Participants received a rifaximin placebo tablet 3 times daily orally for 3 days.
Measure Participants	182	186	178
Median (Full Range) [hours]	65.25	65.75	67.01

3. Secondary Outcome

Title	Percentage of Participants Who Achieved Microbiological Cure at TOC Visit (Within 24 to 72 Hours From the Time of Last Dose)
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Generic Rifaximin 200 mg Tablets	Xifaxan 200 mg Tablets	Rifaximin Placebo Tablets
Arm/Group Description	Participants received a generic rifaximin 200 mg tablet 3 times daily orally for 3 days.	Participants received a xifaxan 200 mg tablet 3 times daily orally for 3 days.	Participants received a rifaximin placebo tablet 3 times daily orally for 3 days.
Measure Participants	51	47	46
Escherichia coli	25.5 10.3%	31.9 12.9%	17.4 7.1%
Enterotoxigenic Escherichia coli (ETEC)	43.5 17.6%	54.5 22%	68.4 28%
Enteroaggregative Escherichia coli (EAEC)	32.0 13%	27.3 11%	26.1 10.7%
Other microorganisms	70.6 28.6%	81.8 33%	92.9 38.1%
Stool microscopy for ova and parasites	83.3 33.7%	100.0 40.3%	100.0 41%

4. Primary Outcome

Title	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
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Generic Rifaximin 200 mg Tablets	Xifaxan 200 mg Tablets	Rifaximin Placebo Tablets
Arm/Group Description	Participants received a generic rifaximin 200 mg tablet 3 times daily orally for 3 days.	Participants received a xifaxan 200 mg tablet 3 times daily orally for 3 days.	Participants received a rifaximin placebo tablet 3 times daily orally for 3 days.
Measure Participants	183	186	180
Count of Participants [Participants]	91 36.8%	95 38.3%	86 35.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Generic Rifaximin 200 mg Tablets, Rifaximin Placebo Tablets
	Comments	95% CIs was calculated using Z-test with Yates' correction.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7899
	Comments	Threshold of significance at 0.05 level.
	Method	Z-test
	Comments
Method of Estimation	Estimation Parameter	Difference in percentage of participants
	Estimated Value	-0.0195
	Confidence Interval	(2-Sided) 95%; -0.09 to 0.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Xifaxan 200 mg Tablets, Rifaximin Placebo Tablets
	Comments	95% CIs was calculated using Z-test with Yates' correction.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5987
	Comments	Threshold for significance at 0.05 level.
	Method	Z-test
	Comments
Method of Estimation	Estimation Parameter	Difference in percentage of participants
	Estimated Value	0.0330
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Day 1 up to Day 7
Adverse Event Reporting Description	Safety population included all randomized participants who received at least 1 dose of study drug.
Arm/Group Title	Generic Rifaximin 200 mg Tablets		Xifaxan 200 mg Tablets		Rifaximin Placebo Tablets
Arm/Group Description	Participants received a generic rifaximin 200 mg tablet 3 times daily orally for 3 days.		Participants received a xifaxan 200 mg tablet 3 times daily orally for 3 days.		Participants received a rifaximin placebo tablet 3 times daily orally for 3 days.
All Cause Mortality
	Generic Rifaximin 200 mg Tablets		Xifaxan 200 mg Tablets		Rifaximin Placebo Tablets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/246 (0%)		0/247 (0%)		0/244 (0%)
Serious Adverse Events
	Generic Rifaximin 200 mg Tablets		Xifaxan 200 mg Tablets		Rifaximin Placebo Tablets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/246 (0%)		0/247 (0%)		0/244 (0%)
Other (Not Including Serious) Adverse Events
	Generic Rifaximin 200 mg Tablets		Xifaxan 200 mg Tablets		Rifaximin Placebo Tablets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/246 (6.9%)		17/247 (6.9%)		24/244 (9.8%)
Blood and lymphatic system disorders
Lymphocytosis	0/246 (0%)		0/247 (0%)		1/244 (0.4%)
Neutropenia	0/246 (0%)		0/247 (0%)		1/244 (0.4%)
Thrombocytopenia	1/246 (0.4%)		0/247 (0%)		1/244 (0.4%)
Gastrointestinal disorders
Abdominal pain	3/246 (1.2%)		0/247 (0%)		3/244 (1.2%)
Defecation urgency	1/246 (0.4%)		1/247 (0.4%)		2/244 (0.8%)
Dry mouth	1/246 (0.4%)		0/247 (0%)		1/244 (0.4%)
Dyspepsia	0/246 (0%)		1/247 (0.4%)		0/244 (0%)
Flatulence	4/246 (1.6%)		3/247 (1.2%)		4/244 (1.6%)
Nausea	0/246 (0%)		3/247 (1.2%)		3/244 (1.2%)
Rectal tenesmus	3/246 (1.2%)		4/247 (1.6%)		8/244 (3.3%)
Vomiting	0/246 (0%)		0/247 (0%)		1/244 (0.4%)
Immune system disorders
Food allergy	0/246 (0%)		1/247 (0.4%)		0/244 (0%)
Seasonal allergy	0/246 (0%)		1/247 (0.4%)		0/244 (0%)
Infections and infestations
Urinary tract infection	1/246 (0.4%)		0/247 (0%)		0/244 (0%)
Investigations
Alanine aminotransferase increased	0/246 (0%)		0/247 (0%)		1/244 (0.4%)
Blood bilirubin increased	1/246 (0.4%)		0/247 (0%)		0/244 (0%)
Protein urine present	0/246 (0%)		1/247 (0.4%)		0/244 (0%)
Urine leukocyte esterase	1/246 (0.4%)		0/247 (0%)		0/244 (0%)
Weight decreased	0/246 (0%)		1/247 (0.4%)		0/244 (0%)
White blood cells urine positive	1/246 (0.4%)		1/247 (0.4%)		0/244 (0%)
Nervous system disorders
Dizziness	0/246 (0%)		1/247 (0.4%)		0/244 (0%)
Headache	2/246 (0.8%)		2/247 (0.8%)		3/244 (1.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.