Study to Evaluate Safety and Efficacy of Rifamycin SV Multi-Matrix System (MMX) for the Treatment of Traveler's Diarrhea (TD)

• Sponsor: Cosmo Technologies Ltd (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01142089
• Collaborator: Bausch Health Americas, Inc. (Industry)
• Enrollment: 264
• Locations: 12
• Arms: 2
• Duration (Months): 24.2
• Patients Per Site: 22
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether Rifamycin SV MMX is a safe and effective treatment for Traveler's Diarrhea.

Condition or Disease	Intervention/Treatment	Phase
Traveler's Diarrhea	Drug: Placebo; Drug: Rifamycin SV MMX	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 264 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Rifamycin SV MMX for the Treatment of Traveler's Diarrhea
• Study Start Date: May 27, 2010
• Actual Primary Completion Date: Jun 1, 2012
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo (two matching tablets) orally twice daily for 3 days (72 hours)	Drug: Placebo; Placebo (two matching tablets) orally twice daily for 3 days (72 hours).
Experimental: Rifamycin SV MMX Rifamycin SV MMX® 400 mg (two 200 mg tablets) orally twice daily for 3 days (72 hours).	Drug: Rifamycin SV MMX; Rifamycin SV MMX® 400 mg (two 200 mg tablets) orally twice daily for 3 days (72 hours).

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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

Eligibility Criteria

Criteria

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Santarus Investigational Site 03	Antigua		Guatemala	03001
2	Santarus Investigational Site 14	Antigua		Guatemala
3	Santarus Investigational Site 04	Quetzaltenango		Guatemala	09001
4	Santarus Investigational Site 05	Guadalajara	Jalisco	Mexico	42670
5	Santarus Investigational Site 06	Cuernavaca	Morelos	Mexico	62240
6	Santarus Investigational Site 12	Cabo San Lucas		Mexico	23440
7	Santarus Investigational Site 10	Cancun		Mexico	77500
8	Santarus Investigational Site 07	Oaxaca		Mexico	6800
9	Santarus Investigational Site 08	Puebla		Mexico	72197
10	Santarus Investigational Site 09	Puerto Escondido		Mexico	71980
11	Santarus Investigational Site 11	Puerto Vallarta		Mexico	48330
12	Santarus Investigational Site 13	Tulum		Mexico	77760

Sponsors and Collaborators

• Cosmo Technologies Ltd
• Bausch Health Americas, Inc.

Investigators

• Principal Investigator: Herbert DuPont, MD, Bausch Health Americas, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Cosmo Technologies Ltd
• ClinicalTrials.gov Identifier: NCT01142089
• Other Study ID Numbers: C2009-0201
• First Posted: Jun 11, 2010
• Last Update Posted: Jun 8, 2018
• Last Verified: Apr 1, 2018

• Keywords provided by Cosmo Technologies Ltd: traveler's; diarrhea; Rifamycin SV MMX; Rifamycin; MMX; Traveler's Diarrhea
• Additional relevant MeSH terms: Dysentery; Diarrhea; Rifamycins; Rifamycin SV

Study Results

Participant Flow

Arm/Group Title	Placebo	Rifamycin SV MMX
Arm/Group Description	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)	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)
Period Title: Overall Study
STARTED	65	199
COMPLETED	53	178
NOT COMPLETED	12	21

Baseline Characteristics

Arm/Group Title	Placebo	Rifamycin SV MMX	Total
Arm/Group Description	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)	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)	Total of all reporting groups
Overall Participants	65	199	264
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28.9 (12.72)	28 (11.43)	28.3 (11.74)
Sex: Female, Male (Count of Participants)
Female	33 50.8%	100 50.3%	133 50.4%
Male	32 49.2%	99 49.7%	131 49.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 1.5%	9 4.5%	10 3.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	5 7.7%	10 5%	15 5.7%
White	56 86.2%	175 87.9%	231 87.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	3 4.6%	5 2.5%	8 3%
Baseline Pathogen Identified (Count of Participants)
Yes	48 73.8%	133 66.8%	181 68.6%
No	17 26.2%	66 33.2%	83 31.4%

Outcome Measures

1. Primary Outcome

Title	Time to Last Unformed Stool (TLUS)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Rifamycin SV MMX
Arm/Group Description	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)	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)
Measure Participants	65	199
25th percentile	37.4	21.
50th percentile	68	46
75th percentile	NA	72.2

2. Secondary Outcome

Title	Clinical Cure
Description	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

Outcome Measure Data

Analysis Population Description

Intent to treat (ITT)

Arm/Group Title	Placebo	Rifamycin SV MMX
Arm/Group Description	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)	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)
Measure Participants	65	199
Count of Participants [Participants]	35 53.8%	162 81.4%

Adverse Events

Time Frame	The Investigator must completely and promptly record each new AE/SAE that occurs after the first dose of study drug through Visit 4 (i.e., treatment emergent AEs) on the appropriate CRF, even if the relationship of an AE to study drug is assessed by the Investigator to be "unlikely" or "not related". In addition, the investigator must document and follow SAEs that occur from Visit 4 through 30 days after the last dose of study drug.
Arm/Group Title	Placebo		Rifamycin SV MMX
Arm/Group Description	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)		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)
All Cause Mortality
	Placebo		Rifamycin SV MMX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/65 (0%)		0/199 (0%)
Serious Adverse Events
	Placebo		Rifamycin SV MMX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/65 (1.5%)		2/199 (1%)
Gastrointestinal disorders
Abdominal pain/vomiting	0/65 (0%)	0	1/199 (0.5%)	1
Infections and infestations
Clostridium difficile colitis	1/65 (1.5%)	1	0/199 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neuroblastoma	0/65 (0%)	0	1/199 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Placebo		Rifamycin SV MMX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/65 (38.5%)		58/199 (29.1%)
Blood and lymphatic system disorders
Neutropenia	1/65 (1.5%)	1	0/199 (0%)	0
Ear and labyrinth disorders
Motion sickness	0/65 (0%)	0	1/199 (0.5%)	1
Eye disorders
Conjunctivitis	0/65 (0%)	0	2/199 (1%)	2
Gastrointestinal disorders
Abdominal distension	0/65 (0%)	0	1/199 (0.5%)	1
Constipation	1/65 (1.5%)	1	7/199 (3.5%)	7
Diarrhoea	6/65 (9.2%)	6	10/199 (5%)	10
Diarrhoea haemorrhagic	1/65 (1.5%)	1	0/199 (0%)	0
Dyspepsia	0/65 (0%)	0	1/199 (0.5%)	1
Gastrointestinal motility disorder	1/65 (1.5%)	1	0/199 (0%)	0
General disorders
Asthenia	1/65 (1.5%)	1	0/199 (0%)	0
Fatigue	0/65 (0%)	0	2/199 (1%)	2
Pain	0/65 (0%)	0	1/199 (0.5%)	1
Infections and infestations
Amoebic dysentery	2/65 (3.1%)	2	0/199 (0%)	0
Bronchitis	0/65 (0%)	0	2/199 (1%)	2
Clostridium difficile colitis	1/65 (1.5%)	1	0/199 (0%)	0
Diarrhoea infectious	5/65 (7.7%)	5	10/199 (5%)	10
Gastrointestinal infection	2/65 (3.1%)	2	0/199 (0%)	0
Nasopharyngitis	0/65 (0%)	0	1/199 (0.5%)	1
Parasitic gastroenteritis	1/65 (1.5%)	1	2/199 (1%)	2
Pharyngitis	0/65 (0%)	0	1/199 (0.5%)	1
Urinary tract infection	0/65 (0%)	0	2/199 (1%)	2
Injury, poisoning and procedural complications
Ligament sprain	0/65 (0%)	0	1/199 (0.5%)	1
Muscle rupture	0/65 (0%)	0	1/199 (0.5%)	1
Metabolism and nutrition disorders
Decreased appetite	0/65 (0%)	0	1/199 (0.5%)	1
Dehydration	1/65 (1.5%)	1	0/199 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/65 (0%)	0	1/199 (0.5%)	1
Muscle spasms	1/65 (1.5%)	1	2/199 (1%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neuroblastoma	0/65 (0%)	0	1/199 (0.5%)	1
Nervous system disorders
Dizziness	1/65 (1.5%)	1	1/199 (0.5%)	1
Headache	6/65 (9.2%)	6	17/199 (8.5%)	17
Somnolence	0/65 (0%)	0	1/199 (0.5%)	1
Psychiatric disorders
Insomnia	0/65 (0%)	0	1/199 (0.5%)	1
Renal and urinary disorders
Dysuria	0/65 (0%)	0	2/199 (1%)	2
Reproductive system and breast disorders
Dysmenorrhoea	0/65 (0%)	0	3/199 (1.5%)	3
Respiratory, thoracic and mediastinal disorders
Epistaxis	0/65 (0%)	0	1/199 (0.5%)	1
Rhinitis allergic	1/65 (1.5%)	1	0/199 (0%)	0
Rhinorrhoea	0/65 (0%)	0	1/199 (0.5%)	1
Skin and subcutaneous tissue disorders
Rash	0/65 (0%)	0	1/199 (0.5%)	1
Vascular disorders
Orthostatic hypotension	0/65 (0%)	0	1/199 (0.5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Principal Investigator will provide Sponsor an opportunity of at least 30 days to review and comment on any proposed publication before it is disclosed and Sponsor shall have the right to require the removal of any Confidential Information. Sponsor shall have the right to require the publication be delayed for an additional period not to exceed 60 days to permit the filing of patent applications or to seek intellectual property protection related to information contained in such publication.