Effects of S. Boulardii and Amoxicillin/Clavulanate on Gut Microbiota

• Sponsor: Beth Israel Deaconess Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01473368
• Collaborator: Biocodex (Industry)
• Enrollment: 53
• Location: 1
• Arms: 4
• Duration (Months): 10.1
• Patients Per Site Per Month: 5.3

Study Details

Study Description

Brief Summary

The purpose of this study is to compare and contrast the effects of the probiotic Saccharomyces boulardii, the antibiotic amoxicillin/clavulanate and the combination on the gut microbiota of healthy volunteers.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Dietary Supplement: Saccharomyces boulardii; Drug: Amoxicillin Clavulanate	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 53 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Open Label, Randomized Pilot Study to Examine The Effects of the Probiotic Saccharomyces Boulardii, the Antibiotic Amoxicillin/Clavulanate and the Combination on the Gut Microbiota of Healthy Volunteers
• Study Start Date: Apr 1, 2012
• Actual Primary Completion Date: Feb 1, 2013
• Actual Study Completion Date: Feb 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: prebiotic (Saccharomyces boulardii) 500 mg, 2 times daily for 14 days	Dietary Supplement: Saccharomyces boulardii; 500 mg, 2 times daily for 14 days
Active Comparator: antibiotic (Amoxicillin Clavulanate) 875/125 mg 2 times daily at least 1 hour before meals for 7 days	Drug: Amoxicillin Clavulanate; 875/125 mg 2 times daily at least 1 hour before meals for 7 days
Active Comparator: combination (prebiotic and antibiotic) Amoxicillin Clavulanate for 7 days (days 1 to 7; 875/125 mg 2 times daily at least 1 hour before meals) in addition to the dietary supplement Saccharomyces boulardii for 14 days (days 1 to 14; 500 mg, 2 times daily).	Dietary Supplement: Saccharomyces boulardii; 500 mg, 2 times daily for 14 days; Drug: Amoxicillin Clavulanate; 875/125 mg 2 times daily at least 1 hour before meals for 7 days
No Intervention: control

Outcome Measures

Primary Outcome Measures

1. Gastrointestinal Symptom Rating Scale [Day 0]

   Mean Gastrointestinal Symptom Rating Scale scores Range from 15 to 90 Increasing score means increasing symptoms

2. Gastrointestinal Symptom Rating Scale [Day 7]

   Mean Gastrointestinal Symptom Rating Scale scores Range from 15 to 90 Increasing score means increasing symptoms

3. Gastrointestinal Symptoms Response Score [Day 14]

   Mean Gastrointestinal Symptom Rating Scale scores Range from 15 to 90 Increasing score means increasing symptoms

4. Gastrointestinal Symptoms Response Scale [Day 21]

   Mean Gastrointestinal Symptom Rating Scale scores Range from 15 to 90 Increasing score means increasing symptoms

5. Prevalence of Escherichia in Stool [Day -7 to Day 21]

   Control arm was not assessed as there was no intervention for this group. Before Treatment: Average of Day -7 and Day 0 During Treatment: Average of Day 3, Day 7, Day 10, Day 13 After Treatment: Average of Day 21

6. Operational Taxonomic Units [Day 0 to Day 21]

   Core Microbiome includes control samples and baseline samples (Day -7 and Day 0) for antibiotic, probiotic, and combination groups. Data for Core microbiome for individual arms are not available. Before Treatment: Average of Day -7 and Day 0 During Treatment: Average of Day 3, Day 7, Day 10, Day 13 After Treatment: Average of Day 21

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Age 18 to 65 years (male or female)

• Good general health

• Able to comply with study requirements and to provide informed consent

• For women of childbearing potential oA negative urine pregnancy test immediately prior to starting the study treatment oAgreement to comply with approved methods of contraception during the period of active study treatment (not required during follow-up)

Exclusion Criteria:

• History of organ transplantation

• Known chronic or recurrent systemic disorder associated with immunocompromise

• A history of allergy or hypersensitivity to Saccharomyces boulardii, brewer's or baker's yeast, amoxicillin, penicillins, or cephalosporins

• History of severe allergic reaction (requiring hospital admission and/or the administration of parenteral medication or associated with dyspnoea, wheezing, hypotension, loss of consciousness).

• Oral or systemic antibacterial therapy during the 3 months prior to study enrollment

• New prescription medications during the 4 weeks prior to study enrollment

• Prescription, OTC medications or supplements that are known to alter gut function or microflora (i.e. acid antisecretory drugs, probiotics) during the 4 weeks prior to study enrollment

• Active gastrointestinal disease

• Patients with a central venous catheter

• Patients taking antifungals or laxatives within 14 days of enrolment

• Patients enrolled in other clinical trials within the past 60 days

• Prior gastrointestinal surgery (apart from appendectomy or cholecystectomy)

• History of chronic constipation with passage of fewer than 3 bowel movements per week on average

• Any condition or personal circumstance that, in the opinion of the investigator, renders the subject unlikely or unable to comply with the full study protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• Beth Israel Deaconess Medical Center
• Biocodex

Investigators

• Principal Investigator: Ciaran P Kelly, MD, Beth Israel Deaconess Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ciaran Kelly, Professor of Medicine, Beth Israel Deaconess Medical Center
• ClinicalTrials.gov Identifier: NCT01473368
• Other Study ID Numbers: 2011P000389
• First Posted: Nov 17, 2011
• Last Update Posted: Apr 4, 2017
• Last Verified: Mar 1, 2017

• Keywords provided by Ciaran Kelly, Professor of Medicine, Beth Israel Deaconess Medical Center: human Gut Microbiota; gut microbiota; gut microbiome; probiotic; antibiotic; antibiotic-associated diarrhea; intestinal bacterial overgrowth
• Additional relevant MeSH terms: Amoxicillin; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination

Study Results

Participant Flow

Arm/Group Title	Prebiotic (Saccharomyces Boulardii)	Antibiotic (Amoxicillin Clavulanate)	Combination (Prebiotic and Antibiotic)	Control
Arm/Group Description	Saccharomyces boulardii: 500 mg, 2 times daily for 14 days	Amoxicillin Clavulanate: 875/125 mg 2 times daily at least 1 hour before meals for 7 days	Saccharomyces boulardii AND Amoxicillin Clavulanate: Amoxicillin Clavulanate for 7 days (days 1 to 7; 875/125 mg 2 times daily at least 1 hour before meals) in addition to the dietary supplement Saccharomyces boulardii for 14 days (days 1 to 14; 500 mg, 2 times daily).	Control group
Period Title: Overall Study
STARTED	14	12	15	12
COMPLETED	13	12	12	12
NOT COMPLETED	1	0	3	0

Baseline Characteristics

Arm/Group Title	Prebiotic (Saccharomyces Boulardii)	Antibiotic (Amoxicillin Clavulanate)	Combination (Prebiotic and Antibiotic)	Control	Total
Arm/Group Description	Saccharomyces boulardii: 500 mg, 2 times daily for 14 days	Amoxicillin Clavulanate: 875/125 mg 2 times daily at least 1 hour before meals for 7 days	Saccharomyces boulardii AND Amoxicillin Clavulanate: Amoxicillin Clavulanate for 7 days (days 1 to 7; 875/125 mg 2 times daily at least 1 hour before meals) in addition to the dietary supplement Saccharomyces boulardii for 14 days (days 1 to 14; 500 mg, 2 times daily).	control group	Total of all reporting groups
Overall Participants	13	12	12	12	49
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	13 100%	12 100%	12 100%	12 100%	49 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31.6 (9.9)	27.4 (6.6)	34.2 (11.4)	27.2 (4.3)	30.1 (8.8)
Sex: Female, Male (Count of Participants)
Female	10 76.9%	7 58.3%	7 58.3%	5 41.7%	29 59.2%
Male	3 23.1%	5 41.7%	5 41.7%	7 58.3%	20 40.8%
Region of Enrollment (participants) [Number]
United States	13 100%	12 100%	12 100%	12 100%	49 100%

Outcome Measures

1. Primary Outcome

Title	Gastrointestinal Symptom Rating Scale
Description	Mean Gastrointestinal Symptom Rating Scale scores Range from 15 to 90 Increasing score means increasing symptoms
Time Frame	Day 0

Outcome Measure Data

Analysis Population Description

Control participants were not assessed at this time point.

Arm/Group Title	Prebiotic (Saccharomyces Boulardii)	Antibiotic (Amoxicillin Clavulanate)	Combination (Prebiotic and Antibiotic)
Arm/Group Description	Saccharomyces boulardii: 500 mg, 2 times daily for 14 days	Amoxicillin Clavulanate: 875/125 mg 2 times daily at least 1 hour before meals for 7 days	Saccharomyces boulardii AND Amoxicillin Clavulanate: Amoxicillin Clavulanate for 7 days (days 1 to 7; 875/125 mg 2 times daily at least 1 hour before meals) in addition to the dietary supplement Saccharomyces boulardii for 14 days (days 1 to 14; 500 mg, 2 times daily).
Measure Participants	13	12	12
Mean (Standard Deviation) [units on a scale]	18.7 (5.4)	18.7 (3.8)	17.3 (2.4)

2. Primary Outcome

Title	Gastrointestinal Symptom Rating Scale
Description	Mean Gastrointestinal Symptom Rating Scale scores Range from 15 to 90 Increasing score means increasing symptoms
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Prebiotic (Saccharomyces Boulardii)	Antibiotic (Amoxicillin Clavulanate)	Combination (Prebiotic and Antibiotic)	Control
Arm/Group Description	Saccharomyces boulardii: 500 mg, 2 times daily for 14 days	Amoxicillin Clavulanate: 875/125 mg 2 times daily at least 1 hour before meals for 7 days	Saccharomyces boulardii AND Amoxicillin Clavulanate: Amoxicillin Clavulanate for 7 days (days 1 to 7; 875/125 mg 2 times daily at least 1 hour before meals) in addition to the dietary supplement Saccharomyces boulardii for 14 days (days 1 to 14; 500 mg, 2 times daily).	Control group
Measure Participants	13	12	12	12
Mean (Standard Deviation) [Units on a scale]	23.2 (8.8)	26.9 (14.2)	18.1 (3.0)	19.3 (8.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antibiotic (Amoxicillin Clavulanate), Combination (Prebiotic and Antibiotic)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.026
	Comments
	Method	ANOVA
	Comments

3. Primary Outcome

Title	Gastrointestinal Symptoms Response Score
Description	Mean Gastrointestinal Symptom Rating Scale scores Range from 15 to 90 Increasing score means increasing symptoms
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

Participants analyzed were those with complete data at Day 14

Arm/Group Title	Prebiotic (Saccharomyces Boulardii)	Antibiotic (Amoxicillin Clavulanate)	Combination (Prebiotic and Antibiotic)	Control
Arm/Group Description	Saccharomyces boulardii: 500 mg, 2 times daily for 14 days	Amoxicillin Clavulanate: 875/125 mg 2 times daily at least 1 hour before meals for 7 days	Saccharomyces boulardii AND Amoxicillin Clavulanate: Amoxicillin Clavulanate for 7 days (days 1 to 7; 875/125 mg 2 times daily at least 1 hour before meals) in addition to the dietary supplement Saccharomyces boulardii for 14 days (days 1 to 14; 500 mg, 2 times daily).	Control group
Measure Participants	12	11	12	12
Mean (Standard Deviation) [units on a scale]	19.3 (5.1)	20.3 (5.9)	16.8 (1.6)	18.1 (4.3)

4. Primary Outcome

Title	Gastrointestinal Symptoms Response Scale
Description	Mean Gastrointestinal Symptom Rating Scale scores Range from 15 to 90 Increasing score means increasing symptoms
Time Frame	Day 21

Outcome Measure Data

Analysis Population Description

Participants analyzed were those with complete data at Day 14

Arm/Group Title	Prebiotic (Saccharomyces Boulardii)	Antibiotic (Amoxicillin Clavulanate)	Combination (Prebiotic and Antibiotic)	Control
Arm/Group Description	Saccharomyces boulardii: 500 mg, 2 times daily for 14 days	Amoxicillin Clavulanate: 875/125 mg 2 times daily at least 1 hour before meals for 7 days	Saccharomyces boulardii AND Amoxicillin Clavulanate: Amoxicillin Clavulanate for 7 days (days 1 to 7; 875/125 mg 2 times daily at least 1 hour before meals) in addition to the dietary supplement Saccharomyces boulardii for 14 days (days 1 to 14; 500 mg, 2 times daily).	Control group
Measure Participants	12	11	12	12
Mean (Standard Deviation) [units on a scale]	19.3 (5.7)	18.4 (5.8)	16.5 (2.9)	15.8 (2.3)

5. Primary Outcome

Title	Prevalence of Escherichia in Stool
Description	Control arm was not assessed as there was no intervention for this group. Before Treatment: Average of Day -7 and Day 0 During Treatment: Average of Day 3, Day 7, Day 10, Day 13 After Treatment: Average of Day 21
Time Frame	Day -7 to Day 21

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Prebiotic (Saccharomyces Boulardii) Before Treatment	Prebiotic (Saccharomyces Boulardii) During Treatment	Prebiotic (Saccharomyces Boulardii) After Treatment
Arm/Group Description	Before treatment Saccharomyces boulardii: 500 mg, 2 times daily for 14 days	During treatment Saccharomyces boulardii: 500 mg, 2 times daily for 14 days	After treatment Saccharomyces boulardii: 500 mg, 2 times daily for 14 days
Measure Participants	13	13	12
Mean (Standard Deviation) [percentage of total bacteria]	0.0 (0)	0.0 (0)	0.1 (0)

6. Primary Outcome

Title	Prevalence of Escherichia in Stool
Description	Control arm was not assessed as there was no intervention for this group. Before Treatment: Average of Day -7 and Day 0 During Treatment: Average of Day 3, Day 7, Day 10, Day 13 After Treatment: Average of Day 21
Time Frame	Day -7 to Day 21

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Antibiotic (Amoxicillin Clavulanate) Before Treatment	Antibiotic (Amoxicillin Clavulanate) During Treatment	Antibiotic (Amoxicillin Clavulanate) After Treatment
Arm/Group Description	Before treatment Amoxicillin Clavulanate: 875/125 mg 2 times daily at least 1 hour before meals for 7 days	During treatment Amoxicillin Clavulanate: 875/125 mg 2 times daily at least 1 hour before meals for 7 days	After treatment Amoxicillin Clavulanate: 875/125 mg 2 times daily at least 1 hour before meals for 7 days
Measure Participants	12	12	11
Mean (Standard Deviation) [percentage of total bacteria]	0.1 (0)	4.5 (0)	0.2 (0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Prebiotic (Saccharomyces Boulardii), Antibiotic (Amoxicillin Clavulanate), Combination (Prebiotic and Antibiotic)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANOVA
	Comments

7. Primary Outcome

Title	Prevalence of Escherichia in Stool
Description	Control arm was not assessed as there was no intervention for this group. Before Treatment: Average of Day -7 and Day 0 During Treatment: Average of Day 3, Day 7, Day 10, Day 13 After Treatment: Average of Day 21
Time Frame	Day -7 to Day 21

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combination (Prebiotic and Antibiotic) Before Treatment	Combination (Prebiotic and Antibiotic) During Treatment	Combination (Prebiotic and Antibiotic) After Treatment
Arm/Group Description	Before treatment Saccharomyces boulardii AND Amoxicillin Clavulanate: Amoxicillin Clavulanate for 7 days (days 1 to 7; 875/125 mg 2 times daily at least 1 hour before meals) in addition to the dietary supplement Saccharomyces boulardii for 14 days (days 1 to 14; 500 mg, 2 times daily).	During treatment Saccharomyces boulardii AND Amoxicillin Clavulanate: Amoxicillin Clavulanate for 7 days (days 1 to 7; 875/125 mg 2 times daily at least 1 hour before meals) in addition to the dietary supplement Saccharomyces boulardii for 14 days (days 1 to 14; 500 mg, 2 times daily).	After treatment Saccharomyces boulardii AND Amoxicillin Clavulanate: Amoxicillin Clavulanate for 7 days (days 1 to 7; 875/125 mg 2 times daily at least 1 hour before meals) in addition to the dietary supplement Saccharomyces boulardii for 14 days (days 1 to 14; 500 mg, 2 times daily).
Measure Participants	12	12	12
Mean (Standard Deviation) [percentage of total bacteria]	0.0 (0)	2.9 (0)	0.2 (0)

8. Primary Outcome

Title	Operational Taxonomic Units
Description	Core Microbiome includes control samples and baseline samples (Day -7 and Day 0) for antibiotic, probiotic, and combination groups. Data for Core microbiome for individual arms are not available. Before Treatment: Average of Day -7 and Day 0 During Treatment: Average of Day 3, Day 7, Day 10, Day 13 After Treatment: Average of Day 21
Time Frame	Day 0 to Day 21

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combination (Prebiotic and Antibiotic) During Treatment	Combination (Prebiotic and Antibiotic) After Treatment	Antibiotic (Amoxicillin Clavulanate) During Treatment	Antibiotic (Amoxicillin Clavulanate) After Treatment	Core Microbiome	Prebiotic (Saccharomyces Boulardii) During Treatment	Prebiotic (Saccharomyces Boulardii) After Treatment
Arm/Group Description	During Treatment Saccharomyces boulardii AND Amoxicillin Clavulanate: Amoxicillin Clavulanate for 7 days (days 1 to 7; 875/125 mg 2 times daily at least 1 hour before meals) in addition to the dietary supplement Saccharomyces boulardii for 14 days (days 1 to 14; 500 mg, 2 times daily).	After Treatment Saccharomyces boulardii AND Amoxicillin Clavulanate: Amoxicillin Clavulanate for 7 days (days 1 to 7; 875/125 mg 2 times daily at least 1 hour before meals) in addition to the dietary supplement Saccharomyces boulardii for 14 days (days 1 to 14; 500 mg, 2 times daily).	During Treatment Amoxicillin Clavulanate: 875/125 mg 2 times daily at least 1 hour before meals for 7 days	After Treatment Amoxicillin Clavulanate: 875/125 mg 2 times daily at least 1 hour before meals for 7 days	Core Microbiome	During Treatment Saccharomyces boulardii: 500 mg, 2 times daily for 14 days	After Treatment Saccharomyces boulardii: 500 mg, 2 times daily for 14 days
Measure Participants	13	12	12	11	49	12	12
Mean (Standard Deviation) [units]	449.8 (210.1)	509.9 (251.9)	461.1 (228.2)	668.8 (188.4)	730.9 (240.4)	776.7 (167.6)	776.7 (749.1)

Adverse Events

Arm/Group Title	Prebiotic (Saccharomyces Boulardii)		Antibiotic (Amoxicillin Clavulanate)		Combination (Prebiotic and Antibiotic)		Control
Arm/Group Description	Saccharomyces boulardii: 500 mg, 2 times daily for 14 days		Amoxicillin Clavulanate: 875/125 mg 2 times daily at least 1 hour before meals for 7 days		Saccharomyces boulardii AND Amoxicillin Clavulanate: Amoxicillin Clavulanate for 7 days (days 1 to 7; 875/125 mg 2 times daily at least 1 hour before meals) in addition to the dietary supplement Saccharomyces boulardii for 14 days (days 1 to 14; 500 mg, 2 times daily).
All Cause Mortality
	Prebiotic (Saccharomyces Boulardii)		Antibiotic (Amoxicillin Clavulanate)		Combination (Prebiotic and Antibiotic)		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Prebiotic (Saccharomyces Boulardii)		Antibiotic (Amoxicillin Clavulanate)		Combination (Prebiotic and Antibiotic)		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Prebiotic (Saccharomyces Boulardii)		Antibiotic (Amoxicillin Clavulanate)		Combination (Prebiotic and Antibiotic)		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/13 (38.5%)		6/12 (50%)		2/12 (16.7%)		1/12 (8.3%)
Gastrointestinal disorders
Abdominal distension	4/13 (30.8%)		1/12 (8.3%)		0/12 (0%)		1/12 (8.3%)
Abdominal pain	1/13 (7.7%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)
Abdominal pain upper	0/13 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)
Constipation	2/13 (15.4%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)
diarrhea	1/13 (7.7%)		3/12 (25%)		1/12 (8.3%)		0/12 (0%)
dyspepsia	0/13 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)
eructation	1/13 (7.7%)		0/12 (0%)		0/12 (0%)		0/12 (0%)
flatulence	2/13 (15.4%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)
gastrointestinal motility disorder	0/13 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)
Gastrointestinal sounds abnormal	1/13 (7.7%)		2/12 (16.7%)		0/12 (0%)		0/12 (0%)
infrequent bowel movements	0/13 (0%)		0/12 (0%)		1/12 (8.3%)		0/12 (0%)
regurgitation	1/13 (7.7%)		0/12 (0%)		0/12 (0%)		0/12 (0%)
Metabolism and nutrition disorders
decreased appetite	1/13 (7.7%)		0/12 (0%)		0/12 (0%)		0/12 (0%)
Reproductive system and breast disorders
vulvovaginal rash	0/13 (0%)		2/12 (16.7%)		0/12 (0%)		0/12 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.