Study of LRG-002 Hard Capsules (Lek d.d., Slovenia) Used in the Prophylaxis of Antibiotic-associated Diarrhea in Adults.

• Sponsor: Sandoz (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04321460
• Collaborator: (none)
• Enrollment: 520
• Locations: 3
• Arms: 2
• Actual Duration (Months): 3.1
• Patients Per Site: 173.3
• Patients Per Site Per Month: 55.5

Study Details

Study Description

Brief Summary

The goal of this study was to investigate the efficacy and safety of LRG-002 investigational medicinal product, capsules (Lek d.d., Slovenia) in comparison with placebo, as an adjunct treatment for prophylaxis of antibiotic-associated diarrhea (AAD) in patients with acute respiratory diseases (ARDs) receiving a standard antimicrobial therapy.

Condition or Disease	Intervention/Treatment	Phase
Antibiotic-associated Diarrhea	Drug: LRG-002; Drug: Placebo	Phase 3

Detailed Description

This study was the prospective, multi-centered, double-blinded, randomized, parallel-group clinical study. The study investigated the efficacy and safety of LRG-002 investigational medicinal product, capsules (Lek d.d., Slovenia) in comparison with placebo, as an adjunct treatment for prophylaxis of antibiotic-associated diarrhea (AAD) in patients with acute respiratory diseases (ARDs) receiving a standard antimicrobial therapy.

The study comprised the following periods:

Study Periods Visit 1 (Day 1): Screening + randomization + initiation of treatment

Patients started participating in the study after signing the Informed Consent Form. Having completed screening tests, eligible patients were randomized on the same day to receive either LRG-002 or matching placebo capsules, each as an adjunct to the prescribed antibiotic. The treatment group was determined by randomization at a center ratio. Study subjects were supplied with the patient diary and blinded investigational product (investigational medicinal product or placebo) depending on the assigned treatment group. Patients could start study treatment only after receiving appropriate training. On Day 1, the study started in both groups from randomization and administration of the first dose of the investigational product depending on the assigned group after randomization:

Group T, treated with LRG-002: a single dose of 1 oral hard capsule taken during meals with some water; the product was to be taken orally 2 times per day for 14 days.

Group R, provided with placebo:a single dose of 1 oral hard capsule taken during meals with some water; the product is to be taken orally 2 times per day for 14 days.

Visit 2 (Day 7): Intermediate Follow-up Visit

Visit 3 (Day 15) : Visit 3 was scheduled at Day 15 when a patient was to come to the study site bringing along the completed diary, unused laboratory kit, unused product and empty packages.

Study Design

• Study Type: Interventional
• Actual Enrollment: 520 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Multicentre, Double-blind, Randomized, Placebo-controlled, Parallel-group Efficacy and Safety Study of LRG-002 Hard Capsules (Lek d.d., Slovenia) Used in the Prophylaxis of Antibiotic-associated Diarrhea in Adults.
• Actual Study Start Date: Oct 1, 2020
• Actual Primary Completion Date: Jan 4, 2021
• Actual Study Completion Date: Jan 4, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LRG-002 LRG-002 once daily for 14 days	Drug: LRG-002; Capsules containing live lyophilized probiotic bacteria of Lactobacillus genus
Placebo Comparator: Placebo Placebo once daily for 14 days	Drug: Placebo; Capsules containing placebo

Outcome Measures

Primary Outcome Measures

1. Number of Participants With the Occurrence of Antibiotic-associated Diarrhea (AAD) - Per Protocol (PP) Population [14 days]

   Diarrhea is defined as loose or watery stool (Type 5-7 according to Bristol Stool Form Scale (BSFS)), three times a day (frequent bowel movements with formed stool is not considered as diarrhea) in accordance with WHO criteria; based on the diary data (BSFS) and confirmation of AAD by the investigator. BSFS scale includes Types 1 to 7 where Types 1 and 2 indicate constipation, with 3 and 4 being the ideal stools as they are easy to defecate while not containing excess liquid, 5 indicate lack of dietary fiber, and 6 and 7 indicate diarrhea. AAD (antibiotic-associated diarrhea) is defined as diarrhea associated with the antibiotic use caused by C. difficile or of otherwise not identified etiology, upon analysis of stool samples and differential diagnostics according to investigator's judgment. Diarrhea was assessed in a diary.

2. Number of Participants With the Occurrence of Antibiotic-associated Diarrhea (AAD) - Intention to Treat (ITT) Population [14 days]

   Diarrhea is defined as loose or watery stool (Type 5-7 according to Bristol Stool Form Scale (BSFS)), three times a day (frequent bowel movements with formed stool is not considered as diarrhea) in accordance with WHO criteria; based on the diary data (BSFS) and confirmation of AAD by the investigator. BSFS scale includes Types 1 to 7 where Types 1 and 2 indicate constipation, with 3 and 4 being the ideal stools as they are easy to defecate while not containing excess liquid, 5 indicate lack of dietary fiber, and 6 and 7 indicate diarrhea. AAD (antibiotic-associated diarrhea) is defined as diarrhea associated with the antibiotic use caused by C. difficile or of otherwise not identified etiology, upon analysis of stool samples and differential diagnostics according to investigator's judgment. Diarrhea was assessed in a diary.

Secondary Outcome Measures

1. Mean Number of Bowel Movements Per Day [14 days]

   Bowel movements were assessed based on the data of patient's diary

2. Number of Participants With the Occurrence of Any Diarrhea [14 days]

   Diarrhea is defined as loose or watery stool (Type 5-7 according to Bristol Stool Form Scale (BSFS)), three times a day (frequent bowel movements with formed stool is not considered as diarrhea) in accordance with WHO criteria; based on the diary data (BSFS) and confirmation of AAD by the investigator. BSFS scale includes Types 1 to 7 where Types 1 and 2 indicate constipation, with 3 and 4 being the ideal stools as they are easy to defecate while not containing excess liquid, 5 indicate lack of dietary fiber, and 6 and 7 indicate diarrhea. AAD (antibiotic-associated diarrhea) is defined as diarrhea associated with the antibiotic use caused by C. difficile or of otherwise not identified etiology, upon analysis of stool samples and differential diagnostics according to investigator's judgment. Diarrhea was assessed in a diary.

3. Number of Participants With the Occurrence of C. Difficile-associated Antibiotic-associated Diarrhea (AAD) [14 Days]

   Diarrhea is defined as loose or watery stool (Type 5-7 according to Bristol Stool Form Scale (BSFS)), three times a day (frequent bowel movements with formed stool is not considered as diarrhea) in accordance with WHO criteria; based on the diary data (BSFS) and confirmation of AAD by the investigator. BSFS scale includes Types 1 to 7 where Types 1 and 2 indicate constipation, with 3 and 4 being the ideal stools as they are easy to defecate while not containing excess liquid, 5 indicate lack of dietary fiber, and 6 and 7 indicate diarrhea. AAD (antibiotic-associated diarrhea) is defined as diarrhea associated with the antibiotic use caused by C. difficile or of otherwise not identified etiology, upon analysis of stool samples and differential diagnostics according to investigator's judgment. Diarrhea was assessed in a diary.

4. Number of Participants With the Occurrence of Non-C. Difficile-associated AAD [14 Days]

   Incidence of non-C. difficile-associated AAD assessed based on the data of stool analysis

5. Mean Duration of Antibiotic-associated Diarrhea (AAD) [14 days]

   AAD is defined as diarrhea associated with the antibiotic use caused by C. difficile or of otherwise not identified etiology, upon analysis of stool samples and differential diagnostics according to investigator's judgment.The duration of AAD was the time from the onset of AAD to the normalization of stool form according to Bristol Stool Scale (types 1, 2, 3 and 4 where Types 1 and 2 indicate constipation, with 3 and 4 being the ideal stools as they are easy to defecate while not containing excess liquid) and the presence of normal stool within 48 hours was assessed based on the data of patient's diary.

6. Mean Duration of Any Diarrhea [14 days]

   Duration of any diarrhea is defined as the time from the onset of diarrhea to the normalization of stool shape according to the Bristol Stool Form Scale (BSFS) (Types 1, 2, 3, and 4) and the presence of normal stool for 48 hours). BSFS scale includes Types 1 to 7 where Types 1 and 2 indicate constipation, with 3 and 4 being the ideal stools as they are easy to defecate while not containing excess liquid, 5 indicate lack of dietary fiber, and 6 and 7 indicate diarrhea.

7. Change in Stool Consistency [Baseline, Day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14]

   Individual changes in the stool consistency were classified as improved / unchanged / worsened. The calculations were conducted as follows: if more than 1 observation was available for a specific day, the maximum score was taken; each subsequent day was compared to Day 1 according to the following rules: variations within 3-4 points, 1-2 points, or 5-7 points were qualified as "unchanged"; transfer from 1-2 points or 5-7 points to 3-4 points, as well as transfer from 5-7 points to 1-2 points were qualified as "improved"; transfer from 3-4 points to 1-2 points or 5-7 points, as well as transfer from 1-2 points to 5-7 points were qualified as "worsened". Score interpretation: 1, 2 - hard stool (constipation) 3, 4 - normal value 5, 6, 7 - loose stool

8. Number of Gastrointestinal Symptoms by Severity [14 days]

   The severity of gastrointestinal symptoms, including nausea, vomiting, flatulence, abdominal pain and decreased appetite was assessed based on the data of patient's diary. Severity of symptoms was assessed based on the 5-point verbal scale [0 to 4] where 0- symptoms were absent, 4- symptoms were very severe

9. Change From Baseline in Body Weight [Baseline, Day 15]

   Change from baseline in body weight assessed based on the clinical data

10. Number of Participants Hospitalized [14 days]

    Hospitalization rate was assessed based on the clinical data

11. Number of Participants Using Standard Symptomatic Therapy [14 days]

    The number of participants using standard symptomatic therapy (as "rescue medication") to relieve symptoms of acute diarrhea were assessed based on the clinical data

12. Number of Days of Using Standard Symptomatic Therapy [14 days]

    The number of days of using standard symptomatic therapy (as "rescue medication") to relieve symptoms of acute diarrhea were assessed based on the clinical data

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Patients will be considered eligible for study participation if they meet the following inclusion criteria:

1. An Informed Consent Form for study participation voluntarily signed by a patient;

2. Male and female subjects, 18 to 65 years of age inclusive;

3. Antibacterial treatment for active ARDs started/to be started on the first day of the study (7-day course of oral beta-lactam antibiotic). Only one AB should be used per subject, in an outpatient setting. Diagnostic procedures of ARD and the prescription of antibiotic therapy should be completed before signing of the Informed Consent Form.

4. Female patients will be considered as eligible for study participation if they are: Unable to become pregnant or Capable of childbirth, but with negative pregnancy test at the screening visit, and the patient agrees to continuously and properly use one a following suitable methods of contraception Male participants,. together with their partner, are to use appropriate contraception during the entire study period starting from signing of the Informed Consent Form and until the study end, and for 30 days after study completion;

5. The ability to understand the information about the clinical study, readiness to comply with the study protocol requirements, ability to take the investigational products and evaluate symptoms on his (or her) own using diary/questionnaires as per protocol; 7. Ability to maintain the habitual lifestyle throughout the study, including diet. 8. Willing not to consume any products containing probiotics during participation in the clinical trial. 9. Willing not to take part in any other study during the present trial.

Patients will not be eligible for study enrollment if they have one or more of the following criteria:

1. Any therapy (including medications, medical devices and dietary supplements) that can influence the stool consistency, according to the Investigator's opinion, should not be used within 14 days prior to Visit 1;

2. Use of immunosuppressive, immunostimulating and immunomodulating agents including drugs of herbal origin and dietary supplements within 30 days prior to the study start;

3. Use of anti-rejection medication after stem cell or solid organ transplant;

4. Use of systemic glucocorticosteroids within 8 weeks prior to the study start;

5. Use of proton pump inhibitors within 3 months prior to Visit 1;

6. Chemotherapy or radiation;

7. History of recurrent diarrhea;

8. Patient has diarrhea or loose stool within 2 days prior to the study start;

9. Patient has severe ARD expected to require an administration of antibiotics therapy for more than 7 days or prescription of additional antibiotics;

10. Use of antimicrobials within 3 months prior to the study start;

11. Use of yeast/probiotic/fermented products within 2 weeks prior to the first visit;

12. Known allergy/hypersensitivity to the investigational medicinal product in the medical history;

13. Immunocompromised patients;

14. Known digestion/absorption disorders of the gastrointestinal tract (e.g. inflammatory bowel disease, celiacia, pancreatitis, motility disorders etc.) and/or gastrointestinal surgery;

15. Known irritable bowel syndrome;

16. Known small intestinal bacterial overgrowth;

17. Patient has pyrexia of more than 38°C;

18. Pregnant and/or breastfeeding women;

19. Participation in other clinical trials of medicinal products or medical devices at the screening Visit or within 30 days before the screening Visit;

20. Surgical intervention within 30 days before the screening visit or planned surgical treatment during the trial (before a follow-up visit is completed), including diagnostic procedures or inpatient stay;

21. Known or suspected alcohol and/or drug addiction;

22. A suspected low compliance or incapability of the patient to perform the procedures and comply with restrictions according to the trial protocol (e.g., due to mental disorders);

23. Potential for translocation of probiotic across bowel wall (Presence of an active bowel leak, acute abdomen, active intestinal disease including colitis, or significant bowel dysfunction; presence of neutropenia or anticipation of neutropenia after chemotherapy; radiation therapy);

24. Any disorders of cardiovascular, renal, hepatic, gastrointestinal, endocrine and nervous systems, or other conditions/diseases which, in the Investigator's opinion, may render study participation unsafe for a patient or may affect a test result.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sandoz Investigative Site	Moscow		Russian Federation
2	Sandoz Investigative Site	Nizhniy Novgorod		Russian Federation
3	Sandoz Investigative Site	Saint Petersburg		Russian Federation

Sponsors and Collaborators

• Sandoz

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jun 23, 2020
• Statistical Analysis Plan - Mar 11, 2021

More Information

Publications

None provided.

• Responsible Party: Sandoz
• ClinicalTrials.gov Identifier: NCT04321460
• Other Study ID Numbers: CT_002_LRG_CAP
• First Posted: Mar 25, 2020
• Last Update Posted: Mar 14, 2022
• Last Verified: Dec 1, 2021

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

Study Results

Participant Flow

Recruitment Details	Participants were enrolled from 15 sites in the Russian Federation.
Pre-assignment Detail	Participants were randomized in 1:1 ratio to two arms (Treatment and Placebo).

Arm/Group Title	LRG-002	Placebo
Arm/Group Description	LRG-002 once daily for 14 days	Placebo once daily for 14 days
Period Title: Overall Study
STARTED	260	260
Intention to Treat (ITT) Population	260	260
Per-protocol (PP) Population	252	248
COMPLETED	259	259
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	LRG-002	Placebo	Total
Arm/Group Description	LRG-002 once daily for 14 days	Placebo once daily for 14 days	Total of all reporting groups
Overall Participants	260	260	520
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	40.62 (12.93)	41.65 (12.74)	41.13 (12.83)
Sex: Female, Male (Count of Participants)
Female	142 54.6%	167 64.2%	309 59.4%
Male	118 45.4%	93 35.8%	211 40.6%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	259 99.6%	259 99.6%	518 99.6%
Asian	1 0.4%	1 0.4%	2 0.4%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With the Occurrence of Antibiotic-associated Diarrhea (AAD) - Per Protocol (PP) Population
Description	Diarrhea is defined as loose or watery stool (Type 5-7 according to Bristol Stool Form Scale (BSFS)), three times a day (frequent bowel movements with formed stool is not considered as diarrhea) in accordance with WHO criteria; based on the diary data (BSFS) and confirmation of AAD by the investigator. BSFS scale includes Types 1 to 7 where Types 1 and 2 indicate constipation, with 3 and 4 being the ideal stools as they are easy to defecate while not containing excess liquid, 5 indicate lack of dietary fiber, and 6 and 7 indicate diarrhea. AAD (antibiotic-associated diarrhea) is defined as diarrhea associated with the antibiotic use caused by C. difficile or of otherwise not identified etiology, upon analysis of stool samples and differential diagnostics according to investigator's judgment. Diarrhea was assessed in a diary.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

The per protocol (PP) population included all randomized participants who completed participation in the study in accordance with the protocol (have completed the prescribed period of treatment and follow-up without significant deviations from the protocol)

Arm/Group Title	LRG-002	Placebo
Arm/Group Description	LRG-002 once daily for 14 days	Placebo once daily for 14 days
Measure Participants	252	248
Count of Participants [Participants]	4 1.5%	17 6.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LRG-002, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.564
	Confidence Interval	(2-Sided) 95%; 1.66 to 16.039
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Number of Participants With the Occurrence of Antibiotic-associated Diarrhea (AAD) - Intention to Treat (ITT) Population
Description	Diarrhea is defined as loose or watery stool (Type 5-7 according to Bristol Stool Form Scale (BSFS)), three times a day (frequent bowel movements with formed stool is not considered as diarrhea) in accordance with WHO criteria; based on the diary data (BSFS) and confirmation of AAD by the investigator. BSFS scale includes Types 1 to 7 where Types 1 and 2 indicate constipation, with 3 and 4 being the ideal stools as they are easy to defecate while not containing excess liquid, 5 indicate lack of dietary fiber, and 6 and 7 indicate diarrhea. AAD (antibiotic-associated diarrhea) is defined as diarrhea associated with the antibiotic use caused by C. difficile or of otherwise not identified etiology, upon analysis of stool samples and differential diagnostics according to investigator's judgment. Diarrhea was assessed in a diary.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population included all randomized participants who received at least one dose of the investigational medicinal product/placebo and have completed at least one visit aimed at the evaluation of efficacy parameters (i.e., at least all the procedures of Visit 1)

Arm/Group Title	LRG-002	Placebo
Arm/Group Description	LRG-002 once daily for 14 days	Placebo once daily for 14 days
Measure Participants	260	260
Count of Participants [Participants]	5 1.9%	22 8.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LRG-002, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.716
	Confidence Interval	(2-Sided) 95%; 1.898 to 14.268
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Mean Number of Bowel Movements Per Day
Description	Bowel movements were assessed based on the data of patient's diary
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population included all randomized participants who received at least one dose of the investigational medicinal product/placebo and have completed at least one visit aimed at the evaluation of efficacy parameters (i.e., at least all the procedures of Visit 1).

Arm/Group Title	LRG-002	Placebo
Arm/Group Description	LRG-002 once daily for 14 days	Placebo once daily for 14 days
Measure Participants	259	259
Mean (Standard Deviation) [Number of bowel movements per day]	1.54 (0.64)	1.76 (0.72)

4. Secondary Outcome

Title	Number of Participants With the Occurrence of Any Diarrhea
Description	Diarrhea is defined as loose or watery stool (Type 5-7 according to Bristol Stool Form Scale (BSFS)), three times a day (frequent bowel movements with formed stool is not considered as diarrhea) in accordance with WHO criteria; based on the diary data (BSFS) and confirmation of AAD by the investigator. BSFS scale includes Types 1 to 7 where Types 1 and 2 indicate constipation, with 3 and 4 being the ideal stools as they are easy to defecate while not containing excess liquid, 5 indicate lack of dietary fiber, and 6 and 7 indicate diarrhea. AAD (antibiotic-associated diarrhea) is defined as diarrhea associated with the antibiotic use caused by C. difficile or of otherwise not identified etiology, upon analysis of stool samples and differential diagnostics according to investigator's judgment. Diarrhea was assessed in a diary.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population included all randomized participants who received at least one dose of the investigational medicinal product/placebo and have completed at least one visit aimed at the evaluation of efficacy parameters (i.e., at least all the procedures of Visit 1)

Arm/Group Title	LRG-002	Placebo
Arm/Group Description	LRG-002 once daily for 14 days	Placebo once daily for 14 days
Measure Participants	260	260
Count of Participants [Participants]	6 2.3%	23 8.8%

5. Secondary Outcome

Title	Number of Participants With the Occurrence of C. Difficile-associated Antibiotic-associated Diarrhea (AAD)
Description	Diarrhea is defined as loose or watery stool (Type 5-7 according to Bristol Stool Form Scale (BSFS)), three times a day (frequent bowel movements with formed stool is not considered as diarrhea) in accordance with WHO criteria; based on the diary data (BSFS) and confirmation of AAD by the investigator. BSFS scale includes Types 1 to 7 where Types 1 and 2 indicate constipation, with 3 and 4 being the ideal stools as they are easy to defecate while not containing excess liquid, 5 indicate lack of dietary fiber, and 6 and 7 indicate diarrhea. AAD (antibiotic-associated diarrhea) is defined as diarrhea associated with the antibiotic use caused by C. difficile or of otherwise not identified etiology, upon analysis of stool samples and differential diagnostics according to investigator's judgment. Diarrhea was assessed in a diary.
Time Frame	14 Days

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population included all participants with available data, who received any study drug and had Antibiotic-associated diarrhea (AAD)

Arm/Group Title	LRG-002	Placebo
Arm/Group Description	LRG-002 once daily for 14 days	Placebo once daily for 14 days
Measure Participants	5	22
Count of Participants [Participants]	0 0%	1 0.4%

6. Secondary Outcome

Title	Number of Participants With the Occurrence of Non-C. Difficile-associated AAD
Description	Incidence of non-C. difficile-associated AAD assessed based on the data of stool analysis
Time Frame	14 Days

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population included all participants with available data, who received any study drug and had Antibiotic-associated diarrhea (AAD)

Arm/Group Title	LRG-002	Placebo
Arm/Group Description	LRG-002 once daily for 14 days	Placebo once daily for 14 days
Measure Participants	5	22
Count of Participants [Participants]	5 1.9%	21 8.1%

7. Secondary Outcome

Title	Mean Duration of Antibiotic-associated Diarrhea (AAD)
Description	AAD is defined as diarrhea associated with the antibiotic use caused by C. difficile or of otherwise not identified etiology, upon analysis of stool samples and differential diagnostics according to investigator's judgment.The duration of AAD was the time from the onset of AAD to the normalization of stool form according to Bristol Stool Scale (types 1, 2, 3 and 4 where Types 1 and 2 indicate constipation, with 3 and 4 being the ideal stools as they are easy to defecate while not containing excess liquid) and the presence of normal stool within 48 hours was assessed based on the data of patient's diary.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population included all participants with available data, who received any study drug and had Antibiotic-associated diarrhea (AAD)

Arm/Group Title	LRG-002	Placebo
Arm/Group Description	LRG-002 once daily for 14 days	Placebo once daily for 14 days
Measure Participants	5	22
Mean (Standard Deviation) [Days]	5.4 (2.3)	6.23 (3.72)

8. Secondary Outcome

Title	Mean Duration of Any Diarrhea
Description	Duration of any diarrhea is defined as the time from the onset of diarrhea to the normalization of stool shape according to the Bristol Stool Form Scale (BSFS) (Types 1, 2, 3, and 4) and the presence of normal stool for 48 hours). BSFS scale includes Types 1 to 7 where Types 1 and 2 indicate constipation, with 3 and 4 being the ideal stools as they are easy to defecate while not containing excess liquid, 5 indicate lack of dietary fiber, and 6 and 7 indicate diarrhea.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population included all participants with available data, who received any study drug and had incidence of any diarrhea

Arm/Group Title	LRG-002	Placebo
Arm/Group Description	LRG-002 once daily for 14 days	Placebo once daily for 14 days
Measure Participants	6	23
Mean (Standard Deviation) [Days]	5 (2.28)	6.13 (3.66)

9. Secondary Outcome

Title	Change in Stool Consistency
Description	Individual changes in the stool consistency were classified as improved / unchanged / worsened. The calculations were conducted as follows: if more than 1 observation was available for a specific day, the maximum score was taken; each subsequent day was compared to Day 1 according to the following rules: variations within 3-4 points, 1-2 points, or 5-7 points were qualified as "unchanged"; transfer from 1-2 points or 5-7 points to 3-4 points, as well as transfer from 5-7 points to 1-2 points were qualified as "improved"; transfer from 3-4 points to 1-2 points or 5-7 points, as well as transfer from 1-2 points to 5-7 points were qualified as "worsened". Score interpretation: 1, 2 - hard stool (constipation) 3, 4 - normal value 5, 6, 7 - loose stool
Time Frame	Baseline, Day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population included participants with available Day 1 assessment data

Arm/Group Title	LRG-002	Placebo
Arm/Group Description	LRG-002 once daily for 14 days	Placebo once daily for 14 days
Measure Participants	206	214
improved	78 30%	56 21.5%
unchanged	94 36.2%	124 47.7%
worsened	27 10.4%	27 10.4%
no data available	7 2.7%	7 2.7%
improved	79 30.4%	60 23.1%
unchanged	96 36.9%	118 45.4%
worsened	26 10%	33 12.7%
no data available	5 1.9%	3 1.2%
improved	83 31.9%	62 23.8%
unchanged	95 36.5%	122 46.9%
worsened	25 9.6%	26 10%
no data available	3 1.2%	4 1.5%
improved	78 30%	59 22.7%
unchanged	93 35.8%	119 45.8%
worsened	30 11.5%	27 10.4%
no data available	5 1.9%	9 3.5%
improved	78 30%	59 22.7%
unchanged	100 38.5%	120 46.2%
worsened	18 6.9%	28 10.8%
no data available	10 3.8%	7 2.7%
improved	83 31.9%	60 23.1%
unchanged	94 36.2%	119 45.8%
worsened	23 8.8%	26 10%
no data available	6 2.3%	9 3.5%
improved	78 30%	61 23.5%
unchanged	99 38.1%	123 47.3%
worsened	21 8.1%	17 6.5%
no data available	8 3.1%	13 5%
improved	75 28.8%	61 23.5%
unchanged	100 38.5%	124 47.7%
worsened	20 7.7%	20 7.7%
no data available	11 4.2%	9 3.5%
improved	74 28.5%	61 23.5%
unchanged	96 36.9%	119 45.8%
worsened	23 8.8%	23 8.8%
no data available	13 5%	11 4.2%
improved	83 31.9%	65 25%
unchanged	95 36.5%	119 45.8%
worsened	22 8.5%	24 9.2%
no data available	6 2.3%	6 2.3%
improved	80 30.8%	66 25.4%
unchanged	96 36.9%	124 47.7%
worsened	20 7.7%	19 7.3%
no data available	10 3.8%	5 1.9%
improved	76 29.2%	61 23.5%
unchanged	99 38.1%	118 45.4%
worsened	19 7.3%	22 8.5%
no data available	12 4.6%	13 5%
improved	81 31.2%	63 24.2%
unchanged	91 35%	122 46.9%
worsened	22 8.5%	20 7.7%
no data available	12 4.6%	9 3.5%

10. Secondary Outcome

Title	Number of Gastrointestinal Symptoms by Severity
Description	The severity of gastrointestinal symptoms, including nausea, vomiting, flatulence, abdominal pain and decreased appetite was assessed based on the data of patient's diary. Severity of symptoms was assessed based on the 5-point verbal scale [0 to 4] where 0- symptoms were absent, 4- symptoms were very severe
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population included all randomized participants who received at least one dose of the investigational medicinal product/placebo and have completed at least one visit aimed at the evaluation of efficacy parameters (i.e., at least all the procedures of Visit 1).

Arm/Group Title	LRG-002	Placebo
Arm/Group Description	LRG-002 once daily for 14 days	Placebo once daily for 14 days
Measure Participants	259	259
0. No manifestations	18 6.9%	19 7.3%
1. Mild manifestations	29 11.2%	36 13.8%
2. Moderate manifestations	7 2.7%	4 1.5%
3. Severe manifestations	0 0%	3 1.2%
No data available	205 78.8%	197 75.8%
0. No manifestations	13 5%	13 5%
1. Mild manifestations	34 13.1%	50 19.2%
2. Moderate manifestations	30 11.5%	40 15.4%
3. Severe manifestations	5 1.9%	6 2.3%
No data available	177 68.1%	150 57.7%
0. No manifestations	20 7.7%	21 8.1%
1. Mild manifestations	0 0%	2 0.8%
2. Moderate manifestations	0 0%	0 0%
3. Severe manifestations	0 0%	0 0%
No data available	239 91.9%	236 90.8%
0. No manifestations	11 4.2%	5 1.9%
1. Mild manifestations	43 16.5%	51 19.6%
2. Moderate manifestations	43 16.5%	42 16.2%
3. Severe manifestations	8 3.1%	10 3.8%
No data available	154 59.2%	151 58.1%
0. No manifestations	21 8.1%	20 7.7%
1. Mild manifestations	30 11.5%	21 8.1%
2. Moderate manifestations	1 0.4%	2 0.8%
3. Severe manifestations	0 0%	0 0%
No data available	207 79.6%	216 83.1%

11. Secondary Outcome

Title	Change From Baseline in Body Weight
Description	Change from baseline in body weight assessed based on the clinical data
Time Frame	Baseline, Day 15

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population included all randomized participants who received at least one dose of the investigational medicinal product/placebo and have completed at least one visit aimed at the evaluation of efficacy parameters (i.e., at least all the procedures of Visit 1).

Arm/Group Title	LRG-002	Placebo
Arm/Group Description	LRG-002 once daily for 14 days	Placebo once daily for 14 days
Measure Participants	259	257
Mean (Standard Deviation) [Kg]	0.11 (1.13)	-0.17 (0.92)

12. Secondary Outcome

Title	Number of Participants Hospitalized
Description	Hospitalization rate was assessed based on the clinical data
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population included all randomized participants who received at least one dose of the investigational medicinal product/placebo and have completed at least one visit aimed at the evaluation of efficacy parameters (i.e., at least all the procedures of Visit 1)

Arm/Group Title	LRG-002	Placebo
Arm/Group Description	LRG-002 once daily for 14 days	Placebo once daily for 14 days
Measure Participants	260	260
Count of Participants [Participants]	0 0%	1 0.4%

13. Secondary Outcome

Title	Number of Participants Using Standard Symptomatic Therapy
Description	The number of participants using standard symptomatic therapy (as "rescue medication") to relieve symptoms of acute diarrhea were assessed based on the clinical data
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population included all randomized participants who received at least one dose of the investigational medicinal product/placebo and have completed at least one visit aimed at the evaluation of efficacy parameters (i.e., at least all the procedures of Visit 1)

Arm/Group Title	LRG-002	Placebo
Arm/Group Description	LRG-002 once daily for 14 days	Placebo once daily for 14 days
Measure Participants	260	260
Count of Participants [Participants]	0 0%	1 0.4%

14. Secondary Outcome

Title	Number of Days of Using Standard Symptomatic Therapy
Description	The number of days of using standard symptomatic therapy (as "rescue medication") to relieve symptoms of acute diarrhea were assessed based on the clinical data
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

Included only 1 participants who was prescribed symptomatic therapy for C. difficile-associated diarrhea

Arm/Group Title	LRG-002	Placebo
Arm/Group Description	LRG-002 once daily for 14 days	Placebo once daily for 14 days
Measure Participants	0	1
Number [Days]	NA

Adverse Events

Time Frame	Adverse events were collected throughout the study i.e until visit 3 (Day 15 ± 2) which was the treatment completion / study termination visit
Adverse Event Reporting Description	Any signs or symptoms were collected throughout the study i.e until visit 3 (Day 15 ± 2) which was the treatment completion / study termination visit
Arm/Group Title	LRG-002		Placebo
Arm/Group Description	LRG-002 once daily for 14 days		Placebo once daily for 14 days
All Cause Mortality
	LRG-002		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/260 (0%)		0/260 (0%)
Serious Adverse Events
	LRG-002		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/260 (0%)		1/260 (0.4%)
Respiratory, thoracic and mediastinal disorders
pulmonary embolism	0/260 (0%)		1/260 (0.4%)
Other (Not Including Serious) Adverse Events
	LRG-002		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	116/260 (44.6%)		138/260 (53.1%)
Gastrointestinal disorders
Flatulence	65/260 (25%)		90/260 (34.6%)
Nausea	28/260 (10.8%)		20/260 (7.7%)
Abdominal pain	36/260 (13.8%)		40/260 (15.4%)
Diarrhea	6/260 (2.3%)		24/260 (9.2%)
Metabolism and nutrition disorders
Decreased appetite	92/260 (35.4%)		93/260 (35.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.