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

Phase 3

Completed

Conditions: Antibiotic-associated Diarrhea

Interventions: Drug: LRG-002
Drug: Placebo

Registration Number: NCT04321460

Lead Sponsor: Sandoz

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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 520

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
LRG-002	LRG-002	LRG-002 once daily for 14 days
Placebo	Placebo	Placebo once daily for 14 days

Primary Outcome Measures

Name	Time	Method
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.
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

Name	Time	Method
Mean Number of Bowel Movements Per Day	14 days	Bowel movements were assessed based on the data of patient's diary
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.
Change From Baseline in Body Weight	Baseline, Day 15	Change from baseline in body weight assessed based on the clinical data
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
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.
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
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.
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.
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: 1. if more than 1 observation was available for a specific day, the maximum score was taken; 2. 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: 3. 1, 2 - hard stool (constipation) 4. 3, 4 - normal value 5. 5, 6, 7 - loose stool
Number of Participants Hospitalized	14 days	Hospitalization rate was assessed based on the clinical data
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
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