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

Study Overview
=================
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.

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.

Conditions
-----------------
Antibiotic-associated Diarrhea

Intervention / Treatment
-----------------
* Drug: LRG-002
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Patients will be considered eligible for study participation if they meet the following inclusion criteria: An Informed Consent Form for study participation voluntarily signed by a patient; Male and female subjects, 18 to 65 years of age inclusive; 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. 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; 6. 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: 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; Use of immunosuppressive, immunostimulating and immunomodulating agents including drugs of herbal origin and dietary supplements within 30 days prior to the study start; Use of anti-rejection medication after stem cell or solid organ transplant; Use of systemic glucocorticosteroids within 8 weeks prior to the study start; Use of proton pump inhibitors within 3 months prior to Visit 1; Chemotherapy or radiation; History of recurrent diarrhea; Patient has diarrhea or loose stool within 2 days prior to the study start; Patient has severe ARD expected to require an administration of antibiotics therapy for more than 7 days or prescription of additional antibiotics; Use of antimicrobials within 3 months prior to the study start; Use of yeast/probiotic/fermented products within 2 weeks prior to the first visit; Known allergy/hypersensitivity to the investigational medicinal product in the medical history; Immunocompromised patients; Known digestion/absorption disorders of the gastrointestinal tract (e.g. inflammatory bowel disease, celiacia, pancreatitis, motility disorders etc.) and/or gastrointestinal surgery; Known irritable bowel syndrome; Known small intestinal bacterial overgrowth; Patient has pyrexia of more than 38°C; Pregnant and/or breastfeeding women; Participation in other clinical trials of medicinal products or medical devices at the screening Visit or within 30 days before the screening Visit; 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; Known or suspected alcohol and/or drug addiction; 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); 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); 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LRG-002<br>LRG-002 once daily for 14 days | Drug: LRG-002<br>* Capsules containing live lyophilized probiotic bacteria of Lactobacillus genus<br>|
| Placebo Comparator: Placebo<br>Placebo once daily for 14 days | Drug: Placebo<br>* Capsules containing placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With the Occurrence of Antibiotic-associated Diarrhea (AAD) - Per Protocol (PP) Population | 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. | 14 days | 
| Number of Participants With the Occurrence of Antibiotic-associated Diarrhea (AAD) - Intention to Treat (ITT) Population | 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. | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Number of Bowel Movements Per Day | Bowel movements were assessed based on the data of patient's diary | 14 days | 
| Number of Participants With the Occurrence of Any Diarrhea | 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. | 14 days | 
| Number of Participants With the Occurrence of C. Difficile-associated Antibiotic-associated Diarrhea (AAD) | 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. | 14 Days | 
| Number of Participants With the Occurrence of Non-C. Difficile-associated AAD | Incidence of non-C. difficile-associated AAD assessed based on the data of stool analysis | 14 Days | 
| Mean Duration of Antibiotic-associated Diarrhea (AAD) | 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. | 14 days | 
| Mean Duration of Any Diarrhea | 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. | 14 days | 
| Change in Stool Consistency | 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 | Baseline, Day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14 | 
| Number of Gastrointestinal Symptoms by Severity | 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 | 14 days | 
| Change From Baseline in Body Weight | Change from baseline in body weight assessed based on the clinical data | Baseline, Day 15 | 
| Number of Participants Hospitalized | Hospitalization rate was assessed based on the clinical data | 14 days | 
| Number of Participants Using Standard Symptomatic Therapy | The number of participants using standard symptomatic therapy (as rescue medication) to relieve symptoms of acute diarrhea were assessed based on the clinical data | 14 days | 
| Number of Days of Using Standard Symptomatic Therapy | 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 | 14 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
diarrhea