A randomized, double blind, placebo controlled, Three arm study to evaluate the efficacy & safety of probiotics – different Bacillus clausii strains in the prevention of Antibiotic Associated Diarrhea (AAD) in infants and children.

STUDY TITLE

A randomized, double blind, placebo controlled, Three arm study to evaluate the efficacy & safety of probiotics - different Bacillus clausii strains in the prevention of Antibiotic Associated Diarrhea (AAD) in infants and children.

INTRODUCTION & BACKGROUNDANTIBIOTIC ASSOCIATED DIARRHEA (AAD)Diarrhea, although a preventable disease, remains a major cause of morbidity and mortality in children worldwide, resulting in 525,000 deaths per year among those younger than 5 years. Diarrhoea is a common adverse effect of antibiotic treatments. Antibiotic-associated diarrhoea (AAD) is defined as diarrhoea that develops any time from a few hours after the onset of antibiotic therapy to eight weeks following antibiotic cessation. The direct toxic effects of antibiotics on the intestines include altered digestive function secondary to reduced concentrations of gut bacteria or the overgrowth of pathogenic microorganisms. The bacterial diversity of the intestinal lumen is also diminished after the administration of certain antibiotics, and these alterations in the abundance and composition of gut microbiota further lead to the dysfunction of these microbiota. Moreover, the impact seems considerably more long-standing than originally thought. Antibiotic associated diarrhoea occurs in about 5-30% of participants either early during antibiotic therapy or up to two months after the end of the treatment. The frequency of antibiotic associated diarrhoea depends on the definition of diarrhoea, the inciting antimicrobial agents, and host factors. Antibiotic associated diarrhoea results from disruption of the normal microflora of the gut by antibiotics. This microflora, composed of 1011 bacteria per gram of intestinal content, forms a stable ecosystem that permits the elimination of exogenous organisms. Antibiotics disturb the composition and the function of this flora and enable overgrowth of micro-organisms that induce diarrhoea. As antibiotic associated diarrhoea mostly results from a disequilibrium of the normal intestinal flora, research has focused on the benefits of administering living organisms (probiotics or biotherapeutic agents) to restore the normal flora.

Prospective clinical trials conducted found probiotics especially Bacillus clausii to be effective and safe in the treatment and prevention of antibiotic associated diarrhea.

ROLE OF PROBIOTICS IN PREVENTION OF ANTIBIOTIC ASSOCIATED DIARRHEA

Probiotics are defined by the World Health Organization as “live microorganisms which when administered in adequate amounts confer a health benefit on the host.” The mechanisms of action of different probiotics include providing a physical barrier from pathogens, promoting goblet cell mucus secretion, maintaining the integrity of intestinal epithelial tight junctions, producing antimicrobial factors, and stimulating the immune system. The interaction between diet and gut microbiota, and ultimately their effect on human health, has been the subject of huge interest and research. However, this relationship still needs to be fully characterized, while much of the function of the gut microbiome remains to be fully elucidated, it is established that the microbiota plays an important role in maintaining health. The composition of microbiota is altered in certain disease states, including enteric infections, Helicobacter pylori and Clostridium difficile infection, and antibiotic-associated diarrhea (AAD), resulting in a state of dysbiosis. Dysbiosis is related to various important pathologies and many therapeutic strategies aimed at restoring the balance of the intestinal ecosystem have been implemented. These strategies include the administration of probiotics and Mortality and morbidity rates remain high despite global efforts to treat diarrhea. This necessitates continued efforts to investigate the role of probiotics especially Bacillus clausii strains in the prevention of Antibiotic associated Diarrhea.

STUDY AIMAND OBJECTIVESAIMTo evaluate the efficacy and safety of oral probiotics Bacillus clausii strains in preventing antibiotic associated diarrhea in infants and children.

PRIMARY OBJECTIVES

To assess the effectiveness and safety of the probiotics Bacillus clausii strains in preventing antibiotic associated diarrhea among infants and children in the age group of 6 months to 12 years.

SECONDARY OBJECTIVES

• To assess the effectiveness of Bacillus clausii strains in reducing the incidence of diarrhea events associated with antibiotic therapy in the treatment and control group.

• To assess the effectiveness of Bacillus clausii strains in reducing the gastro-intestinal (GI) related symptoms and the duration of diarrhea days among participants with AAD.

• To assess the impact of Bacillus clausii strains supplementation in the over-all reduction in hospitalization days.

STUDY DESIGNA randomized, double blind, placebo controlled three arm study to evaluate the efficacy & safety of probiotics Bacillus clausii strains in the prevention of Antibiotic Associated Diarrhea (AAD) in infants and children.

All the participants will be randomized in a 1:1:1 ratio into three groups of 30 each:

Group A: n=30

Probiotic Bacillus clausii SNZCLB 1, SNZCLB 2, SNZCLB 3, SNZCLB 4 altogether NLT 2 Billion CFU / 5mL + Beta Lactam Antibiotic

Group B: n=30

Probiotic Bacillus clausii SNZ 1971 NLT 2 Billion CFU / 5mL + Beta Lactam Antibiotic

Group C: n=30

Placebo Liquid + Beta Lactam Antibiotic

 

**Group
A**

(n=30)

Group B

(n=30)

Group C

(n=30)

|Bacillus clausii SNZCLB 1, SNZCLB 2

SNZCLB 3, SNZCLB 4 – 2 Billion CFU

Bacillus clausii SNZ 1971 –

2 Billion CFU

Placebo Liquid

|Beta Lactam Antibiotic (All 3 Groups)

 All the participants will be followed up till 6 weeks (45 days) after discontinuation of Beta Lactam Antibiotic treatment.

STUDY SITE AND DURATION

Study site: Department of Pediatrics

The total study duration is expected to be approximately 8 to 10 months with screening period, treatment period and follow up period of 6 weeks (45 days approx) for each participant after discontinuation of antibiotic.

STUDY POPULATION- SAMPLE SIZE A sample size of 90 completed subjects was calculated with 30 subjects in each group (n=30) with a power of 80% at the 5% level of statistical significance.Considering 20% dropout rate, the total no of subjects to be randomized and enrolled will be 108 subjects with 36 subjects in each group.

  TREATMENT ARMS           A Total of 90 subjects in the age group of 6 months to 12 years who require beta lactam antibiotic therapy for 5-14 days depending on the clinical conditions like Respiratory infections, Genitourinary infections or skin and soft tissue infections will be selected from study sites. The probiotic supplementation is to be started within 24 hours of antibiotic initiation and will be continued until the last day of antibiotic therapy, which is up to a maximum of 14 days.

Group

Study medication

Medication Frequency

Sample size

|A

Probiotic Bacillus clausii SNZCLB 1, SNZCLB 2, SNZCLB 3, SNZCLB 4

2 Billion CFU / 5mL

• Beta Lactam Antibiotic

Twice daily

(Max 14 days)

30

|B

Probiotic Bacillus clausii SNZ 1971

2 Billion CFU / 5mL

Beta Lactam Antibiotic

Twice daily

(Max 14 days)

30

|C

Placebo Liquid

• Beta Lactam Antibiotic

Twice daily

(Max 14 days)

30

**Group
A**

(n=30)

Group B

(n=30)

Group C

(n=30)

|Bacillus clausii SNZCLB 1, SNZCLB 2, SNZCLB 3 and SNZCLB 4 –

2 Billion CFU

Bacillus clausii SNZ 1971 –

2 Billion CFU

Placebo Liquid

|Beta Lactam Antibiotic (All 3 Groups)

Each participant will be identified using a center number, a treatment number (provided by the treatment code found in the intervention drug label) and the participant’s initials.

Children will be treated with the B. clausii SNZCLB 1, SNZCLB 2, SNZCLB 3 and SNZCLB 4 in a dose of 2 Billion CFU/ 5mL and Bacillus clausii SNZ 1971 2 Billion CFU/ 5mL, while on antibiotic therapy and shall be monitored for until the 6th week after the discontinuation of antibiotic therapy.

STUDY OUTCOME MEASURES

 Primary Outcome:

Reduction of the incidence of antibiotic-associated diarrhea

Secondary Outcomes:

Reduction in antibiotic-associated diarrhea events per day

Reduction in severity of diarrhea events

Reduction in GI related symptoms (nausea, vomiting, abdominal pain)

Reduction in hospital days

All the Participants will be evaluated daily from day 0 of antibiotic therapy until day 45 post-intervention.

    ELIGIBILITY CRITERIAINCLUSION CRITERIA

All the following criteria must be met at screening prior to randomization and at enrolment: Candidates for inclusion in the study are clinically stable infants and children: 6 months to 12 years old admitted or seen at the out-participant services in tertiary care hospital for mild to moderate infection of the respiratory, genito-urinary or skin and soft tissue admitted or consulted at the out patient for treatment of bacterial infection requiring Beta lactam antibiotic treatment for 5 to 14 days.

 EXCLUSION CRITERIA

 1.      Clinically unstable infants and children

2.      Subjects with critical illness, chronic diseases of the endocrine, cardiovascular, renal, or respiratory system (or any other clinically significant condition that might jeopardize a patient’s condition or study outcomes in the view of the Investigator),

3.      a history of or current presence of conditions known to produce immunodeficiency (congenital or acquired immunodeficiency syndromes, immunosuppressant therapy),

4.      presence of an in-dwelling vascular access line, a history of or current pancreatitis, history of abdominal surgery, bilious emesis, or

5.      participation in another clinical trial within the past 3 months.

6.      hypersensitivity to B. clausii or excipients in the investigational medical product or to other probiotics.

7.      long-term use of oral or intravenous corticosteroids within 6 months of enrollment.

METHODS AND ASSESSMENTSRandomization and Blinding:Randomization will be performed using a computer-generated randomization numbers. Investigators, participants and research associates will be blinded to treatment. Double blinding will be accomplished by independent blinding of the dosing kits.

Study Visits:Visit 1 – Screening or Baseline or Randomization

Visit 2 – 2 Weeks (or earlier) upon completion of Antibiotic treatment

Visit 3 – 2 weeks after discontinuation of antibiotic treatment

Visit 4 – 4 weeks after discontinuation of antibiotic treatment

Visit 5 – 6 weeks after discontinuation of antibiotic treatment