Use of Probiotics to Reduce Infections, Death and ESBL Colonisation

Study Overview
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Brief Summary
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This study examines the effect of oral probiotic treatment to newborns on preventing hospitalizations, death and colonization with Extended-spectrum beta-lactamase-producing Gram negative bacteria. Half of the babies will receive 4 weeks treatment with an oral mixture of the probiotic Labinic (R) while the other half will receive a placebo mixture.

Detailed Description
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Studies show that probiotics given to prematurely born babies prevents sepsis and is widely used in the western world for this purpose. Probiotics consists of one or more normal gut-bacteria. A large study in India showed that giving probiotics to full-born babies reduced hospitalizations and morbidity. This study investigates giving a probiotic mixture with different combination of bacteria, Lactobacillus acidophilus, Bifidobacterium infantis and Bifidobacterium breve, for a longer duration (4 weeks instead of 7 days). Infections with antibiotic-resistant bacteria is a major threat to health-care world-wide, and sepsis/severe infection caused by such bacteria is a major cause of neonatal death. The study hypothesis is that giving probiotics to newborns prevents them from getting colonized with antibiotic-resistant bacteria, such as Extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE). By preventing colonization with ESBL-PE, severe infections such as sepsis may be prevented, and thereby survival may be improved.

Official Title
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Use of Probiotics to Reduce Infections and Death and Prevent Colonization With Extended-spectrum Beta-lactamase Producing Bacteria, Among Newborn Infants in Haydom and Surrounding Area, Tanzania, a Randomized Controlled Clinical Trial

Conditions
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Neonatal Sepsis

Intervention / Treatment
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* Biological: Labinic (R) probiotic mixture
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy newborn infants with a birth weight equal or above 2.0 kgs, will be included in the study between 0-3 days of life. Newborn infants have to come from families who are long-term or permanent residents in the defined catchment area for this trial (30 km radius from HLH) in Tanzania. Parents are able and willing to complete study visit (including required study procedures) schedules over the six months proposed follow-up, which also includes hospitalizations required for compliance of this study protocol. Parents agrees for the child not to participate in another study during the study period Children less than one year admitted to hospital with suspected infection, not included in the RCT, will be included in a sub-study. A separate inclusion form is prepared for these children. Exclusion Criteria: Birth weight below 2 kg Other health problems/illness, obvious congenital malformations. Multiple pregnancy Parents not consenting

Ages Eligible for Study
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Maximum Age: 3 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Placebo-controlled double-blinded randomized clinical trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Probiotic<br>Study subjects receive probiotic mixture for 4 weeks | Biological: Labinic (R) probiotic mixture<br>* Labinic (R) probiotic mixture containing Lactobacillus acidophilus and Bifidobacterium infantis and B. breve<br>|
| Placebo Comparator: Placebo<br>Study subjects receive placebo mixture for 4 weeks | Other: Placebo<br>* Placebo mixture<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite outcome hospitalization and death | Primary outcome is hospitalization and/or death of study subject | 6 months from inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ESBL colonization | Faecal colonisation with Extended-spectrum beta-lactamase-producing Enterobacteriaceae as detected by fecal swab | 6 weeks and 6 months | 
| Hospitalisation | Hospitalisation | 6 weeks and 6 months | 
| Death | Death during study period | 6 months | 
| Body weight | Growth monitored by weight | 6 months | 
| Body length | Growth monitored by length | 6 months | 
| Stool microbiota | Stool microbiota composition including resistome analysis (metagenome sequencing) | 6 weeks and 6 months | 
| Stool metabolome | Stool metabolome composition | 6 weeks and 6 months | 
| Stool inflammatory markers - Calprotectin | Levels of Calprotectin in participants' stool samples | 6 weeks and 6 months | 
| Stool inflammatory markers - alpha-1 antitrypsin | Levels of alpha-1 antitrypsin (AAT) in participants' stool samples | 6 weeks and 6 months | 
| Stool inflammatory markers - myeloperoxidase | Levels of human myeloperoxidase (MPO) in participants' stool samples | 6 weeks and 6 months | 
| Number of participants with culture-confirmed bacteremia | Bacteremia confirmed by blood culture | 6 months | 
| Genetic characteristics of ESBL-producing Enterobacteriaceae | Genetic characteristics of ESBL-E from colonization and clinical samples (targeted screening) | 6 weeks and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tanzania, East Africa, Antimicrobial resistance, Probiotics, Extended Spectrum Beta-Lactamase Producing Bacteria