Use of Probiotics to Reduce Infections, Death and ESBL Colonisation (ProRIDE)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Neonatal Sepsis
• Intervention / Treatment: Biological: Labinic (R) probiotic mixture; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 2000
• Phase: Phase 3

Contacts and Locations

Study Locations

• Tanzania
  • Manyara
    • Babati, Manyara, Tanzania
      • Haydom Lutheran Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 year (Child)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Haydom Lutheran Hospital
• Collaborators: University of Bergen; Helse Stavanger HF; Muhimbili University of Health and Allied Sciences; UiT The Arctic University of Norway
• Investigators: Principal Investigator: Nina Langeland, MD, PhD, University of Bergen

Publications and helpful links

General Publications

• Panigrahi P, Parida S, Nanda NC, Satpathy R, Pradhan L, Chandel DS, Baccaglini L, Mohapatra A, Mohapatra SS, Misra PR, Chaudhry R, Chen HH, Johnson JA, Morris JG, Paneth N, Gewolb IH. A randomized synbiotic trial to prevent sepsis among infants in rural India. Nature. 2017 Aug 24;548(7668):407-412. doi: 10.1038/nature23480. Epub 2017 Aug 16. Erratum In: Nature. 2017 Nov 29;:
• Esaiassen E, Hjerde E, Cavanagh JP, Pedersen T, Andresen JH, Rettedal SI, Stoen R, Nakstad B, Willassen NP, Klingenberg C. Effects of Probiotic Supplementation on the Gut Microbiota and Antibiotic Resistome Development in Preterm Infants. Front Pediatr. 2018 Nov 16;6:347. doi: 10.3389/fped.2018.00347. eCollection 2018.
• Tellevik MG, Blomberg B, Kommedal O, Maselle SY, Langeland N, Moyo SJ. High Prevalence of Faecal Carriage of ESBL-Producing Enterobacteriaceae among Children in Dar es Salaam, Tanzania. PLoS One. 2016 Dec 9;11(12):e0168024. doi: 10.1371/journal.pone.0168024. eCollection 2016.
• Kuwelker K, Langeland N, Lohr IH, Gidion J, Manyahi J, Moyo SJ, Blomberg B, Klingenberg C. Use of probiotics to reduce infections and death and prevent colonization with extended-spectrum beta-lactamase (ESBL)-producing bacteria among newborn infants in Tanzania (ProRIDE Trial): study protocol for a randomized controlled clinical trial. Trials. 2021 Apr 29;22(1):312. doi: 10.1186/s13063-021-05251-3.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2022
• Primary Completion (Actual): July 10, 2023
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: November 19, 2019
• First Submitted That Met QC Criteria: November 19, 2019
• First Posted (Actual): November 21, 2019

Study Record Updates

• Last Update Posted (Estimated): December 12, 2023
• Last Update Submitted That Met QC Criteria: December 6, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Probiotics; Tanzania; Antimicrobial resistance; East Africa; Extended Spectrum Beta-Lactamase Producing Bacteria
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Infant, Newborn, Diseases; Sepsis; Neonatal Sepsis
• Other Study ID Numbers: 2019/1025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No