The Effect of a Multispecies Probiotic on Reducing the Incidence of Antibiotic-associated Diarrhoea in Children.

In this trial, the investigators aim to assess the effectiveness of a multispecies probiotic consisting of 2 strains of Bifidobacterium (B. bifidum W23, B. lactis W51) and 6 strains of Lactobacillus (L. acidophilus W37, L. acidophilus W55, L. paracasei W20, L. plantarum W62, L. rhamnosus W71, and L. salivarius W24) in reducing the risk of antibiotic-associated diarrhoea in a group of children undergoing antibiotic therapy for common infections.

Study Overview

• Status: Completed
• Conditions: Antibiotic-associated Diarrhea
• Intervention / Treatment: Dietary supplement: Multispecies probiotic; Other: Placebo

Detailed Description

Certain individual probiotic strains have been proven to be effective in reducing the risk of antibiotic-associated diarrhoea (AAD). However, the effects of using multispecies probiotics remain unclear. The investigators aim to assess the effectiveness of a specific multispecies probiotic preparation (Ecologic AAD Kids) in reducing the incidence of AAD in children.

In this trial, a total of 350 children aged 3 months to 18 years, undergoing antibiotic treatment, will be randomly allocated to receive either a multispecies probiotic consisting of 2 strains of Bifidobacterium (B. bifidum W23, B. lactis W51) and 6 strains of Lactobacillus (L. acidophilus W37, L. acidophilus W55, L. paracasei W20, L. plantarum W62, L. rhamnosus W71, and L. salivarius W24) at a total dose of 10^10 colony-forming units daily, or a placebo, from the first day of antibiotic treatment until 7 days after antibiotic cessation. The primary outcome measure will be the incidence of AAD, defined as ≥3 loose or watery stools (a score of A on the Amsterdam Infant Stool Scale for children younger than 1 year and a score of 5-7 on the Bristol Stool Form scale for children older than 1 year) in 24 hours, caused either by Clostridium difficile or of otherwise unexplained aetiology (after testing for common diarrhoeal pathogens), occurring during and/or up to 7 days after the end of the antibiotic therapy.

• Study Type: Interventional
• Enrollment (Actual): 350
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1061
    • OLVG location West
  • Amsterdam, Netherlands, 1081 HV
    • Amsterdam Umc, Location Vumc
  • Amsterdam, Netherlands, 1092
    • OLVG location East
  • Amsterdam, Netherlands, 1105
    • Amsterdam UMC, location AMC
• Poland
  • Warsaw, Poland, 02-091
    • Department of Paediatrics, The Medical University of Warsaw, Poland
  • Silesia
    • Trzebnica, Silesia, Poland, 55-100
      • Department of Paediatrics, St. Hedwig of Silesia Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• children receiving oral or intravenous antibiotics for common infections, willing and able to start the probiotic intervention within 24 hours after the start of antibiotic intake, receiving broad-spectrum antibiotics (broad-spectrum penicillins, cephalosporins, fluoroquinolones, clindamycin).

Exclusion Criteria:

• prior use of antibiotics within the previous 4 weeks, presence of a severe or generalised infection, history of severe chronic disease (e.g., cancer, inflammatory bowel disease, tuberculosis), critical/life-threatening illness, immunodeficiency, history of pre-existing diarrhoea within the previous 4 weeks, exclusive breastfeeding, allergy or hypersensitivity to any component of the study product, tube-feeding, use of proton-pump inhibitors, laxatives or anti-diarrhoeal drugs, as well as use of a probiotic product containing L rhamnosus GG or S boulardii 14 days before and during the study.

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
Experimental: Multispecies probiotic group; 175 participants.	Dietary supplement: Multispecies probiotic; Multispecies probiotic consisting of Bifidobacterium bifidum W23, Bifidobacterium lactis W51, Lactobacillus acidophilus W37, Lactobacillus acidophilus W55, Lactobacillus paracasei W20, Lactobacillus plantarum W62, Lactobacillus rhamnosus W71 and Lactobacillus salivarius W24 at a dose of 5x10^9 Colony Forming Units (CFU), twice daily, orally.
Placebo Comparator: Control group; 175 participants.	Other: Placebo; Placebo identical in taste, smell and color to the multispecies probiotic.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of antibiotic-associated diarrhea	Antibiotic-associated diarrhea will be defined as 3 or more loose or watery stools (a score of A on the Amsterdam Infant Stool Scale or 5-7 on the Bristol Stool Form scale) per day in a 24-hour period, caused by C. difficile infection or of otherwise unexplained aetiology after testing for common diarrhoeal pathogens (rotavirus, adenovirus, norovirus, Campylobacter spp., Salmonella spp., Shigella spp., and Yersinia spp.), occurring during the intervention period.	Up to 7th day after antibiotic cessation.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of antibiotic-associated diarrhea - alternative definition 1	≥3 loose or watery stools per day for a minimum of a 48-hour period caused by C. difficile infection or of otherwise unexplained aetiology.	Up to 7th day after antibiotic cessation.
Incidence of antibiotic-associated diarrhea - alternative definition 2	≥2 loose or watery stools per day for a minimum of a 24-hour period caused by C. difficile infection or of otherwise unexplained aetiology.	Up to 7th day after antibiotic cessation.
Incidence of diarrhea	≥3 loose or watery stools per day for a minimum of 24 hours regardless of its aetiology.	Up to 7th day after antibiotic cessation.
Clostridium difficile-associated diarrhea	≥3 loose or watery stools per day for a minimum of 24 hours caused by C. difficile confirmed by the presence of toxin-producing C. difficile in stools.	Up to 7th day after antibiotic cessation.
Duration of diarrhea	Defined as the time until the normalisation of stool consistency according to the Bristol Stoo Form (BSF) or Amsterdam Infant Stool Scale (AISS) - on BSF numbers 1, 2, 3 and 4; on AISS scale, letters B or C, and the presence of normal stools for 48 h.	Up to 7th day after antibiotic cessation.
Discontinuation of the antibiotic treatment due to severity of diarrhoea		Up to 7th day after antibiotic cessation.
Hospitalisation caused by diarrhoea		Up to 7th day after antibiotic cessation.
Need for intravenous rehydration		Up to 7th day after antibiotic cessation.
Adverse events		Up to 7th day after antibiotic cessation.

Collaborators and Investigators

• Sponsor: Medical University of Warsaw
• Collaborators: Winclove Probiotics B.V.
• Investigators: Principal Investigator: Jan Łukasik, MD, Department of Paediatrics, The Medical University of Warsaw, Poland

Publications and helpful links

General Publications

• Lukasik J, Dierikx T, Besseling-van der Vaart I, de Meij T, Szajewska H; Multispecies Probiotic in AAD Study Group. Multispecies Probiotic for the Prevention of Antibiotic-Associated Diarrhea in Children: A Randomized Clinical Trial. JAMA Pediatr. 2022 Sep 1;176(9):860-866. doi: 10.1001/jamapediatrics.2022.1973. Erratum in: JAMA Pediatr. 2022 Jul 5;:null.
• Lukasik J, Szajewska H. Effect of a multispecies probiotic on reducing the incidence of antibiotic-associated diarrhoea in children: a protocol for a randomised controlled trial. BMJ Open. 2018 Jun 4;8(5):e021214. doi: 10.1136/bmjopen-2017-021214.

Study record dates

Study Major Dates

• Study Start (Actual): February 16, 2018
• Primary Completion (Actual): May 13, 2021
• Study Completion (Actual): May 13, 2021

Study Registration Dates

• First Submitted: October 24, 2017
• First Submitted That Met QC Criteria: November 2, 2017
• First Posted (Actual): November 7, 2017

Study Record Updates

• Last Update Posted (Actual): October 7, 2021
• Last Update Submitted That Met QC Criteria: September 29, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: probiotics; antibiotic-associated diarrhea
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Diarrhea
• Other Study ID Numbers: AAD2017

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The data collected in the course of this study are available from the Principal Investigator upon reasonable request.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No