Evaluation of Lactobacillus Reuteri DSM 17938 + Vitamin D3 in the Prevention of RRI in Paediatric Patients (LR_D3)

Evaluation of a Food Supplement Containing Lactobacillus Reuteri DSM 17938 + Vitamin D3 in the Prevention of Recurrent Respiratory Infections in Paediatric Patients

The aim of this protocol is to evaluate, in a multicenter, randomized, double blind vs placebo clinical trial the effects of a marketed food supplement containing Lactobacillus reuteri DSM 17938 and vitamin D3 (Reuterin® D3) in the prevention of recurrent respiratory infections in pediatric patients suffered from Recurrent Respiratory Infection (RRI) in previous years.

Study Overview

• Status: Terminated
• Conditions: Recurrent Respiratory Tract Infections
• Intervention / Treatment: Dietary supplement: Lactobacillus reuteri DSM 17938 + Vitamine D3; Dietary supplement: Placebo

Detailed Description

Several clinical trials documented the efficacy of probiotics in the prevention and treatment of acute gastroenteritis, while there is little evidence on the efficacy of the probiotics in the prevention of children respiratory infections.

The biological activity of probiotics is linked, partly, to their capacity to adhere to enterocytes. This would avoid the binding of pathogenic bacteria through a competitive exclusion mechanism. This inhibition toward pathogen bacteria on epithelial and mucosal level (substrate), thanks also to the production of antimicrobial substances, can have a beneficial effect on the balance of the intestinal microflora of the host and improve its immunity.

The adhesion of probiotic bacteria to the enterocyte membrane receptors influences the activation of second messengers that induces the production of cytokines. The presence of probiotic bacteria influences the commensal microorganisms in the production of lactic acid and bacteriocins. These substances inhibit the growth of pathogens and modify the balance of commensal bacteria of the intestinal bacterial flora.

Numerous controlled clinical trials show that L. reuteri DSM 17938 colonizes the human gastric and intestinal epithelium and modulates the immune response, particularly through CD4 + T-helper cells in the ileum. These data confirm the pre-clinical evidence obtained in animal models; furthermore these immunomodulatory effects may explain some clinical properties of L. reuteri DSM 17938 such as the prevention of diarrhea, inhibition of pathogen infectionand the following immune system response of the host to these pathogens, as well as the potential modulation of the immune response by the Th1/Th2 balance in the human intestinal epithelium, an answer that has been linked to the prevention and treatment of allergy. In a recent, randomized, double-blind, placebo-controlled clinical trial, L. reuteri DSM 17938, supplemented for three months to healthy children aged 6-36 months attending nursery schools, demonstrated not only a significant reduction of episodes and duration of diarrhea but also of respiratory tract infections with consequent reduction of costs for society.

Despite the prevalence of food with vitamin D and multivitamin products, reports regarding non-optimal vitamin D levels in adults and children in the world have increased, in particular among those subjects overweight and with dark pigmentation of the skin.

In addition to its well-known effects on bone health, vitamin D is indeed an important immune regulator, because it stimulates innate immunity and modulates inflammation. An analysis of data from the National Health and Nutrition Examination Survey (NHANES) between 1988 and 1994 showed an inverse relationship between vitamin D levels and the incidence of upper respiratory tract infections (URTI). These results were supported by other studies showing an increased risk of acute lower respiratory tract infections in subjects with low levels of vitamin D.

Historically, the association between rickets and the risk of serious respiratory infections is well known and vitamin D deficiency has been associated with an increased risk to contract the flu.

These considerations have led to the hypothesis that supplementation with a probiotic added with vitamin D3 may influence the composition of intestinal flora by improving the immune system and therefore reducing episodes of respiratory infections, particularly frequent during preschool age.

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Michele Miraglia del Giudice, Prof.; Phone Number: 337948622; Email: michele.miraglia@alice.it

Study Locations

• Italy
  • Naples, Italy, 80138
    • University of Campania Luigi Vanvitelli

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 6 years (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients between 1 and 6 years of age at the enrollment; both sexes
• Patients with an history of RRI, according to the definition (The definition of Recurrent respiratory infections (RRI) is the onset of 8 or more documented airway infections during the year, in preschool children (up to three years of age) or 6 or more in children older 3 years, in the absence of any other underlying pathological condition) in the previous year.
• Atopic and non-atopic patients
• Willing and able to give informed consent of participation in the study by parent or legal guardian.

Exclusion Criteria:

• Presence of autoimmune diseases, immunodeficiency, neuromuscular diseases, congenital cardiomyopathies, metabolic diseases
• Patients in therapy with other drugs for the treatment of RRI
• Supplementation with probiotics and /or prebiotics in the previous 2 weeks
• Vitamin D intake in the last 4 weeks
• IgA deficiency
• Antibiotic treatment at least 4 week before in inclusion
• Participation in other clinical trials

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Reuterin D3; Patients should take 10 drops once a day during meals for 4 months followed by 2 months of follow up.	Dietary supplement: Lactobacillus reuteri DSM 17938 + Vitamine D3; Lactobacillus reuteri DSM 17938 (10E8 CFU in 5 drops), Vitamin D3 (400 IU in 5 drops), sunflower oil, medium chain triglycerides, silicon dioxide
Placebo Comparator: Placebo; Patients should take 10 drops once a day during meals for 4 months followed by 2 months of follow up.	Dietary supplement: Placebo; sunflower oil, medium chain triglycerides, silicon dioxide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of the number of respiratory infection	Change of the number of respiratory infection respect the previous year	4 months + 2 months of follow up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of number of days with fever	To evaluate the change of the number of days with fever	4 months + 2 months of follow up
Change of the antibiotic use	To evaluate the change of the antibiotic use	4 months + 2 months of follow up
Change of number of visit to Pediatrician	To evaluate the change of the number of visit to Pediatrician	4 months + 2 months of follow up
Change of number of days of absence from the nursery / kindergarten	To evaluate the change of the number of days of absence from the nursery / kindergarten	4 months + 2 months of follow up
Changes of days of absence from work by parents	To evaluate the change of days of absence from work by parents	4 months + 2 months of follow up
Modification of intestinal microflora	To evaluate the modification of intestinal microflora	4 months + 2 months of follow up

Collaborators and Investigators

• Sponsor: Noos S.r.l.
• Investigators: Principal Investigator: Michele Miraglia del Giudice, Prof., University of Campania "Luigi Vanvitelli"

Study record dates

Study Major Dates

• Study Start (Actual): November 25, 2019
• Primary Completion (Actual): September 30, 2021
• Study Completion (Actual): September 30, 2021

Study Registration Dates

• First Submitted: May 25, 2020
• First Submitted That Met QC Criteria: May 28, 2020
• First Posted (Actual): May 29, 2020

Study Record Updates

• Last Update Posted (Actual): March 23, 2023
• Last Update Submitted That Met QC Criteria: March 21, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: RRI, probiotics, vitamin D3, L. reuteri
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Infections; Respiratory Tract Infections; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol
• Other Study ID Numbers: IRR_D3

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