Efficacy and Safety of L. Plantarum and P. Acidilactici in Children With Upper Respiratory Tract Infections

Efficacy and Safety of Lactobacillus Plantarum and Pediococcus Acidilactici as Twice-daily Co-adjuvant Therapy of Upper Respiratory Tract Infections in Children 6 Months to 5 Years Old

Randomized, placebo-controlled trial to evaluate the coadjuvant effect of a combination of L. plantarum and P. acidilactici probiotic strains, taken twice daily, in children 6 months to 5 years-old with upper respiratory tract infections with pharyngitis and/or tonsillitis. Main objective is to evaluate efficacy of this probiotic in reducing fever and pain, as well to evaluate its safety.

Study Overview

• Status: Terminated
• Conditions: Tonsillitis; Pharyngitis; Upper Respiratory Tract Infections
• Intervention / Treatment: Dietary supplement: Probiotic; Other: Placebo

Detailed Description

Randomized, placebo-controlled trial (RCT) to evaluate the coadjuvant effect of probiotic strains L. plantarum CECT30292, L.plantarum CECT7484 and CECT7485 together with P. acidilactici CECT7483, taken twice daily, in children 6 months to 5 years-old with upper respiratory tract infections with pharyngitis and/or tonsillitis, as diagnosed by a physician.

Main objective is to evaluate efficacy of this probiotic in reducing fever (as per infrared thermometer, same model for all recruited subjects) and pain (as per FLACC scale [Face, Legs, Activity, Cry and Consolability]), as well to evaluate its safety. Secondary objectives include effect on cough, rhinorrhea, nasal congestion, use of concomitant medication, emergency visits, hospitalizations, schooling absences and salivary immune markers.

Probiotic intervention will last 15 days, and patients will return for follow-up visits on the last day of probiotic intervention (day 15), and well as day 30 and 60.

The study aims at enrolling and randomizing 80 children fulfilling entry criteria and living in Mexico City area (2,200m over the sea level), after parents or legal guardians sign informed consent.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Pedro Gutierrez-Castrellon, MD, PhD; Phone Number: 1246 5255-4000-3000; Email: pedro.gutierrez@councilforprobiotics.org
• Study Contact Backup: Name: Diana Maria Andrade-Platas, MD; Phone Number: 1246 5255-4000-3000; Email: dianamandrade@yahoo.com

Study Locations

• Mexico
  • Mexico DF
    • Mexico City, Mexico DF, Mexico, 14080
      • Hospital General Dr. Manuel Gea González

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 5 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male and female children, 6 months to 5 years-old
• Diagnosed with upper respiratory tract infection with pharyngitis and/or tonsillitis by a physician
• With fever >37.5 Celsius degrees and FLACC (Face, Legs, Activity, Cry and Consolability) score >3
• Symptom onset no more than 48h before study entry
• Body weight at birth >2500 gr
• Informed consent provided by parents or legal guardians

Exclusion Criteria:

• Failure to thrive
• Asthma or significant allergic disease
• Use of antibiotics, antivirals, probiotics or prebiotics for more than 48h within 2 weeks of study entry
• History of recurrent respiratory infections (>2 otitis, >1 severe sinusitis or >1 pneumonia) within 12 months of study entry
• History of 2 or more invasive infections (meningitis, cellulitis, osteomyelitis, sepsis)
• Chronic diarrhea or short bowel syndrome
• Congenital heart or respiratory deficiency
• Known alpha1-antitrypsin deficiency
• Concurrent participation in other clinical trial(s)
• Other particular conditions which, in the judgment of the Principal Investigator, may interfere with the study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Probiotic; Active test product contains four lactic acid bacteria strains with Qualified Presumption of Safety (QPS) status by European Food Safety Authority (EFSA): Lactobacillus plantarum CECT30292, Lactobacillus plantarum CECT7484, Lactobacillus plantarum CECT7485, and Pediococcus acidilactici CECT7483, with maltodextrin (E1400, qs) as excipient, formulated in a vegetable hydroxymethylpropyl-cellulose capsule (HPMC) of size 0. Active test product is a food supplement and not an investigational medicinal product	Dietary supplement: Probiotic; Combination of strains Lactobacillus plantarum CECT30292, Lactobacillus plantarum CECT7484, Lactobacillus plantarum CECT7485, and Pediococcus acidilactici CECT7483, twice daily for 15 days
Placebo Comparator: Control; The control study product is identical in packaging and formulation except that none of strains Lactobacillus plantarum CECT30292, Lactobacillus plantarum CECT7484, Lactobacillus plantarum CECT7485 and Pediococcus acidilactici CECT7483 (probiotic bacteria) are present. The Control product contains maltodextrin (E1400, qs) only, in a vegetable hydroxymethylpropyl-cellulose capsule (HPMC) of size 0.	Other: Placebo; Combination of maltodextrin (E1400, qs) in a vegetable hydroxymethylpropyl-cellulose capsule (HPMC) of size 0, twice daily for 15 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Daily evolution of fever	Daily severity of fever (Celsius degrees), as measured with an infrared thermometer (same model for all recruited subjects) and noted in patient diary	Day 1 to 15
Daily evolution of pain	Daily severity of pain, as per FLACC scale (Face, Legs, Activity, Cry and Consolability, ranging 0 [no pain] to 10 [maximum pain]) and noted in patient diary	Day 1 to 15

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fever Area Under the Curve	Area Under the Curve (AUC) of daily fever (body temperature, Celsius degrees)	Day 1 to 60
Pain Area Under the Curve	Area Under the Curve (AUC) of daily pain, as per FLACC scale (Face, Legs, Activity, Cry and Consolability, ranging 0 [no pain] to 10 [maximum pain])	Day 1 to 60
Days with fever	Days with body temperature > 37.5 Celsius, as noted in patient diary	Day 1 to 60
Days with pain	Days with pain as per FLACC scale (Face, Legs, Activity, Cry and Consolability), as noted in patient diary	Day 1 to 60
Days with rhinorrhea	Days with runny nose, as noted in patient diary	Day 1 to 60
Days with cough	Days of cough, as noted in patient diary	Day 1 to 60
Days with nasal congestion	Days of nasal congestion, as noted in patient diary	Day 1 to 60
Days with any symptom	Days with one or more of the following symptom: fever, pain, rhinorrhea, cough or nasal congestion (as noted in patient diary)	Day 1 to 60
Days with concomitant medication	Days of intake of NSAIDS (non-steroidal anti-inflammatory drugs) and/or antihistamines, as noted in patient diary	Day 1 to 60
Number of children receiving antibiotics	Number of children receiving antibiotics	Day 1 to 60
Number of hospitalizations	Number of children being hospitalized related to respiratory tract infection	Day 1 to 60
Number of medical or emergency visits	Number of medical or emergency visits related to respiratory tract infection	Day 1 to 60
Days of schooling absence	Days of daycare or kindergarten absence, as noted in patient diary	Day 1 to 60
Change in salivary immune biomarkers	Change in concentration of Immunoglobulin A (IgA), Tumor Necrosis Factor-alpha (TNFa), Interleukin 1-beta (IL-1b) and Interleukin 10 (IL-10) in saliva samples	Day 1 to 15
Total treatment costs	Cost of medical and emergency visits, drug treatments (anti-inflammatory drugs, anti-histamines and antibiotics) and schooling absence	Day 1 to 60
Time to fever resolution	Time to body temperature at or below 37.5 Celsius, as noted in patient diary	Day 1 to 15
Time to pain resolution	Time to FLACC (Face, Legs, Activity, Cry and Consolability, ranging 0 [no pain] to 10 [maximum pain]) score < 2, as noted in patient diary	Day 1 to 15
Time to complete symptom resolution	Time to clearance of all of the following symptoms: fever, pain, rhinorrhea, cough and nasal congestion, as noted in patient diary	Day 1 to 15
Time to fever recurrence	Time to body temperature >37.5 Celsius after initial resolution (see outcome #19), as noted in patient diary	Day 15 to 60
Time to pain recurrence	Time to FLACC (Face, Legs, Activity, Cry and Consolability, ranging 0 [no pain] to 10 [maximum pain]) score > 3 after initial resolution (see outcome #20), as noted in patient diary	Day 15 to 60
Time to any symptom recurrence	Time to recurrence of any symptom (fever, pain, rhinorrhea, cough and nasal congestion) after initial complete symptom resolution (see outcome #21), as noted in patient diary	Day 15 to 60
Change in microbiota	Change in microbiota composition, as determined by 16S gene sequencing	Day 1 to 15

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Etiology of the upper respiratory tract infection at baseline	Identification of the viral or bacterial pathogen responsible for the baseline episode of upper respiratory tract infection by molecular methods	Day 1
Salivary vitamin D at baseline	Concentration of vitamin D at baseline as measured in saliva sample	Day 1

Collaborators and Investigators

• Sponsor: AB Biotics, SA
• Collaborators: Hospital General Dr. Manuel Gea González; Innovacion y Desarrollo de Estrategias en Salud
• Investigators: Principal Investigator: Pedro Gutierrez-Castrellon, MD, PhD, Hospital General Dr. Manuel Gea González

Publications and helpful links

General Publications

• Manworren RC, Hynan LS. Clinical validation of FLACC: preverbal patient pain scale. Pediatr Nurs. 2003 Mar-Apr;29(2):140-6.
• Merkel SI, Voepel-Lewis T, Shayevitz JR, Malviya S. The FLACC: a behavioral scale for scoring postoperative pain in young children. Pediatr Nurs. 1997 May-Jun;23(3):293-7.
• Gutierrez-Castrellon P, Gandara-Marti T, Abreu Y Abreu AT, Nieto-Rufino CD, Lopez-Orduna E, Jimenez-Escobar I, Jimenez-Gutierrez C, Lopez-Velazquez G, Espadaler-Mazo J. Probiotic improves symptomatic and viral clearance in Covid19 outpatients: a randomized, quadruple-blinded, placebo-controlled trial. Gut Microbes. 2022 Jan-Dec;14(1):2018899. doi: 10.1080/19490976.2021.2018899.
• Maya-Barrios A, Lira-Hernandez K, Jimenez-Escobar I, Hernandez L, Ortiz-Hernandez A, Jimenez-Gutierrez C, Lopez-Velazquez G, Gutierrez-Castrellon P. Limosilactobacillus reuteri ATCC PTA 5289 and DSM 17938 as adjuvants to improve evolution of pharyngitis/tonsillitis in children: randomised controlled trial. Benef Microbes. 2021 Apr 12;12(2):137-145. doi: 10.3920/BM2020.0171. Epub 2021 Apr 1.

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2022
• Primary Completion (Actual): June 2, 2023
• Study Completion (Actual): June 2, 2023

Study Registration Dates

• First Submitted: March 7, 2022
• First Submitted That Met QC Criteria: March 7, 2022
• First Posted (Actual): March 15, 2022

Study Record Updates

• Last Update Posted (Actual): October 17, 2023
• Last Update Submitted That Met QC Criteria: October 16, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Probiotic
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Disease Attributes; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Infections; Communicable Diseases; Respiratory Tract Infections; Tonsillitis; Pharyngitis
• Other Study ID Numbers: PROPED-URTI

Drug and device information, study documents

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