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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Upper Respiratory Tract Infections, Pharyngitis, Tonsillitis

Intervention / Treatment
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* Dietary Supplement: Probiotic
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized controlled trials. Study subjects (6 months to 5 years-old) will be allocated to receive a combination of strains Lactobacillus plantarum CECT30292, Lactobacillus plantarum CECT7484, Lactobacillus plantarum CECT7485, and P. acidilactici CECT7483 (arm one) or placebo (arm two)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Probiotic<br>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<br>* Combination of strains Lactobacillus plantarum CECT30292, Lactobacillus plantarum CECT7484, Lactobacillus plantarum CECT7485, and Pediococcus acidilactici CECT7483, twice daily for 15 days<br>|
| Placebo Comparator: Control<br>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<br>* Combination of maltodextrin (E1400, qs) in a vegetable hydroxymethylpropyl-cellulose capsule (HPMC) of size 0, twice daily for 15 days<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Probiotic