Efficacy of Probiotics (LiveSpo Navax) in Preventing Respiratory Diseases in Children

Study Overview
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Brief Summary
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Acute respiratory infections are common diseases worldwide with the highest incidence and mortality rates, especially among children. Currently, the prevention of acute respiratory infections in children still faces certain limitations. Although there is a vaccine available for influenza, there are no vaccines yet for RSV and adenovirus in children, and influenza vaccination needs to be repeated annually to achieve optimal effectiveness. Therefore, maintaining respiratory and throat hygiene is essential for both treatment and prevention, ensuring respiratory health for children and reducing the risk of bacterial co-infections. In recent years, preventive strategies for respiratory inflammation have garnered increasing attention, with probiotics being shown to have the potential to support treatment and prevention & reduce the risk of recurrent respiratory infections, thus decreasing reliance on antibiotics. Here, the investigators propose that direct nasal spraying of probiotics may be safe and effective in preventing respiratory diseases. The aim of the study is to evaluate the effectiveness of two types of nasal- praying Bacillus probiotics including LiveSpo Navax (1 billion/mL x 30 mL B. subtilis and B. clausii) and LiveSpo Navax Kid (0.6 billion/mL x 30 mL B. subtilis and B. clausii) in preventing respiratory diseases. Study Population: The sample size is 600. Description of Sites: The study is conducted at preschools in Son Tay Province, Hanoi, Vietnam. Description of Study Intervention: A total of 600 eligible children are randomly divided into three groups (n = 200/group each). Children in the Control group received 0.9% NaCl physiological saline twice daily (morning and afternoon), with 2 sprays in each nostril and 2 sprays in the throat each time (totally 6 sprays each time), continuously for four weeks. Children in the Probiotic 1 group receive LiveSpo Navax product, and children in the Probiotic 2 group receive LiveSpo Navax Kid, with the same dosage and frequency as the Control group. Study Duration: 12 months.

Detailed Description
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Acute respiratory infections are common diseases worldwide with the highest incidence and mortality rates, especially among children. Vietnam is one of the 15 countries with the highest pneumonia rates in the world, with an estimated 2.9 million cases occurring annually. The age group most susceptible to acute respiratory infections is children under 5 years old, especially bronchiolitis, which often occurs in children under 2 years old. The incidence of acute respiratory infections varies with the seasons, with the highest prevalence of viral respiratory infections typically occurring during the winter and spring. In tropical regions, acute respiratory infections are more common during the rainy months, while in temperate regions, they are more prevalent during the winter months. Approximately 30-60% of outpatient visits for medical care are due to acute respiratory infections. Currently, the prevention of acute respiratory infections in children still faces certain limitations. Although there is a vaccine available for influenza, there are no vaccines yet for RSV and adenovirus in children, and influenza vaccination needs to be repeated annually to achieve optimal effectiveness. Therefore, maintaining respiratory and throat hygiene is essential for both treatment and prevention, ensuring respiratory health for children and reducing the risk of bacterial co-infections. Here, the investigators propose that direct nasal spraying of probiotics may be a safe and effective method for preventing respiratory diseases. The objective of this study is to investigate the safety and preventive effects of two types of nasal-spraying Bacillus probiotics: LiveSpo Navax (1 billion/mL x 30 mL B. subtilis and B. clausii) and LiveSpo Navax Kid (containing 0.6 billion/mL x 30 mL B. subtilis and B. clausii) in preventing respiratory diseases in healthy children attending preschools. The investigators will evaluate the preventive efficacy in terms of reducing the number of respiratory disease episodes and the number of courses of antibiotics in children after 2 weeks and 4 weeks of using LiveSpo Navax and LiveSpo Navax Kid. A randomized, double-blind, and controlled clinical trial will be conducted. Parents of the will be required to provide various information about their children, including their full names, sex, ages, respiratory infection history, and history of antibiotic use... After obtaining informed consent, 600 children will be randomly assigned to three groups (n = 200/group): the control group (referred to as the Control group) will receive 0.9% NaCl physiological saline, the experimental group 1 (referred to as the Probiotic 1 group) will receive the probiotic LiveSpo Navax product, and the experimental group 2 (referred to as the Probiotic 2 group) will receive the probiotic LiveSpo Navax Kid. Children will be provided with coded nasal sprays in blinded samples to ensure the objectivity of the study. Clinical examinations and monitoring will be conducted after 2 weeks and 4 weeks of the experiment. Nasopharyngeal samples will be collected at the same time as the clinical examinations to assess the presence of probiotic spores in the children's nasal mucosa. During the trial, children's typical clinical symptoms of respiratory tract infections are monitored, including runny nose, stuffy nose, sneezing, sore throat, cough, and fatigue. Data is collected on the number of cold or illness episodes, the average duration of each illness episode, the number of days absent from school, and medication history after 2 weeks and 4 weeks of participating in the study. The children's health conditions are observed by caregivers, and the information is recorded in medical records. During this study, parents or caregivers are asked to refrain from giving their children other probiotics, whether via nasal spray or oral administration, and to avoid cleaning their children's noses with other 0.9% NaCl physiological saline sprayers. Data collection and statistical analysis will involve collecting individual medical records and systematically organizing the children's information into a dataset. The prevention efficacy of LiveSpo Navax product (Probiotic 1 group) and LiveSpo Navax Kid (Probiotic 2 group) is evaluated and compared to 0.9% NaCl physiological saline (Control group) based on the following clinical and survey criteria: (i) reduction in the percentage (%) of children with respiratory infections; (ii) reduction in the number of colds, illnesses, or respiratory tract infections in children; (iii) reduction in the duration of medication usage and the number of medication episodes in the treatment of respiratory diseases. Tabular analysis is performed on dichotomous variables using the χ2 test or Fisher's exact test when the expected value of any cell is below five. Continuous variables are compared using either the t-test or the Mann-Whitney test when the data is not normally distributed. Statistical and graphical analyses are conducted using GraphPad Prism v8.4.3 software (GraphPad Software, CA, USA). The significance level for all analyses is set at p < 0.05. Detection of B. subtilis ANA4 and B. clausii ANA39 in nasopharyngeal samples was conducted at 2 weeks and 4 weeks using real-time PCR with SYBR Green following the ISO 17025:2017 guidelines. This testing was performed at the Spobiotic Research Center.

Official Title
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Efficacy of Physiological Saline and Probiotics (LiveSpo Navax) in Preventing Respiratory Diseases in Children Aged 2-6, in Son Tay Province, Hanoi

Conditions
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Respiratory Disease, Respiratory Infections in Children

Intervention / Treatment
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* Drug: 0.9% NaCl physiological saline
* Combination Product: Probiotic 1
* Combination Product: Probiotic 2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children (male/female) aged from 2 to 6 years, currently attending a preschool. Parents of the pediatric agree to participate in the study, explain, and sign the research consent form. Exclusion Criteria: Children with a history of nasal reconstructive surgery, nasal ulcers, or nasal polyps. Children with a history of congenital immunodeficiency or infectious diseases (e.g., HIV). Children who regularly use products that may affect the research outcomes (e.g., immunosuppressive/immunostimulant drugs, pain relievers/anti-inflammatory drugs, anti-cough/expectorant drugs, antihistamines, or other probiotics) within 4 weeks before the start of the study. Children with co-morbidities that affect cognition and perception.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Blind, randomized, and controlled clinical trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control<br>The control group receives 0.9% NaCl physiological saline. Caregivers will spray the children twice daily (morning and afternoon), administering 2 sprays in each nostril and 2 sprays in the throat each time (totally 6 sprays each time) for a continuous period of 4 weeks, starting from the time of study participation. | Drug: 0.9% NaCl physiological saline<br>* Nasal-spraying 0.9% NaCl physiological saline is prepared by extracting 5 mL from 0.9% NaCl intravenous infusion 500 mL PP bottle (B.Braun, Germany, product declaration No. Nasal-spraying 0.9% NaCl physiological saline is prepared by extracting 30 mL from 0.9% NaCl intravenous infusion 500 mL PP bottle (B.Braun, Germany, product declaration No. VD-32732-19), and then pouring it into the same opaque plastic spraying 30 mL-bottle that is used for probiotic 1 and 2.<br>* Other names: Registration number: VD-32723-19;|
| Experimental: Probiotic 1<br>The Probiotic 1 group receives LiveSpo® Navax product which is NaCl 0.9% plus B. subtilis and B. clausii at 1 billion CFU/mL x 30 mL. Caregivers will spray the children twice daily (morning and afternoon), administering 2 sprays in each nostril and 2 sprays in the throat each time (totally 6 sprays each time) for a continuous period of 4 weeks, starting from the time of study participation. | Combination Product: Probiotic 1<br>* In Vietnam, LiveSpo Navax is manufactured as a Class-A medical device (Product declaration: No. 210001337/PCBA-HN) in accordance with manufacturing standards approved by the Hanoi Health Department, Ministry of Health, Vietnam (Certificate No. YT117-19), and ISO 13485:2016. LiveSpo Navax product is prepared in the form of NaCl 0.9% plus B. subtilis and B. clausii at 1 billion CFU/mL x 30 mL.<br>* Other names: Registration number: No.210001337/PCBA-HN;|
| Experimental: Probiotic 2<br>The Probiotic 2 group receives LiveSpo® Navax Kid product which is NaCl 0.9% plus B. subtilis and B. clausii at 0.6 billion CFU/mL x 30 mL. Caregivers will spray the children twice daily (morning and afternoon), administering 2 sprays in the nose and 2 sprays in each nostril, and 2 sprays in the throat each time (totally 6 sprays each time) for a continuous period of 4 weeks, starting from the time of study participation. | Combination Product: Probiotic 2<br>* In Vietnam, LiveSpo Navax Kid is manufactured as a Class-A medical device (Product declaration: No. 220002534/PCBA-HN) in accordance with manufacturing standards approved by the Hanoi Health Department, Ministry of Health, Vietnam (Certificate No. YT117-19), and ISO 13485:2016. LiveSpo Navax Kid is prepared in the form of NaCl 0.9% plus B. subtilis and B. clausii at 0.6 billion CFU/mL x 30 mL.<br>* Other names: Registration number: No. 220002534/PCBA-HN;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of children with respiratory infections | Percentage (%) of children with respiratory infections (runny nose, stuffy nose, sneezing, sore throat, cough, feeling tired...) after 2 weeks and 4 weeks of participating in the study | 2 weeks and 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of episodes of children with cold/illness/respiratory tract infections. | The number of episodes of children with cold/illness/respiratory tract infections after 2 weeks and after 4 weeks of participating in the study | 2 weeks and 4 weeks | 
| Duration of illness | The average number of days per episode of cold/illness/respiratory tract infections at 2 weeks and after 4 weeks of participating in the study | 2 weeks and 4 weeks | 
| Duration of school absence | The average number of days children have to be absent from school due to cold/illness/respiratory tract infections at 2 weeks and after 4 weeks of participating in the study | 2 weeks and 4 weeks | 
| Duration of respiratory tract disease treatment | The average number of days children undergo treatment for each respiratory tract disease (bronchiolitis, pneumonia, pharyngitis, otitis media, asthma...) after 2 weeks and after 4 weeks of participating in the study | 2 weeks and 4 weeks | 
| WURSS-K total score | The average total score of WURSS-K (Wisconsin Upper Respiratory Symptom Survey for Kids) evaluates children's respiratory infections when they are sick. WURSS-K is an instrument that measures illness-specific symptoms and their impact on the quality of life during upper respiratory tract infections (URTI). This tool includes 15 items: one global illness severity item (no. 1); six severity symptom-based items (no. 2-7); seven functional impact items (no. 8-14); one comparison item for assessing change over the days of an illness (no. 15). Items from 1 to 14 are based on a 4-point ordinal Likert-type scale (0 = not sick/do not have this/not at all, 3 = very sick/very bad/very hard). The last item is based on a 5-point Likert-type scale. Happy and sad face representations are included along with the ordinal scales to facilitate survey completion by children. | 2 weeks and 4 weeks | 
| Percentage (%) of children requiring medication treatment | Percentage (%) of children requiring medication treatments (antibiotics, anti-inflammatory, antipyretics, expectorants, infusion, bronchodilators...) after 2 weeks and after 4 weeks of participating in the study | 2 weeks and 4 weeks | 
| The number of medication courses used in the treatment of respiratory tract diseases | The number of medication courses used for treating respiratory tract diseases with each type of medication (antibiotics, anti-inflammatory, antipyretics, expectorants, intravenous fluids, bronchodilators...) after 2 weeks and after 4 weeks of participating in the study. | 2 weeks and 4 weeks | 
| Duration of treatment for respiratory tract diseases with each type of medication | The average number of days children undergo treatment with each type of medication (antibiotics, anti-inflammatory, antipyretics, expectorants, infusion, bronchodilators...) after 2 weeks and after 4 weeks of participating in the study | 2 weeks and 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute respiratory infection, Prevention, Nasal-spraying probiotics, Bacillus spores, Children