Safety Evaluation of Intranasal Use of DSM 32444 Postbiotic in Humans

Study Overview
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Brief Summary
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Influenza is one of the most common URTIs in the world, especially in low middle income countries. It directly causes 3-5 million cases of severe illness and  600K deaths. A common treatment regime for influenza involves a lot of antibiotics. Current concerns about antimicrobial resistance (AMR) have led to an urgent need for a nature-based next generation therapeutic approach that is safe, effective and helps in addressing the issues of AMR. There have been multiple research studies supporting the efficacy of bacterial-based approaches in the prevention of viral respiratory infections, and that have potential for treatment. For use in the respiratory tract, it is necessary to have a completely sterile product to ensure safety in the long-term and there is a need for safety assessment of products both in animal models and human studies. This phase of the study aims to evaluate the safety in humans of a nasal spray using a postbiotic preparation of Bacillus subtilis DSM32444 and that is a sterile inert bioparticle.

Detailed Description
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Influenza is one of the most common URTIs in the world, especially in low middle income countries. It directly causes 3-5 million cases of severe illness and  600K deaths. A common treatment regime for influenza involves a lot of antibiotics. Current concerns about antimicrobial resistance (AMR) have led to an urgent need for a nature-based next generation therapeutic approach that is safe, effective and helps in addressing the issues of AMR. There have been multiple research studies supporting the efficacy of bacterial-based approaches in the prevention of viral respiratory infections, and that have potential for treatment. For use in the respiratory tract, it is necessary to have a completely sterile product to ensure safety in the long-term and there is a need for safety assessment of products both in animal models and human studies. Preclinical studies of inactivated Bacillus subtilis strain DSM32444 conducted by collaborating UK universities and laboratories have shown potential effects in stimulating innate immunity and preventing Covid-19 and influenza. The reason for using an inactivated spore is because various publications have identified risks of inhalation of high doses of live bacteria in the respiratory tract and lungs. DSM32444 also carries GRAS status for human use. An accredited, cGLP, repeat-dose toxicology study also confirmed complete safety in rodent models after high doses of treatment. The investigators think there is a likelihood to apply this postbiotic technology to mitigate the overuse of antibiotics. The aim of this study is to evaluate the safety nasal spray using the postbiotic Bacillus subtilis DSM32444 when used in humans. Study population: Sample size for Phase 1 is 60 healthy volunteers to assess tolerance. Description of Sites: the study is carried out at Thai Binh University of Medicine and Pharmacy and Thai Binh University of Medicine and Pharmacy Hospital. Description of Study intervention: The Phase I study is a double-blind, parallel-group, randomized, placebo controlled study. Study participants who are healthy volunteers were randomly assigned 1:1 to either the postbiotic DSM32444 nasal spray (SPEROVID) or the placebo (0.9% NaCl). Study subjects who are healthy volunteers, confirmed by routine physical examination of the research facility, will be invited to participate in the phase I study. The randomization is carried out according to the 4-block strategy using envelopes with predetermined random codes. Study subjects will be given codes in turn sealed in sequentially numbered envelopes. The research product is prepared in a double-blind form, on the label there are random codes matching the code assigned to the study object. The duration of the study regimen is 7-days, except for early withdrawal from the study for safety reasons. The research product (SPEROVID or placebo) is nasally administered as a spray 2-3 times daily, with each administration being 0.1ml/nostril (total 0.2 mL/administration). Researchers will follow up with volunteers for safety evaluation of the products, analysis of the subject's complaints of disease and other special issues (if applicable), physical examination and laboratory tests. If any adverse events are detected, the investigator should immediately record the information in the source literature and CRF, specifying the nature of the AE, the duration of the AE, and other characteristics. - The study data after collection will be analyzed statistically using SAS 9.4. The normal distribution of statistical samples will be evaluated by the Kolmogorov-Smirnov-Lilliefors test, the uniformity of variance will be verified by Levene's test. The continuous variables will be analyzed using a two-dimensional variance test or covariance analysis (ANOVA/ANCOVA) in the case of a normal distribution and using the ANOVA non-parametric Kruskal-Wallis test in the case of a non-standard distribution. Repeatable measurement analyses will be used where appropriate. Study subject demographics and baseline characteristics were summarized using descriptive statistics (N, mean, standard deviation, median, 25/75 percentiles, minimum, and maximum) for continuous variables, and number and percentages of patients for categorical variables. AE/SAE were described by MedDRA 25.1 preferred term, outcome and relationship to IMP throughout the trial. Analysis of classification data is carried out using the Cochran-Mantel Haenszel test. In the absence of further note, the continuous variables are expressed by the mean ± standard deviation. The Cox analysis model and log-rank testing will be used to compare variables of the time type leading up to an event. - Expected outcomes: The nasal spray using postbiotic Bacillus subtilis DSM32444 (SPEROVID) is safe and well tolerated among healthy volunteers.

Official Title
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A Double-blind, Randomized, Placebo-controlled Study to Evaluate the Safety of Postbiotic Nasal Spray Using Killed Spores of Bacillus Subtilis DSM32444 in Healthy Volunteers

Conditions
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Influenza

Intervention / Treatment
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* Drug: 0.9% NaCl isotonic saline solution
* Combination Product: Bacillus subtilis DSM32444, inactivated


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy volunteers must be ≥18 years of age, at the time of signing the informed consent. Participants who are able to use an e-Diary or Paper Diary during the study to report their health status Participants capable of giving a signed informed consent form (ICF) Exclusion Criteria: Planned travel outside of the study area during the study period. Use of any investigational drug within 30 days prior to Day screening. No investigational products are permitted for use during the conduct of this study A known history of alcohol or drug abuse within the last 2 years Existence of any medical condition, which in the opinion of the investigator, might significantly affect the subject's ability to complete this trial; or their safety in this trial

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control<br>Healthy volunteers in Control group receives a nasal spray containing 0.9% NaCl isotonic saline solution. | Drug: 0.9% NaCl isotonic saline solution<br>* The placebo-control in the phase I study was a 0.9% NaCl isotonic saline solution. This nasal spray solution has no pharmacological effect, but is considered to have a cleansing effect on the nose, supporting the treatment of nasal symptoms in nasal pathology. The solution is prepared by extracting 5 mL from 0.9% NaCl intravenous infusion 500 mL PP bottle (B.Braun, Germany, product declaration No. VD-32732-19). The solution is bottled in the same fully-sealed nasal spray device containing Bacillus subtilis DSM 32444 postbiotic, used for Sperovid.<br>* Other names: 0.9% NaCl;|
| Experimental: SPEROVID<br>Healthy volunteers in SPEROVID group receives a nasal spray containing inactivated Bacillus subtilis DSM32444 (postbiotic) | Combination Product: Bacillus subtilis DSM32444, inactivated<br>* Postbiotic DSM32444 is manufactured by HURO BIOTECH Company as a drug-grade active pharmaceutical ingredient. The Class A medical device containing Postbiotic DSM32444 is called Sperovid, which is manufactured by Dong Duoc Viet under ISO 13485:2016 standards for medical device. Sperovid has registration number: 220000033/PCBA-LA<br>* Other names: Sperovid, SPOR-COV;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the safety and tolerability following multiple doses of postbiotic DSM32444 nasal spray for 7 days with Placebo in Heathy Volunteers | Incidence of Adverse Events (Nasal Congestion, Itchy Nose, Allergic Reaction/Rash, Sneezing, Nasal Discharge, Weeping, Itchy eyes, Itchy ears, Sore throat, Nausea/Vomiting) Incidence of Serious Adverse Events (Adverse events leading to discontinuation of study products, Adverse events leading to withdrawal of subjects from the study, Deaths up to the time of study data cut off) Incidence of Related Adverse Events Incidence of Related Serious Adverse Events | Day 1 to Day 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Influenza A, Influenza B, URTIs