Safety and Efficacy of DSM 32444 in the Treatment of Acute Upper Respiratory Infection

An Open-label, Randomized, Active-controlled Study to Evaluate the Safety of Bacillus Subtilis DSM32444 in the Treatment of Upper Respiratory Infection

Respiratory infection is the leading cause of disease burden worldwide, measured by years lost through death or disability. Of all respiratory infections, influenza is one of the most common illnesses the low middle income countries, and in Vietnam. It is directly responsible for 3-5 million cases of severe illnesses, and 600K deaths. According to the latest data published by World Health Organisation ("WHO") , in 2020, Influenza and Pneumonia deaths in Viet Nam reached 27,836 or 4.06% of total deaths. It also ranks 6th in the leading causes of deaths in Vietnam. As with COVID-19, in Vietnam alone, there were in total 11.5 million cases causing nearly 45,000 deaths. Total hospitalized cases due to SARS-CoV-2 were not measurable, but they created unprecedented pressure on the country's health system. The most common treatment for influenza is antivirals and antibiotics. However, these regimes do have a lot of negative consequences on patients' health in the long term. 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. This phase purpose is to evaluate the safety and efficacy of DSM 32444 in the treatment of influenza and acute upper respiratory infections.

Respiratory infection is the leading cause of disease burden worldwide, measured by years lost through death or disability. Of all respiratory infections, influenza is one of the most common illnesses the low middle income countries, and in Vietnam. It is directly responsible for 3-5 million cases of severe illnesses, and 600K deaths. According to the latest data published by World Health Organisation ("WHO") , in 2020, Influenza and Pneumonia deaths in Viet Nam reached 27,836 or 4.06% of total deaths. It also ranks 6th in the leading causes of deaths in Vietnam. As with COVID-19, in Vietnam alone, there were in total 11.5 million cases causing nearly 45,000 deaths. Total hospitalized cases due to SARS-CoV-2 were not measurable, but they created unprecedented pressure on the country's health system. The most common treatment for influenza is antivirals and antibiotics. However, these regimes do have a lot of negative consequences on patients' health in the long term. Current concerns about antimicrobial resistance (AMR) as well as side effects of corticosteroids and antihistamines 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. - The aim of this study is to evaluate the safety of a nasal spray using a preparation of Bacillus subtilis DSM32444, and the efficacy in treating symptoms of influenza as compared to antibiotics. Study population: Sample size is 60 volunteered patients with influenza. 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: This phase is a randomized, parallel controlled, open-label, product-controlled study (Neomycin nasal spray). 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 formulated as an open label due to the different shape of the product. Participants in the study who are patients with influenza are randomized in a 1:1 ratio to one of two groups using Sperovid or Neomycin nasal spray for a period of 10 days. The research product (Sperovid or Neomycin nasal spray) is sprayed 2-3 times daily, sprayed on both sides of the nose, each time 1-2 sprays corresponding to 0.2 ml/spray. Daily symptom assessment (TSS) is performed using a diary from Day 1 to Day 10 (end of regime). The response assessment is done on Day 5 (±1) and the decision to continue or change the treatment regimen will be made by the research physician at this time. 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. Differences between treatment groups in terms of duration of major symptoms of acute respiratory infection and average time to resolution will be assessed using the Student's t-test or the Mann-Whitney test. Chi-Square (or Fisher's exact test) will be used to evaluate the difference between the ratios. Analysis of classification data is carried out using the Cochran-Mantel- Haenszel test. Expected outcomes: Bacillus subtilis DSM32444 ("Sperovid") has similar efficacy as compared to Neomycin in addressing influenza symptoms.

Subjects in Experimental group receive a nasal spray containing Bacillus subtilis DSM32444 ("Sperovid") for 10 days.

The active-control in the phase II study was a commercial form of nasal spray containing Neomycin. Neomycin sulfate is an antibiotic belonging to the group of aminoglycosides that have a bactericidal mechanism due to inhibition of bacterial protein biosynthesis.

DSM32444 is manufactured by HURO BIOTECH Company as a drug-grade active pharmaceutical ingredient. The Class A medical device is called Sperovid, which is manufactured by Dong Duoc Viet under ISO 13485:2016 standards for medical device.

To compare efficacy following multiple doses of the SPEROVID Nasal Spray for 10 days with those of the Neomycin Nasal Spray in Influenza Patients assessed by time to symptom resolution

Time to symptom resolution based on total symptom score (TSS) TSS includes the following symptoms, each will be scored from 0 to 6: Nasal obstruction/blockage/congestion Discoloured nasal drainage: anterior/posterior Headache Fatigue Decreased sense of smell Ear pain/pressure/fullness Cough Halitosis Dental pain Fever Score Descriptions 0 or 1 None - to an occasional limited episode 2 or 3 Mild - Steady symptoms but easily tolerable 4 or 5 Moderately bothersome - Symptoms hard to tolerate, might interfere with activities of daily living, sleep, or both 6 Very severe - Symptoms are so bad that person cannot function virtually all the time

To compare safety following multiple doses of the SPEROVID Nasal Spray for 10 days with those of the Neomycin Nasal Spray in Influenza Patients

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

To compare the efficacy following multiple doses of SPEROVID Nasal Spray for 10 days with those of Neomycin Nasal Spray in Influenza Patients assessed by time to symptom improvement

Time to symptom significant improvement based on total symptom score (TSS) TSS is defined in the description of Primary Outcome

To compare the efficacy following multiple doses of the SPEROVID Nasal Spray for 10 days with those of the Neomycin Nasal Spray in Influenza Patients assessed by Change From Baseline in Total Symptom Score (TSS)

Change From Baseline in Total Symptom Score (TSS) TSS is defined in the description of Primary Outcome

To compare the efficacy following multiple doses of the SPEROVID Nasal Spray for 10 days with those of the Neomycin Nasal Spray in Influenza Patients assessed by Clinical Failure Rate at the End of Treatment

Clinical failure is defined as the persistence of 1 or more signs and symptoms of influenza or patients who have received additional (or new) antibiotics

Inclusion Criteria: Confirmed influenza patients (according to Vietnam's MOH guidelines for diagnosis of influenza), ≥18 years of age, at the time of signing the informed consent. Must be in generally good health, except influenza Patients who are able to use an e-Diary or Paper Diary during the study to report their health status Patients capable of giving a signed informed consent form (ICF) Exclusion Criteria: 1. Presence of any nasal mucosal erosion, nasal ulceration, or nasal septal perforation (Grade 1b - 4) Other disease(s) likely to affect deposition of intranasal medication Asthma (with the exception of mild, intermittent asthma). Subjects with mild, intermittent asthma who only require short-acting inhaled bronchodilators (not more often than twice per week) and who do not have nocturnal awakening as a result of asthma are eligible for enrolment. 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. 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.

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