Safety of an aerosol having as its active ingredient 8.4 % sodium bicarbonate and xylitol 5% when administered to the nasopharynx and oropharynx

• Conditions: Influenza Like Illnesses including Covid-19

• Registration Number: CTRI/2020/11/029396
• Lead Sponsor: Myself Health Check Ltd

Brief Summary

**1.** **Title of Study**:

A prospective, open label, single arm consumer research to study the safety and tolerability of an aerosol having as its active ingredient 8.4 % sodium bicarbonate, when administered to the nasopharynx and oropharynx; and to assess the preventive strength of the aerosol against the development of Influenza Like Illness (ILI) including the Covid-19 infection in the general as well as high risk population.

 **2.** **Introduction**:

The present pandemic of Covid-19 is caused by a novel member of the Corona group of viruses viz SARS-CoV-2;2019-nCoV.

The In Vivo behavior of SARS-CoV-2 and its pathological processes have come under intense investigation and study in recent times.

 It has been reported from China (Reference 1) that high viral loads were detected in the nose and the throat of both asymptomatic patients and symptomatic patients as well.

 The infectivity of SARS-CoV-2 depends on the ability of this virus to enter the cells. Since oral cavity is one of the first interfaces between the exterior and body, there is a high potentiality that this pathway of viral colonization and infection is critical for the onset of Covid-19. (Reference 2,3)

 So the question which needs to be examined is whether the oral cavity is relevant in the development of SARS-CoV-2 disease pathology?

 **3.** **Scientific Rationale for Hypothesis:**

The role of oral cavity, as the entrance to the body of SARS-CoV-2 and its possible role as protective or aggravating factor in infectivity and in the progression of the viral infection was explored and has been well answered by the authors in a discussion paper wherein they reviewed the entire available literature up to April-2020. (Reference 4)

 It is shown that viruses incubate within a person’s upper respiratory tract for 1 to 3 days prior to multiplying and spreading to neighbouring cells. This can be referred to as Stage 1. In Stage 2, the virus enters the person’s lungs. (Reference 5,6)

 Apparently, in the first 10 days after the transmission, when the patient usually remains asymptomatic but is highly contagious, the virus accumulates at the nasal, oral, and pharyngeal mucosa, and only later will further accumulate in the lungs. (Reference 7)

 This possible role of the oral cavity both as portal of entrance of the virus in the body and as the virus reservoir may be potentially put to a good use.

 A possible beneficial impact here could become even more relevant under the light of the foreseen evolution of the pandemic, which suggests that in spite of the implementation of hygienic measures and social distance, SARS-CoV-2 may not be eradicated up to 2024. (Reference 8)

 This seems to be borne out by the second wave of covid infection seen in Europe and other parts of the world.

 Respiratory infections are caused by bacteria, viruses, fungi, and parasites. (Reference 9) Microbes require for their growth a particular range of external pH which affects their many biological actions such as enzyme activity, reaction rates, protein stability and structure of nucleic acids. (Reference 10,11)

 The airway surface liquid (ASL) contains a complex mixture of antimicrobial factors that kill inhaled or aspirated organisms and act as a first line of defense. The composition of ASL is critical for antimicrobial effectiveness. Changes in the ASL occur with inflammation or infection such as local acidosis. (Reference 12,13)

 In respiratory tract infections caused by bacteria, viruses, fungi, and mycobacteria, there will be an expected local acidic medium in the secretions. Changing the local pH of respiratory tract secretions to alkaline side by adding Sodium Bicarbonate (SB) 8.4% can affect growth and/or may be lethal for the respiratory tract pathogens. (Reference 14)

 There is evidence in literature that viruses belonging to the Corona group need a low PH environment to allow the first connectivity of the virus to the cell wall. (Reference 13,14,15) It has also been observed that viruses thrive at a pH level of 6 and a body temperature of 37 degrees.(Reference 16) It has been shown that saliva has a pH normal range of 6.2-7.6 with 6.7 being the average pH. (Reference 17) This presently allows the virus to enter the cells and then multiply.

 If one can stop the ability of the virus to multiply in the initial stages in the upper respiratory tract (URT) by modulating the pH of the area, one can expect that its serious sequelae can be either prevented or minimized.

 If one can devise a method wherein the pH of the oropharynx and the nasopharynx can be raised to an alkaline level of pH 8 or more, then it would be logical to expect that any member of Corona group of viruses which gain access to this area of the body will not be able to gain entry into the tissue cells of this area. Denying entry into the cells, by implication also means denying the virus an opportunity to multiply. Further logic would also dictate that slowing down or stopping the multiplication of the virus would also translate into a reduced rate of further transmission to other humans, and equally importantly would also prevent the development of the disease pathology.

 Sodium Bicarbonate inhalations (4.2% & 8.4%) have been used as a treatment measure in pathological respiratory conditions such as cystic fibrosis and chlorine gas inhalations. Its safety, tolerability and efficacy in improvement in those clinical conditions have been well established. (Reference 18,19)

 **4.** **Study Hypothesis:**

A unique formulation, having 8.4 % sodium bicarbonate and Xylitol as its main active ingredients was proposed to be used in the form of an aerosol administered to the oropharynx and nasopharynx areas. This would increase the pH of this area to an alkaline range from pH 8 to pH 9.5. This would prevent a virus belonging to the Corona group from gaining entry into the cells.

 **5.** **Study Aim:**

The aim of the present study was to test the above hypothesis.

 **6.** **Methodology:**

The monitoring of the recruited subjects was done based on a Patient Reported Outcome Measure (PROM) methodology. It has been shown that diagnosis of ILI based on clinical diagnostic criteria recorded through a PROM method can have an accuracy of 77 % of adults.(Reference 20,21) The US Food and Drug Administration released a guidance document “Patient-Reported Outcome Measures: Use in Medical Product Development to support labelling claims in December 2009. (Reference 22)

 If a PROM designed as per the criteria laid out in the USFDA guidance is used to determine the effectiveness of investigational agent on ILI presence/severity, it is considered as a valid method in medical product development to support labelling claims. (Reference 22)

The present consumer research study has used a PROM device called FluPro – Plus (trademark…) licenced from Leidos Biomedical Research Inc. FluPro – Plus is a PROM device developed as per the USFDA guidance document on this subject.(Reference 23,24,25,26,27,28).

Study subjects would be recruited as per the inclusion and exclusion criteria listed. They would be issued the FluPro Plus questionnaire in the form of Subject Diaries (SD). They would be asked to fill in the questionnaire on a daily basis.

 The subject would be issued the Investigational Product (IP) and would be explained in detail how to administer it. They would be given a demonstration of the method of using it. They would be explained the frequency with which the product has to be used.

 Each subject would be monitored by telephonic monitoring on once in three days frequency to ascertain the appropriate use of the product. They would be monitored on a personal meeting on Day–1, Day–15 and Day–28. At each of these three meetings the subject would be asked to use the aerosol pump to ensure that the IP was administered appropriately in the nasopharynx and oropharynx areas. The sputum would be checked for its pH one minute after the administration of the product and the pH would be recorded in the SD. This would ensure that the primary purpose of creating an alkaline status with a pH of 8 or more was being achieved.

 The SD’s would be checked on Day–15 and Day-28 to ensure that the data/answers to the questionnaire was captured on a daily basis.

 At the end of the study period the data would be analysed to ascertain the results.

There are total 3 visits in this study. Study visits will include.

·        Visit 1: (Day 00) Screening and Enrollment

Day01 to Day14 IP application

·        Visit 2: (Day 15) Interim follow up and new spray (IP) dispensing

·        Visit 3: (Day 28) Last visit and post study

Screening and enrollment will be done on same day.

Subject self-assessment questionnaires will be filled in this study as per specified study endpoints. Safety will be assessed throughout the study by monitoring of adverse events.

The study can be conducted in multiple groups.

Study subjects would be recruited as per the inclusion and exclusion criteria listed. They would be issued questionnaire in the form of Subject Diaries (SD). They will be asked to fill in the questionnaire on a daily basis.

The subject will issued the test Investigational Product (IP) and will be explained in detail how to administer it. They will be given a demonstration of the method of using it. They will be explained the frequency with which the product has to be used.

Each subject will be monitored by telephonic monitoring on once in three days frequency to ascertain the appropriate use of the product. They will be monitored on a personal meeting on Day–1, Day–15 and Day–28. At each of these three meetings the subject will be asked to use the aerosol pump to ensure that the test IP is being administered appropriately in the nasopharynx and oropharynx areas. The sputum will be checked for its pH one minute after the administration of the product and the pH will be recorded in the SD. This will ensure that the primary purpose of creating an alkaline status with a pH of 8 or more is being achieved.

The SD’s will be checked on Day–15 and Day-28 to ensure that the data/answers to the questionnaire is captured on a daily basis.

At the end of the study period the data will be analysed to ascertain the results.

**References**

1.  SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients. Zou et al. Correspondence: N Engl J Med. (2020).

2.  High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Xu H et al, Int J Oral Sci 12(1):8 (2020)

PubMed:<https://doi.org/10.1038/s41368-020-0074-x>}

3.  Salivary glands: potential reservoirs for COVID-19 symptomatic infection. Xu J et al, J Dent Res:22034520918518 (2020),  PubMed:<https://doi.org/10.1177/0022034520918518>}

4.  Is the oral cavity relevant in SARS-CoV-2 Pandemic? David Harrerra et al. Clinical Oral Investigation (2020).

5.  A New Insight, Bassam H. Mahboub, IntechOpen, DOI: 10.5772/54287  Pathogenesis of Viral Respiratory Infection, Respiratory Disease and Infection - Ma. Eugenia Manjarrez-Zavala et al, (2013).

6.      Virological assessment of hospitalized patients with COVID-2019, Wolfel R et al, Nature 581:465– 469, (2020).

PubMed:<https://doi.org/10.1038/s41586-020-2196-x>

7.      Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period. Kissler SM et al, Science 368:860–868, (2020).

PubMed:https://doi.org/10.1126/science.abb5793

8.      Effect of sodium bicarbonate 8.4% on respiratory tract pathogens. El Badrawy MK et al. Chest Lung Res. 2018;1(1):3-7.

9.      pH modulates the activity and synergism of the airway surface liquid antimicrobials defensin-3 and LL-37. Alaiwa AMH et al.  Proc Natl Acad Sci. 2014;111(52):18703-8.

10.   Cytoplasmic pH measurement and homeostasis in bacteria and archaea. Slonczewski JL et al. Adv Micro Physiol. 2009;55:1-79.

11.   Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung. Pezzulo AA et al, Nature. 2012;487(7405):109-13.

12.   A review on probable Lysosomotropic properties of Sodium bicarbonate to restrain viral entry of Coronavirus 2 (SARS-CoV-2) Mudasir A. Mir 1\*, Sheikh Mansoor 2, Abida Bhat 3.

13.   pH-Dependent Entry of Severe Acute Respiratory Syndrome Coronavirus Is Mediated by the Spike Glycoprotein and Enhanced by Dendritic Cell Transfer through DC-SIGN. Yang ZY, Huang Y, Ganesh L, Leung K, Kong wp. et al. J Virol. 2004; 78: 5642-5650.

PubMed:<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC415834/>

14.   The Avian Coronavirus Infectious Bronchitis undergoes direct low PH dependent Fusion activation during entry into the host cells. 1. Chu, V et al, J Virol. 2006; 80:3180-3188.

PubMed:<https://www.ncbi.nlm.nih.gov/pubmed/16537586>

15.   Conformational change of the coronavirus peplomer glycoprotein at pH 8.0 and 37 degrees C correlates with virus aggregation and virus-induced cell fusion. Sturman et al - Journal of virology, 64(6), 3042–3050 (1990).

16.   Salivary pH: A diagnostic biomarker. Baliga, S., Muglikar et al, Journal of Indian Society of Periodontology, 17(4), 461–465 (2013).

17.   Safety, tolerability and effects of sodium bicarbonate inhalation in cystic fi brosis. Gomez CCS, Parazzi PLF, Clinckspoor KJ, Mauch RM, Pessine FBT, et al, Clin Drug Investig. 2019; 40: 105-117.

PubMed:<https://www.ncbi.nlm.nih.gov/pubmed/31721070>

18.   The effect of nebulized sodium bicarbonate treatment on RADS patients due to chlorine gas inhalation. Aslan S, KandiÅŸ H et al, Inhal. Tox. 2006; 18: 895-900.

PubMed: <https://www.ncbi.nlm.nih.gov/pubmed/16864407>

19.    Archives of Internal Medicine – ARCH INTERN MED 2001; 161: 2116-

2122

20.   The US Food and Drug Administration guidance for Industry Patient-

Reported Outcome Measures: Use in Medical Product Development to support labelling claims in December 2009. Available from: <http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf> (Accessed February 2015,2010)

21.   Diagnosis of Influenza in the Community. ARCH INTERN MED/ VOL  161, SEP 24, 2001. Available from: <http://archinte.jamanetwork.com/>

22.   Evaluation of Efficacy Endpoints for a Phase IIb Study of a Respiratory Syncytial Virus Vaccine in Older Adults Using Patient-Reported Outcomes with Laboratory Confirmation. Jing Yu, PhD, et al.

Contents lists available at <http://www.sciencedirect.com>

23.   Patient-Reported Outcome Assessments as Endpoints in Studies in Infectious Diseases. John H. Powers III et al, Clinical Infectious Diseases® 2016;63(S2):S52–6

24.   Using the Influenza Patient-reported Outcome (FLU-PRO) diary to evaluate symptoms of influenza viral infection in a healthy human challenge model, Alison Han1 et al, Han et al. BMC Infectious Diseases (2018) 18:353

25.   Reliability, Validity, and Responsiveness of InFLUenza Patient-Reported Outcome (FLU-PRO©) Scores in Influenza-Positive Patients. John H. Powers III, MD1 et al, journal homepage: <http://www.elsevier.com/locate/jval> (2018).

26.   Development of the Flu-PRO: a patient-reported outcome (PRO) instrument to evaluate symptoms of influenza. John H. Powers1 et al, Powers et al. BMC Infectious Diseases (2016) 16:1

27.   Evaluation of Efficacy Endpoints for a Phase IIb Study of a Respiratory

Syncytial Virus Vaccine in Older Adults Using Patient-Reported Outcomes With Laboratory Confirmation. Jing Yu, PhD et al, Journal homepage: <http://www.elsevier.com/locate/jval> (2020).

28.   Performance of the inFLUenza Patient-Reported Outcome (FLU-PRO) diary in patients with influenza-like illness (ILI). John H. Powers et al, <https://doi.org/10.1371/journal.pone.0194180> (2018).

29.   Accuracy of Emergency Department Clinical Findings for Diagnosis of Coronavirus Disease 2019. Olivier Peyrony, MD, PhD et al, <https://doi.org/10.1016/j.annemergmed.2020.05.022>

Detailed Description

Not available

Study Timeline

• Study Start: 2020-01-12
• Last Update Posted: 2021-07-06

Recruitment & Eligibility

• Status: Other
• Sex: All
• Target Recruitment: 325

Inclusion Criteria

• 1. Age: For adult 18 years and above at the time of consent.
• 2. Sex: For adult, Healthy male and Non-pregnant/non-lactating females, 3) Females of childbearing potential and menarche children both must have a negative urine pregnancy test performed on screening visit.
• 4. Use effective contraception (see below) for the duration of the trial period (females only) 5) Subjects are in good general health as determined by the Investigator on the basis of medical history reported by subjects, including absence of any symptoms/signs of covid-19 infection or any other ILI.
• 6. Subjects must be able to understand and provide written informed consent to participate in the study.
• 7. Chest radiograph normal 8) No relevant findings in medical history or on physical examination 9) Able and willing to comply with all the trial requirements.

Exclusion Criteria

• 1. Pregnant or lactating female subjects should be excluded as these conditions impact the condition of the skin.
• 2. Clinically significant history of skin disorder, allergy, atopy, immunodeficiency (including HIV), cancer (except BCC or CIS), cardiovascular disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder, neurological illness, psychiatric disorder, drug or alcohol abuse.
• 3. Subjects who have a clinically significant active Oral Cavity and Nasal disease.
• 4. Subjects who have a history of recent Oral or Nasal Surgery or ongoing treatment.
• 5. Subjects who have a condition or are taking medication(s) which, in the judgment of the Investigator or Designate, makes the subject ineligible or places the subject at undue risk.
• 6. Subjects who have received treatment (chemotherapy, radiation, immune suppressant medications) for any type of cancer within the last 6 months.
• 7. Subjects who have history of an autoimmune or immune deficiency disease (e.g. lupus, myositis, Crohns disease, autoimmune thyroid diseases, autoimmune hepatitis, etc.).
• 8. Subjects who are currently taking any immunosuppressant medication.
• 9. Subjects who have history of insulin-dependent diabetes.
• 10. Subjects who have history of asthma or any other chronic respiratory condition requiring daily therapy.
• 11. Subjects who are currently taking/using any antihistamines or systemic/topical anti-inflammatory medications (e.g. ibuprofen, corticosteroid, etc.) on a routine or frequent basis.
• 12. Subjects who are currently receiving allergy injections, expects to start injections before the conclusion of the study or has had the final injection within a week of the study start.
• 13. Subjects who are currently participating in any another study related to Oral and Nasal applications.
• 14. Subjects who are currently participating in any clinical study, which in the judgment of the Investigator, could potentially affect responses in either study.
• 15. Subjects who have a known sensitivity or allergy relating to the substance(s) being evaluated.
• 16. Pregnancy, lactation or intention to become pregnant during trial period Any respiratory disease, including asthma 17) Any nasal, pharyngeal, or laryngeal finding which precludes bronchoscopy 18) Past treatment for TB disease 19) Subjects who are currently participating in any clinical study, which in the judgment of the Investigator, could potentially affect responses in either study.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
To assess the preventive strength of the aerosol containing as its active ingredient 8.4 % sodium bicarbonate when administered to the nasopharynx and oropharynx against the development of Influenza Like Illness (ILI) including Covid-19 infection in the general as well as high risk population as assessed by the proportion of subjects not getting ILI symptoms at the end of the study using the FLU-Pro Plus Patient Reported Outcome Measure (PROM).	28 days

Secondary Outcome Measures

Name	Time	Method
To evaluate safety and tolerability of an aerosol having as its active ingredient 8.4 % sodium bicarbonate and xylitol 5% when administered to the nasopharynx and oropharynx.	6 months

Trial Locations

Locations (1)

Welcare Hospital; 🇮🇳 Vadodara, GUJARAT, India

Welcare Hospital

🇮🇳Vadodara, GUJARAT, India

Manoj Parmar

Principal investigator

communication@welcarehospital.co.in