Clinical trial NCT05618483: Xylitol Based Nasal Spray for COVID-19 Treatment
Official title: Clinical Efficacy of Xylitol Based Nasal Spray for the Treatment of Mild COVID-19 Infection
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Respiratory Viral Infection
Lead sponsor: Xlear, Inc
Sponsor class: INDUSTRY
Collaborators: name: Metanoic Health Ltd.
First posted: 2022-11-16
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomization to Nasal Spray or Placebo
Primary purpose: TREATMENT

Brief summary: Xlear have developed and patented a xylitol containing nasal spray for the treatment of upper-respiratory tract infections. The nasal spray is comprised of xylitol and GSE (Grapefruit Seed extract) which provides antibacterial properties as well as preventing viral adhesion in the nasal passage. Studies into Xlear's antiviral effects on SARS-CoV-2 are currently ongoing but hypothetically, a Xylitol Based Nasal spray may prove to be a useful and inexpensive treatment for COVID-19 infection.

Detailed description: 1. BACKGROUND and RATIONALE

In the wake of the Coronavirus disease 2019 (COVID-19) pandemic, worldwide healthcare has rapidly evolved in response. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel virus responsible for COVID-19, which at the most severe end of the spectrum of disease can require hospitalisation or ICU admission. Preventative measures are currently being taken with numerous vaccination programs across the world. However, there is currently no established treatment for mild COVID-19 infection, i.e., symptomatic infection not requiring hospitalisation, which makes up a significant proportion of cases. Xylitol has shown promising results in combating SARS-CoV-2 in vitro and this study aims to explore whether Xlear's Xylitol based Nasal Spray has an effect in vivo.

1.1 COVID-19 Infection SARS-CoV-2 is a positive-sense, single-strand RNA virus comprised of four structural proteins: Nucleocapsid (N) protein, Membrane (M) protein, Spike (S) protein and Envelope (E) protein. These structural proteins play an important role in receptor binding, transcription, replication and assembly of the virus in host cells (Boopathi et al., 2020). The nasal epithelium acts as the primary site for SARS-CoV-2 binding to angiotensin converting enzyme-2 (ACE2) - the receptor responsible for COVID-19 infection (Zhou et al., 2020). With nasal carriage playing a vital role in transmission, drugs administered intranasally could be a viable therapeutic option (Sungnak et al., 2020).

1.2 Drug: Xylitol Xylitol is a sugar alcohol derived from plants. It is used in the dental profession to prevent plaque build-up and inhibit enamel demineralisation by interfering with the metabolism of Streptococcus mutans, causing cell death and thus preventing dental caries (Janakiram et al., 2017). Xylitol not only demonstrates antimicrobial behaviour but can also modulate immunity and contribute to wound healing (Salli et al., 2019).

1.2.1 Xylitol and Respiratory Tract Infections Xylitol's inhibitory effect on Streptococcus mutans growth has prompted more research into its interactions with other nasopharyngeal pathogens responsible for respiratory tract infections. An in vitro study into alpha-haemolytic Streptococcus pneumoniae and beta-haemolytic Streptococci treated with 1% and 5% xylitol showed statistically significant inhibition of growth over a 24-hour incubation period (Kontiokari et al., 1999).

Another team established xylitol's ability to kill coagulase-negative Staphylococcus. 5% xylitol administered to 21 participants compared to a control group using a saline solution showed a significant decrease in Staphylococcus count from 597 colony forming units (CFU) per swab to 99 CFU per swab (Zabner et al., 2000).

1.2.2 Xylitol and Viruses Xylitol's inhibitory effects on bacteria are well documented but little is known regarding its antiviral properties. Dietary xylitol was used to treat influenza A virus in vivo. Mice given a combination of xylitol and red ginseng had 100% survival rate at 33mg/kg/day of xylitol and 60% survival rate at 3.3mg/kg/day after day 14 of infection versus 0% survival rate on PBS (control), red ginseng and xylitol separately. This suggests a synergistic effect between xylitol and red ginseng (Yin et al., 2014).

A study into xylitol and its interactions with human respiratory syncytial virus (hRSV) was conducted in 2015. Xylitol was tested in vitro on a hRSV suspension and in vivo in mice. The in vitro effect of xylitol showed complete inhibition at concentrations of 3.13mg/ml. Xylitol significantly reduced lung viral titres in mice with 3.3mg/kg/d proving the most effective dose (Xu et al., 2016).

1.3 Grapefruit Seed Extract (GSE) Grapefruit seed extract (GSE) is made from grapefruit seeds. It is used as a natural remedy due to its antioxidant and antimicrobial properties (Reagor et al., 2002; Salehi et al., 2019).

1.3.1 GSE and Viruses GSE was tested on multiple viruses to determine if it had any inhibitory effects. GSE exhibited virucidal activity against avian influenza virus (AIV) and Newcastle disease virus (NDV) but not against infectious bursal disease virus (IBDV) (Komura et al., 2019). These findings may be important as AIV and NDV are enveloped viruses like SARS-CoV-2 whilst IBDV is not (Schoeman et al., 2019). It could be hypothesised that GSE could exhibit similar inhibition on SARS-CoV-2.

1.4 Xlear's Xylitol based Nasal Spray Xlear have developed and patented a xylitol containing nasal spray for the treatment of upper-respiratory tract infections. The nasal spray is comprised of xylitol and GSE which provides antibacterial properties as well as preventing viral adhesion in the nasal passage. Studies into Xlear's antiviral effects on SARS-CoV-2 are currently ongoing but hypothetically, a Xylitol Based Nasal spray may prove to be a useful and inexpensive treatment for COVID-19 infection.

1.4.1 Xlear and Coronavirus Xylitol has been shown to exhibit antiviral properties against SARS-CoV-2 in vitro (Bansal et al., 2021; Ferrer et al., 2020).

USA-WAI/2020 strain was prepared and passaged in Vero 76 cells for testing with Xlear (experiment 2) and its components xylitol and GSE separately (experiment 1). GSE 0.2% reduced SARS-CoV-2 from 3.67 log10 CCID50/0.1 mL to undetectable in experiment 1. Xlear in virucidal assays completely inhibited viral infectively at varying concentrations (90%, 80%, 50%) and reduced viral titre by 2.17 log in 20% concentration indicating a dose-dependent response (Appendix 1) (Ferrer et al., 2020). A subsequent study showed statistically significant reduction in viral titres treated with Xlear nasal spray treatment - 4.2 log10 CCID50/0.1mL to 1.7, a reduction of 2.5 log10 CCID50 (Cannon et al., 2020).

A recent private report by Dr Cagno's team in Lausanne (April 2021) has confirmed the viral killing properties of Xlear in 2021 SARS-CoV-2 strains. Viral stocks were grown in Vero E6 cells belonging to two lineages, B1.1.7 and B1.351. Complete inhibition of viral infectivity was observed in 90%, 60% and 20% concentration Xlear virucidal assays for B1.351. Viral infectivity was similarly completely inhibited in B1.17 at 90% and 60% concentration with a 3.06 log reduction at 20% illustrated in Appendix 2.

A case study was conducted on individuals who had taken Xlear as treatment for COVID-19 infection. Participants were required to spray into each nostril four times per day (140 µL per spray). All individuals showed improvement in symptoms with quicker turnarounds from turning positive to negative via COVID-19 reverse transcriptase polymerase chain reaction (RT-PCR) nasal swabs. Importantly, some individuals had relevant co-morbidities such as current smoking status and obesity. Although it is difficult to attribute symptom improvement and viral load decrease to Xlear's spray, it does provide rationale for a double-blind placebo controlled randomised clinical trial (Go et al., 2020).

Eligibility criteria: Inclusion Criteria:

* Capable of understanding and providing signed informed consent and ability to adhere to the requirements and restrictions of this protocol;
* Adult aged ≥18 years old with at least two comorbidities: diabetes (type 1 \&2), obesity (BMI \>30), hypertension, chronic heart disease, chronic pulmonary disease, chronic liver disease.
* Internet access and capability and willingness to participate in audio or audio/video engagements with medical professionals, receive texts, emails, and phone calls from study staff and have a device and reasonable cellular data or other internet access to submit daily study required information using a smart phone, tablet, laptop, or desktop computer during the study period;
* COVID-19 infection confirmed with a laboratory SARS-CoV-2 RT-PCR nasal swab;
* Specimen collected within the past 48 hours;
* Mild COVID-19 symptoms which may include fever, cough, sore throat, malaise, headache, muscle pain, gastrointestinal symptoms, lack of taste or smell without shortness of breath

Exclusion Criteria:

* Not fit to consent and unable to follow the protocol;
* Age \<18 years;
* Current tracheostomy or laryngectomy;
* Hypersensitivity to the active substance or to any of the excipients;
* Concomitant respiratory therapy such as oxygen or ventilator support. Positive airway pressure for obstructive sleep apnea is permitted if treatment was established with good compliance at least 3 months before enrolment;
* Need for hospitalisation for any reason;
* Inability to safely self-administer nasal spray
* Any clinical contraindications, as judged by the Qualified Medical Practitioner;
* Clinical signs indicative of moderate, severe or critical COVID severity symptoms (as defined by FDA COVID-19 Guidance Document)
* Mentally or neurologically disabled patients who are considered not fit to consent to their participation in the study;
* Lactating, pregnant or planning to become pregnant during the study period;
* Diagnosed with prior COVID-19 infection (\>48 hours from the time the test is reported prior to the time of screening).
* No relevant comorbidity or only one comorbidity

Primary outcomes:
measure: Viral load reduction
timeFrame: Day 0 (baseline), Day 2, 4 6 and 8
Secondary outcomes:
measure: Undetectable viral load
timeFrame: baseline to Day 2, 4, 6 and 8
measure: Hospitalization requirement
timeFrame: Baseline through Day 8
measure: Reduction of clinical symptoms score
timeFrame: Baseline through Day 14
measure: Tolerability of Nasal Spray
timeFrame: Baseline through Day 14
measure: Safety of Nasal Spray
timeFrame: Baseline through Day 14
Other outcomes:
Locations:
Study officials:
affiliation: University of Health Sciences Lahore
name: Ahsan W Rathore, MBBS
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Health Sciences Lahore
name: Saqib Mahmood, MBBS PhD
role: PRINCIPAL_INVESTIGATOR
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