By: Isabelle Lim, PharmD Candidate c/o 2024 and Hadeel Aldasooky, PharmD Candidate c/o 2024
As the threat of coronavirus disease 2019 (COVID-19) continues to loom over the healthcare world, there is still a need to uncover new treatment options for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The COVID-19 Treatment Guidelines Panel’s current recommendation for the primary management of mild to moderate COVID-19 in all nonhospitalized adults includes symptomatic relief with over-the-counter (OTC) medications. For those who are at a high risk of developing severe COVID-19, it is recommended that Paxlovid™️ (ritonavir-boosted nirmatrelvir) or Veklury® (remdesivir) is utilized, with ritonavir-boosted nirmatrelvir being preferred as an oral formulation versus remdesivir, which is administered intravenously. If either of these medications cannot be used, another option for preventing progression to severe COVID-19 is Lagevrio™️ (molnupiravir).1
Nitric Oxide Nasal Spray
One alternative to the aforementioned COVID-19 treatments is nitric oxide nasal spray (NONS), a formulation that is not available in the United States (U.S.) but has been studied and used internationally. SaNOtize, a Canadian research and development company, manufactures NONS which is marketed as VirX™️ in Thailand, Singapore, Hong Kong, South Africa, Malaysia, Cambodia, and Germany; enovid™️ in Israel and Indonesia; and FabiSpray in India.2 Currently, only gaseous inhaled nitric oxide (iNO) products are approved in the U.S.; in contrast, NONS is based on a liquid formulation. SaNOtize’s NONS uses the company’s patented NO-releasing solution (NORS™️), a product that releases NO gas in therapeutic concentrations with each spray.3
Nitric Oxide’s Antiviral Mechanism of Action
NO is a free radical that plays a significant role not only in vasodilation, neurotransmission, and angiogenesis but in innate immunity as well.4 The ability of macrophages and lipopolysaccharides to kill bacteria and tumors is attributed to their production of NO.5 In COVID-19, NO was seen to suppress levels of SARS-CoV-2 via two different mechanisms of action. The first method involved decreasing palmitoylation of newly expressed spike proteins, which is a critical step in the virus’s ability to bind to angiotensin-converting enzyme 2 (ACE2) receptors. The inability to bind to this receptor ultimately inhibits the virus from being able to enter the host cell and replicate its viral DNA. The second mechanism of action involves the inhibition of the early stages of viral RNA replication. This is hypothesized to be due to the effect that NO can have on cysteine proteases that are encoded by SARS-CoV-2.6 Recent clinical studies concerning the use of NONS as treatment in COVID-19 infection have further supported the use of the novel product in ill patients.
In a randomized, double-blind, placebo-controlled, phase IIb clinical trial conducted in the United Kingdom, researchers evaluated the clinical efficacy of NONS in patients with mild COVID-19. Patients were eligible for the study if they were between the ages of 18 and 70 years and had mild COVID-19 infection confirmed by a SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) test within 48 hours of randomization.7
80 patients with mild, symptomatic COVID-19 were randomized in a 1:1 ratio to receive either NONS 120-140 microliters of solution/spray or a placebo nasal spray for 9 days. Many of the patients included in the study completed in India were vaccinated as well, which may be another contributing factor to the lack of hospitalization observed. Still, the ratio of vaccinated to unvaccinated was maintained in both the intervention and the placebo group. The nasal sprays were initiated within 4 days of symptom onset and self-administered as 2 sprays per nostril 5 to 6 times a day. Nasal and throat swabs were conducted by the patients themselves on days 1, 2, 4, and 6 before administration of the sprays to evaluate the patients’ SARS-CoV-2 RNA levels during the treatment period. Participants were also instructed to fill out a daily questionnaire throughout the duration of the study, in which they self-reported their symptoms, compliance, and treatment tolerance. Follow-up self-reporting continued for 18 days after the study ended.7
The primary endpoint of this study was the decrease in log10 SARS-CoV-2 RNA concentration. It was seen that there was a significant decrease in the concentration of viral RNA in the NONS group compared to the placebo group 2 days (difference -1.21; 95% confidence interval [CI] -2.07 to -0.35; p = 0.01) and 4 days (difference -1.21, 95% CI -2.19 to -0.24; p = 0.02) after treatment initiation. The authors of this study also noted that there was a 95% reduction of SARS-CoV-2 RNA observed within 24 hours of the study and a 99% reduction after 72 hours in the NONS treatment group. Based on the daily questionnaire, 46.7% of the NONS respondents reported feeling better while only 8% of the placebo group reported similarly. On average, patients in the NONS treatment group reported feeling better by day 2 to 4 of treatment while those receiving the placebo reported feeling better after day 5.7 There were no serious adverse effects reported in either treatment arm, and no additional information was provided on the nature of milder adverse effects, if any.7 Overall, the use of NONS in patients with mild, symptomatic COVID-19 was found to be safe and effective in reducing viral load, as well as decreasing symptoms.
An additional study that was completed in India was a randomized, double-blind, parallel-group, multicenter phase III clinical trial. The primary analysis of the study assessed the efficacy of NONS in nonhospitalized, high-risk patients with mild COVID-19. Individuals were considered high-risk patients if they were > 45 years old, had 1 or more comorbidities, or had not been vaccinated against SARS-CoV-2 at the time of the trial. Adult patients between 18 and 70 years with symptomatic COVID-19 indicated by a positive rapid SARS-CoV-2 antigen test received either NONS or placebo nasal spray within 3 days of symptom onset. Participants were later excluded from the primary analysis if the results of their RT-PCR test returned as negative up to one day after randomization. Pregnant or lactating patients and those with a creatinine clearance (CrCl) less than 30mL/min2 were also excluded from the study.8
Participants were randomized in a 1:1 manner with a total of 306 participants at the beginning of the study. Day 1 marked the baseline visit during which qualitative and quantitative RT-PCR tests were conducted and subject diaries were allotted to participants. Patients were instructed to self-administer 2 sprays of either NONS 0.45 mL/spray or a placebo nasal spray in each nostril 6 times a day for the next 7 days. Participants also documented their health status, COVID-19-related symptoms, adverse events, and adherence daily.8
The primary efficacy endpoint of the study was the mean SARS-CoV-2 viral load change from baseline throughout the study period. The results reflected a mean change of -2.62 log10 copies/mL in the intervention group and -2.10 log10 copies/mL in the placebo group on day 8, yielding a statistically significant mean treatment difference of -0.52 log10 copies/mL (95% CI -0.92 to -0.12; p = 0.010).8 The second efficacy endpoint assessed the viricidal activity of NONS dictated by the presence of a negative SARS-CoV-2 RT-PCR result on days 2, 3, 4, or 8, where time to achieve a negative RCT-PCR result was measured using the Kaplan-Meier method and log-rank. The Kaplan-Meier curve demonstrated that the median time to attain a negative RT-PCR conversion in the intervention group (3 days after treatment initiation [day 4])] was significantly shorter compared to the placebo group (7 days after treatment initiation [day 8]) (hazard ratio [HR] 1.354; 95% CI 0.949 to 1.932; p = 0.044). In the NONS group, 53 subjects (82.8%) became RT-PCR negative by day 8 in comparison to 46 subjects (66.7%) in the placebo group (difference 16.1%; 95% CI 0.2 to 32.1; p = 0.046).8 There were no serious adverse effects reported in this study. The most common adverse effect observed in the NONS group was nasal discomfort, which was categorized as a mild effect.8
These studies have provided evidence of a faster reduction in viral load, quicker recovery from infection, and minimal adverse effects when NONS is used in patients with COVID-19 when compared to the placebo. It is evident that NONS has potential as a form of therapeutic management of COVID-19 in most patients, including those considered “high-risk,” when administered around 6 times a day for 7 days. All in all, the U.S. should consider NONS as adjunctive therapy in cases of mild COVID-19 to prevent progression to severe COVID-19.
- COVID-19 Treatment Guidelines Panel. Therapeutic Management of Nonhospitalized Adults With COVID-19. National Institutes of Health. https://www.covid19treatmentguidelines.nih.gov/management/clinical-management-of-adults/nonhospitalized-adults–therapeutic-management/. Last Updated 12/28/2022.
- FAQ. SaNOtize. https://sanotize.com/faq/. Accessed June 16, 2023.
- Our Patented Platform Technology. SaNOtize. https://sanotize.com/our-patented-platform-technology/. Accessed June 16, 2023.
- Chavda VP, Baviskar KP, Vaghela DA, Raut SS, Bedse AP. Nasal sprays for treating COVID-19: a scientific note. Pharmacol Rep. 2023;75(2):249-265. doi:10.1007/s43440-023-00463-7
- Uehara EU, Shida Bde S, de Brito CA. Role of nitric oxide in immune responses against viruses: beyond microbicidal activity. Inflamm Res. 2015;64(11):845-852. doi:10.1007/s00011-015-0857-2
- Winchester S, John S, Jabbar K, John I. Clinical efficacy of nitric oxide nasal spray (NONS) for the treatment of mild COVID-19 infection. J Infect. 2021;83(2):237-279. doi:10.1016/j.jinf.2021.05.009
- Tandon M, Wu W, Moore K, et al. SARS-CoV-2 accelerated clearance using a novel nitric oxide nasal spray (NONS) treatment: a randomized trial. Lancet Reg Health Southeast Asia. 2022;3:100036. doi:10.1016/j.lansea.2022.100036
- Tandon M, Wu W, Moore K, et al. SARS-CoV-2 accelerated clearance using a novel nitric oxide nasal spray (NONS) treatment: a randomized trial [supplementary material]. Lancet Reg Health Southeast Asia. 2022;3:100036. doi:10.1016/j.lansea.2022.100036