Nitric Oxide for COVID-19: real-time analysis of all 7 studies

Nitric Oxide for COVID-19: real-time meta analysis of 6 studies

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvements are seen for cases and viral clearance. 4 studies from 3 independent teams in 3 different countries show statistically significant improvements in isolation (2 for the most serious outcome).

• Meta analysis using the most serious outcome reported shows 46% [-4‑72%] improvement, without reaching statistical significance. Results are similar for Randomized Controlled Trials and slightly worse for peer-reviewed studies.

• No treatment, vaccine, or intervention is 100% effective and available. All practical, effective, and safe means should be used based on risk/benefit analysis. Multiple treatments are typically used in combination, and other treatments may be more effective. Only 33% of nitric oxide studies show zero events with treatment.

• All data to reproduce this paper and sources are in the appendix.

Covid Analysis et al., 20 Sep 2022, preprint, 1 author.

Utility of NO and H2S donating platforms in managing COVID-19: Rationale and promise

Oza et al., Nitric Oxide, doi:10.1016/j.niox.2022.08.003 (Review)

Extensive review of the mechanisms of action and potential benefits of nitric oxide and hydrogen sulfide for SARS-CoV-2 and other viral infections.

Oza et al., 24 Aug 2022, peer-reviewed, 2 authors.

High-Dose Inhaled Nitric Oxide for the Treatment of Spontaneously Breathing Pregnant Patients With Severe Coronavirus Disease 2019 (COVID-19) Pneumonia

Valsecchi et al., Obstetrics & Gynecology, doi:10.1097/AOG.0000000000004847

Retrospective 71 hospitalized patients in Israel, 20 treated with inhaled nitric oxide, showing

risk of death, 58.2% lower, RR 0.42, p = 1.00, treatment 0 of 20 (0.0%), control 1 of 51 (2.0%), NNT 51, relative risk is not 0 because of continuity correction due to zero events.

risk of mechanical ventilation, 68.1% lower, RR 0.32, p = 0.08, treatment 2 of 20 (10.0%), control 16 of 51 (31.4%), NNT 4.7.

risk of ICU admission, 39.3% lower, RR 0.61, p = 0.28, treatment 5 of 20 (25.0%), control 21 of 51 (41.2%), NNT 6.2.

Valsecchi et al., 7 Jul 2022, retrospective, Israel, peer-reviewed, 20 authors, study period March 2020 - December 2021.

SARS-CoV-2 accelerated clearance using a novel nitric oxide nasal spray (NONS) treatment: A randomized trial

Tandon et al., The Lancet Regional Health - Southeast Asia, doi:10.1016/j.lansea.2022.100036

RCT with 153 patients treated with a nitric oxide nasal spray, and 153 placebo patients, showing faster viral clearance with treatment. NO generated by a nasal spray (NONS) self-administered six times daily as two sprays per nostril (0.45mL of solution/dose) for seven days.

risk of no improvement, 41.9% lower, RR 0.58, p = 0.06, treatment 14 of 64 (21.9%), control 26 of 69 (37.7%), NNT 6.3, mITT high risk, day 18.

risk of no improvement, 66.8% lower, RR 0.33, p = 0.04, treatment 4 of 64 (6.2%), control 13 of 69 (18.8%), NNT 7.9, mITT high risk, day 16.

risk of no improvement, 67.7% lower, RR 0.32, p = 0.08, treatment 3 of 64 (4.7%), control 10 of 69 (14.5%), NNT 10, mITT high risk, day 8.

risk of no improvement, 22.3% lower, RR 0.78, p = 0.63, treatment 8 of 105 (7.6%), control 10 of 102 (9.8%), NNT 46, day 18, modified intention-to-treat.

risk of no improvement, 17.8% lower, RR 0.82, p = 0.67, treatment 11 of 105 (10.5%), control 13 of 102 (12.7%), NNT 44, day 16, modified intention-to-treat.

risk of no improvement, 8.9% lower, RR 0.91, p = 0.76, treatment 30 of 105 (28.6%), control 32 of 102 (31.4%), NNT 36, day 8, modified intention-to-treat.

viral load, 19.8% lower, relative load 0.80, p < 0.001, treatment mean 2.62 (±0.145) n=64, control mean 2.1 (±0.141) n=69, mITT high risk, day 8.

viral load, 13.5% lower, relative load 0.86, p < 0.001, treatment mean 2.51 (±0.114) n=105, control mean 2.17 (±0.118) n=102, day 8, modified intention-to-treat.

time to viral-, 26.1% lower, relative time 0.74, p = 0.09, treatment 64, control 69, inverted to make RR<1 favor treatment, mITT high risk, Kaplan–Meier.

time to viral-, 6.5% lower, relative time 0.94, p = 0.66, treatment 105, control 102, inverted to make RR<1 favor treatment, Kaplan–Meier, modified intention-to-treat.

Tandon et al., 29 Jun 2022, Double Blind Randomized Controlled Trial, placebo-controlled, India, peer-reviewed, 10 authors, study period 10 August, 2021 - 25 January, 2022, trial CTRI/2021/08.

Retrospective clinical study for COVID-19 prevention after exposure

SaNOtize (Preprint)

PEP retrospective 625 university students in Thailand offered nitric oxide nasal spray, showing significantly lower cases for students that chose to use the treatment.

risk of case, 75.0% lower, RR 0.25, p < 0.001, treatment 13 of 203 (6.4%), control 108 of 422 (25.6%), NNT 5.2.

SaNOtize et al., 30 Apr 2022, retrospective, Thailand, preprint, 1 author.

Clinical efficacy of nitric oxide nasal spray (NONS) for the treatment of mild COVID-19 infection

Winchester et al., Journal of Infection, doi:10.1016/j.jinf.2021.05.009

RCT with 40 nitric oxide and 40 placebo patients in the UK, showing faster viral clearance and greater improvement with treatment.

risk of no improvement, 42.0% lower, RR 0.58, p = 0.008, treatment 8 of 15 (53.3%), control 23 of 25 (92.0%), NNT 2.6.

viral load, 51.3% lower, relative load 0.49, p = 0.001, treatment 40, control 40, AUC relative mean change.

Winchester et al., 13 May 2021, Double Blind Randomized Controlled Trial, placebo-controlled, United Kingdom, peer-reviewed, 4 authors.

Clinical Efficacy of Inhaled Nitric Oxide in Preventing the Progression of Moderate to Severe COVID-19 and Its Correlation to Viral Clearance: Results of a Pilot Study

Moni et al., Infectious Microbes and Diseases, doi:10.1097/IM9.0000000000000079 (preprint 4/20/2021)

RCT 29 ICU patients in India, showing improved clinical outcomes and faster viral clearance with inhaled nitric oxide treatment. The treatment group was younger (mean 54 vs. 66) and had more patients on NIV at baseline (29% vs. 18%).

risk of death, 90.1% lower, RR 0.10, p = 0.03, treatment 0 of 14 (0.0%), control 4 of 11 (36.4%), NNT 2.8, relative risk is not 0 because of continuity correction due to zero events, day 28.

risk of mechanical ventilation, 90.1% lower, RR 0.10, p = 0.03, treatment 0 of 14 (0.0%), control 4 of 11 (36.4%), NNT 2.8, relative risk is not 0 because of continuity correction due to zero events, day 28.

risk of <2 point WOS improvement, 42.5% better, RR 0.58, p = 0.47, treatment 3 of 14 (21.4%), control 7 of 11 (63.6%), NNT 2.4, adjusted, inverted to make RR<1 favor treatment, OR converted to RR, day 14.

time to viral load reduction, 64.4% lower, RR 0.36, p = 0.005, treatment 14, control 11, adjusted, inverted to make RR<1 favor treatment, N gene.

time to viral load reduction, 63.4% lower, RR 0.37, p = 0.005, treatment 14, control 11, adjusted, inverted to make RR<1 favor treatment, Orf1ab gene.

Moni et al., 20 Apr 2021, Randomized Controlled Trial, India, peer-reviewed, 16 authors, study period September 2020 - December 2020, average treatment delay 6.78 days, trial ISRCTN16806663.

Inhaled Nitric Oxide via High-Flow Nasal Cannula in Patients with Acute Respiratory Failure Related to COVID-19

Chandel et al., Clinical Medicine Insights: Circulatory, Respiratory and Pulmonary Medicine, doi:10.1177/11795484211047065

Retrospective 272 acute respitory failure patients in the USA treated with high-flow nasal cannula, 66 treated with inhaled nitric oxide, showing increased mortality with inhaled nitric oxide. There were significant differences in the usage of several other treatments between the groups.

risk of death, 54.1% higher, RR 1.54, p = 0.25, treatment 12 of 66 (18.2%), control 36 of 206 (17.5%), adjusted, OR converted to RR, multivariable.

risk of mechanical ventilation, 27.2% higher, RR 1.27, p = 0.26, treatment 29 of 66 (43.9%), control 79 of 206 (38.3%), adjusted, OR converted to RR, multivariable.

Chandel et al., 31 Jan 2021, retrospective, USA, peer-reviewed, 14 authors, study period 1 March, 2020 - 9 June, 2020.

Inhaled nitric oxide for critically ill Covid-19 patients: a prospective study

Abou-Arab et al., Critical Care, doi:10.1186/s13054-020-03371-x

Retrospective 34 ICU patients in France treated with inhaled nitric oxide, showing 65% had an increase in PaO₂/FiO₂ of >20% 30 min following administration.

Abou-Arab et al., 12 Nov 2020, prospective, France, peer-reviewed, 6 authors.