Summary of COVID-19 nitric oxide studies

1. Moni et al., 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

25 patient nitric oxide ICU RCT: 90% lower mortality (p=0.03), 90% lower ventilation (p=0.03), 42% greater improvement (p=0.47), and 64% faster viral clearance (p=0.005).
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%).
Apr 2021, Infectious Microbes and Diseases, https://journals.lww.com/10.1097/IM9.0000000000000079, https://c19p.org/moni

2. Winchester et al., Clinical efficacy of nitric oxide nasal spray (NONS) for the treatment of mild COVID-19 infection

80 patient nitric oxide early treatment RCT: 42% greater improvement (p=0.008) and 51% improved viral clearance (p=0.001).
RCT with 40 nitric oxide and 40 placebo patients in the UK, showing faster viral clearance and greater improvement with treatment.
May 2021, J. Infection, https://www.journalofinfection.com/article/S0163-4453(21)00251-6/fulltext, https://c19p.org/winchester

3. Wolak et al., A safety evaluation of intermittent high-dose inhaled nitric oxide in viral pneumonia due to COVID-19: a randomised clinical study

35 patient nitric oxide late treatment RCT: 64% lower need for oxygen therapy (p=0.03) and 41% shorter hospitalization (p=0.24).
RCT 35 hospitalized patients with viral pneumonia (34 with COVID-19) showing improved recovery with high-dose inhaled nitric oxide (iNO) treatment. The treatment group received intermittent inhalations of 150 ppm iNO for 40 minutes, 4 times daily for up to 7 days. The treatment group had significantly reduced oxygen support duration and a greater number of patients reaching oxygen saturation ≥93%. There was also a trend towards earlier hospital discharge in the iNO group, without statistical significance. The study was terminated early. There was no ICU admission or mortality in either group.
Jul 2024, Scientific Reports, https://www.nature.com/articles/s41598-024-68055-w, https://c19p.org/wolak

4. Di Fenza et al., High-Dose Inhaled Nitric Oxide in Acute Hypoxemic Respiratory Failure Due to COVID-19: A Multicenter Phase II Trial

193 patient nitric oxide ICU RCT: 23% lower mortality (p=0.36), 30% lower progression (p=0.67), and 83% improvement (p=0.01).
RCT 193 mechanically ventilated COVID-19 patients showing improved oxygenation at 48 hours but no difference in mortality with high-dose (80ppm) inhaled nitric oxide (NO) for 48 hours. The NO group had a higher proportion attaining PaO2/FiO2 > 300 mmHg and reduced rates of neurologic symptoms at 90 days. NO was associated with faster viral clearance. No serious adverse events were reported with NO.
Dec 2023, American J. Respiratory and Critical Care Medicine, https://www.atsjournals.org/doi/10.1164/rccm.202304-0637OC, https://c19p.org/difenza

5. Tandon et al., SARS-CoV-2 accelerated clearance using a novel nitric oxide nasal spray (NONS) treatment: A randomized trial

207 patient nitric oxide early treatment RCT: 68% greater improvement (p=0.08) and 20% improved viral clearance (p<0.0001).
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.
Jun 2022, The Lancet Regional Health - Southeast Asia, https://www.sciencedirect.com/science/article/pii/S2772368222000464, https://c19p.org/tandon

6. SaNOtize et al., Retrospective clinical study for COVID-19 prevention after exposure

625 patient nitric oxide prophylaxis study: 75% fewer cases (p<0.0001).
PEP retrospective 625 university students in Thailand offered nitric oxide nasal spray, showing significantly lower cases for students that chose to use the treatment.
Apr 2022, SaNOtize, https://sanotize.com/clinical-trials-covid/, https://c19p.org/sanotizepep

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

71 patient nitric oxide late treatment study: 68% lower ventilation (p=0.08) and 39% lower ICU admission (p=0.28).
Retrospective 71 hospitalized patients in Israel, 20 treated with inhaled nitric oxide, showing no significant differences.
Jul 2022, Obstetrics & Gynecology, https://journals.lww.com/10.1097/AOG.0000000000004847, https://c19p.org/valsecchi

8. Poonam et al., Nitric oxide versus epoprostenol for refractory hypoxemia in Covid-19

103 patient nitric oxide ICU study: 14% lower mortality (p=0.1).
Retrospective 103 mechanically ventilated patients, 41 treated with inhaled nitric oxide, and 62 with inhaled epoprostenol, showing no significant difference in outcomes.
Jun 2022, PLOS ONE, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0270646, https://c19p.org/poonam

9. Al Sulaiman et al., Evaluation of inhaled nitric oxide (iNO) treatment for moderate-to-severe ARDS in critically ill patients with COVID-19: a multicenter cohort study

815 patient nitric oxide ICU study: 40% higher mortality (p=0.1).
Retrospective 815 COVID-19 ICU patients in Saudi Arabia, showing significant improvement in oxygenation. There was no significant difference in mortality, and ICU and hospitalization time was longer.
Oct 2022, Critical Care, https://ccforum.biomedcentral.com/articles/10.1186/s13054-022-04158-y, https://c19p.org/alsulaiman4

10. Bryan et al., The Efficacy of Nitric Oxide Generating Lozenges on Outcome in Newly Diagnosed COVID-19 Patients of African American and Hispanic Origin

524 patient nitric oxide early treatment RCT: 1% higher progression (p=1) and 11% faster recovery (p=0.3).
RCT 524 outpatients in the USA for a nitric oxide generating lozenge, showing no significant difference in combined hospitalization, ICU admission, intubation, dialysis, and death. There were only 3 events in each arm, all occuring in 2020, with zero events in 2021 or 2022. Recovery was 11% faster with treatment, without statistical significance. Authors note that a higher dose may have been more effective. Trials showing greater efficacy have used a nasal spray.
Jun 2023, The American J. Medicine, https://www.sciencedirect.com/science/article/pii/S0002934323003911, https://c19p.org/bryan

11. Chandel et al., Inhaled Nitric Oxide via High-Flow Nasal Cannula in Patients with Acute Respiratory Failure Related to COVID-19

272 patient nitric oxide late treatment study: 54% higher mortality (p=0.25) and 27% higher ventilation (p=0.26).
Retrospective 272 acute respiratory 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.
Jan 2021, Clinical Medicine Insights: Circulatory, Respiratory and Pulmonary Medicine, http://journals.sagepub.com/doi/10.1177/11795484211047065, https://c19p.org/chandel

12. Strickland et al., Safety and practicality of high dose inhaled nitric oxide in emergency department COVID-19 patients

34 patient nitric oxide late treatment RCT: 179% higher ventilation (p=1), 21% lower hospitalization (p=1), and 38% worse results (p=0.72).
Early terminated RCT with 47 ER patients in the USA, less than 12 days of symptoms, showing no significant difference in outcomes with a single high-dose administration of inhaled nitric oxide by mask, 250ppm for 30 min.
May 2022, The American J. Emergency Medicine, https://www.sciencedirect.com/science/article/pii/S0735675722002832, https://c19p.org/strickland

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