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
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Abstract
Hypoxic patients with coronavirus disease 2019 (COVID-19) are at high risk of adverse outcomes. Inhaled nitric oxide (iNO) has shown anti-viral and immunomodulatory effects in vitro. However, in vivo evidence of efficacy in hypoxic COVID-19 is sparse. This open label feasibility study was conducted at a single referral center in South India and evaluated the effectiveness of repurposed iNO in improving clinical outcomes in COVID-19 and its correlation with viral clearance. We recruited hypoxemic COVID-19 patients and allocated them into treatment (iNO) and control groups (1:1). Viral clearance on day 5 favored the treatment group (100% vs 72%, P < 0.01). The speed of viral clearance as adjudged by normalized longitudinal cycle threshold (Ct) values was positively impacted in the treatment group. The proportion of patients who attained clinical improvement, defined as a ≥2-point change on the World Health Organization ordinal scale, was higher in the iNO cohort (n = 11, 79%) as compared to the control group (n = 4, 36%) (odds ratio 6.42, 95% confidence interval 1.09-37.73, P = 0.032). The proportion of patients progressing to mechanical ventilation in the control group (4/11) was significantly higher than in the treatment group (0/14). The all-cause 28-day mortality was significantly different among the study arms, with 36% (4/11) of the patients dying in the control group while none died in the treatment group. The numbers needed to treat to prevent an additional poor outcome of death was estimated to be 2.8. Our study demonstrates the putative role of repurposed iNO in hypoxemic COVID-19 patients and calls for extended validation.
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SciScore for 10.1101/2021.04.15.21255300: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: Consent was obtained from the Institutional Ethics Committee of the Amrita Institute of Medical Sciences and Research Centre, Kochi and the Drug Controller General of India for permission to repurpose iNO.
IRB: Consent was obtained from the Institutional Ethics Committee of the Amrita Institute of Medical Sciences and Research Centre, Kochi and the Drug Controller General of India for permission to repurpose iNO.Sex as a biological variable not detected. Randomization Design: The study was conducted as a Phase II open-label, randomised controlled feasibility trial at a single tertiary referral centre in South India. Blinding The laboratory obtaining and analysing specimens was blinded … SciScore for 10.1101/2021.04.15.21255300: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: Consent was obtained from the Institutional Ethics Committee of the Amrita Institute of Medical Sciences and Research Centre, Kochi and the Drug Controller General of India for permission to repurpose iNO.
IRB: Consent was obtained from the Institutional Ethics Committee of the Amrita Institute of Medical Sciences and Research Centre, Kochi and the Drug Controller General of India for permission to repurpose iNO.Sex as a biological variable not detected. Randomization Design: The study was conducted as a Phase II open-label, randomised controlled feasibility trial at a single tertiary referral centre in South India. Blinding The laboratory obtaining and analysing specimens was blinded to allocation. Power Analysis not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:This report suffers from several limitations. First, larger conclusions as to the size of the treatment effect cannot be made from this small feasibility trial. Since other antivirals were also used, it cannot be conclusively shown that the antiviral efficacy was predominantly or solely owing to iNO. The doses used in this study use the highest doses available on the SLE Inosys (SLE Surrey, UK) delivery platform and it is uncertain whether a different dosing regimen will be efficacious. Since dexamethasone was also used universally in the study population, clinical improvement may have also accrued to it (4). Finally, it is uncertain whether iNO would be equally efficacious in sicker patients. In sum, we offer the first composite evidence of the utility of inhaled Nitric Oxide on accelerating viral clearance of SARS CoV-2 infection in hypoxemic patients with Covid-19. Its use appears to improve clinical recovery without any attendant harms and the results of this trial should be extended in a larger trial population.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title ISRCTN16806663 NA NA Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a protocol registration statement.
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