Nitric Oxide for COVID-19: real-time meta analysis of 12 studies
Abstract
Statistically significant lower risk is seen for cases and viral clearance. 6 studies from 5 independent teams in 5 countries show significant
improvements.
Meta analysis using the most serious outcome reported shows
31% [-1‑52%] lower risk, without reaching statistical significance. Results are similar for Randomized Controlled Trials and worse for peer-reviewed studies.
Early treatment is more effective than late treatment.
Mortality results are negative, however all results
to date are from late treatment trials.
No treatment or intervention
is 100% effective. 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.
Nitric Oxide may affect the natural microbiome, especially with prolonged use.
All data to reproduce this paper and
sources are in the appendix.
Nitric Oxide for COVID-19 — Highlights
Nitric Oxide reduces
risk with high confidence for viral clearance, low confidence for cases and in pooled analysis, and very low confidence for ICU admission and hospitalization.
Outcome specific analyses and combined evidence from all
studies, incorporating treatment delay, a primary confounding factor.
Real-time updates and corrections,
transparent analysis with all results in the same format, consistent protocol
for 109
treatments.
Figure 1.
A. Random effects
meta-analysis. This plot shows pooled effects,
see the specific outcome analyses for individual outcomes.
Analysis validating pooled outcomes for
COVID-19 can be found below.
Effect extraction is pre-specified, using the most serious outcome reported.
For details see the appendix.
B. Timeline of results in nitric oxide studies. The marked dates indicate the time when efficacy was known with a statistically significant improvement of ≥10% from ≥3 studies for one or more specific outcome and pooled outcomes in RCTs.
Naso/oropharyngeal treatments
AllAstodrimer Sodium
Cetylpyridin..
Chlorhexidine
Hydrogen Per..
Iota-carragee..
Nitric Oxide
Phthalocyan..
Plasma-activ..
Povidone-Iod..
Sodium Bicar..
SARS-CoV-2 infection typically starts in the upper respiratory tract, and
specifically the nasal respiratory epithelium. Entry via the eyes and
gastrointestinal tract is possible, but less common, and entry via other
routes is rare.
Infection may progress to the lower respiratory tract, other tissues, and the
nervous and cardiovascular systems. The primary initial route for entry into
the central nervous system is thought to be the olfactory nerve in the nasal
cavity1.
Progression may lead to cytokine storm, pneumonia, ARDS, neurological
injury2-12 and cognitive
deficits4,9, cardiovascular
complications13-15, organ failure, and death.
Systemic treatments may be insufficient to prevent
neurological damage8.
Minimizing replication as early as possible is recommended.
Logically, stopping replication in the upper respiratory tract should be
simpler and more effective.
Wu et al., using an airway organoid model incorporating many in
vivo aspects, show that SARS-CoV-2 initially attaches to cilia —
hair-like structures responsible for moving the mucus layer and where ACE2 is
localized in nasal epithelial cells18. The mucus layer and the
need for ciliary transport slow down infection, providing more time for
localized treatments16,17.
Early or prophylactic nasopharyngeal/oropharyngeal treatment may avoid the
consequences of viral replication in other tissues, and avoid the requirement
for systemic treatments with greater potential for side effects.
SARS-CoV-2 infection and replication involves the complex interplay of 50+
host and viral proteins and other factorsA,19-24, providing many
therapeutic targets for which many existing compounds have known activity.
Scientists have predicted that over 8,000 compounds may
reduce COVID-19 risk25, either by
directly minimizing infection or replication, by supporting immune system
function, or by minimizing secondary complications.
We analyze all significant
controlled studies of
nitric oxide
for COVID-19.
Search methods, inclusion criteria, effect extraction criteria (more serious
outcomes have priority), all individual study data, PRISMA answers, and
statistical methods are detailed in Appendix 1. We present random
effects meta-analysis results for all studies, studies within each treatment stage, individual outcomes, peer-reviewed studies, and Randomized Controlled Trials (RCTs).
Figure 3 shows stages of possible treatment for
COVID-19. Prophylaxis refers to regularly taking medication before
becoming sick, in order to prevent or minimize infection. Early
Treatment refers to treatment immediately or soon after symptoms appear,
while Late Treatment refers to more delayed treatment.
Figure 3. Treatment stages.
Preclinical research is an important part of the development of
treatments, however results may be very different in clinical trials.
Preclinical results are not used in this paper.
Table 1 summarizes the results for all stages combined, for Randomized Controlled Trials, for peer-reviewed studies, with different exclusions, and for specific outcomes.
Table 2 shows results by treatment stage.
Figure 4 plots individual results by treatment stage.
Figure 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15
show forest plots for random effects meta-analysis of
all studies with pooled effects, early treatment and prophylaxis, mortality results, ventilation, ICU admission, hospitalization, progression, recovery, cases, viral clearance, and peer reviewed studies.
| Improvement | Studies | Patients | Authors | |
|---|---|---|---|---|
| All studies | 31% [-1‑52%] | 12 | 2,236 | 171 |
| Exc. late treatmentExc. late | 58% [25‑77%] ** | 4 | 1,322 | 18 |
| Peer-reviewed studiesPeer-reviewed | 17% [-14‑39%] | 11 | 1,611 | 170 |
| Randomized Controlled TrialsRCTs | 41% [19‑57%] ** | 7 | 984 | 102 |
| RCTs exc. late treatmentRCTs exc. late | 44% [13‑64%] ** | 3 | 697 | 17 |
| Mortality | -4% [-46‑27%] | 6 | 845 | 138 |
| VentilationVent. | 33% [-114‑79%] | 4 | 402 | 58 |
| HospitalizationHosp. | 39% [-40‑74%] | 2 | 69 | 15 |
| Viral | 43% [8‑65%] * | 3 | 238 | 30 |
| RCT mortality | 55% [-163‑92%] | 2 | 218 | 70 |
| Early treatment | Late treatment | Prophylaxis | |
|---|---|---|---|
| All studies | 44% [13‑64%] ** | 5% [-34‑33%] | 75% [57‑86%] **** |
| Exc. late treatmentExc. late | 44% [13‑64%] ** | 75% [57‑86%] **** |
|
| Peer-reviewed studiesPeer-reviewed | 44% [13‑64%] ** | 5% [-34‑33%] | |
| Randomized Controlled TrialsRCTs | 44% [13‑64%] ** | 44% [-17‑73%] | |
| Mortality | -4% [-46‑27%] | ||
| VentilationVent. | 33% [-114‑79%] | ||
| HospitalizationHosp. | 39% [-40‑74%] | ||
| Viral | 35% [-6‑60%] | 64% [26‑83%] ** | |
| RCT mortality | 55% [-163‑92%] |
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Figure 4. Scatter plot showing the most serious outcome in all studies, and for studies within each stage. Diamonds shows the results of random effects meta-analysis.
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Figure 5. Random effects meta-analysis for all studies.
This plot shows pooled effects,
see the specific outcome analyses for individual outcomes.
Analysis validating pooled outcomes for
COVID-19 can be found below.
Effect extraction is pre-specified, using the most serious outcome reported.
For details see the appendix.
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Figure 6. Random effects meta-analysis for early treatment and prophylaxis.
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Figure 7. Random effects meta-analysis for mortality results.
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Figure 8. Random effects meta-analysis for ventilation.
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Figure 9. Random effects meta-analysis for ICU admission.
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Figure 10. Random effects meta-analysis for hospitalization.
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Figure 11. Random effects meta-analysis for progression.
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Figure 12. Random effects meta-analysis for recovery.
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Figure 13. Random effects meta-analysis for cases.
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Figure 14. Random effects meta-analysis for viral clearance.
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Figure 15. Random effects meta-analysis for peer reviewed studies.
Effect extraction is pre-specified, using the most serious outcome reported,
see the appendix for details.
Analysis validating pooled outcomes for
COVID-19 can be found below.
Zeraatkar et al. analyze 356 COVID-19 trials, finding no significant
evidence that preprint results are inconsistent with peer-reviewed studies.
They also show extremely long peer-review delays, with a median of 6 months to
journal publication. A six month delay was equivalent to around 1.5 million
deaths during the first two years of the pandemic. Authors recommend using
preprint evidence, with appropriate checks for potential falsified data, which
provides higher certainty much earlier. Davidson et al. also showed no
important difference between meta analysis results of preprints and
peer-reviewed publications for COVID-19, based on 37 meta analyses including
114 trials.
Figure 16 shows a comparison of results for RCTs and non-RCT studies.
Random effects meta analysis of RCTs shows
41% improvement,
compared to 17% for other studies.
Figure 17, 18, and 19
show forest plots for random effects meta-analysis of
all Randomized Controlled Trials, all early treatment and prophylaxis RCTs, and RCT mortality results.
RCT results are included in Table 1 and Table 2.
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Figure 16. Results for RCTs and non-RCT studies.
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Figure 17. Random effects meta-analysis for all Randomized Controlled Trials.
This plot shows pooled effects,
see the specific outcome analyses for individual outcomes.
Analysis validating pooled outcomes for
COVID-19 can be found below.
Effect extraction is pre-specified, using the most serious outcome reported.
For details see the appendix.
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Figure 18. Random effects meta-analysis for all early treatment and prophylaxis RCTs.
Effect extraction is pre-specified, using the most serious outcome reported,
see the appendix for details.
Analysis validating pooled outcomes for
COVID-19 can be found below.
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Figure 19. Random effects meta-analysis for RCT mortality results.
RCTs help to make study groups more similar and can provide a higher level of
evidence, however they are subject to many biases30, and
analysis of double-blind RCTs has identified extreme levels of bias31.
For COVID-19, the overhead may delay treatment, dramatically compromising
efficacy; they may encourage monotherapy for simplicity at the cost of
efficacy which may rely on combined or synergistic effects; the participants
that sign up may not reflect real world usage or the population that benefits
most in terms of age, comorbidities, severity of illness, or other factors;
standard of care may be compromised and unable to evolve quickly based on
emerging research for new diseases; errors may be made in randomization and
medication delivery; and investigators may have hidden agendas or vested
interests influencing design, operation, analysis, reporting, and the
potential for fraud. All of these biases have been observed with COVID-19
RCTs. There is no guarantee that a specific RCT provides a higher level of
evidence.
RCTs are expensive and many RCTs are funded
by pharmaceutical companies or interests closely aligned with pharmaceutical
companies. For COVID-19, this creates an incentive to show efficacy for
patented commercial products, and an incentive to show a lack of efficacy for
inexpensive treatments. The bias is expected to be significant, for example
Als-Nielsen et al. analyzed 370 RCTs from Cochrane reviews, showing that
trials funded by for-profit organizations were 5 times more likely to
recommend the experimental drug compared with those funded by nonprofit
organizations. For COVID-19, some major philanthropic organizations are
largely funded by investments with extreme conflicts of interest for and
against specific COVID-19 interventions.
High quality RCTs for novel acute diseases are more challenging, with
increased ethical issues due to the urgency of treatment, increased risk due
to enrollment delays, and more difficult design with a rapidly evolving
evidence base. For COVID-19, the most common site of initial infection is the
upper respiratory tract. Immediate treatment is likely to be most successful
and may prevent or slow progression to other parts of the body. For a
non-prophylaxis RCT, it makes sense to provide treatment in advance and
instruct patients to use it immediately on symptoms, just as some governments
have done by providing medication kits in advance. Unfortunately, no RCTs have
been done in this way. Every treatment RCT to date involves delayed treatment.
Among the 109 treatments we have analyzed,
65% of RCTs involve very late treatment 5+ days after
onset. No non-prophylaxis COVID-19 RCTs match the potential real-world use of
early treatments. They may more accurately represent results for treatments
that require visiting a medical facility, e.g., those requiring intravenous
administration.
For COVID-19, observational study results do not systematically
differ from RCTs, RR 1.00 [0.92‑1.08]
across 109 treatments33.
Evidence shows that observational studies
can also provide reliable results. Concato et al. found that well-designed
observational studies do not systematically overestimate the magnitude of the
effects of treatment compared to RCTs. Anglemyer et al. analyzed reviews
comparing RCTs to observational studies and found little evidence for
significant differences in effect estimates.
We performed a similar analysis across the 109 treatments
we cover, showing no significant difference in the results of RCTs compared to
observational studies, RR 1.00 [0.92‑1.08]. Similar results are found for all low-cost treatments, RR
1.02 [0.92‑1.12]. High-cost treatments
show a non-significant trend towards RCTs showing greater efficacy,
RR 0.92 [0.82‑1.03].
Details can be found in the
supplementary data.
Lee (B) et al. showed that only 14% of the guidelines of the Infectious
Diseases Society of America were based on RCTs. Evaluation of studies relies
on an understanding of the study and potential biases. Limitations in an RCT
can outweigh the benefits, for example excessive dosages, excessive treatment
delays, or remote survey bias may have a greater effect on results. Ethical
issues may also prevent running RCTs for known effective treatments. For more
on issues with RCTs see37,38.
Currently, 48 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. Of these, 60% have been confirmed in RCTs, with a mean delay of 7.1 months (68% with 8.2 months delay for low-cost treatments). The remaining treatments either have no RCTs, or the point estimate is consistent.
We need to
evaluate each trial on its own merits. RCTs for a given medication and disease
may be more reliable, however they may also be less reliable. For off-patent
medications, very high conflict of interest trials may be more likely to be
RCTs, and more likely to be large trials that dominate meta analyses.
Figure 20.
Optimal spray angle may increase nasopharyngeal drug delivery 100x for nasal sprays,
adapted from Akash et al.
In addition to the dosage and frequency of administration,
efficacy for nasopharyngeal/oropharyngeal treatments may depend on many
other details. For example considering sprays, viscosity, mucoadhesion,
sprayability, and application angle are important.
Akash et al. performed a computational fluid dynamics study
of nasal spray administration showing 100x improvement in nasopharyngeal drug
delivery using a new spray placement protocol, which involves holding the spay
nozzle as horizontally as possible at the nostril, with a slight tilt towards
the cheeks. The study also found the optimal droplet size range for
nasopharyngeal deposition was ~7-17µm.
Heterogeneity in COVID-19 studies arises from many factors including:
The time
between infection or the onset of symptoms and treatment may critically affect
how well a treatment works. For example an antiviral may be very effective
when used early but may not be effective in late stage disease, and may even
be harmful. Oseltamivir, for example, is generally only considered effective
for influenza when used within 0-36 or 0-48 hours40,41.
Baloxavir marboxil studies for influenza also show that treatment delay is critical
— Ikematsu et al. report an 86% reduction in cases for post-exposure
prophylaxis, Hayden et al. show a 33 hour reduction in the time to
alleviation of symptoms for treatment within 24 hours and a reduction of 13
hours for treatment within 24-48 hours, and Kumar et al. report only 2.5
hours improvement for inpatient treatment.
| Treatment delay | Result |
| Post-exposure prophylaxis | 86% fewer cases42 |
| <24 hours | -33 hours symptoms43 |
| 24-48 hours | -13 hours symptoms43 |
| Inpatients | -2.5 hours to improvement44 |
Figure 21 shows a mixed-effects meta-regression of efficacy as
a function of treatment delay in COVID-19 nitric oxide studies, with group estimates for different stages when a specific value is not provided. For comparison, Figure 22 shows a meta-regression for
all studies providing specific values across 109 treatments.
Efficacy declines rapidly with treatment delay. Early treatment is
critical for COVID-19.
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Figure 22. Early treatment is more effective. Meta-regression showing efficacy as a function of treatment delay in COVID-19 nitric oxide studies.
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Figure 22. Early treatment is more effective. Meta-regression showing efficacy as a function of treatment delay in COVID-19 studies from 109 treatments.
Details of the patient population including age and comorbidities may
critically affect how well a treatment works. For example, many COVID-19
studies with relatively young low-comorbidity patients show all patients
recovering quickly with or without treatment. In such cases, there is little
room for an effective treatment to improve results, for example as in
López-Medina et al.
Efficacy may
depend critically on the distribution of SARS-CoV-2 variants encountered by
patients. Risk varies significantly across variants46, for
example the Gamma variant shows significantly different characteristics47-50. Different mechanisms of action may be
more or less effective depending on variants, for example the degree to which
TMPRSS2 contributes to viral entry can differ across variants51,52.
Effectiveness may depend strongly on the dosage and treatment regimen.
The use
of other treatments may significantly affect outcomes, including supplements,
other medications, or other interventions such as prone positioning.
Treatments may be synergistic53-64, therefore
efficacy may depend strongly on combined treatments.
The
quality of medications may vary significantly between manufacturers and
production batches, which may significantly affect efficacy and safety.
Williams et al. analyze ivermectin from 11 different sources, showing
highly variable antiparasitic efficacy across different manufacturers.
Xu et al. analyze a treatment from two different manufacturers, showing 9
different impurities, with significantly different concentrations for each
manufacturer.
Across all
studies there is a strong association between different outcomes, for example
improved recovery is strongly associated with lower mortality. However,
efficacy may differ depending on the effect measured, for example a treatment
may be more effective against secondary complications and have minimal effect
on viral clearance.
The
distribution of studies will alter the outcome of a meta analysis. Consider a
simplified example where everything is equal except for the treatment delay,
and effectiveness decreases to zero or below with increasing delay. If there
are many studies using very late treatment, the outcome may be negative, even
though early treatment is very effective.
All meta analyses combine heterogeneous studies, varying in population,
variants, and potentially all factors above, and therefore may obscure
efficacy by including studies where treatment is less effective. Generally, we
expect the estimated effect size from meta analysis to be less than that for
the optimal case.
Looking at all studies is valuable for providing an overview of all research,
important to avoid cherry-picking, and informative when a positive result is
found despite combining less-optimal situations. However, the resulting
estimate does not apply to specific cases such as
early treatment in high-risk populations.
While we present results for all studies, we also present treatment time and
individual outcome analyses, which may be more informative for specific use
cases.
This section validates the use of pooled effects for COVID-19, which enables
earlier detection of efficacy, however note that pooled effects are no longer
required for nitric oxide as of June 2022.
Efficacy is now known based on specific outcomes.
For COVID-19, delay in clinical results translates into
additional death and morbidity, as well as additional economic and societal
damage. Combining the results of studies reporting different outcomes is
required.
There may be no mortality in a trial with low-risk patients,
however a reduction in severity or improved viral clearance may translate
into lower mortality in a high-risk population.
Different studies may report lower severity, improved recovery, and lower mortality,
and the significance may be very high when combining the results.
"The studies reported different outcomes"
is not a good reason for disregarding results.
We present both specific outcome and pooled analyses.
In order to combine the results of studies reporting different outcomes we use
the most serious outcome reported in each study, based on the thesis that
improvement in the most serious outcome provides comparable measures of
efficacy for a treatment. A critical advantage of this approach is
simplicity and transparency.
There are many other ways to combine evidence for different outcomes, along
with additional evidence such as dose-response relationships, however these
increase complexity.
Another way to view pooled analysis is that we are using more of
the available information. Logically we should, and do, use additional
information. For example dose-response and
treatment delay-response relationships provide significant additional evidence
of efficacy that is considered when reviewing the evidence for a
treatment.
Trials with high-risk patients may be restricted due to ethics for treatments
that are known or expected to be effective, and they increase difficulty for
recruiting. Using less severe outcomes as a proxy for more serious outcomes
allows faster collection of evidence.
For many COVID-19 treatments, a reduction in mortality logically
follows from a reduction in hospitalization, which follows from a reduction in
symptomatic cases, which follows from a reduction in PCR positivity. We can
directly test this for COVID-19.
Analysis of the the association between different outcomes across studies from
all 109
treatments we cover confirms the validity of pooled outcome analysis for COVID-19.
Figure 23 shows that lower hospitalization is very strongly associated
with lower mortality (p < 0.000000000001).
Similarly, Figure 24 shows that improved recovery is very strongly associated
with lower mortality (p < 0.000000000001).
Considering the extremes, Singh et al. show an association between viral clearance and
hospitalization or death, with p = 0.003 after excluding one large
outlier from a mutagenic treatment, and based on 44 RCTs including 52,384
patients.
Figure 25 shows that improved viral clearance is strongly associated
with fewer serious outcomes. The association is very similar to
Singh et al., with higher confidence due to the larger number of
studies. As with Singh et al., the confidence increases
when excluding the outlier treatment, from p = 0.00000042 to p = 0.00000002.
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Figure 23. Lower hospitalization is associated with lower mortality, supporting pooled outcome analysis.
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Figure 24. Improved recovery is associated with lower mortality, supporting pooled outcome analysis.
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Figure 23. Improved viral clearance is associated with fewer serious outcomes, supporting pooled outcome analysis.
Currently, 48 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. 89% of these have been confirmed with one or more specific outcomes, with a mean delay of 5.1 months. When restricting to RCTs only, 56% of treatments showing statistically significant efficacy/harm with pooled effects have been confirmed with one or more specific outcomes, with a mean delay of 6.4 months.
Figure 26 shows when treatments were found effective during the
pandemic. Pooled outcomes often resulted in earlier detection of efficacy.
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Figure 26. The time when studies showed that
treatments were effective, defined as statistically significant improvement of
≥10% from ≥3 studies.
Pooled results typically show efficacy earlier than specific
outcome results. Results from all studies often shows efficacy much earlier
than when restricting to RCTs.
Results reflect conditions as used in trials to date, these depend on the
population treated, treatment delay, and treatment regimen.
Pooled analysis could hide efficacy, for example a treatment that is
beneficial for late stage patients but has no effect on viral clearance may
show no efficacy if most studies only examine viral clearance. In practice, it
is rare for a non-antiviral treatment to report viral clearance and to not
report clinical outcomes; and in practice other sources of heterogeneity such
as difference in treatment delay is more likely to hide efficacy.
Analysis validates the use of pooled effects and shows significantly faster
detection of efficacy on average.
However, as with all meta analyses, it is important to review the different
studies included. We also present individual outcome analyses, which may be
more informative for specific use cases.
Analysis of short-term changes in viral load using PCR may not detect
effective treatments because PCR is unable to differentiate between intact
infectious virus and non-infectious or destroyed virus particles. For example
Tarragó‐Gil, Alemany perform RCTs with cetylpyridinium chloride
(CPC) mouthwash that show no difference in PCR viral load, however there was
significantly increased detection of SARS-CoV-2 nucleocapsid protein,
indicating viral lysis. CPC inactivates SARS-CoV-2 by degrading its membrane,
exposing the nucleocapsid of the virus. To better estimate changes in viral
load and infectivity, methods like viral culture that can
differentiate intact vs. degraded virus are preferred.
Studies to
date use a variety of administration methods to the respiratory tract,
including nasal and oral sprays, nasal irrigation, oral rinses, and
inhalation. Table 4 shows the relative efficacy for nasal, oral,
and combined administration. Combined administration shows the best results,
and nasal administration is more effective than oral. Precise efficacy depends
on the details of administration, e.g., mucoadhesion and sprayability for
sprays.
| Nasal/oral administration to the respiratory tract | Improvement | Studies |
| Oral spray/rinse | 38% [25‑49%] | 8 |
| Nasal spray/rinse | 56% [46‑64%] | 14 |
| Nasal & oral | 94% [74‑99%] | 6 |
Nasopharyngeal/oropharyngeal treatments may not be highly selective. In
addition to inhibiting or disabling SARS-CoV-2, they may also be harmful to
beneficial microbes, disrupting the natural microbiome in the oral cavity and
nasal passages that have important protective and metabolic roles70. This may be
especially important for prolonged use or overuse.
Table 5 summarizes the potential for common
nasopharyngeal/oropharyngeal treatments to affect the natural
microbiome.
| Treatment | Microbiome disruption potential | Notes |
|---|---|---|
| Iota-carrageenan | Low | Primarily antiviral, however extended use may mildly affect the microbiome |
| Nitric Oxide | Low to moderate | More selective towards pathogens, however excessive concentrations or prolonged use may disrupt the balance of bacteria |
| Alkalinization | Moderate | Increases pH, negatively impacting beneficial microbes that thrive in a slightly acidic environment |
| Cetylpyridinium Chloride | Moderate | Quaternary ammonium broad-spectrum antiseptic that can disrupt beneficial and harmful bacteria |
| Phthalocyanine | Moderate to high | Photodynamic compound with antimicrobial activity, likely to affect the microbiome |
| Chlorhexidine | High | Potent antiseptic with broad activity, significantly disrupts the microbiome |
| Hydrogen Peroxide | High | Strong oxidizer, harming both beneficial and harmful microbes |
| Povidone-Iodine | High | Potent broad-spectrum antiseptic harmful to beneficial microbes |
Publishing is often biased
towards positive results, however evidence suggests that there may be a negative bias for
inexpensive treatments for COVID-19. Both negative and positive results are
very important for COVID-19, media in many countries prioritizes negative
results for inexpensive treatments (inverting the typical incentive for
scientists that value media recognition), and there are many reports of
difficulty publishing positive results71-74.
For nitric oxide, there is currently not
enough data to evaluate publication bias with high confidence.
One method to evaluate bias is to compare prospective vs.
retrospective studies. Prospective studies are more likely to be published
regardless of the result, while retrospective studies are more likely to
exhibit bias. For example, researchers may perform preliminary analysis with
minimal effort and the results may influence their decision to continue.
Retrospective studies also provide more opportunities for the specifics of
data extraction and adjustments to influence results.
Figure 27 shows a scatter plot of
results for prospective and retrospective studies.
20% of retrospective studies
report a statistically significant positive effect for
one or more outcomes, compared to
71% of prospective studies, consistent with a bias toward publishing negative results.
The median effect size for
retrospective studies is 14% improvement,
compared to 42% for prospective
studies, suggesting a potential bias towards publishing results showing lower efficacy.
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Figure 27. Prospective vs. retrospective studies.
The diamonds show the results of random effects meta-analysis.
Studies for nitric oxide were primarily late treatment studies, in
contrast with typical patented treatments that were tested with early
treatment as recommended.
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Figure 28. Patented treatments received mostly early treatment studies, while low cost treatments were typically tested for late treatment.
Funnel
plots have traditionally been used for analyzing publication bias. This is
invalid for COVID-19 acute treatment trials — the underlying assumptions
are invalid, which we can demonstrate with a simple example. Consider a set of
hypothetical perfect trials with no bias. Figure 29 plot A
shows a funnel plot for a simulation of 80 perfect trials, with random group
sizes, and each patient's outcome randomly sampled (10% control event
probability, and a 30% effect size for treatment). Analysis shows no asymmetry
(p > 0.05). In plot B, we add a single typical variation in COVID-19 treatment
trials — treatment delay. Consider that efficacy varies from 90% for
treatment within 24 hours, reducing to 10% when treatment is delayed 3 days.
In plot B, each trial's treatment delay is randomly selected. Analysis now
shows highly significant asymmetry, p < 0.0001, with six variants of
Egger's test all showing p < 0.0575-82.
Note that these tests fail even though treatment delay is uniformly
distributed. In reality treatment delay is more complex — each trial has
a different distribution of delays across patients, and the distribution
across trials may be biased (e.g., late treatment trials may be more common).
Similarly, many other variations in trials may produce asymmetry, including
dose, administration, duration of treatment, differences in SOC,
comorbidities, age, variants, and bias in design, implementation, analysis,
and reporting.
Figure 29. Example funnel plot analysis for simulated perfect trials.
Pharmaceutical drug
trials often have conflicts of interest whereby sponsors or trial staff have a
financial interest in the outcome being positive. Nitric Oxide for COVID-19
lacks this because it is off-patent, has multiple manufacturers, and is very low cost.
In contrast, most COVID-19 nitric oxide trials have been run by
physicians on the front lines with the primary goal of finding the best
methods to save human lives and minimize the collateral damage caused by
COVID-19. While pharmaceutical companies are careful to run trials under
optimal conditions (for example, restricting patients to those most likely to
benefit, only including patients that can be treated soon after onset when
necessary, and ensuring accurate dosing), not all nitric oxide trials
represent the optimal conditions for efficacy.
Summary statistics from
meta analysis necessarily lose information. As with all meta analyses, studies
are heterogeneous, with differences
in treatment delay, treatment regimen, patient demographics, variants,
conflicts of interest, standard of care, and other factors. We provide analyses for specific
outcomes and by treatment delay, and we aim to identify key characteristics in
the forest plots and summaries. Results should be viewed in the context of
study characteristics.
Some analyses classify treatment based on early or late
administration, as done here, while others distinguish between mild, moderate,
and severe cases. Viral load does not indicate degree of symptoms — for
example patients may have a high viral load while being asymptomatic. With
regard to treatments that have antiviral properties, timing of treatment is
critical — late administration may be less helpful regardless of
severity.
Details of treatment delay per patient is often not available.
For example, a study may treat 90% of patients relatively early, but the
events driving the outcome may come from 10% of patients treated very late.
Our 5 day cutoff for early treatment may be too conservative, 5 days may be too late in many cases.
Comparison across treatments is confounded by differences in
the studies performed, for example dose, variants, and conflicts of interest.
Trials with conflicts of interest may use designs better suited to the
preferred outcome.
In some cases, the most serious outcome has very few events,
resulting in lower confidence results being used in pooled analysis, however
the method is simpler and more transparent. This is less critical as the
number of studies increases. Restriction to outcomes with sufficient power may
be beneficial in pooled analysis and improve accuracy when there are few
studies, however we maintain our pre-specified method to avoid any
retrospective changes.
Studies show that combinations of treatments can be highly
synergistic and may result in many times greater efficacy than individual
treatments alone53-64.
Therefore standard of care may be critical and benefits may diminish or
disappear if standard of care does not include certain treatments.
This real-time analysis is constantly updated based on
submissions. Accuracy benefits from widespread review and submission of
updates and corrections from reviewers. Less popular treatments may receive
fewer reviews.
No treatment or intervention is 100% available and
effective for all current and future variants. Efficacy may vary significantly
with different variants and within different populations. All treatments have
potential side effects. Propensity to experience side effects may be predicted
in advance by qualified physicians. We do not provide medical advice. Before
taking any medication, consult a qualified physician who can compare all
options, provide personalized advice, and provide details of risks and
benefits based on individual medical history and situations.
1 of the 12
studies compare against other treatments, which may reduce the effect
seen.
SARS-CoV-2 infection and replication involves a complex interplay of 50+ host
and viral proteins and other factors19-24,
providing many therapeutic targets.
Over 8,000 compounds have been predicted to reduce COVID-19
risk25, either by directly
minimizing infection or replication, by supporting immune system function, or
by minimizing secondary complications.
Figure 30 shows an overview of the results for nitric oxide
in the context of multiple COVID-19 treatments, and Figure 31 shows a plot
of efficacy vs. cost for COVID-19 treatments.
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Figure 30.
Scatter plot showing results within the context of multiple COVID-19 treatments.
Diamonds shows the results of random effects meta-analysis.
0.6% of 8,000+ proposed treatments show efficacy88.
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Figure 31. Efficacy vs. cost for COVID-19 treatments.
SARS-CoV-2 infection typically starts in the upper respiratory tract.
Progression may lead to cytokine storm, pneumonia, ARDS, neurological issues,
organ failure, and death. Stopping replication in the upper respiratory tract,
via early or prophylactic nasopharyngeal/oropharyngeal treatment, can avoid
the consequences of progression to other tissues, and avoid the requirement
for systemic treatments with greater potential for side effects.
Statistically significant lower risk is seen for cases and viral clearance. 6 studies from 5 independent teams in 5 countries show significant
improvements.
Meta analysis using the most serious outcome reported shows
31% [-1‑52%] lower risk, without reaching statistical significance. Results are similar for Randomized Controlled Trials and worse for peer-reviewed studies.
Early treatment is more effective than late treatment.
Mortality results are negative, however all results
to date are from late treatment trials.
Nitric Oxide may affect the natural microbiome, especially with prolonged use.
Al Sulaiman:
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.
Bryan:
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.
Chandel:
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.
Di Fenza:
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.
Moni:
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%).
Poonam:
Retrospective 103 mechanically ventilated patients, 41 treated with inhaled nitric oxide, and 62 with inhaled epoprostenol, showing no significant difference in outcomes.
SaNOtize:
PEP retrospective 625 university students in Thailand offered nitric oxide nasal spray, showing significantly lower cases for students that chose to use the treatment.
Strickland:
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.
Tandon:
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.
Valsecchi:
Retrospective 71 hospitalized patients in Israel, 20 treated with inhaled nitric oxide, showing no significant differences.
Winchester:
RCT with 40 nitric oxide and 40 placebo patients in the UK, showing faster viral clearance and greater improvement with treatment.
Wolak:
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.
We perform ongoing searches of PubMed, medRxiv, Europe PMC,
ClinicalTrials.gov, The Cochrane Library, Google Scholar, Research
Square, ScienceDirect, Oxford University Press, the reference lists of other
studies and meta-analyses, and submissions to the site c19early.org.
Search terms are nitric oxide and COVID-19 or SARS-CoV-2. Automated searches are performed twice daily, with all matches reviewed for inclusion.
All studies regarding the use of nitric oxide for COVID-19 that report
a comparison with a control group are included in the main analysis.
This is a living analysis and is updated regularly.
We extracted effect sizes and associated data from all studies.
If studies report multiple kinds of effects then the most serious
outcome is used in pooled analysis, while other outcomes are included in the
outcome specific analyses. For example, if effects for mortality and cases are
both reported, the effect for mortality is used, this may be different to the
effect that a study focused on.
If symptomatic
results are reported at multiple times, we used the latest time, for example
if mortality results are provided at 14 days and 28 days, the results at 28
days have preference. Mortality alone is preferred over combined outcomes.
Outcomes with zero events in both arms are not used, the next most serious
outcome with one or more events is used. For example, in low-risk populations
with no mortality, a reduction in mortality with treatment is not possible,
however a reduction in hospitalization, for example, is still valuable.
Clinical outcomes are considered more important than viral test status. When
basically all patients recover in both treatment and control groups,
preference for viral clearance and recovery is given to results mid-recovery
where available. After most or all patients have recovered there is little or
no room for an effective treatment to do better, however faster recovery is
valuable.
If only individual symptom data is available, the most serious symptom has
priority, for example difficulty breathing or low SpO2 is more
important than cough.
When results provide an odds ratio, we compute the relative risk when
possible, or convert to a relative risk according to101.
Reported confidence intervals and p-values were used when available,
using adjusted values when provided. If multiple types of adjustments are
reported propensity score matching and multivariable regression has preference
over propensity score matching or weighting, which has preference over
multivariable regression. Adjusted results have preference over unadjusted
results for a more serious outcome when the adjustments significantly alter
results. When needed, conversion between reported p-values and
confidence intervals followed Altman, Altman (B), and Fisher's exact
test was used to calculate p-values for event data. If continuity
correction for zero values is required, we use the reciprocal of the opposite
arm with the sum of the correction factors equal to 1104.
Results are expressed with RR < 1.0 favoring treatment, and using the risk of
a negative outcome when applicable (for example, the risk of death rather than
the risk of survival). If studies only report relative continuous values such
as relative times, the ratio of the time for the treatment group versus the
time for the control group is used. Calculations are done in Python
(3.13.0) with
scipy (1.14.1), pythonmeta (1.26), numpy (1.26.4), statsmodels (0.14.4), and plotly (5.24.1).
Forest plots are computed using PythonMeta105
with the DerSimonian and Laird random effects model (the fixed effect
assumption is not plausible in this case) and inverse variance weighting.
Results are presented with 95% confidence intervals. Heterogeneity among studies was
assessed using the I2 statistic.
Mixed-effects meta-regression results are computed with R (4.4.0) using the metafor
(4.6-0) and rms (6.8-0) packages, and using the most serious sufficiently powered outcome.
For all statistical tests, a p-value less than 0.05 was considered statistically significant.
Grobid 0.8.0 is used to parse PDF documents.
We have classified studies as early treatment if most patients
are not already at a severe stage at the time of treatment (for example based
on oxygen status or lung involvement), and treatment started within 5 days of
the onset of symptoms. If studies contain a mix of early treatment and late
treatment patients, we consider the treatment time of patients contributing
most to the events (for example, consider a study where most patients are
treated early but late treatment patients are included, and all mortality
events were observed with late treatment patients).
We note that a shorter time may be preferable. Antivirals are typically only
considered effective when used within a shorter timeframe, for example 0-36 or
0-48 hours for oseltamivir, with longer delays not being effective40,41.
We received no funding, this research is done in our spare
time. We have no affiliations with any pharmaceutical companies or political
parties.
A summary of study results is below. Please submit
updates and corrections at https://c19early.org/nometa.html.
Effect extraction follows pre-specified rules as detailed above
and gives priority to more serious outcomes.
For pooled analyses, the first (most serious) outcome is used, which may
differ from the effect a paper focuses on.
Other outcomes are used in outcome specific analyses.
| Bryan, 6/24/2023, Double Blind Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, 3 authors, study period 1 November, 2020 - 30 November, 2022, trial NCT04601077 (history). | risk of progression, 0.8% higher, RR 1.01, p = 1.00, treatment 3 of 261 (1.1%), control 3 of 263 (1.1%), combined hospitalization, ICU admission, intubation, dialysis, and death. |
| recovery time, 11.2% lower, relative time 0.89, p = 0.30, treatment 261, control 263. | |
| Tandon, 6/29/2022, Double Blind Randomized Controlled Trial, placebo-controlled, India, peer-reviewed, 10 authors, study period 10 August, 2021 - 25 January, 2022, trial CTRI/2021/08. | 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 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, 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 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 (±0.14) n=64, control mean 2.1 (±0.14) n=69, mITT high risk, day 8. | |
| viral load, 13.5% lower, relative load 0.86, p < 0.001, treatment mean 2.51 (±0.11) n=105, control mean 2.17 (±0.12) 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. | |
| Winchester, 5/13/2021, Double Blind Randomized Controlled Trial, placebo-controlled, United Kingdom, peer-reviewed, 4 authors, study period 15 December, 2020 - 31 March, 2021. | 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. |
Effect extraction follows pre-specified rules as detailed above
and gives priority to more serious outcomes.
For pooled analyses, the first (most serious) outcome is used, which may
differ from the effect a paper focuses on.
Other outcomes are used in outcome specific analyses.
| Al Sulaiman, 10/3/2022, retrospective, Saudi Arabia, peer-reviewed, mean age 62.5, 29 authors, study period 1 March, 2020 - 31 July, 2021. | risk of death, 40.0% higher, HR 1.40, p = 0.10, treatment 44 of 56 (78.6%), control 52 of 125 (41.6%), adjusted per study, in-hospital mortality, multivariable, Cox proportional hazards. |
| risk of death, 18.0% higher, HR 1.18, p = 0.45, treatment 41 of 56 (73.2%), control 44 of 122 (36.1%), adjusted per study, multivariable, Cox proportional hazards, day 30. | |
| Chandel, 1/31/2021, retrospective, USA, peer-reviewed, 14 authors, study period 1 March, 2020 - 9 June, 2020. | 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 per study, odds ratio converted to relative risk, 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 per study, odds ratio converted to relative risk, multivariable. | |
| Di Fenza, 12/15/2023, Single Blind Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, 54 authors, study period 22 March, 2020 - 21 May, 2021, trial NCT04306393 (history). | risk of death, 23.0% lower, RR 0.77, p = 0.36, treatment 94, control 99, including additional covariates with SMD > 0.20, day 90, Table E1. |
| risk of death, 26.0% lower, RR 0.74, p = 0.36, treatment 94, control 99, including additional covariates with SMD > 0.20, day 28, Table E1. | |
| risk of death, 13.0% lower, RR 0.87, p = 0.60, treatment 94, control 99, day 90. | |
| risk of death, 15.0% lower, RR 0.85, p = 0.56, treatment 94, control 99, day 28. | |
| VV-ECMO, 30.0% lower, RR 0.70, p = 0.67, treatment 94, control 99. | |
| neurological symptoms, 83.0% lower, RR 0.17, p = 0.01, treatment 94, control 99, day 90. | |
| Moni, 4/20/2021, Randomized Controlled Trial, India, peer-reviewed, 16 authors, study period September 2020 - December 2020, average treatment delay 6.78 days, trial ISRCTN16806663. | 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 (with reciprocal of the contrasting arm), 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 (with reciprocal of the contrasting arm), 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 per study, inverted to make RR<1 favor treatment, odds ratio converted to relative risk, day 14. | |
| time to viral load reduction, 64.4% lower, RR 0.36, p = 0.005, treatment 14, control 11, adjusted per study, 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 per study, inverted to make RR<1 favor treatment, Orf1ab gene. | |
| Poonam, 6/27/2022, retrospective, USA, peer-reviewed, 5 authors, study period 1 March, 2020 - 30 June, 2020, this trial compares with another treatment - results may be better when compared to placebo. | risk of death, 13.6% lower, RR 0.86, p = 0.10, treatment 32 of 41 (78.0%), control 56 of 62 (90.3%), NNT 8.1. |
| Strickland, 5/4/2022, Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, 8 authors. | risk of mechanical ventilation, 178.9% higher, RR 2.79, p = 1.00, treatment 1 of 19 (5.3%), control 0 of 15 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm). |
| risk of hospitalization, 21.1% lower, RR 0.79, p = 1.00, treatment 1 of 19 (5.3%), control 1 of 15 (6.7%), NNT 71. | |
| return to ER, 38.2% higher, RR 1.38, p = 0.72, treatment 7 of 19 (36.8%), control 4 of 15 (26.7%). | |
| Valsecchi, 7/7/2022, retrospective, Israel, peer-reviewed, 20 authors, study period March 2020 - December 2021. | 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 (with reciprocal of the contrasting arm). |
| 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. | |
| Wolak, 7/26/2024, Randomized Controlled Trial, Israel, peer-reviewed, 7 authors. | oxygen support time, 64.3% lower, HR 0.36, p = 0.03, treatment 16, control 19, inverted to make HR<1 favor treatment, Cox proportional hazards. |
| time to SpO2≥93, 81.5% lower, HR 0.19, p = 0.049, treatment 16, control 19, inverted to make HR<1 favor treatment, Cox proportional hazards. | |
| hospitalization time, 41.2% lower, HR 0.59, p = 0.24, treatment 16, control 19, inverted to make HR<1 favor treatment, Cox proportional hazards. |
Effect extraction follows pre-specified rules as detailed above
and gives priority to more serious outcomes.
For pooled analyses, the first (most serious) outcome is used, which may
differ from the effect a paper focuses on.
Other outcomes are used in outcome specific analyses.
| SaNOtize, 4/30/2022, retrospective, Thailand, preprint, 1 author. | 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. |
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