Iota-carrageenan for COVID-19: real-time meta analysis of 1 study
Abstract
Statistically significant lower risk is seen for cases.
Meta analysis using the most serious outcome reported shows
80% [22‑95%] lower risk.
Currently there is very limited data, with only one study to date.
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.
Carvallo et al. has been excluded due to combined treatments that may significantly contribute to efficacy.
All data to reproduce this paper and
sources are in the appendix.
Highlights
Iota-carrageenan reduces
risk for COVID-19 with low confidence for cases and in pooled analysis.
We show traditional outcome specific analyses and combined
evidence from all studies.
Real-time updates and corrections,
transparent analysis with all results in the same format, consistent protocol
for 66
treatments.
Naso/oropharyngeal treatments
AlkalinizationCetylpyridin..
Chlorhexidine
Hydrogen Per..
Iota-carragee..
Nitric Oxide
Phthalocyanine
Povidone-Iod..
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
cavity Dai.
Progression may lead to cytokine storm, pneumonia, ARDS, neurological issues
Duloquin, Hampshire, Scardua-Silva, Yang, cardiovascular complications
Eberhardt, organ failure, and death. Minimizing replication as early
as possible is recommended.
Logically, stopping replication in the upper respiratory tract should be
simpler and more effective.
Early or prophylactic nasopharyngeal/oropharyngeal treatment can 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 factors Note A, Malone, Murigneux, Lv, Lui, Niarakis, providing many
therapeutic targets for which many existing compounds have known activity.
Scientists have predicted that over 7,000 compounds may
reduce COVID-19 risk c19early.org, either by
directly minimizing infection or replication, by supporting immune system
function, or by minimizing secondary complications.
Studies have shown efficacy with iota-carrageenan for coronavirus OC43 or 229E Hemilä, influenza A Hemilä, and rhinovirus Hemilä.
We analyze all significant
controlled studies of
iota-carrageenan
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, individual outcomes, and Randomized Controlled Trials (RCTs).
Figure 2 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 2. Treatment stages.
10 In Vitro studies support the efficacy of iota-carrageenan Alsaidi, Bansal, Bovard, Fröba, Meister, Morokutti-Kurz, Morokutti-Kurz (B), Setz, Song, Varese.
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 studies and for Randomized Controlled Trials.
Figure 3 and 4
show forest plots for random effects meta-analysis of
all studies with pooled effects and cases.
Improvement | Studies | Patients | Authors | |
---|---|---|---|---|
All studies | 80% [22‑95%] * | 1 | 394 | 18 |
Randomized Controlled TrialsRCTs | 80% [22‑95%] * | 1 | 394 | 18 |
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Figure 5 shows a forest plot for random
effects meta-analysis of all Randomized Controlled Trials.
RCT results are included in Table 1.
Currently there is only one study which is an RCT.
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1 iota-carrageenan
RCT has not reported results Jessop.
The trial reports
total actual enrollment of 480 patients.
The result is delayed over 1 year.
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 hours McLean, Treanor.
Baloxavir 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 cases Ikematsu |
<24 hours | -33 hours symptoms Hayden |
24-48 hours | -13 hours symptoms Hayden |
Inpatients | -2.5 hours to improvement Kumar |
Figure 6 shows a mixed-effects meta-regression for efficacy
as a function of treatment delay in COVID-19 studies from 66 treatments, showing
that efficacy declines rapidly with treatment delay. Early treatment is
critical for COVID-19.
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Figure 6. Early treatment is more effective. Meta-regression showing efficacy as a function of treatment delay in COVID-19 studies from 66 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 (as in
López-Medina et al.).
Efficacy may
differ significantly depending on the effect measured, for example a treatment
may be very effective at reducing mortality, but less effective at minimizing
cases or hospitalization. Or a treatment may have no effect on viral clearance
while still being effective at reducing mortality.
Efficacy may
depend critically on the distribution of SARS-CoV-2 variants encountered by
patients. Risk varies significantly across variants Korves, for
example the Gamma variant shows significantly different characteristics
Faria, Karita, Nonaka, Zavascki. 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 variants
Peacock, Willett.
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 kinds of treatment such as prone positioning.
Treatments may be synergistic Alsaidi, Andreani, De Forni, Fiaschi, Jeffreys, Jitobaom, Jitobaom (B), Ostrov, Said, Thairu, Wan, 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.
We present both pooled analyses and specific outcome analyses. Notably, pooled
analysis often results in earlier detection of efficacy as shown in
Figure 7. For many COVID-19 treatments, a reduction in mortality
logically follows from a reduction in hospitalization, which follows from a
reduction in symptomatic cases, etc. An antiviral tested with a low-risk
population may report zero mortality in both arms, however a reduction in
severity and improved viral clearance may translate into lower mortality among
a high-risk population, and including these results in pooled analysis allows
faster detection of efficacy. Trials with high-risk patients may also be
restricted due to ethical concerns for treatments that are known or expected
to be effective.
Pooled analysis enables using more of the available
information. While there is much more information available, for example
dose-response relationships, the advantage of the method used here is
simplicity and transparency. Note that pooled analysis could hide efficacy,
for example a treatment that is beneficial for late stage patients but has no
effect on viral replication or early stage disease could show no efficacy in
pooled analysis if most studies only examine viral clearance.
While we present pooled results, we also present individual
outcome analyses, which may be more informative for specific use cases.
Currently, 44 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. 85% of treatments showing statistically significant efficacy/harm with pooled effects have been confirmed with one or more specific outcomes, with a mean delay of 3.7 months. When restricting to RCTs only, 50% of treatments showing statistically significant efficacy/harm with pooled effects have been confirmed with one or more specific outcomes, with a mean delay of 6.1 months.
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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. This may have a greater effect than
pooling different outcomes such as mortality and hospitalization. For example
a treatment may have 50% efficacy for mortality but only 40% for
hospitalization when used within 48 hours. However efficacy could be 0% when
used late.
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.
Studies have also shown efficacy with iota-carrageenan for coronavirus OC43 or 229E Hemilä, influenza A Hemilä, and rhinovirus Hemilä.
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 3 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 | 54% [42‑63%] | 11 |
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 roles. This may be
especially important for prolonged use or overuse.
Table 4 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 results
Boulware, Meeus, Meneguesso.
For iota-carrageenan, there is currently not
enough data to evaluate publication bias with high confidence.
Pharmaceutical drug
trials often have conflicts of interest whereby sponsors or trial staff have a
financial interest in the outcome being positive. Iota-carrageenan for COVID-19
lacks this because it is off-patent, has multiple manufacturers, and is very low cost.
In contrast, most COVID-19 iota-carrageenan 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 iota-carrageenan 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 by 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 affiliated with special interests 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 alone Alsaidi, Andreani, De Forni, Fiaschi, Jeffreys, Jitobaom, Jitobaom (B), Ostrov, Said, Thairu, Wan.
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, vaccine, 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 1 studies
combine treatments. The results of
iota-carrageenan
alone may differ.
None of the RCTs use combined treatment.
Currently all studies are peer-reviewed.
SARS-CoV-2 infection and replication involves a complex interplay of 50+ host
and viral proteins and other factors Lui, Lv, Malone, Murigneux, Niarakis,
providing many therapeutic targets.
Over 7,000 compounds have been predicted to reduce COVID-19
risk, either by directly minimizing infection or replication, by supporting
immune system function, or by minimizing secondary complications.
Figure 8 shows an overview of the results for iota-carrageenan
in the context of multiple COVID-19 treatments, and Figure 9 shows a plot
of efficacy vs. cost for COVID-19 treatments.
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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.
Studies to date show that iota-carrageenan is
an effective treatment for COVID-19.
Statistically significant lower risk is seen for cases.
Meta analysis using the most serious outcome reported shows
80% [22‑95%] lower risk.
Currently there is very limited data, with only one study to date.
Carvallo et al. has been excluded due to combined treatments that may significantly contribute to efficacy.
Figueroa:
Prophylaxis RCT with 394 healthcare workers, 196 treated with iota-carrageenan, showing significantly lower symptomatic cases with treatment. There were no deaths or hospitalizations. There was a significant number of PCR- symptomatic cases (7.6% treatment and 8.6% control). The two treatment cases occurred shortly after randomization - infection may have occurred before the start of treatment.
Jessop:
480 participant iota-carrageenan prophylaxis RCT with results not reported over 1 year after completion.
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 iota-carrageenan 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 iota-carrageenan 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 to Zhang.
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 1 Sweeting.
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
(3.12.2) with
scipy (1.12.0), pythonmeta (1.26), numpy (1.26.4), statsmodels (0.14.1), and plotly (5.19.0).
Forest plots are computed using PythonMeta Deng
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 (4.1.2) using the metafor
(3.0-2) and rms (6.2-0) 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 effective
McLean, Treanor.
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/gmeta.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.
Carvallo (B), 11/17/2020, prospective, Argentina, peer-reviewed, 4 authors, this trial uses multiple treatments in the treatment arm (combined with ivermectin) - results of individual treatments may vary, excluded: combined treatment may significantly contribute to efficacy, concern about potential data issues. | risk of case, 99.9% lower, RR 0.001, p < 0.001, treatment 0 of 788 (0.0%), control 237 of 407 (58.2%), NNT 1.7, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm). |
Figueroa, 4/15/2021, Double Blind Randomized Controlled Trial, Argentina, peer-reviewed, 18 authors, study period 24 July, 2020 - 20 December, 2020, trial NCT04521322 (history) (CARR-COV-02). | risk of symptomatic case, 80.2% lower, RR 0.20, p = 0.03, treatment 2 of 196 (1.0%), control 10 of 198 (5.1%), NNT 25, odds ratio converted to relative risk. | Jessop, 11/18/2022, Double Blind Randomized Controlled Trial, placebo-controlled, United Kingdom, trial NCT04590365 (history) (ICE-COVID). | 480 patient RCT with results unknown and over 1 year late. |
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