Bromhexine for COVID-19: real-time meta analysis of 7 studies
Abstract
Significantly lower risk is seen for ventilation and ICU admission. 3 studies from 3 independent teams in 2 countries show significant
benefit.
Meta analysis using the most serious outcome reported shows
43% [-5‑69%] lower risk, without reaching statistical significance. Results are similar for peer-reviewed studies.
Early treatment is more effective than late treatment. Currently all studies are RCTs.
Bromhexine efficacy may vary depending on the degree of TMPRSS-dependent fusion for different variants3,4.
Bromhexine for COVID-19 — Highlights
Bromhexine reduces
risk with low confidence for mortality, ventilation, ICU admission, cases, and in pooled analysis, and very low confidence for recovery, however increased risk is seen with very low confidence for viral clearance.
Efficacy may vary depending on the degree of TMPRSS-dependent fusion for different variants.
Real-time updates
and corrections with a consistent protocol for 112 treatments. Outcome specific analysis and combined evidence from all
studies including treatment delay, a primary confounding factor.
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 bromhexine studies.
SARS-CoV-2 infection primarily begins in the upper respiratory
tract and may progress to the lower respiratory tract, other tissues, and the
nervous and cardiovascular systems, which may lead to cytokine storm,
pneumonia, ARDS, neurological injury5-16 and
cognitive deficits8,13, cardiovascular
complications17-20, organ failure, and death.
Minimizing replication as early as possible is recommended.
SARS-CoV-2 infection and replication involves the complex interplay of 50+
host and viral proteins and other factorsA,21-27, providing many
therapeutic targets for which many existing compounds have known activity.
Scientists have predicted that over 8,000 compounds may
reduce COVID-19 risk28, either by
directly minimizing infection or replication, by supporting immune system
function, or by minimizing secondary complications.
In Silico studies predict inhibition of SARS-CoV-2 with bromhexine or metabolites via binding to the spikeB,29, MproC,29, RNA-dependent RNA polymeraseD,29, and TMPRSS2E,30 proteins.
In Vitro studies demonstrate inhibition of the TMPRSS2E,31 and acid sphingomyelinaseF,32 proteins.
Bromhexine is a mucolytic agent that helps thin mucus
secretions in the respiratory tract and has been shown to have antiviral
properties against respiratory viruses.
Bromhexine inhibits the expression of TMPRSS2 which plays an important role in SARS-CoV-2 cell entry and replication30,31,33 and bromhexine metabolite ambroxol inhibits SARS-CoV-2 via inhibition of acid sphingomyelinase in epithelial cells32.
We analyze all significant
controlled studies of
bromhexine
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 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.
In Silico studies predict inhibition of SARS-CoV-2 with bromhexine or metabolites via binding to the spikeB,29, MproC,29, RNA-dependent RNA polymeraseD,29, and TMPRSS2E,30 proteins.
In Vitro studies demonstrate inhibition of the TMPRSS2E,31 and acid sphingomyelinaseF,32 proteins.
Bromhexine inhibits the expression of TMPRSS2 which plays an important role in SARS-CoV-2 cell entry and replication30,31,33 and bromhexine metabolite ambroxol inhibits SARS-CoV-2 via inhibition of acid sphingomyelinase in epithelial cells32.
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, and for specific outcomes.
Table 2 shows results by treatment stage.
Figure 3 plots individual results by treatment stage.
Figure 4, 5, 6, 7, 8, 9, 10, 11, and 12
show forest plots for random effects meta-analysis of
all studies with pooled effects, mortality results, ventilation, ICU admission, hospitalization, recovery, cases, viral clearance, and peer reviewed studies.
| Improvement | Studies | Patients | Authors | |
|---|---|---|---|---|
| All studies | 43% [-5‑69%] | 7 | 875 | 110 |
| Peer-reviewed studiesPeer-reviewed | 54% [-4‑79%] | 6 | 503 | 94 |
| Randomized Controlled TrialsRCTs | 43% [-5‑69%] | 7 | 875 | 110 |
| Mortality | 77% [-39‑96%] | 3 | 550 | 34 |
| HospitalizationHosp. | 10% [-8‑24%] | 4 | 679 | 82 |
| Recovery | 46% [-39‑79%] | 3 | 181 | 68 |
| Cases | 62% [-11‑87%] | 2 | 422 | 24 |
| Viral | -24% [-131‑34%] | 3 | 321 | 65 |
| RCT mortality | 77% [-39‑96%] | 3 | 550 | 34 |
| RCT hospitalizationRCT hosp. | 10% [-8‑24%] | 4 | 679 | 82 |
| Early treatment | Late treatment | Prophylaxis | |
|---|---|---|---|
| All studies | 84% [-35‑98%] | 44% [-48‑78%] | 65% [-212‑96%] |
| Peer-reviewed studiesPeer-reviewed | 84% [-35‑98%] | 44% [-48‑78%] | 80% [-297‑99%] |
| Randomized Controlled TrialsRCTs | 84% [-35‑98%] | 44% [-48‑78%] | 65% [-212‑96%] |
| Mortality | 91% [-59‑99%] | 76% [-703‑99%] | 33% [-946‑96%] |
| HospitalizationHosp. | 67% [-694‑99%] | 8% [-9‑23%] | 74% [-46‑95%] |
| Recovery | 71% [-168‑97%] | 43% [-86‑83%] | |
| Cases | 62% [-11‑87%] | ||
| Viral | -7% [-77‑36%] | 30% [-713‑94%] | |
| RCT mortality | 91% [-59‑99%] | 76% [-703‑99%] | 33% [-946‑96%] |
| RCT hospitalizationRCT hosp. | 67% [-694‑99%] | 8% [-9‑23%] | 74% [-46‑95%] |
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Figure 3. 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 4. 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 5. Random effects meta-analysis for mortality results.
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Figure 6. Random effects meta-analysis for ventilation.
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Figure 7. Random effects meta-analysis for ICU admission.
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Figure 8. Random effects meta-analysis for hospitalization.
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Figure 9. Random effects meta-analysis for recovery.
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Figure 10. Random effects meta-analysis for cases.
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Figure 11. Random effects meta-analysis for viral clearance.
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Figure 12. 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.
Currently all studies are RCTs.
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 hours36,37. 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 cases38 |
| <24 hours | -33 hours symptoms39 |
| 24-48 hours | -13 hours symptoms39 |
| Inpatients | -2.5 hours to improvement40 |
Figure 13 shows a mixed-effects meta-regression for efficacy
as a function of treatment delay in COVID-19 studies from 112 treatments, showing
that efficacy declines rapidly with treatment delay. Early treatment is
critical for COVID-19.
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Figure 13. Early treatment is more effective. Meta-regression showing efficacy as a function of treatment delay in COVID-19 studies from 112 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
variants42, for example the Gamma variant shows significantly
different characteristics43-46. 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 variants3,4.
Effectiveness may depend strongly on the dosage and treatment regimen.
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.
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.
Pooling the results of studies reporting different outcomes allows us to use
more of the available information. Logically we should, and do, use additional
information when evaluating treatments—for example dose-response and
treatment delay-response relationships provide additional evidence of efficacy
that is considered when reviewing the evidence for a treatment.
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.
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 and safer 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 112
treatments we cover confirms the validity of pooled outcome analysis for COVID-19.
Figure 14 shows that lower hospitalization is very strongly associated
with lower mortality (p < 0.000000000001).
Similarly, Figure 15 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 16 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 = 0.00000032 to p = 0.000000011.
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Figure 14. Lower hospitalization is associated with lower mortality, supporting pooled outcome analysis.
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Figure 15. Improved recovery is associated with lower mortality, supporting pooled outcome analysis.
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Figure 14. 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 5.0 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 17 shows when treatments were found effective during the
pandemic. Pooled outcomes often resulted in earlier detection of efficacy.
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Figure 17. 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.
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 results62-65.
For bromhexine, there is currently not
enough data to evaluate publication bias with high confidence.
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 18 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 < 0.0567-74.
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 18. 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. Bromhexine for COVID-19
lacks this because it is off-patent, has multiple manufacturers, and is very low cost.
In contrast, most COVID-19 bromhexine 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 bromhexine 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 alone49-60.
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.
3 of 7 studies
combine treatments. The results of
bromhexine
alone may differ.
3 of 7 RCTs use combined treatment.
SARS-CoV-2 infection and replication involves a complex
interplay of 50+ host and viral proteins and other
factors21-27, providing many therapeutic
targets.
Over 8,000 compounds have been predicted to reduce COVID-19
risk28, either by directly
minimizing infection or replication, by supporting immune system function, or
by minimizing secondary complications.
Figure 19 shows an overview of the results for bromhexine
in the context of multiple COVID-19 treatments, and Figure 20 shows a plot
of efficacy vs. cost for COVID-19 treatments.
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Figure 19.
Scatter plot showing results within the context of multiple COVID-19 treatments.
Diamonds shows the results of random effects meta-analysis.
0.5% of 8,000+ proposed treatments show efficacy78.
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Figure 20. Efficacy vs. cost for COVID-19 treatments.
Significantly lower risk is seen for ventilation and ICU admission. 3 studies from 3 independent teams in 2 countries show significant
benefit.
Meta analysis using the most serious outcome reported shows
43% [-5‑69%] lower risk, without reaching statistical significance. Results are similar for peer-reviewed studies.
Early treatment is more effective than late treatment. Currently all studies are RCTs.
RCT with 39 bromhexine and 39 control patients showing lower mortality, intubation, and ICU admission with treatment. The treatment group received bromhexine hydrochloride 8 mg three times a day for two weeks. All patients received SOC including HCQ.
Estimated 214 participant bromhexine + HCQ prophylaxis RCT with results not reported over 3 years after estimated completion.
Tiny RCT with 12 bromhexine and 6 control patients showing non-statistically significant improvements in chest CT, need for oxygen therapy, and discharge rate within 20 days. Authors recommend a larger scale trial.
Prospective 103 PCR+ patients in Russia, 33 treated with bromexhine+spironolactone, showing lower PCR+ at day 10 or hospitalization >10 days with treatment. Bromhexine 8mg 4 times daily, spironolactone 25-50 mg/day for 10 days.
Estimated 90 patient bromhexine + HCQ late treatment RCT with results not reported over 4 years after estimated completion.
Small prophylaxis RCT with 25 treatment and 25 control health care workers, showing lower PCR+, symptomatic cases, and hospitalization with treatment, although not statistically significant with the small sample size.
PEP RCT with 372 close contacts of COVID+ patients, 187 treated with bromhexine, showing significantly lower cases with treatment. IRCT20120703010178N22.
Small RCT with 100 patients, 48 with bromhexine added to SOC, showing slower viral- conversion but lower mortality and greater clinical improvement with bromhexine (not statistically significant with few deaths and very high recovery). The very large difference between unadjusted and adjusted results is due to much higher risk for patients with renal disease and the much higher prevalence of renal disease in the bromhexine group.
The study also shows 90% of patients in the control group had BMI>=30 compared to 0% in the treatment group, suggesting a possible problem with randomization. Due to the imbalance between groups, results were adjusted for BMI>30, smoking, and renal disease.
11 patients were lost to followup in the treatment group compared to zero in the control group, perhaps in part due to faster recovery in the treatment group. 9 patients were excluded from the treatment group because they did not want to take bromhexine after discharge. Therefore up to 29% of treatment patients may have been excluded because they recovered quickly.
The study also shows 90% of patients in the control group had BMI>=30 compared to 0% in the treatment group, suggesting a possible problem with randomization. Due to the imbalance between groups, results were adjusted for BMI>30, smoking, and renal disease.
11 patients were lost to followup in the treatment group compared to zero in the control group, perhaps in part due to faster recovery in the treatment group. 9 patients were excluded from the treatment group because they did not want to take bromhexine after discharge. Therefore up to 29% of treatment patients may have been excluded because they recovered quickly.
RCT 191 low risk (no mortality) outpatients in Spain, showing no significant differences with bromhexine. Authors note that "statistical differences between the study groups were observed in the percentage of patients treated with bronchodilators (p = 0.033) and receiving symptomatic treatment (p = 0.034), which were higher in the SOC alone group", but do not provide details or perform adjustments. There were more moderate/severe cases in the treatment group (9 vs. 5).
Many results appear to be missing including: reduction in the severity of each symptom (0–10 NRS score) at days 4, 7, 14, and 28 as compared with baseline; proportion of patients with clinical improvement and time to clinical improvement; proportion of patients with disappearance of each symptom at days 4, 7, 14, and 28, and time to disappearance; proportion of asymptomatic patients at days 4, 7, 14, and 28.
Bromhexine 48 mg/day for seven days. SOC included acetaminophen.
Many results appear to be missing including: reduction in the severity of each symptom (0–10 NRS score) at days 4, 7, 14, and 28 as compared with baseline; proportion of patients with clinical improvement and time to clinical improvement; proportion of patients with disappearance of each symptom at days 4, 7, 14, and 28, and time to disappearance; proportion of asymptomatic patients at days 4, 7, 14, and 28.
Bromhexine 48 mg/day for seven days. SOC included acetaminophen.
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 bromhexine 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 bromhexine 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 to79.
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 182.
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
(3.13.1) 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 PythonMeta83
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 effective36,37.
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/bmeta.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.
| Ansarin, 7/19/2020, Randomized Controlled Trial, Iran, peer-reviewed, 11 authors, study period 18 April, 2020 - 19 May, 2020. | risk of death, 90.9% lower, RR 0.09, p = 0.05, treatment 0 of 39 (0.0%), control 5 of 39 (12.8%), NNT 7.8, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm). |
| risk of mechanical ventilation, 88.9% lower, RR 0.11, p = 0.01, treatment 1 of 39 (2.6%), control 9 of 39 (23.1%), NNT 4.9. | |
| risk of ICU admission, 81.8% lower, RR 0.18, p = 0.01, treatment 2 of 39 (5.1%), control 11 of 39 (28.2%), NNT 4.3. | |
| Vila Méndez, 12/24/2022, Randomized Controlled Trial, Spain, peer-reviewed, 38 authors, study period 24 February, 2022 - 28 July, 2022, trial EudraCT2021-001227-41. | risk of oxygen therapy, 67.3% lower, RR 0.33, p = 0.49, treatment 0 of 98 (0.0%), control 1 of 93 (1.1%), NNT 93, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm). |
| risk of hospitalization, 67.3% lower, RR 0.33, p = 0.49, treatment 0 of 98 (0.0%), control 1 of 93 (1.1%), NNT 93, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm). | |
| risk of no recovery, 71.2% lower, RR 0.29, p = 0.33, treatment 1 of 52 (1.9%), control 3 of 45 (6.7%), NNT 21, dyspnea. | |
| risk of no recovery, 186.5% higher, RR 2.87, p = 1.00, treatment 1 of 52 (1.9%), control 0 of 45 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), fever. | |
| viral load, 6.6% higher, relative load 1.07, p = 0.82, treatment mean 13.54 (±26.02) n=98, control mean 14.43 (±26.94) n=93, relative change in ORF1ab Ct value, day 4, primary outcome. | |
| viral load, 17.4% lower, relative load 0.83, p = 0.60, treatment mean 6.36 (±17.05) n=98, control mean 7.7 (±18.47) n=93, relative change in N Ct value, day 4, primary outcome. | |
| viral load, 41.5% higher, relative load 1.41, p = 0.32, treatment mean 9.74 (±29.54) n=98, control mean 13.78 (±26.81) n=93, relative change in S Ct value, day 4, primary outcome. | |
| risk of no viral clearance, 13.4% lower, RR 0.87, p = 0.31, treatment 52 of 98 (53.1%), control 57 of 93 (61.3%), NNT 12, day 14. | |
| risk of no viral clearance, 13.6% higher, RR 1.14, p = 0.21, treatment 73 of 98 (74.5%), control 61 of 93 (65.6%), day 7. |
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.
| Li, 9/3/2020, Randomized Controlled Trial, China, peer-reviewed, 10 authors, study period 16 February, 2020 - 10 May, 2020, trial NCT04273763 (history). | risk of no hospital discharge, 75.0% lower, RR 0.25, p = 0.11, treatment 2 of 12 (16.7%), control 4 of 6 (66.7%), NNT 2.0. |
| risk of oxygen therapy, 50.0% lower, RR 0.50, p = 0.57, treatment 2 of 12 (16.7%), control 2 of 6 (33.3%), NNT 6.0. | |
| Mareev, 12/3/2020, Randomized Controlled Trial, Russia, peer-reviewed, 20 authors, this trial uses multiple treatments in the treatment arm (combined with spironolactone) - results of individual treatments may vary, trial NCT04424134 (history). | relative SHOKS-COVID score, 11.3% better, RR 0.89, p = 0.47, treatment mean 2.12 (±1.39) n=33, control mean 2.39 (±1.59) n=33. |
| risk of PCR+ on day 10 or hospitalization >10 days, 38.8% lower, RR 0.61, p = 0.02, treatment 14 of 24 (58.3%), control 20 of 21 (95.2%), NNT 2.7, odds ratio converted to relative risk. | |
| hospitalization time, 8.2% lower, relative time 0.92, p = 0.35, treatment 33, control 33. | |
| risk of no viral clearance, 87.4% lower, RR 0.13, p = 0.08, treatment 0 of 17 (0.0%), control 3 of 13 (23.1%), NNT 4.3, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 10. | Mežnar, 7/31/2020, Randomized Controlled Trial, this trial uses multiple treatments in the treatment arm (combined with HCQ) - results of individual treatments may vary, trial NCT04355026 (history). | Estimated 90 patient RCT with results unknown and over 4 years late. |
| Tolouian, 3/15/2021, Randomized Controlled Trial, Iran, peer-reviewed, 7 authors. | risk of death, 76.0% lower, OR 0.24, p = 0.43, treatment 48, control 52, adjusted per study, Table 3, RR approximated with OR. |
| risk of no improvement, 75.9% better, OR 0.24, p = 0.43, treatment 48, control 52, adjusted per study, inverted to make OR<1 favor treatment, Table 2, RR approximated with OR. | |
| risk of no viral clearance, 74.5% higher, RR 1.75, p = 0.02, treatment 29 of 48 (60.4%), control 18 of 52 (34.6%), mid-recovery day 7. |
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.
| Granados-Montiel, 6/30/2021, Double Blind Randomized Controlled Trial, placebo-controlled, Mexico, peer-reviewed, this trial uses multiple treatments in the treatment arm (combined with HCQ) - results of individual treatments may vary, trial NCT04340349 (history) (ELEVATE). | Estimated 214 patient RCT with results unknown and over 3 years late. |
| Mikhaylov, 3/8/2021, Randomized Controlled Trial, Russia, peer-reviewed, 8 authors, study period 13 May, 2020 - 25 July, 2020, trial NCT04405999 (history). | risk of hospitalization, 80.0% lower, RR 0.20, p = 0.49, treatment 0 of 25 (0.0%), control 2 of 25 (8.0%), NNT 12, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm). |
| risk of symptomatic case, 90.9% lower, RR 0.09, p = 0.05, treatment 0 of 25 (0.0%), control 5 of 25 (20.0%), NNT 5.0, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm). | |
| risk of case, 71.4% lower, RR 0.29, p = 0.14, treatment 2 of 25 (8.0%), control 7 of 25 (28.0%), NNT 5.0, primary outcome. | |
| Tolouian (B), 12/20/2021, Double Blind Randomized Controlled Trial, placebo-controlled, Iran, preprint, 16 authors, study period 21 December, 2020 - 25 July, 2021. | risk of death, 32.9% lower, RR 0.67, p = 0.76, treatment 0 of 187 (0.0%), control 1 of 185 (0.5%), odds ratio converted to relative risk, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm). |
| risk of hospitalization, 70.3% lower, RR 0.30, p = 0.14, treatment 1 of 187 (0.5%), control 6 of 185 (3.2%), adjusted per study, odds ratio converted to relative risk. | |
| risk of symptomatic case, 53.0% lower, RR 0.47, p = 0.007, treatment 16 of 187 (8.6%), control 34 of 185 (18.4%), NNT 10, odds ratio converted to relative risk. | |
| risk of case, 50.2% lower, RR 0.50, p = 0.03, treatment 13 of 187 (7.0%), control 26 of 185 (14.1%), NNT 14, odds ratio converted to relative risk. |
Viral infection and replication involves attachment, entry, uncoating and release, genome replication and transcription, translation and protein processing, assembly and budding, and release. Each step can be disrupted by therapeutics.
The trimeric spike (S) protein is a glycoprotein that mediates viral entry by binding to the host ACE2 receptor, is critical for SARS-CoV-2's ability to infect host cells, and is a target of neutralizing antibodies. Inhibition of the spike protein prevents viral attachment, halting infection at the earliest stage.
The main protease or Mpro, also known as 3CLpro or nsp5, is a cysteine protease that cleaves viral polyproteins into functional units needed for replication. Inhibiting Mpro disrupts the SARS-CoV-2 lifecycle within the host cell, preventing the creation of new copies.
RNA-dependent RNA polymerase (RdRp), also called nsp12, is the core enzyme of the viral replicase-transcriptase complex that copies the positive-sense viral RNA genome into negative-sense templates for progeny RNA synthesis. Inhibiting RdRp blocks viral genome replication and transcription.
Transmembrane protease serine 2 (TMPRSS2) is a host cell protease that primes the spike protein, facilitating cellular entry. TMPRSS2 activity helps enable cleavage of the spike protein required for membrane fusion and virus entry. Inhibition may especially protect respiratory epithelial cells, buy may have physiological effects.
Acid sphingomyelinase (ASM) is a lysosomal enzyme that hydrolyzes sphingomyelin into ceramide and phosphorylcholine. ASM activity is upregulated by SARS-CoV-2 infection, leading to ceramide-enriched membrane domains that facilitate viral entry and replication. Inhibiting ASM may disrupt viral entry and reduce infection severity while potentially restoring membrane stability and immune homeostasis.
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