Bromhexine for COVID-19: real-time analysis of all 11 studies

Bromhexine for COVID-19: real-time meta analysis of 6 studies

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvements are seen for ventilation, ICU admission, and viral clearance. 4 studies from 4 independent teams in 3 different countries show statistically significant improvements in isolation (1 for the most serious outcome).

• Meta analysis using the most serious outcome reported shows 50% [-8‑77%] improvement, without reaching statistical significance. Results are similar for peer-reviewed studies. Early treatment is more effective than late treatment. Currently all studies are RCTs.

• Currently there is limited data, with only 684 patients and only 12 control events for the most serious outcome in trials to date.

• Bromhexine may be less effective for omicron due to the entry process moving towards TMPRSS2-independent fusion [Peacock, Willett].

• While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 50% of bromhexine studies show zero events in the treatment arm. Multiple treatments are typically used in combination, and other treatments may be more effective.

• No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used. Denying the efficacy of treatments increases mortality, morbidity, collateral damage, and endemic risk.

• All data to reproduce this paper and sources are in the appendix.

Covid Analysis et al., 6/22/2022, preprint, 1 author.

The SARS-CoV-2 variant, Omicron, shows rapid replication in human primary nasal epithelial cultures and efficiently uses the endosomal route of entry

Peacock et al., bioRxiv, doi:10.1101/2021.12.31.474653 (Preprint) (In Vitro)

In Vitro study showing that omicron can efficiently enter cells via the endosomal route, independent of TMPRSS2.

Peacock et al., 1/3/2022, preprint, 10 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

The hyper-transmissible SARS-CoV-2 Omicron variant exhibits significant antigenic change, vaccine escape and a switch in cell entry mechanism

Willett et al., medRxiv, doi:10.1101/2022.01.03.21268111 (Preprint) (In Vitro)

In Vitro study showing that the entry process for omicron has moved towards TMPRSS2-independent fusion, indicating that TMPRSS2 inhibitors may be less effective for omicron.

Willett et al., 1/3/2022, preprint, 38 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Bromhexine, for Post Exposure COVID-19 Prophylaxis: A Randomized, Double-Blind, Placebo Control Trial

Tolouian et al., SSRN, doi:10.2139/ssrn.3989 (Preprint)

PEP RCT with 372 close contacts of COVID+ patients, 187 treated with bromhexine, showing significantly lower cases with treatment. IRCT20120703010178N22.

risk of death, 32.9% lower, RR 0.67, p = 0.76, treatment 0 of 187 (0.0%), control 1 of 185 (0.5%), OR converted to RR, relative risk is not 0 because of continuity correction due to zero events.

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, OR converted to RR.

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, OR converted to RR.

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, OR converted to RR.

Tolouian et al., 12/20/2021, Double Blind Randomized Controlled Trial, placebo-controlled, Iran, Middle East, preprint, 16 authors.

Computational Identification of a Putative Allosteric Binding Pocket in TMPRSS2

Sgrignani et al., Frontiers in Molecular Biosciences, doi:10.3389/fmolb.2021.666626

In Silico study of TMPRSS2 inhibition by camostat, nafamostat, and bromhexine, suggesting allosteric binding for bromhexine, compared to camostat and nafamostat which bind to the active site of TMPRSS2 forming covalent adducts.

Sgrignani et al., 4/30/2021, peer-reviewed, 2 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Effect of bromhexine in hospitalized patients with COVID-19

Tolouian et al., J. Investig. Med., doi:10.1136/jim-2020-001747

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.

risk of death, 76.0% lower, OR 0.24, p = 0.43, treatment 48, control 52, Table 3, adjusted, RR approximated with OR.

risk of no improvement, 75.9% lower, OR 0.24, p = 0.43, treatment 48, control 52, Table 2, adjusted, RR approximated with OR.

risk of case, 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.

Tolouian et al., 3/15/2021, Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 7 authors.

Bromhexine Hydrochloride Prophylaxis of COVID-19 for Medical Personnel: A Randomized Open-Label Study

Mikhaylov et al., medRxiv, doi:10.1101/2021.03.03.21252855 (Preprint)

Small prophylaxis RCT with 25 treatment and 25 control health care worker, showing lower PCR+, symptomatic cases, and hospitalization with treatment, although not statistically significant with the small sample size.

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.

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.

risk of no viral clearance, 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.

Mikhaylov et al., 3/8/2021, Randomized Controlled Trial, Russia, Europe, preprint, 8 authors.

Inhibition of acid sphingomyelinase by ambroxol prevents SARS-CoV-2 entry into epithelial cells

Carpinteiro et al., Journal of Biological Chemistry, doi:10.1016/j.jbc.2021.100701 (In Vitro)

In Vitro study showing that ambroxol (a metabolite of bromhexine) inhibits SARS-CoV-2 infection.

Carpinteiro et al., 1/31/2021, peer-reviewed, 10 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

The potential role of Bromhexine in the management of COVID-19: Decipher and a real game-changer

Al-Kuraishy et al., Current Medical and Drug Research (Review) (Preprint)

Review article noting that bromhexine is a TMPRSS2 inhibitor with greater effect in lung tissue and attenuates the entry and proliferation of SARS‐CoV‐2.

Al-Kuraishy et al., 12/31/2020, preprint, 5 authors.

Results of Open-Label non-Randomized Comparative Clinical Trial: “BromhexIne and Spironolactone for CoronаvirUs Infection requiring hospiTalization (BISCUIT)

Mareev et al., Кардиология, doi:10.18087/cardio.2020.11.n1440

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.

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, OR converted to RR.

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, day 10.

Mareev et al., 12/3/2020, Randomized Controlled Trial, Russia, Europe, peer-reviewed, 20 authors, this trial uses multiple treatments in the treatment arm (combined with spironolactone) - results of individual treatments may vary.

Bromhexine Hydrochloride Tablets for the Treatment of Moderate COVID‐19: An Open‐Label Randomized Controlled Pilot Study

Li et al., Clinical and Translational Science, doi:10.1111/cts.12881

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.

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.

recovery time, 3.2% higher, relative time 1.03, treatment 12, control 6.

Li et al., 9/3/2020, Randomized Controlled Trial, China, Asia, peer-reviewed, 10 authors.

Effect of bromhexine on clinical outcomes and mortality in COVID-19 patients: A randomized clinical trial

Ansarin et al., Bioimpacts, doi:10.34172/bi.2020.27

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.

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.

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.

Ansarin et al., 7/19/2020, Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 11 authors.

Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy?

Depfenhart et al., Internal and Emergency Medicine, doi:10.1007/s11739-020-02383-3 (Theory)

Proposal to use bromhexine to inhibit TMPRSS2-specific viral entry for prophylaxis and treatment of COVID-19.

Depfenhart et al., 5/26/2020, peer-reviewed, 5 authors.

Possible use of the mucolytic drug, bromhexine hydrochloride, as a prophylactic agent against SARS-CoV-2 infection based on its action on the Transmembrane Serine Protease 2

Habtemariam et al., Pharmacol. Res., doi:10.1016/j.phrs.2020.104853 (Theory)

Note on the potential use of bromhexine hydrochloride for prophylaxis of SARS-CoV-2, based on the role of TMPRSS2 in SARS-CoV-2 infection, and the TMPRSS2 inhibition of bromhexine hydrochloride.

Habtemariam et al., 4/30/2020, peer-reviewed, 6 authors.

Repurposing the mucolytic cough suppressant and TMPRSS2 protease inhibitor bromhexine for the prevention and management of SARS-CoV-2 infection

Maggio et al., Pharmacol Res., doi:10.1016/j.phrs.2020.104837 (Review)

Proposal to use bromhexine for prophylaxis and treatment of COVID-19 based on TMPRSS2 inhibition, widespread clinical use, and supporting pharmacokinetic and safety data.

Maggio et al., 4/22/2020, peer-reviewed, 2 authors.

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibito

Hoffman et al., Cell, doi:10.1016/j.cell.2020.02.052 (In Vitro)

In Vitro study showing that SARS-CoV-2 uses ACE2 for entry and TMPRSS2 for S protein priming, and that TMPRSS2 inhibitor camostat blocked entry and may be an effective treaetment.

Hoffman et al., 3/5/2020, peer-reviewed, 13 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

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