Effect of bromhexine in hospitalized patients with COVID-19

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

Mar 2021

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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.

Bromhexine efficacy may vary depending on the degree of TMPRSS-dependent fusion for different variants Peacock, Willett.

Viral load measured by PCR may not accurately reflect infectious virus measured by viral culture. Porter show that viral load early in infection was correlated with infectious virus, but viral load late in infection could be high even with low or undetectable infectious virus. Assessing viral load later in infection may underestimate reductions in infectious virus with treatment.

1. Peacock et al., The SARS-CoV-2 variant, Omicron, shows rapid replication in human primary nasal epithelial cultures and efficiently uses the endosomal route of entry, bioRxiv, doi:10.1101/2021.12.31.474653.biorxiv.org, doi.org.

2. Porter et al., The ratio between SARS-CoV-2 RNA viral load and culturable viral titer differs depending on stage of infection, medRxiv, doi:10.1101/2023.07.06.23292300.medrxiv.org, doi.org.

3. Willett et al., The hyper-transmissible SARS-CoV-2 Omicron variant exhibits significant antigenic change, vaccine escape and a switch in cell entry mechanism, medRxiv, doi:10.1101/2022.01.03.21268111.medrxiv.org, doi.org.

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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 prioritizing more serious outcomes. Submit updates

Tolouian et al., 15 Mar 2021, Randomized Controlled Trial, Iran, peer-reviewed, 7 authors.

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Effect of bromhexine in hospitalized patients with COVID-19

Ramin Tolouian, Zuber D Mulla, Hamidreza Jamaati, Abdolreza Babamahmoodi, Majid Marjani, Raha Eskandari, Dr Farzaneh Dastan

Journal of Investigative Medicine, doi:10.1136/jim-2020-001747

Background Bromhexine is a potent inhibitor of transmembrane serine protease 2 and appears to have an antiviral effect in controlling influenza and parainfluenza infection; however, its efficacy in COVID-19 is controversial. Methods A group of hospitalized patients with confirmed COVID-19 pneumonia were randomized using 1:1 allocation to either standard treatment lopinavir/ritonavir and interferon beta-1a or bromhexine 8 mg four times a day in addition to standard therapy. The primary outcome was clinical improvement within 28 days, and the secondary outcome measures were time to hospital discharge, all-cause mortality, duration of mechanical ventilation, the temporal trend in 2019-nCoV reverse transcription-polymerase chain reaction positivity and the frequency of adverse drug events within 28 days from the start of medication. Results A total of 111 patients were enrolled in this randomized clinical trial and data from 100 patients (48 patients in the treatment arm and 52 patients in the control arm) were analyzed. There was no significant difference in the primary outcome of this study, which was clinical improvement. There was no significant difference in the average time to hospital discharge between the two arms. There were also no differences observed in the mean intensive care unit stay, frequency of intermittent mandatory ventilation, duration of supplemental oxygenation or risk of death by day 28 noted between the two arms. Conclusion Bromhexine is not an effective treatment for hospitalized patients with COVID-19. The potential prevention benefits of bromhexine in asymptomatic postexposure or with mild infection managed in the community remain to be determined.

Competing interests None declared. Patient consent for publication Not required. Ethics approval The study was approved by the ethics committee of the Shahid Beheshti University of Medical Sciences, Tehran, Iran (IR.SBMU.NRITLD. REC.1399.142). Provenance and peer review Not commissioned; externally peer reviewed. Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. The deidentified subject data are available in a secure space under the control of corresponding author [ fzh. dastan@ gmail. com]. This article is made freely available for use in accordance with BMJ's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained. ORCID iDs Ramin Tolouian http:// orcid. org/ 0000-0003-2242-9310 Zuber D Mulla http:// orcid. org/ 0000-0003-1670-5702

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Late treatment
is less effective

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