Bromhexine, for post exposure COVID-19 prophylaxis: A Randomized, Double-Blind, Placebo Control Trial

doi:10.21203/rs.3.rs-1612290/v1

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Research Article

Bromhexine, for post exposure COVID-19 prophylaxis: A Randomized, Double-Blind, Placebo Control Trial

https://doi.org/10.21203/rs.3.rs-1612290/v1

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Purpose

Limited number of medications are available for the post-exposure prophylaxis of COVID-19 infection. Whether bromhexine can prevent or mitigate symptomatic infection after virus exposure is undetermined.

Methods

A multi-center randomized; double-blind, placebo-controlled clinical trial was conducted. The 372 adults (≥ 18 years) who had close contact within 4 days with a household member with confirmed COVID-19 were randomly assigned to receive bromhexine (n = 187) or placebo (n = 185) three times a day for two weeks. The primary outcome was the incidence of symptomatic COVID-19. Secondary outcomes included the incidence of hospitalization or death, the incidence of confirmed COVID-19 detection by PCR in symptomatic patients and presence of adverse drug reactions.

Results

The incidence of symptomatic COVID-19 was significantly lower in individuals who received bromhexine than in those who received the placebo (16 [8.6%] vs 34 [18.4%], relative risk = 0.47, p = 0.005). PCR-confirmation was reported in 13 (7.0%) and 26 (14.1%) of the individuals in the bromhexine and placebo groups, respectively (p = 0.025), with a relative risk reduction of 50%. The hospitalization rate, death and medication side effects did not vary significantly between the bromhexine or placebo arms.

Conclusion

Bromhexine is an effective, non-invasive, and affordable agent with a low side-effect profile to prevent symptomatic COVID-19. Early use of bromhexine potentially provides another layer of protection and hence it can play a prominent role in ending the pandemic especially given the emergence of new variants and the vaccination challenges faced by developing countries.

Bromhexine

COVID-19

Prophylaxis

Post exposure

Randomized trial

The novel coronavirus disease 2019 (COVID-19) pandemic has spread around the world. Currently, the preexposure preventive strategies for this global threat are to vaccinate and implement hygienic recommendations, such as using face masks, hand washing, physical distancing, rapid identification of cases, and isolation.[1, 2] The postexposure prophylaxis for COVID-19 is very important and challenging. Several agents including hydroxychloroquine have been investigated, but none of them have been shown to prevent or mitigate postexposure COVID-19 infection.[3, 4] The NIH panel on COVID-19 treatment guidelines on August 17, 2021, recommended using monoclonal antibodies against SARS-CoV-2 [Casirivimab 600 mg plus Imdevimab 600 mg] subcutaneous injection or intravenous infusion for individuals at risk of progression of severe COVID-1, such as unvaccinated or immunocompromised individuals who had close contact with COVID-19 patients.[5]

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to human angiotensin-converting enzyme 2 (ACE2) receptors via its spike glycoprotein (S-Protein). After binding, the virus via two different pathways, can enter the cell. In the endosomal pathway, virus entry is mediated by activation of cathepsin [Cysteine protease] which causes membrane fusion and endocytosis. In the non-endosomal pathway, transmembrane protease serine 2 (TMPRSS2), facilitates priming the spikes and virus entry is at the plasma membrane. Newer viruses tend to infect the cell through activation of serine protease. TMPRSS2 inhibitors showed promising effect on blocking SARS-CoV-2 from cell entry.[6, 7] It has been observed that bromhexine can prevent influenza infection, [8] therefore, usage of bromhexine to prevent or treat COVID-19 infection has been proposed. One small clinical trial showed the efficacy of bromhexine on hospitalized symptomatic patients with COVID-19.[9, 10] The other important concern is the emergence of variants of SARS-COV-2 during the course of pandemic. It has been noted that most of the clinically important mutations have involved the spike proteins. Any mutation in that area may have a negative impact on the efficacy of vaccines and monoclonal antibody treatments against the new variants.[11] Therefore, blocking non-endosomal cell entry of virus might be an effective method to counter new variants of the virus.

With the increasing rate of household transmission due to the emerging variants of SARS-CoV-2 such as Delta and Omicron, it is wise to focus on breaking the chain of infection transmission in order to change the course of the pandemic. We hypothesized that bromhexine could be utilized as an affordable, widely available prophylactic agent to prevent symptomatic infection after exposure to SARS-CoV-2.

Study design

A multi-center randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy of bromhexine as a serine protease inhibitor (TMPRSS2) for postexposure prophylaxis against COVID-19 was conducted. The study’s methodological framework was modified and partially adopted with permission, from Boulware’s et al. study which was published in the New England Journal of Medicine [NEJM] on June 3, 2020. All participants were randomly assigned in a 1:1 ratio to receive either bromhexine or placebo. All participants had exposure to a household member confirmed positive COVID-19 by polymerase chain reaction (PCR) assay.

The trial was conducted from December 21, 2020, to July 25, 2021, in four medical centers, in Tehran, Iran. The trial was approved by the ethics committee review board at the Shahid Beheshti University of Medical Sciences with the code of IR.SBMU.PHARMACY.REC.1399.247. The trial was registered with the Iranian Registry of Clinical Trials (https://www.irct.ir/), a primary registry in the World Health Organization network, registration code IRCT20120703010178N22.

Patient selection and setting

In this trial, asymptomatic individuals ≥ 18 years old who had close contact with a hospitalized household member with confirmed COVID-19 within 4 days were tracked and recruited. Close contact was defined as exposure at fewer than 2 meters for more than 15 minutes in 24 hours. Moderate risk exposure was defined as individuals who were wearing only a face mask and no eye shield. A high-risk exposure was defined as an individual wearing neither an eye shield nor face mask. All participants agreed not to enroll in another study of an investigational agent before the completion of day 14 of the study. The exclusion criteria were age of less than 18 years, current hospitalization, experiencing signs or symptoms of COVID-19 within the 30 days prior to and on the day of screening, receipt of any experimental treatment for COVID-19 (off-label, compassionate use, or trial related) within the 30 days prior to the screening, history of COVID-19 vaccination and allergy to cough syrup.

Participant recruitment was performed via the tracking of household members of the patients with confirmed COVID-19 within four days of exposure in the province of Tehran, Iran. The written informed consent was obtained in person for 93% of participants and the rest obtained by the phone. All participants were given their medication/placebo on the enrollment day. Participants subsequently were followed in virtual visits on days 5, 10, 14 and were asked about the signs and symptoms of COVID-19, medication adherence, COVID testing, hospitalization, and adverse drug reactions. Participants had no routine screening for COVID-19 during the 14 day follow up, unless symptomatic enough to seek care.

Intervention

The random allocation sequence was generated using Sealed Envelope Ltd.'s online service. A permuted block randomization sequence with the variable block size contained 4, 6, or 8 patients was used. All participants, investigators, outcome assessors, and data analyzers were blinded to the assignment. Only one person was aware of the randomization sequence. This individual was not aware of the patients’ recruitment and follow-up process.

Bromhexine and an identical placebo were purchased from Mofid Nikan Pharmaceutical Company (Tehran, Iran). All tablets and packaging were identical (except for the active ingredient component). The medication was provided in a sealed, masked bottle containing 50 bromhexine hydrochloride or placebo tablets. The pill count method was used to evaluate the adherence of the participants. All bottles had a distinctive label as serine protease inhibitor and were dispensed directly to the participants on day 0. Bromhexine hydrochloride tab [8 mg] or a placebo tab was taken three times a day for two weeks.

Outcomes

The primary outcome of this study was defined as the incidence of symptomatic COVID-19 disease based on signs and symptoms during the study period. The signs and symptoms of possible SARS-CoV-2 infection were considered as acute onset of cough and fever or two of the following symptoms: fever, chills, dyspnea, general weakness/fatigue, headache, myalgia, sore throat, and recent onset of anosmia or ageusia in the absence of any other possible identifiable cause. Reverse transcriptase-polymerase chain reaction (RT-PCR) assays were used to confirm the diagnosis of COVID-19.

Secondary outcomes included the incidence of hospitalization or death, the incidence of confirmed COVID-19 detection by PCR in symptomatic patients, the incidence of all-cause medication discontinuation or withdrawal, adherence to the instructions of the medication use, and presence of adverse drug reactions. Side effect data were collected by direct question about adverse events, with open-ended free text.

Sample Size

Assuming that COVID-19 would develop in 10% of participants who had close exposure and using Fisher’s exact test with a 50% relative effect size to reduce new symptomatic infections, 80% power, and a two-sided alpha of 0.05, it was calculated that a sample size of 435 individuals in each arm would be required. The addition of a 20% estimated dropout rate increased the final enrollment size to 525 persons in each arm.

Interim Analysis

The spread of the highly contagious Delta variant of SARS-COV-2 Finding asymptomatic household contacts was a challenge in the setting of delta infection and hence a request was made to the safety monitoring board to conduct an interim analysis. This unplanned interim analysis of the primary outcome (symptomatic COVID-19 illness) with 187 and 185 participants in the Bromhexine and placebo groups, respectively, was performed and the trial was halted.

To account for the unplanned nature of the analysis, the significance level of 0.05 was adjusted to 0.03. Pocock published nominal significance levels that are required for repeated two-sided significance testing which preserve an overall significance level (alpha) of 0.05.[12] These significance levels are stopping rules, and they can be used for binary or normally distributed response variables. When the maximum number of tests to be performed is two (and the desired overall alpha is 0.05), then the nominal significance level for each repeated test is 0.029. This value was rounded to 0.03 and used as the level of significance for the analyses presented in this paper.

Role of the funding source:

The funders of the study had no role in study design, data collection, data analysis, interpretation, or writing of the manuscript.

STATISTICAL ANALYSIS

Statistical analysis was primarily performed using SPSS 25. Qualitative variables were analyzed by the chi-square or Fisher’s exact test, as appropriate. Age as a continuous variable was presented as median interquartile range (IQR). The relative risk (RR) reduction and absolute risk reduction of developing a symptomatic COVID-19 infection were calculated. The number needed to treat (NNT) was computed as the reciprocal of the absolute risk reduction.

Logistic regression analyses were performed using SAS 9.4. The four binary outcomes in these models were symptomatic case of COVID-19, PCR-confirmed case of COVID-19, admission to medical center, and death. Odds ratios (OR) comparing patients in the bromhexine arm with those in the placebo arm were reported along with 97% confidence intervals (CI), and p-values. Given the rarity of two of the outcomes under study (admission to a medical center and death), Firth’s penalized maximum likelihood estimation was used when fitting these two models in order to avoid triggering sparse data bias. [13] An OR was considered to be statistically significant if the p-value was less than or equal to 0.03.

Imbalances between the two study treatment arms in the prevalence of the following factors that were deemed to be of clinical importance were observed: male sex, smoking, hypertension, and diabetes. These imbalances may have led to confounding. Assessment of confounding is not an issue of statistical significance and therefore the change-in-estimate method was used to determine if joint confounding by the four variables listed above was present.[14] If the unadjusted and adjusted bromhexine ORs for a particular outcome differed by 10% or more, then the variable or variables that were adjusted for remained in the logistic regression model and the adjusted OR was reported. Per-protocol analyses were performed given that subjects who consumed trial medications for less than 3 days were excluded from the study.

We evaluated 5110 subjects who were in close contact with 2373 PCR positive patients. Eventually, 372 asymptomatic subjects were recruited and randomly assigned to bromhexine (n = 187) or placebo (n = 185). The study diagram is presented in Fig. 1. The median age (IQR) of the included patients was 40 (21) years. Out of 372 participants, 198 (53.2%) were male and 174 (46.8%) were female. Baseline demographics and related clinical parameters of each group of participants are reported in Table 1. Two hundred and forty-one (64.8%) subjects had a moderate-risk exposure. Most of the participants were enrolled in the first 2 days after exposure to the COVID-19 patient (262 [70.4%]).

Table 1

Baseline Demographic and Related Clinical Characteristics of the 372 Participants
Characteristic			Bromhexine (n = 187)	Placebo (n = 185)
Age in years (IQR) [Min, Max]			40 (21) [19,82]	41 (20) [18, 86]
Time from exposure variable (IQR) [Min, Max]			1.0 (2.00) [0, 4]	2.00 (2.00) [0, 4]
Body Mass Index- no (%)	< 30 kg/m²		162 (86.7%)	155 (83.8%)
Body Mass Index- no (%)	≥ 30 kg/m²		25 (13.4%)	30 (16.2%)
Sex (Female) - no (%)			80 (42.8.0%)	94:91 (50.8%)
Sex (Male) – no (%)			107 (57.2%)	91 (49.2)
Habit- no (%)		Current Smoker	26 (13.9%)	20 (10.8%)
		Opioid User	6 (3.2%)	5 (2.7%)
		Alcohol	3 (1.6%)	1 (0.5%)
Past medical History- no (%)		Hypertension	19 (10.2%)	14 (7.6%)
		Diabetes Mellitus	14 (7.5%)	20 (10.8%)
		Coronary artery disease	17 (9.1%)	14 (7.6%)
		Chronic Kidney Disease	2 (1.1%)	4 (2.2%)
		Asthma	2 (1.1%)	2 (1.1%)
		COPD	2 (1.1%)	0 (0.0%)
		Immunocompromised	0 (0.0%)	3 (1.6%)
		Malignancy	1 (0.5%)	1 (0.5%)
Past medication history- no (%)		ARB/ ACEi	16 (8.6%)	14 (7.6%)
		Aspirin	21 (11.2%)	18 (9.7%)
		Non-steroidal anti-inflammatory drugs	6 (3.2%)	9 (4.9%)
		Other	47 (25.1%)	40 (21.6%)
Risk of Exposure- no (%)		High	72 (38.5%)	59 (31.9%)
Risk of Exposure- no (%)		Intermediate	115 (61.5%)	126 (68.1%)
(IQR); interquartile range

The overall incidence of being a symptomatic participant based on compatible signs/symptoms of COVID-19 was 13.4%. The incidence of COVID-19 was significantly lower in individuals who received bromhexine than in those who received placebo (16 [8.6%] vs 34 [18.4%], RR = 0.47, p = 0.005). The relative risk reduction was 53%, while relative risk reduction within 5 days of the initiation of bromhexine was 63%. (Fig. 2) The timing of the onset of COVID-19 (counts of new cases by trial day) during the study by treatment group is presented in Fig. 2. PCR-confirmation was reported in 13 (7.0%) and 26 (14.1%) of the symptomatic participants in the bromhexine and placebo group, respectively (p = 0.025). The relative risk reduction for the outcome of being a PCR-confirmed case was 50%. The hospitalization rate did not vary significantly between the treatment arms, bromhexine: 1 (0.5%); placebo: 6 (3.2%), (p = 0.067). The incidence of death was 0 (0.0%) in the bromhexine group and 1 (0.5%) in the placebo group (p = 0.497). The decedent was a 53-year-old woman with diabetes who passed away due to COVID-19 complications after hospitalization and admission to ICU.

Table 2 presents bromhexine vs. placebo ORs for four outcomes. ORs for being a symptomatic case and PCR-confirmed case of COVID-19 are unadjusted while the OR for admission to a medical center is adjusted for the patient’s sex, diabetes, and smoking. The bromhexine OR for death is adjusted for the patient’s sex, diabetes, and hypertension. The odds of being a symptomatic case of COVID-19 were reduced by 58% in participants who received bromhexine compared to those who received placebo: OR = 0.42, 97% CI: 0.21–0.84, p = 0.007. Bromhexine also protected against being a PCR-confirmed case of COVID-19: OR = 0.46, 97% CI: 0.21–0.99, p = 0.028. Associations between bromhexine and the outcomes of admission to medical center, and death were not detected.

Table 2

Bromhexine versus placebo odds ratios (OR) for four outcomes in 372 subjects estimated via logistic regression. Absolute number of outcome events are presented by study arm.
Outcome	Events in bromhexine arm	Events in placebo arm	OR	97% confidence interval	P
Symptomatic case of COVID-19	16	34	0.42^†	0.21–0.84	0.007
PCR-confirmed case of COVID-19	13	26	0.46^†	0.21–0.99	0.028
Admission to medical center	1	6	0.29^*	0.05–1.83	0.145
Death	0	1	0.67^‡	0.04–11.03	0.759
^†Unadjusted.
^*Adjusted for the patient’s sex, diabetes, and smoking using logistic regression with Firth’s penalized maximum likelihood estimation.
^‡ Adjusted for the patient’s sex, diabetes, and hypertension using logistic regression with Firth’s penalized maximum likelihood estimation.

In the 50 symptomatic cases, fever 39 (78.0%), Chills 29 (58.0%), fatigue and weakness 27 (54.0%) were the most frequently reported symptoms. Participant self-report adherence is represented in Table 3. Furthermore, a post-hoc calculation for the primary outcome of symptomatic infection for an alpha of 0.03 (two-sided testing) revealed a power of approximately 73% (and for the same outcome in our study, the power, if one assumes an alpha of 0.05, would be about 79%).

Table 3

Participant Self-report Adherence and Side Effects
Variables		Bromhexine (n = 187)	Placebo (n = 185)	p-value
Median duration of study participation in days (IQR)^* [Range]		14 (6) [3–14]	10 (7) [3–14]	0.007
Adherence to trial intervention^** No (%)		140 (74.9%)	131 (70.8%)	0.379
Average cumulative trial intervention Adherence (%)		88.00%	83.24%	< 0.001
Reasons for medication discontinuation- no (%)	Adverse Drug Reactions	5 (2.7%)	3 (1.6%)	0.724
	Felt no longer at risk	38 (20.3%)	40 (21.6%)	0.758
	Advised to not to take the medication	7 (3.7%)	5 (2.7%)	0.570
Adverse Drug Reactions- no (%)	Any	27 (14.4%)	19 (10.3%)	0.222
	Nausea, Vomiting	6 (3.2%)	4 (2.2%)	0.751
	Upset stomach	5 (2.7%)	3 (1.6%)	0.724
	Abdominal discomfort	12 (6.4%)	8 (4.3%)	0.371
	Diarrhea	8 (4.3%)	4 (2.2%)	0.248
	Constipation	0 (0.0%)	1 (0.5%)	0.497
	Irritability	1 (0.5%)	0 (0.0%)	1.000
	Paresthesia	1 (0.5%)	0 (0.0%)	1.000
	Myalgia	0 (0.0%)	1 (0.5%)	0.497
	Dizziness	3 (1.6%)	2 (1.1%)	1.000
	Headache	4 (2.1%)	1 (0.5%)	0.372
	Vertigo	2.0 (1.1%)	0 (0.0%)	0.499
	Dry throat	2 (1.1%)	1 (0.5%)	1.000
	Increased in respiratory secretion	2 (1.1.%)	0 (0.0%)	0.499
	Skin sensitivity, Rash	0 (0.0%)	1 (0.5%)	0.497
^*IQR; interquartile range
^** Participants who consumed ≥ 80% of assigned medication were considered adherent to the medication regimen
The cumulative number of symptomatic COVID-19 cases [50 patients] over the course of two weeks follow up in both bromhexine and placebo groups.

Adverse Events:

Adverse drug reactions occurred in 46 (12.4%) of the participants. Abdominal discomfort was the most frequently reported adverse reaction (Table 3).

Our study validated the clinical efficacy of oral bromhexine hydrochloride in the postexposure prophylaxis of COVID-19 infection and likely against delta variant.

It has been shown that SARS-CoV-2 and its new variants use the non-endosomal pathway for cell entry and are more dependent on TMPRSS2 expression compared to SARS-CoV-1.[15, 16] Bromhexine, by blocking TMPRSS2, inhibits virus entry into the cell and mitigates or prevents SARS-CoV-2 infection. In addition, bromhexine may have an important role in restoring airway surface liquid and enhance mucociliary transport by inhibition of the epithelial sodium channel (ENaC). These channels upregulate and are activated by serine proteases.[17, 18] It has been shown that the spike protein of SARS-CoV-2 at the cleavage site has the same sequence of amino acids as that found at its cut site in ENaC-α. It has been postulated that COVID-19, by hijacking TMPRSS2, activates ENaC and interferes with the water and salt balance in the lungs.[19]

Our relative risk reduction within 5 days of the initiation of bromhexine was 63%. This measure is comparable to the relative risk reduction of 72% reported by O’Brien et al. in the subcutaneous REGEN-COV2 antibody combination prevention trial.[5] Furthermore, the incidence of symptomatic COVID-19 disease in our study was 8.6% in the bromhexine group and 18.4% in placebo group (absolute risk reduction = 9.8%). The NNT in our study (1/0.098) was 10.2 indicating that, on average, 10 patients must be treated with bromhexine in order to prevent one case of symptomatic disease. In the subcutaneous REGEN-COV antibody combination prevention trial the incidence was 1.3% in the treatment arm and 7.8% in the placebo group (absolute risk reduction = 6.5%, NNT = 15.4). It is reasonable to say that the magnitude of the bromhexine effect was similar to the report of REGEN-COV2, although this is not a head-to-head comparison. The higher risk of symptomatic illness in both the treatment and placebo arms in our study might be explained by the spread of the highly contagious delta variant.

It has been noted that the efficacy of REGEN-COV2 antibodies in the first week post injection is low. It is shown that it takes 7–8 days for those antibodies to reach high concentrations in the serum. Therefore, during the first week of the REGEN-COV treatment, the effect may not be at its maximum and the addition of another layer of protection is justified. Lastly, bromhexine has been used since 1963 as an over-the-counter mucolytic medicine without any major side effects[20] while we are still learning about REGEN-COV treatment.

One small single center, open-label, randomized clinical trial, observed a lower intensity of lung involvement such as cough, dyspnea and lassitude in hospitalized patients with COVID-19 who received bromhexine.[10] In our trial bromhexine strongly protected against the development of the primary outcome of symptomatic illness, OR = 0.42. Taking the reciprocal of this OR (1/0.42) reveals that patients in the placebo arm had more than twice the odds of becoming a symptomatic case of COVID-19 than patients in the bromhexine arm (OR = 2.38). This protective effect of bromhexine on the primary outcome persisted even after controlling for smoking, sex, hypertension, and diabetes (data not shown). This is a valuable finding that can have a significant impact on public health, and global socioeconomic wellbeing.

Our per-protocol data analysis also showed that the number of positive PCR results (confirmed cases) in participants who received bromhexine treatment was significantly lower than the placebo group. This finding may reflect the mitigation or a way to break the chain of virus transmission in the participants who received bromhexine. Mikhaylov et al. reported a lower frequency of positive PCR tests, symptomatic cases of SARS-CoV-2 infection among medical personnel, in a small sample size of 50 healthcare workers.[21]

The incidence of hospitalization and death was lower in the bromhexine group compared to the placebo. The lack of any mortality in the bromhexine group support the hypothesis that bromhexine is effective. The frequency of medication side effects in both placebo and control groups were comparable and support the safety of bromhexine.

Male gender is associated with a higher rate of morbidity and mortality in Covid-19 disease. The role of androgen-responsive elements [AREs] of the transmembrane serine proteases type II (TMPRSS2) gene as one of the major players in the male predominance in the incidence of severe COVID-19 infection has been discussed.[22] Despite a higher prevalence of men in the bromhexine arm, the incidence and severity of symptoms were less as compared to the placebo arm. This difference may support the notion of the effectiveness of bromhexine in COVID-19 by blocking TMPRSS2.

In addition to our data collection on self-report by all participants, lack of serologic tests to assess the immunity of the individuals against COVID-19 prior to enrollment is one of the limitations of our study. To minimize those issues, any individuals who had any signs or symptoms suggestive of COVID-19 infection were excluded. Random allocation of the participants into the bromhexine and placebo groups reduced the chance of confounding bias by immunity/immune status. In a similar fashion, it is to be expected that prevalence of non-COVID-19 diseases which could mimic the signs and symptoms of COVID-19 such as influenza and the common cold would be distributed in an equal manner between the two groups. Despite the rejection of the null hypothesis corresponding to our primary outcome, it may be argued that our clinical trial was underpowered. Nevertheless, continuing the dialogue about the efficacy of bromhexine is crucial to identifying a relatively inexpensive, safe therapeutic agent against SARS-CoV-2. We hope the results of this study will inspire other investigators and provide material for a future meta-analysis.

There is no doubt that vaccines are effective, valuable and the cornerstone to preventing COVID-19 disease,[23] however, the new SARS-CoV-2 variants such as delta and Omicron with their higher transmissibility and virulence may negatively affect the efficacy of vaccines and monoclonal antibodies.[24] There are several clinical trials underway to test new antiviral medications for post exposure treatment. Even if the efficacy of those drugs is validated, it may still take years to evaluate side effects and safety profile. Therefore, it is judicious to have another layer of postexposure protection, a medication with a safety profile that has been tested for more than half a century.

Our data demonstrated clear benefits of using bromhexine as post exposure prophylaxis. The new NIH recommendations on postexposure prophylaxis using Casirivimab plus Imdevimab injection are based on solid evidence from clinical trials, but the cost and availability of those medications are limiting factors.[25] Access to widely available and inexpensive oral medications such as bromhexine may provide another effective layer of protection in ending the pandemic in a timely fashion, especially given the emergence of new variants and the mass vaccination challenges faced by developing countries.

Further investigation is required to assess whether the new variants are susceptible to this postexposure prophylaxis method and to gauge optimal dosing. Additionally, another clinical trial to assess the efficacy of the combination of bromhexine and subcutaneous REGEN-COV antibody will be necessary.

Nothing to report except Dr. Ramin Tolouian received speaker honorarium from Sanofi-Genzyme and consulting fee from Travere therapeutics.

Support: This study was supported by a Grant [#24886] received from office of Deputy of Research and Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Acknowledgement: We would like to thank all the participants in this trial, Faezeh Nesaei RN, for helping in data collection and the research and safety monitoring board members of school of pharmacy Drs. Niayesh Mohebbi, Amir Behnam Kharazmi, Farzaneh Dastan, Bahador Mirrahimi, and Mahsa Azami Movahed.

Data availability statement: The date that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy and ethical restrictions.

Author Contribution: All authors approved the manuscript for submission. RT, AT contributed to study conceptualization, methodology, original draft, writing, review, and editing. OM and ZDM contributed to software, data Curation, investigation, formal analysis and validation, SZ, MH, HE, HA, RH, EP, MK, SS, SA, and ST contributed to investigation, resources, and supervisory duties. AMR, AZ contributed to resources, funding acquisition and project administration. MS contributed to supervision, project administration, methodology, writing, review, and editing.

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Competing interest reported. Dr. Ramin Tolouian received speaker honorarium from Sanofi-Genzyme and consulting fee from Travere therapeutics.

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Bromhexine, for post exposure COVID-19 prophylaxis: A Randomized, Double-Blind, Placebo Control Trial

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Abstract

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Introduction

Methods

Study design

Patient selection and setting

Intervention

Outcomes

Sample Size

Interim Analysis

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STATISTICAL ANALYSIS

RESULTS

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Discussion

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