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0 0.5 1 1.5 2+ Oxygen therapy 67% Improvement Relative Risk Hospitalization 67% Recovery, dyspnea 71% Recovery, fever -187% Viral load -7% primary Viral load (b) 17% primary Viral load (c) -41% primary Viral clearance, day 14 13% Viral clearance, day 7 -14% Bromhexine  Vila Méndez et al.  EARLY TREATMENT  RCT Is early treatment with bromhexine beneficial for COVID-19? RCT 191 patients in Spain (February - July 2022) Lower need for oxygen therapy (p=0.49) and lower hospitalization (p=0.49), not sig. Vila Méndez et al., J. Clinical Medicine, Dec 2022 Favors bromhexine Favors control

Efficacy of Bromhexine versus Standard of Care in Reducing Viral Load in Patients with Mild-to-Moderate COVID-19 Disease Attended in Primary Care: A Randomized Open-Label Trial

Vila Méndez et al., Journal of Clinical Medicine, doi:10.3390/jcm12010142, EudraCT2021-001227-41
Dec 2022  
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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.
Bromhexine efficacy may vary depending on the degree of TMPRSS-dependent fusion for different variants Peacock, Willett.
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 prioritizing more serious outcomes. Submit updates
Vila Méndez et al., 24 Dec 2022, Randomized Controlled Trial, Spain, peer-reviewed, 38 authors, study period 24 February, 2022 - 28 July, 2022, trial EudraCT2021-001227-41. Contact: (corresponding author),
This PaperBromhexineAll
Efficacy of Bromhexine versus Standard of Care in Reducing Viral Load in Patients with Mild-to-Moderate COVID-19 Disease Attended in Primary Care: A Randomized Open-Label Trial
María Luz Vila Méndez, Carmen Antón Sanz, Alicia Del Rocío Cárdenas García, Amparo Bravo Malo, Francisco Javier Torres Martínez, José María Martín Moros, María Real Torrijos, José Francisco Javier Vendrell Covisa, Olga Guzmán Sierra, Verónica Molina Barcena, Nuria Viejo Pinero, Carlos Fernández Díaz, Purificación Arroyo Burguillo, Ana María Blanco Gallego, Carmen Guirao Sánchez, Aránzazu Montilla Bernabé, María Del Pilar Villanueva Morán, Salvador Juárez Antón, Ángela Fernández Rodríguez, María Ángeles Somoza Calvo, Ernesto Cerrada Cerrada, Gemma Pérez Mañas, Antonio Sánchez Calso, Frida Vallejo Somohano, Carmen Cauqui Díaz, Gloria Viñas Fernández, Jesús Molina París, Marina González Godoy, Gonzalo Lumbreras García, Javier Rosado Martín, Aida Rodríguez Hernández, Sara López Antúñez, Gabriel Vázquez Perfecto, María Concepción Marcello Andrés, Nieves Marina Puente García, Carmen Gil, Ana Martínez, Begoña Soler López
Journal of Clinical Medicine, doi:10.3390/jcm12010142
A 28-day randomized open-label multicenter study was conducted to assess the efficacy of bromhexine plus standard of care (SOC) (n = 98) vs. SOC alone (n = 93) in 191 outpatients with mildto-moderate COVID-19 in the primary health care setting. Bromhexine three daily doses of 10 mL (48 mg/day) were administered for seven days. The primary efficacy endpoint was the reduction of viral load estimated as the cycle thresholds (Ct) to detect ORF1ab, N Protein, and S Protein genes by RT-qPCR in saliva samples on day 4 as compared with baseline. Ct values of the three genes increased from baseline throughout days 4 to 14 (p < 0.001) but significant differences between the study groups were not found. Differences in the percentages of patients with low, medium, and high viral loads at 4, 7, and 14 days were not found either. In summary, treatment with bromhexine plus SCO was associated with a viral load reduction of ORF1ab, N Protein, and S Protein genes at day 4, which was not significantly different than similar viral load reductions observed with SOC alone. The present findings do not seem to favor the use of bromhexine as an antiviral in patients with COVID-19.
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Conflicts of Interest: A. Martínez and C. Gil are employees of the sponsor Agencia Estatal Consejo Superior de Investigaciones Científicas, M.P. (CSIC); B. Soler López was contracted to carry out the design, monitoring, statistical analysis and management of the publications derived from the study. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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