Low-dose Hydroxychloroquine and Bromhexine: a Novel Regimen for COVID-19 Prophylaxis in Healthcare Professionals

Hydroxychloroquine Clinical Trial

— ELEVATE  

Official title:

Low-dose Hydroxychloroquine and Bromhexine: a Novel Regimen for COVID-19 Prophylaxis in Healthcare Professionals (ELEVATE Trial)

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT04340349
• Other study ID #: 25/20
• Status: Enrolling by invitation
• Phase: Early Phase 1
• Start date: February 1, 2021
• Est. completion date: June 30, 2021

Study information

• Verified date: June 2021
• Source: Instituto Nacional de Rehabilitacion
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will investigate the security and efficacy of a daily low dose of hydroxychloroquine and Bromhexine, in preventing the development of the disease from COVID-19 in Health Care Workers at a National Institute of Health In Mexico City.

Description:

This study will combine two drugs (hydroxychloroquine and Bromhexine) to see if hydroxychloroquine is better in combination with Bromhexine in preventing the development of the disease from COVID-19 in Health Care Workers at a National Institute of Health In Mexico City. Hydroxychloroquine will be used in a low dose (200 mg every 24 hrs). Bromhexine will be 8mg every 8 hrs. The study groups will be the following: 1) HCQ 200mg/d + BHH placebo 2) HCQ placebo plus BHH placebo

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 214
• Est. completion date: June 30, 2021
• Est. primary completion date: May 30, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 59 Years

Eligibility

Inclusion criteria

• Health personnel working at INR LGII or INCMNSZ who wish to participate in the study and sign the informed consent.
• Over 18 and under 60 years of age, both genders.
• Contacting with suspected or confirmed SARS-CoV-2 infection.
• Normal electrocardiogram. Exclusion criteria
• Positive quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) test for SARS-CoV-2 at the time of inclusion.
• Panel of IgG or IgM antibodies positive for SARS-CoV-2 at the time of inclusion.
• Development of respiratory symptoms suspicious of SARS-CoV-2 infection during the first 7 days after treatment is initiated, confirmed by qRT-PCR and IgG or IgM antibodies postiver for SARS-CoV-2.
• History of allergies to any hydroxychloroquine or bromhexine related compound or medication.
• Use of immunosuppressors for any reason.
• History of bone marrow transplant.
• Known glucose-6-phosphate dehydrogenase deficiency.
• Chronic kidney disease or glomerular filtration <20ml/min.
• Use of other drugs with reported pharmacological interactions (i.e., digitalis, flecainide, amiodarone, procainamide, or propafenone).
• History of long QT syndrome.
• Electrocardiogram with QTc>500 msec.
• Pregnant or breastfeeding personnel.
• Epilepsy.
• Known liver disease.
• Personnel who have received the Covid-19 vaccine Elimination criteria
• Personnel who decide to leave the study for any reason not related to adverse events.
• Personnel with incomplete information on the primary outcome (qRT-PCR for SARS-CoV-2).
• Personnel who are relocated to work in another institution.
• Personnel who do not wish to participate in the study

Related Conditions & MeSH terms

• Antimalarials
• Antirheumatic Agents
• Enzyme Inhibitors
• Hydroxychloroquine

Intervention

Drug:
• Hydroxychloroquine Sulfate
A daily low dose of Hydroxychloroquine Sulfate. Increase the endosomal pH and inhibits of ACE2 glycosylation receptor.
• Bromhexine 8 MG
TMPRSS2 blocker

Locations

Country	Name	City	State
Mexico	National Institute of Rehabilitation, Luis Guillermo Ibarra Ibarra	Mexico City	Cdmx

Sponsors (1)

Lead Sponsor	Collaborator
Instituto Nacional de Rehabilitacion

Country where clinical trial is conducted

Mexico, 

References & Publications (30)

Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms. ACS Chem Neurosci. 2020 Apr 1;11(7):995-998. doi: 10.1021/acschemneuro.0c00122. Epub 20 — View Citation

Chang R, Sun WZ. Repositioning chloroquine as antiviral prophylaxis against COVID-19: potential and challenges. Drug Discov Today. 2020 Jul 3. pii: S1359-6446(20)30258-0. doi: 10.1016/j.drudis.2020.06.030. [Epub ahead of print] — View Citation

Chude CI, Amaravadi RK. Targeting Autophagy in Cancer: Update on Clinical Trials and Novel Inhibitors. Int J Mol Sci. 2017 Jun 16;18(6). pii: E1279. doi: 10.3390/ijms18061279. Review. — View Citation

Depfenhart M, de Villiers D, Lemperle G, Meyer M, Di Somma S. Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy? Intern Emerg Med. 2020 Aug;15(5):801-812. doi: 10.1007/s11739-020-02383-3. Epub 2020 May 26. Review. — View Citation

Dutta D, Sharma M, Sharma R. Short-term Hydroxychloroquine in COVID-19 Infection in People With or Without Metabolic Syndrome - Clearing Safety Issues and Good Clinical Practice. Eur Endocrinol. 2020 Oct;16(2):109-112. doi: 10.17925/EE.2020.16.2.109. Epub 2020 Oct 6. Review. — View Citation

Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020 Mar 16;14(1):72-73. doi: 10.5582/bst.2020.01047. Epub 2020 Feb 19. — View Citation

Geleris J, Sun Y, Platt J, Zucker J, Baldwin M, Hripcsak G, Labella A, Manson DK, Kubin C, Barr RG, Sobieszczyk ME, Schluger NW. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med. 2020 Jun 18;382(25):2411-2418. — View Citation

Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ — View Citation

Han H, Ma Q, Li C, Liu R, Zhao L, Wang W, Zhang P, Liu X, Gao G, Liu F, Jiang Y, Cheng X, Zhu C, Xia Y. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg Microbes Infect. 2020 Dec;9(1):1123-1130. — View Citation

Helal GK, Gad MA, Abd-Ellah MF, Eid MS. Hydroxychloroquine augments early virological response to pegylated interferon plus ribavirin in genotype-4 chronic hepatitis C patients. J Med Virol. 2016 Dec;88(12):2170-2178. doi: 10.1002/jmv.24575. Epub 2016 May — View Citation

Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C, Pöhlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibi — View Citation

Juurlink DN. Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection. CMAJ. 2020 Apr 27;192(17):E450-E453. doi: 10.1503/cmaj.200528. Epub 2020 Apr 8. Review. Erratum in: CMAJ. 2020 May 25;192(21):E590. — View Citation

Lai C, Yu R, Wang M, Xian W, Zhao X, Tang Q, Chen R, Zhou X, Li X, Li Z, Li Z, Deng G, Wang F. Shorter incubation period is associated with severe disease progression in patients with COVID-19. Virulence. 2020 Dec;11(1):1443-1452. doi: 10.1080/21505594.20 — View Citation

Levy A, Yagil Y, Bursztyn M, Barkalifa R, Scharf S, Yagil C. ACE2 expression and activity are enhanced during pregnancy. Am J Physiol Regul Integr Comp Physiol. 2008 Dec;295(6):R1953-61. doi: 10.1152/ajpregu.90592.2008. Epub 2008 Oct 22. — View Citation

Li C, Ji F, Wang L, Wang L, Hao J, Dai M, Liu Y, Pan X, Fu J, Li L, Yang G, Yang J, Yan X, Gu B. Asymptomatic and Human-to-Human Transmission of SARS-CoV-2 in a 2-Family Cluster, Xuzhou, China. Emerg Infect Dis. 2020 Jul;26(7):1626-1628. doi: 10.3201/eid2 — View Citation

Liu Q, Bi G, Chen G, Guo X, Tu S, Tong X, Xu M, Liu M, Wang B, Jiang H, Wang J, Li H, Wang K, Liu D, Song C. Time-Dependent Distribution of Hydroxychloroquine in Cynomolgus Macaques Using Population Pharmacokinetic Modeling Method. Front Pharmacol. 2021 J — View Citation

Luzzi GA, Peto TE. Adverse effects of antimalarials. An update. Drug Saf. 1993 Apr;8(4):295-311. Review. — View Citation

Mareev VY, Orlova YA, Pavlikova EP, Matskeplishvili ST, Akopyan ZA, Plisyk AG, Seredenina EM, Asratyan DA, Potapenko AV, Malakhov PS, Samokhodskaya LM, Mershina EA, Sinitsyn VE, Bulanova MM, Fuks AA, Mareev YV, Begrambekova YL, Kamalov AA. [Combination th — View Citation

Paiardini M, Müller-Trutwin M. HIV-associated chronic immune activation. Immunol Rev. 2013 Jul;254(1):78-101. doi: 10.1111/imr.12079. Review. — View Citation

Pal M, Berhanu G, Desalegn C, Kandi V. Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2): An Update. Cureus. 2020 Mar 26;12(3):e7423. doi: 10.7759/cureus.7423. Review. — View Citation

Ravi N, Cortade DL, Ng E, Wang SX. Diagnostics for SARS-CoV-2 detection: A comprehensive review of the FDA-EUA COVID-19 testing landscape. Biosens Bioelectron. 2020 Oct 1;165:112454. doi: 10.1016/j.bios.2020.112454. Epub 2020 Jul 18. Review. — View Citation

Remuzzi A, Remuzzi G. COVID-19 and Italy: what next? Lancet. 2020 Apr 11;395(10231):1225-1228. doi: 10.1016/S0140-6736(20)30627-9. Epub 2020 Mar 13. Review. — View Citation

Wang LF, Lin YS, Huang NC, Yu CY, Tsai WL, Chen JJ, Kubota T, Matsuoka M, Chen SR, Yang CS, Lu RW, Lin YL, Chang TH. Hydroxychloroquine-inhibited dengue virus is associated with host defense machinery. J Interferon Cytokine Res. 2015 Mar;35(3):143-56. doi — View Citation

Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269-271. doi: 10.1038/s41422-020-0282-0. Epub 2 — View Citation

Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020 Apr 7;323(13):1239-1242. — View Citation

Xu H, Zhong L, Deng J, Peng J, Dan H, Zeng X, Li T, Chen Q. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci. 2020 Feb 24;12(1):8. doi: 10.1038/s41368-020-0074-x. — View Citation

Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, Liu X, Zhao L, Dong E, Song C, Zhan S, Lu R, Li H, Tan W, Liu D. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrom — View Citation

Zahr N, Urien S, Llopis B, Pourcher V, Paccoud O, Bleibtreu A, Mayaux J, Gandjbakhch E, Hekimian G, Combes A, Benveniste O, Saadoun D, Allenbach Y, Pinna B, Cacoub P, Funck-Brentano C, Salem JE. Pharmacokinetics and pharmacodynamics of hydroxychloroquine — View Citation

Zanasi A, Mazzolini M, Kantar A. A reappraisal of the mucoactive activity and clinical efficacy of bromhexine. Multidiscip Respir Med. 2017 Mar 20;12:7. doi: 10.1186/s40248-017-0088-1. eCollection 2017. Review. — View Citation

Zhan M, Qin Y, Xue X, Zhu S. Death from Covid-19 of 23 Health Care Workers in China. N Engl J Med. 2020 Jun 4;382(23):2267-2268. doi: 10.1056/NEJMc2005696. Epub 2020 Apr 15. — View Citation

* Note: There are 30 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Positive SARS-CoV-2 result during the treatment	The proportion of health personnel positive for SARS-CoV-2 and result in the need for oxygen use, admission to the intensive care unit (ICU), presence of pneumonia by computer tomography scan (CT), death, severe pneumonia defined by the American Thoracic Association, time from hospitalization to recovery in days.	Day 30 and day 90
Other	Adverse events	The proportion of health personnel presenting any of the following during the study period: death, nausea, vomiting, abdominal pain, diarrhea, rash, itchy skin, hair loss, lengthening of the QT interval in the electrocardiogram (>500msec), corneal opacity, cardiac arrhythmias, heart failure or kidney failure (renal clearance <20ml/min). The proportion of the compound of adverse events between the groups will be analyed using RR and ARI for 60 days with their respective 95% confidence intervals	Day 60
Primary	Quantification of the expression of mRNA SARS-CoV-2 and presence or absence of antibodies anti-SARS-CoV-2	Primary endpoint will be the proportion of health personnel infected by SARS-CoV-2 at day 60 after starting treatment, in both groups. The infection will be diagnosed using qRT-PCR for relative expression of the mRNA of SARS-CoV-2 and the measure of IgM and IgG antibodies anti-SARS-CoV-2 after day 7 of treatment using rapid test Cellex qSARS-CoV-2 IgG/IgM	Day 60
Secondary	Quantification of the expression of mRNA SARS-CoV-2 and presence or absence of antibodies anti-SARS-CoV-2	The secondary endpoint will be the proportion of health personnel infected 90 days after starting treatment in both groups. The infection will be diagnosed using qRT-PCR for relative expression of the mRNA of SARS-CoV-2 and the measure of IgM and IgG antibodies anti-SARS-CoV-2 after day 7 of the start of treatment using rapid test Cellex qSARS-CoV-2 IgG/IgM	Day 90

External Links

•   Dashboard Mexico 2021