Azelastine Nasal Spray in Non-Hospitalized Subjects with Mild COVID-19 Infection: A Randomized Placebo-Controlled, Parallel-Group, Multicentric, Phase II Clinical Trial
Peter Meiser, Michael Flegel, Frank Holzer, Dorothea Groß, Charlotte Steinmetz, Barbara Scherer, Rajesh Jain
Viruses, doi:10.3390/v16121914
Nasal spray treatments that inhibit the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) entry into nose and nasopharynx at early stages can be an appropriate approach to stop or delay the progression of the disease. We performed a prospective, randomized, doubleblind, placebo-controlled, parallel-group, multicentric, phase II clinical trial comparing the rate of hospitalization due to COVID-19 infection between azelastine 0.1% nasal spray and placebo nasal spray treatment groups. The study furthermore assessed the reduction in virus load in SARS-CoV-2infected subjects estimated via quantitative reverse transcriptase polymerase chain reaction (RT-PCR) using nasopharyngeal swabs in both groups during the treatment period. A total of 294 subjects with mild COVID-19 infection were screened and randomized in a 1:1 ratio. There was no incidence of COVID-19-related hospitalization in either treatment group. Mean virus load was significantly reduced in both groups during the 11 treatment days as compared with baseline viral load values. The reduction in virus load in the azelastine 0.1% nasal spray group was significantly higher than the reduction in the placebo group at day 11 (log 10 5.93 vs. log 10 5.85 copies/mL, respectively, p = 0.0041). A total of 39 (32.0%) subjects in the azelastine 0.1% treatment group and 40 (31.0%) subjects in the placebo group reported 48 and 51 adverse events, respectively. It is therefore concluded that azelastine 0.1% nasal spray is an efficacious, safe, and well-tolerated treatment of mild COVID-19 infection.
Supplementary Materials: The following supporting information can be downloaded at https:// www.mdpi.com/article/10.3390/v16121914/s1 : Table S1 : List of IECs or IRBs; Table S2 : Inclusion and Exclusion Criteria; Table S3 : Randomization Procedure; S10 : Overall Summary of Adverse Events (Safety Population). Author Contributions: Conceptualization, P.M., M.F. and F.H.; methodology, P.M. and R.J.; software, R.J.; validation, R.J.; formal analysis, P.M., D.G., C.S., B.S. and R.J.; investigation, CARVIN-II Study Group; resources, P.M., R.J. and F.H.; data curation, R.J.; writing-original draft preparation, R.J.; writing-review and editing, P.M. and all involved authors; supervision, P.M.; project administration, P.M. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. The Clinical Trial was funded by URSAPHARM Arzneimittel GmbH.
Institutional Review Board Statement: The study was approved by all involved Institutional Review Boards and Ethics Committees. A full list of the Institutional Review Boards and Ethics Committees involved is provided in the Supplementary Table S1 . The study was conducted in accordance with the Good Clinical Practice, the Declaration of Helsinki, and all applicable local and national regulatory requirements. Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Conflicts of Interest: Peter Meiser, Michael Flegel,..
References
Balasubramani, Ravichandran, Prasad, Ramkumar, Shekhar et al., Spatio-Temporal Epidemiology and Associated Indicators of COVID-19 (Wave-I and Ii) in India, Sci. Rep,
doi:10.1038/s41598-023-50363-2Bernal, Silva, Musungaie, Kovalchuk, Gonzalez et al., Molnupiravir for Oral Treatment of COVID-19 in Nonhospitalized Patients, N. Eng. J. Med,
doi:10.1056/NEJMoa2116044Cascella, Rajnik, Aleem, Dulebohn, Napoli et al., Evaluation, and Treatment of Coronavirus (COVID-19)
Dings, Meiser, Holzer, Flegel, Selzer et al., Pharmacometric Modeling of the Impact of Azelastine Nasal Spray on SARS-CoV-2 Viral Load and Related Symptoms in COVID-19 Patients, Pharmaceutics,
doi:10.3390/pharmaceutics14102059Fischhuber, Bánki, Kimpel, Kragl, Rössler et al., Antiviral Potential of Azelastine against Major Respiratory Viruses, Viruses,
doi:10.3390/v15122300Ghahremanpour, Tirado-Rives, Deshmukh, Ippolito, Zhang et al., Identification of 14 Known Drugs as Inhibitors of the Main Protease of SARS-CoV-2, ACS Med. Chem. Lett,
doi:10.1021/acsmedchemlett.0c00521Jain, Mujwar, Repurposing Metocurine as Main Protease Inhibitor to Develop novel Antiviral Therapy for COVID-19, Struct. Chem,
doi:10.1007/s11224-020-01605-wKillingley, Mann, Kalinova, Boyers, Goonawardane et al., Tolerability and Viral Kinetics During SARS-CoV-2 Human Challenge in Young Adults, Nat. Med,
doi:10.1038/s41591-022-01780-9Klussmann, Grosheva, Meiser, Lehmann, Nagy et al., Early Intervention with Azelastine Nasal Spray may Reduce Viral Load in SARS-CoV-2 infected patients, Sci. Rep,
doi:10.1038/s41598-023-32546-zKonrat, Papp, Kimpel, Rössler, Szijártó et al., The Anti-Histamine Azelastine, Identified by Computational Drug Repurposing, Inhibits Infection by Major Variants of SARS-CoV-2 in Cell Cultures and Reconstituted Human Nasal Tissue, Front. Pharmacol,
doi:10.3389/fphar.2022.861295Marc, Kerioui, Blanquart, Bertrand, Mitjà et al., Quantifying the Relationship Between SARS-CoV-2 Viral Load and Infectiousness, eLife,
doi:10.7554/eLife.69302Odhar, Ahjel, Albeer, Hashim, Rayshan et al., Molecular Docking And Dynamics Simulation of FDA Approved Drugs with the Main Protease from 2019 Novel Coronavirus, Bioinformation,
doi:10.6026/97320630016236Panahi, Gorabi, Talaei, Beiraghdar, Akbarzadeh et al., An Overview on the Treatments and Prevention against COVID-19, Virol. J,
doi:10.1186/s12985-023-01973-9Reznikov, Norris, Vashisht, Bluhm, Li et al., Identification of Antiviral Antihistamines for COVID-19 Repurposing, Biochem. Biophys. Res. Commun,
doi:10.1016/j.bbrc.2020.11.095Shmuel, Dalia, Tair, Yaakov, Low pH Hypromellose (Taffix) Nasal Powder Spray could Reduce SARS-CoV-2 Infection Rate Post Mass-Gathering Event at a Highly Endemic Community: An Observational Prospective Open Label User Survey, Expert Rev. Anti Infect. Ther,
doi:10.1080/14787210.2021.1908127Sinha, Suram, Chary, Naik, Singh et al., Efficacy and Safety of Molnupiravir in Mild COVID-19 Patients in India, Cureus,
doi:10.7759/cureus.31508Tandon, Wu, Moore, Winchester, Tu et al., SARS-CoV-2 Accelerated Clearance Using a Novel Nitric Oxide Nasal Spray (Nons) Treatment: A Randomized Trial, Lancet Reg. Health Southeast Asia,
doi:10.1016/j.lansea.2022.100036Winchester, John, Jabbar, John, Clinical Efficacy of Nitric Oxide Nasal Spray (Nons) for the Treatment of Mild COVID-19 Infection, J. Infect,
doi:10.1016/j.jinf.2021.05.009Yang, Pei, Li, Ma, -N et al., Identification of SARS-CoV-2 Entry Inhibitors among Already Approved Drugs, Acta Pharmacol. Sin,
doi:10.1038/s41401-020-00556-6{ 'indexed': { 'date-parts': [[2024, 12, 14]],
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'abstract': '<jats:p>Nasal spray treatments that inhibit the Severe Acute Respiratory Syndrome Coronavirus '
'2 (SARS-CoV-2) entry into nose and nasopharynx at early stages can be an appropriate approach '
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'double-blind, placebo-controlled, parallel-group, multicentric, phase II clinical trial '
'comparing the rate of hospitalization due to COVID-19 infection between azelastine 0.1% nasal '
'spray and placebo nasal spray treatment groups. The study furthermore assessed the reduction '
'in virus load in SARS-CoV-2-infected subjects estimated via quantitative reverse '
'transcriptase polymerase chain reaction (RT-PCR) using nasopharyngeal swabs in both groups '
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'hospitalization in either treatment group. Mean virus load was significantly reduced in both '
'groups during the 11 treatment days as compared with baseline viral load values. The '
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'respectively. It is therefore concluded that azelastine 0.1% nasal spray is an efficacious, '
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'member': '1968',
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'reference': [ { 'key': 'ref_1',
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'first-page': '23',
'DOI': '10.1186/s12985-023-01973-9',
'article-title': 'An Overview on the Treatments and Prevention against COVID-19',
'volume': '20',
'author': 'Panahi',
'year': '2023',
'journal-title': 'Virol. J.'},
{ 'key': 'ref_2',
'unstructured': 'Cascella, M., Rajnik, M., Aleem, A., Dulebohn, S.C., and Napoli, S.D. '
'(2023). Features, Evaluation, and Treatment of Coronavirus (COVID-19), '
'StatPearls Publishing.'},
{ 'key': 'ref_3',
'unstructured': 'World Health Organization (2023, December 22). COVID-19 Epidemiological '
'Update. Available online: '
'https://www.who.int/publications/m/item/covid-19-epidemiological-update---22-december-2023.'},
{ 'key': 'ref_4',
'unstructured': 'COVID-19, Ministry of Health and Family Welfare (2024, January 09). '
'COVID-19, Available online: https://www.mohfw.gov.in/.'},
{ 'key': 'ref_5',
'doi-asserted-by': 'crossref',
'unstructured': 'Balasubramani, K., Ravichandran, V., Prasad, K.A., Ramkumar, M., '
'Shekhar, S., James, M.M., Kodali, N.K., Behera, S.K., Gopalan, N., and '
'Sharma, R.K. (2024). Spatio-Temporal Epidemiology and Associated '
'Indicators of COVID-19 (Wave-I and Ii) in India. Sci. Rep., 14.',
'DOI': '10.1038/s41598-023-50363-2'},
{ 'key': 'ref_6',
'doi-asserted-by': 'crossref',
'first-page': '312',
'DOI': '10.1136/postgradmedj-2020-138577',
'article-title': 'COVID-19: Current Understanding of Its Pathophysiology, Clinical '
'Presentation and Treatment',
'volume': '97',
'author': 'Parasher',
'year': '2020',
'journal-title': 'Postgrad. Med. J.'},
{ 'key': 'ref_7',
'doi-asserted-by': 'crossref',
'first-page': '1031',
'DOI': '10.1038/s41591-022-01780-9',
'article-title': 'Safety, Tolerability and Viral Kinetics During SARS-CoV-2 Human '
'Challenge in Young Adults',
'volume': '28',
'author': 'Killingley',
'year': '2022',
'journal-title': 'Nat. Med.'},
{ 'key': 'ref_8',
'doi-asserted-by': 'crossref',
'first-page': '1347',
'DOI': '10.1038/s41401-020-00556-6',
'article-title': 'Identification of SARS-CoV-2 Entry Inhibitors among Already Approved '
'Drugs',
'volume': '42',
'author': 'Yang',
'year': '2021',
'journal-title': 'Acta Pharmacol. Sin.'},
{ 'key': 'ref_9',
'doi-asserted-by': 'crossref',
'first-page': '2526',
'DOI': '10.1021/acsmedchemlett.0c00521',
'article-title': 'Identification of 14 Known Drugs as Inhibitors of the Main Protease of '
'SARS-CoV-2',
'volume': '11',
'author': 'Ghahremanpour',
'year': '2020',
'journal-title': 'ACS Med. Chem. Lett.'},
{ 'key': 'ref_10',
'doi-asserted-by': 'crossref',
'first-page': '2487',
'DOI': '10.1007/s11224-020-01605-w',
'article-title': 'Repurposing Metocurine as Main Protease Inhibitor to Develop novel '
'Antiviral Therapy for COVID-19',
'volume': '31',
'author': 'Jain',
'year': '2020',
'journal-title': 'Struct. Chem.'},
{ 'key': 'ref_11',
'doi-asserted-by': 'crossref',
'first-page': '236',
'DOI': '10.6026/97320630016236',
'article-title': 'Molecular Docking And Dynamics Simulation of FDA Approved Drugs with '
'the Main Protease from 2019 Novel Coronavirus',
'volume': '16',
'author': 'Odhar',
'year': '2020',
'journal-title': 'Bioinformation'},
{ 'key': 'ref_12',
'doi-asserted-by': 'crossref',
'first-page': '173',
'DOI': '10.1016/j.bbrc.2020.11.095',
'article-title': 'Identification of Antiviral Antihistamines for COVID-19 Repurposing',
'volume': '538',
'author': 'Reznikov',
'year': '2021',
'journal-title': 'Biochem. Biophys. Res. Commun.'},
{ 'key': 'ref_13',
'doi-asserted-by': 'crossref',
'unstructured': 'Konrat, R., Papp, H., Kimpel, J., Rössler, A., Szijártó, V., Nagy, G., '
'Madai, M., Zeghbib, S., Kuczmog, A., and Lanszki, Z. (2022). The '
'Anti-Histamine Azelastine, Identified by Computational Drug Repurposing, '
'Inhibits Infection by Major Variants of SARS-CoV-2 in Cell Cultures and '
'Reconstituted Human Nasal Tissue. Front. Pharmacol., 13.',
'DOI': '10.3389/fphar.2022.861295'},
{ 'key': 'ref_14',
'doi-asserted-by': 'crossref',
'unstructured': 'Fischhuber, K., Bánki, Z., Kimpel, J., Kragl, N., Rössler, A., Bolze, '
'A., Muellauer, B., Angerer, J., Nagy, G., and Nagy, E. (2023). Antiviral '
'Potential of Azelastine against Major Respiratory Viruses. Viruses, 15.',
'DOI': '10.3390/v15122300'},
{ 'key': 'ref_15',
'doi-asserted-by': 'crossref',
'unstructured': 'Klussmann, J.P., Grosheva, M., Meiser, P., Lehmann, C., Nagy, E., '
'Szijártó, V., Nagy, G., Konrat, R., Flegel, M., and Holzer, F. (2023). '
'Early Intervention with Azelastine Nasal Spray may Reduce Viral Load in '
'SARS-CoV-2 infected patients. Sci. Rep., 13.',
'DOI': '10.1038/s41598-023-32546-z'},
{ 'key': 'ref_16',
'unstructured': 'AIIMS/ICMR-COVID-19 National Task Force/Joint Monitoring Group (2024, '
'December 01). AIIMS/ICMR-COVID-19 National Task Force/Joint Monitoring '
'Group (Dte.GHS) Ministry of Health & Family Welfare, Government of '
'India. Clinical Guidance for the Syndromic Management of Suspected '
'COVID–19 Cases, Available online: '
'https://dghs.gov.in/WriteReadData/News/202104290258250563281SyndromicapproachforCOVID-19.pdf.'},
{ 'key': 'ref_17',
'doi-asserted-by': 'crossref',
'first-page': 'e69302',
'DOI': '10.7554/eLife.69302',
'article-title': 'Quantifying the Relationship Between SARS-CoV-2 Viral Load and '
'Infectiousness',
'volume': '10',
'author': 'Marc',
'year': '2021',
'journal-title': 'eLife'},
{ 'key': 'ref_18',
'doi-asserted-by': 'crossref',
'first-page': '237',
'DOI': '10.1016/j.jinf.2021.05.009',
'article-title': 'Clinical Efficacy of Nitric Oxide Nasal Spray (Nons) for the Treatment '
'of Mild COVID-19 Infection',
'volume': '83',
'author': 'Winchester',
'year': '2021',
'journal-title': 'J. Infect.'},
{ 'key': 'ref_19',
'doi-asserted-by': 'crossref',
'first-page': '1325',
'DOI': '10.1080/14787210.2021.1908127',
'article-title': 'Low pH Hypromellose (Taffix) Nasal Powder Spray could Reduce SARS-CoV-2 '
'Infection Rate Post Mass-Gathering Event at a Highly Endemic Community: '
'An Observational Prospective Open Label User Survey',
'volume': '19',
'author': 'Shmuel',
'year': '2021',
'journal-title': 'Expert Rev. Anti Infect. Ther.'},
{ 'key': 'ref_20',
'first-page': 'e31508',
'article-title': 'Efficacy and Safety of Molnupiravir in Mild COVID-19 Patients in India',
'volume': '14',
'author': 'Sinha',
'year': '2022',
'journal-title': 'Cureus'},
{ 'key': 'ref_21',
'doi-asserted-by': 'crossref',
'first-page': '509',
'DOI': '10.1056/NEJMoa2116044',
'article-title': 'Molnupiravir for Oral Treatment of COVID-19 in Nonhospitalized Patients',
'volume': '386',
'author': 'Bernal',
'year': '2022',
'journal-title': 'N. Eng. J. Med.'},
{ 'key': 'ref_22',
'doi-asserted-by': 'crossref',
'first-page': '100036',
'DOI': '10.1016/j.lansea.2022.100036',
'article-title': 'SARS-CoV-2 Accelerated Clearance Using a Novel Nitric Oxide Nasal Spray '
'(Nons) Treatment: A Randomized Trial',
'volume': '3',
'author': 'Tandon',
'year': '2022',
'journal-title': 'Lancet Reg. Health Southeast Asia'},
{ 'key': 'ref_23',
'doi-asserted-by': 'crossref',
'unstructured': 'Dings, C., Meiser, P., Holzer, F., Flegel, M., Selzer, D., Nagy, E., '
'Mösges, R., Klussmann, J.P., and Lehr, T. (2022). Pharmacometric '
'Modeling of the Impact of Azelastine Nasal Spray on SARS-CoV-2 Viral '
'Load and Related Symptoms in COVID-19 Patients. Pharmaceutics, 14.',
'DOI': '10.3390/pharmaceutics14102059'}],
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