Chloroquine nasal drops in asymptomatic & mild COVID-19: An exploratory randomized clinical trial
Alok Thakar, Smriti Panda, Pirabu Sakthivel, Megha Brijwal, Shivram Dhakad, Avinash Choudekar, Anupam Kanodia, Sushma Bhatnagar, Anant Mohan, Subir K Maulik, Lalit Dar
Indian Journal of Medical Research, doi:10.4103/ijmr.ijmr_3665_20
Background & objectives: Chloroquine (CQN) administered as nasal drops has the potential to achieve much greater local tissue levels than with oral/systemic administration. This trial was undertaken to study the efficacy and safety profile of topical nasal administration of CQN drops in reducing viral load and preventing clinical progression in early COVID-19 infection. Methods: This randomized clinical trial was done with a sample size of 60. Reverse transcriptionpolymerase chain reaction (RT-PCR) confirmed asymptomatic patients or those with mild COVID-19 illness [National Early Warning Score (NEWS) ≤4] were included. Patients were randomized in a 1:1 manner. Control arm (standard supportive treatment, n=30) was compared with intervention arm (n=30) of standard treatment plus CQN eye drops (0.03%) repurposed as nasal drops administered six times daily (0.5 ml/dose) for 10 days. Outcome measures were adverse events and adherence; clinical progression and outcomes were measured by NEWS; sequential RT-PCR cycle threshold (Ct) values were also noted on days 0, 3, 7 and 10. Results: Nasal CQN was associated with local irritation in seven and non-compliance in one of 30 patients. Eleven patients were excluded due to enrolment error (2 -recovered; 9 -false-positive referral), and 49 patients were analyzed as per modified intention-to-treat analysis. Clinical recovery was noted as similar with 100 per cent asymptomatic by day seven in both arms. Virological outcomes also indicated similarly improving Ct values in both arms, and similar proportion of patients transitioning to non-infectivity by day 10 (controls -19/25; nasal CQN -15/24). Nine false-positive patients with enrolment error and day 0 RT-PCR negative were initially uninfected but had continuing COVID-19 exposure and treatment as per randomization. Patients receiving nasal CQN (n=5) demonstrated stable Ct values from day 0 to 10, while patients with no nasal CQN (n=4) demonstrated significant dip in Ct value indicating to infection (Ct<35) and infectivity (Ct<33). Interpretation & conclusions: The present study suggests to the potential of topical nasal CQN in the prevention of COVID-19 infection if administered before the infection is established. No significant differences in clinical or virological outcome were however, demonstrated in patients with mild but established illness.
Conflicts of Interest: None.
References
Bhavsar, Bhavsar, Jain, Evaluation of the effects of chloroquine phosphate eye drops in patients with dry eye syndrome, Int J Biomed Adv Res
Borba, Val, Sampaio, Alexandre, Melo et al., Effect of high vs. low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: A randomized clinical trial, JAMA Netw Open
Boulware, Pullen, Bangdiwala, Pastick, Lofgren et al., A randomized trial of hydroxychloroquine as postexposure prophylaxis for COVID-19, N Engl J Med
Chatterjee, Anand, Singh, Rasaily, Singh et al., Healthcare workers & SARS-CoV-2 infection in India: A case-control investigation in the time of COVID-19, Indian J Med Res
Clinicaltrials, Healthcare Worker Exposure Response and Outcomes of Hydroxychloroquine (HERO-HCQ)
Elavarasi, Prasad, Seth, Sahoo, Madan et al., Chloroquine and hydroxychloroquine for the treatment of COVID-19: A systematic review and meta-analysis, J Gen Intern Med
Gao, Tian, Yang, Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies, Biosci Trends
Gautret, Lagier, Parola, Hoang, Meddeb et al., Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label nonrandomized clinical trial, Int J Antimicrob Agents
Keyaerts, Li, Vijgen, Rysman, Verbeeck et al., Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice, Antimicrob Agents Chemother
Keyaerts, Vijgen, Maes, Neyts, Van Ranst, In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine, Biochem Biophys Res Commun
Lee, Son, Peck, Can post-exposure prophylaxis for COVID-19 be considered as an outbreak response strategy in long-term care hospitals?, Int J Antimicrob Agents
Million, Lagier, Gautret, Colson, Fournier et al., Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France, Travel Med Infect Dis
Rio, Malani, Translating science on COVID-19 to improve clinical care and support the public health response, JAMA
Risch, Early outpatient treatment of symptomatic, highrisk COVID-19 patients that should be ramped up immediately as key to the pandemic crisis, Am J Epidemiol
Rosenberg, Dufort, Udo, Wilberschied, Kumar et al., Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in new york state, JAMA
Savarino, Trani, Donatelli, Cauda, Cassone, New insights into the antiviral effects of chloroquine, Lancet Infect Dis
Scola, Bideau, Andreani, Hoang, Grimaldier et al., Viral RNA load as determined by cell culture as a management tool for discharge of SARS-CoV-2 patients from infectious disease wards, Eur J Clin Microbiol Infect Dis
Titiyal, Kaur, Falera, Bharghava, Sah et al., Efficacy and safety of topical chloroquine in mild to moderate dry eye disease, Curr Eye Res
Trial, No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19
Wang, Cao, Zhang, Yang, Liu et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res
Wang, Wu, Zuo, You, Yang et al., Evaluation of current medical approaches for COVID-19: A systematic review and meta-analysis, BMJ Support Palliat Care
Yang, Chou, Yang, Chien, Yarmishyn et al., Systematic review and meta-analysis of the effectiveness and safety of hydroxychloroquine in treating COVID-19 Patients, J Chin Med Assoc,
doi:10.1097/JCMA.0000000000000425Yao, Ye, Zhang, Cui, Huang et al., In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Clin Infect Dis
Zang, Han, He, Shi, Li, Hydroxychloroquine use and progression or prognosis of COVID-19: A systematic review and meta-analysis, Naunyn Schmiedebergs Arch Pharmacol
DOI record:
{
"DOI": "10.4103/ijmr.ijmr_3665_20",
"ISSN": [
"0971-5916"
],
"URL": "http://dx.doi.org/10.4103/ijmr.IJMR_3665_20",
"alternative-id": [
"307446"
],
"author": [
{
"affiliation": [],
"family": "Thakar",
"given": "Alok",
"sequence": "first"
},
{
"affiliation": [],
"family": "Panda",
"given": "Smriti",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Sakthivel",
"given": "Pirabu",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Brijwal",
"given": "Megha",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Dhakad",
"given": "Shivram",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Choudekar",
"given": "Avinash",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Kanodia",
"given": "Anupam",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Bhatnagar",
"given": "Sushma",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Mohan",
"given": "Anant",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Maulik",
"given": "SubirK",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Dar",
"given": "Lalit",
"sequence": "additional"
}
],
"container-title": "Indian Journal of Medical Research",
"container-title-short": "Indian J Med Res",
"content-domain": {
"crossmark-restriction": false,
"domain": []
},
"created": {
"date-parts": [
[
2021,
1,
19
]
],
"date-time": "2021-01-19T12:07:22Z",
"timestamp": 1611058042000
},
"deposited": {
"date-parts": [
[
2024,
4,
18
]
],
"date-time": "2024-04-18T16:32:58Z",
"timestamp": 1713457978000
},
"indexed": {
"date-parts": [
[
2024,
4,
19
]
],
"date-time": "2024-04-19T00:39:47Z",
"timestamp": 1713487187635
},
"is-referenced-by-count": 4,
"issue": "1",
"issued": {
"date-parts": [
[
2021
]
]
},
"journal-issue": {
"issue": "1",
"published-print": {
"date-parts": [
[
2021
]
]
}
},
"language": "en",
"member": "10894",
"original-title": [],
"page": "151",
"prefix": "10.25259",
"published": {
"date-parts": [
[
2021
]
]
},
"published-print": {
"date-parts": [
[
2021
]
]
},
"publisher": "Scientific Scholar",
"reference": [
{
"DOI": "10.1016/j.bbrc.2004.08.085",
"article-title": "In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine",
"author": "Keyaerts",
"doi-asserted-by": "crossref",
"first-page": "264",
"journal-title": "Biochem Biophys Res Commun",
"key": "key-10.4103/0971-5916.307446-1",
"year": "2004"
},
{
"DOI": "10.1128/AAC.01509-08",
"article-title": "Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice",
"author": "Keyaerts",
"doi-asserted-by": "crossref",
"first-page": "3416",
"journal-title": "Antimicrob Agents Chemother",
"key": "key-10.4103/0971-5916.307446-2",
"year": "2009"
},
{
"DOI": "10.1038/s41422-020-0282-0",
"article-title": "Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro",
"author": "Wang",
"doi-asserted-by": "crossref",
"first-page": "269",
"journal-title": "Cell Res",
"key": "key-10.4103/0971-5916.307446-3",
"year": "2020"
},
{
"DOI": "10.1093/cid/ciaa237",
"article-title": "In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)",
"author": "Yao",
"doi-asserted-by": "crossref",
"first-page": "732",
"journal-title": "Clin Infect Dis",
"key": "key-10.4103/0971-5916.307446-4",
"year": "2020"
},
{
"DOI": "10.1016/S1473-3099(06)70361-9",
"article-title": "New insights into the antiviral effects of chloroquine",
"author": "Savarino",
"doi-asserted-by": "crossref",
"first-page": "67",
"journal-title": "Lancet Infect Dis",
"key": "key-10.4103/0971-5916.307446-5",
"year": "2006"
},
{
"DOI": "10.5582/bst.2020.01047",
"article-title": "Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies",
"author": "Gao",
"doi-asserted-by": "crossref",
"first-page": "72",
"journal-title": "Biosci Trends",
"key": "key-10.4103/0971-5916.307446-6",
"year": "2020"
},
{
"DOI": "10.1016/j.ijantimicag.2020.105949",
"article-title": "Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial",
"author": "Gautret",
"doi-asserted-by": "crossref",
"first-page": "105949",
"journal-title": "Int J Antimicrob Agents",
"key": "key-10.4103/0971-5916.307446-7",
"year": "2020"
},
{
"DOI": "10.1016/j.tmaid.2020.101738",
"doi-asserted-by": "crossref",
"key": "key-10.4103/0971-5916.307446-8",
"unstructured": "Million M, Lagier JC, Gautret P, Colson P, Fournier PE, Amrane S, et al. Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France. Travel Med Infect Dis 2020; 35 : 101738."
},
{
"DOI": "10.1001/jama.2020.8630",
"article-title": "Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in new york state",
"author": "Rosenberg",
"doi-asserted-by": "crossref",
"first-page": "2493",
"journal-title": "JAMA",
"key": "key-10.4103/0971-5916.307446-9",
"year": "2020"
},
{
"DOI": "10.1001/jamanetworkopen.2020.8857",
"article-title": "Effect of high vs.low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: A randomized clinical trial",
"author": "Borba",
"doi-asserted-by": "crossref",
"first-page": "e208857",
"journal-title": "JAMA Netw Open",
"key": "key-10.4103/0971-5916.307446-10",
"year": "2020"
},
{
"key": "key-10.4103/0971-5916.307446-11",
"unstructured": "RECOVERY Trial. No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19. Available from: https://www.recoverytrial.net/news/statement-from-the-chief-investigators-of-the-rand omised-evaluation-of-covid-19-therapy-recovery-trial-on-hydroxychloroquine-5-june-2020-no-clinical-benefit-from-use-of-hydroxychloroquine-in-hospitalised-patients-with-covid-19, accessed on June 26, 2020."
},
{
"key": "key-10.4103/0971-5916.307446-12",
"unstructured": "Solidarity Clinical Trial for COVID-19 Treatments. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments, accessed on June 26, 2020."
},
{
"DOI": "10.1001/jama.2020.9252",
"article-title": "Translating science on COVID-19 to improve clinical care and support the public health response",
"author": "Del",
"doi-asserted-by": "crossref",
"first-page": "2464",
"journal-title": "JAMA",
"key": "key-10.4103/0971-5916.307446-13",
"year": "2020"
},
{
"DOI": "10.1093/aje/kwaa093",
"article-title": "Early outpatient treatment of symptomatic, high-risk COVID-19 patients that should be ramped up immediately as key to the pandemic crisis",
"author": "Risch",
"doi-asserted-by": "crossref",
"first-page": "1218",
"journal-title": "Am J Epidemiol",
"key": "key-10.4103/0971-5916.307446-14",
"year": "2020"
},
{
"article-title": "Healthcare workers & SARS-CoV-2 infection in India: A case-control investigation in the time of COVID-19",
"author": "Chatterjee",
"first-page": "459",
"journal-title": "Indian J Med Res",
"key": "key-10.4103/0971-5916.307446-15",
"year": "2020"
},
{
"key": "key-10.4103/0971-5916.307446-16",
"unstructured": "Royal College of Physicians. National Early Warning Score (NEWS) 2. Available from: https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-score-news-2, accessed on June 14, 2020."
},
{
"DOI": "10.1080/02713683.2019.1641824",
"article-title": "Efficacy and safety of topical chloroquine in mild to moderate dry eye disease",
"author": "Titiyal",
"doi-asserted-by": "crossref",
"first-page": "1306",
"journal-title": "Curr Eye Res",
"key": "key-10.4103/0971-5916.307446-17",
"year": "2019"
},
{
"article-title": "Evaluation of the effects of chloroquine phosphate eye drops in patients with dry eye syndrome",
"author": "Bhavsar",
"first-page": "198",
"journal-title": "Int J Biomed Adv Res",
"key": "key-10.4103/0971-5916.307446-18",
"year": "2011"
},
{
"article-title": "Viral RNA load as determined by cell culture as a management tool for discharge of SARS-CoV-2 patients from infectious disease wards",
"author": "La",
"first-page": "1059",
"journal-title": "Eur J Clin Microbiol Infect Dis",
"key": "key-10.4103/0971-5916.307446-19",
"year": "2020"
},
{
"DOI": "10.1007/s11606-020-06146-w",
"article-title": "Chloroquine and hydroxychloroquine for the treatment of COVID-19: A systematic review and meta-analysis",
"author": "Elavarasi",
"doi-asserted-by": "crossref",
"first-page": "3308",
"journal-title": "J Gen Intern Med",
"key": "key-10.4103/0971-5916.307446-20",
"year": "2020"
},
{
"DOI": "10.1007/s00210-020-01964-5",
"doi-asserted-by": "crossref",
"key": "key-10.4103/0971-5916.307446-21",
"unstructured": "Zang Y, Han X, He M, Shi J, Li Y. Hydroxychloroquine use and progression or prognosis of COVID-19: A systematic review and meta-analysis. Naunyn Schmiedebergs Arch Pharmacol 2020; 1-8."
},
{
"DOI": "10.1136/bmjspcare-2020-002554",
"doi-asserted-by": "crossref",
"key": "key-10.4103/0971-5916.307446-22",
"unstructured": "Wang M, Wu T, Zuo Z, You Y, Yang X, Pan L, et al. Evaluation of current medical approaches for COVID-19: A systematic review and meta-analysis. BMJ Support Palliat Care 2020; bmjspcare-2020-002554."
},
{
"DOI": "10.1101/2020.05.07.20093831",
"doi-asserted-by": "crossref",
"key": "key-10.4103/0971-5916.307446-23",
"unstructured": "Yang TH, Chou CY, Yang YF, Chien CS, Yarmishyn AA, Yang TY, et al. Systematic review and meta-analysis of the effectiveness and safety of hydroxychloroquine in treating COVID-19 Patients. J Chin Med Assoc 2020. doi: 10.1097/JCMA.0000000000000425."
},
{
"DOI": "10.1016/j.ijantimicag.2020.105988",
"article-title": "Can post-exposure prophylaxis for COVID-19 be considered as an outbreak response strategy in long-term care hospitals?",
"author": "Lee",
"doi-asserted-by": "crossref",
"first-page": "105988",
"journal-title": "Int J Antimicrob Agents",
"key": "key-10.4103/0971-5916.307446-24",
"year": "2020"
},
{
"DOI": "10.1056/NEJMoa2016638",
"article-title": "A randomized trial of hydroxychloroquine as postexposure prophylaxis for COVID-19",
"author": "Boulware",
"doi-asserted-by": "crossref",
"first-page": "517",
"journal-title": "N Engl J Med",
"key": "key-10.4103/0971-5916.307446-25",
"year": "2020"
},
{
"key": "key-10.4103/0971-5916.307446-26",
"unstructured": "ClinicalTrials.gov. Healthcare Worker Exposure Response and Outcomes of Hydroxychloroquine (HERO-HCQ). Available from: https://clinicaltrials.gov/ct2/show/NCT04334148, accessed on June 23, 2020."
}
],
"reference-count": 26,
"references-count": 26,
"relation": {},
"resource": {
"primary": {
"URL": "https://journals.lww.com/ijmr/Fulltext/2021/01000/Chloroquine_nasal_drops_in_asymptomatic___mild.12.aspx"
}
},
"score": 1,
"short-title": [],
"source": "Crossref",
"subject": [],
"subtitle": [],
"title": "Chloroquine nasal drops in asymptomatic & mild COVID-19: An exploratory randomized clinical trial",
"type": "journal-article",
"volume": "153"
}
