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CTRI Number  CTRI/2020/04/024729 [Registered on: 20/04/2020] Trial Registered Prospectively
Last Modified On: 20/04/2020
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Other 
Public Title of Study   Topical Chloroquine Nasal Drops in Early Stage Covid 19- Impact on Viral load and cure rates  
Scientific Title of Study   Topical Chloroquine Nasal Drops in Early Stage Covid 19- Impact on Viral load and cure rates  
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
NIL  NIL 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Alok Thakar 
Designation  Professor 
Affiliation  AIIMS, New Delhi 
Address  Department of Otolaryngology and Head and Neck Surgery, Teaching Block 4th Floor, AIIMS, Ansari Nagar East, New Delhi

New Delhi
DELHI
110029
India 
Phone    
Fax    
Email  drathakar@gmail.com  
 
Details of Contact Person
Scientific Query
 
Name  Alok Thakar 
Designation  Professor 
Affiliation  AIIMS, New Delhi 
Address  Department of Otolaryngology and Head and Neck Surgery, Teaching Block 4th Floor, AIIMS, Ansari Nagar East, New Delhi

New Delhi
DELHI
110029
India 
Phone    
Fax    
Email  drathakar@gmail.com  
 
Details of Contact Person
Public Query
 
Name  Alok Thakar 
Designation  Professor 
Affiliation  AIIMS, New Delhi 
Address  Department of Otolaryngology and Head and Neck Surgery, Teaching Block 4th Floor, AIIMS, Ansari Nagar East, New Delhi

New Delhi
DELHI
110029
India 
Phone    
Fax    
Email  drathakar@gmail.com  
 
Source of Monetary or Material Support  
All India Institute of Medical Sciences, New Delhi 
 
Primary Sponsor  
Name  All India Institute of Medical Sciences New Delhi 
Address  Ansari Nagar East, New Delhi 110029 
Type of Sponsor  Research institution 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study  
No of Sites = 1  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Prof Alok Thakar  National Cancer Institute  NCI Jhajjar. Badsa, Haryana
Jhajjar
HARYANA 
9999755916

drathakar@gmail.com 
 
Details of Ethics Committee  
No of Ethics Committees= 1  
Name of Committee  Approval Status 
Institute Ethics Committee, AIIMS, New Delhi  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Not Applicable 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  (1) ICD-10 Condition: B972||Coronavirus as the cause of diseases classified elsewhere, (2) ICD-10 Condition: B338||Other specified viral diseases,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Comparator Agent  Standard Treatment  Control Arm - all treatments & observations recommended by the treatment team No nasal drops  
Intervention  Topical Nasal 0.03% chloroquine eye drops  To receive 0.03% Chloroquine drops 1ml – 6 times daily X 10 days. + all treatments & observations recommended by the treatment team  
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  85.00 Year(s)
Gender  Both 
Details  Adult patients testing positive on the RT-PCR Covid-19 test with minimal symptoms and no hypoxemia.  
 
ExclusionCriteria 
Details  Age<18 years
b) Pregnancy and lactation
c) Known hypersensitivity to chloroquine
d) known case of G6PD deficiency, Long QT syndrome and retinopathy
 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Centralized 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
1) The Ct values on Day 0, 3, 7, 10 shall be plotted on a graph for all patients.
2) The rate of decline for each patient shall be calculated.
The time to cure (Covid 19 RT PCR -ve.) shall be determined
3) The two groups shall be compared for
a. Rate of decline of Ct values
b. Time to Cure
c. Rate of Cure or alternate outcome
 
1) The Ct values on Day 0, 3, 7, 10 shall be plotted on a graph for all patients.
2) The rate of decline for each patient shall be calculated.
The time to cure (Covid 19 RT PCR -ve.) shall be determined
3) The two groups shall be compared for
a. Rate of decline of Ct values
b. Time to Cure
c. Rate of Cure or alternate outcome
 
 
Secondary Outcome  
Outcome  TimePoints 
Day of Cure  Day 3,7,10 of admission 
 
Target Sample Size   Total Sample Size="60"
Sample Size from India="60" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   Phase 2 
Date of First Enrollment (India)   21/04/2020 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="0"
Months="6"
Days="0" 
Recruitment Status of Trial (Global)   Not Applicable 
Recruitment Status of Trial (India)  Not Yet Recruiting 
Publication Details    
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Brief Summary  

Background:

Chloroquine [CQ] is used to prevent and treat malaria and is efficacious as an anti-inflammatory agent for the treatment of rheumatoid arthritis and lupus erythematosus. Chloroquine (C18H26ClN3), a 4-amino-quinoline, has been demonstrated to have broad-spectrum antiviral activities by increasing endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV in cell culture and in animal studies [1,2]. Interest in anti-corona virus treatments was generated after the SARS coronavirus epidemic of 2003 [1], and has now been greatly reignited with the Covid-19 epidemic ravaging the world. A recent open-label non-randomized clinical trial from France in humans infected with Covid 19 receiving the related compound hydro-chloroquine sulfate [HCQS] showed a rapid decline in viral cell counts and rapid progression to cure [3].

Mechanism of action:

Chloroquine has both antiviral and anti-inflammatory actions. Initial in-vitro evaluation indicates the anti-viral action of chloroquine is mediated by inhibition of the entry of the virus into the cells. On tissue culture therefore its efficacy is therefore noted to be maximal in the early phase of the tissue culture being infected, and its efficacy is noted to be limited in the late phase of the infection [1, 2]

 

Both CQ and HCQ are weak bases that are known to elevate the pH of acidic intracellular organelles, such as endosomes/lysosomes, essential for membrane fusion [4]. In addition, CQ could inhibit SARS-CoV entry through changing the glycosylation of ACE2 receptor and spike protein [5]. Time-of-addition experiment confirmed that HCQ effectively inhibited the entry step, as well as the post-entry stages of SARS-CoV-2, which was also found upon CQ treatment. Endosome maturation might be blocked by CQ at intermediate stages of endocytosis, resulting in failure of further transport of virions to the ultimate releasing site [6].

A number of recent publications have favoured the use of chloroquine and its related compound HCQS against the novel corona virus 2019-nCoV; SARS-CoV-2 [6-12]. Recently, the US Food and Drug Administration and the ICMR has recommended weekly HCQS for health care workers exposed to Covid-19 [13, 14]. However there is no data on usage of topical CQ against COVID-19 pandemic.

Topical chloroquine:

Topical 0.03% Chloroquine Eye Drops are used in the treatment of Dry Eye Disease (DED). A recently published prospective comparative pilot study in 150 patients with mild to moderate DED, from our institute, demonstrated its efficacy (and so its bio-availability) & superiority to artificial tear drops alone (Carboxy methyl cellulose). Further, there were also no adverse effects such as conjunctival hyperemia, increase in ocular irritation or pain, blurring of vision or decreased field of vision was reported in any case, indicating the safety of topical chloroquine drops [15].

Study proposal: [Dosage, safety, efficacy]

This study proposes to repurpose Chloroquine eye drops for nasal use in Covid-19 patients. There is no scientific evidence so far that eye drops is not safe for nasal mucosa. In fact, all eye drops administered to the eye, in any case rapidly transit to the nose via the naso-lacrimal duct. The demonstrated efficacy and safety of the available 0.03% Chloroquine eye drops (Uv Lubi Unims 0.03% Drops, Manufactured by FDC Ltd)., as also regulatory approval of the same indicates of its safety for such use [12].  The very low total dose per aliquot (0.3mg/ 1ml aliquot) again indicates to no concerns with regard to the total dose exceeding the oral systemic dose.  

 

The in-vitro studies report that the 50% effective concentration (EC50) of chloroquine for the inhibition of SARS-CoV to be 8.8 microMolar (282 ug/100ml), and for HCoV-OC43 to be 0.4 microMolar (12.8 ug/ml) [1, 2].  For novel SARS CoV -2, chloroquine at EC50 = 1.13 μM potently blocked virus infection and showed high safety index [7]. The concentration of chloroquine in the drops planned for treatment (0.03% i.e. 30 mg/ 100ml) is significantly above this EC50 and so inspires confidence with regard to efficacy.


Outcome measure-

        Nasal & Oropharyngeal Swabs on Day 0, Day 3, Day 7, Day 10 if necessary.

 (Day of admission taken as Day 0)

        Swabs shall be tested for  a) Covid 19 Ag

                                                  b) Ct ( cycles to Test +ve- surrogate marker of viral test load)

                                                                   

           

. Analysis-

1)      The Ct values on Day 0, 3, 7, 10 shall be plotted on a graph for all patients.

2)      The rate of decline for each patient shall be calculated.

The time to cure (Covid 19 RT PCR -ve.) shall be determined

3)      The two groups shall be compared for

a.       Rate of decline of Ct values

b.       Time to Cure

c.       Rate of Cure or alternate outcome

 

 

References:

 

1. Keyaerts E, Vijgen L,  Maes P, Neyts J,  Van Ranst M.  In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine.Biochem. Biophys. Res. Commun. 2004; 323:264–268.

2. Keyaerts E, Li S, Vijgen L, Rysman E, Verbeeck J, Van Ranst M, Maes P.  Antiviral Activity of Chloroquine against Human Coronavirus OC43 Infection in Newborn Mice. Antimicrobial Agents and Chemotherapy, 2009, 58: 3416–3421

3. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Dupont HT, Honoré S, Colson P, Chabrière E, La Scola B, Rolain JM, Brouqui P, Raoult D. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical  trial. Int J Antimicrob Agents. 2020 Mar 20:105949.

4. Mauthe, M. et al. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy 14, 1435–1455 (2018).

5. Savarino, A. et al. New insights into the antiviral effects of chloroquine. Lancet Infect. Dis. 6, 67–69 (2006)

6. Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. [Internet]. 2020;6:16. Available from: https://doi.org/10.1038/s41421-020-0156-0.

7. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020;10-0282.

8. Chen Z, Hu J, Zhang Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. Version 2. medRxiv 2020.03.22.20040758. [Preprint.] 10.1101/2020.03.22.20040758

9. Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, 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. 2020 Mar 9. pii: ciaa237. doi: 10.1093/cid/ciaa237. [Epub ahead of print]

10. 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 Feb 19. doi: 10.5582/bst.2020.01047. [Epub ahead of print]

11. Colson P, Rolain JM, Lagier JC, Brouqui P, Raoult D. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents. 2020 [Epub ahead of print]

12. Colson P, Rolain JM, Raoult D. Chloroquine for the 2019 novel coronavirus SARS-CoV- 2. Int J Antimicrob Agents. 2020 Feb 15:105923. doi: 10.1016/j.ijantimicag.2020.105923. [Epub ahead of print]

13. Lenzer J. Covid-19: US gives emergency approval to hydroxychloroquine despite lack of evidence. BMJ 2020;369:m1335. 10.1136/bmj.m1335 32238355

14. Indian Council for Medical Research. Recommendation for empiric use of hydroxychloroquine for prophylaxis of SARS-CoV-2 infection. https://icmr.nic.in/sites/ default/files/upload_documents/HCQ_Recommendation_22March_final_MM_V2.pdf. Accessed 3 April 2020

15. Titiyal JS, Kaur M, Falera R, Bharghava A, Sah R, Sen S. Efficacy and Safety of Topical Chloroquine in Mild to Moderate Dry Eye Disease. Curr Eye Res. 2019 Dec;44(12):1306-1312. doi: 10.1080/02713683.2019.1641824.

 


 
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