Hydroxychloroquine and Zinc With Either Azithromycin or Doxycycline for Treatment of COVID-19 in Outpatient Setting

COVID-19 Clinical Trial

Official title:

A Randomized Study Evaluating the Safety and Efficacy of Hydroxychloroquine and Zinc in Combination With Either Azithromycin or Doxycycline for the Treatment of COVID-19 in the Outpatient Setting

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04370782
• Other study ID #: 20-21
• Status: Completed
• Phase: Phase 4
• Start date: April 28, 2020
• Est. completion date: September 30, 2020

Study information

• Verified date: December 2020
• Source: St. Francis Hospital, New York
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a randomized, open-label trial to assess the safety and efficacy of hydroxychloroquine, and zinc in combination with either azithromycin or doxycycline in a higher risk COVID-19 positive outpatient population.

Description:

COVID-19 is an aggressive and contagious virus, found to have high mortality especially in persons with comorbidities (Age>60, hypertension [HTN], diabetes mellitus [DM], Cancer, and otherwise immunocompromised). Zinc is a supplement with possible antiviral properties, having been shown to have effect in the common cold, many of which are due to coronavirus. In addition, elderly patients and patients with co-morbidities have high incidence of zinc deficiency. We are repleting zinc in all patients and studying its direct effect in combination with hydroxychloroquine, and an antibiotic, either azithromycin or doxycycline to see if there is enhanced treatment efficacy in early COVID-19 infection and assess the safety of these two regimen.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 18
• Est. completion date: September 30, 2020
• Est. primary completion date: September 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years and older

Eligibility

Inclusion Criteria:

• Able to read and understand informed consent.

• High initial clinical suspicion by physician based on signs and symptoms (fever, cough, myalgias, fatigue, shortness of breath) followed by RT-PCR for confirmation of COVID-19 diagnosis

• Any gender

• Age 60 years and older

• Age 30-59 years with one or more of the following:

• abnormal lung exam

• abnormal oxygen staturation <95%

• abnormal chest x-ray or chest CT

• persistent fever >100.4 degrees Fahrenheit upon arrival to Emergency department (ED)

• one of the following co-morbidities: hypertension, diabetes mellitus, history of coronary artery disease, chronic kidney disease (CKD), asthma, chronic obstructive pulmonary disease, current or former smoker, or morbid obesity (Body Mass Index =35)

Exclusion Criteria:

• Pregnant or breastfeeding female

• Severe COVID-19 requiring admission for inpatient treatment

• Need for any oxygen supplementation

• Need for mechanical ventilatory support

• History of oxygen supplementation dependency

• History of cancer with ongoing chemotherapy or radiation therapy

• Concurrent antimicrobial therapy

• Known hypersensitivity to hydroxychloroquine or other 4-aminoquinoline compounds

• Already taking hydroxychloroquine or chloroquine within 1 month

• Known G6-PD deficiency

• History of retinopathy

• History of current cardiac diseases (heart failure, ventricular arrhythmias, Left bundle branch block and/or Right bundle branch block, QTc prolongation >480ms), or family history of sudden cardiac death

• Ongoing use of drugs that prolong the QTc interval (antipsychotics, antidepressants, class I and III antiarrhythmics, triptans)

• Severe renal disease: glomerular filtration rate (GFR) <30ml/min

• Severe hepatic impairment (elevated total bilirubin >2 mg/dL, decreased albumin <2.8 g/dL, signs of jaundice and ascites.)

• Active alcohol abuse (>5 drinks per day or >20 drinks per week.)

• Seizure disorder, currently on medications

• Known hypersensitivity to any tetracyclines.

Related Conditions & MeSH terms

• COVID-19

Intervention

Drug:
• Hydroxychloroquine
Hydroxychloroquine 400mg twice a day (BID) on day 1, followed by 200mg BID for days 2-5
• Azithromycin
Azithromycin 500mg on day 1, followed by 250mg once daily for days 2-5
• Zinc Sulfate
Zinc sulfate 220mg once daily for 5 days
• Doxycycline
Doxycycline 200 mg once daily for 5 days

Locations

Country	Name	City	State
United States	St Francis Hospital	Roslyn	New York

Sponsors (1)

Lead Sponsor	Collaborator
St. Francis Hospital, New York

Country where clinical trial is conducted

United States, 

References & Publications (15)

Bao S, Knoell DL. Zinc modulates airway epithelium susceptibility to death receptor-mediated apoptosis. Am J Physiol Lung Cell Mol Physiol. 2006 Mar;290(3):L433-41. Epub 2005 Nov 11. — View Citation

Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. 2020 May;55(5):105938. doi: 10.1016/j.ijantimicag.2020.105938. Epub 2020 Mar 12. — View Citation

Eby GA, Davis DR, Halcomb WW. Reduction in duration of common colds by zinc gluconate lozenges in a double-blind study. Antimicrob Agents Chemother. 1984 Jan;25(1):20-4. — View Citation

Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Tissot Dupont H, 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 Jul;56(1):105949. doi: 10.1016/j.ijantimicag.2020.105949. Epub 2020 Mar 20. — View Citation

Katz E, Margalith E. Inhibition of vaccinia virus maturation by zinc chloride. Antimicrob Agents Chemother. 1981 Feb;19(2):213-7. — View Citation

Kim AHJ, Sparks JA, Liew JW, Putman MS, Berenbaum F, Duarte-García A, Graef ER, Korsten P, Sattui SE, Sirotich E, Ugarte-Gil MF, Webb K, Grainger R. A Rush to Judgment? Rapid Reporting and Dissemination of Results and Its Consequences Regarding the Use of Hydroxychloroquine for COVID-19. Ann Intern Med. 2020 Jun 16;172(12):819-821. doi: 10.7326/M20-1223. Epub 2020 Mar 30. Erratum in: Ann Intern Med. 2020 Jun 16;172(12):844. — View Citation

Korant BD, Butterworth BE. Inhibition by zinc of rhinovirus protein cleavage: interaction of zinc with capsid polypeptides. J Virol. 1976 Apr;18(1):298-306. — View Citation

Kümel G, Schrader S, Zentgraf H, Daus H, Brendel M. The mechanism of the antiherpetic activity of zinc sulphate. J Gen Virol. 1990 Dec;71 ( Pt 12):2989-97. — View Citation

Singh M, Das RR. Zinc for the common cold. Cochrane Database Syst Rev. 2013 Jun 18;(6):CD001364. doi: 10.1002/14651858.CD001364.pub4. Review. Update in: Cochrane Database Syst Rev. 2015;(4):CD001364. — View Citation

Suara RO, Crowe JE Jr. Effect of zinc salts on respiratory syncytial virus replication. Antimicrob Agents Chemother. 2004 Mar;48(3):783-90. — View Citation

te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ, van Hemert MJ. Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. 2010 Nov 4;6(11):e1001176. doi: 10.1371/journal.ppat.1001176. — 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 2020 Feb 4. — View Citation

Wu C, Liu Y, Yang Y, Zhang P, Zhong W, Wang Y, Wang Q, Xu Y, Li M, Li X, Zheng M, Chen L, Li H. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm Sin B. 2020 May;10(5):766-788. doi: 10.1016/j.apsb.2020.02.008. Epub 2020 Feb 27. — View Citation

Xue J, Moyer A, Peng B, Wu J, Hannafon BN, Ding WQ. Chloroquine is a zinc ionophore. PLoS One. 2014 Oct 1;9(10):e109180. doi: 10.1371/journal.pone.0109180. eCollection 2014. — 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 Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020 Jul 28;71(15):732-739. doi: 10.1093/cid/ciaa237. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to Resolution of Symptoms relative to baseline (day 1 of trial)	Patients will be assessed on day 5 for when COVID-19 symptoms completely resolve compared to baseline (day 1 of trial)	Day 5
Primary	Time to Resolution of Symptoms relative to baseline (day 1 of trial)	Patients will be assessed on day 14 for when COVID-19 symptoms completely resolve compared to baseline (day 1 of trial)	Day 14
Primary	Time to Resolution of Symptoms relative to baseline (day 1 of trial)	Patients will be assessed on day 21 for when COVID-19 symptoms completely resolve compared to baseline (day 1 of trial)	Day 21
Primary	Number of participants hospitalized and/or requiring repeat ER visits	Number of participants hospitalized and/or requiring repeat ER visits related to COVID-19 complications	21 days
Primary	ICU Length of Stay	If hospitalized, number of participants admitted to the ICU, and number of days in the ICU	Until Discharged up to 30 days
Primary	Ventilator	If placed on ventilator, number of days on a ventilator	Until extubated up to 30 days
Secondary	Severity of symptoms	Severity of symptoms evaluated at day 5, day 14, and day 21 scored by the participant for feverishness, sore throat, cough, shortness of breath, myalgias. (0 =none; 1 = mild; 2 = moderate; 3 = severe)	Day 5, Day 14, and Day 21
Secondary	Number of participants with adverse events due to drug regimen	Number of participants with adverse events due to drug regimen	21 days
Secondary	Number of participants with QTc prolongation >500ms	Assess all patients to evaluate for QTc prolongation >500ms	Days 1 thru 5, Day 10, Day 21