Clinical trial NCT04370782: Hydroxychloroquine and Zinc With Either Azithromycin or Doxycycline for Treatment of COVID-19 in Outpatient Setting
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: COVID-19
Keywords: coronavirus
hydroxychloroquine
zinc sulfate
Lead sponsor: St. Francis Hospital, New York
Sponsor class: OTHER
First posted: 2020-05-01
Enrollment: 18
Sex: ALL
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Time to Resolution of Symptoms relative to baseline (day 1 of trial)
timeFrame: Day 5
measure: Time to Resolution of Symptoms relative to baseline (day 1 of trial)
timeFrame: Day 14
measure: Time to Resolution of Symptoms relative to baseline (day 1 of trial)
timeFrame: Day 21
measure: Number of participants hospitalized and/or requiring repeat ER visits
timeFrame: 21 days
measure: ICU Length of Stay
timeFrame: Until Discharged up to 30 days
measure: Ventilator
timeFrame: Until extubated up to 30 days
Secondary outcomes:
measure: Severity of symptoms
timeFrame: Day 5, Day 14, and Day 21
measure: Number of participants with adverse events due to drug regimen
timeFrame: 21 days
measure: Number of participants with QTc prolongation >500ms
timeFrame: Days 1 thru 5, Day 10, Day 21
Other outcomes:
Locations:
city: Roslyn
country: United States
facility: St Francis Hospital
state: New York
Study officials:
affiliation: Saint Francis Hospital
name: Avni Thakore, MD
role: PRINCIPAL_INVESTIGATOR
References:
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. No abstract available.
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.
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.
citation: Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Tissot Dupont H, Honore S, Colson P, Chabriere E, La Scola B, Rolain JM, Brouqui P, Raoult D. RETRACTED: 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.
citation: Kim AHJ, Sparks JA, Liew JW, Putman MS, Berenbaum F, Duarte-Garcia A, Graef ER, Korsten P, Sattui SE, Sirotich E, Ugarte-Gil MF, Webb K, Grainger R; COVID-19 Global Rheumatology Alliance. 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.
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.
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. doi: 10.1128/JVI.18.1.298-306.1976.
citation: Katz E, Margalith E. Inhibition of vaccinia virus maturation by zinc chloride. Antimicrob Agents Chemother. 1981 Feb;19(2):213-7. doi: 10.1128/AAC.19.2.213.
citation: Kumel 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. doi: 10.1099/0022-1317-71-12-2989.
citation: Suara RO, Crowe JE Jr. Effect of zinc salts on respiratory syncytial virus replication. Antimicrob Agents Chemother. 2004 Mar;48(3):783-90. doi: 10.1128/AAC.48.3.783-790.2004.
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. doi: 10.1128/AAC.25.1.20.
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.
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.
citation: 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. doi: 10.1152/ajplung.00341.2005. Epub 2005 Nov 11.
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.