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

• ClinicalTrials.gov Identifier: NCT04370782
• Recruitment Status: Completed
• First Posted: May 1, 2020
• Last Update Posted: December 9, 2020
• Sponsor: St. Francis Hospital, New York
• Information provided by (Responsible Party): Avni Thakore MD, St. Francis Hospital, New York

Study Description

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.

Condition or disease	Intervention/treatment	Phase
COVID-19	Drug: Hydroxychloroquine; Drug: Azithromycin; Drug: Zinc Sulfate; Drug: Doxycycline	Phase 4

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: April 28, 2020
• Actual Primary Completion Date: September 30, 2020
• Actual Study Completion Date: September 30, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Time to Resolution of Symptoms relative to baseline (day 1 of trial) [ Time Frame: Day 5 ]
   Patients will be assessed on day 5 for when COVID-19 symptoms completely resolve compared to baseline (day 1 of trial)
2. Time to Resolution of Symptoms relative to baseline (day 1 of trial) [ Time Frame: Day 14 ]
   Patients will be assessed on day 14 for when COVID-19 symptoms completely resolve compared to baseline (day 1 of trial)
3. Time to Resolution of Symptoms relative to baseline (day 1 of trial) [ Time Frame: Day 21 ]
   Patients will be assessed on day 21 for when COVID-19 symptoms completely resolve compared to baseline (day 1 of trial)
4. Number of participants hospitalized and/or requiring repeat ER visits [ Time Frame: 21 days ]
   Number of participants hospitalized and/or requiring repeat ER visits related to COVID-19 complications
5. ICU Length of Stay [ Time Frame: Until Discharged up to 30 days ]
   If hospitalized, number of participants admitted to the ICU, and number of days in the ICU
6. Ventilator [ Time Frame: Until extubated up to 30 days ]
   If placed on ventilator, number of days on a ventilator

Secondary Outcome Measures :

1. Severity of symptoms [ Time Frame: Day 5, Day 14, and Day 21 ]
   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)
2. Number of participants with adverse events due to drug regimen [ Time Frame: 21 days ]
   Number of participants with adverse events due to drug regimen
3. Number of participants with QTc prolongation >500ms [ Time Frame: Days 1 thru 5, Day 10, Day 21 ]
   Assess all patients to evaluate for QTc prolongation >500ms

Eligibility Criteria

• Ages Eligible for Study: 30 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, New York

St Francis Hospital

Roslyn, New York, United States, 11576

Sponsors and Collaborators

St. Francis Hospital, New York

Investigators

• Principal Investigator: Avni Thakore, MD; Saint Francis Memorial Hospital

More Information

Publications:

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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.

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.

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. 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.

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. Erratum In: Ann Intern Med. 2020 Jun 16;172(12):844.

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.

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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.

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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.

• Responsible Party: Avni Thakore MD, Principal Investigator, St. Francis Hospital, New York
• ClinicalTrials.gov Identifier: NCT04370782
• Other Study ID Numbers: 20-21
• First Posted: May 1, 2020
• Last Update Posted: December 9, 2020
• Last Verified: December 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Avni Thakore MD, St. Francis Hospital, New York:

coronavirus; hydroxychloroquine; zinc sulfate

Additional relevant MeSH terms:

COVID-19; Coronavirus Infections; Coronaviridae Infections; Hydroxychloroquine; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Azithromycin; Doxycycline; Zinc Sulfate; Anti-Bacterial Agents; Anti-Infective Agents; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Astringents; Physiological Effects of Drugs; Dermatologic Agents