Hydroxychloroquine in Patients With Newly Diagnosed COVID-19 Compared to Standard of Care

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ClinicalTrials.gov Identifier: NCT04334967

Recruitment Status : Suspended (suspected unfavorable risk/benefit assessment)

First Posted : April 6, 2020

Last Update Posted : September 16, 2020

Sponsor:

Collaborators:

Center for Outcomes Research and Education

Providence Cancer Center, Earle A. Chiles Research Institute

Information provided by (Responsible Party):

Providence Health & Services

Study Description

Brief Summary:

This study will assess the efficacy of hydroxychloroquine in reducing the severity of symptoms in patients with COVID-19

Condition or disease	Intervention/treatment	Phase
COVID-19 Corona Virus Infection SARS-CoV-2 2019-nCoV 2019 Novel Coronavirus	Drug: Hydroxychloroquine Dietary Supplement: Vitamin C	Phase 4

Detailed Description:

Hydroxychloroquine has primarily been raised as a potential treatment of SARS-Cov-2 based on in vitro antiviral activity. A draft paper was released recently in March by Didier Raoult from Aix-Marseille University in France on a preliminary trial of 36 COVID-19 patients. In this trial, 6 patients were asymptomatic, 22 had upper respiratory symptoms, and 8 had lower respiratory symptoms. Between early and mid-March, they treated 20 of these patients with 600 mg of hydroxychloroquine daily in a hospital setting. Some patient also received the antibiotic azithromycin. 16 patients served as the controls. They observed a significant reduction in viral load in patients with hydroxychloroquine. After 6 days, 70% of the treated patients were considered cured (no virus detected in their samples) compared to 12.5% of controls. All 6 patients who received both hydroxychloroquine and azithromycin were negative for the virus after 6 days. This was an unblinded, non-randomized trial.

Vitamin C has multiple in-vivo effects on immune modulation that may, in sum, limit the development of the cytokine excess associated with critical illness. It is currently being studied in a clinical trial as a treatment for severe SARS-CoV-2 pneumonia in China and recommended as a supplement in standard treatment of COVID-19.

There are no medications currently approved for treatment of COVID-19. Hydroxychloroquine is a known drug with low toxicity that may reduce progression of respiratory symptoms and resulting hospitalizations. This randomized control study will assess its potential as an off-label treatment in reducing the rates of hospitalization and subsequent mechanical ventilation from COVID-19 infection compared to standard of care treatment with Vitamin C. A randomized control trial with placebo is impractical due to the increasing availability of this medication to the public.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	13 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Intervention Model Description:	Upon confirmation of positive nasopharyngeal test for SARS-CoV-2, eligible patients will be randomized 1:1 to either a treatment group or control group.
Masking:	Single (Outcomes Assessor)
Masking Description:	Analysts will be blinded to patient randomization; outcome data analyses will be conducted with patient identifiers removed.
Primary Purpose:	Treatment
Official Title:	Randomized Study to Evaluate the Safety and Antiviral Efficacy of Hydroxychloroquine in Patients With Newly Diagnosed COVID-19 Compared to Standard of Care Treatment
Actual Study Start Date :	March 30, 2020
Estimated Primary Completion Date :	May 27, 2021
Estimated Study Completion Date :	May 27, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: COVID-19 (Coronavirus Disease 2019) Vitamin C

Drug Information available for: Ascorbic acid Hydroxychloroquine Sodium ascorbate Hydroxychloroquine sulfate Magnesium ascorbate

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment Arm Patients in the treatment arm will receive 200 mg oral hydroxychloroquine. Day 1: 400 mg doses twice (800 mg total). Days 2-5: 200 mg dose twice (400 mg total daily).	Drug: Hydroxychloroquine Treatment arm medication will be administered on an outpatient basis. Due to the emergent health crisis, study drug will be delivered to patients by institution staff or contract courier using a non-contact protocol.
Active Comparator: Control Arm Patients in the control arm will receive 500 mg oral Vitamin C. Day 1: 1000 mg dose twice (2000 mg total) Days 2-5: 500 mg dose twice (1000 mg total daily).	Dietary Supplement: Vitamin C Control arm supplement will be administered on an outpatient basis. Due to the emergent health crisis, study supplies will be delivered to patients by institution staff or contract courier using a non-contact protocol. Other Name: ascorbic acid

Outcome Measures

Primary Outcome Measures :

Total Hospitalization [ Time Frame: 14 days ]
This outcome will be assessed by comparing the percentages of enrolled patients that are hospitalized in the treatment and control arms.
Total Mechanical Ventilation [ Time Frame: 14 days ]
This outcome will be assessed by comparing the percentages of enrolled patients that have received mechanical ventilation in the treatment and control arms.

Secondary Outcome Measures :

Fever intensity measure [ Time Frame: 2 days ]
Self-reported body temperature. Each report scored low (less than 100.4), medium (100.4-102.2), or high (higher than 102.2). Outcome will be assessed by calculating percentage of patients with reported high, medium, low temperature at specified time points.
Fever intensity measure [ Time Frame: 5 days ]
Self-reported body temperature. Each report scored low (less than 100.4), medium (100.4-102.2), or high (higher than 102.2). Outcome will be assessed by calculating percentage of patients with reported high, medium, low temperature at specified time points.
Fever intensity measure [ Time Frame: 10 days ]
Self-reported body temperature. Each report scored low (less than 100.4), medium (100.4-102.2), or high (higher than 102.2). Outcome will be assessed by calculating percentage of patients with reported high, medium, low temperature at specified time points.
Fever intensity measure [ Time Frame: 14 days ]
Self-reported body temperature. Each report scored low (less than 100.4), medium (100.4-102.2), or high (higher than 102.2). Outcome will be assessed by calculating percentage of patients with reported high, medium, low temperature at specified time points.
Shortness of breath measure [ Time Frame: 2 days ]
Self-reported worsening shortness of breath. Each report scored yes/no. Outcome will be assessed by calculating percentage of patients with reported worsening of shortness of breath at specified time points.
Shortness of breath measure [ Time Frame: 5 days ]
Self-reported worsening shortness of breath. Each report scored yes/no. Outcome will be assessed by calculating percentage of patients with reported worsening of shortness of breath at specified time points.
Shortness of breath measure [ Time Frame: 10 days ]
Self-reported worsening shortness of breath. Each report scored yes/no. Outcome will be assessed by calculating percentage of patients with reported worsening of shortness of breath at specified time points.
Shortness of breath measure [ Time Frame: 14 days ]
Self-reported worsening shortness of breath. Each report scored yes/no. Outcome will be assessed by calculating percentage of patients with reported worsening of shortness of breath at specified time points.
Changes in daytime cough measure [ Time Frame: 2 days ]
Self reported changes in daytime cough. Each report scored 0 (no cough), 1 (one short coughing attack), 2 (two or more short coughing attacks), 3 (frequent coughing that did not interfere with activities), 4 (frequent coughing that did interfere with activities, 5 (distressing cough throughout most of the day). Outcome will be measured by calculating change in reported cough at each time point.
Changes in daytime cough measure [ Time Frame: 5 days ]
Self reported changes in daytime cough. Each report scored 0 (no cough), 1 (one short coughing attack), 2 (two or more short coughing attacks), 3 (frequent coughing that did not interfere with activities), 4 (frequent coughing that did interfere with activities, 5 (distressing cough throughout most of the day). Outcome will be measured by calculating change in reported cough at each time point.
Changes in daytime cough measure [ Time Frame: 10 days ]
Self reported changes in daytime cough. Each report scored 0 (no cough), 1 (one short coughing attack), 2 (two or more short coughing attacks), 3 (frequent coughing that did not interfere with activities), 4 (frequent coughing that did interfere with activities, 5 (distressing cough throughout most of the day). Outcome will be measured by calculating change in reported cough at each time point.
Changes in daytime cough measure [ Time Frame: 14 days ]
Self reported changes in daytime cough. Each report scored 0 (no cough), 1 (one short coughing attack), 2 (two or more short coughing attacks), 3 (frequent coughing that did not interfere with activities), 4 (frequent coughing that did interfere with activities, 5 (distressing cough throughout most of the day). Outcome will be measured by calculating change in reported cough at each time point.
Changes in nighttime cough measure [ Time Frame: 2 days ]
Self reported changes in nighttime cough. Each report scored 0 (no cough), 1 (cough on waking only), 2 (wake once or early due to cough), 3 (frequent waking due to cough), 4 (frequent coughing throughout the night, 5 (distressing cough preventing any sleep). Outcome will be measured by calculating change in reported cough at each time point.
Changes in nighttime cough measure [ Time Frame: 5 days ]
Self reported changes in nighttime cough. Each report scored 0 (no cough), 1 (cough on waking only), 2 (wake once or early due to cough), 3 (frequent waking due to cough), 4 (frequent coughing throughout the night, 5 (distressing cough preventing any sleep). Outcome will be measured by calculating change in reported cough at each time point.
Changes in nighttime cough measure [ Time Frame: 10 days ]
Self reported changes in nighttime cough. Each report scored 0 (no cough), 1 (cough on waking only), 2 (wake once or early due to cough), 3 (frequent waking due to cough), 4 (frequent coughing throughout the night, 5 (distressing cough preventing any sleep). Outcome will be measured by calculating change in reported cough at each time point.
Changes in nighttime cough measure [ Time Frame: 14 days ]
Self reported changes in nighttime cough. Each report scored 0 (no cough), 1 (cough on waking only), 2 (wake once or early due to cough), 3 (frequent waking due to cough), 4 (frequent coughing throughout the night, 5 (distressing cough preventing any sleep). Outcome will be measured by calculating change in reported cough at each time point.
Total mortality [ Time Frame: 28 days ]
Number of enrolled patients who have died within the specified time frame

Eligibility Criteria

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Ages Eligible for Study:	45 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Must have positive nasopharyngeal swab for SARS-CoV-2 diagnosed via outpatient testing within the previous 48 hours
Age ≥ 45 years
Not hospitalized at the time of enrollment
Established care with Providence provider
Ability to understand a written or electronic informed consent document
Reliable access to a computer or smartphone that can facilitate study communications via remote messaging or telephone and willingness to provide daily verbal check ins

Exclusion Criteria:

Hypersensitivity to chloroquine or hydroxychloroquine
History of retinal disease (macular degeneration, diabetic retinopathy, retinal rear/detachment, retinitis pigmentosa)
History of seizure disorder
History of ventricular tachycardia/fibrillation, history of long-QT syndrome, or ICD
Current creatinine clearance <10 ml/min or on hemodialysis (as evidenced in EMR)
Known G6PD deficiency
Current use of the following medications: digoxin, amiodarone, flecainide, procainamide, oral dapsone. If other meds of concern, route to pharmacist to evaluate
Concomitant use of the following only at Pharmacist/Investigator discretion: Abiraterone acetate, agalsidase, conivaptan, dabrafenib, dacomitinib, dapsone (systemic), digoxin, enzalutamide, fexinidazole, flecainide, fusidic acid (systemic), idelalisib, mifepristone, mitotane, pimozide, amiodarone, digoxin, procainamide, propafenone, stiripentol
Currently on hospice
Women of childbearing potential must not be pregnant, and must avoid becoming pregnant while on treatment and for 30 days following treatment discontinuation. Men must avoid fathering a child while on treatment and for 30 days following treatment discontinuation
Any clinical factors such as bleeding, active infection, or psychiatric factors that in the judgment of the investigator would preclude safe participation and compliance with study procedures.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04334967

Locations

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United States, Oregon
Portland Providence Medical Center
Portland, Oregon, United States, 97213

Sponsors and Collaborators

Providence Health & Services

Center for Outcomes Research and Education

Providence Cancer Center, Earle A. Chiles Research Institute

Investigators

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Principal Investigator:	Brian Kendal, MD	Providence Medical Group Infectious Disease
Study Director:	Trista Johnson, PhD, MPH	Providence Ambulatory Quality and Clinical Services

More Information

Publications:

CDC COVID-19 Response Team. Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) - United States, February 12-March 16, 2020. MMWR Morb Mortal Wkly Rep. 2020 Mar 27;69(12):343-346. doi: 10.15585/mmwr.mm6912e2.

Cortegiani A, Ingoglia G, Ippolito M, Giarratano A, Einav S. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Crit Care. 2020 Jun;57:279-283. doi: 10.1016/j.jcrc.2020.03.005. Epub 2020 Mar 10.

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.

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 Mar 16;14(1):72-73. doi: 10.5582/bst.2020.01047. Epub 2020 Feb 19.

Novel Coronavirus (2019-nCOV) Situation Report - 1. World Health Organization (WHO), 21 January 2020.

Novel Coronavirus disease 2019 (2019-nCOV) Situation Report - 60. World Health Organization (WHO), 19 March 2020.

Tricou V, Minh NN, Van TP, Lee SJ, Farrar J, Wills B, Tran HT, Simmons CP. A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults. PLoS Negl Trop Dis. 2010 Aug 10;4(8):e785. doi: 10.1371/journal.pntd.0000785. Erratum in: PLoS Negl Trop Dis. 2012 Jun;6(6). doi:10.1371/annotation/8683caec-b309-46d7-bc47-dc9cc27108e4. PLoS Negl Trop Dis. 2012 Jun;6(6). doi:10.1371/annotation/c5c14905-8792-4d2e-8179-f8c70064e773. PLoS Negl Trop Dis. 2012 Jun;6(6). doi:10.1371/annotation/e00ee8fb-4ab9-46db-be8e-3696bb362db4.

Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Res. 2020 May;177:104762. doi: 10.1016/j.antiviral.2020.104762. Epub 2020 Mar 5. Review.

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.

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Responsible Party:	Providence Health & Services
ClinicalTrials.gov Identifier:	NCT04334967
Other Study ID Numbers:	2020000186
First Posted:	April 6, 2020 Key Record Dates
Last Update Posted:	September 16, 2020
Last Verified:	May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

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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

Additional relevant MeSH terms:

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COVID-19 Hydroxychloroquine Coronavirus Infections Respiratory Tract Infections Infections Pneumonia, Viral Pneumonia Virus Diseases Coronaviridae Infections Nidovirales Infections RNA Virus Infections Lung Diseases Respiratory Tract Diseases	Ascorbic Acid Vitamins Micronutrients Physiological Effects of Drugs Antimalarials Antiprotozoal Agents Antiparasitic Agents Anti-Infective Agents Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antirheumatic Agents Antioxidants Protective Agents

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