Hydroxychloroquine in SARS-CoV-2 (COVID-19) Pneumonia Trial

Novel coronavirus SARS(Severe Acute Respiratory Syndrome)-CoV-2 was first identified during the outbreak in Wuhan, China in December 2019 with the now resulting pandemic. Aggressive supportive care is the mainstay of treatment currently and rescue with lung protective mechanical ventilation is essential for survival in patients with severe acute respiratory distress syndrome. Despite supportive care, mortality is significant in hospitalized patients in the U.S., especially among patients > 65 years of age. Pharmacologic treatments to decrease disease severity are urgently needed. Hydroxychloroquine is currently widely used for treatment of autoimmune disease including systemic lupus erythematosus and rheumatoid arthritis, and it has been used to prevent and treat malaria. In vitro and in vivo antiviral activity towards SARS-CoV-2 has been reported. Since hydroxychloroquine has been used for decades its properties as a drug are well known. The investigators propose a pragmatic trial of hydroxychloroquine in moderately ill hospitalized adults with SARS-CoV-2 pneumonia with the hypothesis that hydroxychloroquine reduces severity of acute lung injury caused by SARS-CoV-2 infection.

Study Overview

• Status: Withdrawn
• Conditions: COVID-19; SARS-CoV-2 Pneumonia
• Intervention / Treatment: Drug: Hydroxychloroquine

Detailed Description

Novel coronavirus SARS-CoV-2 was first identified during the outbreak in Wuhan, China in December 2019 with the now resulting pandemic. Aggressive supportive care is the mainstay of treatment currently and rescue with lung protective mechanical ventilation is essential for survival in patients with severe acute respiratory distress syndrome. Despite supportive care, mortality is significant in hospitalized patients in the U.S., especially among patients > 65 years of age. Pharmacologic treatments to decrease disease severity are urgently needed. Candidate treatments with antiviral activity and/or immune-modulating effects include hydroxychloroquine (HCQ), lopinavir/ritonavir, remdesivir, and tocilizumab among others. There is limited high quality clinical data prompting a dilemma of how to use and review potential treatments and ensure patient safety now as the pandemic begins to peak. There are also significant limitations in drug supplies at many institutions.

Hydroxychloroquine is currently widely used for treatment of autoimmune disease including systemic lupus erythematosus and rheumatoid arthritis, and it has been used to prevent and treat malaria. In vitro and in vivo antiviral activity towards SARS-CoV-2 has been reported. Since hydroxychloroquine has been used for decades its properties as a drug are well known. Pertinent adverse events to monitor in a hospitalized patient include QTc (corrected QT interval) prolongation, elevation of liver enzymes/acute liver injury, and hypokalemia.

Acute lung injury and progressive respiratory failure is the major cause of mortality in SARS-CoV-2 infection. In acute lung injury and respiratory distress syndrome, the severity of hypoxia is categorized by the Pao2/FIO2 (fraction of inspired oxygen) ration as mild (200 mm Hg<Pao2/Fio2≤300 mm Hg), moderate (100 mm Hg<Pao2/Fio2≤200 mm Hg), and severe (Pao2/Fio2 ≤100 mm Hg). A persistently low Pao2/Fio2 ratio is associated with worse outcomes and may be a marker of failure to respond to conventional therapy. PaO2/FIO2 is a clinically useful measure in patients regardless of if they are receiving noninvasive supplemental O2 or mechanical ventilation, and low ratios are associated with duration of ICU stay and hospital mortality.

The care of hospitalized patients with covid-19 is evolving with hospital guidelines arising across the U.S. with several commonalities. Patients receive clinical assessment, chest x-ray, covid-19 testing, basic labs (WBC, CMP), and additional labs based on protocol or clinical judgment (ABG, CRP-C reactive protein, LDH), antibiotics for possible bacterial pneumonia, acetaminophen for fever, supplemental O2, close monitoring for worsening respiratory status and consideration for mechanical ventilation. Since covid-19 is a novel illness, there is no proven clinically efficacious drug treatment. Candidate drugs are being used, some in the context of trials and others by physician discretion. Early intubation over escalating noninvasive support (ie. High flow nasal canula and bipap) has been adopted due to the frequency of rapidly worsening oxygenation, hemodynamic instability, and to protect staff from virus aerosolization. Low tidal volume ventilation and prone positioning are lung protective strategies used in critically ill covid-19 patients that are based on management of acute respiratory distress syndrome generally. Arrhythmias, cardiomyopathy, and shock are serious complications from covid-19 that warrant avoidance of acidosis, electrolyte monitoring and replacement, and pressor support. Conservative fluid replacement is used to avoid worsening oxygenation. In sum, multiple factors including timeliness and quality of care likely affect patient outcomes. Hospitalists and pulmonary critical care physicians direct the care of covid-19 patients with support from specialists as needed including infectious disease, cardiology, and nephrology.

Pragmatic trials focus on studying the real-world effect of an intervention, such as a medication, in the context of other care a patient is likely to receive. The intervention is delivered by staff normally taking care of the patient with monitoring that is routinely available. Advantages can include generalizability, increased physician participation due to less burdensome study protocols, and feasibility. Disadvantages include allowance of unblinded design, bias from physicians and patients about the intervention, and more heterogeneity in treatment than in a mechanistic protocolized trial. Efforts to minimize bias include selecting objective outcomes (e.g. PaO2/FIO2 rather than cough or dyspnea).

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Idaho
    • Coeur d'Alene, Idaho, United States, 83814
      • Kootenai Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age > 18 years of age
2. SARS-CoV-2 positive per FDA approved RT-PCR (reverse transcription-polymerase chain reaction)
3. Acute hypoxia (O2 sat < 90 % or paO2 < 60 on room air), or above baseline chronic O2 requirement
4. Inpatient admission

Exclusion Criteria:

1. Requires supplemental O2 >10 litres per minute or mechanical ventilation on admission
2. Pregnancy
3. AST/ALT > 5 times the upper limit normal
4. Baseline prolonged QT
5. Child-Pugh Score B or greater
6. ESRD(end-stage renal disease) requiring dialysis
7. Known allergy to medication component,
8. History of severe G6PD (glucose-6-phosphate dehydrogenase)
9. Myasthenia gravis
10. Porphyria
11. Ongoing treatment for epilepsy
12. Life expectancy < 6 months,
13. Patient lacks capacity to provide consent and does not have a surrogate decision maker.
14. Retinal Disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hydroxychloroquine (HCQ); Initial dose: HCQ 400mg x 2 (800mg) then 200mg by mouth, three times per day (600mg/24hr period) starting 8 hours after the initial dose for a total of 14 doses over 5 days Plus Usual Care (See below for full description)	Drug: Hydroxychloroquine; Hydroxychloroquine is currently widely used for treatment of autoimmune disease including systemic lupus erythematosus and rheumatoid arthritis, and it has been used to prevent and treat malaria.; Other Names: Plaquenil
No Intervention: Usual Care; The care of hospitalized patients with covid-19 is evolving with hospital guidelines arising across the U.S. with several commonalities. Patients receive clinical assessment, chest x-ray, covid-19 testing, basic labs (WBC, CMP), and additional labs based on protocol or clinical judgment (ABG, CRP, LDH), antibiotics for possible bacterial pneumonia, acetaminophen for fever, supplemental O2, and consideration for mechanical ventilation. Early intubation over escalating noninvasive support. Low tidal volume ventilation and prone positioning are lung protective strategies used in critically ill covid-19 patients that are based on management of acute respiratory distress syndrome generally. Conservative fluid replacement is used to avoid worsening oxygenation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline Oxygenation on Day 1 to Day 5	paO2	Day 1 of treatment to day 5 of treatment
Change from Baseline Oxygenation at Day 5	FIO2	Day 1 of treatment to day 5 of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intensive Care length of stay	Length in hours	Day 0 to Day 28
Required Mechanical Ventilation	Length in hours	Day 0 to Day 28
Required Oxygen supplementation	Length in hours	Day 0 to Day 28
Hospitalization length of Stay	Length in hours	Day 0 to Day 28
Mortality	Date of Death	Day 0 to Day 28
Cardiac Arrhythmia - Polymorphic Ventricular Tachycardia	Cardiologist Diagnostic Documentation	Day 0 to Day 28
Cardiac Arrhythmia - Ventricular Tachycardia	Cardiologist Diagnostic Documentation	Day 0 to Day 28
Cardiac Arrhythmia - Lengthening QTc	Cardiologist Diagnostic Documentation	Day 0 to Day 28

Collaborators and Investigators

• Sponsor: Kootenai Health
• Collaborators: Washington State University
• Investigators: Principal Investigator: Sterling McPherson, PhD, Washington State University; Principal Investigator: Sean Cook, D.O., Kootenai Health; Principal Investigator: Jeanette Berg, MD, PhD, Kootenai Health; Principal Investigator: John Roll, PhD, Washington State University

Study record dates

Study Major Dates

• Study Start (Anticipated): October 1, 2020
• Primary Completion (Anticipated): January 1, 2022
• Study Completion (Anticipated): June 1, 2022

Study Registration Dates

• First Submitted: April 14, 2020
• First Submitted That Met QC Criteria: May 8, 2020
• First Posted (Actual): May 11, 2020

Study Record Updates

• Last Update Posted (Actual): February 5, 2021
• Last Update Submitted That Met QC Criteria: February 4, 2021
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: SARS-CoV-2; Pneumonia; COVID-19; Hydroxychloroquine
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Lung Diseases; COVID-19; Pneumonia; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Hydroxychloroquine
• Other Study ID Numbers: 18244

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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.: Yes