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