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

• ClinicalTrials.gov Identifier: NCT04382625
• Recruitment Status: Withdrawn
• First Posted: May 11, 2020
• Last Update Posted: February 5, 2021
• Sponsor: Kootenai Health
• Collaborator: Washington State University
• Information provided by (Responsible Party): Kootenai Health

Tracking Information

• First Submitted Date: April 14, 2020
• First Posted Date: May 11, 2020
• Last Update Posted Date: February 5, 2021
• Estimated Study Start Date: October 2020
• Estimated Primary Completion Date: January 1, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 8, 2020)

• Change from Baseline Oxygenation on Day 1 to Day 5 [ Time Frame: Day 1 of treatment to day 5 of treatment ]
  paO2
• Change from Baseline Oxygenation at Day 5 [ Time Frame: Day 1 of treatment to day 5 of treatment ]
  FIO2

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: May 8, 2020)

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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Hydroxychloroquine in SARS-CoV-2 (COVID-19) Pneumonia Trial
• Official Title: Hydroxychloroquine in SARS-CoV-2 (COVID-19) Pneumonia Trial
• Brief Summary: 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.

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
• Study Phase: Phase 4

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Single-center pragmatic randomized open-label trial of hydroxychloroquine + usual care in hospitalized adults with confirmed SARS-CoV-2 infection and acute hypoxia compared to usual care.

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• SARS-CoV-2 Pneumonia
• COVID-19

Intervention

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 Name: Plaquenil

Study Arms

• 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)
  Intervention: Drug: Hydroxychloroquine
• 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.

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Withdrawn
• Actual Enrollment (submitted: February 4, 2021): 0
• Original Estimated Enrollment (submitted: May 8, 2020): 120
• Estimated Study Completion Date: June 1, 2022
• Estimated Primary Completion Date: January 1, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04382625
• Other Study ID Numbers: 18244
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Kootenai Health
• Original Responsible Party: Same as current
• Current Study Sponsor: Kootenai Health
• Original Study Sponsor: Same as current
• Collaborators: Washington State University

Investigators

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

• PRS Account: Kootenai Health
• Verification Date: May 2020