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

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ClinicalTrials.gov Identifier: NCT04382625
Recruitment Status : Withdrawn (Secondary to other study results, suspended for a scientific review)
First Posted : May 11, 2020
Last Update Posted : February 5, 2021
Sponsor:
Collaborator:
Washington State University
Information provided by (Responsible Party):
Kootenai Health

Tracking Information
First Submitted Date  ICMJE April 14, 2020
First Posted Date  ICMJE May 11, 2020
Last Update Posted Date February 5, 2021
Estimated Study Start Date  ICMJE October 2020
Estimated Primary Completion Date January 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Hydroxychloroquine in SARS-CoV-2 (COVID-19) Pneumonia Trial
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE 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  ICMJE
  • SARS-CoV-2 Pneumonia
  • COVID-19
Intervention  ICMJE 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  ICMJE
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Withdrawn
Actual Enrollment  ICMJE
 (submitted: February 4, 2021)
0
Original Estimated Enrollment  ICMJE
 (submitted: May 8, 2020)
120
Estimated Study Completion Date  ICMJE June 1, 2022
Estimated Primary Completion Date January 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04382625
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: No
Responsible Party Kootenai Health
Study Sponsor  ICMJE Kootenai Health
Collaborators  ICMJE Washington State University
Investigators  ICMJE
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

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP