See the published version of this preprint at Trials.
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Study protocol
František Duška
Charles University, 3rd Faculty of Medicine and FNKV University Hospital
Corresponding Author
ORCiD: https://orcid.org/0000-0003-1559-4078
License:
This work is licensed under a CC BY 4.0 License. Read Full License
• Background: Novel coronavirus SARS-CoV-2 is known to be susceptible in vitro to exposure to hydroxychloroquine and its effect have been found to be potentiated by azithromycin. We hypothesize, that early administration of hydroxychloroquine alone or in combination with azithromycin can prevent respiratory deterioration in patients admitted to intensive care due to rapidly progressive COVID-19 infection.
• Methods: Design: Prospective, multi-centre, double blind, randomised, controlled trial (RCT). Participants: Adult (>18 years) within 24 hours of admission to intensive care unit with proven or suspected COVID-19 infection, whether or not mechanically ventilated. Exclusion criteria include duration symptoms of febrile disease for ≥1 week, treatment limitations in place or moribund patients, allergy or intolerance of any study treatment, pregnancy. Interventions: Patients will be randomized in 1:1:1 ratio to receive Hydroxychloroquine 800mg orally in two doses followed by 400mg daily in two doses and Azithromycin 500 mg orally in one dose followed by 250 mg in one dose for a total of 5 days (HC-A group) or Hydroxychloroquine+ placebo (HC group) or placebo + placebo (C-group) in addition to best standard of care, which may evolve during the trial period but will not differ between groups. Primary outcome is the composite percentage of patients alive and not on end-of-life pathway who are free of mechanical ventilation at day 14. Secondary outcomes: The percentage of patients who were prevented from needing intubation until day 14; ICU length of stay; mortality (in hospital) at day 28 and 90.
• Discussion: Although both investigational drugs are often administered off label to patients with severe COVID-19, at present, there is no data from RCTs on their safety and efficacy. In vitro and observational trial suggest their potential to limit viral replication and the damage to lungs as the most common reason for ICU admission. Therefore, patients most likely to benefit from the treatment are those with severe, but early disease. This trial is designed and powered to investigate whether the treatment in this cohort of patients leads to improved clinical patients-centered outcomes, such as mechanical ventilation-free survival.
Trial registration: Clinical trials.gov: NCT04339816 (Registered on 9th April 2020); Eudra CT number: 2020-001456-18 (Registered on 29th March 2020)
Keywords
novel coronavirus, covid-19, SARS-CoV-2, Azithromycin, Hydroxychloroquine, respiratory failure
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See the published version of this preprint at Trials.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Study protocol
František Duška
Charles University, 3rd Faculty of Medicine and FNKV University Hospital
Corresponding Author
ORCiD: https://orcid.org/0000-0003-1559-4078
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Trials.
Version 2
Posted 20 May, 2020
No community comments so far
Editor assigned
On 09 May, 2020
Submission checks complete
On 19 Apr, 2020
No comments provided
Editorial decision: Major revision
On 04 May, 2020
Review #2 received
Received 02 May, 2020
Reviewer #2 agreed
On 23 Apr, 2020
Review #1 received
Received 22 Apr, 2020
Reviewers invited
Invitations sent on 21 Apr, 2020
Reviewer #1 agreed
On 21 Apr, 2020
Submission checks complete
On 19 Apr, 2020
Editor assigned
On 19 Apr, 2020
First submitted
On 15 Apr, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Trials.
• Background: Novel coronavirus SARS-CoV-2 is known to be susceptible in vitro to exposure to hydroxychloroquine and its effect have been found to be potentiated by azithromycin. We hypothesize, that early administration of hydroxychloroquine alone or in combination with azithromycin can prevent respiratory deterioration in patients admitted to intensive care due to rapidly progressive COVID-19 infection.
• Methods: Design: Prospective, multi-centre, double blind, randomised, controlled trial (RCT). Participants: Adult (>18 years) within 24 hours of admission to intensive care unit with proven or suspected COVID-19 infection, whether or not mechanically ventilated. Exclusion criteria include duration symptoms of febrile disease for ≥1 week, treatment limitations in place or moribund patients, allergy or intolerance of any study treatment, pregnancy. Interventions: Patients will be randomized in 1:1:1 ratio to receive Hydroxychloroquine 800mg orally in two doses followed by 400mg daily in two doses and Azithromycin 500 mg orally in one dose followed by 250 mg in one dose for a total of 5 days (HC-A group) or Hydroxychloroquine+ placebo (HC group) or placebo + placebo (C-group) in addition to best standard of care, which may evolve during the trial period but will not differ between groups. Primary outcome is the composite percentage of patients alive and not on end-of-life pathway who are free of mechanical ventilation at day 14. Secondary outcomes: The percentage of patients who were prevented from needing intubation until day 14; ICU length of stay; mortality (in hospital) at day 28 and 90.
• Discussion: Although both investigational drugs are often administered off label to patients with severe COVID-19, at present, there is no data from RCTs on their safety and efficacy. In vitro and observational trial suggest their potential to limit viral replication and the damage to lungs as the most common reason for ICU admission. Therefore, patients most likely to benefit from the treatment are those with severe, but early disease. This trial is designed and powered to investigate whether the treatment in this cohort of patients leads to improved clinical patients-centered outcomes, such as mechanical ventilation-free survival.
Trial registration: Clinical trials.gov: NCT04339816 (Registered on 9th April 2020); Eudra CT number: 2020-001456-18 (Registered on 29th March 2020)
Figure 1
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