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      Zilucoplan in patients with acute hypoxic respiratory failure due to COVID-19 (ZILU-COV): A structured summary of a study protocol for a randomised controlled trial

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          Abstract

          Objectives

          Zilucoplan (complement C5 inhibitor) has profound effects on inhibiting acute lung injury post COVID-19, and can promote lung repair mechanisms that lead to improvement in lung oxygenation parameters. The purpose of this study is to investigate the efficacy and safety of Zilucoplan in improving oxygenation and short- and long-term outcome of COVID-19 patients with acute hypoxic respiratory failure.

          Trial design

          This is a phase 2 academic, prospective, 2:1 randomized, open-label, multi-center interventional study.

          Participants

          Adult patients (≥18y old) will be recruited at specialized COVID-19 units and ICUs at 9 Belgian hospitals. The main eligibility criteria are as follows:

          1) Inclusion criteria:

          a. Recent (≥6 days and ≤16 days) SARS-CoV-2 infection.

          b. Chest CT scan showing bilateral infiltrates within the last 2 days prior to randomisation.

          c. Acute hypoxia (defined as PaO 2/FiO 2 below 350 mmHg or SpO2 below 93% on minimal 2 L/min supplemental oxygen).

          d. Signs of cytokine release syndrome characterized by either high serum ferritin, or high D-dimers, or high LDH or deep lymphopenia or a combination of those.

          2) Exclusion criteria:

          e. Mechanical ventilation for more than 24 hours prior to randomisation.

          f. Active bacterial or fungal infection.

          g. History of meningococcal disease (due to the known high predisposition to invasive, often recurrent meningococcal infections of individuals deficient in components of the alternative and terminal complement pathways).

          Intervention and comparator

          Patients in the experimental arm will receive daily 32,4 mg Zilucoplan subcutaneously and a daily IV infusion of 2g of the antibiotic ceftriaxone for 14 days (or until hospital discharge, whichever comes first) in addition to standard of care. These patients will receive additional prophylactic antibiotics until 14 days after the last Zilucoplan dose: hospitalized patients will receive a daily IV infusion of 2g of ceftriaxone, discharged patients will switch to daily 500 mg of oral ciprofloxacin.

          The control group will receive standard of care and a daily IV infusion of 2g of ceftriaxone for 1 week (or until hospital discharge, whichever comes first), to control for the effects of antibiotics on the clinical course of COVID-19.

          Main outcomes

          The primary endpoint is the improvement of oxygenation as measured by mean and/or median change from pre-treatment (day 1) to post-treatment (day 6 and 15 or at discharge, whichever comes first) in PaO 2/FiO 2 ratio, P(A-a)O 2 gradient and a/A PO 2 ratio.

          (PAO 2= Partial alveolar pressure of oxygen, PaO 2=partial arterial pressure of oxygen, FiO 2=Fraction of inspired oxygen).

          Randomisation

          Patients will be randomized in a 2:1 ratio (Zilucoplan: control). Randomization will be done using an Interactive Web Response System (REDCap).

          Blinding (masking)

          In this open-label trial neither participants, caregivers, nor those assessing the outcomes will be blinded to group assignment.

          Numbers to be randomised (sample size)

          A total of 81 patients will be enrolled: 54 patients will be randomized to the experimental arm and 27 patients to the control arm.

          Trial Status

          ZILU-COV protocol Version 4.0 (June 10 2020). Participant recruitment started on June 23 2020 and is ongoing. Given the uncertainty of the pandemic, it is difficult to predict the anticipated end date.

          Trial registration

          The trial was registered on Clinical Trials.gov on May 11 th, 2020 (ClinicalTrials.gov Identifier: NCT04382755) and on EudraCT (Identifier: 2020-002130-33).

          Full protocol

          The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s13063-020-04884-0.

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          Author and article information

          Contributors
          jozefien.declercq@irc.vib-ugent.be
          cedric.bosteels@irc.vib-ugent.be
          karel.vandamme@irc.vib-ugent.be
          elisabeth.deleeuw@irc.vib-ugent.be
          bastiaan.maes@irc.vib-ugent.be
          ans.vandecauter@uzgent.be
          stefanie.vermeersch2@uzgent.be
          anja.delporte@uzgent.be
          benedicte.demeyere@uzgent.be
          marnikv@irc.vib-ugent.be
          marianna.lalla@ucb.com
          trevor.smart@ucb.com
          laurent.detalle@ucb.com
          rene.bouw@ucb.com
          johannes.streffer@ucb.com
          thibo.degeeter@ugent.be
          marie.vergotte@ugent.be
          tanguy.guisez@ugent.be
          eva.vanbraeckel@uzgent.be
          catherine.vanderstraeten@uzgent.be
          bart.lambrecht@ugent.be
          Journal
          Trials
          Trials
          Trials
          BioMed Central (London )
          1745-6215
          19 November 2020
          19 November 2020
          2020
          : 21
          : 934
          Affiliations
          [1 ]GRID grid.5342.0, ISNI 0000 0001 2069 7798, VIB Center for Inflammation Research, Ghent, Belgium and Department of Internal Medicine and Pediatrics, , Ghent University, ; Ghent, Belgium
          [2 ]GRID grid.410566.0, ISNI 0000 0004 0626 3303, University Hospital Ghent, ; Ghent, Belgium
          [3 ]GRID grid.11486.3a, ISNI 0000000104788040, VIB-UGent Center for Inflammation Research, ; Ghent, Belgium
          [4 ]UCB Biopharma SRL, Braine-l’Alleud, Belgium
          [5 ]GRID grid.418727.f, ISNI 0000 0004 5903 3819, UCB Pharma, ; Slough, UK
          [6 ]GRID grid.5342.0, ISNI 0000 0001 2069 7798, Ghent University, ; Ghent, Belgium
          Article
          4884
          10.1186/s13063-020-04884-0
          7675383
          33213529
          e39bc9c0-9d6e-4b0b-bcbe-c201c3f67d2f
          © The Author(s) 2020

          Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

          History
          : 4 November 2020
          : 10 November 2020
          Funding
          Funded by: FundRef http://dx.doi.org/10.13039/100011110, UCB;
          Categories
          Letter
          Custom metadata
          © The Author(s) 2020

          Medicine
          covid-19,randomised controlled trial,protocol,zilucoplan,complement system,complement c5 inhibition,systemic cytokine release syndrome,cytokine storm,hypoxic respiratory failure,acute respiratory distress syndrome,ards

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