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    Summary
    EudraCT Number:2020-002130-33
    Sponsor's Protocol Code Number:ZILU-COV
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-05-06
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2020-002130-33
    A.3Full title of the trial
    A prospective, randomized, open-label, interventional study to investigate the efficacy of complement C5 inhibition with Zilucoplan® in improving oxygenation and short- and long-term outcome of COVID-19 patients with acute hypoxic respiratory failure.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Zilucoplan® in patients with acute hypoxic respiratory failure due to COVID-19
    A.3.2Name or abbreviated title of the trial where available
    ZILU-COV
    A.4.1Sponsor's protocol code numberZILU-COV
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity Hospital Ghent
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportRa Pharmaceuticals, Inc., a member of the UCB group of companies
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Ghent
    B.5.2Functional name of contact pointHIRUZ CTU
    B.5.3 Address:
    B.5.3.1Street AddressC. Heymanslaan 10
    B.5.3.2Town/ cityGhent
    B.5.3.3Post code9000
    B.5.3.4CountryBelgium
    B.5.4Telephone number+3293320500
    B.5.5Fax number+3293320520
    B.5.6E-mailhiruz.ctu@uzgent.be
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameZilucoplan
    D.3.4Pharmaceutical form Solution for injection in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNZILUCOPLAN
    D.3.9.1CAS number 1841136-73-9
    D.3.9.2Current sponsor codeRA101495
    D.3.9.4EV Substance CodeSUB194709
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Yes
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    COVID-19 patients with acute hypoxic respiratory failure.
    E.1.1.1Medical condition in easily understood language
    COVID-19 patients with acute hypoxic respiratory failure.
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this intervention is to study if Zilucoplan® affects the the median and/or mean change in oxygenation between enrolment (baseline) and at predose day 6 and day 15 (or discharge, whichever comes first) through assessment of the PaO2/FiO2 ratio and through measurement of the P(A-a)O2 gradient, which can easily be performed in the setting of clinical observation of patients admitted to the COVID-19 ward or ICU COVID-19 unit. For patients on ECMO the PaO2/FiO2 ratio and Aa-gradient cannot be calculated as in this case the FiO2 will be missing. Therefore, the last available value of PaO2/FiO2 ratio and Aa gradient prior to ECMO can be used at that timepoint.
    E.2.2Secondary objectives of the trial
    -to study if early intervention with Zilucoplan® is safe (number of AEs/SAEs)
    -to study if early intervention with Zilucoplan® affects clinical outcome defined by duration of hospital stay, 6-point ordinal scale, time to defervescence, supplemental oxygen use and SOFA score
    - to study if early intervention with Zilucoplan® affects progression to mechanical ventilation and/or ARDS and duration of ICU stay
    -to study if early intervention with Zilucoplan® affects the rate of nosocomial infection
    -to study if treatment with Zilucoplan® has a favourable effect on long term at follow up 12-22 weeks post-randomization
    -to study if treatment with Zilucoplan® affects all-cause mortality rate at day 28 and at 12-22 weeks post-randomization
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    -Recent (≥6 days and ≤16 days of flu-like symptoms or malaise prior to randomization) infection with COVID-19.
    -COVID-19 diagnosis confirmed by antigen detection test and/or PCR and/or positive serology, or any emerging and validated diagnostic laboratory test for COVID-19 within this period. For patients with a negative SARS-CoV-2 PCR and either a positive SARS-CoV-2 antigen or antibody test, the presence of suggestive lesions for COVID-19 on chest-CT scan is mandatory.
    -In some patients, it may be impossible to get a confident laboratory confirmation of COVID-19 diagnosis after 24h of hospital admission because viral load is low and/or problems with diagnostic sensitivity. In those cases, in absence of an alternative diagnosis, and with highly suspect bilateral ground glass opacities on recent (<24h) chest-CT scan (confirmed by a radiologist and pulmonary physician as probable COVID-19), and a typical clinical and chemical diagnosis with signs of cytokine release syndrome, a patient can be enrolled as probable SARS-CoV-2-infected. In all cases, this needs confirmation by later seroconversion.
    -Presence of hypoxia defined as
    1)O2 saturation below 93% on minimal 2l/min O2 therapy;
    and/or 2) Patient on ECMO or PaO2/FiO2 below 350 mmHg (Strongly recommended: patient in upright position, after minimal 3 minutes without supplemental oxygen; In ventilated patients PaO2 can be taken from invasive arterial line and FiO2 taken directly from mechanical ventilation settings).
    -Signs of acute lung injury and/or cytokine release syndrome defined as
    ANY of the following
    -serum ferritin concentration >1000 mcg/L and rising since last 24h
    -single ferritin above 2000 mcg/L in patients requiring immediate high flow oxygen device (Optiflow) or non-invasive or invasive mechanical ventilation
    -lymphopenia defined as <800 lymphocytes/microliter and two of the following extra criteria
    -Ferritin > 700 mcg/L and rising since last 24h
    -increased LDH (above 300 IU/L) and rising since last 24h
    -D-Dimers > 1000 ng/mL and rising since last 24h
    -CRP above 70 mg/L and rising since last 24h and absence of bacterial infection
    -if three of the above are present at admission, no need to document 24h rise
    -Low dose Chest CT or HRCT or Angio Chest CT scan showing bilateral infiltrates within last 2 days prior to randomization
    -Admitted to specialized COVID-19 ward or an ICU ward taking care of COVID-19 patients
    -Age ≥ 18 years
    - Women of childbearing potential must have a negative serum pregnancy test pre-dose on day 1. Women of childbearing potential must consistently and correctly use (during the entire treatment period and 4weeks after last Zilucoplan® administration ) at least 1 highly effective method for contraception.
    Male subjects (who have not been surgically sterilized by vasectomy) must agree to use effective contraception during the study.
    -Willing and able to provide informed consent or legal representative willing to provide informed consent
    E.4Principal exclusion criteria
    -Patients with known history of serious allergic reactions, including anaphylaxis, to Zilucoplan® or inability to receive antibiotic prophylaxis due to allergy to ALL of the antibiotics that can be given for prophylaxis of meningococcal disease
    -History of active or past meningococcal disease
    -Invasive mechanical ventilation > 24 h at randomization
    -Clinical frailty scale above 3 before onset of the COVID-19 episode
    -Weight below 54 kg as measured max 1 week prior to inclusion
    -Weight above 150 kg as measured max 1 week prior to inclusion
    -Active bacterial or fungal infection
    -Unlikely to survive beyond 48h
    -Neutrophil count below 1500 cells/microliter
    -Platelets below 50.000/microliter
    -Patients enrolled in another investigational drug study
    -Patients on high dose systemic steroids (> 8 mg methylprednisolone or equivalent for more than 1 month) or other moderately immunosuppressive drugs (in the opinion of the investigator) for COVID-19 unrelated disorder
    -Patients on current complement inhibiting drugs
    -Serum transaminase levels >5 times upper limit of normal, unless there are clear signs of cytokine release syndrome defined by LDH >300 IU/L and ferritin >700 ng/ml
    -Pregnant or breastfeeding females (all female subjects deemed of childbearing potential by the investigator must have negative pregnancy test at screening)
    E.5 End points
    E.5.1Primary end point(s)
    To measure the effectiveness of SC Zilucoplan® treatment on restoring lung homeostasis, the primary endpoint of this intervention is measuring oxygenation at predose day 6 and day 15 (or at discharge, whichever comes first) through assessment of the mean and/or median change from pretreatment (day 1) to post-treatment (day 6 and 15 or at discharge, whichever comes first) PaO2/FiO2 ratio, P(A-a)O2 gradient and a/A pO2 ratio, which can easily be performed in the setting of clinical observation of patients admitted to the COVID-19 ward or ICU COVID-19 unit. These measurements derived from an arterial blood gas sampling are taken when the patient is sitting upright and breathing room air. Since supplemental oxygen will be indispensable in some patients, the A-a gradient will be normalized against age and FiO2 expected A-a gradient, according to validated formulas. If patients leave hospital between day 6 and day 15, that day of discharge will be taken as measurement point for primary endpoint instead of day 15. For patients on ECMO the PaO2/FiO2 ratio and Aa-gradient cannot be calculated as in this case the FiO2 will be missing. Therefore, the last available value of PaO2/FiO2 ratio and Aa gradient prior to ECMO can be used at that timepoint.
    E.5.1.1Timepoint(s) of evaluation of this end point
    day 6
    day 15
    at discharge
    E.5.2Secondary end point(s)
    -To study if early intervention with Zilucoplan® is safe (number of AEs/SAEs)
    -To study if early intervention with Zilucoplan® affects clinical outcome
    defined by mean change in 6-point ordinal scale change between day 1 and respectively day 6, day 15 (or discharge, whichever comes first) and day 28 (by phone call). 6-point ordinal scale defined as
    1. Death
    2. Hospitalized, on invasive mechanical ventilation or ECMO;
    3. Hospitalized, on non-invasive ventilation or high flow oxygen devices;
    4. Hospitalized, requiring supplemental oxygen
    5. Hospitalized, not requiring supplemental oxygen
    6. Not hospitalized
    -Time since randomization until improvement in oxygenation, defined as independence from supplemental oxygen
    -Number of days with hypoxia defined as SpO2 < 93% breathing room air or the dependence on supplemental oxygen
    -Number of days of supplemental oxygen use
    -Time since randomization until absence of fever (defined as 37.1°C or more) for more than 48h without antipyretics
    -Number of days with fever (defined as 37.1°C or more)
    - Mean change in CRP levels between day 1 and day 6, and between day 1 and day 15 (or discharge whichever comes first).
    - Mean change in ferritin levels between day 1 and day 6, and between day 1 and day 15 (or discharge whichever comes first).
    -Incidence of AEs/SAEs/SARs/SUSARs during 28 days
    -Duration of hospital stay
    -Duration of hospital stay in survivors
    -Mean change of SOFA score between day 1 and day 6 or between day 1 and day 15 (or on discharge, whichever is first)
    -Percentage of patients reporting each severity rating on a 6-point ordinal scale at randomization, day 6 and 15 (or discharge, whichever comes first) and day 28 (phone call)
    -6-point Ordinal Scale at 6 and 15 days (or discharge whichever comes first) and day 28 (phone call), in relation to serum D-dimers and complement C5a levels at randomization
    -Incidence of nosocomial bacterial or invasive fungal infection for 28 days (phone call) after enrolment in trial
    Patients with viral respiratory infection are at risk of secondary bacterial infections. As part of routine clinical care, sputum or BAL samples will be collected in patients suspected of secondary bacterial pneumonia, and checked for the presence of bacteria. Measurements of procalcitonin levels will be performed at least three times per week until day 14 or hospital discharge.
    -Time since randomization until first use of high-flow oxygen devices, non-invasive or invasive mechanical ventilation in non-ventilated patients (excluding patients who are ventilated less than 24h prior to or after randomization)
    -Ventilator-free days over 28 days from randomization
    -Duration of invasive and non-invasive mechanical ventilation in ventilated patients
    -Duration of ICU stay in patients that enrolled in trial on invasive or non-invasive mechanical ventilation for less than 24h prior to or after randomization
    -Time since randomization to progression to ARDS
    criteria-defined ARDS according to the adapted Berlin criteria as follow:
    * Within 1 week of a known clinical insult or new or worsening respiratory symptoms
    * bilateral infiltrates not supposed to be of cardiac origin or fluid overload
    * PaO2/FiO2 < 300 mmHg
    * PEEP > 5 cm H2O on invasive or non-invasive ventilation or flow ≥ 60L/min on HFOT (Optiflow)
    -Time since randomization to progression to ARDS according to D-dimers and complement C5a at randomization
    -All-cause mortality rate at 28 days post inclusion (excluding group that entered during ventilation)
    -All-cause mortality rate at 28 days post inclusion (including group that entered during ventilation)
    -Percentage of patients in clinical status on 6-point Ordinal Scale at follow up 12-22 weeks post-randomization
    -Incidence of lung function abnormalities at follow up 12-22 weeks post-randomization
    -Incidence of lung fibrosis on chest CT scan at follow up 12-22 weeks post-randomization
    -All cause mortality at follow up 12-22 weeks post-randomization for the entire study population
    E.5.2.1Timepoint(s) of evaluation of this end point
    day 6
    day 15
    day 28
    follow up 12-22 weeks
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    standard of care
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned9
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 41
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    If a potential subject ends up in the intensive care unit very quickly after admission, and is mechanically ventilated, permission will be sought from a family member.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state81
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-05-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-05-22
    P. End of Trial
    P.End of Trial StatusOngoing
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