E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
COVID-19 patients with acute hypoxic respiratory failure. |
|
E.1.1.1 | Medical condition in easily understood language |
COVID-19 patients with acute hypoxic respiratory failure. |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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.2.2 | Secondary 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.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.4 | Principal 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 -Patient on ECMO at screening -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.5.1 | Primary 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.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary 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 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 Not hospitalized -Number of days requiring supplemental oxygen after randomization to Day 28 (or discharge, whichever comes first) -Number of days with fever (defined as 37.1°C or more) during 28-day assessment period - change from baseline in SOFA score to D6, D15 (or on discharge, whichever is first) - Time to at least a 2-point improvement or discharge sustained up to D28 on the 6-point ordinal scale during 28-day assessment period -Incidence of nosocomial bacterial or invasive fungal infection during 28-day assessment period 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. - All-cause mortality rate at 28 days post randomization (all treated participants) -All-cause mortality rate at 28 days post randomization (excluding participants that required invasive mechanical ventilation or ECMO, non-invasive mechanical ventilation or high-flow oxygen devices within 24 hours prior to or after randomization) -All-cause mortality rate at 28 days post randomization (excluding participants that required invasive mechanical ventilation or ECMO within 24 hours prior to or after randomization) -All-cause mortality rate at 28 days post randomization (only including patients that required invasive mechanical ventilation or ECMO within 24 hours prior to or after randomization) -Incidence of patients in each category of the 6-point Ordinal Scale at follow up 12-22 weeks postrandomization -All cause mortality at follow up 12-22 weeks post-randomization for all treated participants - Results from 6 minute walking test - Incidence of participants in each category of the WHO performance scale |
|
E.5.2.1 | Timepoint(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.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
|
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |