Respiratory failure during COVID-19 pneumonia and hyperinflammation MedDRA version: 23.0 Level: PT Classification code 10051905 Term: Coronavirus infection System Organ Class: 10021881 - Infections and infestations
Conditions
Interventions
Product Name: mavrilimumab
Product Code: [KPL-301]
Pharmaceutical Form: Solution for injection
INN or Proposed INN: mavrilimumab
Current Sponsor code: KPL-301
Concentration unit: mg/ml milligram(s)/mi
Sponsors
OSPEDALE SAN RAFFAELE
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Adults (= 18 years old) 2. Signed informed consent 3. Patients clinically diagnosed with SARS-CoV-2 virus by PCR or by other approved diagnostic methodology 4. Hospitalized with COVID-19-induced pneumonia evidenced by chest x-ray or CT scan with pulmonary infiltrates 5. Patient requiring oxygen supplementation (i.e. with a SpO2 = 94% while breathing room air) and having a PAO2/FIO2 ratio = 300 mmHg 6. Lactate dehydrogenase (LDH) > normal range and at least one of the following: - fever > 38.0 °C; - increased levels of C-reactive Protein (CRP) = 10x UNL mg/L (= 60 mg/lL); - increased levels of ferritin = 2.5x UNL ( = 1000 ¿gmg/L) Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 25 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 25
Exclusion criteria
Exclusion criteria: 1. Onset of COVID-19 pneumonia symptoms (i.e. dyspnea/respiratory insufficiency) >14 days 2. On mechanical ventilation at the time of randomization 3. A PaO2/FiO2 < 100 mmHg 4. Uncontrolled systemic infection (other than COVID-19) 5. Hypersensitivity to the active substance or to any of the excipients of the experimental drug 6. Total neutrophil count < 1500/mm3 7. Severe hepatic cirrhosis 8. History of chronic HBV or HCV infection 9. Known or active tuberculosis (TB) or a history of incompletely treated TB; suspected or known extrapulmonary tuberculosis 10. Moderate/severe heart failure (NYHA Class 3 or 4) 11. Any prior (within the defined periods below) or concurrent use of immunosuppressive therapies including but not limited to the following: a. Anti-IL-6, anti-IL-6R antagonists or Janus kinase inhibitors (JAKi) in the past 30 days or plans to receive during the study period; b. Cell-depleting agents (e.g., anti CD20) without evidence of recovery of B cells to baseline level; c. Anakinra within 1 week of baseline; canakinumab within 8 weeks of baseline; abatacept within 8 weeks of baseline. d. Tumor necrosis factor (TNF) inhibitors within 2-8 weeks (etanercept within 2 weeks, infliximab, certolizumab, golimumab, or adalimumab within 8 weeks), or after at least 5 half-lives have elapsed, whichever is longer; e. Alkylating agents including cyclophosphamide (CYC) within 6 months of baseline; f. Cyclosporine (CsA), azathioprine (AZA) or mycophenolate mofetil (MMF) or leflunomide or methotrexate within 4 weeks of baseline. 12. Pregnancy or lactation (Note: Women of childbearing age should use effective contraception/abstinence after treatment with mavrilimumab and for 3 months after the dosing) 13. Any serious medical condition or abnormality of clinical laboratory tests that, in the investigator’s judgment, precludes the patient’s safe participation in and completion of the study 14. In the opinion of the investigator, progression to death is imminent and highly likely within the next 24 hours, irrespective of the provision of treatments 15. Current participation in any other interventional investigational trials
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To demonstrate the benefit of mavrilimumab vs placebo added to best standard of care in reducing the dependency on oxygen supplementation in patients with COVID-19 pneumonia and signs of systemic hyperinflammation;Secondary Objective: To evaluate clinical outcomes using the WHO 7-point ordinal scale To evaluate the time to disappearance of fever if present at baseline To demonstrate the potential benefit of mavrilimumab in reducing the case fatality rate over 4 weeks in the study cohort regardless of other subsequent clinical interventions To evaluate the in-hospital outcomes in the study cohort To evaluate change in laboratory parameters through follow up To evaluate changes in the National Early Warning Score 2 (NEWS2) To evaluate the variations in radiological findings in patients that underwent a repeated radiological evaluation (mavrilimumab vs placebo) To evaluate safety of mavrilimumab in the study cohort To evaluate the clinical efficacy of mavrilimumab compared to the control arm by clinical severity (i.e. mild vs moderate subgroup) To measure the time course of the effects of mavrilimumab on biomarkers;Primary end point(s): Time to the absence of need for oxygen supplementation (time to first period of 24 hrs with a SpO2 of 94%) within day 14 of treatment, stated as Kaplan-Mayer estimates of the proportion of patients on room air at day 14 and median time to room air attainment in each arm.;Timepoint(s) of evaluation of this end point: Daily evaluation until day 14 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Variations from baseline to subsequent CT scans (when available) in terms of percentage of lung involvement, modifications in the normal parenchyma, ground glass opacities (GGO), crazy paving pattern, parenchymal consolidations, and evolution towards fibrosis.; Number of patients with treatment-related side effects (as assessed by Common Terminology Criteria for Adverse Event (CTCAE) v.5.0), serious adverse events, adverse events of special interest, clinically significant changes in laboratory measurements and vital signs; To evaluate the primary and secondary endpoints in different subgroups of patients: - mild respiratory failure: PaO2/FiO2 = 300 and > 200 mmHg; - moderate respiratory failure: PaO2/FiO2 = 200 and > 100 mmHg; Median changes in exploratory biomarkers: - Inflammatory biomarkers (i.e. IL-6, IL-1RA, TNF-alpha, CBC and differential) - Levels of antibodies to SARS-CoV-2 - Levels of anti-drug antibiodies (ADA); Proportion of patients not requiring oxygen supplementation (i.e., response rate. Response is defined as a 7- point ordinal scale of 3 or less based on the WHO 7-point ordinal scale).; Proportion of patients with at least 2 levels improvement in clinical status as evaluated the WHO 7-point ordinal scale; Median time to resolution of fever (for at least 48 hours) in absence of antipyretics, or discharge, whichever is sooner in the 4-week period after study treatment.; COVID-19-related death during the 4-week period after study treatment (in hospital and overall); Proportion of hospitalized patients who died or required mechanical ventilations (WHO Categories 1 or 2) by day 14; Median variations of the following serological markers over follow-up: - C-reactive protein - Ferritin - D-Dimer; Median change in NEWS2 score from baseline; Time to clinical improvement (as defined as a NEWS2 score of 2 or less maintained for at least 24 hours or discharge, whichever comes first);Timepoint(s) of evaluation of this end point: From ba | — |
Countries
Italy
Contacts
Public ContactSegreteria UnIRAR
IRCCS Ospedale San Raffaele
Outcome results
None listed