A randomized double-blind placebo-controlled trial of intravenous plasma-purified alpha-1 antitrypsin for severe COVID-19 illness

INTERVENTION: Trade Name: Prolastin Pharmaceutical Form: Powder and solvent for solution for infusion INN or Proposed INN: HUMAN ALPHA1‐PROTEINASE INHIBITOR CAS Number: 9041‐92‐3 Other descriptive name: HUMAN ALPHA1‐PROTEINASE INHIBITOR Pharmaceutical form of the placebo: Solution for infusion Route of administration of the placebo: Intravenous use CONDITION: acute respiratory distress sydnrome (ARDS) secondary to Covid‐19 ; MedDRA version: 20.0 Level: LLT Classification code 10051905 Term: Coronavirus infection System Organ Class: 100000004862 Therapeutic area: Diseases [C] ‐ Immune System Diseases [C20] PRIMARY OUTCOME: Main Objective: The aim of the study is to conduct a clinical trial of IV AAT as a prospective anti‐inflammatory therapy for severely ill COVID‐19 patients with ARDS requiring ICU admission.; ; The primary objective is to demonstrate a biological effect of IV Prolastin administered weekly at 120mg per kilogram of ideal body weight in patients with severe COVID‐19 illness requiring intubation and mechanical ventilation for ARDS by reducing circulating levels of IL‐6 as measured by plasma ELISA. The study sample size is sufficient to demonstrate a significant difference in patients receiving Prolastin versus patients receiving placebo. Primary end point(s): The primary effectiveness outcome measure, a continuous variable, is IL‐6 in plasma as measured by ELISA. Secondary Objective: determine the safety and tolerability of [IV Prolastin administered once at 120mg/kg of ideal body weight] and [IV Prolastin administered weekly at 120mg/kg of ideal body weight for 4 weeks], as assessed by the number of AEs and SAEs and determine the effects of [IV Prolastin administered once at 120mg per kilogram of ideal body weight] and [IV Prolastin administered weekly at 120mg per kilogram of ideal body weight for 4 weeks] on: ; Physiological indices of respiratory dysfunction reflecting severity of ARDS, as measured by oxygenation index (OI), respiratory compliance; Sequential organ failure assessment (SOFA) score; Mortality; Time on ventilator in days; Circulating alpha‐1 antitrypsin (AAT) levels; Circulating levels of IL‐1ß, IL‐8, IL‐10, soluble TNF receptor 1; Development of shock; Acute kidney injury; Need for renal replacement therapy; Clinical relapse; Length of ICU stay in days Timepoint(s) of evaluation of this end point: day 2 , day 7, day 14, day 21 and day 28 INCLUSION CRITERIA: 1. Laboratory‐confirmed diagnosis of COVID‐19 infection 2. Moderate to severe ARDS with a PaO2/FiO2 ratio <200 and a requirement for vasopressors (0.05‐0.1µg/kg/min) 3. >18 years of age 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 36 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 36 SECONDARY OUTCOME: Secondary end point(s): Safety and tolerability of IMP in the respective groups, as defined by the number of SEAs and AEs, binary variable; • PaO2/FiO2 ratio, continuous variable; • Respiratory compliance, continuous variable; • Sequential organ failure assessment (SOFA) score, continuous variable; • Mortality, binary variable; • Time on ventilator in days, continuous variable; • Circulating AAT levels as measured by nephelometry, continuous variable; • Plasma levels of IL‐1ß as measured by ELISA, continuous variable; • Plasma levels of IL‐8 as measured by ELISA, continuous variable; • Plasma levels of IL‐10 as measured by ELISA, continuous variable; • Plasma levels levels of soluble TNF receptor 1 (sTNFR1, a surrogate marker for TNF‐a) as measured by ELISA, continuous variable; • Development of shock, defined for the purpose of this study as life‐threatening organ dysfunction caused by a dysregulated response to infection, with critical reduction in tissue perfusion and acute failure of multiple organs, including the lungs, kidneys, and liver, binary variable; • Acute kidney injury defined as an abrupt sustained rise in urea and creatinine, binary variable; • Need for renal replacement therapy, binary variable; • Clinical relapse, as defined by the need for readmission to the ICU or a marked decline in PaO2/FiO2 or development of shock or mortality following a period of sustained clinical improvement, binary variable; • Secondary bacterial pneumonia as defined by the combination of radiographic findings and sputum/airway secretion microscopy and culture, binary variable; Timepoint(s) of evaluation of this end point: day 2 , day 7, day 14, day 21 and day 28