Study to Evaluate the Safety and Efficacy of Liquid Alpha1-Proteinase Inhibitor (Human) in Hospitalized Participants With Coronavirus Disease (COVID-19)

Study Overview
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Brief Summary
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The purpose of the study is to determine if Liquid Alpha1-Proteinase Inhibitor (Human) (Liquid Alpha1-PI) plus SMT can reduce the proportion of participants dying or requiring intensive care unit (ICU) admission on or before Day 29 or who are dependent on high flow oxygen devices or invasive mechanical ventilation on Day 29 versus placebo plus SMT in hospitalized participants with COVID-19.

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-Controlled, Parallel Group Study to Evaluate the Safety and Efficacy of Liquid Alpha1-Proteinase Inhibitor (Human) Plus Standard Medical Treatment (SMT) Versus Placebo Plus SMT in Hospitalized Subjects With COVID-19

Conditions
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COVID-19

Intervention / Treatment
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* Biological: Liquid Alpha1-Proteinase Inhibitor (Human)
* Drug: Placebo
* Drug: Standard Medical Treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hospitalized male or female participant ≥ 18 years of age at time of screening who is being treated for COVID-19. Participants must be screened within 48 hours (≤ 48 hours) of hospital admission. Has laboratory-confirmed novel coronavirus {SARS-CoV-2} infection as determined by qualitative polymerase chain reaction (PCR) (reverse transcriptase [RT]-PCR), or other commercial or public health assay approved by regulatory authorities as a diagnostic test for COVID-19 in any specimen during the current hospital admission OR 96 hours prior to the hospital admission date and prior to randomization (the SARS-CoV-2 test results must be performed by a hospital laboratory and the documentation available). COVID-19 illness (symptoms) of any duration, including both of the following: a) Radiographic infiltrates by imaging (chest X-Ray, computed tomography (CT) scan, etc.) and/or clinical assessment (evidence of rales/crackles on exam) with peripheral oxygen saturation by pulse oximetry (SpO2) <94% on room air; b) Any one of the following related to COVID-19: i. Ferritin > 400 nanogram per milliliter (ng/mL), ii. lactate dehydrogenase (LDH) > 300 units per liter (U/L), iii. D-Dimers > reference range, or iv. C-reactive protein (CRP) > 40 milligram per liter (mg/L). Participant provides informed consent prior to initiation of any study procedures. Female participants of childbearing potential (and males with female partners of childbearing potential) must agree to use of acceptable contraception methods during study (example, oral, injectable, or implanted hormonal methods of contraception, placement of an intrauterine device or intrauterine system, condom or occlusive cap with spermicidal foam/gel/film/cream/suppository, male sterilization, or true abstinence) throughout the study. Exclusion Criteria: Participants requiring invasive mechanical ventilation or ICU admission or with partial pressure of arterial oxygen/ fraction of inspired oxygen (PaO2/FIO2) ≤ 150 mmHg (i.e., arterial oxygen in millimeter of mercury (mmHg) divided by fraction inspired oxygen concentration [example, 0.21 for room air]). Clinical evidence of any significant acute or chronic disease that, in the opinion of the investigator, may place the participant at undue medical risk. The participant has had a known serious anaphylactic reaction to blood, any blood-derived or plasma product, or known selective immunoglobulin A (IgA) deficiency with anti-IgA antibodies. A medical condition in which the infusion of additional fluid is contraindicated (example, decompensated congestive heart failure or renal failure with fluid overload). This includes currently uncontrolled congestive heart failure New York Heart Association Class III or IV stage heart failure. Shock that is unresponsive to fluid challenge and/or multiple vasopressors and accompanied by multiorgan failure considered not able to be reversed by the Principal Investigator. Known alpha-1 antitrypsin deficiency for which the participant is already receiving alpha1-proteinase inhibitor augmentation therapy. Women who are pregnant or breastfeeding. Female participants of child-bearing potential must have a negative test for pregnancy blood or urine human chorionic gonadotropin (HCG)-based assay at screening/baseline visit. Participants for whom there is limitation of therapeutic effort such as Do not resuscitate status. Currently participating in another interventional clinical trial with investigational medical product or device. Participants previously requiring long-term oxygen therapy (home oxygen therapy). History (within the last 2 years) of myocardial infarction, unstable angina, stroke or transient ischemic attacks, pulmonary embolism or deep venous thrombosis. Participant has medical condition (other than COVID-19) that is projected to limit lifespan to ≤ 1 year. Systolic blood pressure < 100 mm Hg or > 160 mm Hg (uncontrolled hypertension) at the time of Screening. Alanine aminotransferase (ALT) ≥ 2 times the upper limit of normal (ULN). Any elevation of total bilirubin at the time of Screening. Estimated glomerular filtration rate (eGFR) < 45 mL/min (or participant is dependent on dialysis/renal replacement therapy) at the time of Screening. eGFR is calculated by the Cockcroft-Gault equation. Hemoglobin < 10 g/dL at the time of Screening. Absolute neutrophil count < 1000/mm^3 at the time of Screening. Platelet count < 75,000/mm^3 at the time of Screening. Participant has history of drug or alcohol abuse within the past 24 months. Participant is unwilling to commit to follow-up visits. Known history of prothrombin gene mutation 20210, homozygous Factor V Leiden mutations, antithrombin III deficiency, protein C deficiency, protein S deficiency or antiphospholipid syndrome.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Liquid Alpha1-Proteinase Inhibitor + Standard Medical Treatment<br>Participants received the first intravenous (IV) infusion of liquid alpha1-proteinase inhibitor (human) 120 milligrams per kilogram (mg/kg), based on body weight on Day 1, followed by second liquid alpha1-proteinase inhibitor (human) dose of 120 mg/kg based on body weight, on Day 8 (second dose was not mandatory and was given at the principal investigator's [PI] discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29. | Biological: Liquid Alpha1-Proteinase Inhibitor (Human)<br>* Intravenous infusion 120 mg/kg<br>* Other names: Alpha1-proteinase inhibitor;Drug: Standard Medical Treatment<br>* SMT<br>|
| Placebo Comparator: Placebo + Standard Medical Treatment<br>Participants received IV infusions of 0.9% normal saline of commensurate volume to that of liquid alpha1-proteinase inhibitor as placebo on Day 1 and Day 8 (Day 8 was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29. | Drug: Placebo<br>* Intravenous infusion<br>* Other names: 0.9% Normal Saline;Drug: Standard Medical Treatment<br>* SMT<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Dying or Requiring Intensive Care Unit (ICU) Admission |  | Up to Day 29 | 
| Percentage of Participants Who Are Dependent on High Flow Oxygen Devices or Invasive Mechanical Ventilation |  | Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in National Early Warning Score (NEWS) | NEWS is clinical scoring developed to improve detection of deterioration in ill participant. It is based on 7 clinical parameters: Respiration rate, oxygen saturation, supplemental oxygen, systolic blood pressure (BP), pulse rate, level of consciousness, and temperature. A score of 0 and 2 was allocated to supplemental oxygen, 0 and 3 for level of consciousness and score of 0, 1, 2 and 3 for remaining parameters (i.e. respiration rate, oxygen saturation, systolic BP, pulse rate and temperature) where 0 = normal health condition to 3 = worst health condition; Higher scores indicated more severity. All scores were summed to get an aggregate score. Aggregate NEWS score ranged from 0 to 20, with higher scores indicating more severity/higher risk. | Baseline, Days 15 and 29 | 
| Time to Clinical Response as Assessed by NEWS Score ≤ 2 Maintained for 24 Hours | Time to clinical response was reported at 50th percentile in days. | Up to Day 29 | 
| Time to Hospital Discharge | Time to hospital discharge is defined as duration of hospitalization from Day 1 through Day 29. | Up to Day 29 | 
| Duration of ICU Stay | Duration of ICU stay in days is analyzed for participants admitted to ICU post randomization. | Up to Day 29 | 
| Duration of Any Oxygen Use |  | Up to Day 30 | 
| Duration of Mechanical Ventilation | Duration of Mechanical Ventilation is analyzed for participants requiring mechanical ventilation post randomization. | Up to Day 29 | 
| Mean Change From Baseline in Ordinal Scale | The ordinal scale is a 7-point scale ranging from 1 to 7 used to measure clinical status based on the following points: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (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, limitation on activities; 7) Not hospitalized, no limitations on activities. Higher score indicated no severe illness. Mean change in Ordinal scale was evaluated by fitting a linear mixed-effects model for repeated measures (MMRM). | Baseline, Days 15 and 29 | 
| Absolute Change From Baseline in Ordinal Scale | The ordinal scale is a 7-point scale ranging from 1 to 7 used to measure clinical status based on the following points: 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, limitation on activities; 7) Not hospitalized, no limitations on activities. Higher score indicated no severe illness. | Baseline, Days 15 and 29 | 
| Percentage of Participants in Each Severity Category of the 7-point Ordinal Scale | The ordinal scale is a 7-point scale ranging from 1 to 7 used to measure clinical status based on the following points: 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, limitation on activities; 7) Not hospitalized, no limitations on activities. The percentages are rounded off to the single decimal point. | Day 15 and Day 29 | 
| Time to Sustained Normalization of Temperature | Time to sustained normalization of temperature was reported at 50th percentile in days. | Up to Day 29 | 
| Percentage of Participants Who Experienced Sustained Normalization of Fever | Normalization of fever is defined as temperature < 36.6 °C armpit, < 37.2 °C oral, or < 37.8 °C rectal sustained for at least 24 hours. | Up to Day 29 | 
| Number of Participants Who Develop Acute Respiratory Distress Syndrome (ARDS) | ARDS was defined based on Berlin criteria (chest imaging, origin of edema, oxygenation). | Up to Day 29 | 
| Time to Clinical Progression | Time to clinical progression is defined as the time to death, mechanical ventilation, or ICU admission. Time to clinical progression was reported at 50th percentile in days. | Up to Day 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronavirus Disease, Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2