Study to Evaluate the Safety and Efficacy of High Dose Intravenous Immune Globulin (IVIG) Plus Standard Medical Treatment (SMT) Versus SMT Alone in Participants in Intensive Care Unit (ICU) 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 a high dose of Intravenous Immune Globulin (IVIG) plus Standard Medical Treatment (SMT) can reduce all-cause mortality versus SMT alone in hospitalized participants with COVID-19 requiring admission to the ICU through Day 29.

Official Title
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A Multicenter, Randomized, Open-label Parallel Group Pilot Study to Evaluate Safety and Efficacy of High Dose Intravenous Immune Globulin (IVIG) Plus Standard Medical Treatment (SMT) Versus SMT Alone in Subjects With COVID-19 Requiring Admission to the Intensive Care Unit

Conditions
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COVID-19

Intervention / Treatment
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* Biological: GAMUNEX-C
* Drug: Standard Medical Treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hospitalized male or female subjects of ≥ 18 years of age at time of Screening who are being treated in the ICU for COVID-19 for not longer than 48 hours or for whom a decision has been made that COVID-19 disease severity warrants ICU admission. Has laboratory-confirmed novel coronavirus {SARS-CoV-2} infection as determined by qualitative polymerase chain reaction (PCR) (reverse transcriptase [RT]-PCR), or other United States Food and Drug Administration (FDA)-approved diagnostic assay for COVID-19 in any specimen during the current hospital admission prior to randomization. Illness (symptoms of COVID-19 of any duration requiring ICU level care), and the following: Radiographic infiltrates by imaging (chest X-Ray, computerized tomography (CT) scan, etc.), and Requiring mechanical ventilation and/or supplemental oxygen. 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). Subject provides informed consent prior to initiation of any study procedures. Exclusion Criteria: Clinical evidence of any significant acute or chronic disease or pathophysiologic manifestations (eg, complications of COVID-19 standard medical treatments) that, in the opinion of the investigator, may place the subject at undue medical risk. The subject has had a known (documented) serious anaphylactic reaction to blood, any blood-derived or plasma product or a past history of any hypersensitivity reactions to commercial immunoglobulin. A medical condition in which the infusion of additional fluid is contraindicated. Shock that is unresponsive to fluid challenge and/or multiple vasopressors and accompanied by multiorgan failure considered by the Principal Investigator not able to be reversed. Subjects with known (documented) thrombotic complications to polyclonal IVIG therapy in the past. Subjects with current or prior myocardial infarction, stroke, deep vein thrombosis, or thromboembolic event (within the past 12 months) or who have a history of thromboembolic events of unknown etiology. Subjects with limitations of therapeutic effort. Female subjects who are pregnant or of child-bearing potential with a positive test for pregnancy blood or urine human chorionic gonadotropin (HCG)-based assay at Screening/Baseline. Subjects participating in another interventional clinical trial with investigational medical product or device. Known history of prothrombin gene mutation 20210, homozygous Factor V Leiden mutations, antithrombin III deficiency, protein C deficiency, protein S deficiency or antiphospholipid syndrome. Presence of malignancy (either new diagnosis of malignancy or known residual disease) within the past 12 months. Creatinine at Screening is ≥ 4 mg/dL (or subject is dependent on dialysis/renal replacement therapy). Known Immunoglobulin A (IgA) deficiency with anti-IgA serum antibodies. Uncontrolled hypertension at the time of Screening (systolic blood pressure > 200 mm Hg) or refractory severe hypotension with sustained systolic blood pressure < 90 mm Hg unresponsive to vasopressors.

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GAMUNEX-C + Standard Medical Treatment<br>Participants received 2 grams per kilogram (g/kg) of GAMUNEX-C, which was capped to a maximum of 160 g infusion intravenously (IV) for participants weighing more than 80 kg on Day 1. The 2 g/kg net total dose was divided either into infusions of 500 mg/kg body weight over 4 days or 400 mg/kg body weight over 5 days as per investigator's decision. Participants received standard of care interventions as per Principal Investigator's discretion from Day 1 up to Day 29. | Biological: GAMUNEX-C<br>* Intravenous Immune Globulin (Human), 10% Caprylate/Chromatography Purified.<br>* Other names: IGIV-C;Drug: Standard Medical Treatment<br>* SMT per local policies or guidelines.<br>|
| Active Comparator: Standard Medical Treatment<br>Participants received all standard of care interventions required as per Principal Investigator's discretion throughout the participant's hospitalization, from Day 1 to Day 29. | Drug: Standard Medical Treatment<br>* SMT per local policies or guidelines.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-Cause Mortality Rate Through Day 29 | All-cause mortality rate is percentage of participants in each treatment group who experienced mortality up to Day 29. | Up to Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Actual Intensive Care Unit (ICU) Discharge Time | Percentage of participants who were discharged from ICU were recorded. Time to actual ICU discharge was defined as duration of actual ICU stay from Day 1 through Day 29. | Up to Day 29 | 
| Duration of Mechanical Ventilation | Duration (number of days) of ICU stay from post-randomization through Day 29 was calculated based on ICU admission and discharge (actual and medical equivalence) dates. | Up to Day 29 | 
| Percentage of Participants With Actual Hospital Discharge Time | Percentage of participants who were discharged from the hospital were recorded. Time to hospital discharge was defined as duration of hospitalization from Day 1 through Day 29. | Up to Day 29 | 
| Duration of Any Oxygen Use From Day 1 Through Day 29 | Duration (number of days) of any oxygen use from Day 1 through Day 29 was calculated based on the start/stop dates. | 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). The data is reported for average across all postbaseline. | Baseline up to Day 29 | 
| Absolute Change From Baseline in Ordinal Scale at Day 29 | 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. | Baseline, Day 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 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. | Days 15 and 29 | 
| Percentage of Participants Who Develop Acute Respiratory Distress Syndrome (ARDS) | Acute Respiratory Distress Syndrome was defined based on Berlin criteria (chest imaging, origin of edema, oxygenation). | Days 1, 5, 15 and 29 | 
| Percentage of Participants Who Develop ARDS Distributed by Severity | ARDS was defined by Berlin's criteria as: 1) Timing is usually within 1 week of a known clinical insult or new or worsening respiratory symptoms 2) Chest imaging: bilateral opacities-not fully explained by effusions, lobar/lung collapse, or nodules 3) Respiratory failure not fully explained by cardiac failure or fluid overload Need objective assessment (eg, echocardiography) to exclude hydrostatic edema if no risk factor present 4) Oxygenation: Mild 200 mm Hg < partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) ≤ 300 mm Hg with positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) ≥ 5 cm H2Oc; Moderate 100 mm Hg < PaO2/FIO2 ≤ 200 mm Hg with PEEP ≥ 5 cm H2O; Severe PaO2/FIO2 ≤100 mm Hg with PEEP ≥ 5 cm H2O. | Days 1, 5, 15 and 29 | 
| Change From Baseline in Sequential Organ Failure Assessment (SOFA) Score at Day 5, Day 15, and Day 29 | SOFA score is a mortality prediction score that is based on the degree of dysfunction of six organ systems. The score is calculated on admission and every 24 hours until discharge using the worst parameters measured during the prior 24 hours SOFA score ranges from 0 (no organ dysfunction) to 24 (highest possible score / organ dysfunction). Higher score indicated severe illness. | Days 5, 15, and 29 | 
| 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 score indicated more severity. All scores were summed to get an aggregate score. Aggregate NEWS score ranged from 0 to 20, with higher scores meaning more severity/higher risk. | Baseline and Day 29 | 
| Percentage of Participants Achieving Clinical Response: NEWS ≤ 2 Maintained for 24 Hours | Percentage of participants who achieved clinical response (i.e the NEWS score ≤2 maintained for 24 hours from Day 1 through Day 29) was estimated using the Kaplan-Meier method. | 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, Coronavirus Infections, Coronaviridae Infections, Virus Diseases, Immunoglobulins, Antibodies, Gamma-globulins, Immunoglobulins, Intravenous, Immunologic Factors, Physiological Effects of Drugs