Octagam 10% Therapy in COVID-19 Patients With Severe Disease Progression

Study Overview
=================
Brief Summary
-----------------
This is a randomized, double-blind, placebo-controlled, multicenter, Phase 3 study to evaluate if high-dose Octagam 10% therapy can stabilize or improve clinical status in patients with severe Coronavirus disease

Official Title
-----------------
Efficacy and Safety of Octagam 10% Therapy in COVID-19 Patients With Severe Disease Progression

Conditions
-----------------
Covid-19

Intervention / Treatment
-----------------
* Biological: Octagam 10%
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult aged ≥18years old Provide voluntary, fully informed written and signed consent before any study-related procedures are conducted Able to understand and comply with the relevant aspects of the study protocol Laboratory (RT-PCR) confirmed COVID-19 infection on throat swab and/or sputum and/or lower respiratory tract samples Hospitalized with a resting room-air SpO2 of ≤93% or PaO2/FiO2 ratio <300mmHg. Measurement can be taken from documented source records in the 24 hours prior to screening Chest imaging confirming lung involvement Exclusion Criteria: Existence of other evidence that can explain pneumonia including but not limited to: Influenza A virus, influenza B virus, bacterial pneumonia (as suggested by the combined clinical picture, radiological findings and known laboratory results [eg, elevated procalcitonin >0.5ng/mL and concomitant neutrophilia]), known fungal pneumonia, suspected fungal pneumonia based on compromised immune system with a history of past fungal infections, noninfectious causes, etc. Known history of serious allergic reactions, including anaphylaxis, to IVIG or its preparation components Subjects with a history of thromboembolic event (TEE) within the last 12 months, such as deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke, transient ischemic attack, peripheral artery disease (Fontaine IV) Subjects with an underlying medical condition that can lead to hypercoagulable states and hyperviscosity such as antithrombin III deficiency, Factor V Leiden, Protein C deficiency, antiphospholipid syndrome and malignancy Known history of selective IgA deficiency with antibodies against IgA Subjects with conditions such as human immunodeficiency virus (HIV) infection, known acute or chronic hepatitis B or C (HBsAg positive or HCV ribonucleic acid (RNA) PCR positive or currently treated with antivirals), pulmonary fibrosis, elevated procalcitonin (> 0.5) with concomitant neutrophilia (elevated polys), heparin induced thrombocytopenia (HIT), and moderate to severe renal dysfunction (per investigator discretion based on estimated glomerular filtration rate [eGFR] <59 mL/min/1.73 m2, as defined by KDIGO Clinical Practice Guideline): Moderately reduced GFR (G3a): GFR = 45 to 59 ml/min/1.73 m2 Moderately reduced GFR (G3b): GFR = 30 to 44 ml/min/1.73 m2 Severely reduced GFR (G4): GFR = 15 to 29 ml/min/1.73 m2 Kidney failure (G5): GFR <15 ml/min/1.73 m2 Currently requiring IMV (invasive mechanical ventilation or having received IMV during the last 30 days Known clinically significant preexisting lung, heart, or neuromuscular disease that, in the investigator's opinion, would impact subject's ability to complete study or may confound the study results Body weight >125 kg Women who are pregnant or breast-feeding Subjects who received COVID-19 convalescent plasma, IVIG products, anti-interleukin agents (eg, Tocilizumab), or interferons for their COVID-19 disease before enrollment or plan to receive this treatment during the course of the study Enrolled in other experimental interventional studies or taking experimental medications (ie, convalescent plasma). Diagnostic studies can be allowed if the anticipated total blood volume to be drawn across both studies and for therapeutic purposes does not exceed 450 mL over any 8-week period.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Octagam 10%<br>Octagam 10% | Biological: Octagam 10%<br>* Octagam 10%, 2 g/kg divided by 4 days (0.5 g/kg/day), administered by intravenous infusion over approximately 2 hours per day over 4 consecutive days<br>|
| Placebo Comparator: Placebo<br>Placebo | Other: Placebo<br>* Placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stabilization or Improvement in Clinical Status | Proportion of subjects with stabilized or improved clinical status at Day 7 on at least one category on a 6-point clinical status scale. Clinical status categories will be defined as: Hospital discharge or meet discharge criteria (discharge criteria are defined as clinical recovery, i.e. fever, respiratory rate, oxygen saturation return to normal, and cough relief). Hospitalization, not requiring supplemental oxygen. Hospitalization, requiring supplemental oxygen (but not NIV/HFNC). ICU/hospitalization, requiring NIV/HFNC therapy. ICU, requiring Extracorporeal Membrane Oxygenation (ECMO) and/or IMV. Death. | 7 days | 
| Descriptive Clinical Status Analysis | Change from Baseline (Day 1) at Day 7 in terms of the 6-point clinical status scale (descriptive analysis). Clinical status categories will be defined as: Hospital discharge or meet discharge criteria (discharge criteria are defined as clinical recovery, i.e. fever, respiratory rate, oxygen saturation return to normal, and cough relief). Hospitalization, not requiring supplemental oxygen. Hospitalization, requiring supplemental oxygen (but not NIV/HFNC). ICU/hospitalization, requiring NIV/HFNC therapy. ICU, requiring Extracorporeal Membrane Oxygenation (ECMO) and/or IMV. Death. | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Status Assessment | Proportion of subjects with maintenance or improvement by at least one category on the 6-point clinical status scale on Day 14. (This endpoint will go into formal hypothesis testing procedure) Clinical status categories will be defined as: Hospital discharge or meet discharge criteria (discharge criteria are defined as clinical recovery, i.e. fever, respiratory rate, oxygen saturation return to normal, and cough relief). Hospitalization, not requiring supplemental oxygen. Hospitalization, requiring supplemental oxygen (but not NIV/HFNC). ICU/hospitalization, requiring NIV/HFNC therapy. ICU, requiring Extracorporeal Membrane Oxygenation (ECMO) and/or IMV. Death. | 14 days | 
| Time to death | Time to death | Up to 33 days | 
| Mechanical Ventilation Initiation | Proportion of subjects requiring invasive mechanical ventilation by Day 33. | Up to 33 days | 
| Mechanical Ventilation Duration | Duration of invasive mechanical ventilation | Up to 33 days | 
| SARS-CoV-2 Test Result | Results of RT-PCR for SARS-CoV-2 from nares/throat swab and/or sputum and/or lower respiratory tract sample on Day 7. | 7 days | 
| Incidence of all AEs | Incidence of all AEs | Up to 33 days | 
| Incidence of AEs considered related to the IMP | Incidence of AEs considered related to the IMP | Up to 33 days | 
| Incidence of serious adverse events (SAEs) | Incidence of serious adverse events (SAEs) | Up to 33 days | 
| Radiological findings (chest CT/chest X-ray) | Radiological findings (chest CT/chest X-ray) | Up to 7 days | 
| Blood glucose | Change from baseline in blood glucose | Up to 33 daya | 
| Blood calcium | Change from baseline in blood calcium | Up to 33 days | 
| Sodium | Change from baseline in sodium | Up to 33 days | 
| Potassium | Change from baseline in potassium | Up to 33 days | 
| Carbon dioxide | Change from baseline in carbon dioxide | Up to 33 days | 
| Chloride | Change from baseline in chloride | Up to 33 days | 
| Albumin | Change from baseline in albumin | Up to 33 days | 
| Total protein | Change from baseline in total protein | Up to 33 days | 
| Alkaline phosphatase | Change from baseline in alkaline phosphatase | Up to 33 days | 
| Alanine transaminase | Change from baseline in alanine transaminase | Up to 33 days | 
| Aspartate aminotransferase | Change from baseline in aspartate aminotransferase | Up to 33 days | 
| Bilirubin | Change from baseline in bilirubin | Up to 33 days | 
| Blood urea nitrogen | Change from baseline in blood urea nitrogen | Up to 33 days | 
| D-dimer | Change from baseline in D-dimer | Up to 33 days | 
| Fibrinogen | Change from baseline in fibrinogen | Up to 33 days | 
| PT | Change from baseline in PT | Up to 33 days | 
| PTT | Change from baseline in PTT | Up to 33 days | 
| INR | Change from baseline in INR | Up to 33 days | 
| hsCRP | Change from baseline in hsCRP | Up to 33 days | 
| Ferritin | Change from baseline in ferritin | Up to 33 days | 
| LDH | Change from baseline in LDH | Up to 33 days | 
| IgG | Change from baseline in IgG | Up to 33 days | 
| IgM | Change from baseline in IgM | Up to 33 days | 
| IgA | Change from baseline in IgA | Up to 33 days | 
| IFE | Change from baseline in IFE | Up to 33 days | 
| Troponin | Change from baseline in troponin | Up to 33 days | 
| Red blood cell count | Change from baseline in red blood cell count | Up to 33 days | 
| Hemoglobin | Change from baseline in hemoglobjn | Up to 33 days | 
| Hematocrit | Change from baseline in hematocrit | Up to 33 days | 
| Mean corpuscular volume | Change from baseline in mean corpuscular volume | Up to 33 days | 
| Mean corpuscular hemoglobin | Change from baseline in mean corpuscular hemoglobin | Up to 33 days | 
| Mean corpuscular hemoglobin concentration | Change from baseline in mean corpuscular hemoglobin concentration | Up to 33 days | 
| Red cell distribution width | Change from baseline in red cell distribution width | Up to 33 days | 
| White blood cell count | Change from baseline in white blood cell count | Up to 33 days | 
| White blood cell differential | Change from baseline in white blood cell differential | Up to 33 days | 
| Platelet count | Change from baseline in platelet count | Up to 33 days | 
| Mean platelet volume | Change from baseline in mean platelet volume | Up to 33 days | 
| Platelet distribution width | Change from baseline in platelet distribution width | Up to 33 days | 
| SpO2 | Change from baseline in SpO2 | Up to 33 days | 
| A-a gradient | Change from baseline in A-a gradient | Up to 33 days | 
| Blood Pressure | Change from baseline in blood pressure | Up to 33 days | 
| Pulse | Change from baseline in pulse | Up to 33 days | 
| Respiration Rate | Change from baseline in respiration rate | Up to 33 days | 
| Body Temperature | Change from baseline in body temperature | Up to 33 days |