Inpatient Treatment of COVID-19 With Anti-Coronavirus Immunoglobulin (ITAC)

Study Overview
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Brief Summary
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This protocol will serve as a platform for assessing treatments for adult patients hospitalized for medical management of COVID-19 without related serious end-organ failure. Trials will involve sites around the world strategically chosen to ensure rapid enrollment. This trial will compare hyperimmune intravenous immunoglobulin (hIVIG) with matched placebo, when added to standard of care (SOC), for preventing further disease progression and mortality related to COVID-19. SOC will include remdesivir unless it is contraindicated for an individual patient.

Detailed Description
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The primary endpoint of this trial in hospitalized patients is an ordinal outcome based on the patient's clinical status on Day 7. It includes 7 mutually exclusive categories capturing the range of organ dysfunction that may be associated with progression of COVID-19, such as respiratory dysfunction and coagulation-related complications. The ordinal endpoint is defined as follows: 7. Death 6. End-organ failure 5. Life-threatening end-organ dysfunction 4. Serious end-organ dysfunction 3. Moderate end-organ dysfunction 2. Limiting symptoms due to COVID-19 1. No limiting symptoms due to COVID-19 Secondary endpoints include time to the 3 least favorable categories, time to the 2 most favorable categories, and the pulmonary only and thrombotic only components of the primary ordinal outcome. Mortality, adverse events (AEs), including infusion reactions, and biological correlates of therapeutic activity are also assessed. Because there is no established endpoint for evaluating the clinical efficacy of treatments for COVID-19, other clinically relevant outcomes, including outcomes used in other COVID-19 treatment trials, will be recorded. Thus, the randomized groups (hIVIG + SOC versus placebo + SOC ) can be compared for multiple outcomes, and results can be compared or combined with other trials. Participants will be randomized (1:1) to a single infusion of hIVIG + SOC or placebo + SOC on the day of randomization (Day 0). Participants taking remdesivir prior to randomization may be enrolled if eligibility criteria are met. Randomized participants who were not taking remdesivir before randomization will start taking remdesivir immediately following the infusion of hIVIG or placebo unless remdesivir is contraindicated. Participants will be followed for 28 days and, if the trial goes to completion, the primary analysis will be completed after all participants are followed for 28 days.

Official Title
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An International Multicenter, Adaptive, Randomized Double-Blind, Placebo-Controlled Trial of the Safety, Tolerability and Efficacy of Anti-Coronavirus Hyperimmune Intravenous Immunoglobulin for the Treatment of Adult Hospitalized Patients at Onset of Clinical Progression of COVID-19

Conditions
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COVID, COVID-19, SARS-CoV-2, SARS (Severe Acute Respiratory Syndrome)

Intervention / Treatment
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* Biological: Hyperimmune immunoglobulin to SARS-CoV-2 (hIVIG)
* Other: Placebo
* Drug: Remdesivir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: SARS-CoV-2 infection documented by polymerase chain reaction (PCR) or other nucleic acid test (NAT) within 3 days prior to randomization OR documented by NAT more than 3 days prior to randomization AND progressive disease suggestive of ongoing SARS-CoV-2 infection Symptomatic COVID-19 disease Duration of symptoms attributable to COVID-19 ≤ 12 days Requiring inpatient hospital medical care for clinical manifestations of COVID-19 (admission for public health or quarantine only is not included) Willingness to abstain from participation in other COVID-19 treatment trials until after study Day 7 Provision of informed consent by participant or legally authorized representative Exclusion Criteria: Prior receipt of SARS-CoV-2 hIVIG or convalescent plasma from a person who recovered from COVID-19 at any time Prior receipt of standard IVIG (not hyperimmune to SARS-CoV-2) within 45 days Current or predicted imminent (within 24 hours) requirement for any of the following: Invasive ventilation Non-invasive ventilation Extracorporeal membrane oxygenation Mechanical circulatory support Continuous vasopressor therapy History of allergy to IVIG or plasma products History of selective IgA deficiency with documented presence of anti-IgA antibodies Any medical conditions for which receipt of the required volume of intravenous fluid may be dangerous to the patient (includes New York Association Class III or IV stage heart failure) Any of the following thrombotic or procoagulant disorders: Acute coronary syndromes, cerebrovascular syndromes and pulmonary or deep venous thrombosis within 28 days of randomization History of prothrombin gene mutation 20210, homozygous Factor V Leiden mutations, antithrombin III deficiency, protein C deficiency, protein S deficiency or antiphospholipid syndrome Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject or that could prevent, limit, or confound the protocol-specified assessments

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention Group<br>Participants in this group will receive the investigational product and standard of care (SOC). | Biological: Hyperimmune immunoglobulin to SARS-CoV-2 (hIVIG)<br>* Hyperimmune immunoglobulin to SARS-CoV-2 (hIVIG) is derived from the plasma of individuals who recover and develop neutralizing antibodies. Participants will receive a single infusion.<br>Drug: Remdesivir<br>* Remdesivir will be given to participants in both groups as standard of care (SOC).<br>|
| Placebo Comparator: Control Group<br>Participants in this group will receive a placebo and standard of care (SOC). | Other: Placebo<br>* Participants will receive a single infusion of the placebo (saline).<br>Drug: Remdesivir<br>* Remdesivir will be given to participants in both groups as standard of care (SOC).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ordinal Outcome Scale - Day 7 | The primary objective is to compare the clinical status of patients in each group on day 7 of follow-up using the primary ordinal outcome with 7 mutually exclusive categories: 7. Death 6. End-organ failure 5. Life-threatening end-organ dysfunction 4. Serious end-organ dysfunction 3. Moderate end-organ dysfunction 2. Limiting symptoms due to COVID-19 1. No limiting symptoms due to COVID-19 Outcome is reported as the percent of participants in each of 7 categories. Primary ordinal outcome based on the patient's clinical status on Day 7. It includes 7 mutually exclusive categories capturing the range of organ dysfunction that may be associated with progression of COVID-19, such as respiratory dysfunction and coagulation-related complications. Minimum value = 1, Maximum value = 7 Higher scores mean a worse outcome | 7 days | 
| Primary Safety Outcome - Death, SAE or Grade 3 or 4 Events Through Day 7 | Number of participants with death, SAE or Grade 3 or 4 event through Day 7 | Through Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| N Reaching 3 Least Favorable Categories | N Reaching 3 least favorable categories of ordinal outcome (Categories 5, 6, 7: life-threatening end organ dysfunction, end organ failure, or death) | All of follow-up (through Day 28) | 
| N Reaching 2 Most Favorable Categories | N Reaching 2 most favorable categories of ordinal outcome (Categories 1 and 2: not requiring oxygen with or without limiting symptoms due to COVID-19) | All of follow-up (through Day 28) | 
| N Discharged or in Most Favorable Category | N discharged from hospital or reaching most favorable ordinal category (category 1: not requiring oxygen and no limiting symptoms due to COVID-19) | All of follow-up (through Day 28) |