Outpatient Treatment With Anti-Coronavirus Immunoglobulin

Study Overview
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Brief Summary
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The primary objective of the Outpatient Treatment with Anti-Coronavirus Immunoglobulin (OTAC) (INSIGHT 012) trial is to compare the safety and efficacy of a single infusion of anti-COVID-19 hyperimmune intravenous immunoglobulin (hIVIG) versus placebo among adults with recently diagnosed severe acute respiratory syndrome - coronavirus 2 (SARS-CoV2) infection who do not require hospitalization. The primary endpoint of this double-blind randomized trial is a five-category ordinal outcome that assesses the participant's clinical status seven days after the infusion of hIVIG or placebo. Asymptomatic and no limitations in usual activity due to COVID-19 Mild COVID-19 illness or minor limitations to usual activity Moderate COVID-19 illness and with major limitations to usual activity Severe COVID-19 or serious disease manifestation from COVID-19 Critical illness from COVID-19 or Death Two strata of participants will be identified for analysis purposes. Stratum 2 will be participants who receive direct-acting antivirals (DAAs) or other anti-SARS-CoV2 agents that are approved/available and recommended for use as part of standard of care (SOC), estimated to be about 20% of participants. Stratum 1 will be participants who do not receive this agents, estimated to be about 80% of participants.

Detailed Description
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The primary objective will be addressed by testing two hypotheses aimed at assessing whether hIVIG + standard of care (SOC) is superior to placebo + SOC for the primary ordinal endpoint at Day 7. These hypotheses will be tested for the following two groups: a) among all randomized participants (stratum 1 and 2), and b) among only participants enrolled in stratum 1. For the primary analysis, overall type 1 error will be controlled at 5% by using a 2-sided significance level of 0.035 for each hypothesis. This significance level was obtained using the correlation between the test statistics for the proportional log odds ratio for all randomized participants and for this log odds ratio for those in stratum 1. This correlation was determined to be 0.895. With this approach hIVIG will be considered superior to placebo if either of the two hypotheses is rejected. Participants will be randomized to a single infusion of an hIVIG product or placebo in a 1:1 allocation. Randomization will be stratified by study site pharmacy and the two SOC strata.

Official Title
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An International Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of the Safety and Efficacy of Anti-Coronavirus Hyperimmune Intravenous Immunoglobulin for the Treatment of Adult Outpatients in Early Stages of COVID-19

Conditions
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COVID, Covid19, SARS-CoV2 Infection

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical risk based on age ≥ 55 years or an adult (age ≥ 18 years) with an immunosuppressed condition. Positive test for SARS-CoV-2 within ≤5 days (if >1 test, the first positive is within ≤5 days). Tests may include an institutional-based nucleic acid amplification test (NAAT), or any protocol-approved rapid test. Within ≤5 days from symptom onset, if symptomatic from current SARS-CoV-2 infection. Agrees to not participate in another clinical trial for the treatment or management of SARS-CoV-2 infection through Day 7, or until hospitalized or significant disease progression if prior to Day 7 (defined by ordinal category 4 or 5). Participant provides written informed consent prior to study procedures, and understands and agrees to adhere to planned study procedures through Day 28. Ongoing immunosuppressive condition or immunosuppressive treatment, includes: Steroids equivalent to prednisone > 10 mg/day for at least the last 28 days Rheumatologic or autoimmune disorder treated with a biologic or non-biologic immunosuppressive therapy Antirejection medicine after solid organ or stem cell transplantation Cancer treatment with systemic chemotherapy, biologic and/or cell-based therapy in the last 12 months Primary or acquired severe B- or T-lymphocyte immune dysfunction HIV infection Splenectomy or functional asplenia Exclusion Criteria: Asymptomatic and had prior symptoms from the current infection that have now resolved (for >24 hours). Asymptomatic and has received a vaccination for COVID-19 (≥1 dose). Undergoing evaluation for possible admission to hospital for medical management (this does not include evaluation of possible hospitalization for public health purposes). Evidence of pneumonia and/or hypoxia due to COVID-19 (NOTE: chest imaging is not required, but if available it should not show new infiltrates suggestive of pneumonia; hypoxia is defined by new oxygen supplementation or increase above pre-illness level). Prior receipt of immunoglobulin product or passive immune therapy for SARS-CoV-2 in the past 90 days (i.e., convalescent plasma, SARS-CoV-2 monoclonal antibodies, or any IVIG). Any of the following thrombotic or procoagulant conditions or disorders: acute coronary syndrome, cerebrovascular syndrome, pulmonary embolism, or deep venous thrombosis within 28 days of randomization. prothrombin gene mutation 20210, homozygous Factor V Leiden mutations, antiphospholipid syndrome, or a deficiency in antithrombin III, protein C, or protein S. History of hypersensitivity to blood, plasma or IVIG excipients. Known immunoglobulin A (IgA) deficiency or anti-IgA antibodies. In the opinion of the investigator, any condition for which participation would not be in the best interest of the participant or that could prevent or confound protocol 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: Treatment Group<br>Participants in this group will receive the investigational treatment in addition to standard of care. | Biological: Hyperimmune immunoglobulin to SARS-CoV-2 (hIVIG)<br>* The hIVIG product is administered as a single dose of 3.5 grams, or 35 milliliter at a concentration of 0.1 grams/milliliter.<br>|
| Placebo Comparator: Placebo Group<br>Participants in this group will receive a placebo in addition to standard of care. | Other: Placebo<br>* Infusion of 35 milliliters standard isotonic saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Status | The primary outcome is to compare the safety and efficacy of a single infusion of hIVIG versus placebo on clinical status after seven days. Outcome will be reported as the percent of participants who fall into each of 5 clinical status categories as defined below. Asymptomatic and no limitations in usual activity due to COVID-19 Mild COVID-19 illness or minor limitations to usual activity Moderate COVID-19 illness and with major limitations to usual activity Severe COVID-19 or serious disease manifestation from COVID-19 Critical illness from COVID-19 or Death | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause hospitalization or death through 28 days. | Outcome reported as the percent of participants who are hospitalized or who expire for any reason by day 28 post treatment. | 28 days | 
| All-cause mortality through 28 days. | Outcome reported as the percent of participants who expire for any reason by day 28 post treatment. | 28 days | 
| Significant Disease Progression | Outcome is reported as the number of participants with significant disease progression through 28 days, which is defined by fulfilling criteria for category 4 or 5 on the ordinal scale using a time to event analysis. | 28 days | 
| Ordinal Scale Distribution | Outcome will be reported as the percent of participants who fall into each of 5 clinical status categories as defined below at days 4, 14, and 28 following treatment. Asymptomatic and no limitations in usual activity due to COVID-19 Mild COVID-19 illness or minor limitations to usual activity Moderate COVID-19 illness and with major limitations to usual activity Severe COVID-19 or serious disease manifestation from COVID-19 Critical illness from COVID-19 or Death | 4, 14, 28 days | 
| Disease Progression Through 7 Days | Outcome is reported as the proportion of participants with any disease progression at Day 7, using a sliding dichotomous scale progression defined by a categorization on the ordinal scale that is worse than the status at entry. | 7 days | 
| Significant Disease Progression Through 7 Days | Outcome is reported as the proportion of participants who progress to categories 3-5 on the clinical ordinal scale at Day 7 among participants in categories 1 or 2 of the ordinal scale at entry. | 7 days | 
| Disease Progression at Follow-up | Outcome is reported as the percent of participants who experience severe disease progression during follow-up, defined by the worst health status achieved on the clinical ordinal scale at any point by Day 7, 14, and 28. | 7, 14, 28 days | 
| Activity Limitations at Follow-up | Outcome is reported as the percent of participants who attain their pre-COVID health status without limitations in usual activity (defined as category 1 on the ordinal scale) at Day 7, 14, and 28. | 7, 14, 28 days | 
| Change in Viral Burden from Serum Antigen | Outcome is reported as the change between Day 0 and Day 7 in viral burden as determined by serum antigen levels from nasal and saliva specimens. | 7 days | 
| Change in Viral Burden from PCR | Outcome is reported as the change between Day 0 and Day 7 in viral burden as determined by polymerase chain reaction (PCR) from nasal and saliva specimens. | 7 days | 
| Change in SARS-CoV-2 Antibody Concentration | Outcome is reported as the change in SARS-CoV-2 antibody levels between Day 0 and Day 7, including subclasses and neutralizing titers. | 7 days | 
| Healthcare Utilization at Follow-up | Outcome is reported as the percent of participants who had health care engagement for the purposes of medical evaluation and/or management of COVID-19 illness (e.g., via telehealth, clinic, urgent care, emergency room, or hospitalization) at 28 days follow-up. | 28 days | 
| Worst Status Through 28 Days | Outcome is reported as the number of participants who experience each of the following categories as their worst respiratory status through 28 days, including: a) no respiratory symptoms, b) upper respiratory symptoms, c) lower respiratory symptoms without hypoxia, c) hypoxia requiring conventional oxygen supplementation by nasal canula, d) respiratory failure requiring high-flow oxygen delivery device or non-invasive ventilation, or e) respiratory failure requiring mechanical ventilation or extra-corporeal membrane oxygenation (ECMO). | 28 days | 
| Hypoxemia Through Day 7 | Outcome is reported as the mean oxygen saturation (percentage) level in each group at 7 days. | 7 days | 
| Additional COVID-19 Treatment | Outcome is reported as the number of patients starting other treatments targeting COVID-19 through 28 days post treatment. | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immunotherapy, hIVIG, early treatment