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 ofanti-COVID-19 hyperimmune intravenous immunoglobulin (hIVIG) versus placebo among adultswith recently diagnosed severe acute respiratory syndrome - coronavirus 2 (SARS-CoV2)infection who do not require hospitalization. The primary endpoint of this double-blindrandomized trial is a five-category ordinal outcome that assesses the participant'sclinical status seven days after the infusion of hIVIG or placebo. 1. Asymptomatic and no limitations in usual activity due to COVID-19 2. Mild COVID-19 illness or minor limitations to usual activity 3. Moderate COVID-19 illness and with major limitations to usual activity 4. Severe COVID-19 or serious disease manifestation from COVID-19 5. Critical illness from COVID-19 or DeathTwo strata of participants will be identified for analysis purposes. Stratum 2 will beparticipants who receive direct-acting antivirals (DAAs) or other anti-SARS-CoV2 agentsthat 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 notreceive this agents, estimated to be about 80% of participants.
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.
Biological: Hyperimmune immunoglobulin to SARS-CoV-2 (hIVIG)
The hIVIG product is administered as a single dose of 3.5 grams, or 35 milliliter at a
concentration of 0.1 grams/milliliter.
Other: Placebo
Infusion of 35 milliliters standard isotonic saline
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:
1. Steroids equivalent to prednisone > 10 mg/day for at least the last 28 days
2. Rheumatologic or autoimmune disorder treated with a biologic or non-biologic
immunosuppressive therapy
3. Antirejection medicine after solid organ or stem cell transplantation
4. Cancer treatment with systemic chemotherapy, biologic and/or cell-based therapy in
the last 12 months
5. Primary or acquired severe B- or T-lymphocyte immune dysfunction
6. HIV infection
7. 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:
1. acute coronary syndrome, cerebrovascular syndrome, pulmonary embolism, or deep
venous thrombosis within 28 days of randomization.
2. 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.
Southern Arizona VA Healthcare System (074-009)
Tucson, Arizona, United States
VA Northern California Health Care System (074-023)
Mather, California, United States
San Francisco VAMC (Site 074-002)
San Francisco, California, United States
Rocky Mountain Regional VA Medical Center (074-010)
Aurora, Colorado, United States
MedStar Health Research Institute
Washington, District of Columbia, United States
Washington DC Veterans Affairs Medical Center
Washington, District of Columbia, United States
University of Maryland Medical System
Baltimore, Maryland, United States
Henry Ford Health System Site (014-001)
Detroit, Michigan, United States
Infusion Associates
Grand Rapids, Michigan, United States
Mount Sinai Beth Israel Hospital
New York, New York, United States
Icahn School of Medicine at Mount Sinai
New York, New York, United States
Cleveland Clinic Foundation (Site 207-001)
Cleveland, Ohio, United States
Penn State Health Milton S. Hershey Medical Center (209-002)
Hershey, Pennsylvania, United States
Hendrick Medical Center
Abilene, Texas, United States
CHRISTUS Spohn Shoreline Hospital
Corpus Christi, Texas, United States
UT Southwestern Medical Center
Dallas, Texas, United States
Intermountain Medical Center (211-001)
Murray, Utah, United States
Carilion Medical Center (Site 080-018)
Roanoke, Virginia, United States
Salem VA Medical Center (074-014)
Salem, Virginia, United States
Swedish Hospital First Hill
Seattle, Washington, United States
Instituto Medico Platense
La Plata, Buenos Aires, Argentina
Hospital General de Agudos JM Ramos Mejia
Buenos Aires, Argentina
St. Vincent's Hospital
Sydney, New South Wales, Australia
Odense University Hospital
Odense, C, Denmark
Aarhus Universitetshospital, Skejby
Aarhus, N, Denmark
Department of Infectious Diseases
Aalborg, Denmark
Rigshospitalet, CHIP
Copenhagen, Denmark
Bispebjerg Hospital
Copenhagen, Denmark
Herlev/Gentofte Hospital
Hellerup, Denmark
Hvidovre University Hospital, Department of Infectious Diseases
Hvidovre, Denmark
Kolding Sygehus
Kolding, Denmark
Dept of Critical Care and Pulmonary Medicine, Evangelismos General Hospital
Athens, Attica, Greece
3rd Dept of Medicine, Medical School
Athens, Attica, Greece
Laiko Athens General Hospital
Athens, Attica, Greece
Department of Clinical Therapeutics of Alexandra Hospital
Athens, Attica, Greece
4th Department of Internal Medicine
Athens, Attica, Greece
All India Institute of Medical Sciences (AIIMS)
Jodhpur, Rajasthan, India
Postgraduate Institute of Medical Education and Research (PGIMER)
Chandigarh, India
Hospital General Dr. Manuel Gea Gonzáles
Mexico City, Cdmx, Mexico
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Mexico City, Cdmx, Mexico
Instituto Nacional de Enfermedades Respiratorias Ismael Cosió Villegas
Mexico City, Cdmx, Mexico
CHRISTUS Centro de Excelencia en Investigacion (Obispado)
Monterrey, NL, Mexico
Hospital General Dr. Aurelio Valdivieso
Oaxaca City, OA, Mexico
Hospital Universitari Germans Trias i Pujol
Badalona, Barcelona, Spain
CAP Can Bou
Castelldefels, Barcelona, Spain
CAP El Maresme
Mataro, Barcelona, Spain
CAP Corbera
Barcelona, Spain
Siriraj Hospital (Site 613-002)
Bangkok Noi, Bangkok, Thailand
Chulalongkorn University and The HIV-NAT
Pathum Wan, Bangkok, Thailand
Khon Kaen University, Srinagarind Hospital (Site 613-003)
Khon Kaen, Thailand
Bamrasnaradura Infections Diseases Institute (613-007)
Nonthaburi, Thailand
MRC/UVRI & LSHTM Uganda Research Unit
Entebbe, Uganda
Joint Clinical Research Center (JCRC)
Kampala, Uganda
St. Francis Hospital, Nsambya
Kampala, Uganda
Lira Regional Referral Hospital
Lira, Uganda
Masaka Regional Referral Hospital
Masaka, Uganda
Central City Clinical Hospital of Ivano-Frankivsk City Council
Ivano-Frankivs'k, Ukraine
University College London Hospitals
London, United Kingdom
Royal Victoria Infirmary
Newcastle upon Tyne, United Kingdom
Gary Collins
612-626-9006
gary-c@ccbr.umn.edu
Cavan Reilly, PhD, Principal Investigator
University of Minnesota