Clinical trial NCT04910269: Outpatient Treatment With Anti-Coronavirus Immunoglobulin
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: COVID
SARS-CoV2 Infection
Covid19
Keywords: immunotherapy
hIVIG
early treatment
Lead sponsor: University of Minnesota
Sponsor class: OTHER
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: National Institutes of Health (NIH)
name: International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)
First posted: 2021-06-02
Enrollment: 820
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Clinical Status
timeFrame: 7 days
Secondary outcomes:
measure: All-cause hospitalization or death through 28 days.
timeFrame: 28 days
measure: All-cause mortality through 28 days.
timeFrame: 28 days
measure: Significant Disease Progression
timeFrame: 28 days
measure: Ordinal Scale Distribution
timeFrame: 4, 14, 28 days
measure: Disease Progression Through 7 Days
timeFrame: 7 days
measure: Significant Disease Progression Through 7 Days
timeFrame: 7 days
measure: Disease Progression at Follow-up
timeFrame: 7, 14, 28 days
measure: Activity Limitations at Follow-up
timeFrame: 7, 14, 28 days
measure: Change in Viral Burden from Serum Antigen
timeFrame: 7 days
measure: Change in Viral Burden from PCR
timeFrame: 7 days
measure: Change in SARS-CoV-2 Antibody Concentration
timeFrame: 7 days
measure: Healthcare Utilization at Follow-up
timeFrame: 28 days
measure: Worst Status Through 28 Days
timeFrame: 28 days
measure: Hypoxemia Through Day 7
timeFrame: 7 days
measure: Additional COVID-19 Treatment
timeFrame: 28 days
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Southern Arizona VA Healthcare System (074-009)
state: Arizona
city: Mather
country: United States
facility: VA Northern California Health Care System (074-023)
state: California
city: Palo Alto
country: United States
facility: Stanford University Hospital & Clinics (Site 203-003)
state: California
city: San Francisco
country: United States
facility: San Francisco VAMC (Site 074-002)
state: California
city: Aurora
country: United States
facility: Rocky Mountain Regional VA Medical Center (074-010)
state: Colorado
city: Washington
country: United States
facility: MedStar Health Research Institute
state: District of Columbia
city: Washington
country: United States
facility: Washington DC Veterans Affairs Medical Center
state: District of Columbia
city: Baltimore
country: United States
facility: University of Maryland Medical System
state: Maryland
city: Detroit
country: United States
facility: Henry Ford Health System Site (014-001)
state: Michigan
city: Grand Rapids
country: United States
facility: Infusion Associates
state: Michigan
city: New York
country: United States
facility: Mount Sinai Beth Israel Hospital
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation (Site 207-001)
state: Ohio
city: Hershey
country: United States
facility: Penn State Health Milton S. Hershey Medical Center (209-002)
state: Pennsylvania
city: Abilene
country: United States
facility: Hendrick Medical Center
state: Texas
city: Corpus Christi
country: United States
facility: CHRISTUS Spohn Shoreline Hospital
state: Texas
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center (211-001)
state: Utah
city: Roanoke
country: United States
facility: Carilion Medical Center (Site 080-018)
state: Virginia
city: Salem
country: United States
facility: Salem VA Medical Center (074-014)
state: Virginia
city: Seattle
country: United States
facility: Swedish Hospital First Hill
state: Washington
city: La Plata
country: Argentina
facility: Instituto Medico Platense
state: Buenos Aires
city: Mar del Plata
country: Argentina
facility: Centro de Investigaciones Medicas de Mar del Plata (Site 611-031)
state: Buenos Aires
city: Buenos Aires
country: Argentina
facility: Hospital General de Agudos JM Ramos Mejia
city: Sydney
country: Australia
facility: St. Vincent's Hospital
state: New South Wales
city: Odense
country: Denmark
facility: Odense University Hospital
state: C
city: Aarhus
country: Denmark
facility: Aarhus Universitetshospital, Skejby
state: N
city: Aalborg
country: Denmark
facility: Department of Infectious Diseases
city: Copenhagen
country: Denmark
facility: Rigshospitalet, CHIP
city: Copenhagen
country: Denmark
facility: Bispebjerg Hospital
city: Hellerup
country: Denmark
facility: Herlev/Gentofte Hospital
city: Hvidovre
country: Denmark
facility: Hvidovre University Hospital, Department of Infectious Diseases
city: Kolding
country: Denmark
facility: Kolding Sygehus
city: Athens
country: Greece
facility: Dept of Critical Care and Pulmonary Medicine, Evangelismos General Hospital
state: Attica
city: Athens
country: Greece
facility: 3rd Dept of Medicine, Medical School
state: Attica
city: Athens
country: Greece
facility: Laiko Athens General Hospital
state: Attica
city: Athens
country: Greece
facility: Department of Clinical Therapeutics of Alexandra Hospital
state: Attica
city: Athens
country: Greece
facility: 4th Department of Internal Medicine
state: Attica
city: Jodhpur
country: India
facility: All India Institute of Medical Sciences (AIIMS)
state: Rajasthan
city: Chandigarh
country: India
facility: Postgraduate Institute of Medical Education and Research (PGIMER)
city: Mexico City
country: Mexico
facility: Hospital General Dr. Manuel Gea Gonzáles
state: Cdmx
city: Mexico City
country: Mexico
facility: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
state: Cdmx
city: Mexico City
country: Mexico
facility: Instituto Nacional de Enfermedades Respiratorias Ismael Cosió Villegas
state: Cdmx
city: Monterrey
country: Mexico
facility: CHRISTUS Centro de Excelencia en Investigacion (Obispado)
state: NL
city: Oaxaca City
country: Mexico
facility: Hospital General Dr. Aurelio Valdivieso
state: OA
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
state: Barcelona
city: Castelldefels
country: Spain
facility: CAP Can Bou
state: Barcelona
city: Mataro
country: Spain
facility: CAP El Maresme
state: Barcelona
city: Barcelona
country: Spain
facility: CAP Corbera
city: Bangkok Noi
country: Thailand
facility: Siriraj Hospital (Site 613-002)
state: Bangkok
city: Pathum Wan
country: Thailand
facility: Chulalongkorn University and The HIV-NAT
state: Bangkok
city: Khon Kaen
country: Thailand
facility: Khon Kaen University, Srinagarind Hospital (Site 613-003)
city: Nonthaburi
country: Thailand
facility: Bamrasnaradura Infections Diseases Institute (613-007)
city: Entebbe
country: Uganda
facility: MRC/UVRI & LSHTM Uganda Research Unit
city: Kampala
country: Uganda
facility: Joint Clinical Research Center (JCRC)
city: Kampala
country: Uganda
facility: Makerere University Lung Institute (Site 634-604)
city: Kampala
country: Uganda
facility: St. Francis Hospital, Nsambya
city: Lira
country: Uganda
facility: Lira Regional Referral Hospital
city: Masaka
country: Uganda
facility: Masaka Regional Referral Hospital
city: Ivano-Frankivs'k
country: Ukraine
facility: Central City Clinical Hospital of Ivano-Frankivsk City Council
city: London
country: United Kingdom
facility: University College London Hospitals
city: Newcastle upon Tyne
country: United Kingdom
facility: Royal Victoria Infirmary
Study officials:
affiliation: University of Minnesota
name: Cavan Reilly, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jha A, Barker D, Lew J, Manoharan V, van Kessel J, Haupt R, Toth D, Frieman M, Falzarano D, Kodihalli S. Efficacy of COVID-HIGIV in animal models of SARS-CoV-2 infection. Sci Rep. 2022 Oct 10;12(1):16956. doi: 10.1038/s41598-022-21223-2.