Outpatient Treatment With Anti-Coronavirus Immunoglobulin

Covid19 Clinical Trial

— OTAC  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04910269
• Other study ID #: INSIGHT12
• Secondary ID: 2021-001663-24
• Status: Recruiting
• Phase: Phase 3
• Start date: August 6, 2021
• Est. completion date: August 1, 2024

Study information

• Verified date: December 2023
• Source: University of Minnesota
• Contact: Gary Collins
• Phone: 612-626-9006
• Email: gary-c[@]ccbr.umn.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 820
• Est. completion date: August 1, 2024
• Est. primary completion date: August 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• COVID
• COVID-19
• Covid19
• SARS-CoV2 Infection

Intervention

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

Locations

Country	Name	City	State
Argentina	Hospital General de Agudos JM Ramos Mejia	Buenos Aires
Argentina	Instituto Medico Platense	La Plata	Buenos Aires
Denmark	Department of Infectious Diseases	Aalborg
Denmark	Aarhus Universitetshospital, Skejby	Aarhus	N
Denmark	Rigshospitalet, CHIP	Copenhagen
Denmark	Herlev/Gentofte Hospital	Hellerup
Denmark	Hvidovre University Hospital, Department of Infectious Diseases	Hvidovre
Denmark	Kolding Sygehus	Kolding
Denmark	Odense University Hospital	Odense	C
Greece	3rd Dept of Medicine, Medical School	Athens	Attica
Greece	4th Department of Internal Medicine	Athens	Attica
Greece	Department of Clinical Therapeutics of Alexandra Hospital	Athens	Attica
Greece	Dept of Critical Care and Pulmonary Medicine, Evangelismos General Hospital	Athens	Attica
Greece	Laiko Athens General Hospital	Athens	Attica
India	Postgraduate Institute of Medical Education and Research (PGIMER)	Chandigarh
India	All India Institute of Medical Sciences (AIIMS)	Jodhpur	Rajasthan
Mexico	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
Spain	Hospital Universitari Germans Trias i Pujol	Badalona	Barcelona
Spain	CAP Can Bou	Castelldefels	Barcelona
Spain	CAP El Maresme	Mataro	Barcelona
Uganda	MRC/UVRI & LSHTM Uganda Research Unit	Entebbe
Uganda	Joint Clinical Research Center (JCRC)	Kampala
Uganda	St. Francis Hospital, Nsambya	Kampala
Uganda	Masaka Regional Referral Hospital	Masaka
United States	Hendrick Medical Center	Abilene	Texas
United States	University of Maryland Medical System	Baltimore	Maryland
United States	CHRISTUS Spohn Shoreline Hospital	Corpus Christi	Texas
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Infusion Associates	Grand Rapids	Michigan
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	Mount Sinai Beth Israel Hospital	New York	New York
United States	Swedish Hospital First Hill	Seattle	Washington
United States	MedStar Health Research Institute	Washington	District of Columbia
United States	Washington DC Veterans Affairs Medical Center	Washington	District of Columbia

Sponsors (4)

Lead Sponsor	Collaborator
University of Minnesota	International Network for Strategic Initiatives in Global HIV Trials (INSIGHT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)

Countries where clinical trial is conducted

United States,  Argentina,  Denmark,  Greece,  India,  Mexico,  Spain,  Uganda, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Hypoxemia Through Day 7	Outcome is reported as the mean oxygen saturation (percentage) level in each group at 7 days.	7 days
Secondary	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