OTAC: Outpatient Treatment With Anti-Coronavirus Immunoglobulin

Sponsor

University of Minnesota (Other)

Overall Status

Recruiting

CT.gov ID

NCT04910269

Collaborator

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

820

Enrollment

Locations

Arms

23.8

Anticipated Duration (Months)

21.6

Patients Per Site

0.9

Patients Per Site Per Month

Study Details

Study Description

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 SARS-CoV-2 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 1 will be participants who receive neutralizing monoclonal antibodies (nMAbs) as standard of care (SOC), estimated to be about 20% of participants. Stratum 2 will be participants who do not receive nMAbs, estimated to be about 80% of participants.

Condition or Disease	Intervention/Treatment	Phase
COVID SARS-CoV2 Infection Covid19	Biological: Hyperimmune immunoglobulin to SARS-CoV-2 (hIVIG) Other: Placebo	Phase 3

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

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 (1 of 2) or placebo in a 1:1:2 allocation. After pooling data from each hIVIG product, this will result in 1:1 allocation for hIVIG versus placebo. Randomization will be stratified by study site pharmacy and the two SOC strata.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

820 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Aug 6, 2021

Anticipated Primary Completion Date :

Aug 1, 2023

Anticipated Study Completion Date :

Aug 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment Group Participants in this group will receive the investigational treatment in addition to standard of care.	Biological: Hyperimmune immunoglobulin to SARS-CoV-2 (hIVIG) The hIVIG product is administered as a single dose of 30 grams, or 300 milliliter at a concentration of 0.1 grams/milliliter. This dose corresponds to 400 milligrams/kilogram for a 75 kilogram adult.
Placebo Comparator: Placebo Group Participants in this group will receive a placebo in addition to standard of care.	Other: Placebo Infusion of standard isotonic saline

Arm

Intervention/Treatment

Experimental: Treatment Group

Participants in this group will receive the investigational treatment in addition to standard of care.

Biological: Hyperimmune immunoglobulin to SARS-CoV-2 (hIVIG)

The hIVIG product is administered as a single dose of 30 grams, or 300 milliliter at a concentration of 0.1 grams/milliliter. This dose corresponds to 400 milligrams/kilogram for a 75 kilogram adult.

Placebo Comparator: Placebo Group

Participants in this group will receive a placebo in addition to standard of care.

Other: Placebo

Infusion of standard isotonic saline

Outcome Measures

Primary Outcome Measures

Clinical Status [7 days]
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

Secondary Outcome Measures

All-cause hospitalization or death through 28 days. [28 days]
Outcome reported as the percent of participants who are hospitalized or who expire for any reason by day 28 post treatment.
All-cause mortality through 28 days. [28 days]
Outcome reported as the percent of participants who expire for any reason by day 28 post treatment.
Significant Disease Progression [28 days]
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.
Ordinal Scale Distribution [4, 14, 28 days]
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
Disease Progression Through 7 Days [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.
Significant Disease Progression Through 7 Days [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.
Disease Progression at Follow-up [7, 14, 28 days]
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.
Activity Limitations at Follow-up [7, 14, 28 days]
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.
Change in Viral Burden from Serum Antigen [7 days]
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.
Change in Viral Burden from PCR [7 days]
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.
Change in SARS-CoV-2 Antibody Concentration [7 days]
Outcome is reported as the change in SARS-CoV-2 antibody levels between Day 0 and Day 7, including subclasses and neutralizing titers.
Healthcare Utilization at Follow-up [28 days]
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.
Worst Status Through 28 Days [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).
Hypoxemia Through Day 7 [7 days]
Outcome is reported as the mean oxygen saturation (percentage) level in each group at 7 days.
Additional COVID-19 Treatment [28 days]
Outcome is reported as the number of patients starting other treatments targeting COVID-19 through 28 days post treatment.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 IgA deficiency or anti-IgA antibodies.
Medical conditions for which receipt of a 300 mL volume of IV fluid from study treatment may pose specific risk to the patient (e.g., decompensated congestive heart failure).
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	MedStar Health Research Institute	Washington	District of Columbia	United States	20010
2	Washington DC Veterans Affairs Medical Center	Washington	District of Columbia	United States	20422
3	University of Maryland Medical System	Baltimore	Maryland	United States	21201
4	Infusion Associates	Grand Rapids	Michigan	United States	49525
5	Mount Sinai Beth Israel Hospital	New York	New York	United States	10003
6	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
7	Hendrick Medical Center	Abilene	Texas	United States	79601
8	CHRISTUS Spohn Shoreline Hospital	Corpus Christi	Texas	United States	78404
9	UT Southwestern Medical Center	Dallas	Texas	United States	75390
10	Swedish Hospital First Hill	Seattle	Washington	United States	98122
11	Instituto Medico Platense	La Plata	Buenos Aires	Argentina	B1900AVG
12	Hospital General de Agudos JM Ramos Mejia	Buenos Aires		Argentina	C1221ADC
13	Odense University Hospital	Odense	C	Denmark	5000
14	Aarhus Universitetshospital, Skejby	Aarhus	N	Denmark	8200
15	Department of Infectious Diseases	Aalborg		Denmark	9000
16	Rigshospitalet, CHIP	Copenhagen		Denmark	2100
17	Herlev/Gentofte Hospital	Hellerup		Denmark	2900
18	Hvidovre University Hospital, Department of Infectious Diseases	Hvidovre		Denmark	2650
19	Kolding Sygehus	Kolding		Denmark	6000
20	Dept of Critical Care and Pulmonary Medicine, Evangelismos General Hospital	Athens	Attica	Greece	10676
21	3rd Dept of Medicine, Medical School	Athens	Attica	Greece	11527
22	Laiko Athens General Hospital	Athens	Attica	Greece	11527
23	Department of Clinical Therapeutics of Alexandra Hospital	Athens	Attica	Greece	11528
24	4th Department of Internal Medicine	Athens	Attica	Greece	12462
25	All India Institute of Medical Sciences (AIIMS)	Jodhpur	Rajasthan	India	342005
26	Postgraduate Institute of Medical Education and Research (PGIMER)	Chandigarh		India	160012
27	Hospital General Dr. Manuel Gea Gonzáles	Mexico City	Cdmx	Mexico	14080
28	Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran	Mexico City	Cdmx	Mexico	14080
29	Instituto Nacional de Enfermedades Respiratorias Ismael Cosió Villegas	Mexico City	Cdmx	Mexico	14080
30	CHRISTUS Centro de Excelencia en Investigacion (Obispado)	Monterrey	NL	Mexico	64060
31	Hospital General Dr. Aurelio Valdivieso	Oaxaca City	OA	Mexico	68050
32	Hospital Universitari Germans Trias i Pujol	Badalona	Barcelona	Spain	08916
33	CAP Can Bou	Castelldefels	Barcelona	Spain	08860
34	CAP El Maresme	Mataro	Barcelona	Spain	08303
35	MRC/UVRI & LSHTM Uganda Research Unit	Entebbe		Uganda
36	Joint Clinical Research Center (JCRC)	Kampala		Uganda
37	St. Francis Hospital, Nsambya	Kampala		Uganda
38	Masaka Regional Referral Hospital	Masaka		Uganda