Inpatient Treatment of COVID-19 With Anti-Coronavirus Immunoglobulin (ITAC)

An International Multicenter, Adaptive, Randomized Double-Blind, Placebo-Controlled Trial of the Safety, Tolerability and Efficacy of Anti-Coronavirus Hyperimmune Intravenous Immunoglobulin for the Treatment of Adult Hospitalized Patients at Onset of Clinical Progression of COVID-19

This protocol will serve as a platform for assessing treatments for adult patients hospitalized for medical management of COVID-19 without related serious end-organ failure. Trials will involve sites around the world strategically chosen to ensure rapid enrollment. This trial will compare hyperimmune intravenous immunoglobulin (hIVIG) with matched placebo, when added to standard of care (SOC), for preventing further disease progression and mortality related to COVID-19. SOC will include remdesivir unless it is contraindicated for an individual patient.

Study Overview

• Status: Completed
• Conditions: COVID-19; COVID; SARS-CoV-2; SARS (Severe Acute Respiratory Syndrome)
• Intervention / Treatment: Biological: Hyperimmune immunoglobulin to SARS-CoV-2 (hIVIG); Drug: Remdesivir; Other: Placebo

Detailed Description

The primary endpoint of this trial in hospitalized patients is an ordinal outcome based on the patient's clinical status on Day 7. It includes 7 mutually exclusive categories capturing the range of organ dysfunction that may be associated with progression of COVID-19, such as respiratory dysfunction and coagulation-related complications. The ordinal endpoint is defined as follows:

7. Death

6. End-organ failure

5. Life-threatening end-organ dysfunction

4. Serious end-organ dysfunction

3. Moderate end-organ dysfunction

2. Limiting symptoms due to COVID-19

1. No limiting symptoms due to COVID-19

Secondary endpoints include time to the 3 least favorable categories, time to the 2 most favorable categories, and the pulmonary only and thrombotic only components of the primary ordinal outcome. Mortality, adverse events (AEs), including infusion reactions, and biological correlates of therapeutic activity are also assessed. Because there is no established endpoint for evaluating the clinical efficacy of treatments for COVID-19, other clinically relevant outcomes, including outcomes used in other COVID-19 treatment trials, will be recorded. Thus, the randomized groups (hIVIG + SOC versus placebo + SOC ) can be compared for multiple outcomes, and results can be compared or combined with other trials.

Participants will be randomized (1:1) to a single infusion of hIVIG + SOC or placebo + SOC on the day of randomization (Day 0). Participants taking remdesivir prior to randomization may be enrolled if eligibility criteria are met. Randomized participants who were not taking remdesivir before randomization will start taking remdesivir immediately following the infusion of hIVIG or placebo unless remdesivir is contraindicated. Participants will be followed for 28 days and, if the trial goes to completion, the primary analysis will be completed after all participants are followed for 28 days.

• Study Type: Interventional
• Enrollment (Actual): 593
• Phase: Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark
    • Aarhus Universitetshospital, Skejby
  • Copenhagen, Denmark
    • Bispebjerg Hospital
  • Copenhagen, Denmark
    • CHIP, Department of Infectious Diseases, Section 2100
  • Hellerup, Denmark
    • Herlev-Gentofte Hospital
  • Hillerød, Denmark, 3400
    • Nordsjællands Hospital, Hillerød
  • Hvidovre, Denmark
    • Hvidovre University Hospital, Department of Infectious Diseases
  • Kolding, Denmark
    • Kolding Sygehus
  • Odense, Denmark
    • Odense University Hospital
• Greece
  • Athens, Greece, 11527
    • 3rd Dept of Medicine, Medical School, NKUA
  • Athens, Greece
    • 1st Respiratory Medicine Dept, Athens University Medical School
  • Athens, Greece
    • Attikon University General Hospital
  • Athens, Greece
    • Dept. of Critical Care & Pulmonary Medicine, Evangelismos General Hospital
  • Thrace
    • Alexandroupoli, Thrace, Greece, 68131
      • Democritus University of Thrace
• Japan
  • Tokyo, Japan
    • NCGM
  • Toyoake, Japan
    • Fujita Health University Hospital
• Nigeria
  • Abuja, Nigeria
    • Institute of Human Virology-Nigeria (IHVN)
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clínic de Barcelona
  • Barcelona, Spain, 08002
    • Hospital Del Mar
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Hospital Universitari Germans Trias i Pujol
  • Catalonia
    • Barcelona, Catalonia, Spain, 08035
      • Hospital Universitari Vall d'Hebron
• United Kingdom
  • London, United Kingdom
    • Royal Free Hospital
• United States
  • Colorado
    • Colorado Springs, Colorado, United States, 80907
      • Penrose Hospital
    • Colorado Springs, Colorado, United States, 80907
      • St. Francis Health Services
    • Lakewood, Colorado, United States, 80228
      • St. Anthony Hospital
    • Westminster, Colorado, United States, 80023
      • Saint Anthony North Health Campus
  • District of Columbia
    • Washington, District of Columbia, United States, 20422
      • Washington VA Medical Center
  • Georgia
    • Rome, Georgia, United States, 30165
      • Redmond Regional Medical Center
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center
  • Massachusetts
    • Worcester, Massachusetts, United States, 01665
      • University of Massachusetts
  • Minnesota
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin Healthcare Research Institute/HCMC
  • Missouri
    • Columbia, Missouri, United States, 65212
      • University of Missouri
    • Springfield, Missouri, United States, 65807
      • Cox Medical Centers
  • North Carolina
    • Pinehurst, North Carolina, United States, 28394
      • Firsthealth Moore Regional Hospital
  • Ohio
    • Columbus, Ohio, United States, 43215
      • Ohio Health Research Institute
  • Texas
    • Abilene, Texas, United States, 79601
      • Hendrick Medical Center
    • Corpus Christi, Texas, United States, 78404
      • Christus Spohn Shoreline Hospital
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern Medical Center
  • Virginia
    • Richmond, Virginia, United States, 23225
      • CJW Chippenham Medical Center
    • Richmond, Virginia, United States, 23229
      • Henrico Doctors' Hospital (HCA)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• SARS-CoV-2 infection documented by polymerase chain reaction (PCR) or other nucleic acid test (NAT) within 3 days prior to randomization OR documented by NAT more than 3 days prior to randomization AND progressive disease suggestive of ongoing SARS-CoV-2 infection
• Symptomatic COVID-19 disease
• Duration of symptoms attributable to COVID-19 ≤ 12 days
• Requiring inpatient hospital medical care for clinical manifestations of COVID-19 (admission for public health or quarantine only is not included)
• Willingness to abstain from participation in other COVID-19 treatment trials until after study Day 7
• Provision of informed consent by participant or legally authorized representative

Exclusion Criteria:

• Prior receipt of SARS-CoV-2 hIVIG or convalescent plasma from a person who recovered from COVID-19 at any time
• Prior receipt of standard IVIG (not hyperimmune to SARS-CoV-2) within 45 days

• Current or predicted imminent (within 24 hours) requirement for any of the following:

  1. Invasive ventilation
  2. Non-invasive ventilation
  3. Extracorporeal membrane oxygenation
  4. Mechanical circulatory support
  5. Continuous vasopressor therapy
• History of allergy to IVIG or plasma products
• History of selective IgA deficiency with documented presence of anti-IgA antibodies
• Any medical conditions for which receipt of the required volume of intravenous fluid may be dangerous to the patient (includes New York Association Class III or IV stage heart failure)

• Any of the following thrombotic or procoagulant disorders:

  1. Acute coronary syndromes, cerebrovascular syndromes and pulmonary or deep venous thrombosis within 28 days of randomization
  2. History of prothrombin gene mutation 20210, homozygous Factor V Leiden mutations, antithrombin III deficiency, protein C deficiency, protein S deficiency or antiphospholipid syndrome
• Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject or that could prevent, limit, or confound the protocol-specified assessments

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention Group; Participants in this group will receive the investigational product and standard of care (SOC).	Biological: Hyperimmune immunoglobulin to SARS-CoV-2 (hIVIG); Hyperimmune immunoglobulin to SARS-CoV-2 (hIVIG) is derived from the plasma of individuals who recover and develop neutralizing antibodies. Participants will receive a single infusion.; Drug: Remdesivir; Remdesivir will be given to participants in both groups as standard of care (SOC).
Placebo Comparator: Control Group; Participants in this group will receive a placebo and standard of care (SOC).	Drug: Remdesivir; Remdesivir will be given to participants in both groups as standard of care (SOC).; Other: Placebo; Participants will receive a single infusion of the placebo (saline).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ordinal Outcome Scale - Day 7	The primary objective is to compare the clinical status of patients in each group on day 7 of follow-up using the primary ordinal outcome with 7 mutually exclusive categories: 7. Death 6. End-organ failure 5. Life-threatening end-organ dysfunction 4. Serious end-organ dysfunction 3. Moderate end-organ dysfunction 2. Limiting symptoms due to COVID-19 1. No limiting symptoms due to COVID-19 Outcome is reported as the percent of participants in each of 7 categories. Primary ordinal outcome based on the patient's clinical status on Day 7. It includes 7 mutually exclusive categories capturing the range of organ dysfunction that may be associated with progression of COVID-19, such as respiratory dysfunction and coagulation-related complications. Minimum value = 1, Maximum value = 7 Higher scores mean a worse outcome	7 days
Primary Safety Outcome - Death, SAE or Grade 3 or 4 Events Through Day 7	Number of participants with death, SAE or Grade 3 or 4 event through Day 7	Through Day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
N Reaching 3 Least Favorable Categories	N Reaching 3 least favorable categories of ordinal outcome (Categories 5, 6, 7: life-threatening end organ dysfunction, end organ failure, or death)	All of follow-up (through Day 28)
N Reaching 2 Most Favorable Categories	N Reaching 2 most favorable categories of ordinal outcome (Categories 1 and 2: not requiring oxygen with or without limiting symptoms due to COVID-19)	All of follow-up (through Day 28)
N Discharged or in Most Favorable Category	N discharged from hospital or reaching most favorable ordinal category (category 1: not requiring oxygen and no limiting symptoms due to COVID-19)	All of follow-up (through Day 28)

Collaborators and Investigators

• Sponsor: University of Minnesota
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH); International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)
• Investigators: Study Chair: Mark Polizzotto, MD, The Kirby Institute, University of New South Wales

Publications and helpful links

General Publications

• 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.
• ITAC (INSIGHT 013) Study Group. Hyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomised trial. Lancet. 2022 Feb 5;399(10324):530-540. doi: 10.1016/S0140-6736(22)00101-5. Epub 2022 Jan 28.
• Vandeberg P, Cruz M, Diez JM, Merritt WK, Santos B, Trukawinski S, Wellhouse A, Jose M, Willis T. Production of anti-SARS-CoV-2 hyperimmune globulin from convalescent plasma. Transfusion. 2021 Jun;61(6):1705-1709. doi: 10.1111/trf.16378. Epub 2021 Mar 22.

Study record dates

Study Major Dates

• Study Start (Actual): October 8, 2020
• Primary Completion (Actual): May 21, 2021
• Study Completion (Actual): May 21, 2021

Study Registration Dates

• First Submitted: September 8, 2020
• First Submitted That Met QC Criteria: September 8, 2020
• First Posted (Actual): September 14, 2020

Study Record Updates

• Last Update Posted (Actual): April 4, 2022
• Last Update Submitted That Met QC Criteria: March 31, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Severe Acute Respiratory Syndrome; COVID-19; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites; Immunologic Factors; Antibodies; Immunoglobulins; Immunoglobulins, Intravenous; Remdesivir
• Other Study ID Numbers: INSIGHT 013

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: A public data set will be made available at the end of the trial
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes