Clinical trial NCT04546581: Inpatient Treatment of COVID-19 With Anti-Coronavirus Immunoglobulin (ITAC)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: COVID
COVID-19
SARS-CoV-2
SARS (Severe Acute Respiratory Syndrome)
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: 2020-09-14
Enrollment: 593
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: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Ordinal Outcome Scale - Day 7
timeFrame: 7 days
measure: Primary Safety Outcome - Death, SAE or Grade 3 or 4 Events Through Day 7
timeFrame: Through Day 7
Secondary outcomes:
measure: N Reaching 3 Least Favorable Categories
timeFrame: All of follow-up (through Day 28)
measure: N Reaching 2 Most Favorable Categories
timeFrame: All of follow-up (through Day 28)
measure: N Discharged or in Most Favorable Category
timeFrame: All of follow-up (through Day 28)
Other outcomes:
Locations:
city: Colorado Springs
country: United States
facility: Penrose Hospital
state: Colorado
city: Colorado Springs
country: United States
facility: St. Francis Health Services
state: Colorado
city: Lakewood
country: United States
facility: St. Anthony Hospital
state: Colorado
city: Westminster
country: United States
facility: Saint Anthony North Health Campus
state: Colorado
city: Washington
country: United States
facility: Washington VA Medical Center
state: District of Columbia
city: Rome
country: United States
facility: Redmond Regional Medical Center
state: Georgia
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
city: Worcester
country: United States
facility: University of Massachusetts
state: Massachusetts
city: Minneapolis
country: United States
facility: Hennepin Healthcare Research Institute/HCMC
state: Minnesota
city: Columbia
country: United States
facility: University of Missouri
state: Missouri
city: Springfield
country: United States
facility: Cox Medical Centers
state: Missouri
city: Pinehurst
country: United States
facility: FirstHealth Moore Regional Hospital
state: North Carolina
city: Columbus
country: United States
facility: Ohio Health Research Institute
state: Ohio
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: University of Texas Southwestern Medical Center
state: Texas
city: Richmond
country: United States
facility: CJW Chippenham Medical Center
state: Virginia
city: Richmond
country: United States
facility: Henrico Doctors' Hospital (HCA)
state: Virginia
city: Aarhus
country: Denmark
facility: Aarhus Universitetshospital, Skejby
city: Copenhagen
country: Denmark
facility: Bispebjerg Hospital
city: Copenhagen
country: Denmark
facility: CHIP, Department of Infectious Diseases, Section 2100
city: Hellerup
country: Denmark
facility: Herlev-Gentofte Hospital
city: Hillerød
country: Denmark
facility: Nordsjællands Hospital, Hillerød
city: Hvidovre
country: Denmark
facility: Hvidovre University Hospital, Department of Infectious Diseases
city: Kolding
country: Denmark
facility: Kolding Sygehus
city: Odense
country: Denmark
facility: Odense University Hospital
city: Alexandroupoli
country: Greece
facility: Democritus University of Thrace
state: Thrace
city: Athens
country: Greece
facility: 3rd Dept of Medicine, Medical School, NKUA
city: Athens
country: Greece
facility: 1st Respiratory Medicine Dept, Athens University Medical School
city: Athens
country: Greece
facility: Attikon University General Hospital
city: Athens
country: Greece
facility: Dept. of Critical Care & Pulmonary Medicine, Evangelismos General Hospital
city: Tokyo
country: Japan
facility: NCGM
city: Toyoake
country: Japan
facility: Fujita Health University Hospital
city: Abuja
country: Nigeria
facility: Institute of Human Virology-Nigeria (IHVN)
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
state: Catalonia
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: London
country: United Kingdom
facility: Royal Free Hospital
Study officials:
affiliation: University of Minnesota
name: James Neaton, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Kirby Institute
name: Mark Polizzotto, MD
role: STUDY_CHAIR
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.
citation: 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.
citation: 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.