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Inpatient Treatment With Anti-Coronavirus Immunoglobulin (ITAC)

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ClinicalTrials.gov Identifier: NCT04546581
Recruitment Status : Recruiting
First Posted : September 14, 2020
Last Update Posted : November 13, 2020
Sponsor:
Collaborators:
National Institute of Allergy and Infectious Diseases (NIAID)
National Institutes of Health (NIH)
The International Network for Strategic Initiatives in Global HIV Trials
Information provided by (Responsible Party):
University of Minnesota

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.

Condition or disease Intervention/treatment Phase
COVID COVID-19 SARS-CoV-2 SARS (Severe Acute Respiratory Syndrome) Drug: Hyperimmune immunoglobulin to SARS-CoV-2 (hIVIG) Other: Placebo Drug: Remdesivir Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 500 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : October 8, 2020
Estimated Primary Completion Date : July 2021
Estimated Study Completion Date : July 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Intervention Group
Participants in this group will receive the investigational product and standard of care (SOC).
Drug: 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).
Other: Placebo
Participants will receive a single infusion of the placebo (saline).

Drug: Remdesivir
Remdesivir will be given to participants in both groups as standard of care (SOC).




Primary Outcome Measures :
  1. Ordinal Outcome Scale - Day 7 [ Time Frame: 7 days ]

    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.



Secondary Outcome Measures :
  1. All-cause mortality through Day 28 [ Time Frame: 28 days ]
    Outcome reported as the percent of participants who expire for any reason by day 28 post treatment.

  2. Ordinal Outcome Scale [ Time Frame: 3 days, 5 days, 14 days, and 28 days ]

    A secondary outcome is to compare the clinical status of patients in each group on day 3, 5, 14, and 28 of follow-up using the primary ordinal outcome.

    Outcome is reported as the percent of participants in each of 7 categories.


  3. Change in National Early Warning Score (NEWS) [ Time Frame: 7 days ]
    The National Early Warning Score (NEWS) is used to determine the degree of illness of a patient and prompt critical care intervention. The score takes into account respiratory rate, oxygen saturation, use of respiratory support, body temperature, blood pressure, and heart rate. These data are entered into a program to calculate a NEW score. Scores range from -3 to +3 with scores closer to zero representing a lower degree of illness. Scores will be collected at baseline and day 7 and the change in score at these 2 time points will be reported.

  4. Time to Worsening [ Time Frame: 7 days, 14 days, and 28 days ]
    Time to worsening is defined as the 3 least favorable categories on the primary ordinal scale. Outcome is reported as the percent of participants in each arm who are characterized as categories 5, 6, and 7 on the primary ordinal scale at 7, 14, and 28 days post treatment.

  5. Discharge Status [ Time Frame: 7 days, 14 days, and 28 days ]
    Outcome is reported as the percent of participants in each arm who are alive and discharged from the hospital to home or rehabilitation at days 7, 14, and 28 post treatment.

  6. Days Alive Outside the Hospital [ Time Frame: 28 days ]
    Outcome is reported as the mean number of days alive and outside the hospital from study entry to Day 28 for participants in each arm.

  7. Pulmonary-only Components of the Primary Ordinal Outcome [ Time Frame: 3 days, 5 days, 7 days, 14 days, and 28 days ]
    A secondary outcome is to compare the clinical status of patients in each group on day 3, 5, 7, 14, and 28 post treatment limited to using the pulmonary elements of the primary ordinal outcome (e.g., requirement for invasive ventilation). Outcome is reported as the percent of participants in each arm who fall into each of the 7 categories of the primary ordinal outcome with regard to their pulmonary dysfunction only.

  8. Thrombotic Components of the Primary Ordinal Outcome [ Time Frame: 3 days, 5 days, 7 days, 14 days, and 28 days ]
    A secondary outcome is to compare the clinical status of patients in each group on day 3, 5, 7, 14, and 28 post treatment limited to using the thrombotic conditions (e.g., arterial thrombosis) in the primary ordinal outcome. Outcome is reported as the percent of participants in each arm who fall in each of the 7 categories of the primary ordinal outcome with regard to thrombotic conditions only.

  9. Time to recovery [ Time Frame: 7 days, 14 days, and 28 days ]

    Time to recovery is defined as the 2 most favorable categories on the primary ordinal scale.

    Outcome is reported as the percent of participants in each arm who are characterized as categories 1 or 2 at 7, 14, and 28 days post treatment.


  10. Clinical Organ Dysfunction [ Time Frame: 28 days ]

    Clinical organ dysfunction is defined by new onset of any one or more of the following. Outcome is reported as the percent of participants in each arm who meet any 1 of the following criteria by day 28 post treatment.

    A) Respiratory dysfunction B) Cardiac and vascular dysfunction C) Renal dysfunction D) Hepatic dysfunction E) Neurological dysfunction F) Haematological dysfunction G) Serious infection


  11. Safety and Tolerability - Adverse Events [ Time Frame: 7 days ]
    Outcome is reported as the percent of participants in each arm who experience a new grade 3 or 4 event, a serious adverse event (SAE), or death through day 7 (primary safety endpoint) post treatment.

  12. Safety and Tolerability - Infusion Reactions, Interruptions, or Cessation [ Time Frame: approximately 2 hours ]
    Outcome is reported as the percent of participants in each arm for who had any grade of reaction during the infusion or within 2 hours afterwards, for whom the infusion is interrupted prior to completion, or for whom the infusion is stopped prior to completion.

  13. Safety and Tolerability - Serious Adverse Events [ Time Frame: 28 days ]
    Outcome is reported as the percent of participants in each arm who experience a serious adverse event (SAE) or death through day 28 post treatment.

  14. Safety and Tolerability - Prevalence of Adverse Events [ Time Frame: 1 day, 3 days, 7 days, and 28 days ]
    Outcome is reported as the percent of participants in each arm who experience an adverse event (AE) of any grade present (new or continuing) on days 1, 3, 7, and 28 post treatment.

  15. Change in Neutralizing Antibody Level [ Time Frame: 1 day, 3 days, 7 days, and 28 days ]
    Outcome reported as the change in anti-SARS-CoV-2 IgG antibody level in blood from baseline to 1, 3, 7, and 28 days post treatment. Outcome is reported in units of antibody titer.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • SARS-CoV-2 infection documented by 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04546581


Contacts
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Contact: Jacqueline Nordwall 612-626-8893 jacquie@ccbr.umn.edu
Contact: Eileen Denning 612-626-8049 edenning@umn.ed

Locations
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United States, Georgia
Redmond Regional Medical Center Not yet recruiting
Rome, Georgia, United States, 30165
Contact: Matthew McClain, MD         
United States, Massachusetts
University of Massachusetts Recruiting
Worcester, Massachusetts, United States, 01665
Contact: Jonathan Gerber, MD         
United States, Minnesota
Hennepin Healthcare Research Institute/HCMC Recruiting
Minneapolis, Minnesota, United States, 55415
Contact: Jason Baker, MD         
United States, Missouri
University of Missouri Recruiting
Columbia, Missouri, United States, 65212
Contact: Christian Rojas-Moreno, MD         
Cox Medical Centers Recruiting
Springfield, Missouri, United States, 65807
Contact: Robin Trotman, MD         
United States, North Carolina
FirstHealth Moore Regional Hospital Recruiting
Pinehurst, North Carolina, United States, 28394
Contact: Gretchen Arnoczy, MD         
United States, Ohio
Ohio Health Research Institute Recruiting
Columbus, Ohio, United States, 43215
Contact: Kiran Devulapally, MD         
United States, Texas
Hendrick Medical Center Recruiting
Abilene, Texas, United States, 79601
Contact: Daniel Canario, MD         
University of Texas Southwestern Medical Center Recruiting
Dallas, Texas, United States, 75235
Contact: Mamta Jain, MD         
Denmark
CHIP, Department of Infectious Diseases, Section 2100 Not yet recruiting
Copenhagen, Denmark
Contact: Jens Lundgren, MD,DMSc         
Greece
Dept. of Critical Care & Pulmonary Medicine, Evangelismos General Hospital Not yet recruiting
Athens, Greece
Contact: Ioannis Kalomenidis, MD         
Japan
NCGM Not yet recruiting
Tokyo, Japan
Contact: Norio Ohmagari, MD         
Fujita Health University Hospital Not yet recruiting
Toyoake, Japan
Contact: Yohei Doi, MD         
Nigeria
Institute of Human Virology-Nigeria (IHVN) Not yet recruiting
Abuja, Nigeria
Contact: Eriobu Nnakelu Chukwudalu, MD         
United Kingdom
Royal Free Hospital Not yet recruiting
London, United Kingdom
Contact: Sanjay Bhagani, MD         
Sponsors and Collaborators
University of Minnesota
National Institute of Allergy and Infectious Diseases (NIAID)
National Institutes of Health (NIH)
The International Network for Strategic Initiatives in Global HIV Trials
Investigators
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Principal Investigator: James Neaton, PhD University of Minnesota
Study Chair: Mark Polizzotto, MD The Kirby Institute, University of New South Wales
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Responsible Party: University of Minnesota
ClinicalTrials.gov Identifier: NCT04546581    
Other Study ID Numbers: INSIGHT 013
First Posted: September 14, 2020    Key Record Dates
Last Update Posted: November 13, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: A public data set will be made available at the end of the trial
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)

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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
Additional relevant MeSH terms:
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Coronavirus Infections
Severe Acute Respiratory Syndrome
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Respiratory Tract Diseases
Immunoglobulins
Immunoglobulins, Intravenous
Antibodies
Immunologic Factors
Physiological Effects of Drugs