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ACTIV-3: Therapeutics for Inpatients With COVID-19 (TICO)

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ClinicalTrials.gov Identifier: NCT04501978
Recruitment Status : Recruiting
First Posted : August 6, 2020
Last Update Posted : April 6, 2021
Sponsor:
Collaborators:
International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)
University of Copenhagen
Medical Research Council
Kirby Institute
Washington D.C. Veterans Affairs Medical Center
AIDS Clinical Trials Group
National Heart, Lung, and Blood Institute (NHLBI)
US Department of Veterans Affairs
Prevention and Early Treatment of Acute Lung Injury (PETAL)
Cardiothoracic Surgical Trials Network (CTSN)
Eli Lilly and Company
Vir Biotechnology, Inc.
GlaxoSmithKline
Brii Biosciences Limited
AstraZeneca
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:
This study looks at the safety and effectiveness of different drugs in treating COVID-19 in people who have been hospitalized with the infection. Participants in the study will be treated with either a study drug plus current standard of care (SOC), or with placebo plus current SOC.

Condition or disease Intervention/treatment Phase
Covid19 Biological: LY3819253 Drug: Placebo Biological: Remdesivir Biological: VIR-7831 Biological: BRII-196/BRII-198 Biological: AZD7442 Phase 3

Detailed Description:

This is a master protocol to evaluate the safety and efficacy of multiple investigational agents aimed at modifying the host immune response to SARS-CoV-2 infection, or directly enhancing viral control in order to limit disease progression.

The protocol is for a randomized, blinded, controlled platform study that allows investigational drugs to be added and dropped during the course of the study. This allows for efficient testing of new drugs against placebo and standard of care (SOC) treatment within the same study. When more than one drug is being tested at the same time, participants will be randomly allocated to treatments or placebo.

Randomization will be stratified by study site pharmacy and disease severity. There are 2 disease severity strata: Participants without organ failure (severity stratum 1); and participants with organ failure (severity stratum 2).

An independent Data and Safety Monitoring Board (DSMB) will regularly review interim analyses and summarize safety and efficacy outcomes. For investigational drugs with minimal pre-existing safety knowledge, the pace of enrollment with be initially restricted, and there will be an early review of safety data by the DSMB. For the study of each agent, at the outset of the trial, only participants in disease severity stratum 1 will be enrolled. This will continue until approximately 300 participants are enrolled and followed for 5 days. The exact number will vary according to the speed of enrollment and the timing of DSMB meetings. Prior to expanding enrollment to also include patients in disease severity stratum 2, safety will be evaluated and a pre-specified futility assessment by the DSMB will be carried out using 2 ordinal outcomes assessed at Day 5.

Both ordinal outcomes are used to assess futility because it is currently unclear whether the investigational agents under study will primarily influence non-pulmonary outcomes, for which risk is increased with SARS-CoV-2 infection, in part, through mechanisms that may be different from those that influence pulmonary outcomes.

For investigational agents passing this futility assessment, enrollment of participants will be expanded, seamlessly and without any data unblinding, to include participants in disease severity stratum 2 as well as those in disease severity stratum 1. Future interim analyses will be based on the primary endpoint of sustained recovery and will use pre-specified guidelines to determine early evidence of benefit, harm or futility for the investigational agent. Participants will be followed for 18 months following randomization.

The international trials within this protocol will be conducted in several hundred clinical sites. Participating sites are affiliated with networks funded by the United States National Institutes of Health (NIH) and the US Department of Veterans Affairs.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10000 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Multicenter, Adaptive, Randomized, Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for Hospitalized Patients With COVID-19
Actual Study Start Date : August 4, 2020
Estimated Primary Completion Date : July 2022
Estimated Study Completion Date : July 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: ACTIV-3 Drug plus SOC
Participants in this study will be randomized to receive one of the ACTIV-3 drug treatments plus Standard of Care (SOC) or placebo plus SOC
Biological: LY3819253
Participants are no longer being randomized to this intervention.

Biological: Remdesivir
Provided to all study participants as SOC unless contraindicated for an individual patient.

Biological: VIR-7831
Participants are no longer being randomized to this intervention.

Biological: BRII-196/BRII-198
Participants are no longer being randomized to this intervention.

Biological: AZD7442
600 mg AZD7442 (300 mg AZD8895 + 300 mg AZD1061). Administered by IV infusion as a single dose.
Other Name: AZD8895 + AZD1061

Placebo Comparator: Placebo plus SOC
The placebo arm may be pooled across more than one experimental arm if multiple investigational drugs are available to be tested at the same time. If it is not possible to use matching placebo over more than one experimental arm, additional placebo arms will be included in the study
Drug: Placebo
Commercially available 0.9% sodium chloride solution. Administered by IV infusion

Biological: Remdesivir
Provided to all study participants as SOC unless contraindicated for an individual patient.




Primary Outcome Measures :
  1. Time from randomization to sustained recovery [ Time Frame: Up to Day 90 ]
    Sustained recovery defined as being discharged from the index hospitalization, followed by being alive and home for 14 consecutive days prior to Day 90.


Secondary Outcome Measures :
  1. All-cause mortality [ Time Frame: Thru Day 90 ]
  2. Composite of time to sustained recovery and mortality [ Time Frame: Thru Day 90 ]
  3. Days alive outside short-term acute care hospital [ Time Frame: Up to Day 90 ]
  4. Pulmonary ordinal outcome [ Time Frame: Days 1-7, 14 and 28 ]
    Oxygen requirements measured by 7 categories (1 = least severe, 7 = most severe). The participant's highest (i.e. most severe) observed score is used.

  5. Pulmonary+ ordinal outcome [ Time Frame: Days 1-7 ]
    Extrapulmonary complications and respiratory dysfunction measured by 7 categories (1= least severe, 7 = most severe). The participant's highest (i.e. most severe) observed score is used.

  6. Incidence of clinical organ failure [ Time Frame: Thru Day 28 ]
  7. Composite of death or serious clinical COVID-19 related events [ Time Frame: Thru Day 90 ]
  8. Composite of cardiovascular events and thromboembolic events [ Time Frame: Thru Day 90 ]
  9. Composite of grade 3 and 4 clinical adverse events, serious adverse events (SAEs) or death [ Time Frame: Thru Days 5 and 28 ]
  10. Incidence of infusion reactions [ Time Frame: Thru Day 0 ]
  11. Composite of SAEs or death [ Time Frame: Thru 18 months ]
  12. Change in SARS-CoV-2 neutralizing antibody levels [ Time Frame: Baseline to Days 1, 3, 5, 28 and 90 ]
  13. Change in overall titers of antibodies [ Time Frame: Baseline to Days 1, 3, 5, 28 and 90 ]
  14. Change in neutralizing antibody levels [ Time Frame: Baseline to Days 1, 3, 5, 28 and 90 ]
  15. Incidence of home use of supplemental oxygen above pre-morbid oxygen use [ Time Frame: 18 months ]
    Measured as: Alive at home and no use of continuous supplemental oxygen for an uninterrupted 14 day period

  16. Incidence of no home use of supplemental oxygen above pre-morbid oxygen use [ Time Frame: 14 days ]
    Measured as: Alive at home for an uninterrupted 14 day period and no use of continuous supplemental oxygen at end of 14 day time period.



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:

  • Signed informed consent.
  • Positive test for COVID-19 and progressive disease suggestive of ongoing COVID-19 infection.
  • Symptoms of COVID-19 for ≤ 12 days.
  • Require admission to hospital for acute medical care (not for purely public health or quarantine purposes).

Exclusion Criteria:

  • Patients who have received plasma from a person who recovered from COVID-19 or who have received neutralizing monoclonal antibodies at any time prior to hospitalization.
  • Patients not willing to abstain from participation in other COVID-19 treatment trials until after Day 5 of the study. Co-enrollment in certain trials that compare recommended Standard of Care treatments may be allowed, based on the opinion of the study leadership team.
  • Any condition which, in the opinion of the responsible investigator, participation would not be in the best interest of the participant or that could prevent, limit, or confound the protocol-specified assessments.
  • Patients considered unable to participate in study procedures.
  • Women of child-bearing potential who are not already pregnant at study entry and who are unwilling to acknowledge strong advice to abstain from sexual intercourse with men or practice appropriate contraception through 18 months of the study.
  • Men who are unwilling to acknowledge the strong advice to abstain from sexual intercourse with women of child-bearing potential or to use barrier contraception through 18 months of the study.
  • Presence at study enrollment of any of the following:

    1. stroke
    2. meningitis
    3. encephalitis
    4. myelitis
    5. myocardial ischemia
    6. myocarditis
    7. pericarditis
    8. symptomatic congestive heart failure
    9. arterial or deep venous thrombosis or pulmonary embolism
  • Current or imminent requirement for any of the following:

    1. invasive mechanical ventilation
    2. ECMO (extracorporeal membrane oxygenation)
    3. Mechanical circulatory support
    4. vasopressor therapy
    5. commencement of renal replacement therapy at this admission (i.e. not patients on chronic renal replacement therapy).

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): NCT04501978


Contacts
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Contact: If interested in participating in this study, please contact the appropriate site or send email to tico@insight-trials.org
Contact: Do not include personal information in email. Type ACTIV-3 in subject line.

Locations
Show Show 92 study locations
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)
University of Copenhagen
Medical Research Council
Kirby Institute
Washington D.C. Veterans Affairs Medical Center
AIDS Clinical Trials Group
National Heart, Lung, and Blood Institute (NHLBI)
US Department of Veterans Affairs
Prevention and Early Treatment of Acute Lung Injury (PETAL)
Cardiothoracic Surgical Trials Network (CTSN)
Eli Lilly and Company
Vir Biotechnology, Inc.
GlaxoSmithKline
Brii Biosciences Limited
AstraZeneca
Investigators
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Principal Investigator: Prof. Jens Lundgren INSIGHT Copenhagen International Coordinating Centre, Rigshospitalet, University of Copenhagen
Study Chair: Prof. James Neaton INSIGHT Statistical and Coordinating Centre, University of Minnesota
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT04501978    
Other Study ID Numbers: 014 / ACTIV-3
First Posted: August 6, 2020    Key Record Dates
Last Update Posted: April 6, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
COVID-19
COVID 19
Coronaviridae Infections
Coronavirus Infections
RNA Virus Infections
Virus Diseases
Nidovirales Infections
SARS-CoV-2
SARS Coronavirus
ACTIV-3
ACTIV3