Immune Modulators for Treating COVID-19

Purpose

ACTIV-1 IM is a master protocol designed to evaluate multiple investigational agents for the treatment of moderately or severely ill patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The research objectives are to evaluate each agent with respect to speed of recovery, mortality, illness severity, and hospital resource utilization. Each agent will be evaluated as add-on therapy to the standard of care (SoC) in use at the local clinics, including remdesivir (provided). The SoC may change during the course of the study based on other research findings. Comparisons of the agents among themselves is not a research objective. The study population corresponds to moderately and severely ill patients infected with the coronavirus disease 2019 (COVID-19) virus. Recruitment will target patients already hospitalized for treatment of COVID-19 infection as well as patients being treated for COVID-19 infection in Emergency Departments while waiting to be admitted to the hospital. Patients both in and out of the ICU are included in the study population.

Condition

  • Covid19

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  1. Admitted to a hospital or awaiting admission in the ED with symptoms suggestive of COVID-19. 2. Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures. 3. Subject (or legally authorized representative) understands and agrees to comply with planned study procedures. 4. Male or non-pregnant female adults ≥18 years of age at time of enrollment. 5. Has laboratory-confirmed (within 14 days prior to enrollment) SARS-CoV-2 infection as determined by PCR or other commercial or public health assay in any specimen. 6. Ongoing illness of any duration, and at least one of the following: - Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR - Blood oxygen saturation (SpO2) ≤94% on room air, OR - Requiring supplemental oxygen, OR - Requiring mechanical ventilation or ECMO. 7. Women of childbearing potential must agree to either abstinence or use of at least one primary form of contraception not including hormonal contraception from the time of screening through Day 60. 8. Agrees to not to participate in another interventional trial for the treatment of COVID-19 through Day 60. Exception 1: Participant may co-enroll in ACTIV-4 (ACTIV-4A and ACTIV-4C). Exception 2: Participants in ACTIV-2 who have been hospitalized may be enrolled in ACTIV-1 as long as ACTIV-2 study therapy has been discontinued. They will remain in ACTIV-2 follow-up. Exception 3: If participant is already participating in a COVID-19 vaccine trial but develops COVID-19 disease that requires hospitalization, participant is eligible for this study, assuming all other inclusion/

Exclusion Criteria

are met. Exclusion Criteria: 1. ALT or AST >10 times the upper limit of normal. 2. Estimated glomerular filtration rate (eGFR) <30 mL/min (including patients receiving hemodialysis or hemofiltration). Exception: Participants with an eGFR <30 mL/min may enroll as long as their renal insufficiency has been stable without renal replacement therapy for ≥1 month and they are not current candidates for renal replacement therapy. These participants will not receive remdesivir. 3. Neutropenia (absolute neutrophil count <1000 cells/μL) (<1.0 x 103/μL or <1.0 GI/L). 4. Lymphopenia (absolute lymphocyte count <200 cells/μL) (<0.20 x 103/μL or <0.20 GI/L) 5. Pregnancy or breast feeding. 6. Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours. 7. Known allergy to any study medication. 8. Received cytotoxic or biologictargeted immune-modulator treatments (such as anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab], anti-IL-17, or T-cell or B-cell targeted therapies ([e.g., rituximab), tyrosine kinase], JAK inhibitors [including baricitinib,], TNF inhibitors, or interferon) within 4 weeks or 5 half-lives prior to screening., whichever is longer. Steroid dependency, defined as need for prednisone at a dose >10 mg (or equivalent) for >1 month within 2 weeks of screening, is exclusionary. Note Exception 1: Dexamethasone (at a dose of 6 mg per day for up to 10 days) is permitted for the treatment of COVID-19 in patients who are already mechanically ventilated and in patients who require supplemental oxygen at screening, but who are not mechanically ventilated in accordance with national guidelines. Note Exception 2: Infusion of convalescent plasma given for treatment of COVID-19 while on-study is also allowed. Exception 3: Monoclonal antibody therapy given for COVID-19 treatment at any time prior to enrollment is also allowed. 9. BasedKnown or suspected history of untreated tuberculosis (TB). TB diagnosis may be suspected based on medical history and concomitant therapies that would suggest TB infection, have suspected clinical diagnosis of current active tuberculosis (TB) or, if. Participants are also excluded if they have known, latent TB treated for less than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines (by history only, no screening required). 10. Based on medical history and concomitant therapies that would suggest infection,Known or suspected serious, active bacterial, fungal, or viral (infection (excepting SARS-CoV-2 and including, but not limited to, active HBV, HCV, or HIV/AIDS). with the latter defined as a CD4 count <200 or an unsuppressed HIV viral load), or other infection (besides COVID-19) that in the opinion of the investigator could constitute a risk when taking investigational product. Note: Broad-spectrum empiric antibiotic usage does not exclude participation. 11. Have received any live vaccine (that is,or live attenuated) within 3 months before screening, or intend to receive a live vaccine (or live attenuated) during the study. Note Exception: Use of prior non-live (inactivated) vaccinations is allowed for all participants, including any vaccine for COVID-19. 12. Severe hepatic impairment (defined as liver cirrhosis Child stage C). 13. CurrentKnown severe heart failure (New York Heart Association [NYHA] III-IV).) or new-onset left-systolic or global cardiac dysfunction in the setting of COVID-19. Exception: Right-sided heart dysfunction or pulmonary hypertension thought related to COVID-19 is permitted. 14. In the Investigator's judgment, the patient has any advanced organ dysfunction that would not make participation appropriate.

Study Design

Phase
Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Intervention Model Description
ACTIV-1 IM builds upon findings and the model used for other network COVID studies. Including multiple therapeutic agents under a single protocol avoids duplication of effort in terms of infrastructure, trial governance, information systems (EDC, web-based randomization, etc.) and other aspects of study management. Implementation of the master protocol facilitates discontinuation of less promising agents and addition of possibly newly emergent agents that become available after the study begins, without stopping and starting the study itself for extended pauses. All test agents are evaluated as add-on therapies to the local SoC at each clinic. The master protocol design allows for the efficacy and safety of each agent to be determined based on comparisons with a pooled control group, consisting of patients receiving SoC plus placebo. Sharing control patients across all test agents substantially reduces the sample size requirements for the study.
Primary Purpose
Treatment
Masking
Triple (Participant, Investigator, Outcomes Assessor)
Masking Description
Study Drug and Matching Placebo

Arm Groups

ArmDescriptionAssigned Intervention
Active Comparator
Remdesivir + infliximab or matching placebo
infliximab (single dose IV 5mg/kg given on day 1) or matching placebo
  • Drug: Infliximab
    study drug or matching placebo
    Other names:
    • remicade
  • Drug: Remdesivir
    Standard of Care
Active Comparator
Remdesivir + abatacept or matching placebo
abatacept (single dose IV 10 mg/kg up to 1,000 mg given on day 1) or matching placebo
  • Drug: Abatacept
    study drug or matching placebo
    Other names:
    • orencia
  • Drug: Remdesivir
    Standard of Care
Active Comparator
Remdesivir + cenicriviroc or matching placebo (closed to enrollment as of 3-Sep-2021)
cenicriviroc [tablet, Day 1/Loading Dose: 450 mg (300mg morning and 150mg evening) Day 2 - 29/Maintenance Dose: 300 mg (150 mg BID) through Day 29]. or matching placebo
  • Drug: Remdesivir
    Standard of Care
  • Drug: cenicriviroc (closed to enrollment as of 3-Sep-2021)
    study drug or matching placebo

Recruiting Locations

University of Arkansas Medical Sciences
Little Rock, Arkansas 72205
Contact:
Cindy Witkowski
501-526-5282
witkowskicynthial@uams.edu

UCLA - Ronald Reagan Medical Center
Los Angeles, California 90095
Contact:
Yesenia Calzada
310-794-0345
ycalzada@mednet.ucla.edu

Riverside University
Moreno Valley, California 92555
Contact:
Chris Firek
951-486-2671
c.firek@ruhealth.org

Stanford University Medical Center
Palo Alto, California 94303
Contact:
Ali Dehnad
650-724-6887
alid@stanford.edu

UCLA Medical Center- Santa Monica
Santa Monica, California 06037
Contact:
Adreanne Rivera
adreannerivera@mednet.ucla.edu

Medstar Washington Hospital Center
Washington, District of Columbia 20010
Contact:
Laira Baez Quintana
202-877-7133
laira.m.baezquintana@medstar.net

University of Florida-Jacksonville
Jacksonville, Florida 32218
Contact:
Morgan Henson
904-244-4234
morgan.henson@jax.ufl.edu

University of Illinois at Chicago
Chicago, Illinois 60607
Contact:
Stephanie Echeverria
773-484-4330
secheverria1@sahchicago.org

University of Kansas
Kansas City, Kansas 66160
Contact:
Carolina Aguiar
913-945-9295
caguiar@kumc.edu

Tulane School of Medicine
New Orleans, Louisiana 70112
Contact:
Sofia Marquez
504-988-0642
smarquez1@tulane.edu

University Medical Center New Orleans
New Orleans, Louisiana 70112
Contact:
Sofia Marquez
504-988-0642
smarquez1@tulane.edu

Ochsner Medical Center
New Orleans, Louisiana 70121
Contact:
Randi Kendrick
504-842-1264
randi.kendrick@ochsner.org

Anne Arundel Medical Center
Annapolis, Maryland 21401
Contact:
Kathy gray
443-481-5868
kgray7@aahs.org

Tufts Medical Center
Boston, Massachusetts 02111
Contact:
Abigail Pires
617-636-3269
apires@tuftsmedicalcenter.org

Brigham and Women's Hospital
Boston, Massachusetts 02115
Contact:
Lily Johnsky
860-384-9215
ljohnsky@bwh.harvard.edu

Boston Medical Center
Boston, Massachusetts 02118
Contact:
Ridiane Denis
617-358-7561
ridianed@bu.edu

U Mass Memorial Medical Center
Worcester, Massachusetts 01655
Contact:
Shestruma Parajuli
508-856-5010
shestruma.parajuli@umassmed.edu

U Mass University Medical Center
Worcester, Massachusetts 01655
Contact:
Shestruma Parajuli
508-856-5010
shestruma.parajuli@umassmed.edu

MidMichigan Medical Center- Gratiot
Alma, Michigan 48640
Contact:
Roberta Thrush
989-631-2469
roberta.thrush@midmichigan.org

MidMichigan Medical Center - Midland
Midland, Michigan 48670
Contact:
Roberta Thrush
989-631-2469
roberta.thrush@midmichigan.org

Mayo Clinic
Rochester, Minnesota 55905
Contact:
Sue Donlinger
507-284-9259
donlinger.sueann@mayo.edu

University of Mississippi Medical Center
Jackson, Mississippi 39216
Contact:
Cathy Hudgins
601-815-5000
chudgins@umc.edu

University of Missouri Health Care
Columbia, Missouri 65212
Contact:
Tami Day
573-882-4759
daytm@health.missouri.edu

Washington University School of Medicine
Saint Louis, Missouri 63110
Contact:
Lisa Kessels
314-747-1096
lkessels@wustl.edu

Trinitas Hospital
Elizabeth, New Jersey 07207
Contact:
Thomson Cheriyan
908-994-8728
tcheriyan@trinitas.org

Hackensack University Medical Center
Hackensack, New Jersey 07601
Contact:
Mary Lynn Breslin
732-776-2953
marylynn.breslin@hmhn.org

Rutgers New Jersey Medical School
New Brunswick, New Jersey 08901
Contact:
Deborah McCloskey
732-418-8484
mcclosda@rwjms.rutgers.edu

NYU Brooklyn
Brooklyn, New York 11220
Contact:
Michelle Kim

University at Buffalo
Buffalo, New York 14203
Contact:
Janice Wolfman
716-888-4764
janicewo@buffalo.edu

Flushing Hospital Medical Center
Flushing, New York 11355
Contact:
Kelly Cervellione
kcervell@jhmc.org

Jamaica Hospital Medical Center
Jamaica, New York 11418
Contact:
Kelly Cervellione
888-795-5255
kcervellione@isaclinicalresearch.com

NYU Long Island
Long Island City, New York 10016
Contact:
Anelly Gonzales
646-501-6923
anelly.gonzales@nyulangone.org

New York University Langone Medical Center
New York, New York 10016
Contact:
Anelly Gonzales
646-501-6923
anelly.gonzales@nyulangone.org

Weill Cornell Medicine
New York, New York 10065
Contact:
Britta Witting
212-746-7587
bmw4002@med.cornell.edu

St Lawrence Health System
Potsdam, New York 13676
Contact:
Daniel Jaremczuk
315-261-6013
djaremczuk@cphospital.org

University of Rochester Medical Center-Strong Memorial Hospital
Rochester, New York 14642
Contact:
Amanda Howell
585-273-1725
amanda_howell@urmc.rochester.edu

University of North Carolina - Chapel Hill
Chapel Hill, North Carolina 27599
Contact:
Nayeem Choudhury
417-379-6389
nayeem_choudhury@med.unc.edu

Duke University
Durham, North Carolina 27710
Contact:
Jacob Craven
919-681-9997
jacob.craven@duke.edu

Wake Forest University
Winston-Salem, North Carolina 27157
Contact:
Elizabeth Zieser-Misenheimer
336-716-5685
ezieserm@wakehealth.edu

Mercy Saint Vincent Medical Center
Toledo, Ohio 43608
Contact:
Amy Krueger
419-251-8466
amy_krueger@mercy.com

University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma 73104
Contact:
Brittany Karfonta
405-271-3480
osctr@ouhsc.edu

Oregon Health and Science University
Portland, Oregon 97239
Contact:
Olivia Krol
503-494-6994
krolo@ohsu.edu

University of Tennessee Medical Center
Knoxville, Tennessee 37920
Contact:
Caleb Darby
865-305-5443
cdarby@utmck.edu

University of Texas Health Science Center - Houston
Houston, Texas 77030
Contact:
Jaicey Johnson
713-500-6851
jaicey.johnson@uth.tmc.edu

University of Texas Health Science Center at San Antonio
San Antonio, Texas 78229
Contact:
Robin Tragus
210-567-5262
tragus@uthscsa.edu

Trinity Mother Frances Hospital
Tyler, Texas 75701
Contact:
Amanda Baker
903-606-3536
amanda.baker3@christushealth.org

University of Texas Health Center at Tyler
Tyler, Texas 75708
Contact:
Rebekah Hibbard
903-877-8246
rebekah.hibbard@uthct.edu

University of Utah
Salt Lake City, Utah 84108
Contact:
Macy Barrios
801-581-5811
macy.barrios@hsc.utah.edu

Virginia Commonwealth University Medical Center
Richmond, Virginia 23298
Contact:
Rebecca Collen
804-628-4376
rebecca.collen@vcuhealth.org

University of Washington Medical Center
Seattle, Washington 98195
Contact:
Charlie Gregor
612-203-5269
cgregor2@uw.edu

Providence Medical Research Center
Spokane, Washington 99204
Contact:
Carissa Urbat
509-474-4345
carissa.urbat@providence.org

West Virginia University
Morgantown, West Virginia 26505
Contact:
Louise Moore
304-293-2149
lmoore@hsc.wvu.edu

Gundersen Health System
La Crosse, Wisconsin 54601
Contact:
Cindy Murphy
608-775-6782
camurphy@gundersenhealth.org

More Details

NCT ID
NCT04593940
Status
Recruiting
Sponsor
Daniel Benjamin

Study Contact

Theresa Jasion, MS
919-338-4307
theresa.jasion@duke.edu

Detailed Description

ACTIV-1 IM is a master protocol designed to evaluate immune modulators for the treatment of moderately or severely ill hospitalized patients infected with COVID-19. Trial participants will be assessed daily while hospitalized. If the participants are discharged from the hospital prior to Day 29, they will have follow-up study visits at Days 8, 11, 15, 22, and 29. For discharged participants, it is preferred that the Day 8, 11, 15, and 29 visits are in person to obtain safety laboratory tests and blood (serum/plasma) samples for secondary research as well as clinical outcome data. However, infection control or other restrictions may limit the ability of the participant to return to the clinic. In this case, these visits may be conducted by phone, and only clinical data will be obtained. The Day 22 visit does not have laboratory tests or collection of samples and is conducted by phone. The Day 60 assessment will be conducted by phone. The effectiveness of each therapeutic agent as add-on therapy to SoC plus remdesivir (provided) will be evaluated based on the primary endpoint of time to recovery by Day 29. The sample size requirements are based on the ability to detect a moderate improvement in time to recovery (3-4 fewer days) for each agent. A total of 788 recoveries are required for each comparison to provide approximately 85% power to detect a recovery rate ratio of 1.25. Assuming 73% of participants achieve recovery in 28 days, consistent with the ACTT-1 results, the total sample size to evaluate 1, 2, and 3 agents in ACTIV-1 IM is approximately 1080, 1620, and 2160, respectively. Because each agent is being compared to SoC with no between-agent comparisons, no multiplicity adjustments for multiple agents are planned. The CVC arm of the study was closed to enrollment on 3-Sep-2021.