ACTIV-1 IM: Immune Modulators for Treating COVID-19

Sponsor
Daniel Benjamin (Other)
Overall Status
Completed
CT.gov ID
NCT04593940
Collaborator
National Center for Advancing Translational Science (NCATS) (NIH), Biomedical Advanced Research and Development Authority (U.S. Fed)
1,971
91
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Study Details

Study Description

Brief Summary

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 or Disease Intervention/Treatment Phase
Phase 3

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
1971 participants
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.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.
Masking:
Triple (Participant, Investigator, Outcomes Assessor)
Masking Description:
Study Drug and Matching Placebo
Primary Purpose:
Treatment
Official Title:
Randomized Master Protocol for Immune Modulators for Treating COVID-19
Actual Study Start Date :
Oct 15, 2020
Actual Primary Completion Date :
Jan 30, 2022
Actual Study Completion Date :
Mar 5, 2022

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Standard of Care + 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: Standard of Care + 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: Standard of Care + 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

    Outcome Measures

    Primary Outcome Measures

    1. Number of patients that recovered from COVID-19 [days 1-29]

      time to recovery by Day 29

    Secondary Outcome Measures

    1. Change in number of patients hospitalized on invasive mechanical ventilation [Days 15 and 29]

      Number of patients hospitalized on invasive mechanical ventilation

    2. number of patients that improved clinically [Days 3, 5, 8, 11, 15, 29, and 60]

      8-point ordinal clinical scale assessed

    3. Number of patient deaths [Day 14]

      mortality rate

    4. Number of patients with decreased supplemental oxygenation needed [Day 29]

      compared to baseline the amount of supplementation oxygen

    5. Change in number of patients needing non-invasive ventilation/ high flow oxygen [Day 29]

      assessment of non-invasive ventilation/ high flow oxygen up to day 29

    6. Number of days patients are in the hospital [Days 3, 5, 8, 11, 15, 22, and 29]

      number of days in the hospital

    7. Number of SAEs and AEs of grade 3 and 4 [Days 3, 5, 8, 11, 15, 22, and 29]

      Cumulative incidence of SAEs and AEs of grade 3 and 4

    8. Number of patients with changes in abnormal WBC counts [Days 3, 5, 8, 11, 15, and 29]

      Number of patients with changes in abnormal WBC counts

    Other Outcome Measures

    1. Number of patients with National Early Warning Scores (NEWS) <=2 [Days 3, 5, 8, 11, 15, and 29]

      time to discharge or to a NEWS of <=2 and maintained for 24 hours

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    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.

    1. 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.

    2. 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.

    1. Neutropenia (absolute neutrophil count <1000 cells/μL) (<1.0 x 103/μL or <1.0 GI/L).

    2. Lymphopenia (absolute lymphocyte count <200 cells/μL) (<0.20 x 103/μL or <0.20 GI/L)

    3. Pregnancy or breast feeding.

    4. Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours.

    5. Known allergy to any study medication.

    6. 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.

    1. 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).

    2. 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.

    1. 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.

    2. Severe hepatic impairment (defined as liver cirrhosis Child stage C).

    3. 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.

    1. In the Investigator's judgment, the patient has any advanced organ dysfunction that would not make participation appropriate.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Banner University Medical Center Phoenix Arizona United States 85006
    2 University of Arkansas Medical Sciences Little Rock Arkansas United States 72205
    3 Scripps Clinical Medical Group La Jolla California United States 92037
    4 UCLA - Ronald Reagan Medical Center Los Angeles California United States 90095
    5 Riverside University Moreno Valley California United States 92555
    6 UC Irvine Medical Center Orange California United States 92868
    7 Stanford University Medical Center Palo Alto California United States 94303
    8 UCLA Medical Center- Santa Monica Santa Monica California United States 06037
    9 Medstar Washington Hospital Center Washington District of Columbia United States 20010
    10 University of Florida-Jacksonville Jacksonville Florida United States 32218
    11 University of Illinois at Chicago Chicago Illinois United States 60607
    12 Northwestern University Chicago Illinois United States 60611
    13 Loyola University Medical Center Maywood Illinois United States 60153
    14 University of Iowa Iowa City Iowa United States 52242
    15 University of Kansas Kansas City Kansas United States 66160
    16 University of Kentucky Lexington Kentucky United States 40536
    17 Tulane School of Medicine New Orleans Louisiana United States 70112
    18 University Medical Center New Orleans New Orleans Louisiana United States 70112
    19 Ochsner Medical Center New Orleans Louisiana United States 70121
    20 Anne Arundel Medical Center Annapolis Maryland United States 21401
    21 Johns Hopkins Medical Center Baltimore Maryland United States 21202
    22 Tufts Medical Center Boston Massachusetts United States 02111
    23 Brigham and Women's Hospital Boston Massachusetts United States 02115
    24 Boston Medical Center Boston Massachusetts United States 02118
    25 Beth Israel Deaconess Medical Center Boston Massachusetts United States 02215
    26 U Mass Memorial Medical Center Worcester Massachusetts United States 01655
    27 U Mass University Medical Center Worcester Massachusetts United States 01655
    28 MidMichigan Medical Center- Gratiot Alma Michigan United States 48640
    29 MidMichigan Medical Center - Midland Midland Michigan United States 48670
    30 Mayo Clinic Rochester Minnesota United States 55905
    31 University of Mississippi Medical Center Jackson Mississippi United States 39216
    32 University of Missouri Health Care Columbia Missouri United States 65212
    33 Washington University School of Medicine Saint Louis Missouri United States 63110
    34 Trinitas Hospital Elizabeth New Jersey United States 07207
    35 Hackensack University Medical Center Hackensack New Jersey United States 07601
    36 Rutgers New Jersey Medical School New Brunswick New Jersey United States 08901
    37 NYU Brooklyn Brooklyn New York United States 11220
    38 University at Buffalo Buffalo New York United States 14203
    39 Flushing Hospital Medical Center Flushing New York United States 11355
    40 Jamaica Hospital Medical Center Jamaica New York United States 11418
    41 NYU Long Island Long Island City New York United States 10016
    42 New York University Langone Medical Center New York New York United States 10016
    43 Harlem Hospital Center New York New York United States 10037
    44 Weill Cornell Medicine New York New York United States 10065
    45 St Lawrence Health System Potsdam New York United States 13676
    46 University of Rochester Medical Center-Strong Memorial Hospital Rochester New York United States 14642
    47 University of North Carolina - Chapel Hill Chapel Hill North Carolina United States 27599
    48 Duke University Durham North Carolina United States 27710
    49 Wake Forest University Winston-Salem North Carolina United States 27157
    50 Mercy Saint Vincent Medical Center Toledo Ohio United States 43608
    51 University of Oklahoma Health Sciences Center Oklahoma City Oklahoma United States 73104
    52 Oregon Health and Science University Portland Oregon United States 97239
    53 Temple University Hospital Philadelphia Pennsylvania United States 19140
    54 Reading Hospital Study Wyomissing Pennsylvania United States 19610
    55 Avera McKennan Hospital Sioux Falls South Dakota United States 57105
    56 University of Tennessee Medical Center Knoxville Tennessee United States 37920
    57 Methodist Health System Clinical Research Institute Dallas Texas United States 75203
    58 University of Texas Health Science Center - Houston Houston Texas United States 77030
    59 University of Texas Health Science Center at San Antonio San Antonio Texas United States 78229
    60 Trinity Mother Frances Hospital Tyler Texas United States 75701
    61 University of Texas Health Center at Tyler Tyler Texas United States 75708
    62 University of Utah Salt Lake City Utah United States 84108
    63 Virginia Commonwealth University Medical Center Richmond Virginia United States 23298
    64 University of Washington Medical Center Seattle Washington United States 98195
    65 Providence Medical Research Center Spokane Washington United States 99204
    66 West Virginia University Morgantown West Virginia United States 26505
    67 Gundersen Health System La Crosse Wisconsin United States 54601
    68 Hospital Interzonal Dr Jose Penna Bahia Blanca Bahía Blanca Buenos Aires Argentina 8000
    69 Sanatorio Ramon Cereijo Caba Buenos Aires Argentina C1048
    70 Instituto Medico Platense La Plata Buenos Aires Argentina B1900
    71 Clinica Central S.A. Villa Regina Rio Negro Argentina 8336
    72 Hospital Ramos Mejia Buenos Aires Argentina C1221ADC
    73 Hospital Rawson Cordoba Argentina 5000
    74 Sanatorio Allende Córdoba Argentina X5000JHGQ
    75 Sanatorio Britanico Rosario Argentina 2000
    76 Sanatorio Diagnóstico/ Instituto del Buen Aire Santa Fe Argentina S3000
    77 Hospital Brasília Brasília DF Brazil 71681-603
    78 Hospital Felício Rocho Belo Horizonte MG Brazil 30110-934
    79 Instituto DOR de Ensino e Pesquisa Hospital Glória D'Or Rio De Janeiro Rio De Janeiro / RJ Brazil 22211-230
    80 Hospital Ernesto Dornelles Porto Alegre Rio Grande D Sul /RS Brazil 90160-092
    81 Hospital de Clinicas de Porto Alegre HCPA Porto Alegre Rio Grande Do Sul / RS Brazil 90035-903
    82 Santa Casa de Misericordia de Porto Alegre Porto Alegre Rio Grande Do Sul/RS Brazil 90020-090
    83 Hospital e Maternidade Celso Pierro - PUC Campinas Campinas São Paulo/SP Brazil 13060-904
    84 Nuevo Hospital Civil de Guadalajara "Dr. Juan I. Menchaca" Guadalajara Guadalajara Jalisco Mexico CP 44340
    85 Hospital Universitario "Dr. Jose Eleuterio Gonzalez" Nuevo León Monterrey Mexico 64460
    86 Hospital Central FAP Lima Lima/Lima Peru 51
    87 Hospital Regional Lambayeque Chiclayo Peru 1400
    88 Hospitala Nacional Hipólito Unánue Lima Peru 15007
    89 Hospital Nacional Aezobispo Loayza Lima Peru 15082
    90 Hospital de Chancay y Servicios Basicos de Salud Lima Peru 15131
    91 Clínica Belén SANNA Piura Peru

    Sponsors and Collaborators

    • Daniel Benjamin
    • National Center for Advancing Translational Science (NCATS)
    • Biomedical Advanced Research and Development Authority

    Investigators

    • Principal Investigator: Daniel K Benjamin, MD, PhD, Duke University
    • Study Chair: Bill Powderly, MD, Washington University School of Medicine

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Daniel Benjamin, Kiser-Arena Distinguished Professor, Duke University Pediatrics, Duke University
    ClinicalTrials.gov Identifier:
    NCT04593940
    Other Study ID Numbers:
    • Pro00106301
    First Posted:
    Oct 20, 2020
    Last Update Posted:
    May 6, 2022
    Last Verified:
    May 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Daniel Benjamin, Kiser-Arena Distinguished Professor, Duke University Pediatrics, Duke University
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of May 6, 2022