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

Sponsor
Daniel Benjamin (Other)
Overall Status
Recruiting
CT.gov ID
NCT04593940
Collaborator
National Center for Advancing Translational Science (NCATS) (NIH), Biomedical Advanced Research and Development Authority (U.S. Fed)
1,990
Enrollment
88
Locations
3
Arms
22.5
Anticipated Duration (Months)
22.6
Patients Per Site
1
Patients Per Site Per Month

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 DiseaseIntervention/TreatmentPhase
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
Anticipated Enrollment :
1990 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
Anticipated Primary Completion Date :
Aug 1, 2022
Anticipated Study Completion Date :
Sep 1, 2022

Arms and Interventions

ArmIntervention/Treatment
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

    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

    SiteCityStateCountryPostal Code
    1Banner University Medical CenterPhoenixArizonaUnited States85006
    2University of Arkansas Medical SciencesLittle RockArkansasUnited States72205
    3Scripps Clinical Medical GroupLa JollaCaliforniaUnited States92037
    4UCLA - Ronald Reagan Medical CenterLos AngelesCaliforniaUnited States90095
    5Riverside UniversityMoreno ValleyCaliforniaUnited States92555
    6UC Irvine Medical CenterOrangeCaliforniaUnited States92868
    7Stanford University Medical CenterPalo AltoCaliforniaUnited States94303
    8UCLA Medical Center- Santa MonicaSanta MonicaCaliforniaUnited States06037
    9Medstar Washington Hospital CenterWashingtonDistrict of ColumbiaUnited States20010
    10University of Florida-JacksonvilleJacksonvilleFloridaUnited States32218
    11University of Illinois at ChicagoChicagoIllinoisUnited States60607
    12Northwestern UniversityChicagoIllinoisUnited States60611
    13Loyola University Medical CenterMaywoodIllinoisUnited States60153
    14University of IowaIowa CityIowaUnited States52242
    15University of KansasKansas CityKansasUnited States66160
    16University of KentuckyLexingtonKentuckyUnited States40536
    17Tulane School of MedicineNew OrleansLouisianaUnited States70112
    18University Medical Center New OrleansNew OrleansLouisianaUnited States70112
    19Ochsner Medical CenterNew OrleansLouisianaUnited States70121
    20Anne Arundel Medical CenterAnnapolisMarylandUnited States21401
    21Johns Hopkins Medical CenterBaltimoreMarylandUnited States21202
    22Tufts Medical CenterBostonMassachusettsUnited States02111
    23Brigham and Women's HospitalBostonMassachusettsUnited States02115
    24Boston Medical CenterBostonMassachusettsUnited States02118
    25Beth Israel Deaconess Medical CenterBostonMassachusettsUnited States02215
    26U Mass Memorial Medical CenterWorcesterMassachusettsUnited States01655
    27U Mass University Medical CenterWorcesterMassachusettsUnited States01655
    28MidMichigan Medical Center- GratiotAlmaMichiganUnited States48640
    29MidMichigan Medical Center - MidlandMidlandMichiganUnited States48670
    30Mayo ClinicRochesterMinnesotaUnited States55905
    31University of Mississippi Medical CenterJacksonMississippiUnited States39216
    32University of Missouri Health CareColumbiaMissouriUnited States65212
    33Washington University School of MedicineSaint LouisMissouriUnited States63110
    34Trinitas HospitalElizabethNew JerseyUnited States07207
    35Hackensack University Medical CenterHackensackNew JerseyUnited States07601
    36Rutgers New Jersey Medical SchoolNew BrunswickNew JerseyUnited States08901
    37NYU BrooklynBrooklynNew YorkUnited States11220
    38University at BuffaloBuffaloNew YorkUnited States14203
    39Flushing Hospital Medical CenterFlushingNew YorkUnited States11355
    40Jamaica Hospital Medical CenterJamaicaNew YorkUnited States11418
    41NYU Long IslandLong Island CityNew YorkUnited States10016
    42New York University Langone Medical CenterNew YorkNew YorkUnited States10016
    43Harlem Hospital CenterNew YorkNew YorkUnited States10037
    44Weill Cornell MedicineNew YorkNew YorkUnited States10065
    45St Lawrence Health SystemPotsdamNew YorkUnited States13676
    46University of Rochester Medical Center-Strong Memorial HospitalRochesterNew YorkUnited States14642
    47University of North Carolina - Chapel HillChapel HillNorth CarolinaUnited States27599
    48Duke UniversityDurhamNorth CarolinaUnited States27710
    49Wake Forest UniversityWinston-SalemNorth CarolinaUnited States27157
    50Mercy Saint Vincent Medical CenterToledoOhioUnited States43608
    51University of Oklahoma Health Sciences CenterOklahoma CityOklahomaUnited States73104
    52Oregon Health and Science UniversityPortlandOregonUnited States97239
    53Temple University HospitalPhiladelphiaPennsylvaniaUnited States19140
    54Reading Hospital StudyWyomissingPennsylvaniaUnited States19610
    55Avera McKennan HospitalSioux FallsSouth DakotaUnited States57105
    56University of Tennessee Medical CenterKnoxvilleTennesseeUnited States37920
    57Methodist Health System Clinical Research InstituteDallasTexasUnited States75203
    58University of Texas Health Science Center at San AntonioSan AntonioTexasUnited States78229
    59Trinity Mother Frances HospitalTylerTexasUnited States75701
    60University of UtahSalt Lake CityUtahUnited States84108
    61Virginia Commonwealth University Medical CenterRichmondVirginiaUnited States23298
    62University of Washington Medical CenterSeattleWashingtonUnited States98195
    63Providence Medical Research CenterSpokaneWashingtonUnited States99204
    64West Virginia UniversityMorgantownWest VirginiaUnited States26505
    65Gundersen Health SystemLa CrosseWisconsinUnited States54601
    66Hospital Interzonal Dr Jose Penna Bahia BlancaBahía BlancaBuenos AiresArgentina8000
    67Instituto Medico PlatenseLa PlataBuenos AiresArgentinaB1900
    68Clinica Central S.A.Villa ReginaRio NegroArgentina8336
    69Hospital Ramos MejiaBuenos AiresArgentinaC1221ADC
    70Hospital RawsonCordobaArgentina5000
    71Sanatorio AllendeCórdobaArgentinaX5000JHGQ
    72Sanatorio BritanicoRosarioArgentina2000
    73Sanatorio Diagnóstico/ Instituto del Buen AireSanta FeArgentinaS3000
    74Hospital BrasíliaBrasíliaDFBrazil71681-603
    75Hospital Felício RochoBelo HorizonteMGBrazil30110-934
    76Instituto DOR de Ensino e Pesquisa Hospital Glória D'OrRio De JaneiroRio De Janeiro / RJBrazil22211-230
    77Hospital Ernesto DornellesPorto AlegreRio Grande D Sul /RSBrazil90160-092
    78Hospital de Clinicas de Porto Alegre HCPAPorto AlegreRio Grande Do Sul / RSBrazil90035-903
    79Santa Casa de Misericordia de Porto AlegrePorto AlegreRio Grande Do Sul/RSBrazil90020-090
    80Hospital e Maternidade Celso Pierro - PUC CampinasCampinasSão Paulo/SPBrazil13060-904
    81Nuevo Hospital Civil de Guadalajara "Dr. Juan I. Menchaca"GuadalajaraGuadalajara JaliscoMexicoCP 44340
    82Hospital Universitario "Dr. Jose Eleuterio Gonzalez"Nuevo LeónMonterreyMexico64460
    83Hospital Central FAPLimaLima/LimaPeru51
    84Hospital Regional LambayequeChiclayoPeru1400
    85Hospitala Nacional Hipólito UnánueLimaPeru15007
    86Hospital Nacional Aezobispo LoayzaLimaPeru15082
    87Hospital de Chancay y Servicios Basicos de SaludLimaPeru15131
    88Clínica Belén SANNAPiuraPeru

    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)

    None provided.

    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:
    Oct 8, 2021
    Last Verified:
    Aug 1, 2021
    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 Oct 8, 2021