ACTIV-1 IM: Immune Modulators for Treating COVID-19
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|
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.
Arms and Interventions
|Active Comparator: Remdesivir + infliximab or matching placebo|
infliximab (single dose IV 5mg/kg given on day 1) or matching placebo
study drug or matching placebo
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
study drug or matching placebo
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
Standard of Care
Drug: cenicriviroc (closed to enrollment as of 3-Sep-2021)
study drug or matching placebo
Primary Outcome Measures
- Number of patients that recovered from COVID-19 [days 1-29]
time to recovery by Day 29
Secondary Outcome Measures
- Change in number of patients hospitalized on invasive mechanical ventilation [Days 15 and 29]
Number of patients hospitalized on invasive mechanical ventilation
- number of patients that improved clinically [Days 3, 5, 8, 11, 15, 29, and 60]
8-point ordinal clinical scale assessed
- Number of patient deaths [Day 14]
- Number of patients with decreased supplemental oxygenation needed [Day 29]
compared to baseline the amount of supplementation oxygen
- 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
- Number of days patients are in the hospital [Days 3, 5, 8, 11, 15, 22, and 29]
number of days in the hospital
- 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
- 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
- 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
Admitted to a hospital or awaiting admission in the ED with symptoms suggestive of COVID-19.
Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures.
Subject (or legally authorized representative) understands and agrees to comply with planned study procedures.
Male or non-pregnant female adults ≥18 years of age at time of enrollment.
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.
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.
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.
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.
ALT or AST >10 times the upper limit of normal.
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.
Neutropenia (absolute neutrophil count <1000 cells/μL) (<1.0 x 103/μL or <1.0 GI/L).
Lymphopenia (absolute lymphocyte count <200 cells/μL) (<0.20 x 103/μL or <0.20 GI/L)
Pregnancy or breast feeding.
Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours.
Known allergy to any study medication.
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.
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).
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.
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.
Severe hepatic impairment (defined as liver cirrhosis Child stage C).
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.
- In the Investigator's judgment, the patient has any advanced organ dysfunction that would not make participation appropriate.
Contacts and Locations
|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 at San Antonio||San Antonio||Texas||United States||78229|
|59||Trinity Mother Frances Hospital||Tyler||Texas||United States||75701|
|60||University of Utah||Salt Lake City||Utah||United States||84108|
|61||Virginia Commonwealth University Medical Center||Richmond||Virginia||United States||23298|
|62||University of Washington Medical Center||Seattle||Washington||United States||98195|
|63||Providence Medical Research Center||Spokane||Washington||United States||99204|
|64||West Virginia University||Morgantown||West Virginia||United States||26505|
|65||Gundersen Health System||La Crosse||Wisconsin||United States||54601|
|66||Hospital Interzonal Dr Jose Penna Bahia Blanca||Bahía Blanca||Buenos Aires||Argentina||8000|
|67||Instituto Medico Platense||La Plata||Buenos Aires||Argentina||B1900|
|68||Clinica Central S.A.||Villa Regina||Rio Negro||Argentina||8336|
|69||Hospital Ramos Mejia||Buenos Aires||Argentina||C1221ADC|
|73||Sanatorio Diagnóstico/ Instituto del Buen Aire||Santa Fe||Argentina||S3000|
|75||Hospital Felício Rocho||Belo Horizonte||MG||Brazil||30110-934|
|76||Instituto DOR de Ensino e Pesquisa Hospital Glória D'Or||Rio De Janeiro||Rio De Janeiro / RJ||Brazil||22211-230|
|77||Hospital Ernesto Dornelles||Porto Alegre||Rio Grande D Sul /RS||Brazil||90160-092|
|78||Hospital de Clinicas de Porto Alegre HCPA||Porto Alegre||Rio Grande Do Sul / RS||Brazil||90035-903|
|79||Santa Casa de Misericordia de Porto Alegre||Porto Alegre||Rio Grande Do Sul/RS||Brazil||90020-090|
|80||Hospital e Maternidade Celso Pierro - PUC Campinas||Campinas||São Paulo/SP||Brazil||13060-904|
|81||Nuevo Hospital Civil de Guadalajara "Dr. Juan I. Menchaca"||Guadalajara||Guadalajara Jalisco||Mexico||CP 44340|
|82||Hospital Universitario "Dr. Jose Eleuterio Gonzalez"||Nuevo León||Monterrey||Mexico||64460|
|83||Hospital Central FAP||Lima||Lima/Lima||Peru||51|
|84||Hospital Regional Lambayeque||Chiclayo||Peru||1400|
|85||Hospitala Nacional Hipólito Unánue||Lima||Peru||15007|
|86||Hospital Nacional Aezobispo Loayza||Lima||Peru||15082|
|87||Hospital de Chancay y Servicios Basicos de Salud||Lima||Peru||15131|
|88||Clínica Belén SANNA||Piura||Peru|
Sponsors and Collaborators
- Daniel Benjamin
- National Center for Advancing Translational Science (NCATS)
- Biomedical Advanced Research and Development Authority
- 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.