Clinical trial NCT04593940: Immune Modulators for Treating COVID-19
Official title: Randomized Master Protocol for Immune Modulators for Treating COVID-19
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Covid19
Keywords: COVID19
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: National Center for Advancing Translational Sciences (NCATS)
name: Biomedical Advanced Research and Development Authority
First posted: 2020-10-20
Enrollment: 1971
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants Who Had Recovered by Day 28
timeFrame: Days 1-28
Secondary outcomes:
measure: Number of Participants With Clinical Status for Day 14 Using an 8 Point Ordinal Scale
timeFrame: Day 14
measure: Mortality Through 28 Days
timeFrame: Day 1-28
measure: Number of Participants With Clinical Status for Day 28 Using an 8 Point Ordinal Scale
timeFrame: Day 28
measure: Mortality Through 14 Days
timeFrame: Day 1-14
measure: Number of Participants Who Met a One Point Improvement in One Category From Day 0 (Baseline) to Day 28 Using an 8-point Ordinal Scale
timeFrame: Day 1-day 28
measure: Number of Participants Who Met a One Point Improvement in Two Categories From Day 0 (Baseline) to Day 28 Using an 8-point Ordinal Scale
timeFrame: Day 1- day 28
measure: Mean Change in the 8-point Ordinal Scale From Day 0 to Day 2
timeFrame: Day 0 to day 2
measure: Mean Change in the 8-point Ordinal Scale From Day 0 to Day 4
timeFrame: Day 0 to day 4
measure: Mean Change in the 8-point Ordinal Scale From Day 0 to Day 7
timeFrame: Day 0 to day 7
measure: Mean Change in the 8-point Ordinal Scale From Day 0 to Day 10
timeFrame: Day 0 to day 10
measure: Mean Change in the 8-point Ordinal Scale From Day 0 to Day 14
timeFrame: Day 0 to day 14
measure: Mean Change in the 8-point Ordinal Scale From Day 0 to Day 21
timeFrame: Day 0 to day 21
measure: Mean Change in the 8-point Ordinal Scale From Day 0 to Day 28
timeFrame: Day 0 to day 28
measure: Duration (Days) Alive and Free of Supplemental Oxygen
timeFrame: Day 1 to day 28
measure: Number of Patients With New Supplemental Oxygen Use
timeFrame: Day 1-day 28
measure: Duration (Days) Alive and Free of Non-invasive Ventilation/ High Flow Oxygen
timeFrame: Day 1 to day 28
measure: Number of Patients With New Non-invasive Ventilation/High Flow Oxygen Use
timeFrame: Day 1-day 28
measure: Duration (Days) Alive and Free of Invasive Mechanical Ventilation or ECMO
timeFrame: Day 1 to day 28
measure: Number of Patients With New Mechanical Ventilation or ECMO Use
timeFrame: Day 1 to day 28
measure: Duration (Days) Alive and Out of the Hospital
timeFrame: Through day 28
measure: Number of Patients With SAEs Through Day 28
timeFrame: Day 28
measure: Number of Patients With Grade 3 and 4 Adverse Events
timeFrame: Day 28
measure: Number of Patients With Adverse Events Leading to Dose Modification
timeFrame: Day 1-28
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Banner University Medical Center
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas Medical Sciences
state: Arkansas
city: La Jolla
country: United States
facility: Scripps Clinical Medical Group
state: California
city: Los Angeles
country: United States
facility: UCLA - Ronald Reagan Medical Center
state: California
city: Moreno Valley
country: United States
facility: Riverside University
state: California
city: Orange
country: United States
facility: UC Irvine Medical Center
state: California
city: Palo Alto
country: United States
facility: Stanford University Medical Center
state: California
city: Santa Monica
country: United States
facility: UCLA Medical Center- Santa Monica
state: California
city: Washington
country: United States
facility: Medstar Washington Hospital Center
state: District of Columbia
city: Jacksonville
country: United States
facility: University of Florida-Jacksonville
state: Florida
city: Chicago
country: United States
facility: University of Illinois at Chicago
state: Illinois
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: New Orleans
country: United States
facility: Tulane School of Medicine
state: Louisiana
city: New Orleans
country: United States
facility: University Medical Center New Orleans
state: Louisiana
city: New Orleans
country: United States
facility: Ochsner Medical Center
state: Louisiana
city: Annapolis
country: United States
facility: Anne Arundel Medical Center
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Medical Center
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: U Mass Memorial Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: U Mass University Medical Center
state: Massachusetts
city: Alma
country: United States
facility: MidMichigan Medical Center- Gratiot
state: Michigan
city: Midland
country: United States
facility: MidMichigan Medical Center - Midland
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Columbia
country: United States
facility: University of Missouri Health Care
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Elizabeth
country: United States
facility: Trinitas Hospital
state: New Jersey
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers New Jersey Medical School
state: New Jersey
city: Brooklyn
country: United States
facility: NYU Brooklyn
state: New York
city: Buffalo
country: United States
facility: University at Buffalo
state: New York
city: Flushing
country: United States
facility: Flushing Hospital Medical Center
state: New York
city: Jamaica
country: United States
facility: Jamaica Hospital Medical Center
state: New York
city: Long Island City
country: United States
facility: NYU Long Island
state: New York
city: New York
country: United States
facility: New York University Langone Medical Center
state: New York
city: New York
country: United States
facility: Harlem Hospital Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
city: Potsdam
country: United States
facility: St Lawrence Health System
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center-Strong Memorial Hospital
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina - Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University
state: North Carolina
city: Toledo
country: United States
facility: Mercy Saint Vincent Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Wyomissing
country: United States
facility: Reading Hospital Study
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Avera McKennan Hospital
state: South Dakota
city: Knoxville
country: United States
facility: University of Tennessee Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Methodist Health System Clinical Research Institute
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center - Houston
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Tyler
country: United States
facility: Trinity Mother Frances Hospital
state: Texas
city: Tyler
country: United States
facility: University of Texas Health Center at Tyler
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University Medical Center
state: Virginia
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Spokane
country: United States
facility: Providence Medical Research Center
state: Washington
city: Morgantown
country: United States
facility: West Virginia University
state: West Virginia
city: La Crosse
country: United States
facility: Gundersen Health System
state: Wisconsin
city: Bahía Blanca
country: Argentina
facility: Hospital Interzonal Dr Jose Penna Bahia Blanca
state: Buenos Aires
city: Caba
country: Argentina
facility: Sanatorio Ramon Cereijo
state: Buenos Aires
city: La Plata
country: Argentina
facility: Instituto Medico Platense
state: Buenos Aires
city: Villa Regina
country: Argentina
facility: Clinica Central S.A.
state: Rio Negro
city: Buenos Aires
country: Argentina
facility: Hospital Ramos Mejia
city: Cordoba
country: Argentina
facility: Hospital Rawson
city: Córdoba
country: Argentina
facility: Sanatorio Allende
city: Rosario
country: Argentina
facility: Sanatorio Britanico
city: Santa Fe
country: Argentina
facility: Sanatorio Diagnóstico/ Instituto del Buen Aire
city: Brasília
country: Brazil
facility: Hospital Brasília
state: DF
city: Belo Horizonte
country: Brazil
facility: Hospital Felício Rocho
state: MG
city: Rio De Janeiro
country: Brazil
facility: Instituto DOR de Ensino e Pesquisa Hospital Glória D'Or
state: Rio De Janeiro / RJ
city: Porto Alegre
country: Brazil
facility: Hospital Ernesto Dornelles
state: Rio Grande D Sul /RS
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre HCPA
state: Rio Grande Do Sul / RS
city: Porto Alegre
country: Brazil
facility: Santa Casa de Misericordia de Porto Alegre
state: Rio Grande Do Sul/RS
city: Campinas
country: Brazil
facility: Hospital e Maternidade Celso Pierro - PUC Campinas
state: São Paulo/SP
city: Guadalajara
country: Mexico
facility: Nuevo Hospital Civil de Guadalajara "Dr. Juan I. Menchaca"
state: Guadalajara Jalisco
city: Nuevo León
country: Mexico
facility: Hospital Universitario "Dr. Jose Eleuterio Gonzalez"
state: Monterrey
city: Lima
country: Peru
facility: Hospital Central FAP
state: Lima/Lima
city: Chiclayo
country: Peru
facility: Hospital Regional Lambayeque
city: Lima
country: Peru
facility: Hospitala Nacional Hipólito Unánue
city: Lima
country: Peru
facility: Hospital Nacional Aezobispo Loayza
city: Lima
country: Peru
facility: Hospital de Chancay y Servicios Basicos de Salud
city: Piura
country: Peru
facility: Clínica Belén SANNA
Study officials:
affiliation: Duke University
name: Daniel K Benjamin, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Washington University School of Medicine
name: Bill Powderly, MD
role: STUDY_CHAIR
References:
citation: Ko ER, Anstrom KJ, Panettieri RA, Lachiewicz AM, Maillo M, O'Halloran JA, Boucher C, Smith PB, McCarthy MW, Segura Nunez P, Mendivil Tuchia de Tai S, Khan A, Mena Lora AJ, Salathe M, Kedar E, Capo G, Rodriguez Gonzalez D, Patterson TF, Palma C, Ariza H, Patelli Lima M, Blamoun J, Nannini EC, Sprinz E, Mykietiuk A, Wang JP, Parra-Rodriguez L, Der T, Willsey K, Benjamin DK, Wen J, Zakroysky P, Halabi S, Silverstein A, McNulty SE, O'Brien SM, Al-Khalidi HR, Butler S, Atkinson J, Adam SJ, Chang S, Maldonado MA, Proscham M, LaVange L, Bozzette SA, Powderly WG; ACTIV-1 IM study group members. Abatacept for Treatment of Adults Hospitalized with Moderate or Severe Covid-19. medRxiv [Preprint]. 2022 Sep 26:2022.09.22.22280247. doi: 10.1101/2022.09.22.22280247.
citation: O'Halloran JA, Kedar E, Anstrom KJ, McCarthy MW, Ko ER, Nunez PS, Boucher C, Smith PB, Panettieri RA, de Tai SMT, Maillo M, Khan A, Mena Lora AJ, Salathe M, Capo G, Gonzalez DR, Patterson TF, Palma C, Ariza H, Lima MP, Lachiewicz AM, Blamoun J, Nannini EC, Sprinz E, Mykietiuk A, Alicic R, Rauseo AM, Wolfe CR, Witting B, Benjamin DK, McNulty SE, Zakroysky P, Halabi S, Butler S, Atkinson J, Adam SJ, Melsheimer R, Chang S, LaVange L, Proschan M, Bozzette SA, Powderly WG; ACTIV-1 IM study group members. Infliximab for Treatment of Adults Hospitalized with Moderate or Severe Covid-19. medRxiv [Preprint]. 2022 Sep 26:2022.09.22.22280245. doi: 10.1101/2022.09.22.22280245.
citation: Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.