Clinical trial NCT04401579: Adaptive COVID-19 Treatment Trial 2 (ACTT-2)
Official title: A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Adults (ACTT-2)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: COVID-19
Keywords: Adaptive
COVID-19
Efficacy
Multicenter
novel coronavirus
Safety
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2020-05-26
Enrollment: 1033
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: ACTT-2 will evaluate the combination of baricitinib and remdesivir compared to remdesivir alone. Subjects will be assessed daily while hospitalized. If the subjects are discharged from the hospital, they will have a study visit at Days 15, 22, and 29. For discharged subjects, it is preferred that the Day 15 and 29 visits are in person to obtain safety laboratory tests and oropharyngeal (OP) swab and blood (serum only) samples for secondary research as well as clinical outcome data. However, infection control or other restrictions may limit the ability of the subject 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 primary outcome is time to recovery by Day 29.

Detailed description: This study is an adaptive randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of novel therapeutic agents in hospitalized adults diagnosed with COVID-19. The study is a multicenter trial that will be conducted in up to approximately 100 sites globally. The study will compare different investigational therapeutic agents to a control arm. New arms can be introduced according to scientific and public health needs. There will be interim monitoring to allow early stopping for futility, efficacy, or safety. If one therapy proves to be efficacious, then this treatment may become the control arm for comparison(s) with new experimental treatment(s). Any such change would be accompanied by an updated sample size. This adaptive platform is used to rapidly evaluate different therapeutics in a population of those hospitalized with moderate to severe COVID-19. The platform will provide a common framework sharing a similar population, design, endpoints, and safety oversight. New stages with new therapeutics can be introduced. One independent Data and Safety Monitoring Board (DSMB) will actively monitor interim data in all stages to make recommendations about early study closure or changes to study arms.

ACTT-2 will evaluate the combination of baricitinib and remdesivir compared to remdesivir alone. Subjects will be assessed daily while hospitalized. If the subjects are discharged from the hospital, they will have a study visit at Days 15, 22, and 29. For discharged subjects, it is preferred that the Day 15 and 29 visits are in person to obtain safety laboratory tests and oropharyngeal (OP) swab and blood (serum only) samples for secondary research as well as clinical outcome data. However, infection control or other restrictions may limit the ability of the subject 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.

All subjects will undergo a series of efficacy, safety, and laboratory assessments. Safety laboratory tests and blood (serum and plasma) research samples and oropharyngeal (OP) swabs will be obtained on Days 1 (prior to infusion) and Days 3, 5, 8, and 11 (while hospitalized). OP swabs and blood (serum only) plus safety laboratory tests will be collected on Day 15 and 29 (if the subject attends an in-person visit or are still hospitalized).

The primary outcome is time to recovery by Day 29. A key secondary outcome evaluates treatment-related improvements in the 8-point ordinal scale at Day 15. Each stage may prioritize different secondary endpoints for the purpose of multiple comparison analyses.

Contacts:

20-0006 Central Contact

Telephone: 1 (301) 7617948

Email: DMIDClinicalTrials@niaid.nih.gov

Eligibility criteria: Inclusion Criteria:

1. Admitted to a hospital 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 adult \> / = 18 years of age at time of enrollment.
5. Has laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR) or other commercial or public health assay in any specimen, as documented by either of the following:

   * PCR positive in sample collected \< 72 hours prior to randomization; OR
   * PCR positive in sample collected \>/= 72 hours prior to randomization, documented inability to obtain a repeat sample (e.g. due to lack of testing supplies, limited testing capacity, results taking \>24 hours, etc.) AND progressive disease suggestive of ongoing SARS-CoV-2 infection.
6. Illness of any duration, and at least one of the following:

   * Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR
   * SpO2 \< / = 94% on room air, OR
   * Requiring supplemental oxygen, OR
   * Requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO).
7. Women of childbearing potential must agree to either abstinence or use at least one primary form of contraception not including hormonal contraception from the time of screening through Day 29.
8. Agrees to not participate in another clinical trial for the treatment of COVID-19 through Day 29.

Exclusion Criteria:

1. Alanine Transaminase (ALT) or Aspartate Transaminase (AST) \> 5 times the upper limit of normal.
2. Estimated glomerular filtration rate (eGFR) \< 30 ml/min or patient is receiving hemodialysis or hemofiltration at time of screening.
3. Neutropenia (absolute neutrophil count \<1000 cells/microliter) (\<1.0 x 103/microliter or \<1.0 GI/L).
4. Lymphopenia (absolute lymphocyte count \<200 cells/microliter) (\<0.20 x 103/microliter 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. Allergy to any study medication.
8. Received three or more doses of remdesivir, including the loading dose, outside of the study under the EUA (or similar mechanism) for COVID-19.
9. Received convalescent plasma or intravenous immunoglobulin \[IVIg\]) for COVID-19, the current illness for which they are being enrolled.
10. Received small molecule tyrosine kinase inhibitors (e.g. baricitinib, imatibib, genfinitib), in the 1 week prior to screening
11. Received monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-interleukin-1 \[IL-1\], anti-IL-6 \[tocilizumab or sarilumab\]), or T-cells (e.g., abatacept) in the 4 weeks prior to screening.
12. Received monoclonal antibodies targeting B-cell (e.g., rituximab, and including any targeting multiple cell lines including B-cells) in the 3 months prior to screening.
13. Received other immunosuppressants in the 4 weeks prior to screening and in the judgement of the investigator, the risk of immunosuppression with baricitinib is larger than the risk of COVID-19.
14. Received \>/= 20 mg/day of prednisone or equivalent for \>/=14 consecutive days in the 4 weeks prior to screening.
15. Use of probenecid that cannot be discontinued at study enrollment.
16. Have diagnosis of current active tuberculosis (TB) or, if known, latent TB treated for less than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines (by history only, no screening required).
17. Suspected serious, active bacterial, fungal, viral, or other infection (besides COVID-19) that in the opinion of the investigator could constitute a risk when taking investigational product.
18. Have received any live vaccine (that is, live attenuated) within 4 weeks before screening, or intend to receive a live vaccine (or live attenuated) during the study. Note: Use of non-live (inactivated) vaccinations is allowed for all subjects.
19. Have a history of VTE (deep vein thrombosis \[DVT\] or pulmonary embolism \[PE\]) within 12 weeks prior to screening or have a history of recurrent (\>1) VTE (DVT/PE).
20. Immunocompromised patients, patients with a chronic medical condition, or those taking a medication that cannot be discontinued at enrollment, who, in the judgment of PI, are at increased risk for serious infections or other safety concerns given the study products.

Primary outcomes:
measure: Time to Recovery
timeFrame: Day 1 through Day 29
measure: Time to Recovery by Race
timeFrame: Day 1 through Day 29
measure: Time to Recovery by Ethnicity
timeFrame: Day 1 through Day 29
measure: Time to Recovery by Sex
timeFrame: Day 1 through Day 29
Secondary outcomes:
measure: Change From Baseline in Alanine Transaminase (ALT)
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Aspartate Transaminase (AST)
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Creatinine
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Glucose
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Hemoglobin
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Platelets
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Prothrombin International Normalized Ratio (INR)
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Total Bilirubin
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in White Blood Cell Count (WBC)
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Neutrophils
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Lymphocytes
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Monocytes
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Basophils
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Eosinophils
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change in National Early Warning Score (NEWS) From Baseline
timeFrame: Days 1, 3, 5, 8, 11, 15, 22, and 29
measure: Percentage of Participants Reporting Grade 3 and 4 Clinical and/or Laboratory Adverse Events (AEs)
timeFrame: Day 1 through Day 29
measure: Percentage of Participants Reporting Serious Adverse Events (SAEs)
timeFrame: Day 1 through Day 29
measure: Duration of Hospitalization
timeFrame: Day 1 through Day 29
measure: Duration of New Non-invasive Ventilation or High Flow Oxygen Use
timeFrame: Day 1 through Day 29
measure: Duration of New Oxygen Use
timeFrame: Day 1 through Day 29
measure: Duration of New Ventilator or Extracorporeal Membrane Oxygenation (ECMO) Use
timeFrame: Day 1 through Day 29
measure: Duration of Oxygen Use
timeFrame: Day 1 through Day 29
measure: Percentage of Participants Discontinued or Temporarily Suspended From Investigational Therapeutics
timeFrame: Day 1 through Day 14
measure: Percentage of Participants Requiring New Ventilator or Extracorporeal Membrane Oxygenation (ECMO) Use
timeFrame: Day 1 through Day 29
measure: Percentage of Participants Requiring New Oxygen Use
timeFrame: Day 1 through Day 29
measure: Mean Change in the Ordinal Scale
timeFrame: Day 1, 3, 5, 8, 11, 15, 22, and 29
measure: Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 15
timeFrame: Day 15
measure: Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 1
timeFrame: Day 1
measure: Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 3
timeFrame: Day 3
measure: Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 5
timeFrame: Day 5
measure: Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 8
timeFrame: Day 8
measure: Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 11
timeFrame: Day 11
measure: Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 22
timeFrame: Day 22
measure: Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 29
timeFrame: Day 29
measure: 14-day Participant Mortality
timeFrame: Day 1 through Day 15
measure: 28-day Participant Mortality
timeFrame: Day 1 through Day 29
measure: Time to an Improvement of One Category Using an Ordinal Scale
timeFrame: Day 1 through Day 29
measure: Time to an Improvement of Two Categories Using an Ordinal Scale
timeFrame: Day 1 through Day 29
measure: Time to Discharge or to a NEWS of 2 or Less and Maintained for 24 Hours, Whichever Occurs First
timeFrame: Day 1 through Day 29
measure: Change From Baseline in C-reactive Protein (CRP)
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in D-dimer Concentration
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham School of Medicine - Infectious Disease
state: Alabama
city: La Jolla
country: United States
facility: University of California San Diego Health - Jacobs Medical Center
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles Medical Center - Westwood Clinic
state: California
city: Orange
country: United States
facility: University of California Irvine Medical Center - Infectious Disease
state: California
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care System - Infectious Diseases
state: California
city: Palo Alto
country: United States
facility: Stanford University - Stanford Hospital and Clinics - Pediatrics - Infectious Diseases
state: California
city: Sacramento
country: United States
facility: University of California Davis Medical Center - Internal Medicine - Infectious Disease
state: California
city: San Diego
country: United States
facility: Naval Medical Center San Diego - Infectious Disease Clinic
state: California
city: San Francisco
country: United States
facility: University of California San Francisco - Zuckerberg San Francisco General Hospital - Division of Human Immunodeficiency Virus, Infectious Disease, and Global Medicine
state: California
city: West Hollywood
country: United States
facility: Cedars Sinai Medical Center
state: California
city: Aurora
country: United States
facility: Eastern Colorado Health Care System
state: Colorado
city: Denver
country: United States
facility: Denver Health Division of Hospital Medicine - Main Campus
state: Colorado
city: Washington
country: United States
facility: Georgetown University Medical Center - Division of Infectious Diseases
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida Health - Shands Hospital - Division of Infectious Diseases and Global Medicine
state: Florida
city: Miami
country: United States
facility: University of Miami Miller School of Medicine - Infectious Diseases
state: Florida
city: Decatur
country: United States
facility: Emory Vaccine Center - The Hope Clinic
state: Georgia
city: Decatur
country: United States
facility: Atlanta VA Medical Center - Infectious Diseases Clinic
state: Georgia
city: Chicago
country: United States
facility: Northwestern Hospital - Infectious Disease
state: Illinois
city: Chicago
country: United States
facility: University of Illinois at Chicago College of Medicine - Division of Infectious Diseases
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University School of Medicine - Infectious Diseases
state: Indiana
city: Kenner
country: United States
facility: Ochsner Medical Center - Kenner - Department of Infectious Diseases
state: Louisiana
city: New Orleans
country: United States
facility: Southeast Louisiana Veterans Health Care System (SLVHCS) - Section of Infectious Diseases
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland School of Medicine - Center for Vaccine Development - Baltimore
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Hospital - Medicine - Infectious Diseases
state: Maryland
city: Bethesda
country: United States
facility: Walter Reed National Military Medical Center
state: Maryland
city: Bethesda
country: United States
facility: National Institutes of Health - Clinical Center, National Institute of Allergy and Infectious Diseases Laboratory Of Immunoregulation, Clinical Research Section
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital - Infectious Diseases
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Medical School - Infectious Diseases and Immunology
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center, Fairview - Infectious Diseases and International Medicine
state: Minnesota
city: Saint Louis
country: United States
facility: Saint Louis University - Center for Vaccine Development
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center - Infectious Diseases
state: Nebraska
city: Albuquerque
country: United States
facility: University of New Mexico Clinical and Translational Science Center
state: New Mexico
city: Bronx
country: United States
facility: Montefiore Medical Center - Infectious Diseases
state: New York
city: New York
country: United States
facility: New York University School of Medicine - Langone Medical Center - Microbiology - Parasitology
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center - Vaccine Research Unit
state: New York
city: Durham
country: United States
facility: Duke Human Vaccine Institute - Duke Vaccine and Trials Unit
state: North Carolina
city: Fort Bragg
country: United States
facility: Womack Army Medical Center - Pulmonary and Respiratory Services
state: North Carolina
city: Portland
country: United States
facility: Kaiser Permanente Northwest - Center for Health Research
state: Oregon
city: Hershey
country: United States
facility: Penn State Health Milton S. Hershey Medical Center - Division of Infectious Diseases
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania Perelman School of Medicine - Penn Institute for Immunology
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center - Infectious Diseases
state: Tennessee
city: Dallas
country: United States
facility: Baylor Scott & White Health - Baylor University Medical Center - North Texas Infectious Disease Consultants
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center - Internal Medicine - Infectious Diseases
state: Texas
city: Fort Sam Houston
country: United States
facility: Brooke Army Medical Center
state: Texas
city: Galveston
country: United States
facility: University of Texas Medical Branch - Division of Infectious Disease
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine - Molecular Virology and Microbiology
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio - Infectious Diseases
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah - Infectious Diseases
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia - Acute Care Surgery
state: Virginia
city: Portsmouth
country: United States
facility: Naval Medical Center Portsmouth - Infectious Disease Division
state: Virginia
city: Kirkland
country: United States
facility: EvergreenHealth Infectious Disease Service
state: Washington
city: Spokane
country: United States
facility: Providence Sacred Heart Medical Center
state: Washington
city: Tacoma
country: United States
facility: Madigan Army Medical Center - Infectious Disease Clinic
state: Washington
city: Copenhagen
country: Denmark
facility: University of Copenhagen - Centre of Excellence for Health, Immunity and Infections (CHIP) - Department of Infectious Diseases
city: Tokyo
country: Japan
facility: National Center for Global Health and Medicine Hospital - Disease Control and Prevention Center
city: Bundang-gu Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital - Division of Infectious Diseases
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Mexico City
country: Mexico
facility: Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubirán - Departamento de Infectologia
city: Mexico City
country: Mexico
facility: Instituto Nacional de Enfermedades Respiratorias (INER) - Ismael Cosío Villegas
city: Singapore
country: Singapore
facility: National University Health System - Division of Infectious Diseases
city: Singapore
country: Singapore
facility: National Centre for Infectious Diseases (NCID)
city: Singapore
country: Singapore
facility: Changi General Hospital - Clinical Trials and Research Unit (CTRU)
city: Singapore
country: Singapore
facility: Ng Teng Fong General Hospital - Infectious Disease Service
city: Barcelona
country: Spain
facility: Hospital Clinic Barcelona, Servicio de Salud Internacional
state: Cataluña
city: Barcelona
country: Spain
facility: Hospital Germans Trias i Pujol - Servei Malalties Infeccioses
state: Cataluña
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos - Enfermedades Infecciosas
city: Brighton
country: United Kingdom
facility: Royal Sussex County Hospital - Department of Intensive Care Medicine
city: City Of London
country: United Kingdom
facility: Saint Thomas' Hospital - Directorate of Infection
city: Leeds
country: United Kingdom
facility: St. James's University Hospital - Infectious Diseases
city: Newcastle Upon Tyne
country: United Kingdom
facility: Royal Victoria Infirmary - Department of Infectious Diseases
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
Study officials:
References:
citation: Kramer A, Prinz C, Fichtner F, Fischer AL, Thieme V, Grundeis F, Spagl M, Seeber C, Piechotta V, Metzendorf MI, Golinski M, Moerer O, Stephani C, Mikolajewska A, Kluge S, Stegemann M, Laudi S, Skoetz N. Janus kinase inhibitors for the treatment of COVID-19. Cochrane Database Syst Rev. 2022 Jun 13;6(6):CD015209. doi: 10.1002/14651858.CD015209.
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.
citation: Kalil AC, Patterson TF, Mehta AK, Tomashek KM, Wolfe CR, Ghazaryan V, Marconi VC, Ruiz-Palacios GM, Hsieh L, Kline S, Tapson V, Iovine NM, Jain MK, Sweeney DA, El Sahly HM, Branche AR, Regalado Pineda J, Lye DC, Sandkovsky U, Luetkemeyer AF, Cohen SH, Finberg RW, Jackson PEH, Taiwo B, Paules CI, Arguinchona H, Erdmann N, Ahuja N, Frank M, Oh MD, Kim ES, Tan SY, Mularski RA, Nielsen H, Ponce PO, Taylor BS, Larson L, Rouphael NG, Saklawi Y, Cantos VD, Ko ER, Engemann JJ, Amin AN, Watanabe M, Billings J, Elie MC, Davey RT, Burgess TH, Ferreira J, Green M, Makowski M, Cardoso A, de Bono S, Bonnett T, Proschan M, Deye GA, Dempsey W, Nayak SU, Dodd LE, Beigel JH; ACTT-2 Study Group Members. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. N Engl J Med. 2021 Mar 4;384(9):795-807. doi: 10.1056/NEJMoa2031994. Epub 2020 Dec 11.
citation: Azzi Y, Bartash R, Scalea J, Loarte-Campos P, Akalin E. COVID-19 and Solid Organ Transplantation: A Review Article. Transplantation. 2021 Jan 1;105(1):37-55. doi: 10.1097/TP.0000000000003523.