Clinical trial NCT04280705: Adaptive COVID-19 Treatment Trial (ACTT)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: COVID-19
Keywords: Adaptive
COVID-19
Efficacy
Multicenter
novel coronavirus
Safety
ACTT
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2020-02-21
Enrollment: 1062
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: 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. There will be interim monitoring to introduce new arms and 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. Because background standards of supportive care may evolve/improve over time as more is learned about successful management of COVID-19, comparisons of safety and efficacy will be based on data from concurrently randomized subjects. An independent Data and Safety Monitoring Board (DSMB) will actively monitor interim data to make recommendations about early study closure or changes to study arms. To evaluate the clinical efficacy, as assessed by time to recovery, of different investigational therapeutics as compared to the control arm.

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. There will be interim monitoring to introduce new arms and 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. Because background standards of supportive care may evolve/improve over time as more is learned about successful management of COVID-19, comparisons of safety and efficacy will be based on data from concurrently randomized subjects. An independent Data and Safety Monitoring Board (DSMB) will actively monitor interim data to make recommendations about early study closure or changes to study arms.

The initial sample size is projected to be 572 subjects to achieve 400 subjects with a "recovered" status (per the primary objective). The primary analysis will be based on those subjects enrolled in order to 400 recoveries. An additional analysis of the moderate severity subgroup (those with baseline status of "Hospitalized, requiring supplemental oxygen" or "Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care") is also of public health importance. Hence, enrollment will be permitted until the date of April 20, 2020 to ensure 400 recoveries and provide additional data about this important subgroup. With recent enrollment rates, the total sample size may be 600 to over 800.

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 as an outpatient. For discharged subjects, it is preferred that the Day 15 and 29 visits are in person to obtain safety laboratory tests and 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, Day 15 and 29 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 may also be 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. As little is known about the clinical course of COVID-19, a pilot study will be used for a blinded sample size reassessment.

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 infection.
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 or the following:

   1. PCR positive in sample collected \< 72 hours prior to randomization; OR

      Exclusion Criteria:
   2. 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:

   1. Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR
   2. SpO2 \< / = 94% on room air, OR
   3. Requiring supplemental oxygen, OR
   4. Requiring mechanical ventilation.
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 or SARS-CoV-2 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 (including patients receiving hemodialysis or hemofiltration).
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. Allergy to any study medication.

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 Time (PT)
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 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 15
timeFrame: Day 15
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: 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: Percentage of Participants Discontinued or Temporarily Suspended From Investigational Therapeutics
timeFrame: Day 1 through Day 10
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: Percentage of Participants Requiring New Non-invasive Ventilation or High-flow Oxygen Use
timeFrame: Day 1 through Day 29
measure: Percentage of Participants Requiring New Oxygen Use
timeFrame: Day 1 through Day 29
measure: Percentage of Participants Requiring New Ventilator or Extracorporeal Membrane Oxygenation (ECMO) 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: 14-day Participant Mortality
timeFrame: Day 1 through Day 15
measure: 29-day Participant Mortality
timeFrame: Day 1 through Day 29
measure: Time to an Improvement by at Least One Category Using an Ordinal Scale
timeFrame: Day 1 through Day 29
measure: Time to an Improvement of at Least 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
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: 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: Stanford
country: United States
facility: Stanford University - Stanford Hospital and Clinics - Pediatrics - Infectious Diseases
state: California
city: West Hollywood
country: United States
facility: Cedars Sinai Medical Center
state: California
city: Denver
country: United States
facility: Denver Health Division of Hospital Medicine - Main Campus
state: Colorado
city: Decatur
country: United States
facility: Emory Vaccine Center - The Hope 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: New Orleans
country: United States
facility: Southeast Louisiana Veterans Health Care System - 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: 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: 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: Hospital of the University of Pennsylvania - Infectious Diseases
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center - Infectious Diseases
state: Tennessee
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: 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: Seattle
country: United States
facility: The University of Washington - Virology Research Clinic
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: Bonn
country: Germany
facility: Universitatsklinikum Bonn, Medizinische Klinik I - Bereich Infektiologie/HIV der Medizinischen Klinik
state: Nordrhein-Westfalen
city: Cologne
country: Germany
facility: Universitatsklinikum Koeln Klinik I fur Innere Medizin Klinisches Studienzentrum fur Infektiologie I
city: Frankfurt
country: Germany
facility: Universitätsklinikum Frankfurt -Medizinische Klinik II - Infektiologie
city: Thessaloniki
country: Greece
facility: AHEPA University Hospital - 1st Department of Internal Medicine
state: Central Macedonia
city: Athens
country: Greece
facility: Medical School of Athens University - Evangelismos Hospital - Department of Critical Care and Pulmonary Services
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
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
state: Jongno-gu
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 Centre for Infectious Diseases
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: East Sussex
country: United Kingdom
facility: Royal Sussex County Hospital - Department of Intensive Care Medicine
state: Brighton
city: London
country: United Kingdom
facility: Saint Thomas' Hospital - Directorate of Infection
state: London, City Of
city: Level 6, Ward 19
country: United Kingdom
facility: Royal Victoria Infirmary - Department of Infectious Diseases
state: Newcastle Upon Tyne
city: Leeds
country: United Kingdom
facility: St. James's University Hospital - Infectious Diseases
state: West Yorkshire
city: Headington, Oxford
country: United Kingdom
facility: John Radcliffe Hospital
Study officials:
References:
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: Ansems K, Grundeis F, Dahms K, Mikolajewska A, Thieme V, Piechotta V, Metzendorf MI, Stegemann M, Benstoem C, Fichtner F. Remdesivir for the treatment of COVID-19. Cochrane Database Syst Rev. 2021 Aug 5;8(8):CD014962. doi: 10.1002/14651858.CD014962.
citation: Sultana J, Crisafulli S, Gabbay F, Lynn E, Shakir S, Trifiro G. Challenges for Drug Repurposing in the COVID-19 Pandemic Era. Front Pharmacol. 2020 Nov 6;11:588654. doi: 10.3389/fphar.2020.588654. eCollection 2020.
citation: Maleszewski JJ, Young PM, Ackerman MJ, Halushka MK. Urgent Need for Studies of the Late Effects of SARS-CoV-2 on the Cardiovascular System. Circulation. 2021 Mar 30;143(13):1271-1273. doi: 10.1161/CIRCULATIONAHA.120.051362. Epub 2020 Sep 24. No abstract available.
citation: Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, Lopez de Castilla D, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G, Lye DC, Ohmagari N, Oh MD, Ruiz-Palacios GM, Benfield T, Fatkenheuer G, Kortepeter MG, Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T, Green M, Makowski M, Osinusi A, Nayak S, Lane HC; ACTT-1 Study Group Members. Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med. 2020 Nov 5;383(19):1813-1826. doi: 10.1056/NEJMoa2007764. Epub 2020 Oct 8.