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Adaptive COVID-19 Treatment Trial (ACTT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04280705
Recruitment Status : Completed
First Posted : February 21, 2020
Last Update Posted : July 8, 2020
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information
First Submitted Date  ICMJE February 20, 2020
First Posted Date  ICMJE February 21, 2020
Last Update Posted Date July 8, 2020
Actual Study Start Date  ICMJE February 21, 2020
Actual Primary Completion Date May 21, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 16, 2020)
Time to recovery [ Time Frame: Day 1 through Day 29 ]
Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: 1) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Not hospitalized, no limitations on activities.
Original Primary Outcome Measures  ICMJE
 (submitted: February 20, 2020)
Percentage of subjects reporting each severity rating on the 7-point ordinal scale [ Time Frame: Day 15 ]
The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 16, 2020)
  • Change from baseline in alanine transaminase (ALT) [ Time Frame: Day 1 through Day 29 ]
  • Change from baseline in aspartate transaminase (AST) [ Time Frame: Day 1 through Day 29 ]
  • Change from baseline in creatinine [ Time Frame: Day 1 through Day 29 ]
  • Change from baseline in glucose [ Time Frame: Day 1 through Day 29 ]
  • Change from baseline in hemoglobin [ Time Frame: Day 1 through Day 29 ]
  • Change from baseline in platelets [ Time Frame: Day 1 through Day 29 ]
  • Change from baseline in prothrombin time (PT) [ Time Frame: Day 1 through Day 29 ]
  • Change from baseline in total bilirubin [ Time Frame: Day 1 through Day 29 ]
  • Change from baseline in white blood cell count (WBC) with differential [ Time Frame: Day 1 through Day 29 ]
  • Change in National Early Warning Score (NEWS) from baseline [ Time Frame: Day 1 through Day 29 ]
    The NEW score has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is based on 7 clinical parameters (respiration rate, oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness). The NEW Score is being used as an efficacy measure.
  • Clinical status using ordinal scale [ Time Frame: Day 3 through Day 29 ]
    The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.
  • Cumulative incidence of Grade 3 and 4 clinical and/or laboratory adverse events (AEs) [ Time Frame: Day 1 through Day 29 ]
    Grade 3 AEs are defined as events that interrupt usual activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention. Severe events are usually incapacitating. Grade 4 AEs are defined as events that are potentially life threatening.
  • Cumulative incidence of serious adverse events (SAEs) [ Time Frame: Day 1 through Day 29 ]
    An SAE is defined as an AE or suspected adverse reaction is considered serious if, in the view of either the investigator or the sponsor, it results in death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect.
  • Discontinuation or temporary suspension of investigational therapeutics [ Time Frame: Day 1 through Day 10 ]
    For any reason.
  • Duration of hospitalization [ Time Frame: Day 1 through Day 29 ]
    Measured in days.
  • Duration of new non-invasive ventilation or high flow oxygen use [ Time Frame: Day 1 through Day 29 ]
    Measured in days.
  • Duration of new oxygen use [ Time Frame: Day 1 through Day 29 ]
    Measured in days.
  • Duration of new ventilator or extracorporeal membrane oxygenation (ECMO) use [ Time Frame: Day 1 through Day 29 ]
    Measured in days.
  • Incidence of new non-invasive ventilation or high flow oxygen use [ Time Frame: Day 1 through Day 29 ]
  • Incidence of new oxygen use [ Time Frame: Day 1 through Day 29 ]
  • Incidence of new ventilator or extracorporeal membrane oxygenation (ECMO) use [ Time Frame: Day 1 through Day 29 ]
  • Mean change in the ordinal scale [ Time Frame: Day 1 through Day 29 ]
    The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.
  • Percentage of subjects reporting each severity rating on an 8-point ordinal scale [ Time Frame: Day 15 ]
    The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.
  • Subject 14-day mortality [ Time Frame: Day 1 through Day 15 ]
    Date and cause of death (if applicable).
  • Subject 29-day mortality [ Time Frame: Day 1 through Day 29 ]
    Date and cause of death (if applicable).
  • Time to an improvement of one category using an ordinal scale [ Time Frame: Day 1 through Day 29 ]
    The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.
  • Time to an improvement of two categories using an ordinal scale [ Time Frame: Day 1 through Day 29 ]
    The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.
  • Time to discharge or to a National Early Warning Score (NEWS) of </= 2 and maintained for 24 hours, whichever occurs first [ Time Frame: Day 1 through Day 29 ]
    The NEW score has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is based on 7 clinical parameters (respiration rate, oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness). The NEW Score is being used as an efficacy measure.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 20, 2020)
  • Change from baseline in alanine transaminase (ALT) [ Time Frame: Day 1 through Day 29 ]
  • Change from baseline in aspartate transaminase (AST) [ Time Frame: Day 1 through Day 29 ]
  • Change from baseline in creatinine [ Time Frame: Day 1 through Day 29 ]
  • Change from baseline in glucose [ Time Frame: Day 1 through Day 29 ]
  • Change from baseline in hemoglobin [ Time Frame: Day 1 through Day 29 ]
  • Change from baseline in platelets [ Time Frame: Day 1 through Day 29 ]
  • Change from baseline in total bilirubin [ Time Frame: Day 1 through Day 29 ]
  • Change from baseline in white blood cell count [ Time Frame: Day 1 through Day 29 ]
  • Change in National Early Warning Score (NEWS) from baseline [ Time Frame: Day 3 through Day 29 ]
    The NEW score has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is based on 7 clinical parameters (respiration rate, oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness). The NEW Score is being used as an efficacy measure.
  • Cumulative incidence of serious adverse events (SAEs) [ Time Frame: Day 1 through Day 29 ]
    An SAE is defined as an AE or suspected adverse reaction is considered serious if, in the view of either the investigator or the sponsor, it results in death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect.
  • Cumulative incidence of severe adverse events (AEs) [ Time Frame: Day 1 through Day 29 ]
    Severe AEs include Grade 3 and 4 AEs. Grade 3 AEs are defined as events that interrupt usual activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention. Severe events are usually incapacitating. Grade 4 AEs are defined as events that are potentially life threatening.
  • Discontinuation temporary suspension of infusions [ Time Frame: Day 1 through Day 29 ]
    For any reason.
  • Duration of hospitalization [ Time Frame: Day 1 through Day 29 ]
    Measured in days.
  • Duration of new mechanical ventilation [ Time Frame: Day 1 through Day 29 ]
  • Duration of new oxygen use [ Time Frame: Day 1 through Day 29 ]
  • Incidence of new mechanical ventilation [ Time Frame: Day 1 through Day 29 ]
  • Incidence of new oxygen use [ Time Frame: Day 1 through Day 29 ]
  • Mean change in the ordinal scale from baseline [ Time Frame: Day 3 through Day 29 ]
    The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities.
  • Number of oxygenation free days [ Time Frame: Day 1 to Day 29 ]
  • Number of ventilator free days [ Time Frame: Day 1 to Day 29 ]
  • Subject clinical status using ordinal scale [ Time Frame: Day 3 through Day 29 ]
    The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities.
  • Subject mortality [ Time Frame: Day 1 through Day 29 ]
    Date and cause of death (if applicable).
  • Time to an improvement of one category from admission using an ordinal scale [ Time Frame: Day 1 through Day 29 ]
    The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities.
  • Time to discharge or to a National Early Warning Score (NEWS) of </= 2 and maintained for 24 hours, whichever occurs first [ Time Frame: Day 1 through Day 29 ]
    The NEW score has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is based on 7 clinical parameters (respiration rate, oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness). The NEW Score is being used as an efficacy measure.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Adaptive COVID-19 Treatment Trial (ACTT)
Official Title  ICMJE A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Adults
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE COVID-19
Intervention  ICMJE
  • Other: Placebo
    The supplied placebo lyophilized formulation is identical in physical appearance to the active lyophilized formulation and contains the same inactive ingredients. Alternatively, a placebo of normal saline of equal volume may be given if there are limitations on matching placebo supplies.
  • Drug: Remdesivir
    Drug Remdesivir is a single diastereomer monophosphoramidate prodrug designed for the intracellular delivery of a modified adenine nucleoside analog GS-441524. In addition to the active ingredient, the lyophilized formulation of Remdesivir contains the following inactive ingredients: water for injection, sulfobutylether beta-cyclodextrin sodium (SBECD), and hydrochloric acid and/or sodium hydroxide.
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    200 mg of Remdesivir placebo administered intravenously on Day 1, followed by a 100 mg once-daily maintenance dose of Remdesivir placebo while hospitalized for up to a 10 days total course. n=286.
    Intervention: Other: Placebo
  • Experimental: Remdesivir
    200 mg of Remdesivir administered intravenously on Day 1, followed by a 100 mg once-daily maintenance dose of Remdesivir while hospitalized for up to a 10 days total course. n=286.
    Intervention: Drug: Remdesivir
Publications * 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, Fätkenheuer 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 - Preliminary Report. N Engl J Med. 2020 May 22. doi: 10.1056/NEJMoa2007764. [Epub ahead of print]

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 7, 2020)
1062
Original Estimated Enrollment  ICMJE
 (submitted: February 20, 2020)
394
Actual Study Completion Date  ICMJE May 21, 2020
Actual Primary Completion Date May 21, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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:

    • 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.
  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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 99 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Denmark,   Germany,   Greece,   Japan,   Korea, Republic of,   Mexico,   Singapore,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04280705
Other Study ID Numbers  ICMJE 20-0006
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institute of Allergy and Infectious Diseases (NIAID)
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account National Institute of Allergy and Infectious Diseases (NIAID)
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP