Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Adaptive COVID-19 Treatment Trial 4 (ACTT-4)

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04640168
Recruitment Status : Recruiting
First Posted : November 23, 2020
Last Update Posted : March 26, 2021
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:
ACTT-4 will evaluate the combination of baricitinib and remdesivir compared to dexamethasone and remdesivir. 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, oropharyngeal (OP) swabs, plasma (Day 29), and serum for secondary research as well as clinical outcome data. However, if infection control or other restrictions limit the ability of the subject to return to the clinic, 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 objective is to evaluate the clinical efficacy of baricitinib + remdesivir versus dexamethasone + remdesivir as assessed by the mechanical ventilation free survival by Day 29.

Condition or disease Intervention/treatment Phase
COVID-19 Drug: Baricitinib Drug: Dexamethasone Other: Placebo Drug: Remdesivir Phase 3

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-4 will evaluate the combination of baricitinib and remdesivir compared to dexamethasone and remdesivir. 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, oropharyngeal (OP) swabs, plasma (Day 29), and serum for secondary research as well as clinical outcome data. However, if infection control or other restrictions limit the ability of the subject to return to the clinic, 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 objective is to evaluate the clinical efficacy of baricitinib + remdesivir versus dexamethasone + remdesivir as assessed by the mechanical ventilation free survival by Day 29. The key secondary objective is to evaluate the clinical efficacy of baricitinib + remdesivir versus dexamethasone + remdesivir according to clinical status (8-point ordinal scale) at Day 15.

Contacts:

20-0006 Central Contact

Telephone: 1 (301) 7617948

Email: DMIDClinicalTrials@niaid.nih.gov

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1500 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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-4)
Actual Study Start Date : November 24, 2020
Estimated Primary Completion Date : April 30, 2021
Estimated Study Completion Date : June 30, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Remdesivir plus Baricitinib
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-day total course; 4 mg of baricitinib administered as 2 tablets taken orally daily while hospitalized for up to a 14-day total course; and dexamethasone placebo administered as an intravenous injection daily while hospitalized for up to a 10-day total course.
Drug: Baricitinib
Baricitinib is a Janus kinase (JAK) inhibitor with the chemical name [1-(ethylsulfonyl)-3-(4-(7Hpyrrolo(2,3-d)pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl]acetonitrile. Each tablet contains 2 mg of baricitinib and the following inactive ingredients: croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, ferric oxide, lecithin (soya), polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.

Other: Placebo
Placebo matching oral baricitinib or intravenous dexamethasone.

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.

Experimental: Remdesivir plus Dexamethasone
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-day total course; baricitinib placebo administered as 2 tablets taken orally daily while hospitalized for up to a 14-day total course; and 6 mg of dexamethasone administered as an intravenous injection daily while hospitalized for up to a 10-day total course.
Drug: Dexamethasone
Dexamethasone Sodium Phosphate Injection, USP, is an adrenocortical steroid anti-inflammatory drug. It is a water-soluble inorganic ester of dexamethasone. Each mL contains dexamethasone sodium phosphate equivalent to dexamethasone phosphate 4 mg or dexamethasone 3.33 mg; benzyl alcohol 10 mg added as preservative; sodium citrate dihydrate 11 mg; sodium sulfite 1 mg as an antioxidant.

Other: Placebo
Placebo matching oral baricitinib or intravenous dexamethasone.

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.




Primary Outcome Measures :
  1. The proportion of subjects not meeting criteria for one of the following two ordinal scale categories at any time: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) [ Time Frame: Day 1 through Day 29 ]

Secondary Outcome Measures :
  1. Change from baseline in alanine aminotransferase (ALT) [ Time Frame: Day 1 through Day 29 ]
  2. Change from baseline in aspartate aminotransferase (AST) [ Time Frame: Day 1 through Day 29 ]
  3. Change from baseline in C-reactive protein (CRP) [ Time Frame: Day 1 through Day 29 ]
  4. Change from baseline in creatinine [ Time Frame: Day 1 through Day 29 ]
  5. Change from baseline in d-dimer concentration [ Time Frame: Day 1 through Day 29 ]
  6. Change from baseline in glucose [ Time Frame: Day 1 through Day 29 ]
  7. Change from baseline in hemoglobin [ Time Frame: Day 1 through Day 29 ]
  8. Change from baseline in platelets [ Time Frame: Day 1 through Day 29 ]
  9. Change from baseline in prothrombin time (PT) [ Time Frame: Day 1 through Day 29 ]
    Reported as international normalized ratio (INR)

  10. Change from baseline in total bilirubin [ Time Frame: Day 1 through Day 29 ]
  11. Change from baseline in white blood cell count (WBC) with differential [ Time Frame: Day 1 through Day 29 ]
  12. 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.

  13. 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.

  14. Days of invasive mechanical ventilation/ extracorporeal membrane oxygenation (ECMO) (if applicable) [ Time Frame: Day 1 through Day 29 ]
  15. Days of non-invasive ventilation/high flow oxygen (if applicable) [ Time Frame: Day 1 through Day 29 ]
  16. Days of supplemental oxygen (if applicable) [ Time Frame: Day 1 through Day 29 ]
  17. Desirability of Outcome Ranking (DOOR) [ Time Frame: Day 15 through Day 29 ]
    Desirability of Outcome Ranking (DOOR) based on ordinal scale: 1) Recovered (category 1, 2 or 3 on ordinal scale); 2) Improved (> / = 1 category improvement of ordinal scale compared with baseline) & no serious adverse event (SAE); 3) Improved (> / = 1 category improvement of the ordinal scale compared with baseline) & SAE (related or unrelated); 4) No change in ordinal scale from baseline & no SAE; 5) No change in ordinal scale from baseline & SAE (related or unrelated); 6) Worsening (> / = 1 category worse in ordinal scale from baseline); 7) Death.

  18. Duration of hospitalization [ Time Frame: Day 1 through Day 29 ]
    Measured in days.

  19. Incidence of discontinuation or temporary suspension of study product administration [ Time Frame: Day 1 through Day 10 ]
    For any reason.

  20. Subject 14-day mortality [ Time Frame: Day 1 through Day 15 ]
    Date of death (if applicable).

  21. Subject 28-day mortality [ Time Frame: Day 1 through Day 29 ]
    Date of death (if applicable).

  22. Subject clinical status [ Time Frame: Days 3, 5, 8, 11, 15, 22, and 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: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or ECMO; 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, but has new or increased limitation on activities and/or new or increased requirement for home oxygen over baseline, pre-COVID-19 status; 1) Not hospitalized, patient is back to their baseline, pre-COVID-19 status, that is, no new or increased limitations on activities and no new or increased oxygen use.

  23. The proportion of subjects meeting criteria for one of the 8 ordinal scale categories [ Time Frame: Day 15 ]
    The ordinal scale categories are defined as: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or ECMO; 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, but has new or increased limitation on activities and/or new or increased requirement for home oxygen over baseline, pre-COVID-19 status; 1) Not hospitalized, patient is back to their baseline, pre-COVID-19 status, that is, no new or increased limitations on activities and no new or increased oxygen use.

  24. Time to an improvement of one category from baseline 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: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or ECMO; 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, but has new or increased limitation on activities and/or new or increased requirement for home oxygen over baseline, pre-COVID-19 status; 1) Not hospitalized, patient is back to their baseline, pre-COVID-19 status, that is, no new or increased limitations on activities and no new or increased oxygen use.

  25. Time to an improvement of two categories from baseline 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: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or ECMO; 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, but has new or increased limitation on activities and/or new or increased requirement for home oxygen over baseline, pre-COVID-19 status; 1) Not hospitalized, patient is back to their baseline, pre-COVID-19 status, that is, no new or increased limitations on activities and no new or increased oxygen use.

  26. 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 ordinal scale categories: 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care; 2) Not hospitalized, but has new or increased limitation on activities and/or new or increased requirement for home oxygen over baseline, pre-COVID-19 status; 1) Not hospitalized, patient is back to their baseline, pre-COVID-19 status, that is, no new or increased limitations on activities and no new or increased oxygen use.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Hospitalized with symptoms suggestive of COVID-19.
  2. Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures and understands and agrees to comply with planned study procedures.
  3. Male or non-pregnant female adult > / = 18 years of age at time of enrollment.
  4. Illness of any duration and has laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR) or other commercial or public health assay (e.g. NAAT, antigen test) in any respiratory specimen or saliva < / = 14 days prior to randomization.
  5. Within the 7 days prior to randomization requiring new use of supplemental oxygen (or increased oxygen requirement if on chronic oxygen) and requires at the time of randomization low or high flow oxygen devices or use of non-invasive mechanical ventilation (ordinal scale category 5 or 6).
  6. 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.
  7. Agrees not to participate in another blinded clinical trial (both pharmacologic and other types of interventions) for the treatment of COVID-19 through Day 29.

Exclusion Criteria:

  1. Prior enrollment in ACTT-3 or ACTT-4.
  2. On invasive mechanical ventilation at the time of randomization (ordinal scale category 7).
  3. Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours of randomization.
  4. Positive test for influenza virus during the current illness (influenza testing is not required by protocol).
  5. Subjects with a low glomerular filtration rate (eGFR), specifically:

    1. Subjects with an eGFR 20-30 mL/min are excluded unless in the opinion of the PI, the potential benefit of participation outweighs the potential risk of study participation.
    2. All subjects with an eGFR <20 mL/min (including hemodialysis and hemofiltration) are excluded.
  6. Neutropenia (absolute neutrophil count <700 cells/microliter, 0.7 x 10^3/microliter).
  7. Lymphopenia (absolute lymphocyte count <200 cells/microliter, 0.20 x 10^3/microliter).
  8. Received five or more doses of remdesivir including the loading dose, outside of the study as treatment for COVID-19.
  9. Pregnancy or breast feeding (lactating women who agree to discard breast milk from Day 1 until two weeks after the last study product is given are not excluded).
  10. Allergy to any study medication.
  11. Received convalescent plasma or intravenous immunoglobulin [IVIg] for COVID-19, the current illness for which they are being enrolled.
  12. Received any of the following in the two weeks prior to screening as treatment of COVID-19:

    • small molecule tyrosine kinase inhibitors (e.g. baricitinib, imatinib, gefitinib, acalabrutinib, etc.);
    • monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab], etc.);
    • monoclonal antibodies targeting T-cells or B-cells as treatment for COVID-19.
  13. Use of probenecid that cannot be discontinued at study enrollment.
  14. Received more than one dose of dexamethasone 6 mg or larger (or equivalent for other glucocorticoids) in the 7 days prior to time of randomization. Note: total daily dose equivalents include 40 mg prednisone, 32 mg methylprednisolone and 160 mg hydrocortisone.
  15. Received > / = 20 mg/day of prednisone (or equivalent for other glucocorticoids) for > / = 14 consecutive days in the 4 weeks prior to screening.
  16. Have diagnosis of current active or latent tuberculosis (TB), if known, treated for less than 4 weeks with appropriate therapy (by history only, no screening required).
  17. Serious infection (besides COVID-19), immunosuppressive state, or immunosuppressive medications that in the opinion of the investigator could constitute a risk when taking baricitinib or dexamethasone.
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04640168


Contacts
Layout table for location contacts
Contact: 20-0006 Central Contact 13017617948 DMIDClinicalTrials@niaid.nih.gov

Locations
Show Show 72 study locations
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Layout table for additonal information
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT04640168    
Other Study ID Numbers: 20-0006 ACTT-4
First Posted: November 23, 2020    Key Record Dates
Last Update Posted: March 26, 2021
Last Verified: November 2020

Layout table for additional information
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
Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
ACTT
Adaptive
COVID-19
Efficacy
Multicenter
novel coronavirus
Safety
Additional relevant MeSH terms:
Layout table for MeSH terms
Dexamethasone
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents