Brief Summary
This study looks at the safety and effectiveness of different drugs in treating COVID-19 in people who have been hospitalized with the infection. Participants in the study will be treated with either a study drug plus current standard of care (SOC), or with placebo plus current SOC.
Brief Title
ACTIV-3: Therapeutics for Inpatients With COVID-19
Detailed Description
This is a master protocol to evaluate the safety and efficacy of multiple investigational agents aimed at modifying the host immune response to SARS-CoV-2 infection, or directly enhancing viral control in order to limit disease progression.
The protocol is for a randomized, blinded, controlled platform study that allows investigational drugs to be added and dropped during the course of the study. This allows for efficient testing of new drugs against placebo and standard of care (SOC) treatment within the same study. When more than one drug is being tested at the same time, participants will be randomly allocated to treatments or placebo.
Randomization will be stratified by study site pharmacy and disease severity. There are 2 disease severity strata: Participants without organ failure (severity stratum 1); and participants with organ failure (severity stratum 2).
An independent Data and Safety Monitoring Board (DSMB) will regularly review interim analyses and summarize safety and efficacy outcomes. For investigational drugs with minimal pre-existing safety knowledge, the pace of enrollment with be initially restricted, and there will be an early review of safety data by the DSMB. For the study of each agent, at the outset of the trial, only participants in disease severity stratum 1 will be enrolled. This will continue until approximately 300 participants are enrolled and followed for 5 days. The exact number will vary according to the speed of enrollment and the timing of DSMB meetings. Prior to expanding enrollment to also include patients in disease severity stratum 2, safety will be evaluated and a pre-specified futility assessment by the DSMB will be carried out using 2 ordinal outcomes assessed at Day 5.
Both ordinal outcomes are used to assess futility because it is currently unclear whether the investigational agents under study will primarily influence non-pulmonary outcomes, for which risk is increased with SARS-CoV-2 infection, in part, through mechanisms that may be different from those that influence pulmonary outcomes.
For investigational agents passing this futility assessment, enrollment of participants will be expanded, seamlessly and without any data unblinding, to include participants in disease severity stratum 2 as well as those in disease severity stratum 1. Future interim analyses will be based on the primary endpoint of sustained recovery and will use pre-specified guidelines to determine early evidence of benefit, harm or futility for the investigational agent. Participants will be followed for 18 months following randomization.
The international trials within this protocol will be conducted in several hundred clinical sites. Participating sites are affiliated with networks funded by the United States National Institutes of Health (NIH) and the US Department of Veterans Affairs.
The protocol is for a randomized, blinded, controlled platform study that allows investigational drugs to be added and dropped during the course of the study. This allows for efficient testing of new drugs against placebo and standard of care (SOC) treatment within the same study. When more than one drug is being tested at the same time, participants will be randomly allocated to treatments or placebo.
Randomization will be stratified by study site pharmacy and disease severity. There are 2 disease severity strata: Participants without organ failure (severity stratum 1); and participants with organ failure (severity stratum 2).
An independent Data and Safety Monitoring Board (DSMB) will regularly review interim analyses and summarize safety and efficacy outcomes. For investigational drugs with minimal pre-existing safety knowledge, the pace of enrollment with be initially restricted, and there will be an early review of safety data by the DSMB. For the study of each agent, at the outset of the trial, only participants in disease severity stratum 1 will be enrolled. This will continue until approximately 300 participants are enrolled and followed for 5 days. The exact number will vary according to the speed of enrollment and the timing of DSMB meetings. Prior to expanding enrollment to also include patients in disease severity stratum 2, safety will be evaluated and a pre-specified futility assessment by the DSMB will be carried out using 2 ordinal outcomes assessed at Day 5.
Both ordinal outcomes are used to assess futility because it is currently unclear whether the investigational agents under study will primarily influence non-pulmonary outcomes, for which risk is increased with SARS-CoV-2 infection, in part, through mechanisms that may be different from those that influence pulmonary outcomes.
For investigational agents passing this futility assessment, enrollment of participants will be expanded, seamlessly and without any data unblinding, to include participants in disease severity stratum 2 as well as those in disease severity stratum 1. Future interim analyses will be based on the primary endpoint of sustained recovery and will use pre-specified guidelines to determine early evidence of benefit, harm or futility for the investigational agent. Participants will be followed for 18 months following randomization.
The international trials within this protocol will be conducted in several hundred clinical sites. Participating sites are affiliated with networks funded by the United States National Institutes of Health (NIH) and the US Department of Veterans Affairs.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Covid19
Eligibility Criteria
Inclusion Criteria:
* Signed informed consent.
* Positive test for COVID-19 and progressive disease suggestive of ongoing COVID-19 infection.
* Symptoms of COVID-19 for ≤ 12 days.
* Require admission to hospital for acute medical care (not for purely public health or quarantine purposes).
Exclusion Criteria:
* Patients who have received plasma from a person who recovered from COVID-19 or who have received neutralizing monoclonal antibodies at any time prior to hospitalization.
* Patients not willing to abstain from participation in other COVID-19 treatment trials until after Day 5 of the study. Co-enrollment in certain trials that compare recommended Standard of Care treatments may be allowed, based on the opinion of the study leadership team.
* Any condition which, in the opinion of the responsible investigator, participation would not be in the best interest of the participant or that could prevent, limit, or confound the protocol-specified assessments.
* Patients considered unable to participate in study procedures.
* Women of child-bearing potential who are not already pregnant at study entry and who are unwilling to acknowledge strong advice to abstain from sexual intercourse with men or practice appropriate contraception through 18 months of the study.
* Women of child-bearing potential who are unwilling to acknowledge the strong advice to abstain from sexual intercourse with men or practice appropriate contraception through 5 weeks of the study (PF-07304814 investigational agent).
* Pregnant women (PF-07304814 investigational agents).
* Nursing mothers (PF-07304814 investigational agents).
* Men who are unwilling to acknowledge the strong advice to abstain from sexual intercourse with women of child-bearing potential or to use barrier contraception through 18 months of the study.
* Men who are unwilling to acknowledge the strong advice to abstain from sexual intercourse with women of child-bearing potential or to use barrier contraception through 5 weeks of the study (PF-07304814 investigational agent).
* Presence at study enrollment of any of the following:
1. stroke
2. meningitis
3. encephalitis
4. myelitis
5. myocardial ischemia
6. myocarditis
7. pericarditis
8. symptomatic congestive heart failure
9. arterial or deep venous thrombosis or pulmonary embolism
* Current or imminent requirement for any of the following:
1. invasive mechanical ventilation
2. ECMO (extracorporeal membrane oxygenation)
3. Mechanical circulatory support
4. vasopressor therapy
5. commencement of renal replacement therapy at this admission (i.e. not patients on chronic renal replacement therapy).
* Participants with moderate to severe hepatic impairment (i.e. Child-Pugh class B or C) or acute liver failure (PF-07304814 investigational agent).
* Participants receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450 (CYP) 3A4 (PF-07304814 investigational agent).
* Patients will be excluded if taking drugs which have a narrow therapeutic window that are substrates of CYP3A4, including but not limited to: astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, pimozide, quinidine, sirolimus, tacrolimus, and terfenadine (PF-07304814 investigational agent).
* Patients with a history of deep vein thrombosis or pulmonary thrombotic embolism (Prior to initial futility assessment of PF-07304814 investigational agent).
* Signed informed consent.
* Positive test for COVID-19 and progressive disease suggestive of ongoing COVID-19 infection.
* Symptoms of COVID-19 for ≤ 12 days.
* Require admission to hospital for acute medical care (not for purely public health or quarantine purposes).
Exclusion Criteria:
* Patients who have received plasma from a person who recovered from COVID-19 or who have received neutralizing monoclonal antibodies at any time prior to hospitalization.
* Patients not willing to abstain from participation in other COVID-19 treatment trials until after Day 5 of the study. Co-enrollment in certain trials that compare recommended Standard of Care treatments may be allowed, based on the opinion of the study leadership team.
* Any condition which, in the opinion of the responsible investigator, participation would not be in the best interest of the participant or that could prevent, limit, or confound the protocol-specified assessments.
* Patients considered unable to participate in study procedures.
* Women of child-bearing potential who are not already pregnant at study entry and who are unwilling to acknowledge strong advice to abstain from sexual intercourse with men or practice appropriate contraception through 18 months of the study.
* Women of child-bearing potential who are unwilling to acknowledge the strong advice to abstain from sexual intercourse with men or practice appropriate contraception through 5 weeks of the study (PF-07304814 investigational agent).
* Pregnant women (PF-07304814 investigational agents).
* Nursing mothers (PF-07304814 investigational agents).
* Men who are unwilling to acknowledge the strong advice to abstain from sexual intercourse with women of child-bearing potential or to use barrier contraception through 18 months of the study.
* Men who are unwilling to acknowledge the strong advice to abstain from sexual intercourse with women of child-bearing potential or to use barrier contraception through 5 weeks of the study (PF-07304814 investigational agent).
* Presence at study enrollment of any of the following:
1. stroke
2. meningitis
3. encephalitis
4. myelitis
5. myocardial ischemia
6. myocarditis
7. pericarditis
8. symptomatic congestive heart failure
9. arterial or deep venous thrombosis or pulmonary embolism
* Current or imminent requirement for any of the following:
1. invasive mechanical ventilation
2. ECMO (extracorporeal membrane oxygenation)
3. Mechanical circulatory support
4. vasopressor therapy
5. commencement of renal replacement therapy at this admission (i.e. not patients on chronic renal replacement therapy).
* Participants with moderate to severe hepatic impairment (i.e. Child-Pugh class B or C) or acute liver failure (PF-07304814 investigational agent).
* Participants receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450 (CYP) 3A4 (PF-07304814 investigational agent).
* Patients will be excluded if taking drugs which have a narrow therapeutic window that are substrates of CYP3A4, including but not limited to: astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, pimozide, quinidine, sirolimus, tacrolimus, and terfenadine (PF-07304814 investigational agent).
* Patients with a history of deep vein thrombosis or pulmonary thrombotic embolism (Prior to initial futility assessment of PF-07304814 investigational agent).
Inclusion Criteria
Inclusion Criteria:
* Signed informed consent.
* Positive test for COVID-19 and progressive disease suggestive of ongoing COVID-19 infection.
* Symptoms of COVID-19 for ≤ 12 days.
* Require admission to hospital for acute medical care (not for purely public health or quarantine purposes).
* Signed informed consent.
* Positive test for COVID-19 and progressive disease suggestive of ongoing COVID-19 infection.
* Symptoms of COVID-19 for ≤ 12 days.
* Require admission to hospital for acute medical care (not for purely public health or quarantine purposes).
Gender
All
Gender Based
false
Keywords
COVID-19
COVID 19
Coronaviridae Infections
Coronavirus Infections
RNA Virus Infections
Virus Diseases
Nidovirales Infections
SARS-CoV-2
SARS Coronavirus
ACTIV-3
ACTIV3
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT04501978
Org Class
Nih
Org Full Name
National Institute of Allergy and Infectious Diseases (NIAID)
Org Study Id
014 / ACTIV-3
Overall Status
Completed
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Multicenter, Adaptive, Randomized, Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for Hospitalized Patients With COVID-19
Primary Outcomes
Outcome Description
Sustained recovery defined as being discharged from the index hospitalization, followed by being alive and home for 14 consecutive days prior to Day 90.
Outcome Measure
Time from randomization to sustained recovery
Outcome Time Frame
Up to Day 90
Secondary Outcomes
Outcome Time Frame
Thru Day 90
Outcome Measure
All-cause mortality
Outcome Time Frame
Thru Day 90
Outcome Measure
Composite of time to sustained recovery and mortality
Outcome Time Frame
Up to Day 90
Outcome Measure
Days alive outside short-term acute care hospital
Outcome Description
Oxygen requirements measured by 7 categories (1 = least severe, 7 = most severe). The participant's highest (i.e. most severe) observed score is used.
Outcome Time Frame
Days 1-7, 14 and 28
Outcome Measure
Pulmonary ordinal outcome
Outcome Description
Extrapulmonary complications and respiratory dysfunction measured by 7 categories (1= least severe, 7 = most severe). The participant's highest (i.e. most severe) observed score is used.
Outcome Time Frame
Days 1-7
Outcome Measure
Pulmonary+ ordinal outcome
Outcome Time Frame
Thru Day 28
Outcome Measure
Incidence of clinical organ failure
Outcome Time Frame
Thru Day 90
Outcome Measure
Composite of death or serious clinical COVID-19 related events
Outcome Time Frame
Thru Day 90
Outcome Measure
Composite of cardiovascular events and thromboembolic events
Outcome Time Frame
Thru Days 5 and 28
Outcome Measure
Composite of grade 3 and 4 clinical adverse events, serious adverse events (SAEs) or death
Outcome Time Frame
Thru Day 0
Outcome Measure
Incidence of infusion reactions
Outcome Time Frame
Thru 18 months
Outcome Measure
Composite of SAEs or death
Outcome Time Frame
Baseline to Days 1, 3, 5, 28 and 90
Outcome Measure
Change in SARS-CoV-2 neutralizing antibody levels
Outcome Time Frame
Baseline to Days 1, 3, 5, 28 and 90
Outcome Measure
Change in overall titers of antibodies
Outcome Time Frame
Baseline to Days 1, 3, 5, 28 and 90
Outcome Measure
Change in neutralizing antibody levels
Outcome Description
Measured as: Alive at home and no use of continuous supplemental oxygen for an uninterrupted 14 day period
Outcome Time Frame
18 months
Outcome Measure
Incidence of home use of supplemental oxygen above pre-morbid oxygen use
Outcome Description
Measured as: Alive at home for an uninterrupted 14 day period and no use of continuous supplemental oxygen at end of 14 day time period.
Outcome Time Frame
14 days
Outcome Measure
Incidence of no home use of supplemental oxygen above pre-morbid oxygen use
See Also Links
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Michelle Gong
Investigator Email
mgong@montefiore.org
Investigator Phone
718-920-5464
Categories Mesh Debug
COVID-19 --- COVID-19
COVID-19 --- CORONAVIRIDAE INFECTIONS
COVID-19 --- CORONAVIRUS INFECTIONS
COVID-19 --- RNA VIRUS INFECTIONS
Infectious Disease --- RNA VIRUS INFECTIONS
COVID-19 --- VIRUS DISEASES
Hepatitis --- VIRUS DISEASES
Infectious Disease --- VIRUS DISEASES
COVID-19 --- NIDOVIRALES INFECTIONS
COVID-19 --- PNEUMONIA, VIRAL
COVID-19 --- PNEUMONIA
Lung --- PNEUMONIA
COVID-19 --- RESPIRATORY TRACT INFECTIONS
Lung --- RESPIRATORY TRACT INFECTIONS
COVID-19 --- INFECTIONS
Infectious Disease --- INFECTIONS
Lung & Chest Cancers --- LUNG DISEASES
COVID-19 --- LUNG DISEASES
Lung --- LUNG DISEASES
Asthma and Other Respiratory Diseases --- RESPIRATORY TRACT DISEASES
Lung & Chest Cancers --- RESPIRATORY TRACT DISEASES
COVID-19 --- RESPIRATORY TRACT DISEASES
Lung --- RESPIRATORY TRACT DISEASES
MeSH Terms
COVID-19
CORONAVIRIDAE INFECTIONS
CORONAVIRUS INFECTIONS
RNA VIRUS INFECTIONS
VIRUS DISEASES
NIDOVIRALES INFECTIONS
SEVERE ACUTE RESPIRATORY SYNDROME
PNEUMONIA, VIRAL
PNEUMONIA
RESPIRATORY TRACT INFECTIONS
INFECTIONS
LUNG DISEASES
RESPIRATORY TRACT DISEASES
BAMLANIVIMAB
COUNTERFEIT DRUGS
REMDESIVIR
SOTROVIMAB
CILGAVIMAB AND TIXAGEVIMAB DRUG COMBINATION
ENSOVIBEP
LUFOTRELVIR
SUBSTANDARD DRUGS
PHARMACEUTICAL PREPARATIONS