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 and who have acute respiratory failure. 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-3b: Therapeutics for Severely Ill Inpatients With COVID-19
Detailed Description
This is a master protocol to evaluate the safety and efficacy of investigational agents aimed at improving outcomes for patients with acute respiratory failure related to COVID-19.
Trials within this protocol will be adaptive, randomized, blinded and initially placebo-controlled. Participants will receive standard of care (SOC) treatment as part of the protocol. If an investigational agent shows superiority over placebo, SOC for the study of future investigational agents may be modified accordingly.
The international trials within this protocol will be conducted in up to 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 phase III 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 control within the same trial infrastructure. When more than one agent is being tested concurrently, participants may be randomly allocated across agents (as well as between the agent and its placebo) so the same control group can be shared, when feasible. In some situations, a factorial design may be used to study multiple agents.
Participants will be followed for 90 days following randomization for the primary endpoint and most secondary endpoints. Selected secondary endpoints will be measured at 180 days.
This study is planned to provide 80% power to detect an odds ratio of 1.5 for improvement in recovery status at Day 90 for an investigational agent versus placebo with use of the ordinal outcome. The planned sample size is 640 participants (320 per group) for each investigational agent/placebo. Sample size may be re-estimated before enrollment is complete based on an assessment of whether the pooled proportions of the outcome are still consistent with adequate power for the hypothesized difference measured by the odds ratio.
Randomization will be stratified by study site pharmacy and by receipt of invasive mechanical ventilation, or ECMO at enrollment. Other agent-specific stratification factors may be considered.
Investigational agents suitable for testing in the inpatient setting will be prioritized based on in vitro data, preclinical data, phase I pharmacokinetic and safety data, and clinical data from completed and ongoing trials. In some cases, a vanguard cohort/initial pilot phase may be incorporated into the trial.
An independent Data and Safety Monitoring Board (DSMB) will review interim safety and efficacy data at least monthly. Pre-specified guidelines will be established to recommend early stopping of the trial for evidence of harm or substantial efficacy. The DSMB may recommend discontinuation of an investigational agent if the risks are judged to outweigh the benefits.
Trials within this protocol will be adaptive, randomized, blinded and initially placebo-controlled. Participants will receive standard of care (SOC) treatment as part of the protocol. If an investigational agent shows superiority over placebo, SOC for the study of future investigational agents may be modified accordingly.
The international trials within this protocol will be conducted in up to 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 phase III 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 control within the same trial infrastructure. When more than one agent is being tested concurrently, participants may be randomly allocated across agents (as well as between the agent and its placebo) so the same control group can be shared, when feasible. In some situations, a factorial design may be used to study multiple agents.
Participants will be followed for 90 days following randomization for the primary endpoint and most secondary endpoints. Selected secondary endpoints will be measured at 180 days.
This study is planned to provide 80% power to detect an odds ratio of 1.5 for improvement in recovery status at Day 90 for an investigational agent versus placebo with use of the ordinal outcome. The planned sample size is 640 participants (320 per group) for each investigational agent/placebo. Sample size may be re-estimated before enrollment is complete based on an assessment of whether the pooled proportions of the outcome are still consistent with adequate power for the hypothesized difference measured by the odds ratio.
Randomization will be stratified by study site pharmacy and by receipt of invasive mechanical ventilation, or ECMO at enrollment. Other agent-specific stratification factors may be considered.
Investigational agents suitable for testing in the inpatient setting will be prioritized based on in vitro data, preclinical data, phase I pharmacokinetic and safety data, and clinical data from completed and ongoing trials. In some cases, a vanguard cohort/initial pilot phase may be incorporated into the trial.
An independent Data and Safety Monitoring Board (DSMB) will review interim safety and efficacy data at least monthly. Pre-specified guidelines will be established to recommend early stopping of the trial for evidence of harm or substantial efficacy. The DSMB may recommend discontinuation of an investigational agent if the risks are judged to outweigh the benefits.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Covid19
Eligibility Criteria
Inclusion Criteria:
* Signed informed consent.
* Requiring admission to hospital for acute medical care (not for purely public health or quarantine purposes).
* Current respiratory failure (i.e. receipt of high-flow nasal cannula, non-invasive ventilation, invasive mechanical ventilation, or ECMO (extracorporeal membrane oxygenation) used to treat acute hypoxemic respiratory failure).
* SARS-CoV-2 (COVID-19) infection, documented by a nucleic acid test (NAT) or equivalent testing with most recent rest within 14 days prior to randomization.
* Respiratory failure is believed to be due to SARS-CoV-2 pneumonia.
Exclusion Criteria:
* Known allergy to investigational agent or vehicle.
* More than 4 days since initiation of support for respiratory failure.
* Chronic/home mechanical ventilation (invasive or non-invasive) for chronic lung or neuromuscular disease (non-invasive ventilation used solely for sleep-disordered breathing is not an exclusion).
* Moribund patient (i.e. not expected to survive 24 hours).
* Active use of "comfort care" or other hospice-equivalent standard of care.
* Expected inability to participate in study procedures.
* In the opinion of the investigator, any condition for which, participation would not be in the best interest of the participant or that could limit protocol-specified assessments.
* Previous enrollment in TESICO
Agent-specific exclusion criteria
* Prior receipt of any dose of remdesivir during present illness (remdesivir agent).
* GFR (glomerular filtration rate) \< 30 ml/min and not receiving dialysis (remdesivir agent).
* ALT (alanine aminotransferase) or AST (aspartate aminotransferase) \> 10 times upper limit of normal (remdesivir agent).
* Unwillingness to commit to avoid sex that may result in pregnancy for at least 7 days after completion of remdesivir vs. placebo (remdesivir agent).
* Refractory hypotension (aviptadil agent).
* Severe diarrhea (Aviptadil agent).
* Current C. difficile infection (aviptadil agent).
* Pregnancy or current breast-feeding (aviptadil agent).
* End-stage liver disease (aviptadil agent).
* Signed informed consent.
* Requiring admission to hospital for acute medical care (not for purely public health or quarantine purposes).
* Current respiratory failure (i.e. receipt of high-flow nasal cannula, non-invasive ventilation, invasive mechanical ventilation, or ECMO (extracorporeal membrane oxygenation) used to treat acute hypoxemic respiratory failure).
* SARS-CoV-2 (COVID-19) infection, documented by a nucleic acid test (NAT) or equivalent testing with most recent rest within 14 days prior to randomization.
* Respiratory failure is believed to be due to SARS-CoV-2 pneumonia.
Exclusion Criteria:
* Known allergy to investigational agent or vehicle.
* More than 4 days since initiation of support for respiratory failure.
* Chronic/home mechanical ventilation (invasive or non-invasive) for chronic lung or neuromuscular disease (non-invasive ventilation used solely for sleep-disordered breathing is not an exclusion).
* Moribund patient (i.e. not expected to survive 24 hours).
* Active use of "comfort care" or other hospice-equivalent standard of care.
* Expected inability to participate in study procedures.
* In the opinion of the investigator, any condition for which, participation would not be in the best interest of the participant or that could limit protocol-specified assessments.
* Previous enrollment in TESICO
Agent-specific exclusion criteria
* Prior receipt of any dose of remdesivir during present illness (remdesivir agent).
* GFR (glomerular filtration rate) \< 30 ml/min and not receiving dialysis (remdesivir agent).
* ALT (alanine aminotransferase) or AST (aspartate aminotransferase) \> 10 times upper limit of normal (remdesivir agent).
* Unwillingness to commit to avoid sex that may result in pregnancy for at least 7 days after completion of remdesivir vs. placebo (remdesivir agent).
* Refractory hypotension (aviptadil agent).
* Severe diarrhea (Aviptadil agent).
* Current C. difficile infection (aviptadil agent).
* Pregnancy or current breast-feeding (aviptadil agent).
* End-stage liver disease (aviptadil agent).
Inclusion Criteria
Inclusion Criteria:
* Signed informed consent.
* Requiring admission to hospital for acute medical care (not for purely public health or quarantine purposes).
* Current respiratory failure (i.e. receipt of high-flow nasal cannula, non-invasive ventilation, invasive mechanical ventilation, or ECMO (extracorporeal membrane oxygenation) used to treat acute hypoxemic respiratory failure).
* SARS-CoV-2 (COVID-19) infection, documented by a nucleic acid test (NAT) or equivalent testing with most recent rest within 14 days prior to randomization.
* Respiratory failure is believed to be due to SARS-CoV-2 pneumonia.
* Signed informed consent.
* Requiring admission to hospital for acute medical care (not for purely public health or quarantine purposes).
* Current respiratory failure (i.e. receipt of high-flow nasal cannula, non-invasive ventilation, invasive mechanical ventilation, or ECMO (extracorporeal membrane oxygenation) used to treat acute hypoxemic respiratory failure).
* SARS-CoV-2 (COVID-19) infection, documented by a nucleic acid test (NAT) or equivalent testing with most recent rest within 14 days prior to randomization.
* Respiratory failure is believed to be due to SARS-CoV-2 pneumonia.
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
NCT04843761
Org Class
Nih
Org Full Name
National Institute of Allergy and Infectious Diseases (NIAID)
Org Study Id
015 / ACTIV-3b
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 Acute Respiratory Distress Syndrome Associated With COVID-19
Primary Outcomes
Outcome Description
Recovery categorized as 1 (Best): At home and not receiving new supplemental oxygen for ≥ 77 consecutive days; 2: At home and not receiving new supplemental oxygen for 49-76 consecutive days; 3: At home and not receiving new supplemental oxygen for 1-48 consecutive days; 4: Discharged from hospital but either not yet home or home but receiving new supplemental oxygen; 5: Still hospitalized or receiving hospice care; 6 (Worst): Dead.
Outcome Measure
Recovery, assessed at 90 days
Outcome Time Frame
Thru Day 90
Secondary Outcomes
Outcome Time Frame
Thru Day 90
Outcome Measure
All-cause mortality
Outcome Time Frame
Thru Day 90
Outcome Measure
Time to death
Outcome Description
Measured in number of days
Outcome Time Frame
Thru Day 90
Outcome Measure
Composite of time to recovery, days at home off new supplemental oxygen and time to death
Outcome Time Frame
Thru Day 90
Outcome Measure
Composite of alive, at home and off new supplemental oxygen
Outcome Description
Recovery defined as alive, at home and off new supplemental oxygen
Outcome Time Frame
Thru Day 90
Outcome Measure
Composite of recovered, alive and not recovered, and dead
Outcome Description
Recovery defined as alive, at home and off oxygen (treating death as competing risk)
Outcome Time Frame
Thru Day 90
Outcome Measure
Time from randomization to recovery
Outcome Description
Using "last off" method.
Outcome Time Frame
Up to Day 90
Outcome Measure
Days alive outside short-term acute care hospital
Outcome Description
Defined as any one or more of: Worsening respiratory dysfunction; cardiac and vascular dysfunction; renal dysfunction; hepatic dysfunction; neurological dysfunction, haematological dysfunction; serious infection
Outcome Time Frame
Thru Day 28
Outcome Measure
Incidence of clinical organ failure or serious infections
Outcome Time Frame
Thru Day 90
Outcome Measure
Composite of death, clinical organ failure or serious infections
Outcome Time Frame
Thru Day 28
Outcome Measure
Composite of cardiovascular events and thromboembolic 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 180
Outcome Measure
Incidence of infusion reactions
Outcome Time Frame
Thru Day 90
Outcome Measure
Percentage of participants for whom infusion was interrupted or stopped prior to completion for any reason
Outcome Time Frame
Thru Day 90
Outcome Measure
Percentage of participants for whom infusion was interrupted or stopped prior to completion due to adverse event
Outcome Time Frame
Thru Day 180
Outcome Measure
Composite of hospital readmissions or death
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
Outcome Time Frame
Thru Day 180
Outcome Measure
Time to hospital discharge from initial hospitalization
Outcome Time Frame
Thru Day 90
Outcome Measure
Composite of death or serious clinical COVID-19 related events
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 Time Frame
Thru Day 180
Outcome Measure
Composite of SAEs or death
Outcome Description
Measured as: Alive at home and no use of continuous supplemental oxygen for an uninterrupted 14 day period
Outcome Time Frame
Thru Day 180
Outcome Measure
Incidence of home use of supplemental oxygen above pre-morbid oxygen use
Outcome Description
Categories are 1 (Best): At home an off oxygen for ≥ 77 consecutive days; 2: At home and off oxygen for 49-76 consecutive days; 3: At home and off oxygen for 1-48 consecutive days; 4: Not hospitalized and either at home on oxygen or not at home; 5: Hospitalized for medical care or in hospice care; 6 (Worst): Dead.
Outcome Time Frame
Day 90
Outcome Measure
In category 4, 5 or 6 at Day 90 vs. in categories 1-3 at Day 90
Outcome Description
Categories are 1 (Best): At home an off oxygen for ≥ 77 consecutive days; 2: At home and off oxygen for 49-76 consecutive days; 3: At home and off oxygen for 1-48 consecutive days; 4: Not hospitalized and either at home on oxygen or not at home; 5: Hospitalized for medical care or in hospice care; 6 (Worst): Dead.
Outcome Time Frame
Day 90
Outcome Measure
In category 5 or 6 at Day 90 vs. in categories 1-4 at Day 90
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
REMDESIVIR
COUNTERFEIT DRUGS
AVIPTADIL
VASOACTIVE INTESTINAL PEPTIDE
ADRENAL CORTEX HORMONES
SUBSTANDARD DRUGS
PHARMACEUTICAL PREPARATIONS
GASTROINTESTINAL HORMONES
HORMONES
HORMONES, HORMONE SUBSTITUTES, AND HORMONE ANTAGONISTS
PEPTIDE HORMONES
NEUROPEPTIDES
PEPTIDES
AMINO ACIDS, PEPTIDES, AND PROTEINS
NERVE TISSUE PROTEINS
PROTEINS