ACTIV-3b: Therapeutics for Severely Ill Inpatients With COVID-19 (TESICO)
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| ClinicalTrials.gov Identifier: NCT04843761 |
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Recruitment Status :
Completed
First Posted : April 14, 2021
Last Update Posted : December 19, 2022
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Covid19 | Biological: Remdesivir Drug: Remdesivir Placebo Biological: Aviptadil Drug: Aviptadil Placebo Drug: Corticosteroid | Phase 3 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 473 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Triple (Participant, Care Provider, Investigator) |
| Primary Purpose: | Treatment |
| 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 |
| Actual Study Start Date : | April 20, 2021 |
| Actual Primary Completion Date : | August 22, 2022 |
| Actual Study Completion Date : | November 7, 2022 |
| Arm | Intervention/treatment |
|---|---|
| Experimental: Aviptadil + Remdesivir + SOC |
Biological: Remdesivir
Administered by IV infusion, daily for 10 days. Initial loading dose is 200 mg with all subsequent doses 100 mg. Biological: Aviptadil Administered by IV infusion over 12 hours per day for 3 days. Participants are no longer being randomized to this intervention.
Other Names:
Drug: Corticosteroid In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC. |
| Placebo Comparator: Aviptadil + Remdesivir Placebo + SOC |
Drug: Remdesivir Placebo
Commercially available 0.9% sodium chloride solution. Administered by IV infusion daily for 10 days. Biological: Aviptadil Administered by IV infusion over 12 hours per day for 3 days. Participants are no longer being randomized to this intervention.
Other Names:
Drug: Corticosteroid In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC. |
| Experimental: Aviptadil Placebo + Remdesivir + SOC |
Biological: Remdesivir
Administered by IV infusion, daily for 10 days. Initial loading dose is 200 mg with all subsequent doses 100 mg. Drug: Aviptadil Placebo Commercially available 0.9% sodium chloride solution. Administered by IV infusion over 12 hours per day for 3 days. Drug: Corticosteroid In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC. |
| Experimental: Aviptadil Placebo + Remdesivir Placebo + SOC |
Drug: Remdesivir Placebo
Commercially available 0.9% sodium chloride solution. Administered by IV infusion daily for 10 days. Drug: Aviptadil Placebo Commercially available 0.9% sodium chloride solution. Administered by IV infusion over 12 hours per day for 3 days. Drug: Corticosteroid In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC. |
- Recovery, assessed at 90 days [ Time Frame: Thru Day 90 ]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.
- All-cause mortality [ Time Frame: Thru Day 90 ]
- Time to death [ Time Frame: Thru Day 90 ]
- Composite of time to recovery, days at home off new supplemental oxygen and time to death [ Time Frame: Thru Day 90 ]Measured in number of days
- Composite of alive, at home and off new supplemental oxygen [ Time Frame: Thru Day 90 ]
- Composite of recovered, alive and not recovered, and dead [ Time Frame: Thru Day 90 ]Recovery defined as alive, at home and off new supplemental oxygen
- Time from randomization to recovery [ Time Frame: Thru Day 90 ]Recovery defined as alive, at home and off oxygen (treating death as competing risk)
- Days alive outside short-term acute care hospital [ Time Frame: Up to Day 90 ]Using "last off" method.
- Incidence of clinical organ failure or serious infections [ Time Frame: Thru Day 28 ]Defined as any one or more of: Worsening respiratory dysfunction; cardiac and vascular dysfunction; renal dysfunction; hepatic dysfunction; neurological dysfunction, haematological dysfunction; serious infection
- Composite of death, clinical organ failure or serious infections [ Time Frame: Thru Day 90 ]
- Composite of cardiovascular events and thromboembolic events [ Time Frame: Thru Day 28 ]
- Composite of cardiovascular events and thromboembolic events [ Time Frame: Thru Day 90 ]
- Composite of grade 3 and 4 clinical adverse events, serious adverse events (SAEs) or death [ Time Frame: Thru Days 5 and 28 ]
- Incidence of infusion reactions [ Time Frame: Thru Day 180 ]
- Percentage of participants for whom infusion was interrupted or stopped prior to completion for any reason [ Time Frame: Thru Day 90 ]
- Percentage of participants for whom infusion was interrupted or stopped prior to completion due to adverse event [ Time Frame: Thru Day 90 ]
- Composite of hospital readmissions or death [ Time Frame: Thru Day 180 ]
- Incidence of no home use of supplemental oxygen above pre-morbid oxygen use [ Time Frame: 14 days ]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.
- Time to hospital discharge from initial hospitalization [ Time Frame: Thru Day 180 ]
- Composite of death or serious clinical COVID-19 related events [ Time Frame: Thru Day 90 ]
- Pulmonary ordinal outcome [ Time Frame: Days 1-7, 14 and 28 ]Oxygen requirements measured by 7 categories (1 = least severe, 7 = most severe). The participant's highest (i.e. most severe) observed score is used.
- Composite of SAEs or death [ Time Frame: Thru Day 180 ]
- Incidence of home use of supplemental oxygen above pre-morbid oxygen use [ Time Frame: Thru Day 180 ]Measured as: Alive at home and no use of continuous supplemental oxygen for an uninterrupted 14 day period
- In category 4, 5 or 6 at Day 90 vs. in categories 1-3 at Day 90 [ Time Frame: Day 90 ]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.
- In category 5 or 6 at Day 90 vs. in categories 1-4 at Day 90 [ Time Frame: Day 90 ]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.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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).
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): NCT04843761
Show 40 study locations
| Principal Investigator: | Samuel Brown, MD | Intermountain Medical Center/University of Utah | |
| Study Chair: | Prof. James Neaton | INSIGHT Statistical and Coordinating Centre, University of Minnesota |
Documents provided by National Institute of Allergy and Infectious Diseases (NIAID):
| Responsible Party: | National Institute of Allergy and Infectious Diseases (NIAID) |
| ClinicalTrials.gov Identifier: | NCT04843761 |
| Other Study ID Numbers: |
015 / ACTIV-3b |
| First Posted: | April 14, 2021 Key Record Dates |
| Last Update Posted: | December 19, 2022 |
| Last Verified: | December 2022 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Undecided |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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COVID-19 COVID 19 Coronaviridae Infections Coronavirus Infections RNA Virus Infections Virus Diseases |
Nidovirales Infections SARS-CoV-2 SARS Coronavirus ACTIV-3 ACTIV3 |
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COVID-19 Respiratory Tract Infections Infections Pneumonia, Viral Pneumonia Virus Diseases Coronavirus Infections Coronaviridae Infections Nidovirales Infections RNA Virus Infections Lung Diseases Respiratory Tract Diseases Remdesivir Phentolamine Vasoactive Intestinal Peptide |
Antimetabolites Molecular Mechanisms of Pharmacological Action Antiviral Agents Anti-Infective Agents Adrenergic alpha-Antagonists Adrenergic Antagonists Adrenergic Agents Neurotransmitter Agents Physiological Effects of Drugs Antihypertensive Agents Gastrointestinal Agents Vasodilator Agents Neuroprotective Agents Protective Agents |