TESICO: ACTIV-3b: Therapeutics for Severely Ill Inpatients With COVID-19
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 3 |
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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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.
|
Outcome Measures
Primary Outcome Measures
- Recovery, assessed at 90 days [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.
Secondary Outcome Measures
- All-cause mortality [Thru Day 90]
- Time to death [Thru Day 90]
- Composite of time to recovery, days at home off new supplemental oxygen and time to death [Thru Day 90]
Measured in number of days
- Composite of alive, at home and off new supplemental oxygen [Thru Day 90]
- Composite of recovered, alive and not recovered, and dead [Thru Day 90]
Recovery defined as alive, at home and off new supplemental oxygen
- Time from randomization to recovery [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 [Up to Day 90]
Using "last off" method.
- Incidence of clinical organ failure or serious infections [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 [Thru Day 90]
- Composite of cardiovascular events and thromboembolic events [Thru Day 28]
- Composite of cardiovascular events and thromboembolic events [Thru Day 90]
- Composite of grade 3 and 4 clinical adverse events, serious adverse events (SAEs) or death [Thru Days 5 and 28]
- Incidence of infusion reactions [Thru Day 180]
- Percentage of participants for whom infusion was interrupted or stopped prior to completion for any reason [Thru Day 90]
- Percentage of participants for whom infusion was interrupted or stopped prior to completion due to adverse event [Thru Day 90]
- Composite of hospital readmissions or death [Thru Day 180]
- Incidence of no home use of supplemental oxygen above pre-morbid oxygen use [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 [Thru Day 180]
- Composite of death or serious clinical COVID-19 related events [Thru Day 90]
- Pulmonary ordinal outcome [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 [Thru Day 180]
- Incidence of home use of supplemental oxygen above pre-morbid oxygen use [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 [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 [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.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Signed informed consent.
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Requiring admission to hospital for acute medical care (not for purely public health or quarantine purposes).
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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).
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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.
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Respiratory failure is believed to be due to SARS-CoV-2 pneumonia.
Exclusion Criteria:
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Known allergy to investigational agent or vehicle.
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More than 4 days since initiation of support for respiratory failure.
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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).
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Moribund patient (i.e. not expected to survive 24 hours).
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Active use of "comfort care" or other hospice-equivalent standard of care.
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Expected inability to participate in study procedures.
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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.
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Previous enrollment in TESICO
Agent-specific exclusion criteria
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Prior receipt of any dose of remdesivir during present illness (remdesivir agent).
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GFR (glomerular filtration rate) < 30 ml/min and not receiving dialysis (remdesivir agent).
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ALT (alanine aminotransferase) or AST (aspartate aminotransferase) > 10 times upper limit of normal (remdesivir agent).
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Unwillingness to commit to avoid sex that may result in pregnancy for at least 7 days after completion of remdesivir vs. placebo (remdesivir agent).
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Refractory hypotension (aviptadil agent).
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Severe diarrhea (Aviptadil agent).
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Current C. difficile infection (aviptadil agent).
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Pregnancy or current breast-feeding (aviptadil agent).
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End-stage liver disease (aviptadil agent).
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Banner University Medical Center Tucson (Site 206-004), 1625 N. Campbell Avenue | Tucson | Arizona | United States | 85719 |
2 | UCSF Fresno (Site 203-005), 155 N. Fresno Street | Fresno | California | United States | 93701 |
3 | VA Loma Linda Healthcare System (Site 074-017), 11201 Benton Street | Loma Linda | California | United States | 92357 |
4 | Cedars-Sinai Medical Center (Site 208-002), 8700 Beverly Boulevard | Los Angeles | California | United States | 90048 |
5 | West Los Angeles VA Medical Center (Site 074-001), 11301 Wilshire Blvd. | Los Angeles | California | United States | 90073 |
6 | Ronald Reagan UCLA Medical Center (Site 203-002), 757 Westwood Plaza | Los Angeles | California | United States | 90095 |
7 | UCSF Medical Center at Mount Zion (Site 203-007), 1600 Divisadero St. | San Francisco | California | United States | 94115 |
8 | UCSF Medical Center (Site 203-001), Moffit-Long Hospital, 505 Parnassus Ave. | San Francisco | California | United States | 94143 |
9 | Stanford University Hospital & Clinics (Site 203-003), 300 Pasteur Dr. | Stanford | California | United States | 94305 |
10 | University of Colorado Hospital (Site 204-001), 12605 E. 16th Avenue | Aurora | Colorado | United States | 80045 |
11 | Denver Health Medical Center (Site 204-004), 780 Delaware Street, Pavilion B | Denver | Colorado | United States | 80204 |
12 | MedStar Health Research Institute (Site 009-021), 110 Irving St., NW. | Washington | District of Columbia | United States | 20010 |
13 | Washington DC VA Medical Center (Site 009-004), 50 Irving Street, NW. | Washington | District of Columbia | United States | 20422 |
14 | Emory University (Site 301-008), Bldg. A, Suite 2236, 1365 Clifton Rd., NE. | Atlanta | Georgia | United States | 30322 |
15 | Edward Hines VA Hospital (Site 074-012), 5000 S. 5th Ave. | Hines | Illinois | United States | 60141 |
16 | Massachusetts General Hospital (Site 202-002), 55 Fruit Street | Boston | Massachusetts | United States | 02114 |
17 | Baystate Medical Center (Site 201-001), Critical Care Research, 759 Chestnut Street | Springfield | Massachusetts | United States | 01199 |
18 | Henry Ford Health System (Site 205-006), 2799 W. Grand Blvd. | Detroit | Michigan | United States | 48202 |
19 | Montefiore Medical Center - Moses Hospital (Site 206-001), 111 E. 210th Street | Bronx | New York | United States | 10467 |
20 | Montefiore Medical Center - Weiler campus (Site 206-003), 111 E. 210th Street | Bronx | New York | United States | 10467 |
21 | Mount Sinai Medical Center (Site 301-012), Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place | New York | New York | United States | 10029 |
22 | Columbia University Irving Medical Center (Site 301-027), 177 Fort Washington Ave. | New York | New York | United States | 10032 |
23 | Duke University Hospital (Site 301-006), 2301 Erwin Road | Durham | North Carolina | United States | 27710 |
24 | Wake Forest Baptist Health (Site 210-001), Medical Center Blvd | Winston-Salem | North Carolina | United States | 27157 |
25 | University of Cincinnati Medical Center (Site 207-003), 234 Goodman Street, ML 0740 | Cincinnati | Ohio | United States | 45219 |
26 | Cleveland Clinic Fairview Hosptial (Site 207-005), 18101 Lorain Ave. | Cleveland | Ohio | United States | 44111 |
27 | Cleveland Clinic Foundation (Site 207-001), 9500 Euclid Ave. | Cleveland | Ohio | United States | 44195 |
28 | The Ohio State University Wexner Medical Center (Site 207-004), 410 W. 10th Avenue | Columbus | Ohio | United States | 43210 |
29 | Cleveland Clinic Marymount Campus (Site 207-006), 12300 McCracken Road | Garfield Heights | Ohio | United States | 44125 |
30 | Cleveland Clinic Hillcrest Hospital (Site 207-007), 6780 Mayfield Road | Mayfield Heights | Ohio | United States | 44124 |
31 | Oregon Health & Science University (Site 208-003), 3181 SW Sam Jackson Park Rd. | Portland | Oregon | United States | 97239-3098 |
32 | Medical University of South Carolina (Site 210-002), 96 Jonathan Lucas St., CSB 214 | Charleston | South Carolina | United States | 29425 |
33 | Vanderbilt University Medical Center (Site 212-001), 1211 Medical Center Drive | Nashville | Tennessee | United States | 37232 |
34 | Baylor, Scott and White Health (Site 301-003), Baylor University Medical Center, 3500 Gaston Ave. | Dallas | Texas | United States | 75246 |
35 | Houston Methodist Hospital (Site 301-028), 6565 Fannin Street | Houston | Texas | United States | 77030 |
36 | Texas Heart Institute (Site 301-017), 6770 Bertner, MC4-266 | Houston | Texas | United States | 77030 |
37 | University of Texas Health Science Center (Site 203-006), 7000 Fannin St. | Houston | Texas | United States | 77030 |
38 | Intermountain Medical Center (Site 211-001), 5121 South Cottonwood Street | Murray | Utah | United States | 84107 |
39 | University of Utah Hospital (Site 211-002), 50 North Medical Drive | Salt Lake City | Utah | United States | 84132 |
40 | UVA School of Medicine (Site 210-003), University of Virginia Health System, University Hospital, 1215 Lee St. | Charlottesville | Virginia | United States | 22908 |
41 | Harborview Medical Center (Site 208-001), 325 9th Ave. | Seattle | Washington | United States | 98104 |
42 | Swedish Medical Center (Site 208-005), 747 Broadway | Seattle | Washington | United States | 98122 |
43 | West Virginia University Medicine (Site 301-023), One Medical Center Drive | Morgantown | West Virginia | United States | 26506 |
44 | Unimed Vitória Cooperativa de Trabalho Médico (Site 649-206), Rua Marins Alvarino, 365 | Vitória | Espírito Santo | Brazil | 29047-660 |
45 | Sociedade Literária e Caritativa Santo Agostinho - Hospital São José (Site 649-204), Rua Coronel Pedro Benedet, 630, Pio Corrêa | Criciúma | Santa Catarina | Brazil | 88811-508 |
46 | Hospital Nereu Ramos (Site 649-210), Rua Rui Barbosa, 800 | Florianópolis | Santa Catarina | Brazil | 88025-301 |
47 | Unimed Joinville Cooperativa de Trabalho Médico (Site 649-202), Rua Orestes Guimarães, 905, Bairro América | Joinville | Santa Catarina | Brazil | 82204-061 |
48 | Associação Beneficente Hospital Universitario (Site 649-212), Av. Higino Muzi Filho, 1001-Mirante | Marília | SP | Brazil | 17525-160 |
49 | Associação Hospitalar Moinhos de Vento (Site 649-209), Rua Ramiro Barcelos, 910-3°andar, Bloco A | Porto Alegre | Brazil | ||
50 | Naval Hospital Marcílio Dias (Site 649-213), Rua Cesar Zama, 185 - Lins de Vasconcelos | Rio De Janeiro | Brazil | 20725090 | |
51 | Real e Benemerita Associação Portuguesa de Beneficencia/SP (Site 649-201), R. Maestro Cardim, 769 - Bela Vista | São Paulo | Brazil | 01323-001 | |
52 | Hospital Alemão Oswaldo Cruz (Site 649-215), Rua Treze de Maio, 1815 | São Paulo | Brazil | 01327-001 | |
53 | Hospital 9 de Julho (Site 649-216), 545th, Peixoto Gomide Street | São Paulo | Brazil | 01409-902 | |
54 | Hospital Do Coração/Associação Beneficente Síria - HCOR (Site 649-203), Rua Desembargador Eliseu Guilherme, 147 - 3rd Floor | São Paulo | Brazil | 04004-030 | |
55 | SEPACO Hospital and Maternity (Site 649-207), Vergueiro, 4210 | São Paulo | Brazil | 04102900 |
Sponsors and Collaborators
- National Institute of Allergy and Infectious Diseases (NIAID)
- International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)
- University of Copenhagen
- Medical Research Council
- Kirby Institute
- Washington D.C. Veterans Affairs Medical Center
- AIDS Clinical Trials Group
- National Heart, Lung, and Blood Institute (NHLBI)
- US Department of Veterans Affairs
- Prevention and Early Treatment of Acute Lung Injury (PETAL)
- Cardiothoracic Surgical Trials Network (CTSN)
- NeuroRx, Inc.
- Gilead Sciences
Investigators
- Principal Investigator: Samuel Brown, MD, Intermountain Medical Center/University of Utah
- Study Chair: Prof. James Neaton, INSIGHT Statistical and Coordinating Centre, University of Minnesota
Study Documents (Full-Text)
More Information
Additional Information:
- FDA Safety Alerts and Recalls
- CDC (Centers for Disease Control and Prevention): Coronavirus (COVID-19) website
- A Participant's Guide to Clinical Trials (NIAID)
- Find a Clinical Trial (NIAID)
- Clinical Trials at NIAID
- National Institute for Allergy and Infectious Diseases (NIAID)
- NIH COVID-19 treatment guidelines
- WHO COVID-19 treatment guidelines
Publications
None provided.- 015 / ACTIV-3b