TESICO: ACTIV-3b: Therapeutics for Severely Ill Inpatients With COVID-19

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Active, not recruiting

CT.gov ID

NCT04843761

Collaborator

International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) (Other), University of Copenhagen (Other), Medical Research Council (Other), Kirby Institute (Other), Washington D.C. Veterans Affairs Medical Center (U.S. Fed), AIDS Clinical Trials Group (Other), National Heart, Lung, and Blood Institute (NHLBI) (NIH), US Department of Veterans Affairs (U.S. Fed), Prevention and Early Treatment of Acute Lung Injury (PETAL) (Other), Cardiothoracic Surgical Trials Network (CTSN) (Other), NeuroRx, Inc. (Industry), Gilead Sciences (Industry)

473

Enrollment

Locations

Arms

23.4

Anticipated Duration (Months)

8.6

Patients Per Site

0.4

Patients Per Site Per Month

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
Covid19	Biological: Remdesivir Drug: Remdesivir Placebo Biological: Aviptadil Drug: Aviptadil Placebo Drug: Corticosteroid	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

Study Type:

Interventional

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 :

Apr 20, 2021

Anticipated Primary Completion Date :

Oct 1, 2022

Anticipated Study Completion Date :

Apr 1, 2023

Arms and Interventions

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: Vasoactive Intestinal Peptide VIP 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: Vasoactive Intestinal Peptide VIP 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

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
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