COVID-19Phase 2/3NECTARNCT04924660
Novel Experimental COVID-19 Therapies Affecting Host Response
A Phase 2/3 study testing TXA127, TRV027 and Fostamatinib in people with COVID-19 and SARS-CoV-2 Infection, run by Sean Collins at 51 sites in United States.
Trial summary
The overarching goal of the Master Protocol is to find effective strategies for inpatient management of patients with COVID-19. Therapeutic goals for patients hospitalized for COVID-19 include hastening recovery and preventing progression to critical illness, multiorgan failure, or death. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- COVID-19, SARS-CoV-2 Infection, Coronavirus Infection
- What is being tested?
- TXA127, TRV027 and Fostamatinib
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 1,060 participants
- Where
- 51 sitesUnited States
- Study dates
- 15 Jul 2021to 31 Dec 2023
- Phase
- Phase 2/3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Hospitalized for COVID-19
- ≥18 years of age
- SARS-CoV-2 infection, documented by:
- a nucleic acid test (NAT) or equivalent testing within 3 days prior to randomization OR
- documented by NAT or equivalent testing more than 3 days prior to randomization AND progressive disease suggestive of ongoing SARS-CoV-2 infection per the responsible investigator (For non-NAT tests, only those deemed with equivalent specificity to NAT by the protocol team will be allowed. A central list of allowed non- NAT tests is maintained in Appendix E. Appendix E. Non-NAT Tests Deemed with Equivalent Specificity to NAT by the Protocol Team).
- Hypoxemia, defined as SpO2 <92% on room air, new receipt of supplemental oxygen to maintain SpO2 ≥92%, or increased supplemental oxygen to maintain SpO2 ≥92% for a patient on chronic oxygen therapy
Show all 12Show fewer
- Symptoms or signs of acute COVID-19, defined as one or more of the following:
- cough
- reported or documented body temperature of 100.4 degrees Fahrenheit or greater
- shortness of breath
- chest pain
- infiltrates on chest imaging (x-ray, CT scan, lung ultrasound)
Who cannot join
- Onset of COVID-19 symptom fulfilling inclusion criterion #5 >14 days prior to randomization
- Hospitalized with hypoxemia (as defined in inclusion #4) for >72 hours prior to randomization (the 72-hour window for randomization begins when the patient first meets the hypoxemia inclusion criteria after hospital admission)
- Pregnancy
- Breastfeeding
- Prisoners
- End-stage renal disease (ESRD) on dialysis
Show all 34Show fewer
- Patient undergoing comfort care measures only such that treatment focuses on end-of-life symptom management over prolongation of life.
- The treating clinician expects inability to participate in study procedures or participation would not be in the best interests of the patient
- Known allergy/hypersensitivity to IMP or its excipients
- The following exclusion criteria differ from the master protocol criteria:
- TXA127-specific exclusion criteria(4/20/2022 Closed to Accrual):
- Patient unable to participate or declines participation in the TXA127/Ang(1-7) arm.
- History of sensitivity (including angioedema) or allergic reaction to medication targeting the RAAS system including study medications or other allergy in the opinion of the investigator that contraindicates participation (not applicable to fostamatinib arm)
- Hemodynamic instability - defined as MAP < 65 mmHg at time of randomization confirmed on two measurements 5 minutes apart OR vasopressors at or above norepinephrine equivalent of 0.1 mcg/kg/min in prior 4 hours to maintain MAP > 65 mmHg.
- Known severe renal artery stenosis.
- Known significant left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy or severe aortic or mitral stenosis.
- Randomized in another trial evaluating RAAS modulation in the prior 30 days
- TRV027-specific exclusion criteria (4/20/2022 Closed to Accrual):
- Participants on ARBs will be excluded from this study arm.
- Patient unable to participate or declines participation in the TRV027 arm.
- History of sensitivity (including angioedema) or allergic reaction to medication targeting the RAAS system including study medications or other allergy in the opinion of the investigator that contraindicates participation (not applicable to fostamatinib arm)
- Hemodynamic instability - defined as MAP < 65 mmHg at time of randomization confirmed on two measurements 5 minutes apart OR vasopressors at or above norepinephrine equivalent of 0.1 mcg/kg/min in prior 4 hours to maintain MAP > 65 mmHg.
- Known severe renal artery stenosis.
- Known significant left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy or severe aortic or mitral stenosis.
- Randomized in another trial evaluating RAAS modulation in the prior 30 days
- Fostamatinib specific exclusion criteria:
- The following exclusion criteria differ from the master protocol criteria:
- 1. Randomized in another trial evaluating fostamatinib in the prior 30 days
- Study arm exclusion criteria measured within 24 hours prior to randomization:
- AST or ALT ≥ 5 × upper limit of normal (ULN) or ALT or AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN
- SBP > 160 mmHg or DBP > 100 mmHg at the time of screening and randomization
- ANC < 1000/mL
- Patient is anticipated to require a strong CYP3A inhibitor (Atazanavir, Certinib, Clarithromycin, Cobicistat and cobicistat-containing coformulations, Idelalisib,Indinavir, Itraconazole, Ketoconazole, Levoketoconazole, Lonafarnib, Lopinavir, Mifeprostone, Mibefradil, Nefazodone, Nelfinavir, Ombitasvir-paritaprevir-ritonavir plus dasabuvir, Posaconazole, Ribociclib Ritonavir, Saquinavir, Telithromycin, Troleandomycin, Tucatinib, Voriconazole) from randomization to 21 days post-randomization. For a full list of CYP3A4 substrates, please reference this regularly updated list: https://drug-interactions.medicine.iu.edu/MainTable.aspx.
- Patient unable to participate or declines participation in the fostamatinib arm.
Trial locations and contacts
51 sites in 1 country.
51 sites in 1 country
United States51 sites
Cleveland Clinic Akron General
Akron, Ohio, 44321
University of New Mexico Health Sciences Center
Albuquerque, New Mexico, 87106
Ponce de Leon Clinical Research Site
Atlanta, Georgia, 30303
Emory Johns Creek
Atlanta, Georgia, 30322
Emory St. Joseph's Hospital
Atlanta, Georgia, 30342
University of Colorado Hospital
Aurora, Colorado, 80010
Johns Hopkins Bayview Medical Center
Baltimore, Maryland, 21224
Johns Hopkins University
Baltimore, Maryland, 21287
Our Lady of the Lake Regional Medical Center
Baton Rouge, Louisiana, 70808
University of Alabama Birmingham
Birmingham, Alabama, 35249
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02072
Massachusetts General Hospital
Boston, Massachusetts, 02114
Brigham and Women's Hospital
Boston, Massachusetts, 02115
Chandler Regional Medical Center
Chandler, Arizona, 85224
University of North Carolina Medical Center
Chapel Hill, North Carolina, 27514
Medical University of South Carolina
Charleston, South Carolina, 29425
UVA Health
Charlottesville, Virginia, 22908
University of Cincinnati
Cincinnati, Ohio, 45229
Cleveland Clinic Fairview Hospital
Cleveland, Ohio, 44111
Cleveland Clinic Foundation
Cleveland, Ohio, 44195
Denver Health Medical Center
Denver, Colorado, 80204
Alexian Brothers Medical Center
Elk Grove Village, Illinois, 60007
University of Florida
Gainesville, Florida, 32610
AMITA Health St. Alexius Medical Center
Hoffman Estates, Illinois, 60169
University of Texas, Houston
Houston, Texas, 77030
Cedars-Sinai Medical Center
Los Angeles, California, 90048
Public Health Trust of Miami-Dade County, Florida - Jackson Memorial Hospital
Miami, Florida, 33136
Hennepin County Medical Center
Minneapolis, Minnesota, 55415
Intermountain Medical Center
Murray, Utah, 84107
Vanderbilt University Medical Center
Nashville, Tennessee, 37203
Yale University
New Haven, Connecticut, 06510
Ochsner Clinic Foundation
New Orleans, Louisiana, 70121
Mount Sinai Hospital
New York, New York, 10029
Columbia University Irving Medical Center
New York, New York, 10032
Newton-Wellesley Hospital
Newton, Massachusetts, 02462
Sentara Norfolk General Hospital
Norfolk, Virginia, 23507
University of Nebraska Medical Center
Omaha, Nebraska, 68198
Temple University Hospital
Philadelphia, Pennsylvania, 19140
University of Pittsburgh
Pittsburgh, Pennsylvania, 15213
Oregon Health & Science University
Portland, Oregon, 97239
VCU Health
Richmond, Virginia, 23298
University of Utah Health
Salt Lake City, Utah, 84108
Harborview Medical Center/University of Washington
Seattle, Washington, 98104
Jadestone Clinical Research, LLC
Silver Spring, Maryland, 20904
Baystate Health
Springfield, Massachusetts, 01119
Washington University
St Louis, Missouri, 63110
Stanford University
Stanford, California, 94305
Montefiore Medical Center Weiler Campus
The Bronx, New York, 10461
Montefiore Medical Center Moses Campus
The Bronx, New York, 10467
West Chester Hospital
West Chester, Ohio, 45069
Wake Forest University Health Sciences
Winston-Salem, North Carolina, 27157
About this study
Official title: CONNECTS Master Protocol for Clinical Trials Targeting Macro-, Micro-immuno-thrombosis, Vascular Hyperinflammation, and Hypercoagulability and Renin-angiotensin-aldosterone System (RAAS) in Hospitalized Patients With COVID-19 (ACTIV-4 Host Tissue)
The overarching goal of the Master Protocol is to find effective strategies for inpatient management of patients with COVID-19. Therapeutic goals for patients hospitalized for COVID-19 include hastening recovery and preventing progression to critical illness, multiorgan failure, or death. Our objective is to determine whether modulating the host tissue response improves clinical outcomes among patients with COVID-19. The primary analysis will include data from NCT05593770.
Read the detailed description
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has resulted in a global pandemic. The clinical spectrum of COVID-19 infection is broad, encompassing asymptomatic infection, mild upper respiratory tract illness, and severe viral pneumonia with respiratory failure and death. Between 13 and 40% of patients become hospitalized, up to 30% of those hospitalized require admission for intensive care, and there is a 13% inpatient mortality rate. The reasons for hospitalization include respiratory support, as well as support for failure of other organs, including the heart and kidneys. The risk of thrombotic complications is increased, even when compared to other viral respiratory illnesses, such as influenza. While 82% of hospitalized patients with COVID-19 are ultimately discharged alive, median length of stay is 10-13 days.
Early work in treating COVID-19 has focused on preventing worsening of the initial clinical presentation to prevent hospitalization and disease progression to organ failure and death. Studies conducted under this Master Host Tissue Protocol are expected to extend our knowledge of how to manage patients who are hospitalized for COVID-19 illness. Our objective is to determine whether modulating the host tissue response improves clinical outcomes among patients with COVID-19. This Master Protocol is a randomized, placebo-controlled trial of agents targeting the host response in COVID-19 in hospitalized patients with hypoxemia. The Master Host Tissue Protocol is designed to be flexible in the number of study arms, the use of a single placebo group, and the stopping and adding of new therapies. Our primary outcome is oxygen free days through day 28. This is defined as days alive and without supplemental oxygen use during the first 28 days following randomization. Patients who die on or before day 28 are assigned -1 oxygen free days.
April 20, 2022 TRV027 and TXA127 arms closed to accrual.
- Conditions
- COVID-19, SARS-CoV-2 Infection, Coronavirus Infection
- Being tested
- TXA127, TRV027, Placebo, Fostamatinib
- Keywords
- COVID-19 drug treatment, RAAS
- Medical subject headings
- COVID-19, Coronavirus Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TXA127Drug
TXA127 0.5 mg/kg/day infused 3 hours daily for 5 days or until hospital discharge whichever comes first.
TRV027Drug
TRV027 12mg/h as a continuous 24-hour infusion, infused for 5 days or until hospital discharge whichever comes first.
PlaceboDrug
NaCl 0.9% infused to match the duration of the agent (3 hours for TXA127 and continuous 24-hour infusion for TRV027, over 30 minutes for APN01.
Orange film-coated, plain bioconvex tablets orally twice daily for 14 days or 28 doses for fostamatinib. Study medication will be continued as an outpatient if the patient is discharged prior to completing 28 doses.
FostamatinibDrug
Fostamatinib100-150mg orally twice daily for 14 days or 28 doses. Study medication will be continued as an outpatient if the patient is discharged prior to completing 28 doses.
| Study group | Role | What they receive |
|---|---|---|
| TXA127 (4/20/2022 Arm Closed to Accrual) | Experimental | An investigational peptide agonist of Mas receptors. Receives: Drug: TXA127 |
| TRV027 (4/20/2022 Arm Closed to Accrual) | Experimental | An investigational peptide biased agonist of the AT1 receptor. Receives: Drug: TRV027 |
| Placebo | Placebo comparator | NaCl 0.9% infused to match the duration of the agent for TXA127, TRV027, and APN01.
Orange film-coated, plain, bioconvex tablets for fostamatinib.
For the purposes of interim and final analyses, the route and frequency of placebo will be ignored, and all placebo participants will be pooled together as a single group. In comparing an active drug versus placebo, only those placebo participants that were eligible for the active drug will be included. Receives: Drug: Placebo |
| Fostamatinib | Experimental | An investigational oral spleen tyrosine kinase inhibitor. Receives: Drug: Fostamatinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Oxygen Free Days Through Day 28.
This is defined as days alive and without supplemental oxygen use during the first 28 days following randomization. Patients who die on or before day 28 are assigned -1 oxygen free days. Patients will be considered to be receiving supplemental oxygen therapy when they are receiving any of the following: supplemental oxygen by nasal cannula, supplemental oxygen by face mask, high flow nasal cannula (HFNC), non-invasive ventilation (NIV), invasive mechanical ventilation (IMV), or extracorporeal membrane oxygenation (ECMO).
Measured: Day 1 to Day 28
Secondary outcomes (13)
In-hospital Mortality
Number of patients who die during hospitalization
Measured: Day 1 to hospital discharge or Day 90 whichever comes first
Alive and Oxygen Free at Day 14
Number of patients oxygen free at day 14. Patients will be considered to be receiving supplemental oxygen therapy when they are receiving any of the following: supplemental oxygen by nasal cannula, supplemental oxygen by face mask, high flow nasal cannula (HFNC), non-invasive ventilation (NIV), invasive mechanical ventilation (IMV), or extracorporeal membrane oxygenation (ECMO).
Measured: Day 1 to Day 14
Alive and Oxygen Free at Day 28
Number of patients oxygen-free at day 28. Patients will be considered to be receiving supplemental oxygen therapy when they are receiving any of the following: supplemental oxygen by nasal cannula, supplemental oxygen by face mask, high flow nasal cannula (HFNC), non-invasive ventilation (NIV), invasive mechanical ventilation (IMV), or extracorporeal membrane oxygenation (ECMO).
Measured: Day 1 to Day 28
Alive and Free of New Invasive Mechanical Ventilation at Day 28
Number of patients alive free of new invasive mechanical ventilation at day 28
Measured: Day 1 to Day 28
28-day Mortality
Number of patients who have died at Day 28
Measured: Day 28
60-day Mortality
Number of patients who have died at Day 60
Measured: Day 60
90-day Mortality
Number of patients who have died at Day 90
Measured: Day 90
Clinical Status Assessed Using World Health Organization(WHO) 8-point Ordinal Scale
Number of participants who fell within the ordinal scale per the below criteria. Each row represents the country and number of participants with the score in numerical order.
- Ambulatory - Not hospitalized and no limitation of activities
- Ambulatory - Not hospitalized with limitation of activities or home oxygen use
- Hospitalized Mild Disease - Hospitalized, no oxygen therapy
- Hospitalized Mild Disease - Hospitalized, oxygen by mask or nasal prongs
- Hospitalized Severe Disease - Non-invasive ventilation or high-flow nasal cannula
- Hospitalized Severe Disease -Invasive mechanical ventilation
- Hospitalized Severe Disease - Invasive mechanical ventilation plus additional organ support with- vasopressors, RRT, or ECMO
- Dead
Measured: Day 14
Clinical Status Assessed Using WHO 8-point Ordinal Scale at Day 28
Number of participants who fell within the ordinal scale per the below criteria. Each row represents the country and number of participants with the score in numerical order.
- Ambulatory - Not hospitalized and no limitation of activities
- Ambulatory - Not hospitalized with limitation of activities or home oxygen use
- Hospitalized Mild Disease - Hospitalized, no oxygen therapy
- Hospitalized Mild Disease - Hospitalized, oxygen by mask or nasal prongs
- Hospitalized Severe Disease - Non-invasive ventilation or high-flow nasal cannula
- Hospitalized Severe Disease -Invasive mechanical ventilation
- Hospitalized Severe Disease - Invasive mechanical ventilation plus additional organ support with- vasopressors, RRT, or ECMO
- Dead
Measured: Day 28
Clinical Status Assessed Using WHO 8-point Ordinal Scale at Day 60
Number of participants who fell within the ordinal scale per the below criteria. Each row represents the country and number of participants with the score in numerical order.
- Ambulatory - Not hospitalized and no limitation of activities
- Ambulatory - Not hospitalized with limitation of activities or home oxygen use
- Hospitalized Mild Disease - Hospitalized, no oxygen therapy
- Hospitalized Mild Disease - Hospitalized, oxygen by mask or nasal prongs
- Hospitalized Severe Disease - Non-invasive ventilation or high-flow nasal cannula
- Hospitalized Severe Disease -Invasive mechanical ventilation
- Hospitalized Severe Disease - Invasive mechanical ventilation plus additional organ support with- vasopressors, RRT, or ECMO
- Dead
Measured: Day 60
Hospital-free Days Through Day 28
Days alive and not hospitalized during the first 28 days following randomization. Patients who die on or before day 28 are assigned a value -1.
Measured: Day 1 to Day 28
Ventilator-free Days Through Day 28
Days alive and not receiving mechanical ventilation during the first 28 days following randomization. Patients who die on or before day 28 are assigned a value -1.
Measured: Day 1 to Day 28
Respiratory Failure-free Days Through Day 28
Days alive and not in respiratory failure during the first 28 days following randomization. A respiratory failure-free day is defined as a day alive without the use of HFNC, NIV, IMV, or (ECMO). Patients who die on or before day 28 are assigned a value -1.
Measured: Day 1 to Day 28
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Jun 2021
- Study start15 Jul 2021
- Primary completion25 Oct 2023
- Study completion31 Dec 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for COVID-19Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Participants will be randomly allocated in a two-step process: 1) The participant will first be randomized in an m:1 ratio to receive an active study drug or placebo, where m represents the number of study drug arms for which the participant is eligible. 2) The participant will then be randomly assigned with equal probability to one of the study drug arms. Participants will receive the corresponding study drug or matching placebo. Results data includes data from NCT05593770.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 1,060 participants (actual)
Sponsor and investigators
- Lead sponsor
- Sean Collins
- Sponsor type
- University, hospital or other
- Collaborators
- National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI)
- Responsible party
- Sponsor-investigator, Sean Collins, Vanderbilt University Medical Center
- Investigators
- Sean P. Collins, M.D., Study chair, Vanderbilt University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04924660
- Sponsor's protocol ID
- 210982
- Acronym
- NECTAR
- Status last verified
- Dec 2024
- First submitted
- 9 Jun 2021
- Last updated
- 22 Jan 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Collins SP, Shotwell MS, Strich JR, Gibbs KW, de Wit M, Files DC, Harkins M, Hudock K, Merck LH, Moskowitz A, Apodaca KD, Barksdale A, Safdar B, Javaheri A, Sturek JM, Schrager H, Iovine NM, Tiffany B, Douglas I, Levitt J, Ginde AA, Hager DN, Shapiro N, Duggal A, Khan A, Lanspa M, Chen P, Gentile N, Harris E, Gong M, Sellers S, Goodwin AJ, Tidswell MA, Filbin M, Desai N, Gutierrez F, Estrada V, Burgos J, Boyles T, Pano-Pardo JR, Hussen N, Rosenberg Y, Troendle J, Bernard GR, Bistran-Hall AJ, Walsh K, Casey JD, DeClercq J, Joly MM, Pulley J, Rice TW, Schildcrout JS, Wang L, Semler MW, Self WH; ACTIV-4 Host Tissue Investigators. Fostamatinib for Hospitalized Adults With COVID-19 and Hypoxemia: A Randomized Clinical Trial. JAMA Netw Open. 2024 Dec 2;7(12):e2448215. doi: 10.1001/jamanetworkopen.2024.48215.
PubMed 39625722Self WH, Shotwell MS, Gibbs KW, de Wit M, Files DC, Harkins M, Hudock KM, Merck LH, Moskowitz A, Apodaca KD, Barksdale A, Safdar B, Javaheri A, Sturek JM, Schrager H, Iovine N, Tiffany B, Douglas IS, Levitt J, Busse LW, Ginde AA, Brown SM, Hager DN, Boyle K, Duggal A, Khan A, Lanspa M, Chen P, Puskarich M, Vonderhaar D, Venkateshaiah L, Gentile N, Rosenberg Y, Troendle J, Bistran-Hall AJ, DeClercq J, Lavieri R, Joly MM, Orr M, Pulley J, Rice TW, Schildcrout JS, Semler MW, Wang L, Bernard GR, Collins SP; ACTIV-4 Host Tissue Investigators. Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor-Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials. JAMA. 2023 Apr 11;329(14):1170-1182. doi: 10.1001/jama.2023.3546.
PubMed 37039791
Study at a glance
From the registry record, last updated by the sponsor on 22 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- CONNECTS Master Protocol for Clinical Trials Targeting Macro-, Micro-immuno-thrombosis, Vascular Hyperinflammation, and Hypercoagulability and Renin-angiotensin-aldosterone System (RAAS) in Hospitalized Patients With COVID-19 (ACTIV-4 Host Tissue)
- ClinicalTrials.gov ID
- NCT04924660
- Acronym / sponsor ID
- NECTAR / 210982
- Conditions
- COVID-19, SARS-CoV-2 Infection, Coronavirus Infection
- Keywords
- COVID-19 drug treatment, RAAS
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 1,060 participants (actual)
- Lead sponsor
- Sean CollinsUniversity, hospital or other
- Collaborators
- National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI)
- Study start
- 15 Jul 2021 (actual)
- Primary completion
- 25 Oct 2023 (actual)
- Study completion
- 31 Dec 2023 (actual)
- First posted
- 14 Jun 2021 (actual)
- Results
- Posted 22 Jan 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The overarching goal of the Master Protocol is to find effective strategies for inpatient management of patients with COVID-19. Therapeutic goals for patients hospitalized for COVID-19 include hastening recovery and preventing progression to critical illness, multiorgan failure, or death. Our objective is to determine whether modulating the host tissue response improves clinical outcomes among patients with COVID-19. The primary analysis will include data from NCT05593770.
Detailed description
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has resulted in a global pandemic. The clinical spectrum of COVID-19 infection is broad, encompassing asymptomatic infection, mild upper respiratory tract illness, and severe viral pneumonia with respiratory failure and death. Between 13 and 40% of patients become hospitalized, up to 30% of those hospitalized require admission for intensive care, and there is a 13% inpatient mortality rate. The reasons for hospitalization include respiratory support, as well as support for failure of other organs, including the heart and kidneys. The risk of thrombotic complications is increased, even when compared to other viral respiratory illnesses, such as influenza. While 82% of hospitalized patients with COVID-19 are ultimately discharged alive, median length of stay is 10-13 days.
Early work in treating COVID-19 has focused on preventing worsening of the initial clinical presentation to prevent hospitalization and disease progression to organ failure and death. Studies conducted under this Master Host Tissue Protocol are expected to extend our knowledge of how to manage patients who are hospitalized for COVID-19 illness. Our objective is to determine whether modulating the host tissue response improves clinical outcomes among patients with COVID-19. This Master Protocol is a randomized, placebo-controlled trial of agents targeting the host response in COVID-19 in hospitalized patients with hypoxemia. The Master Host Tissue Protocol is designed to be flexible in the number of study arms, the use of a single placebo group, and the stopping and adding of new therapies. Our primary outcome is oxygen free days through day 28. This is defined as days alive and without supplemental oxygen use during the first 28 days following randomization. Patients who die on or before day 28 are assigned -1 oxygen free days.
April 20, 2022 TRV027 and TXA127 arms closed to accrual.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
- Model description
- Participants will be randomly allocated in a two-step process: 1) The participant will first be randomized in an m:1 ratio to receive an active study drug or placebo, where m represents the number of study drug arms for which the participant is eligible. 2) The participant will then be randomly assigned with equal probability to one of the study drug arms. Participants will receive the corresponding study drug or matching placebo. Results data includes data from NCT05593770.
| Arm | Type | Receives |
|---|---|---|
| TXA127 (4/20/2022 Arm Closed to Accrual) | Experimental | Drug: TXA127An investigational peptide agonist of Mas receptors. |
| TRV027 (4/20/2022 Arm Closed to Accrual) | Experimental | Drug: TRV027An investigational peptide biased agonist of the AT1 receptor. |
| Placebo | Placebo comparator | Drug: PlaceboNaCl 0.9% infused to match the duration of the agent for TXA127, TRV027, and APN01. Orange film-coated, plain, bioconvex tablets for fostamatinib. For the purposes of interim and final analyses, the route and frequency of placebo will be ignored, and all placebo participants will be pooled together as a single group. In comparing an active drug versus placebo, only those placebo participants that were eligible for the active drug will be included. |
| Fostamatinib | Experimental | Drug: FostamatinibAn investigational oral spleen tyrosine kinase inhibitor. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- Hospitalized for COVID-19
- ≥18 years of age
- SARS-CoV-2 infection, documented by:
- Hypoxemia, defined as SpO2 <92% on room air, new receipt of supplemental oxygen to maintain SpO2 ≥92%, or increased supplemental oxygen to maintain SpO2 ≥92% for a patient on chronic oxygen therapy
- Symptoms or signs of acute COVID-19, defined as one or more of the following:
Key exclusion criteria (34 listed)
- Onset of COVID-19 symptom fulfilling inclusion criterion #5 >14 days prior to randomization
- Hospitalized with hypoxemia (as defined in inclusion #4) for >72 hours prior to randomization (the 72-hour window for randomization begins when the patient first meets the hypoxemia inclusion criteria after hospital admission)
- Pregnancy
- Breastfeeding
- Prisoners
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TXA127TXA127 0.5 mg/kg/day infused 3 hours daily for 5 days or until hospital discharge whichever comes first. | Drug | TXA127 (4/20/2022 Arm Closed to Accrual) |
| TRV027TRV027 12mg/h as a continuous 24-hour infusion, infused for 5 days or until hospital discharge whichever comes first. | Drug | TRV027 (4/20/2022 Arm Closed to Accrual) |
| PlaceboNaCl 0.9% infused to match the duration of the agent (3 hours for TXA127 and continuous 24-hour infusion for TRV027, over 30 minutes for APN01. Orange film-coated, plain bioconvex tablets orally twice daily for 14 days or 28 doses for fostamatinib. Study medication will be continued as an outpatient if the patient is discharged prior to completing 28 doses. | Drug | Placebo |
| FostamatinibFostamatinib100-150mg orally twice daily for 14 days or 28 doses. Study medication will be continued as an outpatient if the patient is discharged prior to completing 28 doses. | Drug | Fostamatinib |
Primary outcome
Oxygen Free Days Through Day 28.
Time frame: Day 1 to Day 28
This is defined as days alive and without supplemental oxygen use during the first 28 days following randomization. Patients who die on or before day 28 are assigned -1 oxygen free days. Patients will be considered to be receiving supplemental oxygen therapy when they are receiving any of the following: supplemental oxygen by nasal cannula, supplemental oxygen by face mask, high flow nasal cannula (HFNC), non-invasive ventilation (NIV), invasive mechanical ventilation (IMV), or extracorporeal membrane oxygenation (ECMO).
13 secondary outcomes
In-hospital Mortality
Time frame: Day 1 to hospital discharge or Day 90 whichever comes first
Alive and Oxygen Free at Day 14
Time frame: Day 1 to Day 14
Alive and Oxygen Free at Day 28
Time frame: Day 1 to Day 28
Alive and Free of New Invasive Mechanical Ventilation at Day 28
Time frame: Day 1 to Day 28
28-day Mortality
Time frame: Day 28
60-day Mortality
Time frame: Day 60
90-day Mortality
Time frame: Day 90
Clinical Status Assessed Using World Health Organization(WHO) 8-point Ordinal Scale
Time frame: Day 14
Clinical Status Assessed Using WHO 8-point Ordinal Scale at Day 28
Time frame: Day 28
Clinical Status Assessed Using WHO 8-point Ordinal Scale at Day 60
Time frame: Day 60
Hospital-free Days Through Day 28
Time frame: Day 1 to Day 28
Ventilator-free Days Through Day 28
Time frame: Day 1 to Day 28
Respiratory Failure-free Days Through Day 28
Time frame: Day 1 to Day 28
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Jan 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 39625722Collins SP, Shotwell MS, Strich JR, Gibbs KW, de Wit M, Files DC, Harkins M, Hudock K, Merck LH, Moskowitz A, Apodaca KD, Barksdale A, Safdar B, Javaheri A, Sturek JM, Schrager H, Iovine NM, Tiffany B, Douglas I, Levitt J, Ginde AA, Hager DN, Shapiro N, Duggal A, Khan A, Lanspa M, Chen P, Gentile N, Harris E, Gong M, Sellers S, Goodwin AJ, Tidswell MA, Filbin M, Desai N, Gutierrez F, Estrada V, Burgos J, Boyles T, Pano-Pardo JR, Hussen N, Rosenberg Y, Troendle J, Bernard GR, Bistran-Hall AJ, Walsh K, Casey JD, DeClercq J, Joly MM, Pulley J, Rice TW, Schildcrout JS, Wang L, Semler MW, Self WH; ACTIV-4 Host Tissue Investigators. Fostamatinib for Hospitalized Adults With COVID-19 and Hypoxemia: A Randomized Clinical Trial. JAMA Netw Open. 2024 Dec 2;7(12):e2448215. doi: 10.1001/jamanetworkopen.2024.48215.
- Derived from this study: PubMed 37039791Self WH, Shotwell MS, Gibbs KW, de Wit M, Files DC, Harkins M, Hudock KM, Merck LH, Moskowitz A, Apodaca KD, Barksdale A, Safdar B, Javaheri A, Sturek JM, Schrager H, Iovine N, Tiffany B, Douglas IS, Levitt J, Busse LW, Ginde AA, Brown SM, Hager DN, Boyle K, Duggal A, Khan A, Lanspa M, Chen P, Puskarich M, Vonderhaar D, Venkateshaiah L, Gentile N, Rosenberg Y, Troendle J, Bistran-Hall AJ, DeClercq J, Lavieri R, Joly MM, Orr M, Pulley J, Rice TW, Schildcrout JS, Semler MW, Wang L, Bernard GR, Collins SP; ACTIV-4 Host Tissue Investigators. Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor-Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials. JAMA. 2023 Apr 11;329(14):1170-1182. doi: 10.1001/jama.2023.3546.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sean P. Collins, M.D. study chair
Vanderbilt University Medical Center
51 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing TXA127, TRV027 and Fostamatinib in people with COVID-19 and SARS-CoV-2 Infection, run by Sean Collins at 51 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 34 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 51 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 22 Jan 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Oxygen Free Days Through Day 28. (time frame: Day 1 to Day 28). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04924660, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Jan 2025.