Novel Experimental COVID-19 Therapies Affecting Host Response

COVID-19 Clinical Trial

— NECTAR  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04924660
• Other study ID #: 210982
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: July 15, 2021
• Est. completion date: December 31, 2023

Study information

• Verified date: January 2024
• Source: Vanderbilt University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. Our objective is to determine whether modulating the host tissue response improves clinical outcomes among patients with COVID-19.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 871
• Est. completion date: December 31, 2023
• Est. primary completion date: October 25, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria

1. Hospitalized for COVID-19

2. =18 years of age

3. SARS-CoV-2 infection, documented by:

1. a nucleic acid test (NAT) or equivalent testing within 3 days prior to randomization OR

2. 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).

4. 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

5. Symptoms or signs of acute COVID-19, defined as one or more of the following:

1. cough

2. reported or documented body temperature of 100.4 degrees Fahrenheit or greater

3. shortness of breath

4. chest pain

5. infiltrates on chest imaging (x-ray, CT scan, lung ultrasound) Exclusion criteria

1. Onset of COVID-19 symptom fulfilling inclusion criterion #5 >14 days prior to randomization

2. 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)

3. Pregnancy

4. Breastfeeding

5. Prisoners

6. End-stage renal disease (ESRD) on dialysis

7. Patient undergoing comfort care measures only such that treatment focuses on end-of-life symptom management over prolongation of life.

8. The treating clinician expects inability to participate in study procedures or participation would not be in the best interests of the patient

9. 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):

1. Patient unable to participate or declines participation in the TXA127/Ang(1-7) arm.

2. 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)

3. 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.

4. Known severe renal artery stenosis.

5. Known significant left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy or severe aortic or mitral stenosis.

6. Randomized in another trial evaluating RAAS modulation in the prior 30 days

TRV027-specific exclusion criteria (4/20/2022 Closed to Accrual):

1. Participants on ARBs will be excluded from this study arm.

2. Patient unable to participate or declines participation in the TRV027 arm.

3. 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)

4. 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.

5. Known severe renal artery stenosis.

6. Known significant left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy or severe aortic or mitral stenosis.

7. 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:

1. AST or ALT = 5 × upper limit of normal (ULN) or ALT or AST = 3 × ULN and total bilirubin = 2 × ULN

2. SBP > 160 mmHg or DBP > 100 mmHg at the time of screening and randomization

3. ANC < 1000/mL

4. 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.

5. Patient unable to participate or declines participation in the fostamatinib arm.

Related Conditions & MeSH terms

• Communicable Diseases
• Coronavirus Infection
• Coronavirus Infections
• COVID-19
• Infections
• SARS-CoV-2 Infection

Intervention

Drug:
• TXA127
TXA127 0.5 mg/kg/day infused 3 hours daily for 5 days or until hospital discharge whichever comes first.
• TRV027
TRV027 12mg/h as a continuous 24-hour infusion, infused for 5 days or until hospital discharge whichever comes first.
• Placebo
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.
• Fostamatinib
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.

Locations

Country	Name	City	State
United States	Cleveland Clinic Akron General	Akron	Ohio
United States	University of New Mexico Health Sciences Center	Albuquerque	New Mexico
United States	Emory Johns Creek	Atlanta	Georgia
United States	Emory St. Joseph's Hospital	Atlanta	Georgia
United States	Ponce de Leon Clinical Research Site	Atlanta	Georgia
United States	University of Colorado Hospital	Aurora	Colorado
United States	Johns Hopkins Bayview Medical Center	Baltimore	Maryland
United States	Johns Hopkins University	Baltimore	Maryland
United States	Our Lady of the Lake Regional Medical Center	Baton Rouge	Louisiana
United States	University of Alabama Birmingham	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Montefiore Medical Center Moses Campus	Bronx	New York
United States	Montefiore Medical Center Weiler Campus	Bronx	New York
United States	Chandler Regional Medical Center	Chandler	Arizona
United States	University of North Carolina Medical Center	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	UVA Health	Charlottesville	Virginia
United States	University of Cincinnati	Cincinnati	Ohio
United States	Cleveland Clinic Fairview Hospital	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Denver Health Medical Center	Denver	Colorado
United States	Alexian Brothers Medical Center	Elk Grove Village	Illinois
United States	University of Florida	Gainesville	Florida
United States	AMITA Health St. Alexius Medical Center	Hoffman Estates	Illinois
United States	University of Texas, Houston	Houston	Texas
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Public Health Trust of Miami-Dade County, Florida - Jackson Memorial Hospital	Miami	Florida
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Intermountain Medical Center	Murray	Utah
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale University	New Haven	Connecticut
United States	Ochsner Clinic Foundation	New Orleans	Louisiana
United States	Columbia University Irving Medical Center	New York	New York
United States	Mount Sinai Hospital	New York	New York
United States	Newton-Wellesley Hospital	Newton	Massachusetts
United States	Sentara Norfolk General Hospital	Norfolk	Virginia
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	VCU Health	Richmond	Virginia
United States	Washington University	Saint Louis	Missouri
United States	University of Utah Health	Salt Lake City	Utah
United States	Harborview Medical Center/University of Washington	Seattle	Washington
United States	Jadestone Clinical Research, LLC	Silver Spring	Maryland
United States	Baystate Health	Springfield	Massachusetts
United States	Stanford University	Stanford	California
United States	West Chester Hospital	West Chester	Ohio
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (3)

Lead Sponsor	Collaborator
Sean Collins	National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Renal outcomes: acute kidney Injury (when possible, at participating sites)	Proportion of participants with evidence of acute kidney injury using the KDIGO Stage 2 criteria for serum creatinine relative to baseline at Day 0.	Day 0 to Day 5 or hospital discharge whichever comes first
Other	Myocardial injury (when possible, at participating sites)	Proportion of participants with Myocardial injury described by changes in troponin before, during and after therapy during hospitalization.	Day 0 to Day 5 or hospital discharge whichever comes first
Other	RAAS pathway mechanistic biomarkers (when possible and applicable, at participating sites)	Proportion of participants with changes in RAAS mechanistic biomarkers (AngII, Ang(1-7), ACE activity and ACE2 activity) before, during and after therapy during hospitalization.	Day 0 to Day 5 or hospital discharge whichever comes first
Other	Trajectories of biomarkers related to COVID-19 (when possible, at participating sites)	Proportion of participants with changes in trajectories of biomarkers related to COVID-19	Day 0 to Day 5 or hospital discharge whichever comes first
Other	Changes in NT-proBNP (when possible, at participating sites)	Proportion of participants with changes in NTproBNP before, during and after therapy during hospitalization.	Day 0 to Day 5 or hospital discharge whichever comes first
Other	Hypotension	Proportion of participants with hypotension defined by low arterial blood pressure leading to either [1] initiation or increase in vasopressor therapy, [2] administration of a fluid bolus of 500 ml or more, or [3] modification of the dose or discontinuation of the study drug.	Day 0 to Day 5 or hospital discharge whichever comes first
Other	Allergic reaction	Proportion of participants with allergic reaction, including rash and angioedema	Day 0 to Day 5 or hospital discharge whichever comes first
Other	Incident renal replacement therapy during hospitalization (when possible, at participating sites)	Proportion of participants requiring renal replacement therapy	Day 0 to Day 5 or hospital discharge whichever comes first
Primary	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).	Day 1 to Day 28
Secondary	In-hospital mortality	Proportion of patients who die during hospitalization	Day 1 to hospital discharge or Day 90 whichever comes first
Secondary	Alive and oxygen free at Day 14	Proportion 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).	Day 1 to Day 14
Secondary	Alive and oxygen free at Day 28	Proportion 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).	Day 1 to Day 28
Secondary	Alive and free of new invasive mechanical ventilation at day 28	Proportion of patients alive free of new invasive mechanical ventilation at day 28	Day 1 to Day 28
Secondary	28-day mortality	Proportion of patients alive at Day 28	Day 28
Secondary	60-day mortality	Proportion of patients alive at Day 60	Day 60
Secondary	90-day mortality	Proportion of patients alive at Day 90	Day 90
Secondary	Clinical status assessed using World Health Organization (WHO) 8-point ordinal scale at Day 14	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	Day 14
Secondary	Clinical status assessed using WHO 8-point ordinal scale at Day 28	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	Day 28
Secondary	Clinical status assessed using WHO 8-point ordinal scale at Day 60	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	Day 60
Secondary	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.	Day 1 to Day 28
Secondary	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.	Day 1 to Day 28
Secondary	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.	Day 1 to Day 28