Clinical trial NCT04924660: Novel Experimental COVID-19 Therapies Affecting Host Response
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: COVID-19
SARS-CoV-2 Infection
Coronavirus Infection
Keywords: COVID-19 drug treatment
RAAS
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2021-06-14
Enrollment: 1060
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief 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. 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Oxygen Free Days Through Day 28.
timeFrame: Day 1 to Day 28
Secondary outcomes:
measure: In-hospital Mortality
timeFrame: Day 1 to hospital discharge or Day 90 whichever comes first
measure: Alive and Oxygen Free at Day 14
timeFrame: Day 1 to Day 14
measure: Alive and Oxygen Free at Day 28
timeFrame: Day 1 to Day 28
measure: Alive and Free of New Invasive Mechanical Ventilation at Day 28
timeFrame: Day 1 to Day 28
measure: 28-day Mortality
timeFrame: Day 28
measure: 60-day Mortality
timeFrame: Day 60
measure: 90-day Mortality
timeFrame: Day 90
measure: Clinical Status Assessed Using World Health Organization(WHO) 8-point Ordinal Scale
timeFrame: Day 14
measure: Clinical Status Assessed Using WHO 8-point Ordinal Scale at Day 28
timeFrame: Day 28
measure: Clinical Status Assessed Using WHO 8-point Ordinal Scale at Day 60
timeFrame: Day 60
measure: Hospital-free Days Through Day 28
timeFrame: Day 1 to Day 28
measure: Ventilator-free Days Through Day 28
timeFrame: Day 1 to Day 28
measure: Respiratory Failure-free Days Through Day 28
timeFrame: Day 1 to Day 28
Other outcomes:
measure: Hypotension
timeFrame: Day 0 to Day 5 or hospital discharge whichever comes first
measure: Allergic Reaction
timeFrame: Day 0 to Day 5 or hospital discharge whichever comes first
measure: Incident Renal Replacement Therapy During Hospitalization
timeFrame: Day 0 to Day 5 or hospital discharge whichever comes first
Locations:
city: Birmingham
country: United States
facility: University of Alabama Birmingham
state: Alabama
city: Chandler
country: United States
facility: Chandler Regional Medical Center
state: Arizona
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital
state: Colorado
city: Denver
country: United States
facility: Denver Health Medical Center
state: Colorado
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: Public Health Trust of Miami-Dade County, Florida - Jackson Memorial Hospital
state: Florida
city: Atlanta
country: United States
facility: Ponce de Leon Clinical Research Site
state: Georgia
city: Atlanta
country: United States
facility: Emory Johns Creek
state: Georgia
city: Atlanta
country: United States
facility: Emory St. Joseph's Hospital
state: Georgia
city: Elk Grove Village
country: United States
facility: Alexian Brothers Medical Center
state: Illinois
city: Hoffman Estates
country: United States
facility: AMITA Health St. Alexius Medical Center
state: Illinois
city: Baton Rouge
country: United States
facility: Our Lady of the Lake Regional Medical Center
state: Louisiana
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins Bayview Medical Center
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Silver Spring
country: United States
facility: Jadestone Clinical Research, LLC
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Newton
country: United States
facility: Newton-Wellesley Hospital
state: Massachusetts
city: Springfield
country: United States
facility: Baystate Health
state: Massachusetts
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Albuquerque
country: United States
facility: University of New Mexico Health Sciences Center
state: New Mexico
city: Bronx
country: United States
facility: Montefiore Medical Center Weiler Campus
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center Moses Campus
state: New York
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Akron
country: United States
facility: Cleveland Clinic Akron General
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Fairview Hospital
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: West Chester
country: United States
facility: West Chester Hospital
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: University of Texas, Houston
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah Health
state: Utah
city: Charlottesville
country: United States
facility: UVA Health
state: Virginia
city: Norfolk
country: United States
facility: Sentara Norfolk General Hospital
state: Virginia
city: Richmond
country: United States
facility: VCU Health
state: Virginia
city: Seattle
country: United States
facility: Harborview Medical Center/University of Washington
state: Washington
Study officials:
affiliation: Vanderbilt University Medical Center
name: Sean P. Collins, M.D.
role: STUDY_CHAIR
References: