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Novel Experimental COVID-19 Therapies Affecting Host Response (NECTAR)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04924660
Recruitment Status : Recruiting
First Posted : June 14, 2021
Last Update Posted : June 5, 2023
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Sean Collins, Vanderbilt University Medical Center

Study Description
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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.

Condition or disease Intervention/treatment Phase
COVID-19 SARS-CoV-2 Infection Coronavirus Infection Drug: TXA127 Drug: TRV027 Drug: Placebo Drug: Fostamatinib Phase 2 Phase 3

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
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1600 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Which study drug arm the participant enters will be known to the research sites and the participants, but assignment to active versus placebo will be blinded. The randomized assignment, concealed from the research team, will be transmitted to the site pharmacy, who will provide study medication. The participant, treating clinicians, study personnel (other than the unblinded statistician who will prepare closed DSMB interim reports), and outcome assessors will all remain blinded to group assignment until after the database is locked and blinded analysis is completed.
Primary Purpose: Treatment
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)
Actual Study Start Date : July 15, 2021
Estimated Primary Completion Date : August 29, 2023
Estimated Study Completion Date : October 29, 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: TXA127 (4/20/2022 Arm Closed to Accrual)
An investigational peptide agonist of Mas receptors.
 Drug: TXA127
TXA127 0.5 mg/kg/day infused 3 hours daily for 5 days or until hospital discharge whichever comes first.
Experimental: TRV027 (4/20/2022 Arm Closed to Accrual)
An investigational peptide biased agonist of the AT1 receptor.
 Drug: TRV027
TRV027 12mg/h as a continuous 24-hour infusion, infused for 5 days or until hospital discharge whichever comes first.
Placebo Comparator: Placebo

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.

 Drug: 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.
Experimental: Fostamatinib
An investigational oral spleen tyrosine kinase inhibitor.
 Drug: 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.


Outcome Measures
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Primary Outcome Measures :
  1. 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).


Secondary Outcome Measures :
  1. In-hospital mortality [ Time Frame: Day 1 to hospital discharge or Day 90 whichever comes first ]
    Proportion of patients who die during hospitalization

  2. Alive and oxygen free at Day 14 [ Time Frame: Day 1 to 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).

  3. Alive and oxygen free at Day 28 [ Time Frame: Day 1 to 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).

  4. Alive and free of new invasive mechanical ventilation at day 28 [ Time Frame: Day 1 to Day 28 ]
    Proportion of patients alive free of new invasive mechanical ventilation at day 28

  5. 28-day mortality [ Time Frame: Day 28 ]
    Proportion of patients alive at Day 28

  6. 60-day mortality [ Time Frame: Day 60 ]
    Proportion of patients alive at Day 60

  7. 90-day mortality [ Time Frame: Day 90 ]
    Proportion of patients alive at Day 90

  8. Clinical status assessed using World Health Organization (WHO) 8-point ordinal scale at Day 14 [ Time Frame: Day 14 ]
    1. Ambulatory - Not hospitalized and no limitation of activities
    2. Ambulatory - Not hospitalized with limitation of activities or home oxygen use
    3. Hospitalized Mild Disease - Hospitalized, no oxygen therapy
    4. Hospitalized Mild Disease - Hospitalized, oxygen by mask or nasal prongs
    5. Hospitalized Severe Disease - Non-invasive ventilation or high-flow nasal cannula
    6. Hospitalized Severe Disease -Invasive mechanical ventilation
    7. Hospitalized Severe Disease - Invasive mechanical ventilation plus additional organ support with- vasopressors, RRT, or ECMO
    8. Dead

  9. Clinical status assessed using WHO 8-point ordinal scale at Day 28 [ Time Frame: Day 28 ]
    1. Ambulatory - Not hospitalized and no limitation of activities
    2. Ambulatory - Not hospitalized with limitation of activities or home oxygen use
    3. Hospitalized Mild Disease - Hospitalized, no oxygen therapy
    4. Hospitalized Mild Disease - Hospitalized, oxygen by mask or nasal prongs
    5. Hospitalized Severe Disease - Non-invasive ventilation or high-flow nasal cannula
    6. Hospitalized Severe Disease -Invasive mechanical ventilation
    7. Hospitalized Severe Disease - Invasive mechanical ventilation plus additional organ support with- vasopressors, RRT, or ECMO
    8. Dead

  10. Clinical status assessed using WHO 8-point ordinal scale at Day 60 [ Time Frame: Day 60 ]
    1. Ambulatory - Not hospitalized and no limitation of activities
    2. Ambulatory - Not hospitalized with limitation of activities or home oxygen use
    3. Hospitalized Mild Disease - Hospitalized, no oxygen therapy
    4. Hospitalized Mild Disease - Hospitalized, oxygen by mask or nasal prongs
    5. Hospitalized Severe Disease - Non-invasive ventilation or high-flow nasal cannula
    6. Hospitalized Severe Disease -Invasive mechanical ventilation
    7. Hospitalized Severe Disease - Invasive mechanical ventilation plus additional organ support with- vasopressors, RRT, or ECMO
    8. Dead

  11. Hospital-free days through day 28 [ Time Frame: Day 1 to 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.

  12. Ventilator-free days through day 28 [ Time Frame: Day 1 to 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.

  13. Respiratory failure-free days through day 28 [ Time Frame: Day 1 to 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.


Other Outcome Measures:
  1. Renal outcomes: acute kidney Injury (when possible, at participating sites) [ Time Frame: Day 0 to Day 5 or hospital discharge whichever comes first ]
    Proportion of participants with evidence of acute kidney injury using the KDIGO Stage 2 criteria for serum creatinine relative to baseline at Day 0.

  2. Myocardial injury (when possible, at participating sites) [ Time Frame: Day 0 to Day 5 or hospital discharge whichever comes first ]
    Proportion of participants with Myocardial injury described by changes in troponin before, during and after therapy during hospitalization.

  3. RAAS pathway mechanistic biomarkers (when possible and applicable, at participating sites) [ Time Frame: Day 0 to Day 5 or hospital discharge whichever comes first ]
    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.

  4. Trajectories of biomarkers related to COVID-19 (when possible, at participating sites) [ Time Frame: Day 0 to Day 5 or hospital discharge whichever comes first ]
    Proportion of participants with changes in trajectories of biomarkers related to COVID-19

  5. Changes in NT-proBNP (when possible, at participating sites) [ Time Frame: Day 0 to Day 5 or hospital discharge whichever comes first ]
    Proportion of participants with changes in NTproBNP before, during and after therapy during hospitalization.

  6. Hypotension [ Time Frame: Day 0 to Day 5 or hospital discharge whichever comes first ]
    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.

  7. Allergic reaction [ Time Frame: Day 0 to Day 5 or hospital discharge whichever comes first ]
    Proportion of participants with allergic reaction, including rash and angioedema

  8. Incident renal replacement therapy during hospitalization (when possible, at participating sites) [ Time Frame: Day 0 to Day 5 or hospital discharge whichever comes first ]
    Proportion of participants requiring renal replacement therapy


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04924660


Contacts
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Contact: Sheri L. Dixon, B.S.N., R.N. 615-343-0266 sheri.dixon@vumc.org
Contact: Sean P. Collins, M.D. 615-875-6151 sean.collins@vumc.org

Locations
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Sponsors and Collaborators
Sean Collins
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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Study Chair: Sean P. Collins, M.D. Vanderbilt University Medical Center
More Information
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Responsible Party: Sean Collins, Professor, Emergency Medicine, Vanderbilt University Medical Center
ClinicalTrials.gov Identifier: NCT04924660    
Other Study ID Numbers: 210982
First Posted: June 14, 2021    Key Record Dates
Last Update Posted: June 5, 2023
Last Verified: June 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Sean Collins, Vanderbilt University Medical Center:
COVID-19 drug treatment
RAAS
Additional relevant MeSH terms:
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Infections
Communicable Diseases
COVID-19
Coronavirus Infections
Disease Attributes
Pathologic Processes
Pneumonia, Viral
Pneumonia
Respiratory Tract Infections
 Virus Diseases
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Angiotensin I (1-7)
Antihypertensive Agents
Vasodilator Agents