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Trial record 1 of 1 for:    NCT04924660
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Novel Experimental COVID-19 Therapies Affecting Host Response (NECTAR)

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ClinicalTrials.gov Identifier: NCT04924660
Recruitment Status : Recruiting
First Posted : June 14, 2021
Last Update Posted : August 23, 2021
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

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 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.

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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 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 : May 31, 2022
Estimated Study Completion Date : December 30, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: TXA127
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
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 (3 hours for TXA127 and continuous 24-hour infusion for TRV027).
Drug: Placebo
NaCl 0.9% infused to match the duration of the agent (3 hours for TXA127 and continuous 24-hour infusion for TRV027




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 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 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 [ Time Frame: Day 1 to Day 28 ]
    Number of days outside of the hospital

  12. Ventilator-free days [ Time Frame: Day 1 to Day 28 ]
    Number of days without use of a ventilator

  13. Respiratory failure free days [ Time Frame: Day 1 to Day 28 ]
    A respiratory failure-free day is defined as a day alive without the use of HFNC, NIV, IMV, or (ECMO).


Other Outcome Measures:
  1. Renal outcomes: acute kidney Injury [ Time Frame: Day 0 to Day 5 or hospital discharge whichever comes first ]
    Proportion of participants with acute kidney Injury (following KDIGO) defined as > KDIGO Stage 2 and changes in serum creatinine and estimated Glomerular Filtration Rate.

  2. Myocardial injury (pending funding) [ 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 (pending funding) [ 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), Plasma renin activity, Aldosterone, ACE and ACE2) before, during and after therapy during hospitalization.

  4. Trajectories of biomarkers related to COVID-19 [ 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 (pending funding) [ 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 [ Time Frame: Day 0 to Day 5 or hospital discharge whichever comes first ]
    Proportion of participants requiring renal replacement therapy



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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 in the study protocol)
  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 100.4o F or greater
    3. shortness of breath
    4. chest pain
    5. infiltrates on chest imaging (x-ray, CT scan, lung ultrasound)

Exclusion criteria

  1. 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
  2. COVID-19 symptom onset >14 days prior to randomization
  3. Hospitalized for >72 hours prior to randomization
  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. Pregnancy
  6. Breastfeeding
  7. Prisoners
  8. End-stage renal disease (ESRD) on dialysis
  9. Patient and/or clinical team is not pursuing full medical management (if a patient has a Do Not Resuscitate order that precludes chest compressions in the event of a cardiac arrest but is otherwise pursuing full medical management, he/she is eligible for this trial).
  10. Known severe renal artery stenosis
  11. Known significant left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy or severe aortic or mitral stenosis
  12. Randomized in another trial evaluating RAAS modulation in the prior 30 days
  13. The treating clinician expects inability to participate in study procedures or participation would not be in the best interests of the patient

TRV027-specific exclusion criteria: Participants on Angiotensin receptor blockers (ARBs) will be excluded from this study arm.

TXA127-specific exclusion criteria: eGFR < 30 mL/min/1.73m2


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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United States, Colorado
Denver Health Medical Center Not yet recruiting
Denver, Colorado, United States, 80204
Contact: Ivor S Douglas, MD    303-602-5012    ivor.douglas@dhha.org   
Contact: Terra D Hiller, MSN    303-602-1438    terra.hiller@dhha.org   
Principal Investigator: Ivor S Douglas, MD         
United States, Louisiana
Ochsner Clinic Foundation Not yet recruiting
New Orleans, Louisiana, United States, 70121
Contact: Derek Vonderhaar, MD    504-842-1618    derek.vonderhaar@ochsner.org   
Contact: Hailey Anderson    504-842-1618    hailey.anderson@ochsner.org   
Principal Investigator: Derek Vonderhaar, MD         
United States, New Mexico
University of New Mexico Health Sciences Center Not yet recruiting
Albuquerque, New Mexico, United States, 87106
Contact: Michelle S Harkins, MD    505-272-4751    mharkins@salud.unm.edu   
Contact: Rebecca Brito    505-272-9542    rbrito@salud.unm.edu   
Principal Investigator: Michelle S Harkins, MD         
United States, North Carolina
Wake Forest University Health Sciences Recruiting
Winston-Salem, North Carolina, United States, 27157
Contact: Clark Files, MD    410-530-5719    clark.files@wakehealth.edu   
Contact: Lori Flores, DNP    336-713-0008    lflores@wakehealth.edu   
Principal Investigator: Clark Files, MD         
United States, Ohio
Cleveland Clinic Foundation Not yet recruiting
Cleveland, Ohio, United States, 44195
Contact: Abhijit Duggal, MD    216-444-4838    duggala2@ccf.org   
Contact: Bryan Poynter, BS    216-538-9571    poynteb@ccf.org   
Principal Investigator: Abhijit Duggal, MD         
United States, Tennessee
Vanderbilt University Medical Center Recruiting
Nashville, Tennessee, United States, 37203
Contact: Wesley H. Self, MD, MPH    615-936-8047    wesley.self@vumc.org   
Contact: Sheri L. Dixon, BSN, RN    615-343-0266    sheri.dixon@vumc.org   
United States, Utah
University of Utah Health Not yet recruiting
Salt Lake City, Utah, United States, 84108
Contact: Estelle Harris, MD    801-581-5811    estelle.harris@hsc.utah.edu   
Contact: Macy Barrios    801-581-5811    macy.barrios@hsc.utah.edu   
Principal Investigator: Estelle Harris, MD         
Sponsors and Collaborators
Vanderbilt University Medical Center
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
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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: August 23, 2021
Last Verified: August 2021
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
Respiratory Tract Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Angiotensin I (1-7)
Antihypertensive Agents
Vasodilator Agents