NECTAR: Novel Experimental COVID-19 Therapies Affecting Host Response

Sponsor
Vanderbilt University Medical Center (Other)
Overall Status
Recruiting
CT.gov ID
NCT04924660
Collaborator
National Institutes of Health (NIH) (NIH), National Heart, Lung, and Blood Institute (NHLBI) (NIH)
1,600
Enrollment
65
Locations
4
Arms
21
Anticipated Duration (Months)
24.6
Patients Per Site
1.2
Patients Per Site Per Month

Study Details

Study Description

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 DiseaseIntervention/TreatmentPhase
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.

Study Design

Study Type:
Interventional
Anticipated 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.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 :
Jul 15, 2021
Anticipated Primary Completion Date :
Feb 10, 2023
Anticipated Study Completion Date :
Apr 15, 2023

Arms and Interventions

ArmIntervention/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 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

Primary Outcome Measures

  1. Oxygen free days through day 28. [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 [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 [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 [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 [Day 1 to Day 28]

    Proportion of patients alive free of new invasive mechanical ventilation at day 28

  5. 28-day mortality [Day 28]

    Proportion of patients alive at Day 28

  6. 60-day mortality [Day 60]

    Proportion of patients alive at Day 60

  7. 90-day mortality [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 [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

  9. Clinical status assessed using WHO 8-point ordinal scale at Day 28 [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

  10. Clinical status assessed using WHO 8-point ordinal scale at Day 60 [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

  11. Hospital-free days through day 28 [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 [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 [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) [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) [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, at participating sites) [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) [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) [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 [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 [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) [Day 0 to Day 5 or hospital discharge whichever comes first]

    Proportion of participants requiring renal replacement therapy

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No

Inclusion criteria

  1. Hospitalized for COVID-19

  2. ≥18 years of age

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

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

  5. 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)

  6. 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

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

  8. cough

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

  10. shortness of breath

  11. chest painTXA127-specific exclusion criter

  12. infiltrates on chest imaging (x-ray, CT scan, lung ultrasound)

Exclusion criteria

  1. COVID-19 symptom onset >14 days prior to randomization

  2. Hospitalized for >72 hours prior to randomization

  3. Pregnancy

  4. Breastfeeding

  5. Prisoners

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

  7. 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).

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

The following exclusion criteria differ from the master protocol criteria:
TXA127-specific exclusion criteria:
  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:
  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:
  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 requires use of strong CYP3A modulators from Table above (Clarithromycin, Indinavir, Itraconazole, Ketoconazole, Nefazodone, Nelfinavir, Ritonavir, Saquinavir, Telithromycin, Troleandomycin, Carbamazepine, Efavirenz, Enzalutamide, Modafinil, Nevirapine, Oxcarbazepine, Phenobarbital, Phenytoin, Rifabutin, Rifampin, St. John's Wort, or Troglitazone).

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

Contacts and Locations

Locations

SiteCityStateCountryPostal Code
1University of Alabama BirminghamBirminghamAlabamaUnited States35249
2Chandler Regional Medical CenterChandlerArizonaUnited States85224
3Los Angeles County University of Southern California Medical CenterLos AngelesCaliforniaUnited States90033
4University of Southern CaliforniaLos AngelesCaliforniaUnited States90033
5Cedars-Sinai Medical CenterLos AngelesCaliforniaUnited States90048
6Ronald Reagan UCLA Medical CenterLos AngelesCaliforniaUnited States90095
7UCSF Medical Center - ParnassusSan FranciscoCaliforniaUnited States94143
8Stanford UniversityStanfordCaliforniaUnited States94305
9University of Colorado HospitalAuroraColoradoUnited States80010
10Denver Health Medical CenterDenverColoradoUnited States80204
11Yale UniversityNew HavenConnecticutUnited States06510
12University of FloridaGainesvilleFloridaUnited States32610
13University of Florida, JacksonvilleJacksonvilleFloridaUnited States32209
14Public Health Trust of Miami-Dade County, Florida - Jackson Memorial HospitalMiamiFloridaUnited States33136
15Ponce de Leon Clinical Research SiteAtlantaGeorgiaUnited States30303
16Emory Johns CreekAtlantaGeorgiaUnited States30322
17Emory St. Joseph's HospitalAtlantaGeorgiaUnited States30342
18University of Illinois at ChicagoChicagoIllinoisUnited States60612
19Alexian Brothers Medical CenterElk Grove VillageIllinoisUnited States60007
20AMITA Health St. Alexius Medical CenterHoffman EstatesIllinoisUnited States60169
21University of KentuckyLexingtonKentuckyUnited States40536
22Our Lady of the Lake Regional Medical CenterBaton RougeLouisianaUnited States70808
23Ochsner Clinic FoundationNew OrleansLouisianaUnited States70121
24Johns Hopkins Bayview Medical CenterBaltimoreMarylandUnited States21224
25Johns Hopkins UniversityBaltimoreMarylandUnited States21287
26Beth Israel Deaconess Medical CenterBostonMassachusettsUnited States02072
27Massachusetts General HospitalBostonMassachusettsUnited States02114
28Brigham and Women's HospitalBostonMassachusettsUnited States02115
29Newton-Wellesley HospitalNewtonMassachusettsUnited States02462
30Baystate HealthSpringfieldMassachusettsUnited States01119
31University of MichiganAnn ArborMichiganUnited States48109
32Detroit Receiving HospitalDetroitMichiganUnited States48201
33DMC Detroit Receiving HospitalDetroitMichiganUnited States48201
34Sinai-Grace HospitalDetroitMichiganUnited States48235
35University of Minnesota Fairview SouthdaleEdinaMinnesotaUnited States55435
36Hennepin County Medical CenterMinneapolisMinnesotaUnited States55415
37University of Minnesota Medical CenterMinneapolisMinnesotaUnited States55455
38University of Mississippi Medical CenterJacksonMississippiUnited States39216
39Washington UniversitySaint LouisMissouriUnited States63110
40University of Nebraska Medical CenterOmahaNebraskaUnited States68198
41University of New Mexico Health Sciences CenterAlbuquerqueNew MexicoUnited States87106
42Montefiore Medical Center Weiler CampusBronxNew YorkUnited States10461
43Montefiore Medical Center Moses CampusBronxNew YorkUnited States10467
44Columbia University Irving Medical CenterNew YorkNew YorkUnited States10032
45University of North Carolina Medical CenterChapel HillNorth CarolinaUnited States27514
46Wake Forest University Health SciencesWinston-SalemNorth CarolinaUnited States27157
47Cleveland Clinic Akron GeneralAkronOhioUnited States44321
48University of CincinnatiCincinnatiOhioUnited States45229
49Cleveland Clinic Fairview HospitalClevelandOhioUnited States44111
50Cleveland Clinic FoundationClevelandOhioUnited States44195
51Cleveland Clinic Marymount HospitalGarfield HeightsOhioUnited States44125
52Cleveland Clinic Hillcrest HospitalMayfield HeightsOhioUnited States44124
53Oregon Health & Science UniversityPortlandOregonUnited States97239
54Temple University HospitalPhiladelphiaPennsylvaniaUnited States19140
55Thomas Jefferson UniversityPhiladelphiaPennsylvaniaUnited States19146
56Medical University of South CarolinaCharlestonSouth CarolinaUnited States29425
57Vanderbilt University Medical CenterNashvilleTennesseeUnited States37203
58Tennessee Valley Healthcare System- NashvilleNashvilleTennesseeUnited States37212
59UT Southwestern Medical CenterDallasTexasUnited States75390
60University of Texas, HoustonHoustonTexasUnited States77030
61Intermountain Medical CenterMurrayUtahUnited States84107
62University of Utah HealthSalt Lake CityUtahUnited States84108
63UVA HealthCharlottesvilleVirginiaUnited States22908
64VCU HealthRichmondVirginiaUnited States23298
65Harborview Medical Center/University of WashingtonSeattleWashingtonUnited States98104

Sponsors and Collaborators

  • Vanderbilt University Medical Center
  • National Institutes of Health (NIH)
  • National Heart, Lung, and Blood Institute (NHLBI)

Investigators

  • Study Chair: Sean P. Collins, M.D., Vanderbilt University Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Sean Collins, Professor, Emergency Medicine, Vanderbilt University Medical Center
ClinicalTrials.gov Identifier:
NCT04924660
Other Study ID Numbers:
  • 210982
First Posted:
Jun 14, 2021
Last Update Posted:
Mar 9, 2022
Last Verified:
Mar 1, 2022
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Sean Collins, Professor, Emergency Medicine, Vanderbilt University Medical Center
Additional relevant MeSH terms:

Study Results

No Results Posted as of Mar 9, 2022