NECTAR: Novel Experimental COVID-19 Therapies Affecting Host Response

Sponsor

Sean Collins (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

Locations

Arms

Anticipated Duration (Months)

23.5

Patients Per Site

1.1

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 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

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

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

Primary Outcome Measures

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

In-hospital mortality [Day 1 to hospital discharge or Day 90 whichever comes first]
Proportion of patients who die during hospitalization
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).
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).
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
28-day mortality [Day 28]
Proportion of patients alive at Day 28
60-day mortality [Day 60]
Proportion of patients alive at Day 60
90-day mortality [Day 90]
Proportion of patients alive at Day 90
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
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
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
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.
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.
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

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.
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.
RAAS pathway mechanistic biomarkers (when possible and applicable, 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.
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
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.
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.
Allergic reaction [Day 0 to Day 5 or hospital discharge whichever comes first]
Proportion of participants with allergic reaction, including rash and angioedema
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:

Inclusion criteria

Hospitalized for COVID-19
≥18 years of age
SARS-CoV-2 infection, documented by:
a nucleic acid test (NAT) or equivalent testing within 3 days prior to randomization OR
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).
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
Symptoms or signs of acute COVID-19, defined as one or more of the following:
cough
reported or documented body temperature of 100.4 degrees Fahrenheit or greater
shortness of breath
chest pain
infiltrates on chest imaging (x-ray, CT scan, lung ultrasound)

Exclusion criteria

Onset of COVID-19 symptom fulfilling inclusion criterion #5 >14 days prior to randomization
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)
Pregnancy
Breastfeeding
Prisoners
End-stage renal disease (ESRD) on dialysis
Patient undergoing comfort care measures only such that treatment focuses on end-of-life symptom management over prolongation of life.
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(4/20/2022 Closed to Accrual):

Patient unable to participate or declines participation in the TXA127/Ang(1-7) arm.
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)
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.
Known severe renal artery stenosis.
Known significant left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy or severe aortic or mitral stenosis.
Randomized in another trial evaluating RAAS modulation in the prior 30 days

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

Participants on ARBs will be excluded from this study arm.
Patient unable to participate or declines participation in the TRV027 arm.
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)
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.
Known severe renal artery stenosis.
Known significant left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy or severe aortic or mitral stenosis.
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:

Randomized in another trial evaluating fostamatinib in the prior 30 days

Study arm exclusion criteria measured within 24 hours prior to randomization:

AST or ALT ≥ 5 × upper limit of normal (ULN) or ALT or AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN
SBP > 160 mmHg or DBP > 100 mmHg at the time of screening and randomization
ANC < 1000/mL
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.
Patient unable to participate or declines participation in the fostamatinib arm.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama Birmingham	Birmingham	Alabama	United States	35249
2	Chandler Regional Medical Center	Chandler	Arizona	United States	85224
3	Los Angeles County University of Southern California Medical Center	Los Angeles	California	United States	90033
4	University of Southern California	Los Angeles	California	United States	90033
5	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
6	Ronald Reagan UCLA Medical Center	Los Angeles	California	United States	90095
7	UCSF Medical Center - Parnassus	San Francisco	California	United States	94143
8	Stanford University	Stanford	California	United States	94305
9	University of Colorado Hospital	Aurora	Colorado	United States	80010
10	Denver Health Medical Center	Denver	Colorado	United States	80204
11	Yale University	New Haven	Connecticut	United States	06510
12	University of Florida	Gainesville	Florida	United States	32610
13	University of Florida, Jacksonville	Jacksonville	Florida	United States	32209
14	Public Health Trust of Miami-Dade County, Florida - Jackson Memorial Hospital	Miami	Florida	United States	33136
15	Ponce de Leon Clinical Research Site	Atlanta	Georgia	United States	30303
16	Emory Johns Creek	Atlanta	Georgia	United States	30322
17	Emory St. Joseph's Hospital	Atlanta	Georgia	United States	30342
18	University of Illinois at Chicago	Chicago	Illinois	United States	60612
19	Alexian Brothers Medical Center	Elk Grove Village	Illinois	United States	60007
20	AMITA Health St. Alexius Medical Center	Hoffman Estates	Illinois	United States	60169
21	University of Kentucky	Lexington	Kentucky	United States	40536
22	Our Lady of the Lake Regional Medical Center	Baton Rouge	Louisiana	United States	70808
23	Ochsner Clinic Foundation	New Orleans	Louisiana	United States	70121
24	Johns Hopkins Bayview Medical Center	Baltimore	Maryland	United States	21224
25	Johns Hopkins University	Baltimore	Maryland	United States	21287
26	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02072
27	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
28	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
29	Newton-Wellesley Hospital	Newton	Massachusetts	United States	02462
30	Baystate Health	Springfield	Massachusetts	United States	01119
31	University of Michigan	Ann Arbor	Michigan	United States	48109
32	Detroit Receiving Hospital	Detroit	Michigan	United States	48201
33	DMC Detroit Receiving Hospital	Detroit	Michigan	United States	48201
34	Sinai-Grace Hospital	Detroit	Michigan	United States	48235
35	University of Minnesota Fairview Southdale	Edina	Minnesota	United States	55435
36	Hennepin County Medical Center	Minneapolis	Minnesota	United States	55415
37	University of Minnesota Medical Center	Minneapolis	Minnesota	United States	55455
38	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
39	Washington University	Saint Louis	Missouri	United States	63110
40	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
41	University of New Mexico Health Sciences Center	Albuquerque	New Mexico	United States	87106
42	Montefiore Medical Center Weiler Campus	Bronx	New York	United States	10461
43	Montefiore Medical Center Moses Campus	Bronx	New York	United States	10467
44	Mount Sinai Hospital	New York	New York	United States	10029
45	Columbia University Irving Medical Center	New York	New York	United States	10032
46	University of North Carolina Medical Center	Chapel Hill	North Carolina	United States	27514
47	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
48	Cleveland Clinic Akron General	Akron	Ohio	United States	44321
49	University of Cincinnati	Cincinnati	Ohio	United States	45229
50	Cleveland Clinic Fairview Hospital	Cleveland	Ohio	United States	44111
51	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
52	Cleveland Clinic Marymount Hospital	Garfield Heights	Ohio	United States	44125
53	Cleveland Clinic Hillcrest Hospital	Mayfield Heights	Ohio	United States	44124
54	West Chester Hospital	West Chester	Ohio	United States	45069
55	Oregon Health & Science University	Portland	Oregon	United States	97239
56	Temple University Hospital	Philadelphia	Pennsylvania	United States	19140
57	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19146
58	Medical University of South Carolina	Charleston	South Carolina	United States	29425
59	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37203
60	Tennessee Valley Healthcare System- Nashville	Nashville	Tennessee	United States	37212
61	UT Southwestern Medical Center	Dallas	Texas	United States	75390
62	University of Texas, Houston	Houston	Texas	United States	77030
63	Intermountain Medical Center	Murray	Utah	United States	84107
64	University of Utah Health	Salt Lake City	Utah	United States	84108
65	UVA Health	Charlottesville	Virginia	United States	22908
66	Sentara Norfolk General Hospital	Norfolk	Virginia	United States	23507
67	VCU Health	Richmond	Virginia	United States	23298
68	Harborview Medical Center/University of Washington	Seattle	Washington	United States	98104