ACTIV-4d or Novel Experimental COVID Therapies Affecting Host Response (NECTAR)
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StatusAccepting Candidates
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Age18 Years - N/A
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SexesAll
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Healthy VolunteersNo
Objective
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.
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.
Details
Full study 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) |
Protocol number | OCR40937 |
ClinicalTrials.gov ID | NCT04924660 |
Phase | Phase 2/Phase 3 |
Eligibility
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 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
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):
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.
Lead researcher
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Nicole M Iovine, MD, PhDInfectious Disease Specialist
Participate in a study
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Step1
Contact the research team
Call or email the research team listed within the specific clinical trial or study to let them know that you're interested. A member of the research team, such as the researcher or study coordinator, will be available to tell you more about the study and to answer any questions or concerns you may have.
Primary contact
Nicole Iovine -
Step2
Get screened to confirm eligibility
You may be asked to take part in prescreening to make sure you are eligible for a study. The prescreening process ensures it is safe for you to participate. During the prescreening process, you will be asked some questions and you may also be asked to schedule tests or procedures to confirm your eligibility.
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Step3
Provide your consent to participate
If you are eligible and want to join the clinical trial or study, a member of the research team will ask for your consent to participate. To give consent, you will be asked to read and sign a consent form for the study. This consent form explains the study's purpose, procedures, risks, benefits and provides other important information, such as the study team's contact information.
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Step4
Participate
If you decide to participate in a clinical trial or study, the research team will keep you informed of the study requirements and what you will need to do to throughout the study. For some trials or studies, your health care provider may work with the research team to ensure there are no conflicts with other medications or treatments.