International Sites: Novel Experimental COVID-19 Therapies Affecting Host Response

International Sites: 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)

Status

Terminated

Phases

Phase 2Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT05593770

Acronym

NECTAR

Enrollment

Registered

2022-10-25

Start date

2022-10-27

Completion date

2023-12-14

Last updated

2025-05-02

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Coronavirus Infection, COVID-19, SARS-CoV2 Infection

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.

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.

Interventions

DRUGFostamatinib

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.

DRUGPlacebo

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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, 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.

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.

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Hospitalized for COVID-19 2. ≥18 years of age 3. SARS-CoV-2 infection, documented by: 1. 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 Fostamatinib Arm-Specific

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
Alive and Oxygen Free at Day 14	Day 1 to Day 14	Number 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	Number 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	Number of patients alive free of new invasive mechanical ventilation at day 28
28-day Mortality	Day 28	Number of patients who have died at Day 28
60-day Mortality	Day 60	Number of patients who have died at Day 60
90-day Mortality	Day 90	Number of participants mortality at Day 90
In-hospital Mortality	Day 1 to hospital discharge or Day 90 whichever comes first	Number of patients who die during hospitalization
Clinical Status Assessed Using WHO 8-point Ordinal Scale at Day 28	Day 28	The number of participants who fell within the ordinal scale per the below criteria. A higher score means a worse outcome 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
Clinical Status Assessed Using WHO 8-point Ordinal Scale at Day 60	Day 60	Number of participants who fell within the ordinal scale per the below criteria. A higher score means a worse outcome 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
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.
Clinical Status Assessed Using World Health Organization (WHO) 8-point Ordinal Scale at Day 14	Day 14	Number of participants who fell within the ordinal scale per the below criteria. A higher score indicates a worse outcome. 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

Countries

Brazil, Germany, Italy, South Africa, Spain

Participant flow

Pre-assignment details

Participants were over 18 years old with documented SARS-COV-2 infection confirmed by nucleic acid test. Participants were assigned to receive either the active Fostamatinib drug or matching placebo.

Participants by arm

Arm	Count
Fostamatinib An investigational oral spleen tyrosine kinase inhibitor. 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.	14
Placebo 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. Placebo: 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.	14
Total	28

Baseline characteristics

Characteristic	Fostamatinib	Placebo	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	10 Participants	11 Participants	21 Participants
Age, Categorical Between 18 and 65 years	4 Participants	3 Participants	7 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	2 Participants	2 Participants	4 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants	0 Participants	2 Participants
Race (NIH/OMB) White	10 Participants	12 Participants	22 Participants
Region of Enrollment Brazil	1 participants	0 participants	1 participants
Region of Enrollment Germany	0 participants	1 participants	1 participants
Region of Enrollment Italy	1 participants	1 participants	2 participants
Region of Enrollment South Africa	2 participants	3 participants	5 participants
Region of Enrollment Spain	10 participants	9 participants	19 participants
Sex: Female, Male Female	6 Participants	6 Participants	12 Participants
Sex: Female, Male Male	8 Participants	8 Participants	16 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	1 / 14	3 / 14
other Total, other adverse events	8 / 14	4 / 14
serious Total, serious adverse events	8 / 14	5 / 14

Outcome results

Primary

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. 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).

Time frame: Day 1 to Day 28

Population: The number of participants enrolled by international sites was insufficient for analysis due to the early termination of the trial. This analysis was performed on all participants enrolled to the fostamatinib arm of the ACTIV-4 Host Tissue platform (United states + International sites).The global fostamatinib arm of the ACTIV 4 study enrolled 400 participants, of which 28 were included from international sites and the results are reported in a separate Clinicaltrials.gov record, ref NCT04924660

Arm	Measure	Value (MEAN)	Dispersion
Fostamatinib	Oxygen Free Days Through Day 28	13.4 days	Standard Deviation 12.4
Placebo	Oxygen Free Days Through Day 28	14.2 days	Standard Deviation 12.1

Secondary