Clinical trial NCT05593770: International Sites: Novel Experimental COVID-19 Therapies Affecting Host Response
Official title: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: COVID-19
SARS-CoV2 Infection
Coronavirus Infection
Lead sponsor: NEAT ID Foundation
Sponsor class: OTHER
First posted: 2022-10-25
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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 Exclusion Criteria:

The following exclusion criteria differ from the master protocol criteria:

1. Randomized in another trial evaluating fostamatinib in the prior 30 days

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

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

Primary outcomes:
measure: Oxygen Free Days Through Day 28
timeFrame: Day 1 to Day 28
Secondary outcomes:
measure: In-hospital Mortality
timeFrame: Day 1 to hospital discharge or Day 90 whichever comes first
measure: Alive and Oxygen Free at Day 14
timeFrame: Day 1 to Day 14
measure: Alive and Oxygen Free at Day 28
timeFrame: Day 1 to Day 28
measure: Alive and Free of New Invasive Mechanical Ventilation at Day 28
timeFrame: Day 1 to Day 28
measure: 28-day Mortality
timeFrame: Day 28
measure: 60-day Mortality
timeFrame: Day 60
measure: 90-day Mortality
timeFrame: Day 90
measure: Clinical Status Assessed Using World Health Organization (WHO) 8-point Ordinal Scale at Day 14
timeFrame: Day 14
measure: Clinical Status Assessed Using WHO 8-point Ordinal Scale at Day 28
timeFrame: Day 28
measure: Clinical Status Assessed Using WHO 8-point Ordinal Scale at Day 60
timeFrame: Day 60
measure: Hospital-free Days Through Day 28
timeFrame: Day 1 to Day 28
measure: Ventilator-free Days Through Day 28
timeFrame: Day 1 to Day 28
measure: Respiratory Failure-free Days Through Day 28
timeFrame: Day 1 to Day 28
Other outcomes:
Locations:
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre
city: Rio De Janeiro
country: Brazil
facility: Hospital Federal dos Servidores do Estado
city: Rio De Janeiro
country: Brazil
facility: Instituto Nacional de Infectologia Evandro Chagas
city: Bonn
country: Germany
facility: University Hospital Bonn
city: Frankfurt
country: Germany
facility: University of Frankfurt
city: Genova
country: Italy
facility: Ente Ospedaliero Ospedali Galliera
city: Milan
country: Italy
facility: San Paolo Hospital - ASST Santi Paolo e Carlo
city: Milan
country: Italy
facility: San Raffaele Turro Hospital
city: Milan
country: Italy
facility: University of Milan
city: Benoni
country: South Africa
facility: Worthwhile Clinical Trials (WWCT Lakeview Hospital)
city: Johannesburg
country: South Africa
facility: Clinical HIV Research Unit - Helen Joseph Hospital (WITS CHRU)
city: Pretoria
country: South Africa
facility: Global Clinical Trials (Pty) Ltd
city: Barcelona
country: Spain
facility: Hospital Clinic Barcelona
state: Villarroel
city: Alicante
country: Spain
facility: Hospital General Universitario de Elche
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario Fundacion Alcorcon
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Valladolid
country: Spain
facility: Universidad de Valladolid - Hospital Universitario Río Hortega
city: Zaragoza
country: Spain
facility: Hospital Clinico Universitario Lozano Blesa
Study officials:
affiliation: NEAT ID
name: Anton Pozniak, Prof
role: PRINCIPAL_INVESTIGATOR
References: