Clinical trial NCT04401475: A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of EB05 + SOC Vs. Placebo + SOC in Adult Hospitalized Patients with COVID-19
Official title: A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of EB05 + SOC Vs. Placebo + SOC in Adult Hospitalized Patients with COVID-19
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE2
PHASE3
Conditions: COVID-19
ARDS
Keywords: TLR4
ARDS
COVID-19
Lead sponsor: Edesa Biotech Inc.
Sponsor class: INDUSTRY
Collaborators: name: JSS Medical Research Inc.
First posted: 2020-05-26
Enrollment: 644
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: This is a multicenter, randomized, double-blind, placebo-controlled, study to evaluate the safety and efficacy of EB05 in adult hospitalized patients with COVID-19. Following enrollment in the study, eligible subjects will be randomized at a ratio of 1:1 at baseline to receive an infusion of either EB05 or Placebo. In addition to study treatment, all patients will receive SOC treatment per routine care at each participating site. Randomization is stratified by site and baseline WHO COVID-19 severity strata defined as Levels 3-4 and Levels 5-6 for the phase 2 study and Levels 6-7 for the phase 3 study.

The total follow-up duration of each patient will be until 60-days from treatment with the investigational product. All assessments will take place in-hospital except for the 28-day and 60-day follow-up assessment which will be by telephone if the patient has been discharged before this assessment.
Primary purpose: TREATMENT

Brief summary: COVID-19 patients who develop severe disease often develop acute respiratory distress syndrome (ARDS) as a result of a dysregulated immune response. This in turn stimulates a pro-inflammatory cascade ("cytokine storm") as well as emergency myelopoiesis.

This proinflammatory cascade is activated when viral-mediated cell damage occurs in the lungs, resulting in the release of damage-signaling alarmin molecules such as S100A8/A9 (Calprotectin), HMGB1, Resistin, and oxidized phospholipids. These damage-associated molecular patterns (DAMPs) are recognized by the pattern recognition receptor Toll-Like Receptor 4 (TLR4) found on macrophages, dendritic cells and other innate immune cells and result in additional release of pro-inflammatory molecules. Several recent studies have shown that S100A8/A9 serum levels in hospitalized COVID-19 patients positively correlate with both neutrophil count and disease severity. Taken together the DAMP-TLR4 interaction forms a central axis in the innate immune system and is a key driver of the pathological inflammation observed in COVID-19. We hypothesis that targeting the initial step in the signalling pathways of these DAMPs in innate immunity offers the best hope for controlling the exaggerated host response to SARS-CoV-2 infection.

EB05 has demonstrated safety in two clinical studies (\>120 patients) and was able to block LPS-induced (TLR4 agonist) IL-6 release in humans. Given, this extensive body of evidence we believe EB05 could ameliorate ARDS due to COVID-19, significantly reducing ventilation rates and mortality.


Eligibility criteria: Inclusion Criteria:

1. Men and women ≥18 years of age at the time of consent.
2. Laboratory-confirmed diagnosis of COVID-19.
3. Hospitalized for COVID-19 related respiratory disease.
4. Patient belongs to one of the following two categories in the nine-point COVID-19 severity scale:

   1. Hospitalized, requiring intubation and mechanical ventilation - Level 6 of the nine-point COVID-19 severity scale.
   2. Hospitalized and intubated with additional organ support - pressors, RRT, ECMO - Level 7 of the nine-point COVID-19 severity scale.
5. For women of childbearing potential involved in any sexual intercourse that could lead to pregnancy: Negative pregnancy test and willingness to use contraceptive (consistent with local regulations) during the study period.
6. Signed informed consent obtained by any patient capable of giving consent, or, when the patient is not capable of giving consent, from his or her legal/authorized representatives.

Exclusion Criteria:

1. The subject is a female who is breastfeeding or pregnant.
2. Known hypersensitivity to EB05 or its excipients.
3. In the opinion of the investigator, death is imminent and inevitable or patient will be discharged within the next 48 - 72 hours, irrespective of the provision of treatment.
4. Experiencing cardiac arrest while hospitalized with COVID-19.
5. Active participation in other immunomodulator or immunosuppressant drug clinical trials.

   a. Participation in COVID-19 antiviral, anticoagulant and convalescent plasma trials may be permitted; however, the decision to enroll a patient who is participating in other clinical trials will be dealt with on a case-by-case basis.
6. Treatment with immunomodulator or immunosuppressant drugs, including but not limited to TNF inhibitors and anti-IL-1 agents within 5 half-lives or 30 days (whichever is longer) before randomization. Except for the following, which are permitted:

   1. Treatment with immunomodulator, or immunosuppressant drugs, such as corticosteroids, as part of SOC for COVID-19
   2. Transplant patients
7. Known other clinical conditions that contraindicate EB05 and cannot be treated or solved according to the judgment of the clinician.
8. Patient has been intubated or mechanically ventilated for more than 72 hours prior to administration of the investigational product.
9. Patient has been intubated and then extubated during the current hospitalization prior to administration of the investigational product.
10. Patient has experienced meaningful clinical improvement in the severity of disease prior to administration of the investigational product.

Primary outcomes:
measure: Mortality rate at Day 28 from IP administration.
timeFrame: 28 days
Secondary outcomes:
measure: Proportion of patients with clinical improvement at Day 28
timeFrame: 28 days
measure: Proportion of patients with clinical improvement at Day 60
timeFrame: 60 days
measure: Mortality rate at Day 60
timeFrame: 60 days
Other outcomes:
measure: Number of treatment-emergent adverse events (TEAEs) and serious TEAEs.
timeFrame: 28 and 60 days
Locations:
city: Fresno
country: United States
facility: UCSF Fresno
state: California
city: Fullerton
country: United States
facility: St. Jude Medical Center/ Providence
state: California
city: Coral Gables
country: United States
facility: University of Miami Hospital
state: Florida
city: Springfield
country: United States
facility: Baystate Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Morgantown
country: United States
facility: West Virginia University Medicine Heart & Vascular Institute
state: West Virginia
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Vancouver
country: Canada
facility: Vancouver Coastal Health
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Brampton
country: Canada
facility: William Osler Health System
state: Ontario
city: Markham
country: Canada
facility: Markham Stouffville Hospital
state: Ontario
city: Newmarket
country: Canada
facility: Southlake Regional Health Centre
state: Ontario
city: Oshawa
country: Canada
facility: Lakeridge Health
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital Research Institute
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Greenfield Park
country: Canada
facility: CISS Monteregie-Centre
state: Quebec
city: Montréal
country: Canada
facility: Hôpital Maisonneuve Rosemont
state: Quebec
city: Montréal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Rimouski
country: Canada
facility: Hôpital Régional de Rimouski
state: Quebec
Study officials:
References: