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

Sponsor

Edesa Biotech Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04401475

Collaborator

JSS Medical Research Inc. (Industry)

396

Enrollment

Locations

Arms

4.2

Anticipated Duration (Months)

14.1

Patients Per Site

3.4

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
COVID-19 ARDS	Biological: SOC plus 15mg/kg EB05 IV Other: SOC plus Placebo IV	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

396 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

This study is currently a Phase 2 in the US and is incorporated into a Phase 2/Phase 3 in Canada. 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 will be stratified by site and baseline WHO COVID-19 severity strata defined as Level 3-4 and Levels 5-6. 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.This study is currently a Phase 2 in the US and is incorporated into a Phase 2/Phase 3 in Canada. 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 will be stratified by site and baseline WHO COVID-19 severity strata defined as Level 3-4 and Levels 5-6. 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.

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Nov 25, 2020

Anticipated Primary Completion Date :

Apr 1, 2021

Anticipated Study Completion Date :

Apr 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Stage 1 Stage 1 (Phase II Study) For 80% power (β = 0.20), at a significance level of 5% (α =0.05) and a 1:1 randomization ratio, a total of 316 (EB05: 158, SOC: 158) evaluable patients will be required. Allowing for 20% attrition a total of 396 patients will be recruited.	Biological: SOC plus 15mg/kg EB05 IV Standard of care plus single IV infusion of 15mg/kg of EB05. Other: SOC plus Placebo IV Standard of care plus a single IV infusion of placebo.
Experimental: Stage 2 Stage 2 (Phase III Study - Canada) For a 1:1 ratio of patients treated with EB05 vs. Placebo, 80% power, and a two-sided alpha of 0.05 (equivalent to one sided test with an alpha of 0.025) to detect an Odds Ratio of 1.50, a total of 884 evaluable patients will be required for Stage 2 (Phase III study). Allowing for 20% attrition, a total of 1,105 patients will be enrolled in this Stage.	Biological: SOC plus 15mg/kg EB05 IV Standard of care plus single IV infusion of 15mg/kg of EB05. Other: SOC plus Placebo IV Standard of care plus a single IV infusion of placebo.

Arm

Intervention/Treatment

Experimental: Stage 1

Stage 1 (Phase II Study) For 80% power (β = 0.20), at a significance level of 5% (α =0.05) and a 1:1 randomization ratio, a total of 316 (EB05: 158, SOC: 158) evaluable patients will be required. Allowing for 20% attrition a total of 396 patients will be recruited.

Biological: SOC plus 15mg/kg EB05 IV

Standard of care plus single IV infusion of 15mg/kg of EB05.

Other: SOC plus Placebo IV

Standard of care plus a single IV infusion of placebo.

Experimental: Stage 2

Stage 2 (Phase III Study - Canada) For a 1:1 ratio of patients treated with EB05 vs. Placebo, 80% power, and a two-sided alpha of 0.05 (equivalent to one sided test with an alpha of 0.025) to detect an Odds Ratio of 1.50, a total of 884 evaluable patients will be required for Stage 2 (Phase III study). Allowing for 20% attrition, a total of 1,105 patients will be enrolled in this Stage.

Biological: SOC plus 15mg/kg EB05 IV

Standard of care plus single IV infusion of 15mg/kg of EB05.

Other: SOC plus Placebo IV

Standard of care plus a single IV infusion of placebo.

Outcome Measures

Primary Outcome Measures

the proportion of patients that are alive without any need for oxygen support defined as a score of 3 or less on the WHO COVID-19 nine-point scale [28 days]
The severity of COVID-19 related respiratory disease is assessed on the following WHO COVID-19 nine-point ordinal scale: 0. Uninfected - No clinical or virological evidence of infection Ambulatory - No limitation of Activities Ambulatory - Limitation of Activities Hospitalized Mild Disease - No Oxygen Therapy Hospitalized Mild Disease - Oxygen by mask or Nasal Prongs Hospitalized Severe Disease - Non-Invasive Ventilation or High-Flow Oxygen Hospitalized Severe Disease - Intubation and Mechanical Ventilation Hospitalized Severe Disease - Intubation + Additional Organ Support - Pressors, RRT, ECMO Death For the current study, the primary efficacy outcome measure will be the proportion of patients that are alive without any need for oxygen support defined as a score of 3 or less in the above scale. The primary endpoint will be assessed at 28-days after treatment initiation.

Secondary Outcome Measures

Time to therapeutic response (primary efficacy endpoint). [28 and 60 days]
The proportion of patients with clinical improvement, defined as a decrease of two points or more on the WHO 9 - point ordinal scale at Day 28 [28 days]
or more on the WHO 9 - point ordinal scale at Day 28
The proportion of patients that are alive and discharged home without any need for oxygen support (WHO Scale of ≤ 2) at Day 28. [28 days]
The proportion of patients that are alive and free of respiratory failure (WHO scale ≤ 4) at Day 28. [28 days]
The proportion of patients with clinical improvement, defined as a decrease of two points or more on the WHO 9 - point ordinal scale at Day 60. [60 days]
The proportion of patients with clinical improvement, defined as a decrease of one point or more on the WHO 9 - point ordinal scale at Day 28. [28 days]
The proportion of patients with clinical improvement, defined as a decrease of one point or more on the WHO 9 - point ordinal scale at Day 60. [60 days]
The proportion of patients that are alive and discharged home without any need for oxygen support (WHO Scale of ≤ 2) at Day 60. [60 days]
The proportion of patients that are alive and free of respiratory failure (WHO scale ≤ 4) at Day 60. [60 days]
Time to clinical improvement by 2 points on the WHO ordinal scale described above. [28 and 60 days]
Time to clinical improvement by 1 point on the WHO ordinal scale described above. [28 and 60 days]
Change in the NEWS-2 Scale at 28 days. [28 days]
Time to News-2 = 0. [28 and 60 days]
The proportion of patients that experience disease progression, defined as an increase of one point or more in the WHO 9-point ordinal scale, at Day 28. [28 days]
Ventilator-free days. [28 days]
Duration of ventilation. [28 and 60 days]
Mortality rate at 28-days and 60-days post-treatment initiation. [28 and 60 days]
Duration of hospitalization. [28 and 60 days]
Time to independence from supplementary oxygen therapy. [28 days]
Time to normalization of oxygen saturation, defined as SaO2/SpO2 > 94% sustained a minimum of 24 hours. [28 days]
Change in Sequential Organ Failure Assessment (SOFA) score, while hospitalized. [28 days]
Radiological response to treatment based on Thoracic Computerized Tomography Scan (CT-Scan) or Chest X-Ray. [28 days]
Change in cytokines, including IL-6, and C-reactive protein (CRP) levels. [28 days]
Time to resolution of fever for at least 48 hours without antipyretics. [28 and 60 days]
Defined as body temperature <37.2°C (oral), or <37.6°C (rectal or tympanic) or <36.8°C (temporal or axillary).
The decision by the attending physician to initiate treatment with another targeted immunomodulator (i.e. dexamethasone). [28 and 60 days]
Change in the Berlin ARDS severity scale. [28 days]
Change in Acute Kidney Injury Network (AKIN) classification. [28 days]
Change in troponin levels. [28 days]

Other Outcome Measures

Safety Endpoint: Number of treatment-emergent adverse events (TEAEs) and serious TEAEs. [28 and 60 days]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Men and women ≥18 years of age at the time of consent.
Laboratory-confirmed diagnosis of COVID-19.
Hospitalized for COVID-19 related respiratory disease.
Patient belongs to one of the following four categories in the nine-point COVID-19 severity scale:
Hospitalized, not requiring supplemental oxygen - Level 3 of the nine-point COVID-19 severity scale.
Hospitalized, requiring supplemental oxygen - Level 4 of the nine-point COVID-19 severity scale.
Hospitalized, requiring nasal high-flow oxygen therapy, non-invasive mechanical ventilation, or both - Level 5 of the nine-point COVID-19 severity scale.
Hospitalized, requiring intubation and mechanical ventilation- Level 6 of the nine-point COVID-19 severity scale.
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.
Signed informed consent form by any patient capable of giving consent, or, when the patient is not capable of giving consent, by his or her legal/authorized representatives.

Exclusion Criteria:

The subject is a female who is breastfeeding or pregnant.
Known hypersensitivity to EB05 or its excipients.
Mechanical ventilation (including venovenous ECMO) for ≥5 days (120 hours), or any duration of venoarterial ECMO.
In the opinion of the investigator, death is imminent and inevitable within the next 48 - 72 hours, irrespective of the provision of treatment.
Active participation in other drug clinical trials.
Treatment with immunomodulator or immunosuppressant drugs, including but not limited to IL-6 inhibitors, TNF inhibitors, anti-IL-1 agents, and JAK inhibitors within 5 half-lives or 30 days (whichever is longer) before randomization. (Note treatment with immunomodulator or immunosuppressant drugs, such as corticosteroids, as part of SOC, is permitted).
Known other clinical conditions that contraindicate EB05 and cannot be treated or solved according to the judgment of the clinician.
Possibility of the subject being transferred to a non-study hospital within 72h.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF Fresno	Fresno	California	United States	93701
2	St. Jude Medical Center/ Providence	Fullerton	California	United States	92835
3	St. Joseph Hospital, Orange - Providence	Orange	California	United States	92868
4	University of Miami Hospital	Coral Gables	Florida	United States	33146
5	Augusta University Medical Center	Augusta	Georgia	United States	30912
6	Methodist Medical Center IL	Peoria	Illinois	United States	61636
7	Norton Hospital	Louisville	Kentucky	United States	40202
8	Norton Brownsboro Hospital	Louisville	Kentucky	United States	40241
9	Baystate Medical Center	Springfield	Massachusetts	United States	01199
10	Henry Ford Hospital	Detroit	Michigan	United States	48202
11	Providence Regional Medical Center - Everett	Everett	Washington	United States	98201
12	UW Medicine Valley Medical Center	Renton	Washington	United States	98055
13	West Virginia University Medicine Heart & Vascular Institute	Morgantown	West Virginia	United States	26506-6224
14	Royal Alexandra Hospital	Edmonton	Alberta	Canada	T5H 3V9
15	Misericordia Community Hospital	Edmonton	Alberta	Canada	T5R 4H5
16	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2B7
17	Grey Nuns Community Hospital	Edmonton	Alberta	Canada	T6L 5X8
18	Vancouver General Hospital	Vancouver	British Columbia	Canada	V5Z 1M9
19	University Hospital - LHSC	London	Ontario	Canada	N6A 5A5
20	Victoria Hospital - LHSC	London	Ontario	Canada	N6A 5W9
21	North York General Hospital	Toronto	Ontario	Canada	M2K 1E1
22	Toronto General Hospital	Toronto	Ontario	Canada	M5G 2C4
23	Hôpital Maisonneuve Rosemont	Montréal	Quebec	Canada	H1T 2M4
24	Hôpital Régional de Rimouski	Rimouski	Quebec	Canada	G5L 5T1
25	Clinica de las Americas	Medellín	Antioquia	Colombia
26	IPS de Universidad de Antioquia	Medellín	Antioquia	Colombia
27	FOSCAL	Bucaramanga	Santander	Colombia
28	Fund.Cardiovascular de Colombia-FCV	Bucaramanga	Santander	Colombia

Sponsors and Collaborators

Edesa Biotech Inc.
JSS Medical Research Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Edesa Biotech Inc.

ClinicalTrials.gov Identifier:

NCT04401475

Other Study ID Numbers:

EB05-04-2020

First Posted:

May 26, 2020

Last Update Posted:

May 3, 2021

Last Verified:

Apr 1, 2021

Individual Participant Data (IPD) Sharing Statement:

Undecided

Plan to Share IPD:

Undecided

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Edesa Biotech Inc.

TLR4

ARDS

COVID-19

Additional relevant MeSH terms:

COVID-19

Study Results

No Results Posted as of May 3, 2021