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

• ClinicalTrials.gov Identifier: NCT04401475
• Recruitment Status: Unknown
• First Posted: May 26, 2020
• Last Update Posted: May 3, 2021
• Sponsor: Edesa Biotech Inc.
• Collaborator: JSS Medical Research Inc.
• Information provided by (Responsible Party): Edesa Biotech Inc.

Tracking Information

• First Submitted Date: May 21, 2020
• First Posted Date: May 26, 2020
• Last Update Posted Date: May 3, 2021
• Actual Study Start Date: November 25, 2020
• Estimated Primary Completion Date: April 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 8, 2021)

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 [ Time Frame: 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

1. Ambulatory - No limitation of Activities
2. Ambulatory - Limitation of Activities
3. Hospitalized Mild Disease - No Oxygen Therapy
4. Hospitalized Mild Disease - Oxygen by mask or Nasal Prongs
5. Hospitalized Severe Disease - Non-Invasive Ventilation or High-Flow Oxygen
6. Hospitalized Severe Disease - Intubation and Mechanical Ventilation
7. Hospitalized Severe Disease - Intubation + Additional Organ Support - Pressors, RRT, ECMO
8. 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.

Original Primary Outcome Measures (submitted: May 21, 2020)

An improvement of two points on the seven-point ordinal scale [ Time Frame: 28 days ]

The severity of COVID-19 related respiratory disease is assessed on the following seven-point ordinal scale:

1. not hospitalized with resumption of normal activities;
2. not hospitalized, but unable to resume normal activities;
3. hospitalized, not requiring supplemental oxygen;
4. hospitalized, requiring supplemental oxygen;
5. hospitalized, requiring nasal high-flow oxygen therapy, non-invasive mechanical ventilation, or both;
6. hospitalized, requiring Extracorporeal Membrane Oxygenation (ECMO), invasive mechanical ventilation, or both, and;
7. death. For the current study the primary efficacy outcome measure will be the proportion of patients with clinical improvement at 28 days of follow-up, defined as an improvement of two points on the seven-point ordinal scale.

Current Secondary Outcome Measures (submitted: January 8, 2021)

• Time to therapeutic response (primary efficacy endpoint). [ Time Frame: 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 [ Time Frame: 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. [ Time Frame: 28 days ]
• The proportion of patients that are alive and free of respiratory failure (WHO scale ≤ 4) at Day 28. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 60 days ]
• The proportion of patients that are alive and free of respiratory failure (WHO scale ≤ 4) at Day 60. [ Time Frame: 60 days ]
• Time to clinical improvement by 2 points on the WHO ordinal scale described above. [ Time Frame: 28 and 60 days ]
• Time to clinical improvement by 1 point on the WHO ordinal scale described above. [ Time Frame: 28 and 60 days ]
• Change in the NEWS-2 Scale at 28 days. [ Time Frame: 28 days ]
• Time to News-2 = 0. [ Time Frame: 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. [ Time Frame: 28 days ]
• Ventilator-free days. [ Time Frame: 28 days ]
• Duration of ventilation. [ Time Frame: 28 and 60 days ]
• Mortality rate at 28-days and 60-days post-treatment initiation. [ Time Frame: 28 and 60 days ]
• Duration of hospitalization. [ Time Frame: 28 and 60 days ]
• Time to independence from supplementary oxygen therapy. [ Time Frame: 28 days ]
• Time to normalization of oxygen saturation, defined as SaO2/SpO2 > 94% sustained a minimum of 24 hours. [ Time Frame: 28 days ]
• Change in Sequential Organ Failure Assessment (SOFA) score, while hospitalized. [ Time Frame: 28 days ]
• Radiological response to treatment based on Thoracic Computerized Tomography Scan (CT-Scan) or Chest X-Ray. [ Time Frame: 28 days ]
• Change in cytokines, including IL-6, and C-reactive protein (CRP) levels. [ Time Frame: 28 days ]
• Time to resolution of fever for at least 48 hours without antipyretics. [ Time Frame: 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). [ Time Frame: 28 and 60 days ]
• Change in the Berlin ARDS severity scale. [ Time Frame: 28 days ]
• Change in Acute Kidney Injury Network (AKIN) classification. [ Time Frame: 28 days ]
• Change in troponin levels. [ Time Frame: 28 days ]

Original Secondary Outcome Measures (submitted: May 21, 2020)

• Time to clinical improvement by 2 points on the seven-point ordinal scale described in primary outcome. [ Time Frame: 28 days ]
  Time to clinical improvement by 2 points on the seven-point ordinal scale described in primary outcome.
• Ventilator-free days. [ Time Frame: 28 days ]
  Ventilator-free days.
• Duration of ventilation [ Time Frame: 28 days ]
  Duration of ventilation
• Mortality rate [ Time Frame: 28 days ]
  Mortality rate
• Duration of hospitalization [ Time Frame: 28 days ]
  Duration of hospitalization
• Time to independence from supplementary oxygen therapy [ Time Frame: 28 days ]
  Time to independence from supplementary oxygen therapy
• Time to normalization of oxygen saturation, defined as Sp02 > 94% sustained minimum 24 hours [ Time Frame: 24 hours ]
  Time to normalization of oxygen saturation, defined as Sp02 > 94% sustained minimum 24 hours
• Change in Sequential Organ Failure Assessment (SOFA) score, daily while hospitalized [ Time Frame: 28 days ]
  Change in Sequential Organ Failure Assessment (SOFA) score, daily while hospitalized
• Radiological response to treatment based on Thoracic Computerized Tomography Scan (CT-Scan) or Chest X-Ray [ Time Frame: 28 days ]
  Radiological response to treatment based on Thoracic Computerized Tomography Scan (CT-Scan) or Chest X-Ray
• Change in cytokines, including IL-6, and C-reactive protein (CRP) levels [ Time Frame: 28 days ]
  Change in cytokines, including IL-6, and C-reactive protein (CRP) levels
• Time to resolution of fever for at least 48 hours without antipyretics [ Time Frame: 28 days ]
  Defined as post-baseline body temperature <37.2°C (oral), or <37.6°C (rectal or tympanic) or <36.8°C (temporal or axillary).
• Decision by the attending physician to initiate treatment with another targeted immunomodulator (i.e. IL-6 inhibitors) [ Time Frame: 28 days ]
  Decision by the attending physician to initiate treatment with another targeted immunomodulator (i.e. IL-6 inhibitors)
• Change in the Berlin ARDS severity scale [ Time Frame: 28 days ]
  Change in the Berlin ARDS severity scale
• Change in Acute Kidney Injury Network (AKIN) classification [ Time Frame: 28 days ]
  Change in Acute Kidney Injury Network (AKIN) classification
• Change in troponin levels [ Time Frame: 28 days ]
  Change in troponin levels

• Current Other Pre-specified Outcome Measures (submitted: January 8, 2021): Safety Endpoint: Number of treatment-emergent adverse events (TEAEs) and serious TEAEs. [ Time Frame: 28 and 60 days ]

Original Other Pre-specified Outcome Measures (submitted: May 21, 2020)

Safety Endpoint [ Time Frame: 28 days ]

Number of treatment-emergent adverse events (TEAEs) and serious TEAEs.

Descriptive Information

• Brief 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
• 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

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

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.

Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment

Condition

• COVID-19
• ARDS

Intervention

• 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.

Study Arms

• 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.
  Interventions:

  • Biological: SOC plus 15mg/kg EB05 IV
  • Other: SOC plus Placebo IV
• 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.
  Interventions:

  • Biological: SOC plus 15mg/kg EB05 IV
  • Other: SOC plus Placebo IV

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: January 8, 2021): 396
• Original Estimated Enrollment (submitted: May 21, 2020): 510
• Estimated Study Completion Date: April 2021
• Estimated Primary Completion Date: April 2021 (Final data collection date for primary outcome measure)

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 four categories in the nine-point COVID-19 severity scale:

   1. Hospitalized, not requiring supplemental oxygen - Level 3 of the nine-point COVID-19 severity scale.
   2. Hospitalized, requiring supplemental oxygen - Level 4 of the nine-point COVID-19 severity scale.
   3. Hospitalized, requiring nasal high-flow oxygen therapy, non-invasive mechanical ventilation, or both - Level 5 of the nine-point COVID-19 severity scale.
   4. Hospitalized, requiring intubation and mechanical ventilation- Level 6 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 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:

1. The subject is a female who is breastfeeding or pregnant.
2. Known hypersensitivity to EB05 or its excipients.
3. Mechanical ventilation (including venovenous ECMO) for ≥5 days (120 hours), or any duration of venoarterial ECMO.
4. In the opinion of the investigator, death is imminent and inevitable within the next 48 - 72 hours, irrespective of the provision of treatment.
5. Active participation in other drug clinical trials.
6. 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).
7. Known other clinical conditions that contraindicate EB05 and cannot be treated or solved according to the judgment of the clinician.
8. Possibility of the subject being transferred to a non-study hospital within 72h.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Colombia, United States

Administrative Information

• NCT Number: NCT04401475
• Other Study ID Numbers: EB05-04-2020
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Edesa Biotech Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Edesa Biotech Inc.
• Original Study Sponsor: Same as current
• Collaborators: JSS Medical Research Inc.
• Investigators: Not Provided
• PRS Account: Edesa Biotech Inc.
• Verification Date: April 2021