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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

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

Tracking Information
First Submitted Date  ICMJE May 21, 2020
First Posted Date  ICMJE May 26, 2020
Last Update Posted Date May 3, 2021
Actual Study Start Date  ICMJE November 25, 2020
Estimated Primary Completion Date April 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (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.
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE
 (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  ICMJE 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  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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  ICMJE
  • COVID-19
  • ARDS
Intervention  ICMJE
  • 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  ICMJE
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 8, 2021)
396
Original Estimated Enrollment  ICMJE
 (submitted: May 21, 2020)
510
Estimated Study Completion Date  ICMJE April 2021
Estimated Primary Completion Date April 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Blair Gordon, PhD 289-800-9600 ext 140 info@edesabiotech.com
Listed Location Countries  ICMJE Canada,   Colombia,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04401475
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: Undecided
Responsible Party Edesa Biotech Inc.
Study Sponsor  ICMJE Edesa Biotech Inc.
Collaborators  ICMJE JSS Medical Research Inc.
Investigators  ICMJE Not Provided
PRS Account Edesa Biotech Inc.
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP