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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 Moderate to Severe COVID-19

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04401475
Recruitment Status : Not yet recruiting
First Posted : May 26, 2020
Last Update Posted : July 21, 2020
Sponsor:
Collaborator:
JSS Medical Research Inc.
Information provided by (Responsible Party):
Edesa Biotech Inc.

Brief Summary:

Current standard of care (SOC) for the management of hospitalized COVID-19 cases differs in various North American hospitals, particularly in the pharmacological treatments used, and is constantly changing.

At the moment, available options (depending on the hospital's treatment protocol, the physician's medical judgment, contraindications, and disease presentation) include hydroxychloroquine, chloroquine, remdesivir, ceftriaxone, azithromycin, piperacillin-tazobactam, lopinavir-ritonavir, and IL-6 receptor antagonists. In most hospital treatment protocols, the use of the latter is generally to be considered in patients with evidence of cytokine release syndrome and elevated IL-6, on a case-by-case basis.

Adults who suffer major COVID-19 complications appear to present a major inflammatory storm. Therefore, targeting the inflammatory response may reduce COVID-19-related complications in adults at risk or with evidence of an inflammatory storm. EB05 is a potent inhibitor of TLR4, a key component of the innate immune system which functions to detect molecules generated by pathogens, acting upstream of cytokine storm and IL-6-mediated acute lung injury. EB05 has demonstrated safety in two clinical studies (>165 patients) and was able to block LPS-induced (TLR4 agonist) IL-6 release in humans. Furthermore, TLR4 blockade rescued mice from lethal influenza-induced Acute Respiratory Distress Syndrome (ARDS), a major cause of mortality associated with COVID-19, thus could be useful in the management of COVID-19.

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 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 865 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
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 Moderate to Severe COVID-19
Estimated Study Start Date : September 2020
Estimated Primary Completion Date : February 2021
Estimated Study Completion Date : April 2021

Arm Intervention/treatment
Experimental: Stage 1

Stage 1 (Phase II Study) Based on these response rates, a 4:1 ratio of patients treated with EB05 vs. Placebo, a two-sided alpha of 0.05, and 80% power, a total of 295 evaluable patients will be required for Stage 1 (Phase II study), 236 treated with EB05 and 59 treated with Placebo. Allowing for 20% attrition, a total of 355 patients will be enrolled in this Stage.

There will be one blinded, non comparative Interim Analysis during the Phase II study when 50% of the patients (148 evaluable) have reached the 28-day follow-up time point. There will be no between comparisons conducted for this interim analysis; therefore, there is no need for multiplicity considerations. The purpose of the interim analysis will be to validate the assumptions used in the sample size calculations and to assess the inclusion / exclusion criteria as well as the study outcome. Based on the results of this interim analysis, outcome measures and sample size of the Phase II study can be changed.

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

Based on the above-mentioned response rates, a 4:1 ratio of patients treated with EB05 vs. Placebo, >90% power, and a two-sided alpha of 0.05 using a z-test, a total of 425 evaluable patients will be required for Stage 2 (Phase III study), 340 treated with EB05 and 85 treated with Placebo. Allowing for 20% attrition, a total of 510 patients will be enrolled in this Stage.

During the Phase III study there will be one blinded, comparative interim analysis when approximately 50% (213) of the evaluable patients have reached the 28-day follow up time period. The results of the interim analysis during the Phase III study will be used to determine whether the study should continue or be terminated early for futility or proven efficacy.

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.




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. Ventilator-free days. [ Time Frame: 28 days ]
    Ventilator-free days.

  3. Duration of ventilation [ Time Frame: 28 days ]
    Duration of ventilation

  4. Mortality rate [ Time Frame: 28 days ]
    Mortality rate

  5. Duration of hospitalization [ Time Frame: 28 days ]
    Duration of hospitalization

  6. Time to independence from supplementary oxygen therapy [ Time Frame: 28 days ]
    Time to independence from supplementary oxygen therapy

  7. 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

  8. Change in four-point Sequential Organ Failure Assessment (SOFA) score, daily while hospitalized [ Time Frame: 28 days ]
    Change in four-point Sequential Organ Failure Assessment (SOFA) score, daily while hospitalized

  9. 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

  10. 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

  11. 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).

  12. 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)

  13. Change in the four-point Berlin ARDS severity scale [ Time Frame: 28 days ]
    Change in the four-point Berlin ARDS severity scale

  14. Change in three-point Acute Kidney Injury Network (AKIN) classification [ Time Frame: 28 days ]
    Change in three-point Acute Kidney Injury Network (AKIN) classification

  15. Change in troponin levels [ Time Frame: 28 days ]
    Change in troponin levels


Other Outcome Measures:
  1. Safety Endpoint: Number of treatment-emergent adverse events (TEAEs) and serious TEAEs. [ Time Frame: 28 days ]
    Safety Endpoint: Number of treatment-emergent adverse events (TEAEs) and serious TEAEs.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Men and women between ≥18 years of age at the time of consent.
  2. Laboratory-confirmed diagnosis of COVID-19
  3. Hospitalized for COVID-19 related respiratory disease as indicated by one of the following:

    1. SaO2 /SpO2≤94% on ambient air or PaO2/FiO2 <300 mmHg/40 kPa
    2. Chest imaging findings compatible with COVID-19 pneumonia
  4. Patient belongs to one of the following three categories in the seven-point COVID-19 severity scale:

    1. Requiring supplemental oxygen - Level 4 of the seven-point COVID-19 severity scale.
    2. Requiring nasal high-flow oxygen therapy, non-invasive mechanical ventilation, or both - Level 5 of the seven-point COVID-19 severity scale.
    3. Hospitalized, requiring venovenous Extracorporeal Membrane Oxygenation (ECMO), invasive mechanical ventilation, or both - Level 6 of the seven-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. 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, 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. Participating in other drug clinical trials.

    • participation in COVID-19 antiviral trials may be permitted; a list of permitted anti-virals will be provided at the time of study initiation and will reflect the state of research at that point in time as a guidance to investigators. However, decision to allow patients participating in other clinical trials will be dealt with on a case by case basis.

  6. Immunosuppression, defined as any of the following:

    • treatment with immunosuppressive agents for a non-COVID-19-related condition;
    • chemotherapy within 30 days prior to inclusion or ongoing;
    • immunomodulatory drugs for a non-COVID-19-related condition within 30 days prior to inclusion;
    • use of chronic oral corticosteroids for a non-COVID-19-related condition in a dose higher than prednisolone 20 mg or equivalent per day for 4 weeks
  7. Known other active infections or other clinical condition that contraindicate EB05 and cannot be treated or solved according to the judgement of the clinician.
  8. Possibility of the subject being transferred to a non-study hospital within 72h.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04401475


Contacts
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Contact: Blair Gordon, PhD 289-800-9600 ext 140 info@edesabiotech.com

Sponsors and Collaborators
Edesa Biotech Inc.
JSS Medical Research Inc.
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Responsible Party: Edesa Biotech Inc.
ClinicalTrials.gov Identifier: NCT04401475    
Other Study ID Numbers: EB05-04-2020
First Posted: May 26, 2020    Key Record Dates
Last Update Posted: July 21, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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