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A Phase 2b Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study, Evaluating Efficacy and Safety of Allocetra-OTS in Patients With Severe or Critical COVID-19 With Associated Acute Respiratory Distress Syndrome (ARDS)

Primary Purpose

Covid19

Status
Active
Phase
Phase 2
Locations
Israel
Study Type
Interventional
Intervention
ALLOCETRA-OTS
Placebo
Sponsored by
Enlivex Therapeutics Ltd.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Covid19 focused on measuring Cell therapy, Allocetra-OTS

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Male and female >18 and <85 years of age.
  2. Laboratory confirmation of SARS-CoV-2 infection by RT-PCR from any diagnostic sampling source.
  3. Patient hospitalized due to COVID-19 within 7 days prior to enrollment, meeting the criteria for severe or critical COVID-19 as follows:

    1. Severe COVID-19 - defined as shortness of breath at rest, or respiratory distress, or RR ≥30 per minute, or SpO2≤93% on room air at sea level.
    2. Critical COVID-19 - defined as respiratory failure, requiring at least one of the following: oxygen delivered by high-flow nasal cannula or noninvasive positive pressure ventilation.
  4. Patient with mild to moderate ARDS:

    1. 100< PaO2/FiO2 ≤300; based on the Berlin Definition of ARDS
    2. 148< SpO2/FiO2 ≤315; based on the Kigali modification for ARDS

      • If available, PaO2 will be obtained, otherwise, SpO2 will be used for ARDS assessment.
  5. Signed written informed consent by the patient.
  6. Women and men who are of childbearing potential, willing to use acceptable contraceptive measures during 4 weeks from enrollment.

Exclusion Criteria:

  1. Patient on IMV/ECMO.
  2. Woman who is pregnant or breastfeeding.
  3. Patient with weight <50 kg or >120 kg or BMI >40 kg/m^2.
  4. Patient with stage 4 or 5 chronic kidney disease or estimated glomerular filtration rate <30 mL/min.
  5. Patient with an active malignant tumor (diagnosed or on active treatment for the past 6 months).
  6. Patient who is participating in other concurrent interventional clinical trials or has been treated with any experimental agents within 30 days prior to enrollment.
  7. Patient who based on their medical history and receipt of therapies that would suggest infection, has suspected serious, active bacterial (including a suspected clinical diagnosis of current active tuberculosis [TB] or, if known, latent TB treated for less than 4 weeks with appropriate anti-TB therapy per institutional guidelines), fungal, or viral (including, but not limited to, active HBV, HCV, or HIV/AIDS) infection.
  8. Patient with known immunocompromised state or immunosuppressive medications taken for indications other than SARS-CoV-2 as follows:

    • Prednisone or equivalent to a dose >10 mg/day, methotrexate >15 mg/week, within the last 60 days. cyclophosphamide, cyclosporine A (unless as ophthalmic formulation), leflunomide/teriflunomide (unless as monotherapy), tacrolimus (unless as a topical formulation), everolimus, temsirolimus, or azathioprine, in the last 60 days;
    • Methylprednisolone, dexamethasone, cortisone, or betamethasone for more than 7 days within the last 28 days or within 5 half-lives, whichever is longer;
    • Chemotherapy in the last 3 months;
    • Mycophenolate mofetil (MMF) or sirolimus for solid organ transplant or bone marrow transplant;
    • Thalidomide within the last 72 hours.
    • Anti-tumor necrosis factor (TNF) agents, interleukin (IL)-1 receptor antagonists (IL-1-RA), CTLA-4 fusion proteins, anti-CD20, anti-CD52, anti-IL-2, anti-IL-6R, anti-IL-12/23, anti-B-cell activation factor (BAFF) or integrin inhibitor agents within the last 8 weeks.
  9. Patient with known New York Heart Association (NYHA) class III and IV heart failure or unstable angina, ventricular arrhythmias, ischemic heart disease, or myocardial infarction within 6 months prior to diagnosis of COVID-19.
  10. Patient with known active upper gastrointestinal (GI) tract ulceration or hepatic dysfunction including but not limited to biopsy-proven cirrhosis; end-stage cirrhosis (Child Pugh Class C); portal hypertension; episodes of past upper GI bleeding attributed to portal hypertension; or prior episodes of hepatic failure, encephalopathy, or coma.
  11. Patient with known idiopathic pulmonary fibrosis.
  12. Patient with chronic respiratory disease requiring home oxygen therapy on a regular basis for more than 6 hours per day.
  13. Patient with known chronic obstructive pulmonary disease GOLD 4 (forced expiratory volume in one second <30% predicted).
  14. Patient with any medical, psychiatric or substance abuse condition, concurrent medical therapies, or abnormal laboratory values that in the opinion of the site Investigator may influence response to study product, or interfere with the study assessments.
  15. Patient with GCS <13 with verbal score <5.
  16. Patient with hemoglobin <8 g/dL.
  17. Patient with history of chronic liver disease, evidence of acute cholangitis or cholecystitis. Patients with at least one of the following:

    • ALT or AST >10xULN (upper limit of normal)
    • Bilirubin >5xULN
    • Combination of ALT/AST >7xULN and elevated direct bilirubin >ULN
  18. Patient with known history of transfusion reactions, hemolytic anemia, or repetitive allergic reaction.
  19. Patient with previous history of organ allograft or stem cell transplantation.

Sites / Locations

  • Hadassah Ein Kerem Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

Placebo

ALLOCETRA-OTS

Arm Description

Ringer's lactate solution

Single IV dose of Allocetra-OTS containing 10x10^9 cells

Outcomes

Primary Outcome Measures

Time (days) to improvement
The first day, during the period of 28 days post study treatment, when a patient reached the score of 6, 7 or 8 on the 8-point ordinal scale. If no improvement is reached by Day 28, the patient will be assigned a maximal score of 29. The 8-point ordinal scale of the clinical severity status scores is as follows: Death=1; Hospitalized, on IMV or ECMO=2; Hospitalized, on noninvasive ventilation or high-flow oxygen devices=3; Hospitalized, requiring supplemental oxygen by mask or nasal canula=4; Hospitalized, not requiring supplemental oxygen=5; Hospitalized, not requiring supplemental oxygen and not requiring ongoing inpatient medical care=6; Not hospitalized, limitations on activities=7; Not hospitalized, no limitations on activities=8.
Support by IMV/ECMO
If required during the period of 28 days post study treatment, a patient will be assigned the maximal score of 29.
Mortality
Mortality by Day 28 post study treatment administration. Deceased patients will be assigned the maximal score of 29.

Secondary Outcome Measures

Time (days) to improvement, defined as the first day, during a period of 28 days and 60 days post study treatment administration, when the patient reached the score of 6, 7 or 8 on the 8-point ordinal scale.
All-cause mortality during the period of 28 days and 60 days.
Proportion of patients alive and free of respiratory failure, defined as need for IMV, ECMO, noninvasive ventilation, or high-flow nasal cannula oxygen delivery on Days 28 and 60.
Cumulative number of vasopressor-free days during the period of 28 days and 60 days.
Cumulative number of days in the hospital during the period of 28 days and 60 days.
Cumulative number of days in the ICU or Intermediate Care Unit (IMU) during the period of 28 days and 60 days.

Full Information

First Posted
June 9, 2021
Last Updated
August 29, 2022
Sponsor
Enlivex Therapeutics Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT04922957
Brief Title
A Phase 2b Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study, Evaluating Efficacy and Safety of Allocetra-OTS in Patients With Severe or Critical COVID-19 With Associated Acute Respiratory Distress Syndrome (ARDS)
Official Title
A Phase 2b Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study, Evaluating Efficacy and Safety of Allocetra-OTS in Patients With Severe or Critical COVID-19 With Associated Acute Respiratory Distress Syndrome (ARDS)
Study Type
Interventional

2. Study Status

Record Verification Date
August 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
September 1, 2021 (Actual)
Primary Completion Date
September 1, 2022 (Anticipated)
Study Completion Date
September 1, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Enlivex Therapeutics Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a Phase 2b multi-center, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of intravenous (IV) Allocetra-OTS 10x10^9 cells vs placebo (1:1) in adult hospitalized patients with severe or critical Coronavirus Disease 2019 (COVID-19) with associated acute respiratory distress syndrome (ARDS). Patients will be followed for efficacy and safety for 6 months. The trial will include periodic and ad-hoc DSMB review during the study period.
Detailed Description
This is a Phase 2b multi-center, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of intravenous (IV) Allocetra-OTS 10x10^9 cells vs placebo (1:1) in adult hospitalized patients with severe or critical Coronavirus Disease 2019 (COVID-19) with associated acute respiratory distress syndrome (ARDS). Severe and critical COVID-19 are defined as follows: Severe COVID-19: shortness of breath at rest, or respiratory distress, or respiratory rate (RR) ≥30 per minute, or SpO2 ≤93% on room air at sea level. Critical COVID-19: respiratory failure, requiring at least one of the following: oxygen delivered by high-flow nasal cannula or noninvasive positive pressure ventilation. After a patient has signed the informed consent form (ICF), and after confirmation that the patient meets all eligibility criteria, the patient will be enrolled in the study. The two subpopulations, severely ill and critically ill patients, will be randomized 1:1 into the active treatment and placebo groups via two separate randomizations schemes. Study treatment (Investigational Product or placebo) administration will occur on Day 1 as close as possible to and no later than 48 hours from randomization. Assessments, performed on Day 1 prior to study treatment administration, will be considered as baseline assessments. Patients will be followed for efficacy and safety through 6 months. Following study treatment administration, patients will be assessed daily for a period of 7 days. The next visits are planned to occur on Days 14, 28 and 60. A safety follow-up phone call will be scheduled to occur 6 months post study treatment. Hospitalized patients will be monitored on a daily basis until discharge or up to 60 days post study treatment administration. Blood samples for safety assessment will be analyzed locally as per institutional guidelines. Additional blood samples will be collected for potential exploratory analyses. Such biomarker analyses will be performed centrally as per Sponsor requirements. Patients who drop out within the interval between the randomization and study treatment administration will be replaced to keep the originally planned sample size. The trial will include periodic and ad-hoc Data Safety Monitoring Board (DSMB) review during the study period.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Covid19
Keywords
Cell therapy, Allocetra-OTS

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Sequential Assignment
Model Description
152 patients will be allocated in a 1:1 ratio between the 2 cohorts: Placebo Single Intravenous (IV) dose of Allocetra-OTS (10x10^9 cells)
Masking
ParticipantInvestigator
Masking Description
Randomization will be in a double blinding fashion. The IP will be delivered with a cover to maintain blinding.
Allocation
Randomized
Enrollment
12 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Ringer's lactate solution
Arm Title
ALLOCETRA-OTS
Arm Type
Experimental
Arm Description
Single IV dose of Allocetra-OTS containing 10x10^9 cells
Intervention Type
Drug
Intervention Name(s)
ALLOCETRA-OTS
Other Intervention Name(s)
Cell based therapy, Apoptotic cells
Intervention Description
The product contains allogeneic donor mononuclear enriched cells in the form of a liquid suspension containing early apoptotic cells.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Ringer's lactate solution
Primary Outcome Measure Information:
Title
Time (days) to improvement
Description
The first day, during the period of 28 days post study treatment, when a patient reached the score of 6, 7 or 8 on the 8-point ordinal scale. If no improvement is reached by Day 28, the patient will be assigned a maximal score of 29. The 8-point ordinal scale of the clinical severity status scores is as follows: Death=1; Hospitalized, on IMV or ECMO=2; Hospitalized, on noninvasive ventilation or high-flow oxygen devices=3; Hospitalized, requiring supplemental oxygen by mask or nasal canula=4; Hospitalized, not requiring supplemental oxygen=5; Hospitalized, not requiring supplemental oxygen and not requiring ongoing inpatient medical care=6; Not hospitalized, limitations on activities=7; Not hospitalized, no limitations on activities=8.
Time Frame
28 days
Title
Support by IMV/ECMO
Description
If required during the period of 28 days post study treatment, a patient will be assigned the maximal score of 29.
Time Frame
28 days
Title
Mortality
Description
Mortality by Day 28 post study treatment administration. Deceased patients will be assigned the maximal score of 29.
Time Frame
28 days
Secondary Outcome Measure Information:
Title
Time (days) to improvement, defined as the first day, during a period of 28 days and 60 days post study treatment administration, when the patient reached the score of 6, 7 or 8 on the 8-point ordinal scale.
Time Frame
60 days
Title
All-cause mortality during the period of 28 days and 60 days.
Time Frame
60 days
Title
Proportion of patients alive and free of respiratory failure, defined as need for IMV, ECMO, noninvasive ventilation, or high-flow nasal cannula oxygen delivery on Days 28 and 60.
Time Frame
60 days
Title
Cumulative number of vasopressor-free days during the period of 28 days and 60 days.
Time Frame
60 days
Title
Cumulative number of days in the hospital during the period of 28 days and 60 days.
Time Frame
60 days
Title
Cumulative number of days in the ICU or Intermediate Care Unit (IMU) during the period of 28 days and 60 days.
Time Frame
60 days
Other Pre-specified Outcome Measures:
Title
Safety - Number and severity of adverse events (AEs) and serious adverse events (SAEs) throughout 60-day follow-up period
Time Frame
60 days
Title
Safety - Number and severity of AEs and SAEs throughout 180-day follow-up period
Time Frame
180 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male and female >18 and <85 years of age. Laboratory confirmation of SARS-CoV-2 infection by RT-PCR from any diagnostic sampling source. Patient hospitalized due to COVID-19 within 7 days prior to enrollment, meeting the criteria for severe or critical COVID-19 as follows: Severe COVID-19 - defined as shortness of breath at rest, or respiratory distress, or RR ≥30 per minute, or SpO2≤93% on room air at sea level. Critical COVID-19 - defined as respiratory failure, requiring at least one of the following: oxygen delivered by high-flow nasal cannula or noninvasive positive pressure ventilation. Patient with mild to moderate ARDS: 100< PaO2/FiO2 ≤300; based on the Berlin Definition of ARDS 148< SpO2/FiO2 ≤315; based on the Kigali modification for ARDS If available, PaO2 will be obtained, otherwise, SpO2 will be used for ARDS assessment. Signed written informed consent by the patient. Women and men who are of childbearing potential, willing to use acceptable contraceptive measures during 4 weeks from enrollment. Exclusion Criteria: Patient on IMV/ECMO. Woman who is pregnant or breastfeeding. Patient with weight <50 kg or >120 kg or BMI >40 kg/m^2. Patient with stage 4 or 5 chronic kidney disease or estimated glomerular filtration rate <30 mL/min. Patient with an active malignant tumor (diagnosed or on active treatment for the past 6 months). Patient who is participating in other concurrent interventional clinical trials or has been treated with any experimental agents within 30 days prior to enrollment. Patient who based on their medical history and receipt of therapies that would suggest infection, has suspected serious, active bacterial (including a suspected clinical diagnosis of current active tuberculosis [TB] or, if known, latent TB treated for less than 4 weeks with appropriate anti-TB therapy per institutional guidelines), fungal, or viral (including, but not limited to, active HBV, HCV, or HIV/AIDS) infection. Patient with known immunocompromised state or immunosuppressive medications taken for indications other than SARS-CoV-2 as follows: Prednisone or equivalent to a dose >10 mg/day, methotrexate >15 mg/week, within the last 60 days. cyclophosphamide, cyclosporine A (unless as ophthalmic formulation), leflunomide/teriflunomide (unless as monotherapy), tacrolimus (unless as a topical formulation), everolimus, temsirolimus, or azathioprine, in the last 60 days; Methylprednisolone, dexamethasone, cortisone, or betamethasone for more than 7 days within the last 28 days or within 5 half-lives, whichever is longer; Chemotherapy in the last 3 months; Mycophenolate mofetil (MMF) or sirolimus for solid organ transplant or bone marrow transplant; Thalidomide within the last 72 hours. Anti-tumor necrosis factor (TNF) agents, interleukin (IL)-1 receptor antagonists (IL-1-RA), CTLA-4 fusion proteins, anti-CD20, anti-CD52, anti-IL-2, anti-IL-6R, anti-IL-12/23, anti-B-cell activation factor (BAFF) or integrin inhibitor agents within the last 8 weeks. Patient with known New York Heart Association (NYHA) class III and IV heart failure or unstable angina, ventricular arrhythmias, ischemic heart disease, or myocardial infarction within 6 months prior to diagnosis of COVID-19. Patient with known active upper gastrointestinal (GI) tract ulceration or hepatic dysfunction including but not limited to biopsy-proven cirrhosis; end-stage cirrhosis (Child Pugh Class C); portal hypertension; episodes of past upper GI bleeding attributed to portal hypertension; or prior episodes of hepatic failure, encephalopathy, or coma. Patient with known idiopathic pulmonary fibrosis. Patient with chronic respiratory disease requiring home oxygen therapy on a regular basis for more than 6 hours per day. Patient with known chronic obstructive pulmonary disease GOLD 4 (forced expiratory volume in one second <30% predicted). Patient with any medical, psychiatric or substance abuse condition, concurrent medical therapies, or abnormal laboratory values that in the opinion of the site Investigator may influence response to study product, or interfere with the study assessments. Patient with GCS <13 with verbal score <5. Patient with hemoglobin <8 g/dL. Patient with history of chronic liver disease, evidence of acute cholangitis or cholecystitis. Patients with at least one of the following: ALT or AST >10xULN (upper limit of normal) Bilirubin >5xULN Combination of ALT/AST >7xULN and elevated direct bilirubin >ULN Patient with known history of transfusion reactions, hemolytic anemia, or repetitive allergic reaction. Patient with previous history of organ allograft or stem cell transplantation.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Oren Hershkovitz, PhD
Organizational Affiliation
Enlivex Therapeutics R&D
Official's Role
Study Director
Facility Information:
Facility Name
Hadassah Ein Kerem Medical Center
City
Jerusalem
Country
Israel

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Patient data will not contain any information which would make the patient identifiable. Data will be processes and shared using patient study number only.

Learn more about this trial

A Phase 2b Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study, Evaluating Efficacy and Safety of Allocetra-OTS in Patients With Severe or Critical COVID-19 With Associated Acute Respiratory Distress Syndrome (ARDS)

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