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CORONA: A Study Using DeltaRex-G Gene Therapy for Symptomatic COVID-19 (CORONA)

Primary Purpose

COVID-19, Cytokine Storm, Acute Respiratory Distress Syndrome

Status
Withdrawn
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
DeltaRex-G
Sponsored by
Aveni Foundation
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for COVID-19 focused on measuring cyclin G1, gene therapy, activated T cells

Eligibility Criteria

18 Years - 100 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Individuals must meet all of the inclusion criteria in order to be eligible to participate in the study, as follows:

  • Male or female ≥ 18 years of age
  • Confirmed COVID-19 positive by viral RT PCR
  • Patients with severe disease as evidenced by presence of pneumonia, diagnosis of ARDS in hospitalized patients
  • Ability to understand the purposes and risks of the study and has signed and dated a written informed consent form approved by the investigator's IRB/Ethics Committee
  • Willingness to comply with all study procedures and availability for the duration of the study.
  • Adequate hematologic, renal or hepatic function defined by any of the following screening laboratory
  • Values:

    i) Neutrophils >1000/uL ii) Platelets > 75,000/uL iii) Serum creatinine <1.5 x ULN or creatinine clearance < 60 mL/min (using the Cockcroft Gault formula) iv) AST/ALT, alk phos <3 x ULN vi) Total Bilirubin <1.5 x ULN

  • All women of childbearing potential must have a negative pregnancy test and all subjects must agree to use highly effective means of contraception (surgical sterilization or the use of barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel or an IUD) with their partner from entry into the study through 2 months after the last dose.

Exclusion Criteria:

All individuals meeting any of the exclusion criteria at baseline will be excluded from study participation, as follows:

  • Females who are pregnant or breast-feeding
  • Unwillingness or inability to comply with the study protocol for any reason

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    DeltaRex-G

    Arm Description

    Escalating doses of DeltaRex-G i.v daily for 7 days as follows: Dose Level I: 3-6 patients will receive 1 x 10e11 cfu/dose Dose Level II: 3-6 patients will receive 2 x 10e11 cfu/ dose Dose Level III: 3-6 patients will receive 3 x 10e11 cfu/dose

    Outcomes

    Primary Outcome Measures

    Maximum Tolerated Dose
    The study will employ the standard "cohort of three" design (Storer, 1989). Three patients are treated at each dose level with expansion to six patients per cohort if DLT is observed in one of the three initially-enrolled patients at each dose level. The maximum tolerated dose is defined as the highest safely tolerated dose, where not more than one patient experienced DLT, with the next higher dose level having at least two patients who experienced DLT. No intra-patient escalation will take place.

    Secondary Outcome Measures

    Survival
    Duration of survival
    Hospital Stay
    Time of hospital admission to time of discharge
    Ventilator Therapy
    Time from start of mechanical ventilation to extubation or death
    Intensive Care Unit Stay
    Time from start of intensive care to discarge to regular room
    Cytokine Pattern
    Improvement in serum cytokine IL-6, IL12, TNF alpha

    Full Information

    First Posted
    May 4, 2020
    Last Updated
    August 2, 2023
    Sponsor
    Aveni Foundation
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    1. Study Identification

    Unique Protocol Identification Number
    NCT04378244
    Brief Title
    CORONA: A Study Using DeltaRex-G Gene Therapy for Symptomatic COVID-19
    Acronym
    CORONA
    Official Title
    CORONA: A Phase 1/2 Study Using DeltaRex-G Gene Therapy for Symptomatic COVID-19
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    August 2023
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    Lack of Funding
    Study Start Date
    December 12, 2022 (Anticipated)
    Primary Completion Date
    December 12, 2023 (Anticipated)
    Study Completion Date
    July 12, 2024 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Aveni Foundation

    4. Oversight

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

    5. Study Description

    Brief Summary
    COVID-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2. COVID-19 causes life threatening complications known as Cytokine Release Syndrome or Cytokine Storm and Acute Respiratory Distress Syndrome. These complications are the main causes of death in this global pandemic. Over 1000 clinical trials are on-going worldwide to diagnose, treat, and improve the aggressive clinical course of COVID-19. The investigators propose the first, and so far, only gene therapy solution that has the potential to address this urgent unmet medical need. Rationale There are striking similarities between the damaged lung environment of COVID-19 induced ARDS and the tumor microenvironment (exposed collagen from tissue destruction by invading tumor or by the virus-induced immune response, and presence of activated proliferative cells (cancer cells and tumor associated fibroblasts or activated T cells, macrophages and pulmonary fibroblasts in COVID-19); DeltaRex-G is a disease-seeking retrovector encoding a cytocidal dominant negative human cyclin G1 as genetic payload). When injected intravenously, the DeltaRex-G nanoparticles has a navigational system that targets exposed collagenous proteins (XC proteins) in injured tissues (e.g. inflamed lung, kidney, etc.), thus increasing the effective drug concentration at the sites of injury, in the vicinity of activated/proliferative T cells evoked by COVID-19. Our hypothesis is that DeltaRex-G then enters the rapidly dividing T cells and kills them by arresting the G1cell division cycle, hence, reducing cytokine release and ARDS; Intravenous DeltaRex-G has minimal systemic toxicity due to its navigational system (targeting properties) that limits the biodistribution of DeltaRex-G only to areas of injury where exposed collagenous (XC) proteins are abnormally found; and DeltaRex-G is currently available in FDA approved "Right to Try" or Expanded Access Program for Stage 4 cancers for an intermediate size population. To gain this approval, FDA requires DeltaRex-G to have demonstrated safety and efficacy in early clinical trials.
    Detailed Description
    Background and Proposed Research Importance Coronavirus disease 2019 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2. COVID-19 causes life threatening complications known as Cytokine Release Syndrome or Cytokine Storm and Acute Respiratory Distress Syndrome. These complications are the main causes of death in this global pandemic. Over 1000 clinical trials are on-going worldwide to diagnose, treat, and improve the aggressive clinical course of COVID-19. The investigators propose the first, and so far, only gene therapy solution that has the potential to address this urgent unmet medical need. Rationale There are striking similarities between the damaged lung environment of COVID-19 induced ARDS and the tumor microenvironment (exposed collagen from tissue destruction by invading tumor or by the virus-induced immune response, and presence of activated proliferative cells (cancer cells and tumor associated fibroblasts or activated T cells, macrophages and pulmonary fibroblasts in COVID-19); DeltaRex-G is a disease-seeking retrovector encoding a cytocidal dominant negative human cyclin G1 as genetic payload. The DeltaRex-G nanoparticles has a navigational system that targets exposed collagenous proteins in injured tissues, thus increasing the effective drug concentration at the sites of injury, in the vicinity of activated/proliferative T cells evoked by COVID-19. The DeltaRex-G then enters the rapidly dividing T cells and kills them by arresting the G1cell division cycle, hence, reducing cytokine release; Intravenous DeltaRex-G has minimal systemic toxicity due to its disease-seeking properties that limits the biodistribution of DeltaRex-G only to areas of injury where exposed collagenous proteins are abnormally found; and DeltaRex-G is currently available in FDA approved "Right to Try" or Expanded Access Program for Stage 4 cancers for an intermediate size population. To gain this approval, FDA requires DeltaRex-G to have demonstrated safety and efficacy in early clinical trials. Study Design This is a dose-seeking phase 1/2 study using escalating doses of DeltaRex-G given intravenously for 7 days in a hospital setting, with a randomization schema at the MTD. The study will include up to three cohorts with increasing DeltaRex-G doses as shown below. The study will employ the standard "Cohort of Three" design (Storer, 1989). Three patients are treated at each dose level with expansion to six patients per cohort if DLT is observed in one of the three initially enrolled patients at each dose level. If no DLT occurs in 3 patients, escalation to the next dose level will be permitted. The maximum tolerated dose is defined as the highest safely tolerated dose, where not more than one patient experienced DLT, with the next higher dose level having at least two patients who experienced DLT. No intra-patient dose escalation will take place. Patients within the same cohort of 3 will be treated in a staggered manner, i.e., the next subject will receive the product only after the previous subject has completed administration of all doses and has been evaluated on Day 14 (or one week after last DeltaRex-G infusion) to assess safety. At the MTD, after 3 subjects in same cohort have been evaluated with no DLT, subjects in the same cohort may be treated simultaneously. Patients who do not complete the 7-day treatment will be replaced except if patient developed DLT. Randomization Schema: At the highest dose level or when MTD is determined, nine (9) additional patients will be randomized to the treatment arm + standard of care (SOC) vs. standard of care alone (n = 6 patients DeltaRex-G and 3 SOC in each group). Patients will be matched according to symptomatology (e.g. SpO2 >94% at the time of screening), age (within 10 years or at least less than or greater than 65 years), race (black vs non-black), and gender. Dose of DeltaRex-G: Escalating doses of DeltaRex-G i.v daily for 7 days: Number of Pts. Dose Level Dose, cfu Max.Volume/24 hrs 3-6 I 1 x 10e11 200 ml 3-6 II 2 x 10e11 200 ml 3-6 III 3 x 10e11 200 ml Monitoring Plan: Patient's clinical status including need or duration of mechanical ventilation therapy, change in oxygen saturation, blood counts, lung, liver and kidney function and vital signs, proinflammatory cytokines, including IL-6, IL-12, and tumor necrosis factor α, CRP, LDH, D-Dimer, serum ferritin, chest X-ray are monitored as specified in the protocol and as needed in hospitalized patients during the treatment period, one week later, and every month for 6 months. Analysis of Primary Endpoint Safety analysis will be performed. The study will employ the standard "cohort of three" design. Three patients are treated at each dose level with expansion to six patients per cohort if DLT is observed in one of the three initially-enrolled patients at each dose level. The maximum tolerated dose is defined as the highest safely tolerated dose, where not more than one patient experienced DLT, with the next higher dose level having at least two patients who experienced DLT. No intra-patient escalation will take place. Dose limiting toxicity, maximum tolerated dose, incidence and severity of adverse events and significant laboratory abnormalities is the primary endpoint. Safety analysis will be performed on all patients. Patient incidence of all treatment-related AEs will be tabulated by system organ class and preferred term. Tables of fatal adverse events, serious adverse events, treatment-related AEs, and adverse events leading to withdrawal from investigation product will also be provided. Summary statistics will be provided for total number of doses, average dose administered, and duration of each treatment. Analysis of Secondary Endpoint Efficacy analysis will be conducted. Change in clinical status such as duration of fever, respiratory destress, pneumonia, cough, sneezing, diarrhea will be documented. ECOG score, mortality, length of hospital stay, duration of respirator therapy, duration of intensive care unit stay, and changes in cytokine pattern will be compared to historical controls.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    COVID-19, Cytokine Storm, Acute Respiratory Distress Syndrome
    Keywords
    cyclin G1, gene therapy, activated T cells

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 1, Phase 2
    Interventional Study Model
    Single Group Assignment
    Model Description
    Sequential assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    0 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    DeltaRex-G
    Arm Type
    Experimental
    Arm Description
    Escalating doses of DeltaRex-G i.v daily for 7 days as follows: Dose Level I: 3-6 patients will receive 1 x 10e11 cfu/dose Dose Level II: 3-6 patients will receive 2 x 10e11 cfu/ dose Dose Level III: 3-6 patients will receive 3 x 10e11 cfu/dose
    Intervention Type
    Drug
    Intervention Name(s)
    DeltaRex-G
    Other Intervention Name(s)
    DeltaRex-G Retroviral Vector Encoding a Cyclin G1 Inhibitor
    Intervention Description
    This is an open label, dose-seeking phase 1/2 study using escalating doses of DeltaRex-G given intravenously for 7 days in a hospital setting. The study will employ the standard "Cohort of Three" design (Storer, 1989). Three patients are treated at each dose level with expansion to six patients per cohort if DLT is observed in one of the three initially-enrolled patients at each dose level. If no DLT occurs in 3 patients, escalation to the next dose level will be permitted. The maximum tolerated dose is defined as the highest safely tolerated dose, where not more than one patient experienced DLT, with the next higher dose level having at least two patients who experienced DLT. No intra-patient dose escalation will take place. Patients who do not complete the 7-day treatment will be replaced.
    Primary Outcome Measure Information:
    Title
    Maximum Tolerated Dose
    Description
    The study will employ the standard "cohort of three" design (Storer, 1989). Three patients are treated at each dose level with expansion to six patients per cohort if DLT is observed in one of the three initially-enrolled patients at each dose level. The maximum tolerated dose is defined as the highest safely tolerated dose, where not more than one patient experienced DLT, with the next higher dose level having at least two patients who experienced DLT. No intra-patient escalation will take place.
    Time Frame
    3 weeks
    Secondary Outcome Measure Information:
    Title
    Survival
    Description
    Duration of survival
    Time Frame
    2 months
    Title
    Hospital Stay
    Description
    Time of hospital admission to time of discharge
    Time Frame
    3 weeks
    Title
    Ventilator Therapy
    Description
    Time from start of mechanical ventilation to extubation or death
    Time Frame
    3 weeks
    Title
    Intensive Care Unit Stay
    Description
    Time from start of intensive care to discarge to regular room
    Time Frame
    3 weeks
    Title
    Cytokine Pattern
    Description
    Improvement in serum cytokine IL-6, IL12, TNF alpha
    Time Frame
    3 weeks

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    100 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Individuals must meet all of the inclusion criteria in order to be eligible to participate in the study, as follows: Male or female ≥ 18 years of age Confirmed COVID-19 positive by viral RT PCR Patients with severe disease as evidenced by presence of pneumonia, diagnosis of ARDS in hospitalized patients Ability to understand the purposes and risks of the study and has signed and dated a written informed consent form approved by the investigator's IRB/Ethics Committee Willingness to comply with all study procedures and availability for the duration of the study. Adequate hematologic, renal or hepatic function defined by any of the following screening laboratory Values: i) Neutrophils >1000/uL ii) Platelets > 75,000/uL iii) Serum creatinine <1.5 x ULN or creatinine clearance < 60 mL/min (using the Cockcroft Gault formula) iv) AST/ALT, alk phos <3 x ULN vi) Total Bilirubin <1.5 x ULN All women of childbearing potential must have a negative pregnancy test and all subjects must agree to use highly effective means of contraception (surgical sterilization or the use of barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel or an IUD) with their partner from entry into the study through 2 months after the last dose. Exclusion Criteria: All individuals meeting any of the exclusion criteria at baseline will be excluded from study participation, as follows: Females who are pregnant or breast-feeding Unwillingness or inability to comply with the study protocol for any reason
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Sant P Chawla, MD
    Organizational Affiliation
    Mission Community Hospital
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    No
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    CORONA: A Study Using DeltaRex-G Gene Therapy for Symptomatic COVID-19

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