hCT-MSCs for COVID19 ARDS

Sponsor
Joanne Kurtzberg, MD (Other)
Overall Status
Terminated
CT.gov ID
NCT04399889
Collaborator
The Marcus Foundation (Other)
14
Enrollment
5
Locations
3
Arms
20
Actual Duration (Months)
2.8
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a 50 patient, Phase 1/2a multi-center pilot study to test the safety and to describe the preliminary efficacy of intravenous administration of allogenic human cord tissue mesenchymal stromal cells (hCT-MSC) as an investigational agent, under U.S. INDs 19968 (Duke) and 19937 (U Miami) to patients with acute respiratory distress syndrome (ARDS) due to COVID-19 infection (COVID-ARDS). The first 10 consecutive patients will receive investigational MSCs manufactured by Duke. In the second phase of the study, 40 additional patients will be randomized to receive placebo or investigational MSCs manufactured by Duke or University of Miami.

Patients will be eligible for infusion of 3 daily consecutive doses of hCT-MSC or placebo if they have a confirmed diagnosis of COVID-19 and meet clinical and radiographic criteria for ARDS.

Results from the first 10 patients will be compared with concurrent outcomes utilizing standard of care treatments in participating hospitals and in published reports in the medical literature. Results from the additional 40 patients will be combined with the first 10 and analyzed. The trial is relying on focused eligibility of the participants (patients with ARDS), single cohort with short trial time (4 weeks), and simple assessment of clinical outcome (survival, improvement of ARDS). This is a sequential design in the sense that after the first 10 patients are evaluated a decision will be made by the PIs and the Data Safety Monitoring Board whether to proceed with the exploratory randomized portion of the study.

Condition or DiseaseIntervention/TreatmentPhase
  • Biological: Human cord tissue mesenchymal stromal cells (hCT-MSC) manufactured by Duke University.
  • Other: Placebo
Phase 1/Phase 2

Detailed Description

This is a 50 patient, Phase 1/2a multi-center pilot study to test the safety and to describe the preliminary efficacy of intravenous administration of allogenic human cord tissue mesenchymal stromal cells (hCT- MSC) as an investigational agent, under U.S. INDs 19968 (Duke) and 19937 (U Miami) to patients with acute respiratory distress syndrome (ARDS) due to COVID-19 infection (COVID-ARDS). Patients will be eligible for treatment with 3 daily consecutive doses of hCT-MSC at 1 million cells/kg (max dose 100 million cells) in the phase 1 portion of the study or a fixed dose of 100 million cells daily x 3 days, 12-36 hours apart in the phase 2 portion of the study, if they have a confirmed diagnosis of COVID-19 and meet clinical and radiographic criteria for ARDS. The primary endpoint is short-term safety of hCT-MSC infusions given on this schedule. The key secondary endpoints are 28 day survival, an increase in PaO2/FiO2 ratio by 50% at 96 hours, days to hospital discharge to home or rehab, and number of days requiring mechanical or non-invasive ventilation or high flow nasal cannula.

The study will be executed in two phases. The first 10 consecutive patients will all receive investigational product. The second part of the study is a randomized, controlled trial in 40 additional patients. The overall aim of the study is to establish safety and to gain critical information as to whether patients with COVID-ARDS will benefit from MSC infusions. Results from the first 10 patients will be compared with concurrent outcomes utilizing standard of care treatments in participating hospitals and in published reports in the medical literature. Results from the additional 40 patients will be analyzed as a randomized placebo control trial. The trial is relying on focused eligibility of the participants (patients with ARDS), single cohort with short trial time (4 weeks), and simple assessment of clinical outcome (survival, improvement of ARDS). This is a sequential design in the sense that after the first 10 patients are evaluated a decision will be made by the PIs and the Data Safety Monitoring Board whether to proceed with the exploratory randomized portion of the study.

The MSCs are manufactured from allogeneic cord tissue donated to the Carolinas Cord Blood Bank (CCBB) at Duke University. The CCBB is an FDA licensed public cord blood bank (licensed name DUCORD). Cord tissue is donated by mothers delivering healthy term male babies by Cesarean section, after written informed consent from the newborn infant's mother. Full donor screening and testing is performed in accordance with regulatory requirements (21CFR 1271). The hCT-MSCs will be manufactured in the Marcus Center for Cellular Cures in the Robertson GMP Cell Manufacturing Laboratory and the Clinical Research Cell Manufacturing Program (CRCMP) laboratory, Interdisciplinary Stem Cell Institute (ISCI), Miller School of Medicine, University of Miami. These hCT-MSCs are already being utilized in clinical trials to treat pediatric patients with autism spectrum disorder (IND 17313), cerebral palsy (IND 17921), hypoxic ischemic encephalopathy (IND 17313) and adults with osteoarthritis of the knee (IND18414). To date, over 210 doses of cells have been delivered to patients on these clinical trials with an excellent safety profile. At University of Miami, hCT-MSCs are used in the clinical trial to evaluate cytokine suppression in patients with chronic inflammation due to metabolic syndrome (IND 17324), 12 subjects in the pilot phase of the study had completed the dose without any treatment emergence SAE.

The rationale for using this approach for patients infected with COVID-19 is that ARDS, the rate-limiting complication impacting survival, is caused, at least in part, by a cytokine release syndrome (CRS) which results is severe immune dysregulation. Involved cytokines include IL-6, IL-8, IL-10, THP-1M, TNF-alpha, and others. MSCs have strong anti-inflammatory and immune-modulatory activities without apparent toxicity or further immunosuppression. Approximately 3-5 % of patients with COVID-19 develop ARDS which carries a very high mortality rate (30-60%) due to multi-system organ failure. Effective treatment of ARDS, the most feared complication of COVID-19, may convert the COVID-19 pandemic into a more manageable "flu-like" illness that every American is expected to experience, and most will survive, on an annual basis.

Study Design

Study Type:
Interventional
Actual Enrollment :
14 participants
Allocation:
Randomized
Intervention Model:
Sequential Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
Pilot Study of Safety and Efficacy of Cord Tissue Derived Mesenchymal Stromal Cells (hCT-MSC) in COVID-19 Related Acute Respiratory Distress Syndrome (ARDS)
Actual Study Start Date :
Jun 18, 2020
Actual Primary Completion Date :
Feb 16, 2022
Actual Study Completion Date :
Feb 16, 2022

Arms and Interventions

ArmIntervention/Treatment
Experimental: Open Label infusion of hCT-MSC

The first 10 consecutive patients will all receive investigational product.

Biological: Human cord tissue mesenchymal stromal cells (hCT-MSC) manufactured by Duke University.
Human cord tissue mesenchymal stromal cells (hCT-MSC) manufactured by Duke University or University of Miami.
Other Names:
  • hCT-MSC
  • Experimental: Randomized infusion of hCT-MSC

    An interim analysis, for safety will be conducted and reviewed by the Data Safety and Monitoring Board (DSMB) after the first 10 patients have completed treatment and reached the 28 day endpoint. If there are no safety concerns, the trial will proceed with enrollment on the phase 2 portion of the study where the subsequent 40 patients will be randomized in a 1:1 fashion between treatment with MSCs and placebo. The investigational product will be further randomized to the MSCs manufactured by Duke or University of Miami. These products are considered to be comparable.

    Biological: Human cord tissue mesenchymal stromal cells (hCT-MSC) manufactured by Duke University.
    Human cord tissue mesenchymal stromal cells (hCT-MSC) manufactured by Duke University or University of Miami.
    Other Names:
  • hCT-MSC
  • Placebo Comparator: Randomized infusion of Placebo

    An interim analysis, for safety will be conducted and reviewed by the Data Safety and Monitoring Board (DSMB) after the first 10 patients have completed treatment and reached the 28 day endpoint. If there are no safety concerns, the trial will proceed with enrollment on the phase 2 portion of the study where the subsequent 40 patients will be randomized in a 1:1 fashion between treatment with MSCs and placebo

    Other: Placebo
    Placebo will be comprised of 40-80 mL of Plasmalyte-A + 1% Human Serum Albumin (HAS) prepared in an identical container to the one used for cell administration. The placebo product will undergo the same process of sterility testing including release inspection, transport and product custodian.

    Outcome Measures

    Primary Outcome Measures

    1. Safety of the Investigational Product- Infusion Reactions [24 hours]

      Incidence of infusion reactions measured by any one of the following: fever, anaphlyaxis, rash, hypertension, hypotension, tachycardia, nausea, vomiting, or any other new or worsening symptoms associated with the infusion.

    2. Safety of the Investigational Product- delayed reactions [28 days]

      Incidence of later reactions attributed to the investigational product as measured by any one of the following: rash, infection, allergic reaction, or any other delayed symptoms associated with infusion of the investigational product.

    3. Safety of the Investigational Product- formation of anti-HLA antibodies [28 days]

      Formation of new anti-HLA antibodies as measured by an antibody screen test at 28 days post first infusion of the investigational product.

    Secondary Outcome Measures

    1. Time to recovery [28 days]

      Time to recovery, defined as discharge from the hospital (alive) or remaining in the hospital without the need for supplemental oxygen or other COVID-related medical care.

    2. Increase in PaO2/FiO2 ratio [4 days after MSCs]

      Increase in PaO2/FiO2 ratio by 50% by Day 4 (96 hours after first infusion). PaO2/FiO2 may be calculated from an arterial blood gas or imputed from the SpO2/FiO2 table

    3. Days to hospital discharge to home [90 days]

      The number of days from hospitalization to discharge to home

    4. The number of ventilator free days [90 days]

      The number of ventilator free days

    5. Number of days requiring oxygen support [7 days]

      Number of days requiring oxygen support

    6. Percent of screened patients who are enrolled and randomized [90 days]

      Percent of screened patients who are enrolled and randomized

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. The patient or legally authorized representative (LAR) must have the ability to understand and the willingness to provide a signed and dated informed consent form.

    2. Age 18 years and over

    3. The patient agrees to use adequate contraception for the duration of the treatment protocol and for 6 months post treatment.

    4. Positive RT- PCR testing for COVID-19 nucleic acid using nasopharyngeal swabbing or any other site

    5. Patient meets ARDS criteria and is on non-invasive or mechanical ventilation or high flow nasal cannula

    6. bilateral opacities on chest imaging consistent with pulmonary edema

    7. A need for positive pressure ventilation or high flow nasal cannula

    8. PaO2/FiO2 ratio ≤ 300 mmHg by arterial blood gas or SpO2/FiO2 imputation.

    9. Infiltrates not fully explained by cardiac failure or fluid overload in the physician's best clinical judgement

    10. Subjects requiring dialysis as a result of a COVID-19 infection will not be excluded.

    Exclusion Criteria:
    1. Evidence of multiorgan failure involving one or more organs, excluding the lungs as defined below:

    2. Presence of shock, defined as MAP < 65 mmHg with signs of peripheral hypoperfusion, or continuous infusion of 2 or more vasopressor or inotrope agents to maintain MAP ≥ 65 mmHg.

    3. Serum bilirubin > 10 mg/dl

    4. Platelet count < 50,000/ml

    5. Subjects requiring dialysis as a result of anything other than a COVID-19 infection will be excluded

    6. Evidence of acquired or congenital immunodeficiency (due to immunosuppressive therapy excluding steroid use for treatment of COVID-19 acute respiratory failure, HIV, previous treatment for cancer, etc.)

    7. History of metastatic cancer diagnosis or treatment in the past 1 year

    8. History of previous treatments with MSCs or other cell therapies

    9. Patient is co-enrolled in any other IND-sponsored clinical trials for COVID-19 or ARDs. Drugs that are administered under emergency use authorizations (EUA) by the FDA are permitted.

    10. Evidence of pregnancy or lactation

    11. Moribund patient not expected to survive >24 hours

    12. Unable/unwilling to deliver lung protective ventilation

    13. Patient is receiving Extracorporeal Membrane Oxygenation (ECMO)

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Boca Raton Regional HospitalBoca RatonFloridaUnited States33486
    2Jackson Memorial HospitalMiamiFloridaUnited States33136
    3University of Miami HospitalMiamiFloridaUnited States33136
    4New York Medical CollegeValhallaNew YorkUnited States10595
    5Duke HospitalDurhamNorth CarolinaUnited States27705

    Sponsors and Collaborators

    • Joanne Kurtzberg, MD
    • The Marcus Foundation

    Investigators

    • Principal Investigator: Joanne Kurtzberg, MD, Duke Health
    • Principal Investigator: Lingye Chen, MD, Duke Health

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Joanne Kurtzberg, MD, Jerome S. Harris Distinguished Professor of Pediatrics, Duke University
    ClinicalTrials.gov Identifier:
    NCT04399889
    Other Study ID Numbers:
    • Pro00105410
    First Posted:
    May 22, 2020
    Last Update Posted:
    Mar 4, 2022
    Last Verified:
    Feb 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Joanne Kurtzberg, MD, Jerome S. Harris Distinguished Professor of Pediatrics, Duke University
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Mar 4, 2022