hCT-MSCs for COVID19 ARDS

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Pilot Study of Safety and Efficacy of Cord Tissue Derived Mesenchymal Stromal Cells (hCT-MSC) in COVID-19 Related Acute Respiratory Distress Syndrome (ARDS)

Conditions
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COVID, Corona Virus Infection, COVID19

Intervention / Treatment
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* Biological: Human cord tissue mesenchymal stromal cells (hCT-MSC) manufactured by Duke University.
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Age 18 years and over The patient agrees to use adequate contraception for the duration of the treatment protocol and for 6 months post treatment. Positive RT- PCR testing for COVID-19 nucleic acid using nasopharyngeal swabbing or any other site Patient meets ARDS criteria and is on non-invasive or mechanical ventilation or high flow nasal cannula bilateral opacities on chest imaging consistent with pulmonary edema A need for positive pressure ventilation or high flow nasal cannula PaO2/FiO2 ratio ≤ 300 mmHg by arterial blood gas or SpO2/FiO2 imputation. Infiltrates not fully explained by cardiac failure or fluid overload in the physician's best clinical judgement Subjects requiring dialysis as a result of a COVID-19 infection will not be excluded. Exclusion Criteria: Evidence of multiorgan failure involving one or more organs, excluding the lungs as defined below: 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. Serum bilirubin > 10 mg/dl Platelet count < 50,000/ml Subjects requiring dialysis as a result of anything other than a COVID-19 infection will be excluded 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.) History of metastatic cancer diagnosis or treatment in the past 1 year History of previous treatments with MSCs or other cell therapies 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. Evidence of pregnancy or lactation Moribund patient not expected to survive >24 hours Unable/unwilling to deliver lung protective ventilation Patient is receiving Extracorporeal Membrane Oxygenation (ECMO)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open Label infusion of hCT-MSC<br>The first 10 consecutive patients will all receive investigational product. | Biological: Human cord tissue mesenchymal stromal cells (hCT-MSC) manufactured by Duke University.<br>* Human cord tissue mesenchymal stromal cells (hCT-MSC) manufactured by Duke University or University of Miami.<br>* Other names: hCT-MSC;|
| Experimental: Randomized infusion of hCT-MSC<br>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.<br>* Human cord tissue mesenchymal stromal cells (hCT-MSC) manufactured by Duke University or University of Miami.<br>* Other names: hCT-MSC;|
| Placebo Comparator: Randomized infusion of Placebo<br>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<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Infusion Reactions | Number of infusion reactions measured by any one of the following: fever, anaphylaxis, rash, hypertension, hypotension, tachycardia, nausea, vomiting, or any other new or worsening symptoms associated with the infusion. | 24 hours | 
| Number of Delayed Reactions | Number 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. | 28 days | 
| Number of Participants With Formation of New Anti-HLA Antibodies | Number of participants who form new anti-HLA antibodies as measured by an antibody screen test at 28 days post first infusion of the investigational product. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Recovery | 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. | up to 90 days | 
| Number of Participants With an Increase in PaO2/FiO2 Ratio | 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. | 4 days after MSCs | 
| Days to Hospital Discharge to Home | The number of days from hospitalization to discharge to home. | 90 days | 
| Number of Ventilator Free Days |  | 90 days | 
| Number of Oxygen-free Days | Number of oxygen-free days defined as: 0 if the subject dies within 28 days of supplemental oxygen, 28-x if successfully liberated from supplemental oxygen x days after initiation, and 0 if the subject receives supplemental oxygen for > 28 days. | 28 days | 
| Number of Screened Patients Who Are Enrolled and Randomized |  | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID, Coronavirus infection, COVID19, Covid ARDS, Acute Respiratory Distress Syndrome, ARDS