Study of the Safety of Therapeutic Tx With Immunomodulatory MSC in Adults With COVID-19 Infection Requiring Mechanical Ventilation

Study Overview
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Brief Summary
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This is a phase 1b randomized, double-blind, placebo-controlled study in adult subjects with Coronavirus Disease 2019 (COVID-19). This clinical trial will evaluate the preliminary safety and efficacy of BM-Allo.MSC vs placebo in treating subjects with severe disease requiring ventilator support during COVID 19 infection.

Official Title
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Phase 1b Randomized, Double-Blind, Placebo-Controlled Study Of The Safety Of Therapeutic Treatment With Immunomodulatory Mesenchymal Stem Cells In Adults With COVID-19 Infection Requiring Mechanical Ventilation

Conditions
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COVID

Intervention / Treatment
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* Biological: BM-Allo.MSC
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years old. Able to understand and provide a signed informed consent that fulfills the relevant Institutional Review Board (IRB) or Independent Ethics Committee (IEC) guidelines. For subjects that are intubated and/or sedated, or otherwise unable to provide consent, prospective consent from a legally-authorized representative is required. The subject or his/her legally authorized representative must be able to provide consent. Has laboratory-confirmed positive novel coronavirus (SARS-CoV-2) test, as determined by polymerase chain reaction (PCR), or other commercial or public health assay in any specimen < 72 hours prior to enrollment, or meets the criteria to guide the evaluation and testing of patients under investigation (PUI) for COVID-19 (https://emergency.cdc.gov/han/2020/HAN00428.asp). Requiring mechanical ventilatory support with moderate to severe Acute Respiratory Distress Syndrome (ARDS) as determined by the Berlin criteria: Bilateral opacities present on a chest radiograph or computed tomographic (CT) scan. These opacities are not fully explained by pleural effusions, lobar collapse, lung collapse, or pulmonary nodules. Origin of Edema: Respiratory failure not fully explained by cardiac failure or fluid overload. Oxygenation: Moderate to severe impairment of oxygenation must be present, as defined by the ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2). The severity of the hypoxemia defines the severity of the ARDS: Moderate: PaO2/FiO2 >100 mmHg and ≤ 200 mmHg, on ventilator settings that include PEEP ≥ 5 cm H2O Severe: PaO2/FiO2 ≤100 mmHg on ventilator settings that include PEEP ≥5 cm H2O Subjects receiving extracorporeal membrane oxygenation (ECMO) will not be enrolled in this study. High-sensitivity C-reactive Protein (hs-CRP) serum level > 4.0 mg/dL Acute Physiology and Chronic Health Evaluation (APACHE IV) score > 5 Agrees to the collection of nasopharyngeal (NP) swabs and venous blood per protocol. Ability to attend required study visits and return for adequate follow-up, as required by this protocol. Agreement to practice effective contraception for female subjects of child-bearing potential and non-sterile males. Female subjects of child-bearing potential must agree to use effective contraception while on study and for at least 1 month after the last dose of BM-Allo.MSC. Non-sterile male subjects must agree to use a condom while on study and for up to 1 month after the dose of BM-Allo.MSC. Effective contraception includes surgical sterilization (eg, vasectomy, tubal ligation), two forms of barrier methods (eg, condom, diaphragm) used with spermicide, intrauterine devices (IUDs), oral contraceptives, and abstinence. Exclusion Criteria: Known hypersensitivity to any component of the study medication(s). Signs of multisystem organ failure. Liver function tests (LFTs) > 5x normal. Intubated > 72 continuous hours. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol. Pregnant and nursing women. A negative serum pregnancy test during screening (within 72 hours prior to the first dose) must be documented before MSCs are administered to a female subject of child-bearing potential.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BM-Allo.MSC<br>Subjects in the experimental arm will be administered BM-Allo.MSC | Biological: BM-Allo.MSC<br>* BM-Allo.MSC for Infusion, is manufactured from normal donor derived bone marrow product and are phenotypically CD73+, CD90+, CD105+, and negative for CD14-, CD34-, CD45-, HLA-DR-.<br>|
| Placebo Comparator: Placebo<br>Subjects in the control arm will be treated with placebo | Biological: Placebo<br>* plasmalyte and human albumin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of AEs | Incidence of AEs within 30 days of randomization. | 30 days | 
| Mortality | Mortality within 30 days of randomization. | 30 days | 
| Death | Cause of death within 30 days of randomization | 30 days | 
| Number of ventilator-free days | Number of ventilator-free days within 60 days of randomization. | 60 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement of one category | Time from randomization to an improvement of one category using the ordinal scale. The ordinal scale is as follows: Death Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Hospitalized, on non-invasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen Not hospitalized, limitation on activities Not hospitalized, no limitations on activities | 30 days | 
| 7-point ordinal scale | Change in the 7-point ordinal scale from baseline. The ordinal scale is as follows: Death Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Hospitalized, on non-invasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen Not hospitalized, limitation on activities Not hospitalized, no limitations on activities | 30 days | 
| NEWS | Change in NEWS from baseline. The following 7 clinical parameters will be assessed: Respiration rate Oxygen saturation Any supplemental oxygen Temperature Systolic blood pressure Heart rate Level of consciousness Measurements within normal ranges are assigned a 0. If the measurement in each category is substantially above or below the normal range, it is given a +1, +2, or +3. The more far off than normal, the bigger the number (in each category). A higher number indicates worse outcome. Each category can be 0-3, except for supplemental oxygen which is only 0-2. The highest value a patient can get is 20. | 30 days | 
| NEWS of ≤ 2 | Time from randomization to discharge or to a NEWS of ≤ 2 maintained for 24 hours, whichever occurs first. | 30 days | 
| Sequential Organ Failure Assessment (SOFA) | Change from baseline in Sequential Organ Failure Assessment (SOFA) score on days 8, 15, 22, and 29. System Score for each category is 0-4 with 28 is the maximum score for worst outcome. The following categories are: Respiration Coagulation Liver Cardiovascular Central Nervous System Renal | days 8, 15, 22, and 29 | 
| Oxygen | Number of days requiring oxygen. | 30 days | 
| Hospitalization | Duration of hospitalization from randomization. | 30 days | 
| Incidence of SAEs | Incidence of SAEs within 30 days of randomization | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MSC, IMMUNOMODULATORY MESENCHYMAL STEM CELLS, COVID-19, Mechanical ventilation, Severe respiratory distress