Efficacy of Infusions of MSC From Wharton Jelly in the SARS-Cov-2 (COVID-19) Related Acute Respiratory Distress Syndrome

Study Overview
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Brief Summary
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Mesenchymal stem cells (MSCs) are of potential help in acute respiratory distress syndrome (ARDS), due to their anti-inflammatory properties. The investigators will analyze the effect of 3 iterative infusions of ex vivo expanded Wharton's Jelly MSCs (total dose 2.10^6/kg) in patients with ARDS due to COVID19, who require mechanical ventilation.

Detailed Description
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This study is designed to analyze the impact of Wharton's Jelly Mesenchymal Stem Cells on moderate to severe ARDS due to COVID19 in adult patients who require mechanical ventilation. It is a Phase IIa double-blind randomized controlled trial. 30 patients are planned. Patients will be randomized and will receive, with the conventional treatment recommended to treat ARDS: Either Wharton's Jelly MSCs in a solution of albumin 4% (40% of final volume), NaCl 0,9% (50% of the final volume) et ACD formule A (10% of the final volume) . Treatment will be administered intravenously during 10 minutes following that scheme: Day 0 (or 1): 1. 10^6 MSC/kg (maximum 80.10^6 MSC) Day 3 (or 4): 0.5 . 10^6 MSC/kg (maximum 40. 10^6 MSC) Day 5 (or 6): 0.5 . 10^6 MSC/kg (maximum 40. 10^6 MSC) An interval of 2 days will be respected between 2 infusions. Either a placebo, which contains the same solution of albumin, NaCl 0.9% and ACD without cells. The volume will be of 75 ml, infused in 10 minutes. The main objective is to investigate efficacy of WJ-MSCs, compared to a placebo, on respiratory function evolution during the first 14 days of study treatment in patients with SARS-CoV-2 related moderate to severe ARDS. Secondary objectives are to assess the effect of WJ-MSC, compared to placebo, in patients with SARS-CoV-2 related moderate to severe ARDS, on: the duration of invasive mechanical ventilation during the hospital stay and maximum for 28 days the evolution of organ failures during the hospital stay and maximum for 28 days the duration of stay in intensive care unit, the mortality during intensive care unit, during hospitalization, on D28 and D90, and the respiratory morbidity. the evolution of viral load between D0 and D28 the immediate or delayed tolerance following the WJ-MSCs injection

Official Title
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Efficacy of Infusions of Mesenchymal Stem Cells From Wharton Jelly in the Moderate to Severe SARS-Cov-2 Related Acute Respiratory Distress Syndrome (COVID-19): A Phase IIa Double-blind Randomized Controlled Trial

Conditions
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COVID19 ARDS

Intervention / Treatment
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* Biological: Ex vivo expanded Wharton's Jelly Mesenchymal Stem Cells
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Man or woman 18 years of age or older Patient with a biologically confirmed SARS-CoV-2 infection (by positive RT-PCR on a nasopharyngeal sample or any other sample) Patient with moderate to severe ARDS according to the BERLIN definition defined by a PaO2 / FiO2 ratio <200 and with endotracheal intubation and under invasive mechanical ventilation Patient hospitalized in the intensive care unit Provision of a written informed consent to participate to the study or for whom the consent of a family member or support person has been obtained (if the patient is unable to give consent) or inclusion in an immediate vital emergency if applicable Any woman of childbearing age with a negative Beta HCG test Social Security affiliation Exclusion Criteria: Patient under invasive mechanical ventilation for more than 48 hours Patient with a chronic respiratory disease under oxygen therapy Patients with a history of Class III or IV pulmonary arterial hypertension (WHO classification) Patients under ECMO Immunosuppressive therapy (including corticosteroid therapy> 20 mg prednisolone) Active solid tumor or in remission for less than 2 years, malignant hematological disease, asplenia Patient who has received a hematopoietic stem transplantation or an organ transplant Therapeutic limitations like progression to expected death within 24 hours (according to the opinion of the medical team) Hypersensitivity to albumin or to any of the excipients (caprylic acid or sodium caprylate) Patient included in another ongoing interventional therapeutic trial Pregnant woman, parturient, nursing mother Minor (not emancipated) Person without liberty by judiciary or administrative decision Person undergoing psychiatric care under Articles L. 3212-1 and L. 3213-1 which do not fall under the provisions of Article L. 1121-8 (hospitalization without consent). Adult over 18 who are under a legal protection measure

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: Parallel Assignment
Interventional Model Description: Phase IIa double-blind randomized controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MSC Arm<br>Ex vivo expanded Wharton's Jelly derived mesenchymal stem cells will be infused at day 0, day 3 and day 5 (+/- 1 day), in patients with moderate to severe ARDS with a mechanical ventilation. day 0: 1.10^6 MSC/kg day 3: 0.5. 10^6 MSC/kg day 5: 0.5 . 10^6 MSC/kg | Biological: Ex vivo expanded Wharton's Jelly Mesenchymal Stem Cells<br>* Ex vivo expanded Wharton's Jelly derived mesenchymal stem cells will be infused at day 0, day 3 and day 5 (+/- 1 day), in patients with moderate to severe ARDS with a mechanical ventilation. day 0: 1.10^6 MSC/kg day 3: 0.5. 10^6 MSC/kg day 5: 0.5 . 10^6 MSC/kg<br>|
| Placebo Comparator: Placebo Arm<br>Only the vehicle solution, without MSCs, containing albumin 4% , NaCl 0,9% and ACD will be injected to patients at day 0, 3 and 5 (+/-1 day). | Biological: Placebo<br>* Only the vehicle solution, without MSCs, containing albumin 4% , NaCl 0,9% and ACD will be injected to patients at day 0, 3 and 5 (+/-1 day).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PaO2 / FiO2 ratio | The primary endpoint is the percentage of patients with a PaO2/FiO2 ratio > 200 at D10 of treatment with MSC-GW or placebo. | day 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| respiratory function evolution | The evolution of the PaO2/FiO2 ratio between Day 0 (or Day 1) and Day 14 of treatment with MSC-GW or placebo is a secondary endpoint. | between Day 0 (or Day 1) and Day 14 of treatment | 
| respiratory assistance | The effect of WJ-MSC on respiratory assistance is evaluated by the proportion of days without invasive respiratory assistance during the hospital stay and maximum on Day 28 (number of days without invasive respiratory assistance / number of hospital days fixed at day 28) | between day 0 (or 1) and day 28 (or last day of hospitalization if before day 28) | 
| organ failures 1 | Difference in sequential organ failure assessment score (SOFA score), grading 0 (best) to 4 (worst), between Day 5-Day 0 and D14-Day 0 | Day 0 to day 14 | 
| organ failures 2 | number of days without extra-renal treatment / number of hospital days fixed at day 28 | day 0 to day 28 | 
| organ failures 3 | number of days without vasopressor support | day 0 to day 28 | 
| duration of intensive care | The duration of stay in intensive care unit | day 0 to 90 | 
| Cause of death | Cause of death during the stay in intensive care unit and during the hospital stay, on Day 28 and Day 90 | day 0 to 90 | 
| respiratory morbidity (TDM, functional respiratory measures) | respiratory morbidity on Day 90 | day 90 | 
| viral load | The evolution of the viral load is evaluated by RT PCR SARS-Cov-2 monitoring on a nasopharyngeal swab (or any other sample) at diagnosis, at Day 7, Day 14, Day 21, Day 28 or on the last day of hospitalisation | day 0 to day 28 (or last day of hospitalization if before day 28) | 
| Anti-HLA antibody rate | - The anti-HLA antibody rate measured on Day 0 (before initiating treatment), on Day 28 and on Day 90 | day 0 to day 90 | 
| immediate hypersensitivity reactions | The occurrence of immediate hypersensitivity reactions (chills, hyperthermia associated with hypotension) within 4 to 6 hours of the WJ MSC or placebo infusion. | day 0, day 3, day 5 (+/- 1day) | 
| thromboembolic adverse events 1 | The thromboembolic risks monitored biologically by routinely daily monitoring of hemostasis (TP, TCA, Fibrinogen, D-dimers) | day 0 to day 14 | 
| thromboembolic adverse events 2 | daily monitoring of transthoracic echocardiography | day 0 to day 14 | 
| infectious adverse events | blood cultures in case of T° > 38,5°C | day 0 to day 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID, ARDS, MSC, mesenchymal stem cells, Wharton's Jelly, inflammation