Mesenchymal Stromal Cell Therapy For The Treatment Of Acute Respiratory Distress Syndrome

Study Overview
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Brief Summary
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This is an open label, dose escalating safety study of the advanced therapy investigational medicinal product (ATIMP) KI-MSC-PL-205, where patients diagnosed with SARS-CoV-2-induced severe acute respiratory distress syndrome (ARDS), according to the Berlin Definition, and who are on respirator/ventilator (used synonymously in this protocol) support due to respiratory insufficiency with or without concomitant circulatory problems, will be included and treated with a single dose of KI-MSC-PL-205.

Official Title
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Mesenchymal Stromal Cell Therapy For The Treatment Of Acute Respiratory Distress Syndrome Validation of Mechanistic Pathways and Clinical Efficacy

Conditions
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ARDS, Human, COVID

Intervention / Treatment
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* Drug: Mesenchymal Stromal Stem Cells - KI-MSC-PL-205


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide written informed consent prior to performing study procedures (and have given written consent) Coronavirus (SARS-CoV-2) infection confirmed by polymerase chain reaction (PCR) test at screening Male or female patient aged 18 to 65 years old Patient must fulfil the Berlin Definition of severe ARDS within 3 weeks to 48 hours prior to enrolment (Will be assessed once the patient has been admitted to the ICU) Patient is on respirator support within 3 weeks to 48 hours prior to enrolment (Will be assessed once the patient has been admitted to the ICU) Pregnancy test in blood confirming negative results before enrolment (for women ≤55 years old) Exclusion Criteria: History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the patient at risk because of participation in the study, or influence the results or the patient's ability to participate in the study Patients with history of treated blood and/or solid organ malignancy with recurrence within five years prior to dosing of the ATIMP are to be excluded. Patients with history of cervix cancer and non-melanoma skin cancer with recurrence within two years prior to dosing of the ATIMP are to be excluded Pregnant or breast feeding female Patient with a history of anti-coagulation therapy for other indications that short-term prophylaxis after surgery Patients with a history and/ or on-going treatment for entity associated with bleeding disorder or potential risk for bleeding (e.g. inflammatory bowel disease, gastro-esophagitis with or without ulcers, haemophilia and other bleeding disorders, inflammatory musculo-skeletal disease with potential bleeding complications) Patients with a history during the latest five years and/or on-going treatment for systemic infection (e.g. Septicaemia due to in vivo foreign body (e.g. stents, catheters, heart valve), tuberculosis, malaria, other opportunistic and parasite infections) Prisoner Any other irreversible disease or condition for which six-month mortality is estimated to be greater than 50% Moderate to severe liver failure (Child-Pugh Score >12) Reduced renal function with a creatinine clearance (Cockcroft-Gault Equation) < 45 mL/min/1.73m2 Severe chronic respiratory disease with a PaCO2 >50 mmHg or the use of home oxygen Major trauma in the prior 5 days Lung transplant patient Patients on ECMO-support Patients with a previous history of severe burns Documented deep venous thrombosis or pulmonary embolism within past three months Known hypersensitivity to DMSO Investigator considers the patient unlikely to comply with study procedures, restrictions and requirements

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Intervention Model: Single Group Assignment
Interventional Model Description: This is an open label, dose escalating safety study of the advanced therapy investigational medicinal product (ATIMP) KI-MSC-PL-205, where patients diagnosed with SARS-CoV-2-induced severe acute respiratory distress syndrome (ARDS).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mesenchymal Stromal Stem Cell Treatment<br>Infusion of allogeneic bone marrow derived mesenchymal stromal stem cells (MSC). First three patients receive a singe dose of 1x10^6 MSC/kg dose, next six patients receive a single dose of 2x10^6 MSC/kg. | Drug: Mesenchymal Stromal Stem Cells - KI-MSC-PL-205<br>* Allogeneic bone marrow derived mesenchymal stromal stem cells (MSCs).<br>* Other names: Allogeneic Bone Marrow Derived Mesenchymal Stem Cells;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of pre-specified treatment related adverse events of interest (TRAEIs). | The incidence of pre-specified treatment related adverse events of interest (TRAEIs) occurring during the 10 days interval beginning with the start of the ATIMP infusion: New ventricular tachycardia, ventricular fibrillation or asystole within 10 days after infusion New cardiac arrhythmia requiring cardioversion within 10 days after infusion Clinical scenario consistent with transfusion incompatibility or transfusion-related infection within 10 days after infusion Thromboembolic events (e.g. Pulmonary embolism) within 10 days after infusion Cardiac arrest or death within 10 days after infusion | From drug administration to day 10 post-infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety; All-cause mortality | All-cause mortality at 60 days and then annually | 60 days post-infusion, 6 months, 1, 2, 3, 4 and 5 years post-infusion | 
| Changes in Leucocytes | Changes from baseline (Day 1; prior to administration of ATIMP) in the leucocyte Count (number/L) | Baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4 and 5 years post-infusion | 
| Changes in Trombocytes | Changes from baseline (Day 1; prior to administration of ATIMP) in the trombocyte Count (number/L) | Baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4 and 5 years post-infusion | 
| Changes in plasma concentration of C-reactive protein (CRP) | Changes from baseline (Day 1; prior to administration of ATIMP) in the plasma concentration of CRP (mg/L) | Baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4 and 5 years post-infusion | 
| Changes in plasma concentration of Prothrombin complex (PK) | Changes from baseline (Day 1; prior to administration of ATIMP) in the plasma concentration of PK (INR) | Baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4 and 5 years post-infusion | 
| Changes in plasma concentration of Creatinine | Changes from baseline (Day 1; prior to administration of ATIMP) in the plasma concentration of creatinine (μmol/L) | Baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4 and 5 years post-infusion | 
| Changes in plasma concentration of Aspartate amino transferase (ASAT) | Changes from baseline (Day 1; prior to administration of ATIMP) in the plasma concentration of ASAT (μkat/L) | Baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4 and 5 years post-infusion | 
| Changes in plasma concentration of Alanine amino transferase (ALAT) | Changes from baseline (Day 1; prior to administration of ATIMP) in the plasma concentration of ALAT (μkat/L) | Baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4 and 5 years post-infusion | 
| Changes in plasma concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) | Changes from baseline (Day 1; prior to administration of ATIMP) in the plasma concentration of NT-proBNP (ng/L) | Baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4 and 5 years post-infusion | 
| Changes in Blood pressure | Changes from baseline (Day 1; prior to administration of ATIMP) in blood pressure (mmHg) | Baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4 and 5 years post-infusion | 
| Changes in Body temperature | Changes from baseline (Day 1; prior to administration of ATIMP) in body temperature (°C) | Baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4 and 5 years post-infusion | 
| Efficacy; Changes in pulmonary compliance | Changes from baseline (Day 1; prior to administration of ATIMP) in pulmonary compliance (dynamic and static) until day 10 post-infusion | Baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion | 
| Efficacy; Changes in driving pressure (Plateau pressure- PEEP) | Changes from baseline (Day 1; prior to administration of ATIMP) in driving pressure (Plateau pressure- PEEP) until day 10 post-infusion | Baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion | 
| Efficacy; Changes in oxygenation (PaO2/FiO2) | Changes from baseline (Day 1; prior to administration of ATIMP) in oxygenation (PaO2/FiO2) until day 10 post-infusion | Baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion | 
| Efficacy; Duration of ventilator support | Number of days with ventilator support | Baseline (pre-infusion),day 1, 2, 3, 4, 7, 10 and 60 post-infusion | 
| Efficacy; Pulmonary bilateral infiltrates | Changes in amount of pulmonary bilateral infiltrates assessed by pulmonary X-ray from baseline (Day 1; prior to administration of ATIMP) until day 60 | Baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4 and 5 years post-infusion | 
| Efficacy; Sequential Organ Failure Assessment (SOFA) score | Changes in Sequential Organ Failure Assessment (SOFA) score from baseline (Day 1; prior to administration of ATIMP) and during the ICU-period | Baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, end of ICU | 
| Efficacy; Hospital stay | Duration of ICU stay and hospital stay (number of days; whole hospital period + calculated from Day 1) | Day 60 post-infusion | 
| Lung function | Recovery of lung function assessed by Spirometry (FEV1, Vital Capacity) at day 60 and then annually | Day 60 post-infusion, 6 months, 1, 2, 3, 4 and 5 years post-infusion | 
| Lung fibrosis | To assess development of lung fibrosis using the HRCT Fibrosis Score using Computed tomography (CT) at baseline and on day 1, 3, 7, 10, end of ICU-residence, end of hospital stay, day 60, 6 month and 12 month and end of study (if possible during the infectious stage depending on hospital safety regimen during the pandemic). | Baseline (pre-infusion), day 1, 3, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4 and 5 years post-infusion | 
| Six minutes walk test | Assessment of the patient's physical capacity by 6-Minute-Walk-Test (6MWT), starting at 6 months post Day 1 and then annually | 6 months, 1, 2, 3, 4 and 5 years post-infusion | 
| Changes in Quality of life | Changes in Quality of Life by assessing the Short Form Health Survey (SF-36) score (starting at 6 months post Day 1 and then annually; patient reported outcome) | 6 months, 1, 2, 3, 4 and 5 years post-infusion | 
| Blood biomarkers | Change in blood biomarkers related to the proposed mechanisms of action of KI-MSC-PL-205 in ARDS | Baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4 and 5 years post-infusion | 
| Sensitisation test | Sensitisation tests (test for donor-specific antibodies) against KI-MSC-PL-205 donor | Baseline (pre-infusion), day 60 post-infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mesenchymal Stromal Stem Cells