Treatment of Respiratory Complications Associated With COVID19,Influenza ,Metapneumovirus,RSV Infection Using ProTrans®

Study Overview
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Brief Summary
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To investigate the safety and tolerance of a single infusion of ProTrans® in subjects with severe respiratory complications associated with pneumonia caused by COVID-19, Influenza A, Metapneumovirus or RSV infection.

Detailed Description
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The investigators hypothesize that the systemic delivery of WJ-MSCs exerts an anti-inflammatory action and anti-apoptotic effect in the lung of COVID-19, Influenza A, Metapneumovirus or RSV patients. The nature of these cells to immunomodulate both tissue resident and bloodborne immune cells towards a more anti-inflammatory and tolerogenic profile, results in a reduction of tissue-based inflammation within the lung and triggering of repair responses. This clinically culminates in a beneficial action on patients with severe respiratory complications associated with pneumonia.

Official Title
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Treatment of Respiratory Complications Associated With COVID-19, Influenza A, Metapneumovirus, Respiratory Syncytial Virus Infection Using Wharton's Jelly-Umbilical Cord Mesenchymal Stromal Cells (ProTrans®): Open Phase IB Clinical Trial

Conditions
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COVID-19 Acute Respiratory Distress Syndrome, Influenza A, Metapneumovirus Pneumonia, Respiratory Syncytial Virus (RSV)

Intervention / Treatment
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* Biological: ProTrans®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, aged ≥18 years old Has laboratory-confirmed SARS-CoV-2, Influenza A, Metapneumovirus or RSV infection as determined by reverse-transcription polymerase chain reaction (RT-PCR) in any specimen prior to inclusion. Hospitalized patients. Patients classified as severe pneumonia, as defined by the need for continuous supplemental oxygen 5 L/min 02 OR high flow oxygen, 35% FiO2 > 30l/min and cannot saturate > 96% NOT under non-invasive ventilation NOR invasive mechanical ventilation NOR ECMO. Women of childbearing potential must agree to use contraception or acceptable birth control for the duration of the study. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation 1: oral intravaginal transdermal, progestogen-only hormonal contraception associated with inhibition of ovulation 1: oral injectable implantable 2; intrauterine device (IUD) 2, intrauterine hormone-releasing system (IUS) 2, bilateral tubal occlusion 2, vasectomised partner 2,3, sexual abstinence 4 Hormonal contraception may be susceptible to interaction with the Investigational Medicinal Products (IMP), which may reduce the efficacy of the contraception method Contraception methods that in the context of this guidance are considered to have low user dependency. Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the trial participant and that the vasectomised partner has received medical assessment of the surgical success. 4 In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. Provision of a written informed consent Exclusion Criteria: Inability to provide informed consent Patients not expected to survive for 24 hours or mechanically ventilated at inclusion or previously during present hospitalization Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotrophin (hCG) laboratory test Patients with BMI ≥30 Patients with known, or previous, malignancy Patients with other serious systemic diseases deemed of contra-indication by the physician Patient with any of following laboratory results out of the ranges detailed below at screening: Absolute neutrophil count (ANC) ≤ 1.0 x 10e9/L, Platelets (PLT) < 50 10e9 /L, ASAT or ALAT > 5N, estimated glomerular filtration rate (eGFR) < 30 mL/min Current documented bacterial infection Serological evidence of infection with human immunodeficiency virus, Treponema pallidum, hepatitis B antigen (serology consistent with previous vaccination and a history of vaccination is acceptable) or hepatitis C Latent or previous as well as on-going therapy against tuberculosis, or exposed to tuberculosis or have travelled in areas with high risk of tuberculosis or mycosis within the last 3 months Patients with known allergies to a component of the ProTrans® product Ongoing treatment with Remdesivir Pre-existing chronic respiratory diseases requiring long- term oxygen therapy Pre-existing cirrhosis with basal Child and Pugh of C Patients with history of increased risk for thrombo- embolic and/or co-morbidity for thrombo- embolism Patients with a history of myocardium infarction A history of cardiac dysfunction, as assessed as: Clinical sign of a congestive heart failure refractory; Left ventricular ejection fraction <35% at myocardial scintigraphy or echocardiography; Pulmonary arterial hypertension with systolic pulmonary artery pressure (PAP) at echography > 40 mmHg Chronic atrial fibrillation requiring oral anticoagulant therapy; Uncontrolled ventricular arrhythmia; Pericardial effusion with hemodynamic compromise assessed by echocardiography.

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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Accepts Healthy Volunteers

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, dose escalating Phase IB Clinical Trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Wharton's Jelly (WJ)-Umbilical Cord (UC) Mesenchymal Stromal Cells (ProTrans®).Study patients 1-3 will receive a single dose of 25 million cells, patients 4-6 will receive 100 million cells and patients 7-9 will receive 200 million cells. | Biological: ProTrans®<br>* Allogeneic Wharton's jelly (WJ) Mesenchymal Stromal Cells<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerance of a single infusion of ProTrans® | Grade 3 or 4 adverse event but not usual in natural course of the disease. | 24 months | 
| Effect of ProTrans® -MSC on patient clinical status, including mortality | The rate of use of mechanical ventilation (necessitating intubation) or death. | 15 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of ProTrans® -MSC on patient clinical status, including mortality, at day 7 | Effect of ProTrans® -MSC on patient clinical status assessed on the 7-point ordinal scale; 1. Not hospitalized, no limitations on activities 2. Not hospitalized, limitation on activities 3. Hospitalized, not requiring supplemental oxygen 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 6. Hospitalized, on invasive mechanical ventilation or Extracorporeal membrane oxygenation (ECMO) 7. Death. | 7 days | 
| Effect of ProTrans® -MSC on patient clinical status, including mortality, at day 15 | Effect of ProTrans® -MSC on patient clinical status assessed on the 7-point ordinal scale; 1. Not hospitalized, no limitations on activities 2. Not hospitalized, limitation on activities 3. Hospitalized, not requiring supplemental oxygen 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 6. Hospitalized, on invasive mechanical ventilation or ECMO 7. Death. | 15 days | 
| Effect of ProTrans® -MSC on patient clinical status, including mortality, at day 30 | Effect of ProTrans® -MSC on patient clinical status assessed on the 7-point ordinal scale; 1. Not hospitalized, no limitations on activities 2. Not hospitalized, limitation on activities 3. Hospitalized, not requiring supplemental oxygen 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 6. Hospitalized, on invasive mechanical ventilation or ECMO 7. Death. | 30 days | 
| Time to clinical improvement after ProTrans® - MSC infusion | Time to clinical improvement of one category from admission on the 7-point ordinal scale after ProTrans® - MSC infusion | 30 days | 
| Effect of of ProTrans® -MSC on lung damage | Lung damage using imaging techniques (Chest X ray/CT scan /or on doppler ultrasound) when assessed for clinical need up to hospital discharge X ray/CT scan /or on doppler ultrasound) when assessed for clinical need | Up to 60 days | 
| Duration of hospitalization and Intensive Care Unit (ICU) stay | Duration of hospitalization and ICU stay | Up to 60 days | 
| Kinetics of COVID-19, Influenza A, Metapneumovirus, Respiratory Syncytial Virus (RSV) viral load after ProTrans® -MSC infusion | Quantitative PCR for SARS-CoV, Influenza A, Metapneumovirus, Respiratory Syncytial Virus (RSV) virus in throat swabs (time frame: before MSC infusion on Day 0 and after MSC infusion on day 30) | 30 days |