Safety, Tolerability, and Efficacy of MatriPlax in Subjects With Acute Respiratory Distress Syndrome

Study Overview
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Brief Summary
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The goal of this clinical trial is to explore the safety, tolerability, and efficacy in study intervention, MatriPlax, in subjects with Acute Respiratory Distress Syndrome (ARDS). MatriPlax contains placenta choriodecidual membrane-derived Mesenchymal Stem Cells (pcMSCs). Participants will receive two doses of MatriPlax on Day 1 and Day 4 and conduct efficacy and safety evaluations until 12 months after treatment or withdrawal from the study.

Detailed Description
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This open-label, dose-escalation Phase I study plans to evaluate the safety, tolerability, and efficacy of MatriPlax. This is a conventional 3+3 dose-escalation study in which subjects with moderate or severe ARDS will receive intravenous MatriPlax infusion. Participants will be assigned to one of three dose cohorts (low, middle and high doses of MatriPlax), depending on the time of their enrollment. Each participant will receive two doses of MatriPlax on Day 1 and Day 4. Each dose cohort will have three to six subjects enrolled sequentially with at least 1 week in between. All participants will be followed until 12 months after receiving MatriPlax or withdrawal from the study. A Data Safety and Monitoring Board (DSMB) meeting will be held when all participants of each cohort complete their 28-day of treatment and evaluation period. The DSMB will determine if the study is safe to proceed to the next dose level or it requires to recruit more subjects to the concurrent dose level for safety evaluation.

Official Title
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A Phase I Open-Label, Dose-Escalation Study to Evaluate Safety, Tolerability, and Efficacy of Allogeneic Placenta-derived Human Mesenchymal Stem Cells for the Treatment of Acute Respiratory Distress Syndrome

Conditions
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Acute Respiratory Distress Syndrome

Intervention / Treatment
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* Drug: MatriPlax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of moderate or severe ARDS according to the Berlin definition Acute onset of respiratory failure within 1 week of identified insult Respiratory failure associated with known ARDS risk factors and not fully explained by either cardiac failure or fluid overload Radiological abnormalities on chest X-ray or computerized tomography (CT) scan, i.e., bilateral infiltrates that are not fully explained by effusions, lobar/lung collapse, or nodules Hypoxic respiratory failure Moderate ARDS: PaO2/ FiO2 ratio > 100 mmHg (13.3 kPa) to ≤ 200 mmHg (26.6 kPa) with positive end expiratory pressure (PEEP) ≥ 5 cmH2O Severe ARDS: PaO2/ FiO2 ratio ≤ 100 mmHg (13.3 kPa) with PEEP ≥ 5 cmH2O Administration of study drug must be planned to take place within 72 hours since moderate or severe ARDS diagnosis Either gender, 20   80 years old (inclusive) Dated and signed informed consent A subject has been admitted to an ICU or RCC and is already on or candidates for mechanical ventilation A subject with the primary disease of ARDS caused by documented virus infection (including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) With normal vital sign parameters: Systolic blood pressure ≥ 90 mmHg and ≤ 160 mmHg Diastolic blood pressure ≥ 50 mmHg and ≤ 95 mmHg Pulse rate ≥ 60 beats per minute (bpm) and ≤ 100 bpm Body temperature ≥ 35.5°C and ≤ 37.7°C Exclusion Criteria: No intent/unwillingness to follow lung-protective ventilation strategy or fluid management manual On extracorporeal membrane oxygenation (ECMO) support Severe chronic respiratory disease with a PaCO2 > 50 mm Hg or with any oxygen support A subject who is extremely unlikely to survive more than 24 hours in the opinion of the investigator World Health Organization (WHO) Class III or IV pulmonary hypertension Clinical evidence of left ventricular failure With acute diseases or serious medical conditions include cardiovascular (such as cardiac arrhythmia, QT prolongation), pulmonary (except ARDS), hepatic, neurologic, metabolic, renal, psychiatric condition, autoimmune disease, medical history, physical findings, or laboratory abnormality that in the investigators' opinion are not in stable condition and participating in the study could adversely affect the safety of the subject Severe liver disease (Childs-Pugh Score > 10) Acute or chronic kidney disease (Stage-3B, 4 or 5 renal impair; estimated glomerular filtration rate (eGFR) ˂ 60 mL/min/1.73 m^2 or dialysis) Note: eGFR (mL/min/1.73 m^2) = 186.3 × (serum creatinine in mg/dL)^-1.154 × (age)^-0.203× (0.742 if female) × (1.212 if African American/black) History of pulmonary embolism Previous solid organ transplant With major surgery within 14 days prior to Screening visit Note: Major surgery is defined as an invasive operative procedure where one or more of the following occurred: 1) A body cavity was entered; 2) A mesenchymal barrier was crossed; 3) A fascial plane was opened; 4) An organ was removed; 5) Normal anatomy was operatively altered. All other invasive operative procedures are minor surgeries. Presence of any active malignancy within 2 years prior to Screening visit History of the human immunodeficiency virus (HIV) infection History of severe allergic or anaphylactic reactions Known or suspected hypersensitivity or previous adverse reaction to any ingredients of study product Participation in a clinical trial of an interventional medicinal product within 12 weeks prior to Screening visit With any other uncontrolled illness judged by the principal investigator that entering the trial may be detrimental to the subject Pregnant or lactating or premenopausal with childbearing potential but not taking reliable contraceptive method(s) during the study period. At least one form of birth control must be adopted. Acceptable forms include: Placement of an intrauterine device (IUD) or intrauterine system (IUS). Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) Female subject with childbearing potential who has positive serum or urine pregnancy test at Screening Visit Unable to return for follow-up visits for clinical evaluation or laboratory studies Inappropriate to participate in this clinical study because of psychiatric disorders or any condition as judged by the principal investigator Hypersensitive to penicillin, streptomycin and amphotericin B antibiotics With specific known risk factors for thrombotic events, including obesity (Body mass index (BMI) >35), diabetes mellitus Type I, history of deep vein thrombosis (DVT) or thrombotic episodes, acquired or inherited thrombophilic disorders, hypercoagulable conditions, and other cardiovascular risk factors judged by the investigator Use of estrogens/oral contraceptives within 6 weeks prior to Screening visit Current smoker or has smoked within 3 months prior to Screening visit.

Ages Eligible for Study
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Minimum Age: 20 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
Intervention Model: Single Group Assignment
Interventional Model Description: MatriPlax
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MatriPlax<br>Each subject will receive 2x10^7, 4x10^7, or 8x10^7 pcMSCs per administration | Drug: MatriPlax<br>* MatriPlax contains pcMSCs (placenta choriodecidual membrane-derived mesenchymal stem cells) and will be given intravenously on Day 1 and Day 4<br>* Other names: Placenta choriodecidual membrane-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 treatment-emergent adverse events (TEAEs) up to 28 days after receiving MatriPlax | TEAEs are adverse events (AE) that occur after the study intervention administration | Day 1 to Day 29 | 
| The incidence of serious adverse events (SAEs) up to 28 days after receiving MatriPlax | SAE is an AE that results in any of the following outcomes: Death; Life-threatening; Requires inpatient hospitalization or prolongation of existing hospitalization; Results in persistent or significant disability/incapacity; Congenital anomaly/birth defect; Based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed above | Day 1 to Day 29 | 
| The incidence of suspected unexpected serious adverse reactions (SUSAR) up to 28 days after receiving MatriPlax | SUSAR is an SAE that is considered related to study intervention and unexpected judged by sponsor and investigator | Day 1 to Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in PaO2/FiO2 ratio from baseline | The PaO2/FiO2 ratio is the ratio of arterial oxygen partial pressure (PaO2) to fractional inspired oxygen (FiO2), which is an indicator of the severity of ARDS. | Baseline, Day 4, 6, 8, 15, 29 | 
| Changes in Lung injury score (LIS) from baseline | The LIS is a standard measure of ARDS, which is composed of four components. Each component has 5 scores (0, 1, 2, 3 and 4-point) and the score of LIS is the average of the four components. A higher LIS indicates more severe lung injury. | Baseline, Day 8, 29 | 
| Overall survival | Overall survival is defined as the time from treatment to death. | Baseline, Day 29, Month 3, 6, 9, 12 | 
| All-cause mortality rate | All-cause mortality rate is defined as the rate of deaths from any cause in all participants. | Baseline, Day 29, Month 3, 6, 9, 12 | 
| Cumulative ventilator-free hours (VFH) | Only subjects who wean from the ventilator and have at least 48 consecutive weaning hours | Day 1 to 29 | 
| Time to the first weaning from ventilator | Only subjects who wean from the ventilator and have at least 48 consecutive weaning hours | Up to 12 months | 
| Number of subjects weaned from ventilator | Only subjects who wean from the ventilator and have at least 48 consecutive weaning hours | Day 29 | 
| Intensive Care Unit (ICU) free hours | Only subjects who are stable for discharge from ICU and have at least 48 consecutive hours of discharge | Day 1 to 29 | 
| Time to the first ICU discharge | Only subjects who are stable for discharge from ICU and have at least 48 consecutive hours of discharge | Up to 12 months | 
| Number of subjects discharged from ICU | Only subjects who are stable for discharge from ICU and have at least 48 consecutive hours of discharge | Day 29 | 
| ICU/Respiratory Care Center (RCC) free hours | Only subjects who are stable for discharge from ICU/RCC and have at least 48 consecutive hours of discharge | Day 1 to 29 | 
| Changes in Sequential Organ Failure Assessment (SOFA) score from baseline | The SOFA is a simple and objective score to evaluate the status of organ dysfunction of six organ systems (respiratory, coagulatory, liver, cardiovascular, renal, and neurologic). A subject is defined as free of organ failure when the SOFA score is zero. The total score of SOFA is 24. | Baseline, Day 4, 6, 8, 15, 29 | 
| Cumulative vasopressor free days | The cumulative vasopressor free days are the sum of the days without taking vasopressor up to Day 29 or death. | Day 1 to 29 | 
| Cumulative oxygen support free hours | The cumulative oxygen support free hours are the sum of hours without oxgen support up to Day 29 or death | Day 1 to 29 | 
| The net change in c-reactive protein (CRP) from baseline | C-reactive protein is an inflammatory marker | Baseline, Day 4, 6, 8, 15, and 29 | 
| The net change in D-dimer from baseline | D-dimer is an inflammatory marker | Baseline, Day 4, 6, 8, 15, and 29 | 
| The net change in Lactate Dehydrogenase (LDH) from baseline | LDH is an inflammatory marker | Baseline, Day 4, 6, 8, 15, and 29 | 
| The domain scores and total score of 12-item Short Form Survey (SF-12) Quality of Life (QoL) health survey questionnaire | The SF-12 QoL is a self-evaluated measurement of health status. It consists of eight domains and the score of each domain is transformed to a scale from 0 to 100. Zero indicates the worst health status, while 100 indicates the best health status. | Month 3, 6, 9, 12 | 
| Number of subjects who experienced Dose Limiting Toxicity (DLT) | A DLT is defined as any SAE OR any equal or greater than Grade 3 (CTCAE v5.0) AE judged as MatriPlax-related during Day 1 to 29. The CTCAE (Common Terminology Criteria for Adverse Events) is a classification system used to grade AE. | Day 1 to 29 | 
| Incidence of TEAEs (treatment-emergent AEs) and SAEs | The number of TEAEs (treatment-emergent AEs) and SAEs that occur in the study | 12 months | 
| Number of participants with abnormalities in vital signs | The vital signs include blood pressure, respiratory rate, oxygen saturation, pulse rate, and body temperature | Baseline, Day 1, 4, 6, 8, 15, 29, Month 3, 6, 9, 12 | 
| Number of participants with abnormalities in physical examination | A physical examination includes general appearance, skin, eyes, ears, nose, throat, head and neck (including thyroid), heart, chest and lungs, abdomen, extremities, lymph nodes, musculoskeletal, neurological system, and other body systems if applicable. | Baseline, Day 1, 4, 6, 8, 15, 29, Month 3, 6, 9, 12 | 
| Number of participants with abnormalities in laboratory examination parameters | The laboratory examination parameters include hematology (hemoglobin, hematocrit, red blood cell (RBC), platelet, white blood cell (WBC), neutrophils, lymphocytes, monocytes, eosinophils, basophils) and biochemistry (blood urea nitrogen (BUN), creatinine, albumin, total protein, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, C-reactive protein (CRP), prothrombin time (PT), D-dimer, Lactate Dehydrogenase (LDH)) | Baseline, Day 1, 4, 6, 8, 15, 29 | 
| Number of participants with abnormalities in ECG parameters | The ECG parameters include ventricular rate, PR interval, QRS interval, and QT interval. Each parameters will be evaluated by the investigator as Normal, Abnormal, non-clinical significant (NCS) or Abnormal, clinical significant (CS). | Baseline, Day 29 |