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Safety and Tolerance of Umbilical Cord Mesenchymal Stem Cells in Patients With Acute Respiratory Distress Syndrome

Primary Purpose

Acute Respiratory Distress Syndrome

Status
Not yet recruiting
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Human Umbilical Cord Mesenchymal Stem Cells
Sponsored by
Asia Cell Therapeutics (Shanghai) Co., Ltd.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Respiratory Distress Syndrome focused on measuring Human Umbilical Cord Mesenchymal Stem Cells, Acute Respiratory Distress Syndrome

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: 18-75 years old (including the threshold), male or female A definite diagnosis of mild to moderate acute respiratory distress syndrome (ARDS) (according to the ARDS Berlin definition and diagnostic criteria) ARDS onset ≤ 5 days 100 mmHg < PaO2/FiO2 ≤ 300 mmHg Bilateral pulmonary infiltrates on chest radiograph or chest CT Rule out other causes of pulmonary oedema, such as cardiogenic pulmonary oedema and pulmonary oedema due to fluid overload Have no plans to have children within 2 weeks before screening and 3 months after the end of the trial, and agree to use effective non-pharmacological contraception during the trial Patients voluntarily signed an informed consent form and were willing to co-operate with the trial process Exclusion Criteria: Hypersensitivity to known components of the drug (the main component of this product is human umbilical cord mesenchymal stem cells, excipients include dimethyl sulfoxide, human albumin, compound electrolyte injection), the presence of a history of allergy to gentamicin or other history of severe allergy Patients requiring treatment for any malignancy within 2 years prior to administration (except non-melanoma skin cancer) Lung transplant patients Patients with malignant haematological diseases Persons who have had a cardiovascular event within 3 months prior to dosing (e.g., unstable angina, congestive heart failure, myocardial infarction within the last 12 months, haemodynamic instability or known left ventricular ejection fraction (LVEF) <40% or clinically significant rhythm or conduction abnormalities) A history of deep vein thrombosis or pulmonary embolism during the Screening Period that, in the judgement of the Investigator, may be triggered or increase risk by receiving MSC transplantation therapy A breastfeeding female or a female with a positive blood pregnancy test result during the Screening Period History of immunodeficiency and/or autoimmune disease such as systemic lupus erythematosus (SLE), or other congenital immunodeficiency disease, idiopathic IgA deficiency. Laboratory tests at screening meet any of the following: Albuminous transaminase (AST) or albuminous transaminase (ALT) > 5 x ULN (non-hepatic sources are excluded; Serum creatinine > 1.5 x ULN or glomerular filtration rate < 60 mL/min/1.74 m2; Activated partial thromboplastin time (APTT) > 2.5 x ULN or prothrombin time; (PT) > 2.5 x ULN (not receiving anticoagulation) Positive infectious diseases (HBsAg, HCV, HIV-1, syphilis, active tuberculosis) Currently receiving extracorporeal life support (ECLS) such as continuous haemodialysis (CRRT) and carbon dioxide removal (ECCO2R), or high frequency oscillatory ventilation (HFOV) Presence of any other irreversible condition or symptom for which the subject has an expected survival of <3 months Combined WHO Class III or IV pulmonary hypertension Patients who refuse lung protective ventilation and fluid management Participation in other clinical trials or studies within 3 months prior to administration Persons with prior stem cell therapy Any other condition that, in the judgement of the investigator, makes participation in this trial inappropriate, such as a condition in which the study is not in the subject's current best interest (e.g., detrimental to health)

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    Human Umbilical Cord Mesenchymal Stem Cells

    Arm Description

    The trial was divided into three dose groups: Low-dose group: 1000000 cells/kg Medium-dose group: 2000000 cells/kg High-does group: 4000000 cells/kg

    Outcomes

    Primary Outcome Measures

    Adverse Event (AE)
    Adverse events that occurred during the trials
    Serious Adverse Event (SAE)
    Serious adverse events that occurred during the trial
    Maximum Tolerated Dose (MTD)
    Maximum Tolerated Dose

    Secondary Outcome Measures

    Oxygenation index
    To observe the improvement in oxygenation index (P/F) from baseline
    Chest routine scan
    To explore the improvement in lung imaging (calculation of lung exudate area)
    Intubation rate
    To explore the rate of intubation in subjects within 28 days after infusion
    Length of hospitalisation
    Length of stay in hospital within 28 days
    Time out of ICU
    Observe the time that subjects are not in the ICU for 28 days after infusion
    Rate of Mortality
    Rate of Mortality within 28 days after infusion
    Murray lung injury score
    Improvement in assessment scores from baseline. The higher the score is, the more severe the lung damage is.

    Full Information

    First Posted
    July 26, 2023
    Last Updated
    August 7, 2023
    Sponsor
    Asia Cell Therapeutics (Shanghai) Co., Ltd.
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05983627
    Brief Title
    Safety and Tolerance of Umbilical Cord Mesenchymal Stem Cells in Patients With Acute Respiratory Distress Syndrome
    Official Title
    A Clinical Trial to Evaluate the Safety, Tolerance and Efficacy of aCell Inj. of Allogeneic UC-MSCs in Patients With Mild to Moderate Acute Respiratory Distress Syndrome
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    August 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    August 30, 2023 (Anticipated)
    Primary Completion Date
    June 30, 2025 (Anticipated)
    Study Completion Date
    December 31, 2026 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Asia Cell Therapeutics (Shanghai) Co., Ltd.

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    The goal of this clinical trial is to evaluate the safety and tolerability of multiple doses of human umbilical cord mesenchymal stem cell injection in patients with Mild to Moderate Acute Respiratory Distress Syndrome (ARDS), and to further explore the efficacy, pharmacodynamic profile and appropriate dose of administration to provide a basis for the use of safer and more effective treatments for patients with Mild to Moderate Acute Respiratory Distress Syndrome (ARDS). Participants are required to sign an informed consent form and, after undergoing a series of tests and meeting the protocol's entry and exclusion criteria, are assigned to a dose group for intravenous infusion of human umbilical cord mesenchymal stem cells. Each subject will receive three infusions.
    Detailed Description
    Acute respiratory distress syndrome (ARDS) refers to various pathogenic factors that lead to excessive activation of the lung or even the whole body inflammatory response, which is manifested by the destruction of the lung epithelium and vascular endothelium, the decrease of alveolar clearance, and the occurrence of non-cardiogenic pulmonary edema. According to an international study involving 29144 patients, 10% of patients in ICU are ARDS patients, 23% of patients with mechanical ventilation suffer from ARDS, and the case fatality rate of ARDS ranges from 35% to 46%. At present, the treatment of ARDS includes primary disease treatment, protective mechanical ventilation and drug therapy, such as systemic infection, trauma, shock, burn, acute severe pancreatitis and other common causes of ARDS. It is necessary to control the primary disease and control the systemic uncontrolled inflammatory response induced by it to prevent and treat ARDS. In the treatment of ARDS, in addition to actively treating the primary disease, respiratory support technology is the main treatment mode, which aims to correct intractable hypoxemia, prevent alveolar collapse, reduce the degree of pulmonary edema, improve the oxygenation index, and reduce respiratory muscle fatigue. In addition to the above treatment means, effective drug therapeutic intervention should be carried out early. Reducing ventilator dependence is the key to improve survival rate. Pharmacotherapy for ARDS includes anti-inflammatory drug therapy (such as glucocorticoids), antioxidant therapy for N-acetylcysteine, and alveolar surfactant replacement therapy. Stem cells are a kind of undifferentiated cells that exist in embryonic or adult tissues and have the potential of self-renewal replication and multidirectional differentiation. mesenchymal stem cells (MSCs) are the most widely used stem cells in basic and clinical research. According to literature reports, MSCs have the ability to migrate to damaged tissues and repair damaged tissues through their multidirectional differentiation potential in vivo. Through its paracrine mechanism, MSCs can also improve the local microenvironment, support and promote the regeneration and differentiation of endogenous stem cells, play an anti-inflammatory role and regulate immunity. Human umbilical cord is considered medical waste and the collection of human umbilical cord mesenchymal stem cells is non-invasive, so there are no medical ethical issues with obtaining hUC-MSCs. Similar to other tissue-derived MSCs, hUC-MSCs have unique self-renewal ability and multi-differentiation potential, such as the ability to differentiate into adipose, bone, cartilage, nerve, and liver cells. Clinical trials of MSCs in the treatment of ARDS have been reported. A single-center, randomized, double-blind Phase I clinical trial reported the safety of intravenous injection of allogeneic adipose derived MSCs in the treatment of ARDS, and the results showed that MSCs were safe and non-tumorigenic. Another multi-center Phase I clinical trial reported the safety of different doses of MSCs derived from bone marrow in the treatment of ARDS. Based on this, the Phase II a clinical trial showed that MSCs improved the oxygenation index of ARDS patients. A case report reported that 2 patients with severe refractory ARDS showed improvement in respiratory distress, hemodynamic disturbance, and multiple organ failure after receiving MSCs treatment, which may be related to the reduction of inflammatory markers in the blood. The development of hUC-MSCs stem cell drugs has important clinical application value. At present, the human umbilical cord mesenchymal stem cell injection has completed the pharmacodynamics test of lung injury, the 4-week repeated administration in rats for 8 weeks, the 4-week repeated administration in rats for 8 weeks, the 4-week repeated administration in rhesus monkeys for 8 weeks, and the 4-week repeated administration in rhesus monkeys for 8 weeks Week recovery toxicity test, transfer and validation of toxic bioassay method (qPCR method), in vitro tumorigenesis test (soft AGAR cloning method), in vivo tumorigenesis test in naked mice (non-GLP), in vitro hemolysis test (rabbit blood), tissue distribution study in rats, safety pharmacological test of central nervous system in rats. In summary, the treatment of human umbilical cord mesenchymal stem cells has a wide safety window, and preclinical studies have shown that this product is safe and effective; The sponsors and investigators believe that MSC transplantation may improve the clinical symptoms of ARDS. The clinical trial design of multi-center, single-arm, single administration, dose increment + dose extension was mainly adopted in this study. The "3+3" dose increment design was adopted in 3 preset dose groups, from low-dose group to high-dose group, and 3-6 subjects were included in each dose group Receive a corresponding dose. After all subjects in each dose group have completed the 2-week (14-day) DLT safety observation period, it will be up to the investigator and sponsor to discuss whether to proceed to the next dose group based on relevant safety data. Adverse Events (AE) : All adverse medical events that occur after a clinical trial subject receives the investigational drug, but a clear causal relationship with the investigational drug may not be inferred. Adverse events can be symptoms, signs, diseases, or abnormalities in laboratory tests and include the following: An aggravation of the pre-existing (prior to entry into the clinical trial) medical condition/disease (including an aggravation of symptoms, signs, laboratory abnormalities). Any newly occurring adverse event: Any newly occurring adverse medical condition (including symptoms, signs, and newly diagnosed diseases). Abnormal clinically significant laboratory test values or results that are not caused by concomitant disease. Adverse reaction (ADR) : Any harmful or unintended reaction that may be associated with the investigational drug during a clinical trial. There is at least one reasonable possibility of a causal relationship between the investigational drug product and the adverse reaction, that is, an association cannot be ruled out. Adverse events are monitored throughout the trial and it is the responsibility of the investigator to record all aes observed during the trial. The trial should record any adverse medical events, regardless of severity and causal relationship with the investigational drug, from the time of initial dosing until the end of follow-up, and the investigator should record them on the appropriate AE page in the CRF

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Acute Respiratory Distress Syndrome
    Keywords
    Human Umbilical Cord Mesenchymal Stem Cells, Acute Respiratory Distress Syndrome

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 1
    Interventional Study Model
    Sequential Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    9 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Human Umbilical Cord Mesenchymal Stem Cells
    Arm Type
    Experimental
    Arm Description
    The trial was divided into three dose groups: Low-dose group: 1000000 cells/kg Medium-dose group: 2000000 cells/kg High-does group: 4000000 cells/kg
    Intervention Type
    Biological
    Intervention Name(s)
    Human Umbilical Cord Mesenchymal Stem Cells
    Intervention Description
    The stem cell infusion route is peripheral intravenous infusion. All subjects received experimental drugs and conventional treatment during the study period.
    Primary Outcome Measure Information:
    Title
    Adverse Event (AE)
    Description
    Adverse events that occurred during the trials
    Time Frame
    Day 1 to Day 28
    Title
    Serious Adverse Event (SAE)
    Description
    Serious adverse events that occurred during the trial
    Time Frame
    Day 1 to Day 28
    Title
    Maximum Tolerated Dose (MTD)
    Description
    Maximum Tolerated Dose
    Time Frame
    Day 1 to Day 28
    Secondary Outcome Measure Information:
    Title
    Oxygenation index
    Description
    To observe the improvement in oxygenation index (P/F) from baseline
    Time Frame
    Day 1(Before infusion)、Day 2、Day 3、Day 4、Day 7、Day 14、Day 28
    Title
    Chest routine scan
    Description
    To explore the improvement in lung imaging (calculation of lung exudate area)
    Time Frame
    Baseline、Day 4、Day 14、Day 28
    Title
    Intubation rate
    Description
    To explore the rate of intubation in subjects within 28 days after infusion
    Time Frame
    Day 1 to Day 28
    Title
    Length of hospitalisation
    Description
    Length of stay in hospital within 28 days
    Time Frame
    Day 1 to Day 28
    Title
    Time out of ICU
    Description
    Observe the time that subjects are not in the ICU for 28 days after infusion
    Time Frame
    Day 1 to Day 28
    Title
    Rate of Mortality
    Description
    Rate of Mortality within 28 days after infusion
    Time Frame
    Day 1 to Day 28
    Title
    Murray lung injury score
    Description
    Improvement in assessment scores from baseline. The higher the score is, the more severe the lung damage is.
    Time Frame
    Day 1(Before infusion)、Day 2、Day 3、Day 4、Day 7、Day 14、Day 28
    Other Pre-specified Outcome Measures:
    Title
    Interferon-γ (IFN-γ)
    Description
    The concentration of IFN-γ in blood
    Time Frame
    Baseline (1h before infusion)、Day 2、Day 3、Day 7、Day 14、Day 28
    Title
    Interleukin-1β (IL-1β)
    Description
    The concentration of IL-1β in blood
    Time Frame
    Baseline (1h before infusion)、Day 2、Day 3、Day 7、Day 14、Day 28
    Title
    Interleukin-6 (IL-6)
    Description
    The concentration of IL-6 in blood
    Time Frame
    Baseline (1h before infusion)、Day 2、Day 3、Day 7、Day 14、Day 28
    Title
    Interleukin-8 (IL-8)
    Description
    The concentration of IL-8 in blood
    Time Frame
    Baseline (1h before infusion)、Day 2、Day 3、Day 7、Day 14、D28
    Title
    Interleukin-10 (IL-10)
    Description
    The concentration of IL-10 in blood
    Time Frame
    Baseline (1h before infusion)、Day 2、Day 3、Day 7、Day 14、D28
    Title
    Tumor necrosis factor-α (TNF-α)
    Description
    The concentration of TNF-α in blood
    Time Frame
    Baseline (1h before infusion)、Day 2、Day 3、Day 7、Day 14、D28
    Title
    C-reaction protein (CRP)
    Description
    The concentration of CRP in blood
    Time Frame
    Baseline (1h before infusion)、Day 2、Day 3、Day 7、Day 14、D28
    Title
    Procalcitonin (PCT)
    Description
    The concentration of PCT in blood
    Time Frame
    Baseline (1h before infusion)、Day 2、Day 3、Day 7、Day 14、Day 28

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    75 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: 18-75 years old (including the threshold), male or female A definite diagnosis of mild to moderate acute respiratory distress syndrome (ARDS) (according to the ARDS Berlin definition and diagnostic criteria) ARDS onset ≤ 5 days 100 mmHg < PaO2/FiO2 ≤ 300 mmHg Bilateral pulmonary infiltrates on chest radiograph or chest CT Rule out other causes of pulmonary oedema, such as cardiogenic pulmonary oedema and pulmonary oedema due to fluid overload Have no plans to have children within 2 weeks before screening and 3 months after the end of the trial, and agree to use effective non-pharmacological contraception during the trial Patients voluntarily signed an informed consent form and were willing to co-operate with the trial process Exclusion Criteria: Hypersensitivity to known components of the drug (the main component of this product is human umbilical cord mesenchymal stem cells, excipients include dimethyl sulfoxide, human albumin, compound electrolyte injection), the presence of a history of allergy to gentamicin or other history of severe allergy Patients requiring treatment for any malignancy within 2 years prior to administration (except non-melanoma skin cancer) Lung transplant patients Patients with malignant haematological diseases Persons who have had a cardiovascular event within 3 months prior to dosing (e.g., unstable angina, congestive heart failure, myocardial infarction within the last 12 months, haemodynamic instability or known left ventricular ejection fraction (LVEF) <40% or clinically significant rhythm or conduction abnormalities) A history of deep vein thrombosis or pulmonary embolism during the Screening Period that, in the judgement of the Investigator, may be triggered or increase risk by receiving MSC transplantation therapy A breastfeeding female or a female with a positive blood pregnancy test result during the Screening Period History of immunodeficiency and/or autoimmune disease such as systemic lupus erythematosus (SLE), or other congenital immunodeficiency disease, idiopathic IgA deficiency. Laboratory tests at screening meet any of the following: Albuminous transaminase (AST) or albuminous transaminase (ALT) > 5 x ULN (non-hepatic sources are excluded; Serum creatinine > 1.5 x ULN or glomerular filtration rate < 60 mL/min/1.74 m2; Activated partial thromboplastin time (APTT) > 2.5 x ULN or prothrombin time; (PT) > 2.5 x ULN (not receiving anticoagulation) Positive infectious diseases (HBsAg, HCV, HIV-1, syphilis, active tuberculosis) Currently receiving extracorporeal life support (ECLS) such as continuous haemodialysis (CRRT) and carbon dioxide removal (ECCO2R), or high frequency oscillatory ventilation (HFOV) Presence of any other irreversible condition or symptom for which the subject has an expected survival of <3 months Combined WHO Class III or IV pulmonary hypertension Patients who refuse lung protective ventilation and fluid management Participation in other clinical trials or studies within 3 months prior to administration Persons with prior stem cell therapy Any other condition that, in the judgement of the investigator, makes participation in this trial inappropriate, such as a condition in which the study is not in the subject's current best interest (e.g., detrimental to health)
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Wenli Liu
    Phone
    +86 13402137712
    Email
    liuwenli@xibaozhiliao.cn
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Jieming Qu
    Organizational Affiliation
    SHANGHAI JIAOTONG UNIVERSITY SCHOOL OF MEDICINE RUIJIN HOSPITAL
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

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    Safety and Tolerance of Umbilical Cord Mesenchymal Stem Cells in Patients With Acute Respiratory Distress Syndrome

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