Evaluate the Safety and Efficacy of Allogeneic Umbilical Cord Mesenchymal Stem Cells in Patients With COVID-19

Study Overview
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Brief Summary
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This study is to explore the safety and efficacy of using UCMSC01 in patients with COVID-19 infection via IV stem cell administration. The novelty of the current UMSC01 treatment is the single IV infusion of UMSC01 to the worldwide emergency outbreaks of COVID-19. We hypothesize that sufficient UMSC01 retention in lung may modulate the systemic inflammatory responses.

Detailed Description
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The lead Phase I safety phase will further confirm the safety profile of UMSC01 in 5 COVID-19 patients each at two dose regimens and placebo. To start the Phase IIa study, data analysis will be performed as soon as the 21-day treatment period has been completed in the three groups. With considerations of the pandemic status and clinical practice, only one of the two active treatment groups will be selected to complete the Phase IIa study, which will recruit 60 patients.

Official Title
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A Seamless Phase I/IIa Clinical Study to Evaluate the Safety and Efficacy of Allogeneic Umbilical Cord Mesenchymal Stem Cells in Patients With Severe and Critical COVID-19 Condition

Conditions
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COVID-19 Infection

Intervention / Treatment
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* Biological: Allogeneic umbilical cord mesenchymal stem cells
* Biological: Controlled normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged 20 to 80 years old. Hospitalized severe and critical COVID-19 patients with laboratory confirmation by reverse-transcription polymerase chain reaction (RT-PCR) from nasopharyngeal/ oropharyngeal samples collected using standardized method. Pneumonia or interstitial lung damage that is confirmed by chest radiographs or computed tomography. Severe COVID-19 infection which meets any one of the following: 1) dyspnea (PR ≥ 30 times/min), 2) finger oxygen saturation ≤ 93% in the room air and resting state, 3) arterial oxygen partial pressure (PaO2)/oxygen absorption concentration (FiO2) ≤ 300 mmHg, 4) pulmonary imaging which shows that the focus progress > 50% within 24-48 hours, or Critically severe COVID-19 infection which meets any of the following: 1) respiratory failure treated by mechanical ventilation, 2) shock, 3) combined with other organ failure, 4) patients expected to need ICU monitoring and treatment. High sensitivity C-reactive protein (hs-CRP) serum level > 4.0 mg/dL. All female patients with child-bearing potential (between puberty and 2 years after menopause) should use appropriate contraception method(s) shown below, for at least 4 weeks after UMSC01 treatment and agree to maintain such contraceptive method(s) for another 4 weeks after UMSC01 treatment. Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Female sterilization (bilateral oophorectomy with or without hysterectomy) or tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, the reproductive status of the woman should be confirmed by the hormone level assessment. Male sterilization (at least 6 months prior to screening). For female subjects in the study, the vasectomized male partner should be the sole partner for that subject. Combination of any two of the following listed methods: (d.1 + d.2 or d.1 + d.3, or d.2 + d.3): d.1 Use of oral, injected, or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), such as hormone vaginal ring or transdermal hormone contraception. d.2 Placement of an intrauterine device (IUD) or intrauterine system (IUS). d.3 Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. Exclusion Criteria: Pregnancy, lactation, and those who are not pregnant but did not, or unwilling to, take effective contraceptives measures 4 weeks before and after the treatment. Patients with malignant tumors or other serious systemic diseases. Patients with hemoglobin < 10 g, alanine aminotransferase (ALT) ≥ 5 × ULN, aspartate aminotransferase (AST) ≥ 5 × ULN, alkaline phosphatase (ALP) ≥ 5 × ULN, total bilirubin (TBILI) ≥ 2 × ULN, serum creatinine > 2.5 mg/dl, platelet counts < 100,000/μL, WBC < 3,000 cells/μL, or neutrophil counts < 1,000/μL at screening. Presence of barotrauma or hemodynamic instability defined as hypotension with diastolic blood pressure < 90 mmHg or mean arterial pressure (MAP) < 70 mmHg despite fluid expansion, and vasoactive support or pneumothorax at screening. Uncontrolled hypertension with systolic blood pressure > 170 mmHg and diastolic blood pressure > 100 mmHg which, in the investigator's judgment, would not make participation appropriate. Recent history of (within 2 years) ischemic heart disease or cerebrovascular attack, such as myocardial infarction, unstable angina, or stroke. Recent history (within 2 years) of hypercoagulable disorder, antiphospholipid syndrome, pulmonary embolism, or deep venous thrombosis. Condition other than COVID-19 that is projected to limit lifespan to ≤ 1 year. History of drug or alcohol abuse within the past 24 months. Unwilling to commit to follow-up visits. Patients who are participating in other clinical trials with an investigational product. Co-infection of HIV, tuberculosis, influenza virus, adenovirus, and other respiratory infection virus. Patients with other conditions that are not suitable to participate in this clinical study as determined by the investigator.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: UMSC01<br>UMSC01 cells mixed with normal saline will be administered to patients after COVID-19 infection. | Biological: Allogeneic umbilical cord mesenchymal stem cells<br>* UMSC01 cells will be IV infusion with 12 months of follow up after treatment.<br>|
| Placebo Comparator: Placebo<br>Normal saline will be administered to patients after COVID-19 infection. | Biological: Controlled normal saline<br>* Normal saline will be IV infusion with 12 months of follow up after treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Two Co-Primary Efficacy Endpoints | Proportion of patients alive with sustained improvement within the 21 days of the treatment period (Proportion Analysis), which indicates the capability of UMSC01 to save more lives | 21 days of the treatment period | 
| Two Co-Primary Efficacy Endpoints | Time (days) to reach sustained improvement within the 21 days of the treatment period (Time-to-Event Analysis), which indicates the capability of UMSC01 to enable patients to less suffer from the disease condition. | 21 days of the treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary Efficacy Endpoints | Proportion of enrolled patients alive on Day 21 | 21 days of the treatment period | 
| Secondary Efficacy Endpoints | Proportion of enrolled patients alive and free of respiratory failure on Day 21 | 21 days of the treatment period | 
| Secondary Efficacy Endpoints | Improvement of COVID 19 pneumonia confirmed by chest radiographs or computed tomography on Day 21 or on the day of discharge compared with baseline | 21 days of the treatment period | 
| Secondary Efficacy Endpoints | Improvement of clinical symptoms including duration of fever in degrees C and respiratory failure on Day 21 or on the day of discharge compared with baseline | 21 days of the treatment period | 
| Secondary Efficacy Endpoints | Duration of ventilator usage or oxygen therapy on Day 21 or on the day of discharge compared with baseline | 21 days of the treatment period | 
| Secondary Efficacy Endpoints | Levels of tumor necrosis factor-alpha (TNF-α) in pg/ml, interleukin-6 (IL-6) in pg/ml and interleukin-10 (IL-10) in pg/ml, and C-reactive protein (hsCRP) in mg/dl on Day 21 or on the day of discharge compared to baseline | 21 days of the treatment period | 
| Secondary Efficacy Endpoints | Troponin I level as assessed via serum blood samples on Day 21 or on the day of discharge compared with baseline | 21 days of the treatment period | 
| Secondary Efficacy Endpoints | ICU admission rate on Day 21 or on the day of discharge with historical data | 21 days of the treatment period | 
| Secondary Efficacy Endpoints | Percentage of subjects recorded in each severity rating based on Clinical classification of the COVID-19 (NCOSS scores from 1 to 8；higher scores mean a worse outcome) on Day 14 compared with historical data | 14 days of the treatment period | 
| Secondary Efficacy Endpoints | Percentage of subjects recorded in each severity rating based on Clinical classification of the COVID-19 (NCOSS scores from 1 to 8；higher scores mean a worse outcome) on Day 21 compared with historical data | 21 days of the treatment period | 
| Secondary Efficacy Endpoints | Average time (days) for which the patients are alive and free of respiratory failure during the treatment period | through study completion, an average of 1 year | 
| Secondary Efficacy Endpoints | Proportion of patients who need ICU care on Day 21 based on the clinical indicative of admission to ICU | 21 days of the treatment period | 
| Secondary Efficacy Endpoints | Proportion of patients who has been discharged form hospital on Day 21 | 21 days of the treatment period | 
| Secondary Safety Endpoints | Number of Participants with infusion-related and allergic reactions during the treatment period | 21 days of the treatment period | 
| Secondary Safety Endpoints | Secondary infection, treatment emergent adverse event (TEAE), serious adverse event (SAE), and suspected and unexpected serious adverse reaction (SUSAR) incidences over the study period. The toxicities will be assessed by CTCAE V5.0 during the whole study period (380 days) | through study completion, an average of 1 year |