Study of Human Umbilical Cord Mesenchymal Stem Cells in the Treatment of Severe COVID-19

• ClinicalTrials.gov Identifier: NCT04273646
• Recruitment Status: Unknown
• First Posted: February 18, 2020
• Last Update Posted: April 14, 2020
• Sponsor: Wuhan Union Hospital, China
• Collaborator: Wuhan Hamilton Bio-technology Co., Ltd, China.
• Information provided by (Responsible Party): Yang Jin, Wuhan Union Hospital, China

Tracking Information

• First Submitted Date: February 14, 2020
• First Posted Date: February 18, 2020
• Last Update Posted Date: April 14, 2020
• Estimated Study Start Date: April 20, 2020
• Estimated Primary Completion Date: June 30, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 17, 2020)

• Pneumonia severity index [ Time Frame: From Baseline (0W) to 12 week after treatment ]
  Evaluation of Pneumonia Improvement
• Oxygenation index (PaO2/FiO2) [ Time Frame: From Baseline (0W) to 12 week after treatment ]
  Evaluation of Pneumonia Improvement

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 19, 2020)

• Side effects in the UC-MSCs treatment group [ Time Frame: From Baseline (0W) to 96 week after treatment ]
  Incidence of acute and chronic treatment-related adverse events in patients with novel coronavirus severe pneumonia receiving UC-MSCs infusion as assessed.
• 28-days survival [ Time Frame: Day 28 ]
  Marker for efficacy of treatment
• Sequential organ failure assessment [ Time Frame: Day 28 ]
  Markers of organ function（Score each criterion on a scale of 0 to 4, and the higher the score, the worse the prognosis.）
• C-reactive protein [ Time Frame: From Baseline (0W) to 12 week after treatment ]
  Markers of Infection
• Procalcitonin [ Time Frame: From Baseline (0W) to 12 week after treatment ]
  Markers of Infection
• Lymphocyte count [ Time Frame: From Baseline (0W) to 12 week after treatment ]
  Marker of Immunological function
• CD3+, CD4+ and CD8+ T celll count [ Time Frame: From Baseline (0W) to 12 week after treatment ]
  Marker of Immunological function
• CD4+/CD8+ratio [ Time Frame: From Baseline (0W) to 12 week after treatment ]
  Marker of Immunological function

Original Secondary Outcome Measures (submitted: February 17, 2020)

• Side effects in the UC-MSCs treatment group [ Time Frame: From Baseline (0W) to 96 week after treatment ]
  Incidence of acute and chronic treatmentt-related adverse events in patients with novel coronavirus severe pneumonia receiving UC-MSCs infusion as assessed.
• 28-days survival [ Time Frame: Day 28 ]
  Marker for efficacy of treatment
• Sequential organ failure score [ Time Frame: Day 28 ]
  Markers of organ function
• C-reactive protein [ Time Frame: From Baseline (0W) to 12 week after treatment ]
  Markers of Infection
• Procalcitonin [ Time Frame: From Baseline (0W) to 12 week after treatment ]
  Markers of Infection
• Lymphocyte count [ Time Frame: From Baseline (0W) to 12 week after treatment ]
  Marker of Immunological function
• CD3+, CD4+ and CD8+ T celll count [ Time Frame: From Baseline (0W) to 12 week after treatment ]
  Marker of Immunological function
• CD4+/CD8+ratio [ Time Frame: From Baseline (0W) to 12 week after treatment ]
  Marker of Immunological function

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Human Umbilical Cord Mesenchymal Stem Cells in the Treatment of Severe COVID-19
• Official Title: Clinical Study of Human Umbilical Cord Mesenchymal Stem Cells in the Treatment of Severe COVID-19
• Brief Summary: The novel coronavirus pneumonia is a kind of new emerging respiratory infectious disease, characterized by fever, dry cough, and chest tightness, and caused by the infection of the 2019 novel coronavirus (2019-nCoV). In severe cases, there will be rapid respiratory system failure. The novel coronavirus pneumonia is extremely contagious and the disease progresses rapidly. It has become a urgent and serious public health event that threatens human life and health globally. Among them, severe pneumonia caused by novel coronavirus is characterized by extensive acute inflammation of the lungs and the patient is critically ill. At present, there is no effective treatment in clinical practice.Most of them should receive supportive care to help relieve symptoms. For severe cases, treatment should include care to support vital organ functions. This clinical trial is to inspect the safety and efficiency of Human Umbilical Cord Mesenchymal Stem Cells (UC-MSCs) therapy for severe pneumonia patients infected with 2019-nCoV.

Detailed Description

Since December 2019, Wuhan has successively found multiple cases of patients with pneumonia infected by a novel coronavirus. With the spread of the epidemic, other cases in China and abroad have also found such cases. As of 24:00 on February 1, 2020, a total of 14,380 confirmed cases were reported in China, of which there were 2110 severe cases and 304 death cases. At present, there is no effective treatment for pneumonia in the clinic against new coronavirus infection, especially severe and critical cases. Therefore, it is of great significance to explore more active and effective therapeutic approach to severe pneumonia patients infected with 2019-nCoV.

Human and animal studies have shown that after infection with coronavirus, the rapid replication of the virus in the body and the subsequent inflammatory response cause damage to alveolar epithelial cells and capillary endothelial cells, causing diffuse interstitial and alveolar edema, and pulmonary function. Impaired, leading to acute hypoxic respiratory insufficiency. The National Health and Medical Commission recently released the "New Coronavirus Infected Pneumonia Diagnosis and Treatment Plan (Trial Version 5)", which pointed out that the new type of coronavirus severe pneumonia usually has difficulty breathing after one week, and the severe cases quickly progress to acute respiratory distress syndrome, Septic shock and metabolic acidosis that is difficult to correct. It can be seen that the key to the treatment of new coronavirus severe pneumonia is to inhibit the super-inflammatory immune response caused by the virus, thereby reducing the damage of alveolar epithelial cells and capillary endothelial cells, and then repairing the structure and function of lung tissue.

Mesenchymal stem cells (MSCs) are one of the most studied and important adult stem cells. A large amount of evidence shows that MSCs can migrate to and return to damaged tissues, exert strong anti-inflammatory and immune regulatory functions, promote the regeneration and repair of damaged tissues, resist apoptosis and inhibit tissue fibrosis, and reduce tissue damage. Many studies have shown that the anti-inflammatory effects of MSCs can significantly reduce virus-induced lung injury and mortality in mice. Studies have shown that MSCs can significantly reduce acute lung injury in mice caused by H9N2 and H5N1 viruses by reducing the levels of proinflammatory cytokines and chemokines and reducing the recruitment of inflammatory cells into the lungs. Compared with MSCs from other sources, human umbilical cord-derived MSCs (umbilical cord MSCs, UC-MSCs) have been widely used because of their convenient collection, no ethical controversy, low immunogenicity, fast self-renewal and strong proliferation ability Research on the treatment of various diseases. Early research in this laboratory used UC-MSCs to intervene in endotoxin (LPS) -induced acute lung injury in mice, and confirmed that UC-MSCs can significantly reduce inflammatory cell infiltration in lung tissue, reduce inflammation in lung tissue, and significantly improve lung The structure and function of tissues protect mouse lung tissue from endotoxin-induced damage.

The purpose of this study is to investigate efficiency and safety of UC-MSCs in treating severe pneumonia patients infected with 2019-nCoV. This trial will recruit 48 patients. 24 patients received i.v. transfusion one round (4 times) of 5.0*10E6 cells/kg of UC-MSCs as the treated group, all of them received the conventional treatment. In addition, the equal 24 patients received conventional treatment were used as control group. The respiratory function, pulmonary inflammation, clinical symptoms, pulmonary imaging, side effects, 28-days mortality, immunological characteristics (immune cells, inflammatory factors, etc.) will be evaluated during the 90 days to 96 weeks follow up.

• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Parallel Assignment

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• 2019 Novel Coronavirus Pneumonia
• COVID-19

Intervention

• Biological: UC-MSCs
  4 times of UC-MSCs(0.5*10E6 UC-MSCs/kg body weight intravenously at Day 1, Day 3, Day 5, Day 7).
• Drug: Placebo
  4 times of cell-free stem cell suspension (saline containing 1% human albumin) intravenously at Day 1, Day 3, Day 5, Day 7).

Study Arms

• Experimental: UC-MSCs Treatment Group

  Conventional treatment plus UC-MSCs:

  Participants will receive conventional treatment plus 4 times of UC-MSCs(0.5*10E6 UC-MSCs/kg body weight intravenously at Day 1，Day 3，Day 5，Day7).

  Intervention: Biological: UC-MSCs
• Placebo Comparator: Conventional Control Group

  Conventional treatment plus Placebo:

  Without UC-MSCs Therapy but conventional treatment should be received. Participants will receive conventional treatment plus 4 times of Placebo intravenously at Day 1，Day 3，Day 5，Day7).

  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: February 17, 2020): 48
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: February 15, 2022
• Estimated Primary Completion Date: June 30, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. CT image is characteristic of viral pneumonia;
2. 2019-ncov infection (positive nucleic acid test) is confirmed by pathogenic test;
3. In compliance with the 2019-nCoV infection severe pneumonia diagnosis standard (according to the novel coronavirus infection pneumonia diagnosis and treatment program (Trial Implementation Version 5) issued by the National Health and Medical Commission, and WHO 2019 new coronavirus guidelines standards). It is severe if it meets any of the following: (A) Increased breathing rate (≥30 beats / min), difficulty breathing, cyanosis of the lips; (B) When inhaling, means oxygen saturation ≤93%; (C) Partial pressure of arterial oxygen (PaO2) / Fraction of inspired oxygen (FiO2) ≤300 mmHg (1mmHg = 0.133kPa);
4. 18 years old ≤ age ≤ 65 years old, regardless of gender;
5. The patient or legal donor agrees to participate in the study and signs the informed consent.

Exclusion Criteria:

1. Patients with severe allergies or allergies to stem cell preparations and their components;
2. Patients with serious basic diseases that affect survival, including: blood diseases, cachexia, active bleeding, severe malnutrition, etc .;
3. Patients with pulmonary obstructive pneumonia, severe pulmonary interstitial fibrosis, alveolar proteinosis, allergic alveolitis, and other known viral pneumonia or bacterial pneumonia;
4. Continuous use of immunosuppressive agents or organ transplants in the past 6 months;
5. In vitro life support (ECMO, ECCO2R, RRT);
6. Expected deaths within 48 hours, uncontrolled infections;
7. Patients with malignant blood-borne diseases such as HIV or syphilis;
8. Patient with pregnancy, are planning to become pregnant or breastfeeding;
9. Patients with poor compliance and unable to complete the full study;
10. The investigator determines that there may be increased risk of the subject or other conditions that interfere with the clinical trial and the judgment of the results (such as excessive stress, sensitivity or cognitive impairment, etc.);
11. There are other situations that the researchers think are not suitable to participate in this clinical study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China

Administrative Information

• NCT Number: NCT04273646
• Other Study ID Numbers: 202001
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Yang Jin, Wuhan Union Hospital, China
• Original Responsible Party: Same as current
• Current Study Sponsor: Wuhan Union Hospital, China
• Original Study Sponsor: Same as current
• Collaborators: Wuhan Hamilton Bio-technology Co., Ltd, China.
• Investigators: Not Provided
• PRS Account: Wuhan Union Hospital, China
• Verification Date: April 2020