Treatment With Human Umbilical Cord-derived Mesenchymal Stem Cells for Severe Corona Virus Disease 2019 (COVID-19)

• ClinicalTrials.gov Identifier: NCT04288102
• Recruitment Status: Completed
• First Posted: February 28, 2020
• Last Update Posted: August 19, 2020
• Sponsor: Beijing 302 Hospital
• Collaborators: Huoshenshan Hospital; Maternal and Child Health Hospital of Hubei Province; The General Hospital of Central Theater Command; VCANBIO Cell & Gene Engineering Corporation, Ltd
• Information provided by (Responsible Party): Fu-Sheng Wang, Beijing 302 Hospital

Study Description

Brief Summary:

COVID-19 caused clusters of severe respiratory illness and was associated with 2% mortality. No specific anti-viral treatment exists. The mainstay of clinical management is largely symptomatic treatment, with organ support in intensive care for seriously ill patients. Cellular therapy, using mesenchymal stem cells has been shown to reduce nonproductive inflammation and affect tissue regeneration and is being evaluated in patients with ARDS. This clinical trial is to inspect the safety and efficiency of mesenchymal stem cells (MSCs) therapy for severe COVID-19.

Condition or disease	Intervention/treatment	Phase
Corona Virus Disease 2019(COVID-19)	Biological: UC-MSCs; Biological: Saline containing 1% Human serum albumin（solution without UC-MSCs）	Phase 2

Detailed Description:

The Corona Virus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection has unprecedentedly spread in the worldwide and been declared as a pandemic by the world health organization. COVID-19 is characterized by sustained cytokines production and hyper-inflammation, can cause clusters of severe respiratory illness with a fatality rate around 2-5%. There are currently no prophylactic vaccine and no specific antiviral treatment agents available recommended for COVID-19. Therefore, it is urgent to find a safe and effective therapeutic approach to COVID-19.

During the last decade, the promising features of mesenchymal stem cells (MSCs), including their regenerative properties and ability to differentiate into diverse cell lineages, have generated great interest among researchers whose work has offered intriguing perspectives on cell-based therapies for various diseases. These findings seem to highlight that the beneficial effect of MSC-based treatment could be principally due by the immunomodulation and regenerative potential of these cells. MSCs could significantly reduce the pathological changes of lung and inhibit the cell-mediated immune inflammatory response induced by influenza virus in animal model . MSCs has been shown to reduce nonproductive inflammation and affect tissue regeneration and is being evaluated in patients with ARDS. Our phase I preliminary data of parallel assignment study(NCT04252118) showed that three doses of MSCs was safe in patients with COVID-19. Randomized control trial is needed to assess efficacy and safety.

The investigators will do a prospective, double-blind, multicentre, randomised trial to assess treatment with three intravenous doses of MSCs compared with placebo. 90 severe COVID-19 patients will be recruited in China. 60 patients will receive i.v. transfusion 3 times of MSCs (4.0*10E7 cells per time) and the standard of care as the treated group. In addition, the 30 patients will receive placebo and standard of care as control group.

Change in lesion proportion (%) of full lung volume from baseline to day 10, day28 and 90, change in consolidation/ ground-glass lesion proportion (%) of full lung volume from baseline to day 10, 28 and 90, time to clinical improvement in 28 days, mMRC (Modified Medical Research Council) dyspnea scale, 6-minute walk test, maximum vital capacity (VCmax), Diffusing Capacity (DLCO), oxygen saturation, oxygenation index, duration of oxygen therapy, side effects, immunological characteristics (immune cells, inflammatory factors, etc.) will be evaluated during the 90 days follow up.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomized, double-blind, placebo-controlled study
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase II, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of Human Umbilical Cord-derived Mesenchymal Stem Cells in the Treatment of Severe COVID-19 Patients
• Actual Study Start Date: March 5, 2020
• Actual Primary Completion Date: May 12, 2020
• Actual Study Completion Date: July 9, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Human Umbilical Cord-Mesenchymal Stem Cells (UC-MSCs); Participants will receive standard of care plus 3 does of UC-MSCs	Biological: UC-MSCs; 3 does of UC-MSCs(4.0*10E7 cells per time) intravenously at Day 0, Day 3, Day 6.
Placebo Comparator: Placebo; Participants will receive standard of care plus 3 does of placebo	Biological: Saline containing 1% Human serum albumin（solution without UC-MSCs）; 3 does of placebo（intravenously at Day 0, Day 3, Day 6）

Outcome Measures

Primary Outcome Measures :

1. Change in lesion proportion (%) of full lung volume from baseline to day 28. [ Time Frame: Day 28 ]
   Evaluation of Pneumonia Improvement

Secondary Outcome Measures :

1. Change in lesion proportion (%) of full lung volume from baseline to day 10 and 90 [ Time Frame: Day 10, Day 90 ]
   Evaluation of Pneumonia Improvement
2. Change in consolidation lesion proportion (%) of full lung volume from baseline to day 10, 28 and 90. [ Time Frame: Day 10, Day 28, Day 90 ]
   Evaluation of Pneumonia Improvement
3. Change in ground-glass lesion proportion (%) of full lung volume from baseline to day 10, 28 and 90. [ Time Frame: Day 10, Day 28, Day 90 ]
   Evaluation of Pneumonia Improvement
4. Pulmonary fibrosis - related morphological features in CT scan at day 90 a. cord-like shadow b. honeycomb-like shadows c. interlobular septal thickening d. intralobular interstitial thickening e. pleural thickening [ Time Frame: Day 90 ]
   Evaluation of Pneumonia Improvement
5. Lung densitometry: Change in total voxel 'weight' in lesion area voxel 'weight'=voxel density (in HU) × voxel volume (in voxel) [ Time Frame: Day 10, Day 28, Day 90 ]
   Evaluation of Pneumonia Improvement
6. Lung densitometry: volumes histogram of lung density distribution (<-750, -750~-300, -300~50, >50) at day 10, 28 and 90. [ Time Frame: Day 10, Day 28, Day 90 ]
   Evaluation of Pneumonia Improvement
7. Time to clinical improvement in 28 days. [ Time Frame: Day 28 ]

   Clinical improvement defined as a one-point deduction from baseline in a 6 ordinal scale:

   1. Not hospitalized;
   2. Hospitalized, not requiring supplemental oxygen;
   3. Hospitalized, requiring supplemental oxygen;
   4. Hospitalized, on non-invasive ventilation or high flow oxygen devices;
   5. Hospitalized, on invasive mechanical ventilation or ECMO;
   6. Death.
8. Oxygenation index( PaO2/FiO2) [ Time Frame: Day 6, Day 10, Day 28 ]
   Evaluation of Pneumonia Improvement
9. Duration of oxygen therapy(days) [ Time Frame: Day 28, Day 90 ]
   Evaluation of Pneumonia Improvement
10. Blood oxygen saturation [ Time Frame: Day 6, Day 10, Day 28 ]
    Evaluation of Pneumonia Improvement
11. 6-minute walk test [ Time Frame: Day 28, Day 90 ]
    Evaluation of Pneumonia Improvement
12. Maximum vital capacity (VCmax) [ Time Frame: Baseline, Day 10, Day 14, Day 21, Day 28, Day 90 ]
    Evaluation of Pneumonia Improvement
13. Diffusing Capacity (DLCO) [ Time Frame: Baseline, Day 10, Day 14, Day 21, Day 28, Day 90 ]
    Evaluation of Pneumonia Improvement
14. mMRC (Modified Medical Research Council) dyspnea scale [ Time Frame: Day 28, Day 90 ]

    Evaluation of Pneumonia Improvement

    No limitation of activities, discharged from hospital =Score 1; Hospitalized, no oxygen therapy=Score 2; Oxygen by mask or nasal prongs-Score 3; Non-invasive ventilation or high-flow oxygen=Score 4; Mechanical ventilation or ECMO=Score 5; Death=Score 6.

15. Changes of absolute lymphocyte counts and subsets from baseline to day 6, 10, 28 and 90. [ Time Frame: Day 6, Day 10, Day 28, Day 90 ]
    Marker of Immunological function
16. Changes of cytokine/chemokine levels from baseline to day 6, 10, 28 and 90. [ Time Frame: Day 6, Day 10, Day 28, Day 90 ]
    Marker of Immunological function
17. Adverse events [ Time Frame: Day 0 through Day 90 ]
    Safety endpoints
18. Serious adverse events [ Time Frame: Day 0 through Day 90 ]
    Safety endpoints
19. All-cause mortality [ Time Frame: Day 0 through Day 90 ]
    Safety endpoints

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Male or female, aged at 18 years (including) -75 years old
2. Hospitalized
3. Laboratory confirmation of SARS-CoV-2 infection by reverse-transcription polymerase chain reaction (RT-PCR) from any diagnostic sampling source
4. Pneumonia that is judged by computed tomography
5. In accordance with any one of the following : 1)dyspnea (RR ≥ 30 times / min), 2)finger oxygen saturation ≤ 93% in resting state, 3)arterial oxygen partial pressure (PaO2) / oxygen absorption concentration (FiO2) ≤ 300MMHG, 4)pulmonary imaging shows that the focus progress > 50% in 24-48 hours
6. Interstitial lung damage is judged by computed tomography.

Exclusion Criteria:

1. Pregnancy, lactation and those who are not pregnant but do not take effective contraceptives measures;
2. Patients with malignant tumor, other serious systemic diseases and psychosis;
3. Patients who are participating in other clinical trials;
4. Inability to provide informed consent or to comply with test requirements.
5. Co-Infection of HIV, tuberculosis, influenza virus, adenovirus and other respiratory infection virus.
6. Invasive ventilation
7. Shock
8. Combined with other organ failure( need organ support)
9. Interstitial lung damage caused by other reasons ( in 2 weeks)
10. The pulmonary imaging revealed the interstitial damage of lungs before the COVID-19 confirmed.

Contacts and Locations

Locations

China, Hubei

General Hospital of Central Theater Command

Wuhan, Hubei, China, 430000

Maternal and Child Hospital of Hubei Province

Wuhan, Hubei, China, 430000

Wuhan Huoshenshan Hospital

Wuhan, Hubei, China, 430000

Sponsors and Collaborators

Beijing 302 Hospital

Huoshenshan Hospital

Maternal and Child Health Hospital of Hubei Province

The General Hospital of Central Theater Command

VCANBIO Cell & Gene Engineering Corporation, Ltd

Investigators

• Study Chair: Fu-Sheng Wang, MD, PhD; Beijing 302 Hospital

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Shi L, Yuan X, Yao W, Wang S, Zhang C, Zhang B, Song J, Huang L, Xu Z, Fu JL, Li Y, Xu R, Li TT, Dong J, Cai J, Li G, Xie Y, Shi M, Li Y, Zhang Y, Xie WF, Wang FS. Human mesenchymal stem cells treatment for severe COVID-19: 1-year follow-up results of a randomized, double-blind, placebo-controlled trial. EBioMedicine. 2022 Jan;75:103789. doi: 10.1016/j.ebiom.2021.103789. Epub 2021 Dec 25.

Shi L, Huang H, Lu X, Yan X, Jiang X, Xu R, Wang S, Zhang C, Yuan X, Xu Z, Huang L, Fu JL, Li Y, Zhang Y, Yao WQ, Liu T, Song J, Sun L, Yang F, Zhang X, Zhang B, Shi M, Meng F, Song Y, Yu Y, Wen J, Li Q, Mao Q, Maeurer M, Zumla A, Yao C, Xie WF, Wang FS. Effect of human umbilical cord-derived mesenchymal stem cells on lung damage in severe COVID-19 patients: a randomized, double-blind, placebo-controlled phase 2 trial. Signal Transduct Target Ther. 2021 Feb 10;6(1):58. doi: 10.1038/s41392-021-00488-5.

• Responsible Party: Fu-Sheng Wang, Head of Treatment and Research Center for Infectious Diseases, Principle Investigator, Clinical Professor, Beijing 302 Hospital
• ClinicalTrials.gov Identifier: NCT04288102
• Other Study ID Numbers: 2020-013-D
• First Posted: February 28, 2020
• Last Update Posted: August 19, 2020
• Last Verified: August 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: After approval from the steering committee and the Human Genetic Resources Administration of China, this trial data can be shared with qualifying researchers who submit a proposal with a valuable research question. A contract should be signed.

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

Additional relevant MeSH terms:

Virus Diseases; Coronavirus Infections; Pneumonia, Viral; Respiratory Tract Infections; Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; COVID-19; Pneumonia; Lung Diseases; Respiratory Tract Diseases