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

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

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.

Study Overview

• Status: Completed
• Conditions: Corona Virus Disease 2019(COVID-19)
• Intervention / Treatment: Biological: UC-MSCs; Biological: Saline containing 1% Human serum albumin（solution without UC-MSCs）

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 Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China, 430000
      • General Hospital of Central Theater Command
    • Wuhan, Hubei, China, 430000
      • Maternal and Child Hospital of Hubei Province
    • Wuhan, Hubei, China, 430000
      • Wuhan Huoshenshan Hospital

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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）

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in lesion proportion (%) of full lung volume from baseline to day 28.	Evaluation of Pneumonia Improvement	Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in lesion proportion (%) of full lung volume from baseline to day 10 and 90	Evaluation of Pneumonia Improvement	Day 10, Day 90
Change in consolidation lesion proportion (%) of full lung volume from baseline to day 10, 28 and 90.	Evaluation of Pneumonia Improvement	Day 10, Day 28, Day 90
Change in ground-glass lesion proportion (%) of full lung volume from baseline to day 10, 28 and 90.	Evaluation of Pneumonia Improvement	Day 10, Day 28, Day 90
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	Evaluation of Pneumonia Improvement	Day 90
Lung densitometry: Change in total voxel 'weight' in lesion area voxel 'weight'=voxel density (in HU) × voxel volume (in voxel)	Evaluation of Pneumonia Improvement	Day 10, Day 28, Day 90
Lung densitometry: volumes histogram of lung density distribution (<-750, -750~-300, -300~50, >50) at day 10, 28 and 90.	Evaluation of Pneumonia Improvement	Day 10, Day 28, Day 90
Time to clinical improvement in 28 days.	Clinical improvement defined as a one-point deduction from baseline in a 6 ordinal scale: Not hospitalized;; Hospitalized, not requiring supplemental oxygen;; Hospitalized, requiring supplemental oxygen;; Hospitalized, on non-invasive ventilation or high flow oxygen devices;; Hospitalized, on invasive mechanical ventilation or ECMO;; Death.	Day 28
Oxygenation index( PaO2/FiO2)	Evaluation of Pneumonia Improvement	Day 6, Day 10, Day 28
Duration of oxygen therapy(days)	Evaluation of Pneumonia Improvement	Day 28, Day 90
Blood oxygen saturation	Evaluation of Pneumonia Improvement	Day 6, Day 10, Day 28
6-minute walk test	Evaluation of Pneumonia Improvement	Day 28, Day 90
Maximum vital capacity (VCmax)	Evaluation of Pneumonia Improvement	Baseline, Day 10, Day 14, Day 21, Day 28, Day 90
Diffusing Capacity (DLCO)	Evaluation of Pneumonia Improvement	Baseline, Day 10, Day 14, Day 21, Day 28, Day 90
mMRC (Modified Medical Research Council) dyspnea scale	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.	Day 28, Day 90
Changes of absolute lymphocyte counts and subsets from baseline to day 6, 10, 28 and 90.	Marker of Immunological function	Day 6, Day 10, Day 28, Day 90
Changes of cytokine/chemokine levels from baseline to day 6, 10, 28 and 90.	Marker of Immunological function	Day 6, Day 10, Day 28, Day 90
Adverse events	Safety endpoints	Day 0 through Day 90
Serious adverse events	Safety endpoints	Day 0 through Day 90
All-cause mortality	Safety endpoints	Day 0 through Day 90

Collaborators and Investigators

• Sponsor: Beijing 302 Hospital
• Collaborators: Maternal and Child Health Hospital of Hubei Province; Huoshenshan Hospital; VCANBIO Cell & Gene Engineering Corporation, Ltd; The General Hospital of Central Theater Command
• Investigators: Study Chair: Fu-Sheng Wang, MD, PhD, Beijing 302 Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 5, 2020
• Primary Completion (Actual): May 12, 2020
• Study Completion (Actual): July 9, 2020

Study Registration Dates

• First Submitted: February 24, 2020
• First Submitted That Met QC Criteria: February 25, 2020
• First Posted (Actual): February 28, 2020

Study Record Updates

• Last Update Posted (Actual): August 19, 2020
• Last Update Submitted That Met QC Criteria: August 18, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Coronavirus Infections; Virus Diseases
• Other Study ID Numbers: 2020-013-D

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No