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

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ClinicalTrials.gov Identifier: NCT04288102
Recruitment Status : Completed
First Posted : February 28, 2020
Last Update Posted : August 19, 2020
Sponsor:
Collaborators:
Huoshenshan Hospital
Maternal and Child Health Hospital of Hubei Province
General Hospital of Central Theater Command, Wuhan, China
VCANBIO CELL & GENE ENGINEERING CORP.,LTD, China
Information provided by (Responsible Party):
Fu-Sheng Wang, Beijing 302 Hospital

Tracking Information
First Submitted Date  ICMJE February 24, 2020
First Posted Date  ICMJE February 28, 2020
Last Update Posted Date August 19, 2020
Actual Study Start Date  ICMJE March 5, 2020
Actual Primary Completion Date May 12, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 16, 2020)
Change in lesion proportion (%) of full lung volume from baseline to day 28. [ Time Frame: Day 28 ]
Evaluation of Pneumonia Improvement
Original Primary Outcome Measures  ICMJE
 (submitted: February 25, 2020)
  • Improvement time of clinical critical treatment index within 28 days [ Time Frame: 28 Days ]
    days from randomization to reduction of clinical treatment index by at least 2 points. No limitation of activities, discharged from hospital =Score 1; Limitation of activities=Score 2; Hospitalized, no oxygen therapy=Score 3; Oxygen by mask or nasal prongs-Score 4; Non-invasive ventilation or high-flow oxygen=Score 5; Intubation and mechanical=Score 6; Ventilation+additional organ support-ECMO, CRRT, pressors=Score 7; Death=Score8.
  • Side effects in the MSCs treatment group [ Time Frame: Day 28 ]
    Proportion of participants with treatment-related adverse events as assessed by CTCAE v4.0
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 16, 2020)
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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.
  • Oxygenation index( PaO2/FiO2) [ Time Frame: Day 6, Day 10, Day 28 ]
    Evaluation of Pneumonia Improvement
  • Duration of oxygen therapy(days) [ Time Frame: Day 28, Day 90 ]
    Evaluation of Pneumonia Improvement
  • Blood oxygen saturation [ Time Frame: Day 6, Day 10, Day 28 ]
    Evaluation of Pneumonia Improvement
  • 6-minute walk test [ Time Frame: Day 28, Day 90 ]
    Evaluation of Pneumonia Improvement
  • Maximum vital capacity (VCmax) [ Time Frame: Baseline, Day 10, Day 14, Day 21, Day 28, Day 90 ]
    Evaluation of Pneumonia Improvement
  • Diffusing Capacity (DLCO) [ Time Frame: Baseline, Day 10, Day 14, Day 21, Day 28, Day 90 ]
    Evaluation of Pneumonia Improvement
  • 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.
  • 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
  • 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
  • Adverse events [ Time Frame: Day 0 through Day 90 ]
    Safety endpoints
  • Serious adverse events [ Time Frame: Day 0 through Day 90 ]
    Safety endpoints
  • All-cause mortality [ Time Frame: Day 0 through Day 90 ]
    Safety endpoints
Original Secondary Outcome Measures  ICMJE
 (submitted: February 25, 2020)
  • Proportion of patients in each classification of clinical critical treatment index [ Time Frame: Baseline , Day 7, Day 14, Day 28 ]
    Evaluation of Pneumonia Improvement No limitation of activities, discharged from hospital =Score 1; Limitation of activities=Score 2; Hospitalized, no oxygen therapy=Score 3; Oxygen by mask or nasal prongs-Score 4; Non-invasive ventilation or high-flow oxygen=Score 5; Intubation and mechanical=Score 6; Ventilation+additional organ support-ECMO, CRRT, pressors=Score 7; Death=Score8.
  • All cause mortality on Day 28 [ Time Frame: Day 28 ]
    Evaluation of Pneumonia Improvement
  • Invasive mechanical ventilation rate [ Time Frame: Day 28 ]
    Evaluation of Pneumonia Improvement
  • Duration of oxygen therapy(days) [ Time Frame: Day 28 ]
    Evaluation of Pneumonia Improvement
  • Duration of hospitalization(days) [ Time Frame: Day 28 ]
    Evaluation of Pneumonia Improvement
  • Incidence of nosocomial infection [ Time Frame: Day 28 ]
    Defined as laboratory nucleic acid positive or confirmed infection case by culture
  • CD4+ T cell count by flow cytometry in two groups [ Time Frame: Baseline , Day 3, Day 6, Day 10, Day 14, Day 21, Day 28, ]
    Marker of Immunological function
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Treatment With Human Umbilical Cord-derived Mesenchymal Stem Cells for Severe Corona Virus Disease 2019 (COVID-19)
Official Title  ICMJE 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
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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
Condition  ICMJE Corona Virus Disease 2019(COVID-19)
Intervention  ICMJE
  • Biological: UC-MSCs
    3 does of UC-MSCs(4.0*10E7 cells per time) intravenously at Day 0, Day 3, Day 6.
  • Biological: Saline containing 1% Human serum albumin(solution without UC-MSCs)
    3 does of placebo(intravenously at Day 0, Day 3, Day 6)
Study Arms  ICMJE
  • Experimental: Human Umbilical Cord-Mesenchymal Stem Cells (UC-MSCs)
    Participants will receive standard of care plus 3 does of UC-MSCs
    Intervention: Biological: UC-MSCs
  • Placebo Comparator: Placebo
    Participants will receive standard of care plus 3 does of placebo
    Intervention: Biological: Saline containing 1% Human serum albumin(solution without UC-MSCs)
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 16, 2020)
100
Original Estimated Enrollment  ICMJE
 (submitted: February 25, 2020)
45
Actual Study Completion Date  ICMJE July 9, 2020
Actual Primary Completion Date May 12, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04288102
Other Study ID Numbers  ICMJE 2020-013-D
Has Data Monitoring Committee No
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  ICMJE
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.
Responsible Party Fu-Sheng Wang, Beijing 302 Hospital
Study Sponsor  ICMJE Beijing 302 Hospital
Collaborators  ICMJE
  • Huoshenshan Hospital
  • Maternal and Child Health Hospital of Hubei Province
  • General Hospital of Central Theater Command, Wuhan, China
  • VCANBIO CELL & GENE ENGINEERING CORP.,LTD, China
Investigators  ICMJE
Study Chair: Fu-Sheng Wang, MD, PhD Beijing 302 Hospital
PRS Account Beijing 302 Hospital
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP