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出境医 / 临床实验 / Study of Human Umbilical Cord-derived Mesenchymal Stem Cells for Treatment of Refractory Immune Thrombocytopenia

Study of Human Umbilical Cord-derived Mesenchymal Stem Cells for Treatment of Refractory Immune Thrombocytopenia

Study Description
Brief Summary:

Primary Objective: To evaluate the safety and efficacy of human umbilical cord-derived mesenchymal stem cells（hUC-MSCs） to treat refractory immune thrombocytopenia（ITP）.

Secondary Objective: To observe the changes of immune function in refractory ITP patients with human umbilical cord-derived mesenchymal stem cells（hUC-MSCs） after infusion, and to explore and reveal the mechanism of hUC-MSCs in treating ITP.


Condition or disease Intervention/treatment Phase
Thrombocytopenia Mesenchymal Stem Cells Other: Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) Not Applicable

Detailed Description:

Human umbilical cord (hUC)-derived mesenchymal stem cells (MSCs) have been shown to have marked therapeutic effects in a number of inflammatory diseases and autoimmune diseases in humans based on their potential for immunosuppression and their low immunogenicity. Currently, no more data is available on the safety and effectiveness of hUC-MSCs to treat immune thrombocytopenia patients.

This is a single-arm study to evaluate the safety and efficacy of hUC-MSCs to treat refractory immune thrombocytopenia（ITP）. In addition, it is the objective of this study to observe the changes of immune function in refractory ITP patients after hUC-MSCs infusion, and to explore and reveal the mechanism of hUC-MSCs in treating ITP.

The investigator will assess the changes of the platelet counts after hUC-MSCs infusion from week 1 to week 28, and observe incidence of adverse events during and after hUC-MSCs infusion.The investigator will complete virus detection( including HBV, HCV, HIV, Syphilis, etc) at week 4 and week 16 after hUC-MSCs infusion.

The dose of hUC-MSCs will be successively divided into three increasing dose(group A: hUC-MSCs 0.5×10^6/kg, weekly for 4 weeks, 3 patients; group B: hUC-MSCs 1.0×10^6/kg, weekly for 4 weeks, 3 patients; hUC-MSCs 2.0×10^6/kg, weekly for 4 weeks, 3 patients) with 3 patients in each group according to the dose.

The principle of increasing dose will be carried out successively from low dose to high dose group. According to the results of the safety and efficacy data from these 9 patients, the investigator will determine one of the doses and expand the sample size to 6 cases.

The investigator will observe the concentration of hUC-MSCs in peripheral blood from female patients after the first hUC-MSCs infusion at 10 time points, including 30 minutes before hUC-MSCs infusion, 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 16 hours, 24 hours,48 hours and 96 hours after the first hUC-MSCs infusion.

The investigator will detect antibody production of hUC-MSCs in peripheral blood from the first 9 patients at 2 time points, including 30 minutes before the first hUC-MSCs infusion and 48 hours after the last hUC-MSCs infusion.

The investigator will observe the changes of immune function in refractory ITP patients after hUC-MSCs infusion at 7 time points, including one day before hUC-MSCs infusion, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16weeks and 28 weeks after hUC-MSCs infusion.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Study of Human Umbilical Cord-derived Mesenchymal Stem Cells for Treatment of Refractory Immune Thrombocytopenia
Actual Study Start Date : November 21, 2019
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2022
Arms and Interventions
Arm Intervention/treatment
Experimental: 15 refractory ITP patients
15 enrolled refractory ITP patients will be picked up to infuse hUC-MSCs at the indicated dose.
 Other: Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs)
This is a single-arm study to evaluate the safety and efficacy of hUC-MSCs to treat refractory immune thrombocytopenia. The dose of hUC-MSCs will be successively divided into three increasing dose(group A: hUC-MSCs 0.5×10^6/kg, weekly for 4 weeks, 3 patients; group B: hUC-MSCs 1.0×10^6/kg, weekly for 4 weeks, 3 patients; hUC-MSCs 2.0×10^6/kg, weekly for 4 weeks, 3 patients) with 3 patients in each group according to the dose. The principle of increasing dose will be carried out successively from low dose to high dose group. According to the results of the safety and efficacy data from these 9 patients, the investigator will determine one of the doses and expand the sample size to 6 cases.
Outcome Measures
Primary Outcome Measures :
  1. Changes of the platelet counts after hUC-MSCs infusion [ Time Frame: 28 weeks ]
    The investigator will assess the changes of the platelet counts after hUC-MSCs infusion from week 1 to week 28.

  2. Incidence of adverse events after hUC-MSCs infusion [ Time Frame: 4 weeks ]
    The investigator will observe incidence of adverse events during and after hUC-MSCs infusion, including fever, thrombosis, diarrhea, skin rash and so on.

  3. Changes in virus safety indicators after hUC-MSCs infusion [ Time Frame: 16 weeks ]
    The investigator will complete virus detection( including HBV, HCV, HIV, Syphilis, EB, CMV, etc) at week 4 and week 16 after hUC-MSCs infusion.


Secondary Outcome Measures :
  1. Changes of concentration of hUC-MSCs in peripheral blood [ Time Frame: 96 hours ]
    The investigator will observe the concentration of hUC-MSCs in peripheral blood from female patients after the first hUC-MSCs infusion at 10 time points, including 30 minutes before hUC-MSCs infusion, 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 16 hours, 24 hours,48 hours and 96 hours after the first hUC-MSCs infusion.

  2. Changes of antibody production of hUC-MSCs in peripheral blood [ Time Frame: 24 days ]
    The investigator will detect antibody production of hUC-MSCs in peripheral blood from the first 9 patients at 2 time points, including 30 minutes before the first hUC-MSCs infusion and 48 hours after the last hUC-MSCs infusion.

  3. Changes of immune function in refractory ITP patients after hUC-MSCs infusion [ Time Frame: 28 weeks ]
    The investigator will observe the changes of immune function in refractory ITP patients after hUC-MSCs infusion at 7 time points, including one day before the first hUC-MSCs infusion, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16weeks and 28 weeks after the first hUC-MSCs infusion. The changes of immune function will include the changes of the percentage of Th cell subsets， regulatory T cells (Treg)，supressor T cells（Ts）, activation and proliferation of B and T lymphocyte, apoptosis of platelets by cytotoxic T cells(CTLs) and function of dendritic cells in peripheral blood mononuclear cells（PBMCs）at the 7 time points, and to compare with the healthy controls. The investigator also will assess the changes of cytokines in the cell culture supernatants and plasma at the 7 time points, and to compare with the healthy controls.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Aged 18 to 60 years old, male or female;
  • Conform to the diagnostic criteria of immune Thrombocytopenia (ITP);
  • Three months after splenectomy;
  • Platelet counts <30 ×10^9/L, and bleeding tendency;
  • People who are willing to sign the informed consent voluntarily and follow the research program.
  • Subject is practicing an acceptable method of contraception. Women of childbearing potential must have a negative serum pregnancy test in the whole study;

Exclusion Criteria:

  • ECOG score standard >1；
  • Secondary thrombocytopenic purpura;
  • Patients with poor compliance;
  • Positive serology for HIV, hepatitis B virus (HBV), hepatitis C virus (HCV), and/or hepatitis D virus (HDV), Syphilis; Positive for Epstein-Barr Virus DNA, Cytomegalovirus DNA;
  • Pregnancy or lactation period;
  • History of thrombosis;
  • The serum chemistry results exceed the upper laboratory normal range by more than 20%, such as ALT, AST, TBIL, BUN, Cre etc;
  • Pre-existing cardiac disease, including congestive heart failure of New York Heart Association [NYHA] Grade III/IV, arrhythmia requiring treatment or myocardial infarction within the last 6 months. No arrhythmia known to increase the risk of thrombotic events (e.g. atrial fibrillation), or patients with a QT >450msec or QTc > 480 for patients with a Bundle Branch Block;
  • History of solid organ or bone marrow transplant;
  • Researchers believe that patients should not participate in the test of any other condition.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Yunfei Chen, MD +86-22-23909009 chenyunfei@ihcams.ac.cn
Contact: Lei Zhang, MD +86-22-23909240 zhanglei1@ihcams.ac.cn

Locations
Layout table for location information
China, Tianjin
Yunfei Chen Recruiting
Tianjin, Tianjin, China, 300020
Contact: Yunfei Chen, MD    +86-22-23909009    chenyunfei@ihcams.ac.cn   
Contact: Lijun Liu, MD    +8613920927593    liulijun@ihcams.ac.cn   
Sponsors and Collaborators
Institute of Hematology & Blood Diseases Hospital
Investigators
Layout table for investigator information
Principal Investigator: Lei Zhang, MD Chinese Academy of Medical Science and Blood Disease Hospital
Tracking Information
First Submitted Date  ICMJE July 7, 2019
First Posted Date  ICMJE July 10, 2019
Last Update Posted Date July 21, 2020
Actual Study Start Date  ICMJE November 21, 2019
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 7, 2019)
  • Changes of the platelet counts after hUC-MSCs infusion [ Time Frame: 28 weeks ]
    The investigator will assess the changes of the platelet counts after hUC-MSCs infusion from week 1 to week 28.
  • Incidence of adverse events after hUC-MSCs infusion [ Time Frame: 4 weeks ]
    The investigator will observe incidence of adverse events during and after hUC-MSCs infusion, including fever, thrombosis, diarrhea, skin rash and so on.
  • Changes in virus safety indicators after hUC-MSCs infusion [ Time Frame: 16 weeks ]
    The investigator will complete virus detection( including HBV, HCV, HIV, Syphilis, EB, CMV, etc) at week 4 and week 16 after hUC-MSCs infusion.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 7, 2019)
  • Changes of concentration of hUC-MSCs in peripheral blood [ Time Frame: 96 hours ]
    The investigator will observe the concentration of hUC-MSCs in peripheral blood from female patients after the first hUC-MSCs infusion at 10 time points, including 30 minutes before hUC-MSCs infusion, 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 16 hours, 24 hours,48 hours and 96 hours after the first hUC-MSCs infusion.
  • Changes of antibody production of hUC-MSCs in peripheral blood [ Time Frame: 24 days ]
    The investigator will detect antibody production of hUC-MSCs in peripheral blood from the first 9 patients at 2 time points, including 30 minutes before the first hUC-MSCs infusion and 48 hours after the last hUC-MSCs infusion.
  • Changes of immune function in refractory ITP patients after hUC-MSCs infusion [ Time Frame: 28 weeks ]
    The investigator will observe the changes of immune function in refractory ITP patients after hUC-MSCs infusion at 7 time points, including one day before the first hUC-MSCs infusion, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16weeks and 28 weeks after the first hUC-MSCs infusion. The changes of immune function will include the changes of the percentage of Th cell subsets， regulatory T cells (Treg)，supressor T cells（Ts）, activation and proliferation of B and T lymphocyte, apoptosis of platelets by cytotoxic T cells(CTLs) and function of dendritic cells in peripheral blood mononuclear cells（PBMCs）at the 7 time points, and to compare with the healthy controls. The investigator also will assess the changes of cytokines in the cell culture supernatants and plasma at the 7 time points, and to compare with the healthy controls.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Human Umbilical Cord-derived Mesenchymal Stem Cells for Treatment of Refractory Immune Thrombocytopenia
Official Title  ICMJE Study of Human Umbilical Cord-derived Mesenchymal Stem Cells for Treatment of Refractory Immune Thrombocytopenia
Brief Summary

Primary Objective: To evaluate the safety and efficacy of human umbilical cord-derived mesenchymal stem cells（hUC-MSCs） to treat refractory immune thrombocytopenia（ITP）.

Secondary Objective: To observe the changes of immune function in refractory ITP patients with human umbilical cord-derived mesenchymal stem cells（hUC-MSCs） after infusion, and to explore and reveal the mechanism of hUC-MSCs in treating ITP.
Detailed Description

Human umbilical cord (hUC)-derived mesenchymal stem cells (MSCs) have been shown to have marked therapeutic effects in a number of inflammatory diseases and autoimmune diseases in humans based on their potential for immunosuppression and their low immunogenicity. Currently, no more data is available on the safety and effectiveness of hUC-MSCs to treat immune thrombocytopenia patients.

This is a single-arm study to evaluate the safety and efficacy of hUC-MSCs to treat refractory immune thrombocytopenia（ITP）. In addition, it is the objective of this study to observe the changes of immune function in refractory ITP patients after hUC-MSCs infusion, and to explore and reveal the mechanism of hUC-MSCs in treating ITP.

The investigator will assess the changes of the platelet counts after hUC-MSCs infusion from week 1 to week 28, and observe incidence of adverse events during and after hUC-MSCs infusion.The investigator will complete virus detection( including HBV, HCV, HIV, Syphilis, etc) at week 4 and week 16 after hUC-MSCs infusion.

The dose of hUC-MSCs will be successively divided into three increasing dose(group A: hUC-MSCs 0.5×10^6/kg, weekly for 4 weeks, 3 patients; group B: hUC-MSCs 1.0×10^6/kg, weekly for 4 weeks, 3 patients; hUC-MSCs 2.0×10^6/kg, weekly for 4 weeks, 3 patients) with 3 patients in each group according to the dose.

The principle of increasing dose will be carried out successively from low dose to high dose group. According to the results of the safety and efficacy data from these 9 patients, the investigator will determine one of the doses and expand the sample size to 6 cases.

The investigator will observe the concentration of hUC-MSCs in peripheral blood from female patients after the first hUC-MSCs infusion at 10 time points, including 30 minutes before hUC-MSCs infusion, 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 16 hours, 24 hours,48 hours and 96 hours after the first hUC-MSCs infusion.

The investigator will detect antibody production of hUC-MSCs in peripheral blood from the first 9 patients at 2 time points, including 30 minutes before the first hUC-MSCs infusion and 48 hours after the last hUC-MSCs infusion.

The investigator will observe the changes of immune function in refractory ITP patients after hUC-MSCs infusion at 7 time points, including one day before hUC-MSCs infusion, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16weeks and 28 weeks after hUC-MSCs infusion.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Thrombocytopenia
  • Mesenchymal Stem Cells
Intervention  ICMJE Other: Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs)
This is a single-arm study to evaluate the safety and efficacy of hUC-MSCs to treat refractory immune thrombocytopenia. The dose of hUC-MSCs will be successively divided into three increasing dose(group A: hUC-MSCs 0.5×10^6/kg, weekly for 4 weeks, 3 patients; group B: hUC-MSCs 1.0×10^6/kg, weekly for 4 weeks, 3 patients; hUC-MSCs 2.0×10^6/kg, weekly for 4 weeks, 3 patients) with 3 patients in each group according to the dose. The principle of increasing dose will be carried out successively from low dose to high dose group. According to the results of the safety and efficacy data from these 9 patients, the investigator will determine one of the doses and expand the sample size to 6 cases.
Study Arms  ICMJE Experimental: 15 refractory ITP patients
15 enrolled refractory ITP patients will be picked up to infuse hUC-MSCs at the indicated dose.
Intervention: Other: Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs)
Publications *
  • Wang X, Yin X, Sun W, Bai J, Shen Y, Ao Q, Gu Y, Liu Y. Intravenous infusion umbilical cord-derived mesenchymal stem cell in primary immune thrombocytopenia: A two-year follow-up. Exp Ther Med. 2017 May;13(5):2255-2258. doi: 10.3892/etm.2017.4229. Epub 2017 Mar 14.
  • Wang Y, Han ZB, Ma J, Zuo C, Geng J, Gong W, Sun Y, Li H, Wang B, Zhang L, He Y, Han ZC. A toxicity study of multiple-administration human umbilical cord mesenchymal stem cells in cynomolgus monkeys. Stem Cells Dev. 2012 Jun 10;21(9):1401-8. doi: 10.1089/scd.2011.0441. Epub 2011 Nov 22.
  • Wang Y, Zhang Z, Chi Y, Zhang Q, Xu F, Yang Z, Meng L, Yang S, Yan S, Mao A, Zhang J, Yang Y, Wang S, Cui J, Liang L, Ji Y, Han ZB, Fang X, Han ZC. Long-term cultured mesenchymal stem cells frequently develop genomic mutations but do not undergo malignant transformation. Cell Death Dis. 2013 Dec 5;4:e950. doi: 10.1038/cddis.2013.480.
  • Gong W, Han Z, Zhao H, Wang Y, Wang J, Zhong J, Wang B, Wang S, Wang Y, Sun L, Han Z. Banking human umbilical cord-derived mesenchymal stromal cells for clinical use. Cell Transplant. 2012;21(1):207-16. doi: 10.3727/096368911X586756. Epub 2011 Sep 16.
  • Wu Y, Wang Z, Cao Y, Xu L, Li X, Liu P, Yan P, Liu Z, Zhao D, Wang J, Wu X, Gao C, Da W, Han Z. Cotransplantation of haploidentical hematopoietic and umbilical cord mesenchymal stem cells with a myeloablative regimen for refractory/relapsed hematologic malignancy. Ann Hematol. 2013 Dec;92(12):1675-84. doi: 10.1007/s00277-013-1831-0. Epub 2013 Jul 11.
  • Liang J, Zhang H, Hua B, Wang H, Wang J, Han Z, Sun L. Allogeneic mesenchymal stem cells transplantation in treatment of multiple sclerosis. Mult Scler. 2009 May;15(5):644-6. doi: 10.1177/1352458509104590.
  • Wu Y, Cao Y, Li X, Xu L, Wang Z, Liu P, Yan P, Liu Z, Wang J, Jiang S, Wu X, Gao C, Da W, Han Z. Cotransplantation of haploidentical hematopoietic and umbilical cord mesenchymal stem cells for severe aplastic anemia: successful engraftment and mild GVHD. Stem Cell Res. 2014 Jan;12(1):132-8. doi: 10.1016/j.scr.2013.10.001. Epub 2013 Oct 10.
  • Ma L, Zhou Z, Zhang D, Yang S, Wang J, Xue F, Yang Y, Yang R. Immunosuppressive function of mesenchymal stem cells from human umbilical cord matrix in immune thrombocytopenia patients. Thromb Haemost. 2012 May;107(5):937-50. doi: 10.1160/TH11-08-0596. Epub 2012 Mar 8.

*   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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 7, 2019) 		15
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2022
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Aged 18 to 60 years old, male or female;
  • Conform to the diagnostic criteria of immune Thrombocytopenia (ITP);
  • Three months after splenectomy;
  • Platelet counts <30 ×10^9/L, and bleeding tendency;
  • People who are willing to sign the informed consent voluntarily and follow the research program.
  • Subject is practicing an acceptable method of contraception. Women of childbearing potential must have a negative serum pregnancy test in the whole study;

Exclusion Criteria:

  • ECOG score standard >1；
  • Secondary thrombocytopenic purpura;
  • Patients with poor compliance;
  • Positive serology for HIV, hepatitis B virus (HBV), hepatitis C virus (HCV), and/or hepatitis D virus (HDV), Syphilis; Positive for Epstein-Barr Virus DNA, Cytomegalovirus DNA;
  • Pregnancy or lactation period;
  • History of thrombosis;
  • The serum chemistry results exceed the upper laboratory normal range by more than 20%, such as ALT, AST, TBIL, BUN, Cre etc;
  • Pre-existing cardiac disease, including congestive heart failure of New York Heart Association [NYHA] Grade III/IV, arrhythmia requiring treatment or myocardial infarction within the last 6 months. No arrhythmia known to increase the risk of thrombotic events (e.g. atrial fibrillation), or patients with a QT >450msec or QTc > 480 for patients with a Bundle Branch Block;
  • History of solid organ or bone marrow transplant;
  • Researchers believe that patients should not participate in the test of any other condition.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Yunfei Chen, MD +86-22-23909009 chenyunfei@ihcams.ac.cn
Contact: Lei Zhang, MD +86-22-23909240 zhanglei1@ihcams.ac.cn
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04014166
Other Study ID Numbers  ICMJE SC2019002-EC-1
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  ICMJE
Plan to Share IPD: No
Responsible Party Zhang Lei, Institute of Hematology & Blood Diseases Hospital
Study Sponsor  ICMJE Institute of Hematology & Blood Diseases Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Lei Zhang, MD Chinese Academy of Medical Science and Blood Disease Hospital
PRS Account Institute of Hematology & Blood Diseases Hospital
Verification Date July 2020

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

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