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Safety and Efficacy of Patient's Own AD-MSC and AD-HSC Transplantation in Patients With Severe Aplastic Anemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02407470
Recruitment Status : Unknown
Verified March 2015 by Qinwei Yin, General Hospital of Beijing PLA Military Region.
Recruitment status was:  Recruiting
First Posted : April 3, 2015
Last Update Posted : April 3, 2015
Sponsor:
Collaborators:
Peking Union Medical College Hospital
General Hospital of Beijing PLA Military Region
Chinese Academy of Medical Sciences
Information provided by (Responsible Party):
Qinwei Yin, General Hospital of Beijing PLA Military Region

Brief Summary:

RATIONALE: It has been shown that about 30% of patients do not respond to immunosuppressive therapy or experience recurrence, and graft rejection and graft-versus-host-disease (GVHD) decrease event-free survival to 30% to 50% in the alternative donor (matched unrelated, partially matched family member) transplantation. Although an overall and disease free survival of 85% to 100%, can be obtained in allogeneic blood or bone marrow stem cell transplantation using an human leukocyte antigen (HLA) matched sibling donor, only about 25% of patients have such a donor.

PURPOSE: In an attempt to avoid GVHD, reduce earlier infection rate and decrease regimen-related toxicity while maintaining better engraftment, this study is to evaluate the effectiveness and safety of patient's own adipose-derived mesenchymal stem cell (AD-MSC) or AD-MSC transdifferentiated HSC (AD-HSC) transplant after an immunosuppressive regimen in treating patients who have severe aplastic anemia.

The patient will be in the study for one year for observation and active monitoring. After treatment and active monitoring are over, the patient's medical condition will be followed indefinitely. The principle measures of safety and efficacy will be :

  1. Patient survival probability at 3 months, 6 months and 1 year.
  2. Engraftment at 3 months, 6 months and 1 year
  3. Incidence of graft versus host disease (GVHD), incidence of acute and chronic GVHD and Incidence of earlier infection rate as well as other complications within 6 months and 1 years.

Condition or disease Intervention/treatment Phase
Severe Aplastic Anemia Drug: Rabbit antithymoglobulin (ATG) Procedure: Adipose derived mesenchymal stem cells ( AD-MSCs) Procedure: AD-MSC transdifferentiated HSCs (AD-HSCs) Phase 1 Phase 2

Detailed Description:

Severe aplastic anemia is characterized by severe deficiencies in peripheral-blood platelets, white cells, and red cells. These defects in mature cells occur because aplastic bone marrow contains severely reduced numbers of hematopoietic stem cells. To date, Hematopoietic stem cell (HSC) transplants are routinely used to treat patients with many different diseases, including various cancers and blood disorders, such as aplastic anemia. The main sources of HSCs are bone marrow, cord blood and peripheral blood. However, challenges include obtaining enough functional HSCs to ensure optimal engraftment, and avoiding immune rejection and other complications associated with allogeneic transplantations. Novel abundant sources of clinical-grade HSCs are therefore being sought.

Our novel studies have demonstrated that adipose-derived mesenchymal stem cells (AD-MSCs) can be converted rapidly (in 4 days) into AD-HSCs on a large scale (2X108-9 cluster of differentiation 34(CD34)positive cells) by transfection of small RNAs to the the early region 1A (E1A)-like inhibitor of differentiation 1 (EID1) in the presence of specific cytokines. In vitro, AD-HSCs expanded efficiently and resembled cord-blood HSCs in phenotype, genotype, and colony-forming ability. In a mouse model, primary and secondary transplantation analysis and repopulating assays showed that AD-HSCs homed to the bone marrow, differentiated into functional blood cells, and showed a long-term ability to self-renew. we show that adipose-derived mesenchymal stem cells (AD-MSCs) can be converted into AD-HSCs by transfection of small RNAs to the E1A-like inhibitor of differentiation 1 (EID1) in the presence of specific cytokines. In vitro, AD-HSCs expanded efficiently and resembled cord-blood HSCs in phenotype, genotype, and colony-forming ability. In a mouse model, primary and secondary transplantation analysis and repopulating assays showed that AD-HSCs homed to the bone marrow, differentiated into functional blood cells, and showed a long-term ability to self-renew. In the safety aspect, we saw no evidence of leukemia, teratoma and other cancers in the blood, testes and subcutaneous tissues of transplanted mice. More importantly, our preliminary data have shown that AD-HSCs can reconstitute hematopoietic function in five patients with severe aplastic anemia. Based on these premilitary studies,, we have determined to conduct a further clinical investigation in multiple medical centers. In this study we plan to enroll up to 90 patients, to make a comprehensive assessment for this new treatment regimen and to show it is equal or superior to the current immunosuppressive regimen. Patients will be in the study for one years for treatment and active monitoring. All patients will be followed until death.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter, Randomized, Controlled Study of the Efficacy and Safety of the Combination of Adipose Tissue-derived Hematopoietic Stem Cells (AD-HSCs) and ATG in the Treatment of Severe Aplastic Anemia
Study Start Date : January 2015
Estimated Primary Completion Date : January 2017
Estimated Study Completion Date : July 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Rabbit antithymoglobulin (ATG)
Patient in this arm will receive rabbit ATG at 3.5 mg/kg/dose IV from day -6 to -2 with the goals of ablating host repressive T cells.
Drug: Rabbit antithymoglobulin (ATG)
Rabbit ATG at 3.5 mg/kg/dose IV is given from day -6 to -2.
Other Name: ATG

Experimental: Rabbit ATG & AD-MSCs
Patient in this arm will receive rabbit ATG at 3.5 mg/kg/dose IV from day -6 to -2 and then patient's own adipose derived mesenchymal stem cells (AD-MSCs) at a dose of 3000000/kg/d on day 1 to 3.
Drug: Rabbit antithymoglobulin (ATG)
Rabbit ATG at 3.5 mg/kg/dose IV is given from day -6 to -2.
Other Name: ATG

Procedure: Adipose derived mesenchymal stem cells ( AD-MSCs)
Participants will receive rabbit ATG at 3.5 mg/kg/dose IV from day -6 to -2, and then patient's own AD-MSCs at a dose of 3000000 cells/kg/d on day 1-3.
Other Name: AD-MSCs

Experimental: Rabbit ATG & AD-HSCs
Patient in this arm will receive rabbit ATG at 3.5 mg/kg/dose IV from day -6 to -2 and then patient's own AD-MSC transdifferentiated HSCs (AD-HSCs) at a dose of 3000000/kg/d from day 1 to 4.
Drug: Rabbit antithymoglobulin (ATG)
Rabbit ATG at 3.5 mg/kg/dose IV is given from day -6 to -2.
Other Name: ATG

Procedure: AD-MSC transdifferentiated HSCs (AD-HSCs)
Participants will receive rabbit anti-thymocyte globulin at 3.5 mg/kg/dose IV from day -6 to -2, and then patient's own AD-HSCs at a dose of 3000000 cells/kg/d from day 1 to 4.
Other Name: AD-HSCs




Primary Outcome Measures :
  1. Engraftment at 42 days post AD-HSC transplantation for patients with severe aplastic anemia. [ Time Frame: 42 days posttransplant ]
    Absolute neutrophil count > 0.5 X 109/l and Platelet count > 20 X 109 /l without infusion of platelet for 7 days.


Secondary Outcome Measures :
  1. To estimate the overall survival (OS) at 1 year following AD-HSC transplantation for Patients with Severe Aplastic Anemia [ Time Frame: 1 year ]
    Number of Subjects Alive at 12 months Post Transplant

  2. Relapse [ Time Frame: 1 year post transplant ]
    Return of SAA during the specified post-transplantation period.

  3. Incidence of chronic graft-versus-host disease [ Time Frame: 6 months ]
    Number of patients with chronic graft-versus-host disease by 6 months and 1 year

  4. Evaluation of the occurrence of secondary malignancies [ Time Frame: 6 months post transplant ]
    Occurring of any tumors during the specified post-transplantation period.

  5. Hematology labs [ Time Frame: 12 weeks ]
    Association between AD-HSC transplantation and response in hemoglobin, platelet, total white blood cell count, and absolute neutrophil count to be evaluate by maximal hemoglobin, platelet, total white blood cell count, and absolute neutrophil counts achieved in patients with severe aplastic anemia

  6. Number of participants with adverse events as a measure of safety and tolerability of intravenous AD-HSC infusion in patients with severe aplastic anemia [ Time Frame: weekly untill 12 months ]
    Adverse events like allergic reactions, infectious diseases, organ dysfunction or other related to AD-HSC infusion will be assessed

  7. Transfusional requirements [ Time Frame: weekly untill 6 months ]
    Units of blood or platelets transfused after AD-HSC infusion will be measured and compared to previously.

  8. To assess treatment related mortality [ Time Frame: 12 months ]
    Number of death after transplantation during the specified post-transplantation period.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   14 Years to 70 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Male or female recipients must have histopathologically confirmed diagnosis of SAA-I without or with more than 6 months after less than one treatment with ATG. Diagnostic Criteria for Server Aplastic Anemia will be based on the definitions set forth by the international Aplastic Anemia Study Group.

At least two of the following:

Absolute neutrophil count ≤ 0.5 X 109/l, Platelet count ≤ 20 X 109 /l, Anemia with corrected reticulocyte count ≤ 1%, and Bone marrow cellularity ≤ 25%, or bone marrow cellularity ≤ 50% with fewer than 30% hematopoietic cell, Hepatic: alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) no greater than 4 times normal, Bilirubin: no greater than 2 mg/dl, Renal: Creatinine clearance at least 50 ml/min, Cardiovascular: Shortening fraction or ejection fraction at least 40% of normal for age by echocardiogram or radionuclide scan.

No clinically significant comorbid illnesses (e.g., myocardial infarction or cerebrovascular accident).

Exclusion Criteria:

Active and uncontrolled infection, Active bleeding, Severe allergic history of ATG, HIV-1 infection, Pregnancy or breastfeeding, Carbon monoxide lung diffusion capacity (DLCO) <40% predicted, SAA-II, Patients with severe psychological disorders, Recipients of other clinical trials.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02407470


Contacts
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Contact: James Q Yin, M.D.,Ph.D. 86-01-84008003 Jamesyin2010@126.com
Contact: Jianliang Shen, M.D.,Ph.D. 86-01-66957676 nghxyk@163.com

Locations
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China, Beijing
Navy General Hospital Recruiting
Beijing, Beijing, China, 100048
Contact: Jianliang Shen, M.D.,Ph.D    86-01-66957676    nghxyk@163.com   
Contact: Qinwei Yin, M.D.,Ph.D.    86-01-84008003    jamesyin2010@126.com   
Principal Investigator: James Yin, M.D.,Ph.D         
Sponsors and Collaborators
Navy General Hospital, Beijing
Peking Union Medical College Hospital
General Hospital of Beijing PLA Military Region
Chinese Academy of Medical Sciences
Investigators
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Principal Investigator: james Q Yin, M.D.,Ph.D. The military general hospital of Beijing

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Responsible Party: Qinwei Yin, Professor, General Hospital of Beijing PLA Military Region
ClinicalTrials.gov Identifier: NCT02407470    
Other Study ID Numbers: Ginkgocell-ADHSC-AA-001
First Posted: April 3, 2015    Key Record Dates
Last Update Posted: April 3, 2015
Last Verified: March 2015
Keywords provided by Qinwei Yin, General Hospital of Beijing PLA Military Region:
Severe Aplastic Anemia (SAA), Hematopoietic Stem Cells, HSC Transplantation
ATG, Mesenchymal Stem Cells, Transdifferentiation,
Additional relevant MeSH terms:
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Anemia
Anemia, Aplastic
Hematologic Diseases
Bone Marrow Diseases
Thymoglobulin
Antilymphocyte Serum
Immunologic Factors
Physiological Effects of Drugs
Immunosuppressive Agents