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Unrelated Donor Transplant Versus Immune Therapy in Pediatric 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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02845596
Recruitment Status : Recruiting
First Posted : July 27, 2016
Last Update Posted : January 14, 2020
Sponsor:
Information provided by (Responsible Party):
Michael Pulsipher, MD, Children's Hospital Los Angeles

Tracking Information
First Submitted Date  ICMJE May 9, 2016
First Posted Date  ICMJE July 27, 2016
Last Update Posted Date January 14, 2020
Study Start Date  ICMJE August 2016
Estimated Primary Completion Date May 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 22, 2016)
Percentage of patients randomized to HSCT that actually complete HSCT [ Time Frame: 4 years ]
Feasibility of comparing outcomes of patients treated de novo with IST versus matched unrelated donor HSCT for pediatric acquired severe aplastic anemia as defined by percentage of patients randomized to HSCT that actually complete HSCT.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02845596 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 22, 2016)
  • Time from screening consent to randomization [ Time Frame: 4 years ]
    To measure the time from screening consent and randomization of patients to initiation of the preparative regimen of those randomized to HSCT.
  • Number of patients that fail to receive their primary assigned therapy (HSCT or IST). [ Time Frame: 4 years ]
    Number of patients fail to receive their primary assigned therapy (HSCT or IST).
  • Reasons why patients fail to receive their primary assigned therapy (HSCT or IST). [ Time Frame: 4 years ]
    Reasons why patients fail to receive their primary assigned therapy (HSCT or IST).
  • Treatment-related mortality at one year from randomization in both arms [ Time Frame: 1 Year ]
    Number of deaths that are treatment related
  • Overall Survival at one year from randomization in both arms [ Time Frame: 1 Year ]
    percentage of enrolled patients living at 1 year post randomization
  • Time from randomization to neutrophil recovery in both arms [ Time Frame: 4 years ]
    Time from randomization to neutrophil recovery in both arms
  • Time from randomization to platelet recovery in both arms [ Time Frame: 4 years ]
    Time from randomization to platelet recovery in both arms
  • Time from randomization to red blood cell recovery in both arms [ Time Frame: 4 years ]
    Time from randomization to red blood cell recovery in both arms
  • Time from randomization to cessation of immune suppression recovery in both arms [ Time Frame: 4 years ]
    Time from randomization to cessation of immune suppression recovery in both arms
  • Rates of primary and secondary graft rejection in the MUD HSCT arm [ Time Frame: 4 years ]
    Rates of primary and secondary graft rejection in the MUD HSCT arm
  • Rates of grade II-IV and III-IV acute GVHD, and extensive chronic GVHD in the MUD HSCT arm [ Time Frame: 4 years ]
    Rates of grade II-IV and III-IV acute GVHD, and extensive chronic GVHD in the MUD HSCT arm
  • Rates of IST response [ Time Frame: 4 years ]
    Rates of IST response
  • Rates of IST relapse [ Time Frame: 4 years ]
    Rates of IST relapse
  • Rates of secondary MDS or AML in both treatment arms. [ Time Frame: 4 years ]
    Rates of secondary MDS or AML in both treatment arms.
  • Rates of other secondary malignancies in both treatment arms. [ Time Frame: 4 years ]
    Rates of other secondary malignancies in both treatment arms.
  • Development of symptomatic PNH in both treatment arms. [ Time Frame: 4 years ]
    Development of symptomatic PNH in both treatment arms.
  • Incidence of significant infection in both treatment arms [ Time Frame: 4 years ]
    Incidence of significant infection in both treatment arms
  • Time to immune reconstitution in the HSCT arm [ Time Frame: 4 years ]
    Time to immune reconstitution in the HSCT arm
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 Unrelated Donor Transplant Versus Immune Therapy in Pediatric Severe Aplastic Anemia
Official Title  ICMJE Unrelated Donor Transplant Versus Immune Therapy in Pediatric Severe Aplastic Anemia
Brief Summary The purpose of this study is to determine the feasibility of comparing outcomes of patients treated de novo with immunosuppressive therapy (IST) versus matched unrelated donor (MUD) hematopoietic stem cell transplant (HSCT) for pediatric acquired severe aplastic anemia.
Detailed Description A major challenge in treating pediatric Severe Aplastic Anemia (SAA) is the determination of best primary therapy for patients who lack a fully matched related donor for HSCT. Good survival outcomes have been seen with IST, but initial and late failures, CSA dependence, persistent cytopenias and secondary Myelodysplastic Syndrome (MDS) / Acute Myeloid Leukemia (AML) in a portion of patients leave considerable room for improvement. MUD HSCT survival in SAA has markedly improved, but a direct comparison of this approach with IST is necessary to determine whether this approach is feasible and will lead to better Event Free Survival. This trial will address the feasibility of randomization, test whether patients can be evaluated in a timely fashion and safely begin therapy with MUD HSCT or IST, and give a preliminary assessment of the safety of up-front MUD HSCT. If successful, this trial will lead to a future prospective trial comparing directly IST to MUD HSCT in this disease.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE Severe Aplastic Anemia
Intervention  ICMJE
  • Drug: cyclosporine
    cyclosporine
  • Procedure: Matched Unrelated Donor Hematopoietic Stem Cell Transplant
    Matched Unrelated Donor (MUD) Hematopoietic Stem Cell Transplantation (HSCT)
  • Drug: horse anti-thymocyte globulin (ATG)
    horse anti-thymocyte globulin (ATG)
    Other Name: ATGAM
  • Drug: rabbit anti-thymocyte globulin (ATG)
    rabbit anti-thymocyte globulin (ATG)
    Other Name: Thymoglobulin
  • Drug: methotrexate
    methotrexate
  • Drug: fludarabine
    fludarabine
  • Drug: cyclophosphamide
    cyclophosphamide
  • Radiation: low-dose total body irradiation (TBI)
    low-dose total body irradiation (TBI)
  • Procedure: Immunosuppressive Therapy (IST)
    Immunosuppressive Therapy (IST)
Study Arms  ICMJE
  • Active Comparator: Immunosuppressive Therapy
    Patient will receive standard immunosuppressive therapy combination of drugs: horse anti-thymocyte globulin (ATG) and cyclosporine.
    Interventions:
    • Drug: cyclosporine
    • Drug: horse anti-thymocyte globulin (ATG)
    • Procedure: Immunosuppressive Therapy (IST)
  • Active Comparator: Matched Unrelated Stem Cell Transplant
    Patient will under go matched unrelated donor transplant of hematopoietic stem cells as their therapy using fludarabine, cyclophosphamide, rabbit anti-thymocyte globulin (ATG), and low-dose total body irradiation (TBI) as preparative regimen and cyclosporine and methotrexate for graft versus host disease (GVHD) prevention.
    Interventions:
    • Drug: cyclosporine
    • Procedure: Matched Unrelated Donor Hematopoietic Stem Cell Transplant
    • Drug: rabbit anti-thymocyte globulin (ATG)
    • Drug: methotrexate
    • Drug: fludarabine
    • Drug: cyclophosphamide
    • Radiation: low-dose total body irradiation (TBI)
Publications * Not Provided

*   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 22, 2016)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 2020
Estimated Primary Completion Date May 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Confirmed diagnosis of idiopathic SAA, defined as:

    • Bone marrow cellularity <25%, or <30% hematopoietic cells.
    • Two out of three of the following (in peripheral blood): neutrophils <0.5 x109/L, platelets <20 x109/L, reticulocyte count <60 x109/L with hemoglobin <8g/dL.
  2. Age ≤25 years old.
  3. No suitable fully matched related donor available (minimum 6/6 match for Human Leukocyte antigen (HLA) -A and B at intermediate or high resolution and DRB1 at high resolution using DNA based typing).
  4. At least two unrelated donors noted on National Marrow Donor Program (NMDP) search who are well matched (9/10 or 10/10 for HLA-A, B, C, DRB1, and DQB1 using high resolution).
  5. Signed informed consent for the randomized trial by patient and/or legal guardian.
  6. Adequate organ function defined as in the judgment of the investigator, there is not irreversible organ damage that would preclude the patient from meeting the organ function inclusion criteria for HSCT listed in section 2.3.4 by the intended time of HSCT (6-8 weeks after randomization) or preclude patients from receiving horse ATG.

Exclusion Criteria:

  1. Inherited bone marrow failure syndromes (IBMFS). The diagnosis of Fanconi anemia must be excluded by diepoxybutane (DEB) or equivalent testing on peripheral blood or marrow. Telomere length testing should be sent on all patients to exclude Dyskeratosis congenita, but if results are delayed or unavailable and there are no clinical manifestations of DC, patients may enroll. If patients have clinical characteristics suspicious for Shwachman Diamond syndrome, this syndrome must be excluded by pancreatic isoamylase testing or gene mutation analysis. Note: pancreatic isoamylase testing is not accurate in children less than 3 years.
  2. Clonal cytogenetic abnormalities or fluorescence In Situ Hybridization (FISH) pattern consistent with pre-myelodysplastic syndrome (pre-MDS) or MDS on marrow examination (see section 4.2.3.1 for details of the required MDS FISH panel).
  3. Known severe allergy to horse ATG.
  4. Prior allogeneic stem cell transplant.
  5. Prior solid organ transplant.
  6. Infection with human immunodeficiency virus (HIV).
  7. Active Hepatitis B or C. This should be excluded in patients where there is clinical suspicion of hepatitis (e.g. elevated LFTs).
  8. Female patients who are pregnant or breast-feeding.
  9. Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 25 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Liz Gourdine 323-361-6652 TransIT@chla.usc.edu
Contact: Maggie Malsch, MSN 617-355-4685 maggie.malsch@childrens.harvard.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02845596
Other Study ID Numbers  ICMJE TransIT NMD 1601
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Michael Pulsipher, MD, Children's Hospital Los Angeles
Study Sponsor  ICMJE Michael Pulsipher, MD
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Michael Pulsipher, MD Children's Hospital Los Angeles
Study Chair: David A Williams, MD Boston's Childrens Hospital
PRS Account Children's Hospital Los Angeles
Verification Date January 2020

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