- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00427661
A Pilot Study of HSCT for Patients With High-risk Hemoglobinopathy Using a Nonmyeloablative Preparative Regimen
A Pilot Study of Allogeneic Hematopoietic Stem Cell Transplantation for Patients With High Risk Hemoglobinopathy Using a Non-Myeloablative Preparative Regimen to Achieve Stable Mixed Chimerism
Hypothesis 1: A novel nonmyeloablative condition regimen will be safe and efficacious in producing stable donor chimerism and cure of severe hemoglobinopathy.
Hypothesis 2: Stable donor chimerism will result in amelioration of cerebral vasculopathy, improved cerebral perfusion and neurocognitive function.
Specific Aim 1: Study the safety and efficacy of a novel non-toxic conditioning regimen for HSCT for patients with severe hemoglobinopathies and the kinetics of lineage specific chimerism after HSCT
We will test our hypothesis that a novel nonmyeloablative condition regimen will be safe and efficacious in producing stable donor chimerism and cure of severe hemoglobinopathy:
Specific Aim 2: Optimize the immunosuppressive regimen for HSCT patients through a thorough understanding of the pharmacokinetics of Busulfan (BU) and mycophenolate mofetil (MMF) in the patient population. This will involve:
- Determine the pharmacokinetics of intravenously and orally administered MMF and intravenous BU in patients receiving HSCT.
- Determine the relationship of Area under the curve (AUC) of BU and mean trough concentrations of mycophenolic acid (MPA) to engraftment and graft versus host disease (GVHD).
- Determine the relationship of Area under the curve (AUC) and steady state concentration of BU to engraftment at day 30 and 1 year post HSCT.
Specific Aim 3: Study the effect of complete or partial donor chimerism on silent and overt cerebral vasculopathy, and neurocognitive functioning in patients with SCD undergoing HSCT. We will test our hypothesis that stable donor chimerism will result in improvement in cerebral vasculopathy and neurocognitive function. This will include.
- Determine effect of transplantation silent and overt cerebral vasculopathy by comparison MRA and TCD 1 year after HSCT to pre-HSCT studies.
- Determine effect on HSCT on neurocognitive function. Specific Aim 4: To determine the rate of T cell immune reconstitution in children with sickle cell disease following myeloablative compared to nonmyeloablative stem cell transplantation, using immunophenotyping assays, CDR3 spectratyping TREC analysis, and measurement of T cell specific donor engraftment.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
Pennsylvania
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Pittsburgh, Pennsylvania, United States, 15213
- Children's Hospital of Pittsburgh
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
Patients with SCD 0-35 years of age with an HLA-identical or 1 HLA antigen mismatched bone marrow or up to 2 HLA antigen mismatched umbilical cord blood (UCB) donor with one or more of the following:
- Stroke, CNS hemorrhage or a neurologic event lasting longer than 24 hours, or abnormal cerebral MRI or cerebral arteriogram or MRI angiographic study and impaired neuropsychological testing,
- Acute chest syndrome with a history of recurrent hospitalizations or exchange transfusions,
- Recurrent vaso-occlusive pain 3 or more episodes per year for 3 years or more years or recurrent priapism,
- Impaired neuropsychological function and abnormal cerebral MRI scan,
- Stage I or II sickle lung disease,
- Sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate [GFR] 30-50% of the predicted normal value),
- Bilateral proliferative retinopathy and major visual impairment in at least one eye,
- Osteonecrosis of multiple joints with documented destructive changes,
- Requirement for chronic transfusions but with RBC alloimmunization >2 antibodies during long term transfusion therapy.
- Patients with transfusion dependent Thalassemia 0-35 years of age with an HLA-identical or 1 HLA antigen mismatched bone marrow or up to 2 HLA antigen mismatched UCB donor.
Second Transplants
- Patients with sickle cell disease or Thalassemia who have failed to engraft or have autologous recovery are eligible for this protocol.
- Patients must meet above criteria.
- If first transplant was a non-myeloablative regimen, the second transplant can occur at any time.
- If the first transplant was a myeloablative regimen, then the second transplant must be > 6 months from the first transplant.
Exclusion Criteria:
Patients with one or more of the following:
- Karnofsky or Lansky performance score <70,
- Acute hepatitis or evidence of moderate or severe portal fibrosis or cirrhosis on biopsy,
- Stage III-IV lung disease,
- GFR<30% predicted normal values.
- Pregnant or lactating females.
- Active serious infection whereby patient has been on intravenous antibiotics for one week prior to study entry. Any patient with AIDS or ARC or HIV seropositivity. Any patient with invasive aspergillums infection within one year of study entry.
- Psychologically incapable of undergoing BMT with associated strict isolation or documented history of medical non-compliance.
- Patients not able to receive TLI due to prior radiation therapy.
Donor Inclusion Criteria
- Donor must be in good health based on review of systems and results of physical examination.
- Donor must have a normal hemoglobin, white count, platelet count and PTT.
- Female donors of childbearing potential must have a negative pregnancy test.
Donor Exclusion Criteria
- Donor has active infection (including HIV, hepatitis).
- Donor is a lactating female.
Donor Selection
In the case where more than one donor meets the eligibility criteria, donor selection will be guided by the following considerations:
- HLA A, B, DRB1 identical sibling donor is preferable to an unrelated donor
- Homozygous normal donor is preferable to heterozygote (carrier)
- ABO-compatible donor is preferable to ABO-incompatible donor
- Younger donor is preferable to older
- Cytomegalovirus seronegative donor is preferable to CMV seropositive donor, if the patient is CMV negative
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: NA
- Interventional Model: SINGLE_GROUP
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
OTHER: AHCT in High Risk SCD
Intervention: Busulfan; Fludarabine; cyclosporine A and MMF
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Hematopoietic stem cell transplantation from a matched sibling or unrelated donor following a reduced intensity conditioning regimen
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Development of GVHD Within 1 Year of BMT
Time Frame: 1 year
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GVHD is assessed by physical exam, bloodwork and biopsy.
|
1 year
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Engraftment at 1 Year Post BMT.
Time Frame: 1 year
|
Measurement of total PBMC chimerism
|
1 year
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Incidence of Grade 2-4 Acute GVHD.
Time Frame: 100 days
|
100 days
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Lakshmanan Krishnamurti, MD, Children's Hospital Medical Center, Cincinnati
Study record dates
Study Major Dates
Study Start
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ESTIMATE)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Hematologic Diseases
- Genetic Diseases, Inborn
- Anemia
- Anemia, Hemolytic, Congenital
- Anemia, Hemolytic
- Anemia, Sickle Cell
- Thalassemia
- Hemoglobinopathies
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Enzyme Inhibitors
- Antirheumatic Agents
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Myeloablative Agonists
- Dermatologic Agents
- Antifungal Agents
- Calcineurin Inhibitors
- Fludarabine
- Busulfan
- Cyclosporine
- Cyclosporins
Other Study ID Numbers
- IRB #0504048
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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