Sickle Cell DiseaseNCT00427661
A Pilot Study of HSCT for Patients With High-risk Hemoglobinopathy Using a Nonmyeloablative Preparative Regimen
A study testing Busulfan; Fludarabine; cyclosporine A and MMF in people with Sickle Cell Disease and Thalassemia, run by University of Pittsburgh at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 3 to 35 years
- Conditions the study is for
- Sickle Cell Disease, Thalassemia, Hemoglobinopathies
- What is being tested?
- Busulfan; Fludarabine; cyclosporine A and MMF
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 8 participants
- Where
- 1 siteUnited States
- Study dates
- Jun 2002to May 2014
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 3 to 35 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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,
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- 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.
Who cannot join
- 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.
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- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Children's Hospital of Pittsburgh
Pittsburgh, Pennsylvania, 15213
About this study
Official title: 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.
Read more
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.
Read the detailed description
Severe hemoglobinopathies such as sickle cell disease (SCD) and Thalassemia are associated with considerable morbidity, organ damage and premature mortality. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only therapy that can cure a hemoglobinopathy. The applicability of HSCT for hemoglobinopathies is limited by the paucity of suitable donors, and risk of early regimen-related toxicity and the late effects. Reduction of the dose of myelotoxic drugs in preparative regimens prior to HSCT has the potential to increase the applicability of this curative option for patients with hemoglobinopathies. We hypothesize that a preparative regimen that maximizes host immunosuppression without myeloablation will be well tolerated and sufficient for engraftment of donor hematopoietic stem cells in patients with severe hemoglobinopathies. The long term objective of this research is to develop novel, less toxic approaches to HSCT for patients with severe hemoglobinopathies. Specific aims: 1. To evaluate the safety and efficacy of a novel nontoxic nonmyeloablative approach to hematopoietic stem cell transplantation for hemoglobinopathies. 2. To optimize the immunosuppressive regimen for HSCT patients through a thorough understanding of the pharmacokinetics of Busulfan (BU) and Mycophenolic acid (MPA) 3. To determine the effect of partial or complete donor chimerism on cerebral vasculopathy in patients with SCD. 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. Subjects meeting eligibility criteria in whom an human leukocyte antigen matched, partially mismatched related or unrelated donor of bone marrow or umbilical cord blood will receive a HSCT after a nonmyeloablative preparative regimen consisting of BU, Fludarabine (FLU), total lymphoid radiation and Anti-Thymocyte globulin followed by prophylaxis against graft versus host disease with cyclosporine A and MMF. Patients will be studied for survival, cure of hemoglobinopathy, absence of severe regimen related toxicity and graft versus host disease. The relationship of engraftment, survival and Graft versus host disease to kinetics of lineage specific donor chimerism and area under the curve for Mycophenolic acid and Busulfan will be studied.
- Conditions
- Sickle Cell Disease, Thalassemia, Hemoglobinopathies
- Being tested
- Busulfan; Fludarabine; cyclosporine A and MMF
- Keywords
- Sickle Cell Disease, Thalassemia, Hemoglobinopathies
- Medical subject headings
- Anemia, Sickle Cell, Thalassemia, Hemoglobinopathies
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Busulfan; Fludarabine; cyclosporine A and MMFOther
Also called Busulfex, Fludara, Gengraf, CellCept
Hematopoietic stem cell transplantation from a matched sibling or unrelated donor following a reduced intensity conditioning regimen
| Study group | Role | What they receive |
|---|---|---|
| AHCT in High Risk SCD | Other | Intervention: Busulfan; Fludarabine; cyclosporine A and MMF Receives: Other: Busulfan; Fludarabine; cyclosporine A and MMF |
What is being measured
The primary outcome is the main question the study is designed to answer.
Development of GVHD Within 1 Year of BMT
GVHD is assessed by physical exam, bloodwork and biopsy.
Measured: 1 year
Engraftment at 1 Year Post BMT.
Measurement of total PBMC chimerism
Measured: 1 year
Secondary outcomes (1)
Incidence of Grade 2-4 Acute GVHD.
Measured: 100 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Jan 2007 (estimated)
- Study startJun 2002
- Primary completionMay 2014
- Study completionMay 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Sickle Cell DiseaseStudies of the same condition, open and under way.
- More trials run by University of PittsburghThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Pittsburgh
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Lakshmanan Krishnamurti, University of Pittsburgh
- Investigators
- Lakshmanan Krishnamurti, MD, Principal investigator, Children's Hospital Medical Center, Cincinnati
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00427661
- Sponsor's protocol ID
- IRB #0504048
- Status last verified
- Jul 2016
- First submitted
- 18 Jan 2007
- Last updated
- 18 Aug 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 18 Aug 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT00427661
- Acronym / sponsor ID
- IRB #0504048
- Conditions
- Sickle Cell Disease, Thalassemia, Hemoglobinopathies
- Keywords
- Sickle Cell Disease, Thalassemia, Hemoglobinopathies
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 8 participants (actual)
- Lead sponsor
- University of PittsburghUniversity, hospital or other
- Study start
- Jun 2002
- Primary completion
- May 2014 (actual)
- Study completion
- May 2014 (actual)
- First posted
- 29 Jan 2007 (estimated)
- Results
- Posted 18 Aug 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Severe hemoglobinopathies such as sickle cell disease (SCD) and Thalassemia are associated with considerable morbidity, organ damage and premature mortality. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only therapy that can cure a hemoglobinopathy. The applicability of HSCT for hemoglobinopathies is limited by the paucity of suitable donors, and risk of early regimen-related toxicity and the late effects. Reduction of the dose of myelotoxic drugs in preparative regimens prior to HSCT has the potential to increase the applicability of this curative option for patients with hemoglobinopathies. We hypothesize that a preparative regimen that maximizes host immunosuppression without myeloablation will be well tolerated and sufficient for engraftment of donor hematopoietic stem cells in patients with severe hemoglobinopathies. The long term objective of this research is to develop novel, less toxic approaches to HSCT for patients with severe hemoglobinopathies. Specific aims: 1. To evaluate the safety and efficacy of a novel nontoxic nonmyeloablative approach to hematopoietic stem cell transplantation for hemoglobinopathies. 2. To optimize the immunosuppressive regimen for HSCT patients through a thorough understanding of the pharmacokinetics of Busulfan (BU) and Mycophenolic acid (MPA) 3. To determine the effect of partial or complete donor chimerism on cerebral vasculopathy in patients with SCD. 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. Subjects meeting eligibility criteria in whom an human leukocyte antigen matched, partially mismatched related or unrelated donor of bone marrow or umbilical cord blood will receive a HSCT after a nonmyeloablative preparative regimen consisting of BU, Fludarabine (FLU), total lymphoid radiation and Anti-Thymocyte globulin followed by prophylaxis against graft versus host disease with cyclosporine A and MMF. Patients will be studied for survival, cure of hemoglobinopathy, absence of severe regimen related toxicity and graft versus host disease. The relationship of engraftment, survival and Graft versus host disease to kinetics of lineage specific donor chimerism and area under the curve for Mycophenolic acid and Busulfan will be studied.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| AHCT in High Risk SCD | Other | Other: Busulfan; Fludarabine; cyclosporine A and MMFIntervention: Busulfan; Fludarabine; cyclosporine A and MMF |
Who may qualify
- Ages
- 3 to 35 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (16 listed)
- 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:
- Second Transplants
Key exclusion criteria (23 listed)
- Patients with one or more of the following:
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Busulfan; Fludarabine; cyclosporine A and MMFAlso: Busulfex, Fludara, Gengraf, CellCeptHematopoietic stem cell transplantation from a matched sibling or unrelated donor following a reduced intensity conditioning regimen | Other | AHCT in High Risk SCD |
Primary outcome
Development of GVHD Within 1 Year of BMT
Time frame: 1 year
GVHD is assessed by physical exam, bloodwork and biopsy.
Engraftment at 1 Year Post BMT.
Time frame: 1 year
Measurement of total PBMC chimerism
1 secondary outcome
Incidence of Grade 2-4 Acute GVHD.
Time frame: 100 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Aug 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Lakshmanan Krishnamurti, MD principal investigator
Children's Hospital Medical Center, Cincinnati
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Busulfan; Fludarabine; cyclosporine A and MMF in people with Sickle Cell Disease and Thalassemia, run by University of Pittsburgh at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Aug 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 Aug 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Development of GVHD Within 1 Year of BMT (time frame: 1 year). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Aug 2016.