Bone Marrow TransplantationPhase 1NCT00968162
Sickle Cell Disease Conditioning for Bone Marrow Transplant
A Phase 1 study testing fludarabine in people with Bone Marrow Transplantation and Sickle Cell Disease, run by Emory University at 10 sites in United States.
Trial summary
Most bone marrow transplants for children with sickle cell disease are performed using high doses of two chemotherapy agents: busulfan and cyclophosphamide for the pre-transplant conditioning. This approach produces cure in most cases (approximately 95%). Read more about this study
- Who is it for?
- Ages Up to 18 years
- Conditions the study is for
- Bone Marrow Transplantation, Sickle Cell Disease
- What is being tested?
- fludarabine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 8 participants
- Where
- 10 sitesUnited States
- Study dates
- Feb 2009to 11 Jan 2016
- Phase
- Phase 1
- Are there results?
- None posted in the registry
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 Up to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Up to and including the age of 18 years at time of admission for transplant
- Hemoglobin SS, or hemoglobin S0 thalassemia
- HLA-identical sibling donor (any age) available without HgbSS, SC or S0 thalassemia. As an alternative, HLA identical sibling umbilical cord blood can be used as long as the unit has a pre-cryopreservation TNC dose of greater than 5.0 x 107 TNC/kg recipient weight.
- Clinically severe SCD, defined by one of the following:
- Previous clinical stroke, as evidenced by a neurological deficit lasting longer than 24 hours, which is accompanied by radiographic evidence of ischemic brain injury and cerebral vasculopathy.
- Asymptomatic cerebrovascular disease, as evidenced by one the following:
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- (i)Progressive silent cerebral infarction, as evidenced by serial MRI scans that demonstrate the development of a succession of lesions (at least two temporally discreet lesions, each measuring at least 3 mm in greatest dimension on the most recent scan) or the enlargement of a single lesion, initially measuring at least 3 mm). Lesions must be visible on T2-weighted MRI sequences.
- Cerebral arteriopathy, as evidenced by abnormal TCD testing (confirmed elevated velocities in any single vessel of TAMMV > 200 cm/sec for non-imaging TCD or TAMX > 185 cm/sec for imaging TCD) or by significant vasculopathy on MRA (greater than 50% stenosis of > 2 arterial segments or complete occlusion of any single arterial segment).
- Frequent (≥ 3 per year for preceding 2 years) painful vaso-occlusive episodes (defined as episode lasting ≥ 4 hours and requiring hospitalization or outpatient treatment with parenteral opioids). If patient is on hydroxyurea and its use has been associated with a decrease in the frequency of episodes, the frequency should be gauged from the 2 years prior to the start of this drug.
- Recurrent (≥ 3 in lifetime) acute chest syndrome events that have necessitated erythrocyte transfusion therapy.
- Any combination of ≥ 3 acute chest syndrome episodes and vaso-occlusive pain episodes (defined as above) yearly for 3 years. If patient is on hydroxyurea and its use has been associated with a decrease in the frequency of episodes, the frequency should be gauged from the 3 years prior to the start of this drug.
- Must have been evaluated and adequately counseled regarding treatment options for severe sickle cell disease by a pediatric hematologist.
Who cannot join
- Biopsy proven chronic active hepatitis, portal fibrosis (greater than score I), or cirrhosis, or serologic evidence of active hepatitis.
- SCD chronic lung disease stage III (see appendix 1).
- Severe renal dysfunction defined as < 50% of predicted normal GFR for age.
- Severe cardiac dysfunction defined as shortening fraction < 25%.
- Severe residual neurologic impairment other than hemiplegia alone, defined as full-scale IQ 70, quadriplegia or paraplegia, inability to ambulate, inability to communicate without assistive device, or any impairment resulting in decline of Lansky performance score to < 70%.
- CNS event occurring within 6 months prior to transplant.
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- Karnofsky or Lansky functional performance score < 70%.
- Confirmed HIV seropositivity.
- Patient with unspecified chronic toxicity serious enough to detrimentally affect the patient's capacity to tolerate bone marrow transplantation.
- Patient or patient's guardian(s) unable to understand the nature and risks inherent in the BMT process.
- History of lack of compliance with medical care that would jeopardize transplant course.
- Donor who for psychological, physiologic, or medical reasons is unable to tolerate a bone marrow harvest or receive general anesthesia.
- Donor is HIV infected.
- Donor is pregnant.
Trial locations and contacts
10 sites in 1 country.
10 sites in 1 country
United States10 sites
Children's Healthcare of Atlanta
Atlanta, Georgia, 30322
University of Alabama-Birmingham
Birmingham, Alabama
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, 27516
University of Texas Southwestern
Dallas, Texas
Wayne State University
Detroit, Michigan, 48202
University of Mississippi Medical Center
Jackson, Mississippi
Tulane University
New Orleans, Louisiana, 70112
All Children's Research Institute Inc.
St. Petersburg, Florida, 33701
Montefiore Medical Center
The Bronx, New York
Children's National Medical Center
Washington D.C., District of Columbia
About this study
Official title: Toward a Less Toxic Yet Highly Effective Conditioning Regimen in Allogeneic Hematopoietic Stem Cell Transplantation for Children and Adolescents With Severe Sickle Cell Disease: A Pilot Study
Most bone marrow transplants for children with sickle cell disease are performed using high doses of two chemotherapy agents: busulfan and cyclophosphamide for the pre-transplant conditioning. This approach produces cure in most cases (approximately 95%). It, however, has serious side effects, including seizures and infertility. The primary goal of this study is to determine how much we can lower the dosages of busulfan and cyclophosphamide by incorporating fludarabine, a safer chemotherapy agent, into conditioning. The secondary goal is to develop a better understanding of how bone marrow transplants cause neurologic problems like seizures.
Read the detailed description
Many children with sickle cell disease are severely affected by acute complications, especially stroke, recurrent and debilitating pain, or recurrent acute chest syndrome. As they become adolescents and young adults, patients with sickle cell disease often develop chronic problems, including renal disease, chronic lung disease and pulmonary hypertension. For children who have an HLA matched related donor, a hematopoietic stem cell transplant (HSCT), using bone marrow or cord blood is an effective cure; using the standard approach, which relies on high doses of busulfan (BU) and cyclophosphamide (CY) as well as anti-thymocyte globulin (ATG) for pre-transplant conditioning, the probability of event free survival is now approximately 95%. The standard approach, however, is frequently complicated by acute and often severe neurological events, such as seizure and encephalopathy, as well as hypogonadism. Circumstantial evidence suggests that sickle cell patients are predisposed to transplant related neurological toxicities by disease related cerebrovascular injury, and that the transplant process aggravates this injury, causing cerebral ischemia and, in turn, neurological toxicity. The high dose chemotherapy, which has been shown to induce endothelial injury, appears to be an important contributing factor. The role of high dose chemotherapy in transplant related neurotoxicity needs to be more firmly established. The role of high dose alkylating agents in gonadal injury has been well established. Fludarabine, a non-vasculopathic, non-gonadotoxic agent, amplifies the engraftment promoting effects of Cy; in an effort to lessen the incidence of transplant related neurotoxicity and gonadotoxicity, we will conduct a pilot study in which fludarabine is added to BuCyATG for conditioning, and the dose of Bu and Cy are reduced using a stepwise de-escalation schema. This study will serve as a forerunner to larger trial designed to test the safety and efficacy of a reduced toxicity BuFluCyATG regimen. Central Hypothesis: A safer approach to hematopoietic stem cell transplantation (HSCT) can be developed for children with sickle cell disease without compromising efficacy. Specific Aims: 1) To begin to develop a reduced dose busulfan and cyclophosphamide based conditioning regimen for children with sickle cell disease that still achieves sustained engraftment at least 90% of the time, by conducting a pilot trial, in which the standard busulfan, cyclophosphamide and anti-thymocyte globulin conditioning regimen is modified by adding fludarabine, a non-vasculopathic and non-gonadotoxic, yet highly immunosuppressive agent, in order to determine the feasibility of reducing the total dose of cyclophosphamide from its present standard of 200 mg/kg to 90 mg/kg and the busulfan from its present standard of 12.8 mg/kg (IV) to 6.4 mg/kg, using a four step dose de-escalation schema.. 2) a) To begin to assess the vascular, and more specifically, the cerebrovascular effects of pre-transplant, high-dose busulfan and cyclophosphamide in children with sickle cell disease by obtaining preliminary estimates of longitudinal changes in the blood levels biomarkers of endothelial dysfunction and inflammation (endothelin-1, von Willebrand factor antigen, C-reactive protein, Il-8 thrombin-antithrombin (TAT) complexes) and in the changes in two MRI biomarkers-cortical thickness measurement and diffusion tensor imaging.. b) To begin to assess the long-term effects of replacing sickle erythrocytes with normal erythrocytes (by HSCT) on the vasculature and cerebrovasculature, using the same tests. These estimates will help us to calculate a sample size and refine our testing for the second study.
- Conditions
- Bone Marrow Transplantation, Sickle Cell Disease
- Being tested
- fludarabine
- Keywords
- Bone Marrow Transplant, Sickle Cell Disease
- Medical subject headings
- Anemia, Sickle Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
fludarabineDrug
Conduct a pilot trial using a transplant protocol, in which the standard busulfan, cyclophosphamide and anti-thymocyte globulin conditioning regimen is modified by adding fludarabine, a highly immunosuppressive agent, in order to determine the feasibility of reducing the total dose of cyclophosphamide from its present standard of 200 mg/kg to 90 mg/kg and of busulfan from its present standard of 12.8 mg/kg (IV) to 6.4 mg/kg, using a four step dose de-escalation schema.
| Study group | Role | What they receive |
|---|---|---|
| Dose de-escalation | Experimental | Not described Receives: Drug: fludarabine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Modify the standard dose of busulfan, cyclophosphamide and anti-thymocyte globulin conditioning regimen by adding fludarabine in order to determine the feasibility of reducing the total dose of cyclophosphamide from its present standard of 200 mg/kg.
Measured: 1 year after last patient enrolled
Secondary outcomes (1)
To gain insight into the processes that give rise to neurologic problems following bone marrow transplantation and to develop surrogate outcomes.
Measured: 1 year after last patient enrolled
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Aug 2009 (estimated)
- Study startFeb 2009
- Primary completionMar 2014
- Study completion11 Jan 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Bone Marrow TransplantationStudies of the same condition, open and under way.
- More trials run by Emory UniversityThe 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 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- Emory University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, John Horan, Emory University
- Investigators
- John Horan, MD, Principal investigator, Emory University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00968162
- Sponsor's protocol ID
- IRB00011048
- Other IDs
- BMT for SCD
- Status last verified
- Jul 2017
- First submitted
- 11 Aug 2009
- Last updated
- 25 Jul 2017
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 25 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Toward a Less Toxic Yet Highly Effective Conditioning Regimen in Allogeneic Hematopoietic Stem Cell Transplantation for Children and Adolescents With Severe Sickle Cell Disease: A Pilot Study
- ClinicalTrials.gov ID
- NCT00968162
- Acronym / sponsor ID
- IRB00011048
- Conditions
- Bone Marrow Transplantation, Sickle Cell Disease
- Keywords
- Bone Marrow Transplant, Sickle Cell Disease
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 8 participants (actual)
- Lead sponsor
- Emory UniversityUniversity, hospital or other
- Study start
- Feb 2009
- Primary completion
- Mar 2014 (actual)
- Study completion
- 11 Jan 2016 (actual)
- First posted
- 28 Aug 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Most bone marrow transplants for children with sickle cell disease are performed using high doses of two chemotherapy agents: busulfan and cyclophosphamide for the pre-transplant conditioning. This approach produces cure in most cases (approximately 95%). It, however, has serious side effects, including seizures and infertility. The primary goal of this study is to determine how much we can lower the dosages of busulfan and cyclophosphamide by incorporating fludarabine, a safer chemotherapy agent, into conditioning. The secondary goal is to develop a better understanding of how bone marrow transplants cause neurologic problems like seizures.
Detailed description
Many children with sickle cell disease are severely affected by acute complications, especially stroke, recurrent and debilitating pain, or recurrent acute chest syndrome. As they become adolescents and young adults, patients with sickle cell disease often develop chronic problems, including renal disease, chronic lung disease and pulmonary hypertension. For children who have an HLA matched related donor, a hematopoietic stem cell transplant (HSCT), using bone marrow or cord blood is an effective cure; using the standard approach, which relies on high doses of busulfan (BU) and cyclophosphamide (CY) as well as anti-thymocyte globulin (ATG) for pre-transplant conditioning, the probability of event free survival is now approximately 95%. The standard approach, however, is frequently complicated by acute and often severe neurological events, such as seizure and encephalopathy, as well as hypogonadism. Circumstantial evidence suggests that sickle cell patients are predisposed to transplant related neurological toxicities by disease related cerebrovascular injury, and that the transplant process aggravates this injury, causing cerebral ischemia and, in turn, neurological toxicity. The high dose chemotherapy, which has been shown to induce endothelial injury, appears to be an important contributing factor. The role of high dose chemotherapy in transplant related neurotoxicity needs to be more firmly established. The role of high dose alkylating agents in gonadal injury has been well established. Fludarabine, a non-vasculopathic, non-gonadotoxic agent, amplifies the engraftment promoting effects of Cy; in an effort to lessen the incidence of transplant related neurotoxicity and gonadotoxicity, we will conduct a pilot study in which fludarabine is added to BuCyATG for conditioning, and the dose of Bu and Cy are reduced using a stepwise de-escalation schema. This study will serve as a forerunner to larger trial designed to test the safety and efficacy of a reduced toxicity BuFluCyATG regimen. Central Hypothesis: A safer approach to hematopoietic stem cell transplantation (HSCT) can be developed for children with sickle cell disease without compromising efficacy. Specific Aims: 1) To begin to develop a reduced dose busulfan and cyclophosphamide based conditioning regimen for children with sickle cell disease that still achieves sustained engraftment at least 90% of the time, by conducting a pilot trial, in which the standard busulfan, cyclophosphamide and anti-thymocyte globulin conditioning regimen is modified by adding fludarabine, a non-vasculopathic and non-gonadotoxic, yet highly immunosuppressive agent, in order to determine the feasibility of reducing the total dose of cyclophosphamide from its present standard of 200 mg/kg to 90 mg/kg and the busulfan from its present standard of 12.8 mg/kg (IV) to 6.4 mg/kg, using a four step dose de-escalation schema.. 2) a) To begin to assess the vascular, and more specifically, the cerebrovascular effects of pre-transplant, high-dose busulfan and cyclophosphamide in children with sickle cell disease by obtaining preliminary estimates of longitudinal changes in the blood levels biomarkers of endothelial dysfunction and inflammation (endothelin-1, von Willebrand factor antigen, C-reactive protein, Il-8 thrombin-antithrombin (TAT) complexes) and in the changes in two MRI biomarkers-cortical thickness measurement and diffusion tensor imaging.. b) To begin to assess the long-term effects of replacing sickle erythrocytes with normal erythrocytes (by HSCT) on the vasculature and cerebrovasculature, using the same tests. These estimates will help us to calculate a sample size and refine our testing for the second study.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Dose de-escalation | Experimental | Drug: fludarabine |
Who may qualify
- Ages
- Up to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (12 listed)
- Up to and including the age of 18 years at time of admission for transplant
- Hemoglobin SS, or hemoglobin S0 thalassemia
- HLA-identical sibling donor (any age) available without HgbSS, SC or S0 thalassemia. As an alternative, HLA identical sibling umbilical cord blood can be used as long as the unit has a pre-cryopreservation TNC dose of greater than 5.0 x 107 TNC/kg recipient weight.
- Clinically severe SCD, defined by one of the following:
- (i)Progressive silent cerebral infarction, as evidenced by serial MRI scans that demonstrate the development of a succession of lesions (at least two temporally discreet lesions, each measuring at least 3 mm in greatest dimension on the most recent scan) or the enlargement of a single lesion, initially measuring at least 3 mm). Lesions must be visible on T2-weighted MRI sequences.
Key exclusion criteria (14 listed)
- Biopsy proven chronic active hepatitis, portal fibrosis (greater than score I), or cirrhosis, or serologic evidence of active hepatitis.
- SCD chronic lung disease stage III (see appendix 1).
- Severe renal dysfunction defined as < 50% of predicted normal GFR for age.
- Severe cardiac dysfunction defined as shortening fraction < 25%.
- Severe residual neurologic impairment other than hemiplegia alone, defined as full-scale IQ 70, quadriplegia or paraplegia, inability to ambulate, inability to communicate without assistive device, or any impairment resulting in decline of Lansky performance score to < 70%.
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 |
|---|---|---|
| fludarabineConduct a pilot trial using a transplant protocol, in which the standard busulfan, cyclophosphamide and anti-thymocyte globulin conditioning regimen is modified by adding fludarabine, a highly immunosuppressive agent, in order to determine the feasibility of reducing the total dose of cyclophosphamide from its present standard of 200 mg/kg to 90 mg/kg and of busulfan from its present standard of 12.8 mg/kg (IV) to 6.4 mg/kg, using a four step dose de-escalation schema. | Drug | Dose de-escalation |
Primary outcome
Modify the standard dose of busulfan, cyclophosphamide and anti-thymocyte globulin conditioning regimen by adding fludarabine in order to determine the feasibility of reducing the total dose of cyclophosphamide from its present standard of 200 mg/kg.
Time frame: 1 year after last patient enrolled
1 secondary outcome
To gain insight into the processes that give rise to neurologic problems following bone marrow transplantation and to develop surrogate outcomes.
Time frame: 1 year after last patient enrolled
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Jul 2017.
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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.
John Horan, MD principal investigator
Emory University
10 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing fludarabine in people with Bone Marrow Transplantation and Sickle Cell Disease, run by Emory University at 10 sites 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 12 inclusion and 14 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 25 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 10 sites 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.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Modify the standard dose of busulfan, cyclophosphamide and anti-thymocyte globulin conditioning regimen by adding fludarabine in order to determine the feasibility of reducing the total dose of cyclophosphamide from its present standard of 200 mg/kg. (time frame: 1 year after last patient enrolled). 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 25 Jul 2017.