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Trial record 2 of 3 for:    Recruiting Studies | Sickle Cell Thalassemia | Maryland, United States

Improving the Results of Bone Marrow Transplantation for Patients With Severe Congenital Anemias

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ClinicalTrials.gov Identifier: NCT00061568
Recruitment Status : Recruiting
First Posted : May 29, 2003
Last Update Posted : March 5, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Tracking Information
First Submitted Date  ICMJE May 29, 2003
First Posted Date  ICMJE May 29, 2003
Last Update Posted Date March 5, 2019
Actual Study Start Date  ICMJE July 16, 2004
Estimated Primary Completion Date January 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 1, 2018)
treatment success at one year, defined as full donor type hemoglobin on hemoglobin electrophoresis for patients with SCD and transfusion-independence for patients with thalassemia and DBA. [ Time Frame: 1 year ]
This trial is designed to estimate treatment success, which is anticipated to be about 80%. The study started with a sample size of 25 and this will allow us to estimate the success of engraftment. For example, if the estimated rate is .80, the 95% confidence interval would be approximately (.64, .96). This would allow us to rule out rate of treatment success of less than .64. If the estimated rate is .70, the 95% confidence interval would be approximately (.52, .88) and we could rule out rate of treatment success below .50. If the lower bound of the 95% confidence interval is raised to 0.7, the number of subjects needed to accrue with respect to success rate is listed below.
Original Primary Outcome Measures  ICMJE Not Provided
Change History Complete list of historical versions of study NCT00061568 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 1, 2018)
  • The level of chimerism required to maintain both graft survival as well as hematologic normalcy. The chimeric status of patients will be measured on days, +30, +60 and +100 by microsatellite analysis of the peripheral blood. More frequent monito... [ Time Frame: +30, +60, +100, 1year, 2year ]
  • The chimeric status of patients will be measured on days, +30, +60 and +100 by microsatellite analysis of the peripheral blood. More frequent monitoring may be required. [ Time Frame: days +30, +60, +100, 1 year, 2 year ]
  • Incidence of acute and chronic GVHD or relapse rate. GvHD or relapse together count together toward the combined endpoint for regimen failure [ Time Frame: 1 year ]
  • Disease free survival and overall survival [ Time Frame: 1 year, 2 year ]
  • Transplant related mortality [ Time Frame: 1 year, 2 year ]
  • Immunologic function post transplant [ Time Frame: 1 year ]
  • Quality of life and neuropsychologic function post transplant [ Time Frame: 1 year, 2 year ]
  • Effect of transplant on end organ function (e.g. renal function) [ Time Frame: 1 year ]
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Improving the Results of Bone Marrow Transplantation for Patients With Severe Congenital Anemias
Official Title  ICMJE Nonmyeloablative Allogeneic Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation For Severe Congenital Anemias Including Sickle Cell Disease (SCD) and Beta-Thalassemia
Brief Summary

People with severe congenital anemias, such as sickle cell anemia and beta-thalassemia, have been cured with bone marrow transplantation (BMT). The procedure, however, is limited to children younger than the age of 16 because the risks are lower for children than for adults.

The purpose of this study is to explore the use of a BMT regimen that, instead of chemotherapy, uses a low dose of radiation, combined with two immunosuppressive drugs. This type BMT procedure is described as nonmyeloablative, meaning that it does not destroy the patient s bone marrow. It is hoped that this type of BMT will be safe for patients normally excluded from the procedure because of their age and other reasons.

To participate in this study, patients must be between the ages of 18 and 65 and have a sibling who is a well-matched stem-cell donor. Beyond the standard BMT protocol, study participants will undergo additional procedures. The donor will receive G-CSF by injection for five days; then his or her stem cells will be collected and frozen one month prior to BMT. Approximately one month later, the patient will be given two immune-suppressing drugs, Campath 1-H and Sirolimus, as well as a single low dose of total body irradiation and then the cells from the donor will be infused.

Prior to their participation in this study, patients will undergo the following evaluations: a physical exam, blood work, breathing tests, heart-function tests, chest and sinus x-rays, and bone-marrow sampling.

Detailed Description

Nonmyeloablative allogeneic peripheral blood stem cell (PBSC) transplants are currently being investigated in phase I/II trials assessing engraftment, efficacy, and toxicity at a number of transplant centers. Preliminary data have shown a high rate of complete donor engraftment with a relatively low toxicity profile. The decreased risk of transplant-related complications associated with nonmyeloablative transplants expands eligibility to patients with nonmalignant hematological disorders curable by allogeneic transplantation; however, significant toxicity with current regimens persists including severe graft-versus-host-disease (GVHD) leading to significant morbidity and mortality. Moreover, mixed chimerism has been shown to be sufficient to induce clinical remissions in children with nonmalignant hematologic disorders undergoing conventional allogeneic transplantation. Therefore, newer regimens need to be developed that are more applicable to patients with non-malignant disorders in whom no graft vs. leukemia effect is needed, and where mixed chimerism is sufficient for disease amelioration.

In this protocol, we propose transplantation in patients with severe beta-globin disorders including sickle cell disease (SCD), and beta-thalassemia, considered at high risk for complications from or ineligible for standard BMT, with allogeneic PBSCs from an HLA identical sibling using a novel immunosuppressive regimen without myeloablation in an attempt to further decrease the transplant related morbidity/mortality. The low intensity nonmyeloablative conditioning regimen will consist of low dose radiation, Alemtuzumab (Campath ) and Sirolimus (Rapamune ) as a strategy to provide adequate immunosuppression to allow sufficient engraftment for clinical remission with a lower risk of GVHD development. T-cell replete, donor-derived, granulocyte colony stimulating factor (filgrastim, G-CSF) mobilized PBSCs will be used to establish hematopoietic and lymphoid reconstitution.

The primary endpoint of this study is treatment success at one year, defined as full donor type hemoglobin on hemoglobin electrophoresis for patients with SCD and transfusion-independence for patients with beta-thalassemia. Other end points include degree of donor-host chimerism necessary for long-term graft survival and disease amelioration, incidence of acute and chronic graft-vs-host disease (GVHD), incidence of graft rejection, transplant related morbidity, as well as disease-free and overall survival.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Congenital Hemolytic Anemia
  • Sickle Cell Disease
Intervention  ICMJE
  • Procedure: Peripheral blood hematopoietic progenitor cell (PBPC) transplant
    Peripheral blood hematopoietic progenitor cell (PBPC) transplant
  • Drug: Alemtuzumab
    Alemtuzumab
  • Procedure: Peripheral blood hematopoieticprogenitor cell Apherisis
    Donor-Peripheral blood hematopoieticprogenitor cell(PBPC) apheresis
  • Drug: Sirolimus
    Sirolimus
Study Arms  ICMJE
  • Experimental: 1
    donor
    Interventions:
    • Procedure: Peripheral blood hematopoietic progenitor cell (PBPC) transplant
    • Procedure: Peripheral blood hematopoieticprogenitor cell Apherisis
  • Experimental: 2
    recipient
    Interventions:
    • Procedure: Peripheral blood hematopoietic progenitor cell (PBPC) transplant
    • Drug: Alemtuzumab
    • Drug: Sirolimus
Publications *

*   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 8, 2017)
150
Original Enrollment  ICMJE
 (submitted: June 23, 2005)
25
Estimated Study Completion Date  ICMJE January 31, 2020
Estimated Primary Completion Date January 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:

RECIPIENTS:

Must fulfill one disease category from below:

DISEASE SPECIFIC:

Patients with sickle cell disease at high risk for disease related morbidity or mortality, defined by having irreversible end organ damage (A, B, C, D or E) or potentially reversible complication(s) not ameliorated by hydroxyurea (F):

A. Stroke defined as a clinically significant neurologic event that is accompanied by and infarct on cerebral MRI

OR

an abnormal trans-cranial Doppler examination ( greater than or equal to 200m/s);

OR

B. Sickle cell related renal insufficiency defined by a creatinine level greater than or equal to 1.5 times the upper limit of normal and kidney biopsy consistent with sickle cell nephropathy OR nephritic syndrome OR creatinine clearance less than 60mL/min/1.73m(2) for patients less than or equal to 16 years of age or less than 50mL/min for patients greater than or equal to 16 years of age OR requiring peritoneal or hemodialysis

OR

Age is less than or equal to 5 years of age with the upper limit of normal serum creatinine 0.8mg/dl

Age is greater than 5 years or less than or equal to 10 years of age with the upper limit of normal serum creatinine 1.0mg/dl

Age is greater than 10 years and less than or equal to 15 years of agethe the upper limit of normal serum creatinine 1.2mg/dl

Age greater than 15 years of age with the upper limit of normal serum creatinine 1.3mg/dl

C. Tricuspid regurgitant jet velocity (TRV) of greater than or equal to 2.5m/s in patients greater than or equal to 18 years of age at least 3 weeks after a vaso- occlusive crisis, OR

D. Recurrent tricorporal praipism defined as at least two episodes of an erection lasting greater than or equal to 4 hours involving the corpora cavernosa and corpus spongiosa, OR

E. Sickle hepatopathy defined as EITHER ferritin greater than 100mcg/L OR direct bilirubin greater than 0.4 mg/dL at baseline in patients greater than or equal to 18 years of age; OR

F. Any one of the below complications:

  1. Vaso-occlusive crisis:

    • Eligible for hydroxyurea at least 3 hospital admissions in the last year
    • Eligible for HSCT More than 1 hospital admission per year while on maximal tolerated dose of hydroxyurea
  2. Acute Chest Syndrome (ACS):

    • Eligible for hydroxyurea: 2 prior ACS while greater than 3 years of age and adequately treated for asthma
    • Eligible for HSCT: any ACS while on hydroxyurea*
  3. Osteonecrosis of 2 or more joints:

    • Eligible for hydroxyurea: And significantly affecting their quality of life by Karnofsky score 50-60
    • Eligible for HSCT: And on hydroxyurea* where total hemoglobin increase less than 1g/dL or fetal hemoglobin increases less than 2.5 time the baseline level
  4. Red cell alloimmunization:

    • Eligible for hydroxyurea: Transfusion dependent
    • Eligible for HSCT: Total hemoglobin increase less htan 1 g/dL while on hydroxyurea*

      • hydroxyurea at maximum tolerated dose

    Patients with beta-thalassemia who have grade 2 or 3 iron overload, determined by the presence of 2 or more of the following:

    • portal fibrosis by liver biopsy
    • inadequate chelation history (defined as failure to maintain adequate compliance with chelation with desferoxamine initiated within 18 months of the first transfusion and administered subcutaneously for 8-10 hours at least 5 days each week)
    • Hepatomegaly of greater than 2 cm below the costochondral margin

    NON-DISEASE SPECIFIC:

    • Ages greater than or equal to 4 years
    • 6/6 HLA matched family donor available
    • Ability to comprehend and willing to sign an informed consent, assent obtained from minors
    • Negative serum beta-HCG
    • Pediatric patients less than 16 years of age must decline myeloablative bone marrow transplantation

    DONOR:

    6/6 HLA identical family donor

    Weight greater than or equal to 20 kg (in so far that weight difference between recipient and donor does not exceed a reasonable likelihood of being able to obtain an adequate cell dose from the donor within two aphereses)

    Fit to receive G-CSF and give peripheral blood stem cells (adequate blood counts, stable blood pressure, and no history of stroke)

    Ability to comprehend and willing to sign an informed consent; assent obtained from minors

    EXCLUSION CRITERIA:

    RECIPIENT:

    (Any of the following would exclude the subject from participating)

    ECOG performance status of 3 or more or Lansky performance status of less than 40.

    Diffusion capacity of carbon monoxide (DLCO) less than 35% predicted. (corrected for hemoglobin and alveolar volume)

    Baseline oxygen saturation or less than 85 % or PaOa2 less than 70

    Left ventricular ejection fraction: less than 35% estimated by ECHO.

    Transaminases greater than 5 times the upper limit of normal for age

    Evidence of uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms) within one month prior to starting the conditioning regimen

    Major anticipated illness or organ failure incompatible with survival from PBSC transplant.

    Pregnant or lactating

    Major ABO mismatch

    DONOR:

    (Any of the following would exclude the donor from participating)

    Pregnant or breastfeeding

    HIV positive

    Hemoglobin S greater than or equal to 50%, or beta-thalassemia intermedia

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 65 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Stephanie N Helwing, R.N. (301) 827-0448 stephanie.helwing@nih.gov
Contact: John F Tisdale, M.D. (301) 402-6497 johntis@mail.nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00061568
Other Study ID Numbers  ICMJE 030170
03-H-0170
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
Study Sponsor  ICMJE National Heart, Lung, and Blood Institute (NHLBI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: John F Tisdale, M.D. National Heart, Lung, and Blood Institute (NHLBI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date February 26, 2019

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