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Phase I/II Pilot Study of Mixed Chimerism to Treat Hemoglobinopathies

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00777231
Recruitment Status : Completed
First Posted : October 22, 2008
Last Update Posted : September 19, 2019
Sponsor:
Collaborators:
Duke University
St. Christopher's Hospital for Children
The Western Pennsylvania Hospital
University of Florida
Medical College of Pennsylvania Hospital
Hahnemann University Hospital
Information provided by (Responsible Party):
University of Louisville

Brief Summary:
The goal of this research study is to establish chimerism and avoid graft-versus-host disease in patients with Hemoglobinopathies to halt disease progression.

Condition or disease Intervention/treatment Phase
Sickle Cell Disease Biological: Enriched Hematopoetic Stem Cell Infusion Phase 1 Phase 2

Detailed Description:

Hematopoietic stem cell transplantation (HSCT) is emerging as a therapeutic alternative for patients with sickle cell disease. Conventional HSCT therapy has been limited to extremely high-risk hemoglobinopathy patients. Those patients who may be difficult to identify before end-organ damage develops.

Also, conventional HSCT is only available to the minority of candidates who have Histocompatibility Leukocyte Antigen (HLA) identical siblings to donate bone marrow or mobilized peripheral blood stem cells.

This study proposes two important improvements over conventional HSCT:

  • Donor peripheral blood or bone marrow will be processed via a new technology, which will deplete mature immune cells while enriching hematopoietic stem cells (HSC) and graft facilitating cells (FC).
  • A reduced intensity recipient conditioning regimen will be used to promote mixed allogeneic chimerism, as opposed to full donor chimerism, following HSCT.

These two elements may significantly improve the benefit:risk ratio of HSCT for patients with hemoglobinopathies. Stem cell transplantation may become a more feasible option for patients that do not have HLA-identical siblings that can donate stem cells. Also, transplantation may be offered to patients earlier in the disease progression, before end-organ damage occurs.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 9 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Intervention Model Description: No control group used, single group for each of four different disease groups
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Pilot Study of Mixed Chimerism to Treat Hemoglobinopathies
Study Start Date : January 2005
Actual Primary Completion Date : August 2010
Actual Study Completion Date : August 2013


Arm Intervention/treatment
Experimental: Sickle Cell Disease
Recipients treated with an enriched hematopoetic stem cell infusion
Biological: Enriched Hematopoetic Stem Cell Infusion
Enriched Hematopoetic Stem Cell Infusion

Experimental: Non-Malignant Disorders
Recipients treated with an enriched hematopoetic stem cell infusion
Biological: Enriched Hematopoetic Stem Cell Infusion
Enriched Hematopoetic Stem Cell Infusion

Experimental: Aplastic Anemia
Recipients treated with an enriched hematopoetic stem cell infusion
Biological: Enriched Hematopoetic Stem Cell Infusion
Enriched Hematopoetic Stem Cell Infusion

Experimental: Sickle Cell Disease : Extended Protocol
Recipients treated with an enriched hematopoetic stem cell infusion and Campath 1H conditioning
Biological: Enriched Hematopoetic Stem Cell Infusion
Enriched Hematopoetic Stem Cell Infusion




Primary Outcome Measures :
  1. Level of Donor Chimerism from Enriched Hematopoietic Stem Cell Engraftment [ Time Frame: From one month to three years ]
    Tests are done at key time points to monitor for donor chimerism by evaluating presence of bone marrow-derived hematopoietic stem cells.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

The following criteria are established to identify subjects with sickle cell disease (SCD) who have a high predicted morbidity and are at risk for early mortality. Subjects with S/S disease, S/C disease, Hemoglobin H disease, Alpha Thalassemia Major, Thalassemia Major (also known as Cooley's anemia) or S/B* thalassemia and one or more of the following medical complications will be eligible:

  • History of impaired neurological function and/or findings on Magnetic Resonance Image (MRI)/Magnetic Resonance Angiogram (MRA) that are associated with sickle cell disease
  • More than 1 episode of acute chest syndrome with stage I or II pulmonary disease
  • Osteonecrosis involving ≥ 2 joints
  • Sickle cell nephropathy as evidenced by a glomerular filtration rate of 30% - 50% of the predicted normal
  • Alloimmunization that is sufficient to interfere with the efficacy of chronic transfusion therapy
  • Chronic or recurrent priapism
  • Major visual impairment in one or both eyes with bilateral proliferative retinopathy
  • Persistent disabling pain (≥ 2 episodes per year) despite trials of chronic transfusion and/or hydroxyurea at recommended doses for at least 6 months duration

Additional General Criteria:

Subjects must also meet all of the following general inclusion criteria:

  • Subjects must have a related donor (identical or mismatched for 1, 2 or 3 HLA- A, HLA-B or HLA-DR loci).
  • Subjects must have adequate cardiopulmonary function as documented by a left ventricular ejection fraction ≥ 50% (or within normal limits per Institutional criteria) or a left ventricular shortening fraction Within normal limits (WNL) per Institutional criteria, without inotropic support. If Ejection fraction is 40-50%, the patient may be considered for participation if cleared by a Cardiologist.
  • Subjects must have adequate pulmonary function as documented by Diffusing capacity of the lung for carbon monoxide (DLCO) and Forced expiratory volume in 1 second (FEV1)

    • 50% predicted for age and size. If DLCO and FEV1 are between 40-50%, patient may be considered for participation if cleared by a Pulmonologist.
  • Subjects must have adequate hepatic function as demonstrated by a serum albumin ≥ 3.0 mg/dL, and serum glutamic pyruvic transaminase (SGPT) or serum glutamic oxaloacetic transaminase (SGOT) ≤ 2.5 times the upper limit of normal.
  • Subjects must have adequate renal function as demonstrated by a serum creatinine ≤ 1.5 mg/dL. If serum creatinine is ≥ 1.5 mg/dL, then a creatinine clearance test must be done and the result 50% of normal.
  • Subjects or legal guardians must give written informed consent, and subjects must assent where age and intellectually appropriate.
  • There are no age limits for this protocol.

Exclusion Criteria:

  • Uncontrolled infection or severe concomitant diseases, which in the judgment of the Principal Investigator, could not tolerate transplantation.
  • Severe impairment of functional performance as evidenced by a Karnofsky (patients ≥16 years old) or Lansky (children <16 years old) score <70%
  • Stage III or IV sickle cell pulmonary disease
  • Renal insufficiency (GFR < 25% of predicted normal for age)
  • Subjects with a positive human immunodeficiency virus (HIV) antibody test result
  • Subjects who are pregnant, as indicated by a positive serum human chorionic gonadotrophin (HCG) test
  • Subjects of childbearing potential who are not practicing adequate contraception as defined by the investigator at the site
  • Subjects must not have had previous radiation therapy that would preclude total body irradiation (as determined by a radiation oncologist).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00777231


Locations
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United States, Kentucky
University of Louisville
Louisville, Kentucky, United States, 40202
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27705
United States, Pennsylvania
St. Christopher's Hospital for Children
Pittsburgh, Pennsylvania, United States, 19134
Sponsors and Collaborators
University of Louisville
Duke University
St. Christopher's Hospital for Children
The Western Pennsylvania Hospital
University of Florida
Medical College of Pennsylvania Hospital
Hahnemann University Hospital
Investigators
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OverallOfficial: Suzanne T Ildstad, M.D. University of Louisville
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Responsible Party: University of Louisville
ClinicalTrials.gov Identifier: NCT00777231    
Other Study ID Numbers: ICT-7621-042298
549.02 ( Other Identifier: SCX UofL IRB )
430.98 ( Other Identifier: SC StC IRB )
445.98 ( Other Identifier: NM UofL IRB )
417.98 ( Other Identifier: AA WIRB )
Pro00009281 ( Other Identifier: SC DU IRB )
First Posted: October 22, 2008    Key Record Dates
Last Update Posted: September 19, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Louisville:
Sickle Cell
Stem Cell
Tolerance
Bone Marrow Transplant
Total Body Irradiation (TBI)
Apheresis
Aplastic Anemia
Hemoglobinopathies
Non Malignant
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Hemoglobinopathies
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Genetic Diseases, Inborn