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A Study Evaluating the Efficacy and Safety of LentiGlobin BB305 Drug Product in Beta-Thalassemia Major and Sickle Cell Disease

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. Identifier: NCT02151526
Recruitment Status : Completed
First Posted : May 30, 2014
Last Update Posted : June 12, 2019
Information provided by (Responsible Party):
bluebird bio

Brief Summary:
This is a Phase 1/2, open label, safety, and efficacy study of the administration of LentiGlobin BB305 Drug Product to subjects with either beta-thalassemia major or severe sickle cell disease (SCD).

Condition or disease Intervention/treatment Phase
Beta-Thalassemia Major Sickle Cell Disease Genetic: LentiGlobin BB305 Drug Product Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 7 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Open Label Study Evaluating the Safety and Efficacy of Gene Therapy of the Beta-Hemoglobinopathies (Sickle Cell Disease and Beta-Thalassemia Major) by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With a Lentiviral Beta-A-T87Q Globin Vector (LentiGlobin BB305 Drug Product)
Study Start Date : July 2013
Actual Primary Completion Date : February 26, 2019
Actual Study Completion Date : February 26, 2019

Arm Intervention/treatment
Experimental: LentiGlobin BB305 Drug Product
LentiGlobin BB305 Drug Product (autologous CD34+ hematopoietic stem cells transduced with LentiGlobin BB305 lentiviral vector encoding the human beta-A-T87Q-globin gene)
Genetic: LentiGlobin BB305 Drug Product
  • autologous CD34+ hematopoietic stem cells (HSCs) transduced with the LentiGlobin BB305 lentiviral vector encoding the human beta-A-T87Q globin gene
  • Subjects with beta-thalassemia major will undergo HSC procurement by bone marrow harvest or apheresis after mobilization with filgrastim, a granulocyte-colony stimulating factor (G-CSF), alone or in combination with plerixafor, as decided by the clinical transplant team.
  • Stem cell mobilization by is contraindicated in sickle cell disease (SCD), as it could induce a sickle cell crisis; thus, procurement of HSCs for subjects with severe SCD will be conducted by bone marrow harvest.

Primary Outcome Measures :
  1. Success and kinetics of hematopoietic stem cell (HSC) engraftment [ Time Frame: 1-24 months post-transplant ]
  2. Incidence of transplant related mortality through 100 days post treatment [ Time Frame: 1-24 months post-transplant ]
  3. Overall survival [ Time Frame: 1-24 months post-transplant ]
  4. Detection of vector derived replication-competent lentivirus (RCL) in any subject [ Time Frame: 1-24 months post-transplant ]
  5. Characterization of events of insertional mutagenesis leading to clonal dominance or leukemia [ Time Frame: 1-24 months post-transplant ]
  6. Monitoring of laboratory parameters and frequency and severity of clinical AEs [ Time Frame: 1-24 months post-transplant ]
    AEs assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03.

Secondary Outcome Measures :
  1. Quantify gene transfer efficiency and expression by evaluation [ Time Frame: 1-24 months post-transplant ]
    Therapeutic globin expression, as measured by assessing the ratio of beta A-T87Q-globin to alpha-globin in whole blood, as well as the amount of beta A-T87Q-globin as a fraction of all beta-chains in whole blood

  2. Quantify gene transfer efficiency and expression by evaluation [ Time Frame: 1-24 months post-transplant ]
    Average vector copy number (VCN) in cell populations from peripheral blood and bone marrow containing the integrated LentiGlobin BB305 lentiviral vector.

  3. Efficacy [ Time Frame: 1-24 months post-transplant ]
    For all subjects, red blood cell (RBC) transfusion requirements (measured in milliliters [mL] per kilogram [kg]) per month and per year post transplant

  4. Efficacy [ Time Frame: 1-24 months post-transplant ]
    For sickle cell disease (SCD) subjects only, vaso-occlusive crisis (VOC) and acute chest syndrome (ACS) events in each subject compared with the 2 year pre-treatment period

Information from the National Library of Medicine

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Ages Eligible for Study:   5 Years to 35 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Be between 5 and 35 years of age, inclusive.
  2. Have severe sickle cell disease (SCD) or transfusion dependent beta-thalassemia major, regardless of the genotype with the diagnosis confirmed by Hb studies. Transfusion dependence is defined as requiring at least 100 mL/kg/year of packed red blood cells (pRBCs).
  3. Be eligible for allogeneic HSC transplant based on institutional medical guidelines, but without a matched related donor.
  4. Have been treated and followed for at least the past 2 years in a specialized center that maintained detailed medical records, including transfusion history.

    Subjects with severe SCD also must:

  5. Have failed to achieve adequate clinical benefit following hydroxyurea treatment with sufficient dosage, for at least 4 months unless this treatment was not indicated or not well tolerated.
  6. Have 1 or more of the following poor prognostic risk factors:

    • Recurrent vaso occlusive crises (at least 2 episodes in the preceding year or in the year prior to start of a regular transfusion program).
    • Presence of any significant cerebral abnormality on magnetic resonance imaging (MRI) (such as stenosis or occlusions).
    • Stroke without any severe cognitive disability.
    • Osteonecrosis of 2 or more joints.
    • Anti-erythrocyte alloimmunization (>2 antibodies).
    • Presence of sickle cell cardiomyopathy documented by Doppler echocardiography.
    • Acute chest syndrome (at least 2 episodes) defined by an acute event with pneumonia-like symptoms (e.g., cough, fever [>38.5°C], acute dyspnea, expectoration, chest pain, findings upon lung auscultation, tachypnea, or wheezing) and the presence of a new pulmonary infiltrate. Subjects with a chronic oxygen saturation <90% (excluding periods of SCD crisis) or carbon monoxide diffusing capacity (DLco) less than 60% in the absence of an infection should not be included in the study.

Exclusion Criteria:

  1. Availability of a willing 10 /10 matched HLA identical sibling hematopoietic cell donor, unless recommendation for enrollment is provided by the Comité de Surveillance following a review of the case.
  2. Clinically significant, active bacterial, viral, fungal, or parasitic infection.
  3. Contraindication to anesthesia for bone marrow harvesting.
  4. Any prior or current malignancy, myeloproliferative or immunodeficiency disorder.
  5. A white blood cell (WBC) count <3×10^9/L and/or platelet count <120×10^9/L.
  6. History of major organ damage including:

    • Liver disease, with transaminase levels >3× upper limit of normal.
    • This observation will not be exclusionary if a liver biopsy shows no evidence of extensive bridging fibrosis, cirrhosis, or acute hepatitis.
    • Histopathological evidence of extensive bridging fibrosis, cirrhosis, or acute hepatitis on liver biopsy.
    • Heart disease, with a left ventricular ejection fraction <25%.
    • Kidney disease with a calculated creatinine clearance <30% normal value.
    • Severe iron overload, which in the opinion of the physician is grounds for exclusion.
    • A cardiac T2* <10 ms by magnetic resonance imaging (MRI).
    • Evidence of clinically significant pulmonary hypertension requiring medical intervention.

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 identifier (NCT number): NCT02151526

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Paris, France
Sponsors and Collaborators
bluebird bio
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Study Director: Jean-Antoine Ribeil, MD bluebird bio, Inc.

Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: bluebird bio Identifier: NCT02151526     History of Changes
Other Study ID Numbers: HGB-205
2012-000695-42 ( EudraCT Number )
First Posted: May 30, 2014    Key Record Dates
Last Update Posted: June 12, 2019
Last Verified: June 2019
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hematologic Diseases
Genetic Diseases, Inborn