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A Study of the Efficacy and Safety of Hematopoietic Stem Cells Transduced With Lenti-D Lentiviral Vector for the Treatment of Cerebral Adrenoleukodystrophy (CALD)

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ClinicalTrials.gov Identifier: NCT01896102
Recruitment Status : Completed
First Posted : July 11, 2013
Last Update Posted : April 26, 2021
Sponsor:
Information provided by (Responsible Party):
bluebird bio

Tracking Information
First Submitted Date  ICMJE March 22, 2013
First Posted Date  ICMJE July 11, 2013
Last Update Posted Date April 26, 2021
Actual Study Start Date  ICMJE August 21, 2013
Actual Primary Completion Date March 26, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 14, 2021)
  • Percentage of Participants who are Alive and Have None of the 6 Major Functional Disabilities (MFDs) at Month 24 [ Time Frame: Month 24 post-transplant ]
    The MFDs are loss of communication, cortical blindness, tube feeding, total incontinence, wheelchair dependence, complete loss of voluntary movement.
  • Percentage of Participants who Experience Either Acute (Greater than or Equal [>or=] Grade II) or Chronic Graft Versus Host Disease (GVHD) by Month 24 [ Time Frame: Month 24 post-transplant ]
Original Primary Outcome Measures  ICMJE
 (submitted: July 8, 2013)
Assessment of the proportion of subjects who have no Major Functional Disabilities (MFDs) as determined by key measures in the Neurological Function Score (NFS). [ Time Frame: 24 months (±2 months) post-transplant ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 14, 2021)
  • Percentage of Participants Without Gadolinium Enhancement (GdE) at Month 24 [ Time Frame: Month 24 post-transplant ]
    Percentage of participants without Gadolinium Enhancement (that is [i.e.,] negative for Gadolinium Enhancement [GdE-]) on Magnetic Resonance Imaging (MRI).
  • Time to Sustained Resolution of Gadolinium Positivity on MRI [ Time Frame: Month 24 post-transplant ]
    Sustained is defined as gadolinium resolution without a subsequent evaluation indicating gadolinium positivity.
  • Change in total Neurologic Function Score (NFS) from Baseline to Month 24 post-transplant [ Time Frame: Baseline, Month 24 post-transplant ]
    The NFS is a 25-point score used to evaluate the severity of gross neurologic dysfunction in CALD by scoring 15 symptoms (functional domains) across 6 categories. Listed here are the 15 symptoms followed by their maximal score out of 25 points: a) Hearing / auditory processing problems-1, b) Aphasia / apraxia-1, c) Loss of communication-3, d) Vision impairment /field cut-1, e) Cortical blindness-2, f) Swallowing / other central nervous system (CNS) dysfunctions-2, g) Tube feeding-2, h) Running difficulties / hyperreflexia-1, i) Walking difficulties / spasticity / spastic gait (no assistance)-1, j) Spastic gait (needs assistance)-2, k) Wheelchair dependence-2, l) Complete loss of voluntary movement-3, m) Episodes of incontinence -1, n) Total incontinence-2, o) Nonfebrile seizures-1. A score of "0" denotes absence of clinical signs of cerebral disease. Maximal signs within a domain score the total of all grades within that domain.
  • Major Functional Disability (MFD)-free Survival Over Time [ Time Frame: up to Month 24 (+or- 1 month) post-transplant ]
    MFD-free survival over time is defined as time from drug product infusion to either second transplant, MFD, or death due to any cause, whichever occurs first.
  • Overall Survival [ Time Frame: up to Month 24 (+or- 1 month) post-transplant ]
  • Percentage of Participants with Neutrophil Engraftment by 42 days Post-drug Product Infusion [ Time Frame: 42 days post-drug product infusion ]
  • Time to Neutrophil Engraftment Post-drug Product Infusion [ Time Frame: 42 days post-drug product infusion ]
  • Percentage of Participants with Platelet Engraftment by Month 24 [ Time Frame: Month 24 post-drug product infusion ]
  • Time to Platelet Engraftment Post-drug Product Infusion [ Time Frame: up to Month 24 post-drug product infusion ]
  • Percentage of Participants with Loss of Engraftment Post-drug Product Infusion by Month 24 [ Time Frame: Month 24 post-drug product infusion ]
  • Percentage of Participants who Undergo a Subsequent Hematopoietic Stem Cell (HSC) Infusion by Month 24 [ Time Frame: Month 24 post-transplant ]
  • Percentage of Participants with Transplant-related Mortality Through 100 and 365 days Post-drug Product Infusion [ Time Frame: Through 100 and 365 days post-drug product infusion ]
  • Percentage of Participants with Adverse Events (AEs) in Selected Categories [ Time Frame: Month 24 post-transplant ]
    Percentage of participants with severity of clinical AEs greater than or equal to (> or =) Grade 3 AEs, all drug-product related AEs, all serious adverse events (SAEs), AEs > or = Grade 3 infections by Month 24.
  • Percentage of Participants with Potentially Clinical Significant Changes in Laboratory Parameters by Month 24 [ Time Frame: Month 24 post-transplant ]
    Laboratory parameters will include hematology, clinical chemistry, and liver function tests.
  • Percentage of Participants with Greater Than or Equal to (>or=) Grade II Acute Graft Versus Host Disease (GVHD) by Month 24 [ Time Frame: Month 24 post-transplant ]
  • Percentage of Participants with Chronic Graft Versus Host Disease (GVHD) by Month 24 [ Time Frame: Month 24 post-transplant ]
  • Number of Emergency Room Visits (Post-Neutrophil Engraftment) by Month 24 [ Time Frame: Month 24 post-transplant ]
  • Number of In-patient Hospitalizations (Post-Neutrophil Engraftment) by Month 24 [ Time Frame: Month 24 post-transplant ]
  • Duration of in-patient Hospitalizations (Post-Neutrophil Engraftment) by Month 24 [ Time Frame: Month 24 post-transplant ]
  • Number of Intensive Care Units (ICU) Stays (Post-neutrophil Engraftment) by Month 24 [ Time Frame: Month 24 post-transplant ]
  • Duration of Intensive Care Units (ICU) Stays (Post-neutrophil Engraftment) by Month 24 [ Time Frame: Month 24 post-transplant ]
  • Number of Participants in which Vector-Derived Replication Competent Lentivirus (RCL) is Detected by Month 24 [ Time Frame: Month 24 post-transplant ]
  • Number of Participants with Insertional Oncogenesis by Month 24 [ Time Frame: Month 24 post-transplant ]
    Insertional oncogenesis including Myelodysplasia, Leukemia, Lymphoma by Month 24.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 8, 2013)
  • Change from Baseline in Loes score as measured by brain MRI. [ Time Frame: 24 mon (±2 months) post-transplant ]
  • Change from Baseline in NFS. [ Time Frame: 24 mon (± 2 months) post-transplant ]
  • Resolution of gadolinium positivity on MRI [ Time Frame: 24 mon (± 2 months) post-transplant ]
    Proportion of subjects who demonstrate resolution of gadolinium positivity on MRI (i.e., who are gadolinium negative) at 24 months (± 2 months) post-transplant.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of the Efficacy and Safety of Hematopoietic Stem Cells Transduced With Lenti-D Lentiviral Vector for the Treatment of Cerebral Adrenoleukodystrophy (CALD)
Official Title  ICMJE A Phase 2/3 Study of the Efficacy and Safety of Hematopoietic Stem Cells Transduced With Lenti-D Lentiviral Vector for the Treatment of Cerebral Adrenoleukodystrophy (CALD)
Brief Summary This trial will assess the efficacy and safety of autologous cluster of differentiation 34 (CD34+) hematopoietic stem cells, transduced ex-vivo with Lenti-D lentiviral vector, for the treatment of cerebral adrenoleukodystrophy (CALD). A participant's blood stem cells will be collected and modified (transduced) using the Lenti-D lentiviral vector encoding human adrenoleukodystrophy protein. After modification (transduction) with the Lenti-D lentiviral vector, the cells will be transplanted back into the participant following myeloablative conditioning.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Cerebral Adrenoleukodystrophy (CALD)
Intervention  ICMJE Genetic: Lenti-D Drug Product
Lenti-D Drug Product (autologous CD34+ cell-enriched population that contains cells transduced with Lenti-D lentiviral vector encoding human adrenoleukodystrophy protein, suspended in a cryopreservative solution) is administered intravenously. Lenti-D Drug Product is administered by IV infusion following myeloablative conditioning with busulfan and cyclophosphamide.
Other Names:
  • elivaldogene autotemcel
  • eli-cel
Study Arms  ICMJE Experimental: Lenti-D Drug Product
Intervention: Genetic: Lenti-D Drug Product
Publications * Eichler F, Duncan C, Musolino PL, Orchard PJ, De Oliveira S, Thrasher AJ, Armant M, Dansereau C, Lund TC, Miller WP, Raymond GV, Sankar R, Shah AJ, Sevin C, Gaspar HB, Gissen P, Amartino H, Bratkovic D, Smith NJC, Paker AM, Shamir E, O'Meara T, Davidson D, Aubourg P, Williams DA. Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy. N Engl J Med. 2017 Oct 26;377(17):1630-1638. doi: 10.1056/NEJMoa1700554. Epub 2017 Oct 4.

*   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 Completed
Actual Enrollment  ICMJE
 (submitted: February 17, 2020)
32
Original Estimated Enrollment  ICMJE
 (submitted: July 8, 2013)
15
Actual Study Completion Date  ICMJE March 26, 2021
Actual Primary Completion Date March 26, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Informed consent is obtained from a competent custodial parent or guardian with legal capacity to execute a local institutional review board (IRB)/Independent Ethics Committee (IEC) approved consent (informed assent will be sought from capable participants, in accordance with the directive of the IRB/IEC and with local requirements).
  2. Males aged 17 years and younger, at the time of parental/guardian consent and, where appropriate, participant assent.
  3. Active cerebral adrenoleukodystrophy (ALD) as defined by:

    1. Elevated very long chain fatty acids (VLCFA) values, and
    2. Active CNS disease established by central radiographic review of brain magnetic resonance imaging (MRI) demonstrating:

    i. Loes score between 0.5 and 9 (inclusive) on the 34-point scale, and ii. Gadolinium enhancement on MRI of demyelinating lesions.

  4. NFS less than or equal to (<or=) 1.

Exclusion Criteria:

  1. Receipt of an allogeneic transplant or gene therapy.
  2. Availability of a willing 10/10 HLA-matched sibling donor (excluding female heterozygotes).
  3. Use of statins, Lorenzo's Oil, or dietary regimens used to lower very long chain fatty acids (VLCFA) levels. Note: participants must discontinue use of these medications at time of consent.
  4. Receipt of an investigational study drug or procedure within 3 months before Screening that might confound study outcomes. Use of investigational study drugs is prohibited throughout the course of the study.
  5. Any conditions that make it impossible to perform MRI studies (including allergies to anesthetics or contrast agents).
  6. Hematological compromise as evidenced by:

    • Peripheral blood absolute neutrophil count (ANC) count < 1500 cells/ cubic milli meter (mm3),
    • Platelet count < 100,000 cells/mm3, or
    • Hemoglobin < 10 gram per deciliter (g/dL).
    • Uncorrected bleeding disorder.
  7. Hepatic compromise as evidenced by:

    • Aspartate transaminase (AST) value > 2.5×upper limit of normal (ULN)
    • Alanine transaminase (ALT) value > 2.5×ULN
    • Total bilirubin value > 3.0 milligram per deciliter (mg/dL), except if there is a diagnosis of Gilbert's Syndrome and the participant is otherwise stable
  8. Renal compromise as evidenced by abnormal renal function (actual or calculated creatinine clearance < 50 milliliter per minute [mL/min])
  9. Cardiac compromise as evidenced by left ventricular ejection fraction <40 percent (%)
  10. Immediate family member with a known or suspected familial cancer syndrome (including but not limited to hereditary breast and ovarian cancer syndrome, hereditary non-polyposis colorectal cancer syndrome, and familial adenomatous polyposis).
  11. Clinically significant active bacterial, viral, fungal, parasitic, or prion-associated infection
  12. Positive for human immunodeficiency virus type 1 or 2 (HIV-1, HIV-2); hepatitis B; hepatitis C; human T lymphotrophic virus 1 (HTLV-1). (Note that participants who have been vaccinated against hepatitis B [hepatitis B surface antibody-positive] who are negative for other markers of prior hepatitis B infection [eg, negative for hepatitis B core antibody (Ab)] are eligible. Participants with past exposure to hepatitis B virus (HBV [HBcAb positive and/or HBeAb positive]) are also eligible for the study provided they have a negative test for HBV DNA. Also note that participants who are positive for anti-hepatitis C antibody are eligible as long as they have a negative hepatitis C viral load.
  13. Any clinically significant cardiovascular or pulmonary disease, or other disease or condition that would be contraindicated for any of the other study procedures.
  14. Absence of adequate contraception for fertile participants. Male participants and their female partners are required to use two different effective methods of contraception from Screening through at least 6 months after drug product infusion.
  15. Any contraindications to the use of granulocyte colony stimulating (G-CSF) during the mobilization of HSCs, and any contraindications to the use of busulfan or cyclophosphamide, including known hypersensitivity to the active substances or to any of the excipients in their formulations.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE up to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   France,   Germany,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01896102
Other Study ID Numbers  ICMJE ALD-102
2011-001953-10 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Bluebird bio is committed to transparency and appropriately de-identified patient-level datasets and supporting documents may be shared following attainment of applicable marketing approvals associated with this study and consistent with criteria established by bluebird bio and/or industry best practices to maintain the privacy of study participants. For enquiries, please contact us at datasharing@bluebirdbio.com.
Responsible Party bluebird bio
Study Sponsor  ICMJE bluebird bio
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Andrew Dietz, MD. bluebird bio, Inc.
Principal Investigator: David Williams, MD Boston Children's Hospital
Principal Investigator: Christine Duncan, MD Boston Children's Hospital
Principal Investigator: Florian Eichler, MD Massachusetts General Hospital
Principal Investigator: Satiro de Oliveira, MD University of California, Los Angeles
Principal Investigator: Paul Orchard, MD University of Minnesota
Principal Investigator: Adrian Thrasher, MD, PhD Great Ormond Street Hospital for Chidren NHS Foundation Trust
Principal Investigator: Patrick Aubourg, MD, PhD Hôpital Bicêtre
Principal Investigator: Jorn-Sven Kuhl, MD University of Leipzig
Principal Investigator: Nicholas Smith, MD Women and Children's Hospital
Principal Investigator: Hernan Amartino, MD Medeos SRL
PRS Account bluebird bio
Verification Date April 2021

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