A Clinical Study to Assess the Efficacy and Safety of Gene Therapy for the Treatment of Cerebral Adrenoleukodystrophy (CALD)
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|ClinicalTrials.gov Identifier: NCT03852498|
Recruitment Status : Active, not recruiting
First Posted : February 25, 2019
Last Update Posted : April 4, 2022
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Study ALD-104 is an international, non-randomized, open-label, multi-site study in male participants (Less than or equal to [< or =] 17 years of age at enrollment) with cerebral adrenoleukodystrophy (CALD). Approximately 35 participants will be infused with Lenti-D Drug Product after myeloablative conditioning with busulfan and fludarabine.
This trial will evaluate 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 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.
|Condition or disease||Intervention/treatment||Phase|
|Cerebral Adrenoleukodystrophy (CALD)||Genetic: Lenti-D||Phase 3|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||35 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 3 Study of Lenti-D Drug Product After Myeloablative Conditioning Using Busulfan and Fludarabine in Subjects ≤17 Years of Age With Cerebral Adrenoleukodystrophy (CALD)|
|Actual Study Start Date :||January 24, 2019|
|Estimated Primary Completion Date :||February 2024|
|Estimated Study Completion Date :||February 2024|
Experimental: Lenti-D Drug Product
Participants received a single intravenous (IV) infusion of Lenti-D Drug Product at a dose of > or = 5.0*10^6 CD34+ cells/kilogram (kg) (autologous CD34+ cell-enriched population that contains cells transduced with lentiviral vector encoding ABCD1 cDNA for human adrenoleukodystrophy protein, suspended in a cryopreservative solution) following myeloablative conditioning with busulfan and fludarabine on Day 1.
Participants received a single IV infusion of Lenti-D Drug Product.
- 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 with Neutrophil Engraftment After Drug Product Infusion [ Time Frame: 42 days post-drug product infusion ]
- 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).
- Change in Total Neurologic Function Score (NFS) From Baseline to Protocol Scheduled Visits [ Time Frame: From Baseline through study completion (up to Month 24 [+or- 1 month] 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 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 a rescue cell administration or 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 ]
- Detectable Vector Copy Number (VCN) in Peripheral Blood Cells by Month 6 [ Time Frame: Month 6 post-transplant ]
- Percentage of Participants who Experience Either Acute (Greater Than or Equal to [> or =] Grade II) or Chronic Grafts Versus Host Disease (GVHD) at Month 24 [ Time Frame: Month 24 post-transplant ]
- 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 Neutrophil 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 who Experience 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 clinical > or = Grade 3 AEs, investigational medicinal product (IMP)-related AEs, all serious adverse events (SAEs), AEs > or = Grade 3 infections by Month 24.
- Percentage of Participants with Potentially Clinically 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 who Experience Greater Than or Equal to (> or =) Grade II Acute GVHD by Month 24 [ Time Frame: Month 24 post-transplant ]
- Percentage of Participants who Experience Chronic 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.
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.
|Ages Eligible for Study:||up to 17 Years (Child)|
|Sexes Eligible for Study:||Male|
|Accepts Healthy Volunteers:||No|
- 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.
- Males aged 17 years and younger, at the time of parental/guardian consent and, where appropriate, participant assent.
Active cerebral ALD as defined by:
- Elevated very long chain fatty acids (VLCFA) values, and
- Active central nervous system (CNS) disease established by central radiographic review of brain 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.
- NFS < or = 1.
- Prior receipt of an allogeneic transplant or gene therapy.
- Use of statins, Lorenzo's Oil, or dietary regimens used to lower VLCFA levels. Note: participants must discontinue use of these medications at time of consent.
- 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.
- Any conditions that make it impossible to perform MRI studies (including allergies to anesthetics or contrast agents).
Hematological compromise as evidenced by:
- Peripheral blood absolute neutrophil count (ANC) count <1500 cells/ cubic millimeter (mm^3), and either
- Platelet count <100,000 cells/mm^3, or
- Hemoglobin <10 gram per deciliter (g/dL).
Hepatic compromise as evidenced by:
- Aspartate transaminase (AST) value greater than (>) 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
- Baseline estimated glomerular filtration rate <70 milliliter per minute (mL/min)/1.73 square meter (m^2).
- Cardiac compromise as evidenced by left ventricular ejection fraction <40 percent (%).
- Immediate family member with a known or suspected Familial Cancer Syndrome.
- Clinically significant uncontrolled, active bacterial, viral, fungal, parasitic, or prion associated infection.
- Positive for HIV, hepatitis B or C virus, or human T lymphotrophic virus 1 (HTLV-1).
- Any clinically significant cardiovascular, hematological, or pulmonary disease, or other disease or condition that would be contraindicated for any of the other study procedures.
- Absence of adequate contraception for fertile participants.
- Any contraindications to the use of Granulocyte colony-stimulating factor (G-CSF) or plerixafor during the mobilization of hematopoietic stem cells, and any contraindications to the use of busulfan or fludarabine, including known hypersensitivity to the active substances or to any of the excipients in their formulations.
- Known hypersensitivity to protamine sulfate.
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): NCT03852498
|United States, California|
|Lucile Packard Children's Hospital|
|Palo Alto, California, United States, 94304|
|United States, Massachusetts|
|Boston Children's Hospital/Massachusetts General Hospital|
|Boston, Massachusetts, United States, 02215|
|United States, Minnesota|
|University of Minnesota|
|Minneapolis, Minnesota, United States, 55455|
|Hôpital Robert Debré|
|Paris, France, 75019|
|Universitätsklinikum Leipzig AöR|
|Leipzig, Germany, 04103|
|Ospedale Pediatrico Bambino Gesù|
|Rome, Italy, 00165|
|Prinses Maxima Center|
|Utrecht, Netherlands, 3508AB|
|UCL-ICH/Great Ormond Street Hospital|
|London, United Kingdom, WC1N3JH|
|Study Director:||Andrew Dietz, MD||bluebird bio, Inc.|
|Responsible Party:||bluebird bio|
|Other Study ID Numbers:||
2018-001145-14 ( EudraCT Number )
|First Posted:||February 25, 2019 Key Record Dates|
|Last Update Posted:||April 4, 2022|
|Last Verified:||March 2022|
|Individual Participant Data (IPD) Sharing Statement:|
|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 email@example.com.|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Hematopoietic stem cell
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Central Nervous System Diseases
Nervous System Diseases
Hereditary Central Nervous System Demyelinating Diseases
Mental Retardation, X-Linked
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Heredodegenerative Disorders, Nervous System
Metabolism, Inborn Errors
Adrenal Gland Diseases
Endocrine System Diseases