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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)

Primary Purpose

Cerebral Adrenoleukodystrophy (CALD)

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Lenti-D Drug Product (eli-cel)
Sponsored by
bluebird bio
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cerebral Adrenoleukodystrophy (CALD) focused on measuring Adrenoleukodystrophy, X-linked adrenoleukodystrophy, Gene therapy, Hematopoietic stem cell

Eligibility Criteria

undefined - 17 Years (Child)MaleDoes not accept healthy volunteers

Inclusion Criteria:

  1. Informed consent was 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:
    3. Loes score between 0.5 and 9 (inclusive) on the 34-point scale, and
    4. 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. If subjects are truly sexually abstinent (where true sexual abstinence is defined as being in line with the preferred and usual lifestyle of the subject), no second method is required.
  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.

Sites / Locations

  • Mattel Children's Hospital UCLA/Ronald Reagan UCLA Medical Center
  • Boston Children's Hospital/Massachusetts General Hospital
  • University of Minnesota
  • Medeos SRL
  • Women and Children's Hospital
  • Hôpital Bicêtre
  • University of Leipzig
  • Great Ormond Street Hospital for Children NHS Foundation Trust

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Lenti-D Drug Product

Arm Description

Participants received a single intravenous (IV) infusion of Lenti-D Drug Product at a dose of greater than or equal to (>=) 5.0 × 10^6 CD34+ cells/kilogram (kg) (autologous CD34+ cell-enriched population that contained cells transduced with lentiviral vector encoding ABCD1 cDNA for human adrenoleukodystrophy protein, suspended in a cryopreservative solution) on Day 0.

Outcomes

Primary Outcome Measures

Percentage of Participants Who Were Alive and Have None of the 6 Major Functional Disabilities (MFDs) at Month 24 and Without Allo-HSCT or Rescue Cell Administration
The 6 MFDs consisted of loss of communication, cortical blindness, tube feeding, total incontinence, wheelchair dependence, complete loss of voluntary movement. Month 24 MFD-Free survival criteria was defined as: alive at 24 months post-infusion; had not developed any of the MFDs by 24 months post-infusion; had not received rescue cell administration or allo-HSCT by 24 months post-infusion; and had not withdrawn from the study or had not been lost to follow-up by 24 months post-infusion. Percentage of participants who were alive and have none of the 6 major functional disabilities (MFDs) at Month 24 were reported.
Proportion of Participants Who Had Experienced Either Acute ([>or=] Grade II) or Chronic Graft Versus Host Disease (GVHD) by Month 24
Acute GVHD graded on the Acute GVHD Grading Scale (I-IV): Grade I is characterized as mild disease, Grade II as moderate, Grade III as severe (involvement of any organ system), and Grade IV as life-threatening; chronic GVHD was determined by the Investigator. Percentage of participants who experienced with either acute (>= Grade II) or chronic GVHD at Month 24 were reported.

Secondary Outcome Measures

Percentage of Participants Who Demonstrated Resolution of Gadolinium Positivity on Magnetic Resonance Imaging (MRI) at Month 24
Percentage of participants who demonstrated resolution of gadolinium positivity (i.e., GdE-) on MRI at Month 24 were reported.
Time to Sustained Resolution of Gadolinium Positivity on MRI
Sustained resolution of gadolinium positivity was defined as having at least two consecutive GdE- results by MRI without a subsequent evaluation indicating GdE+.
Number of Participants With Change in Total Neurologic Function Score (NFS) From Baseline up to Month 24
NFS was 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" denoted absence of clinical signs of cerebral disease. Maximal signs within a domain score the total of all grades within that domain. Number of participants with change in total NFS from baseline up to Month 24 were reported.
Major Functional Disability (MFD)-Free Survival Rate
MFD-free survival rate was defined as percentage of participants from drug product infusion to either second transplant, MFD, or death due to any cause, whichever occurs first. MFD-free survival rate was analyzed using Kaplan-Meier Analysis. Kaplan-Meier estimated MFD-free survival rate at 24 months after Lenti-D drug infusion was reported.
Overall Survival Rate
Overall survival rate was defined as percentage of participants alive from date of Lenti-D drug product infusion (Day 0) to date of death of all causes. Overall survival rate was censored at the date of last visit if the participant were alive. Participants who are alive were censored at the date of last contact. Overall survival rate was analyzed using Kaplan-Meier Analysis. Kaplan-Meier estimated overall survival rate at 24 months after Lenti-D drug infusion was reported.
Proportion of Participants With Neutrophil Engraftment by 42 Days Post-drug Product Infusion
Neutrophil engraftment (NE) was defined as achieving 3 consecutive absolute neutrophil count (ANC) laboratory values of >= 0.5×10^9 cells/Liter (L) (after initial post-infusion nadir) obtained on different days by 42 days post-infusion of Lenti-D Drug Product (Relative Day 43). Percentage of participants with neutrophil engraftment by 42 Days post-drug product infusion were reported.
Time to Neutrophil Engraftment Post-drug Product Infusion
Neutrophil Engraftment was defined as achieving 3 consecutive ANC laboratory values of >= 0.5×10^9 cells/L (after initial post-infusion nadir) obtained on different days by 42 days post-infusion of Lenti-D Drug Product (Relative Day 43). Time to neutrophil engraftment post-drug product infusion was reported.
Proportion of Participants With Platelet Engraftment by Month 24
Platelet Engraftment was defined as achieving 3 consecutive unsupported platelet counts of >=20 × 10^9 cells/L (after initial post-infusion nadir) obtained on different days while no platelet transfusions were administered for 7 days immediately preceding and during the evaluation period. The first day of 3 consecutive platelet counts >=20 × 10^9 cells/L was the day of PE. Percentage of participants with Platelet Engraftment by Month 24 (Rel Day 730) were reported.
Time to Platelet Engraftment Post-drug Product Infusion
Platelet Engraftment was defined as achieving 3 consecutive unsupported platelet counts of > or =20 × 10^9 cells/L (after initial post-infusion nadir) obtained on different days while no platelet transfusions were administered for 7 days immediately preceding and during the evaluation period. The first day of 3 consecutive platelet counts >=20 × 10^9 cells/L was the day of PE. Time to Platelet Engraftment post-drug product infusion up to Month 24 was reported.
Proportion of Participants With Engraftment Failure By Month 24
Participants were considered to have primary engraftment failure if they did not achieve NE by Relative Day 43. A participant was considered to have secondary engraftment failure if they achieved and then subsequently lost NE by the Month 24, i.e., if they met both the conditions; Achieved NE by Relative Day 43 as defined above and had sustained decline in ANC to < 0.5×10^9 cells/L for 3 consecutive measurements on different days after Relative Day 43, without alternate etiology. First day of the 3 consecutive ANC decline to < 0.5×10^9 cells/L was considered the day of secondary engraftment failure. Percentage of participants with both primary and secondary engraftment failure at Month 24 were reported.
Proportion of Participants Who Underwent a Subsequent Allo-Hematopoietic Stem Cell (HSC) Infusion by Month 24
Percentage of Participants who have undergone a subsequent allo-HSC infusion at Month 24 were reported.
Percentage of Participants With Transplant-related Mortality Through 100 and 365 Days Post-drug Product Infusion
Transplant-related mortality was determined by the Investigator in participants who had died from transplant-related causes by 100 days post-drug product infusion (Rel Day 101) or 365 days post-drug product infusion (Rel Day 366) respectively or had been followed to at least Rel Day 101 or 366 respectively if no events yet. Percentage of participants with transplant-related mortality through 100 and 365 days post-drug product infusion were reported.
Percentage of Participants With Adverse Events (AEs), Serious AEs, Grade >=3 AE, Related AEs, Related SAEs and Related Grade >=3 AEs
Adverse event was defined as any untoward medical occurrence associated with the use of a drug product in participants, whether or not considered drug related. SAE was any AE, occurring at any dose and regardless of causality, that resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or was considered an important medical event that may jeopardize the participant and may require medical or surgical intervention to prevent an outcome listed previously. Percentage of participants with all AEs, all SAEs, all drug-product related AEs and SAEs Grade >=3 (severe or medically significant but not immediately life threatening AE) and related Grade >=3 AEs were reported.
Percentage of Participants With Potentially Clinical Significant Changes in Laboratory Parameters by Month 24
Laboratory parameters included hematology (Leukocytes [with a threshold (TS) range <4.0 x 10^9/L, >=18 x 10^9/L], Neutrophils [<1.0 x 10^9/L], Erythrocytes [<=3.0 x 10^12/L], Platelets [<=75 x 10^9/L]); clinical chemistry (Sodium [<=126 millimoles per liter (mmol/L), >=156 mmol/L], Potassium [<=3 mmol/L, >=6 mmol/L], Glucose [<=3.0 mmol/L], Urea Nitrogen [>=10.7 mmol/L], Creatinine [>=150 umol/L]) and liver function tests (LFT) (Alanine Aminotransferase [ALA]. Aspartate Aminotransferase [ASA], Alkaline Phosphatase [AP] with TS range of >=3 x upper limit of normal (ULN), Bilirubin [>=34.2 micromoles per liter (umol/L)]). Clinical significance was decided by investigator.
Number of Emergency Room Visits (Post-Neutrophil Engraftment) By Month 24
Number of emergency room visits (post-neutrophil engraftment) up to Month 24 were reported.
Number of In-patient Hospitalizations (Post-Neutrophil Engraftment) By Month 24
Number of In-patient hospitalizations (post-neutrophil engraftment) by Month 24 were reported.
Duration of In-patient Hospitalizations (Post-Neutrophil Engraftment) up to Month 24
Duration of in-patient hospitalizations was calculated as: Duration = (Date of hospital discharge) - (Date of hospital admission before NE) + 1. Duration of In-patient hospitalizations (post-neutrophil engraftment) up to Month 24 was reported.
Number of Intensive Care Units (ICU) Stays (Post-neutrophil Engraftment) By Month 24
Number of ICU Stays (Post-neutrophil Engraftment) By Month 24 were reported.
Duration of ICU Stays (Post-neutrophil Engraftment) By Month 24
Duration of ICU Stays was calculated as: Duration = (Date of hospital discharge) - (Date of hospital admission before NE) + 1. Duration of ICU Stays (Post-neutrophil Engraftment) by Month 24 was reported.
Number of Participants With Vector-Derived Replication Competent Lentivirus (RCL) Detected by Month 24
Number of Participants with Vector-derived RCL detected at Month 24 were reported. Screening participants blood samples for RCL at month 24 following Lenti-D Drug infusion was performed, with the more rigorous co-culture assays used to distinguish any false positives as applicable.
Number of Participants With Insertional Oncogenesis By Month 24
Insertional oncogenesis including myelodysplasia, leukemia, lymphoma. Number of participants with insertional oncogenesis at Month 24 were reported.

Full Information

First Posted
March 22, 2013
Last Updated
March 25, 2022
Sponsor
bluebird bio
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1. Study Identification

Unique Protocol Identification Number
NCT01896102
Brief Title
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
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)
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Completed
Study Start Date
August 21, 2013 (Actual)
Primary Completion Date
March 26, 2021 (Actual)
Study Completion Date
March 26, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
bluebird bio

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This trial assessed the efficacy and safety of autologous cluster of differentiation 34 (CD34+) hematopoietic stem cells, transduced ex-vivo with Lenti-D lentiviral vector (also called elivaldogene autotemcel or eli-cel), for the treatment of cerebral adrenoleukodystrophy (CALD). A participant's blood stem cells were 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 were transplanted back into the participant following myeloablative conditioning. Participants in this study will be continuously followed in study LTF-304.
Detailed Description
For study ALD-102 the Transplant Population (TP), Neutrophil Engraftment Population (NEP), and Intent-to-Treat Population (ITT) were identical.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cerebral Adrenoleukodystrophy (CALD)
Keywords
Adrenoleukodystrophy, X-linked adrenoleukodystrophy, Gene therapy, Hematopoietic stem cell

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
32 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Lenti-D Drug Product
Arm Type
Experimental
Arm Description
Participants received a single intravenous (IV) infusion of Lenti-D Drug Product at a dose of greater than or equal to (>=) 5.0 × 10^6 CD34+ cells/kilogram (kg) (autologous CD34+ cell-enriched population that contained cells transduced with lentiviral vector encoding ABCD1 cDNA for human adrenoleukodystrophy protein, suspended in a cryopreservative solution) on Day 0.
Intervention Type
Genetic
Intervention Name(s)
Lenti-D Drug Product (eli-cel)
Other Intervention Name(s)
elivaldogene autotemcel, eli-cel
Intervention Description
Participants received a single IV infusion of Lenti-D Drug Product.
Primary Outcome Measure Information:
Title
Percentage of Participants Who Were Alive and Have None of the 6 Major Functional Disabilities (MFDs) at Month 24 and Without Allo-HSCT or Rescue Cell Administration
Description
The 6 MFDs consisted of loss of communication, cortical blindness, tube feeding, total incontinence, wheelchair dependence, complete loss of voluntary movement. Month 24 MFD-Free survival criteria was defined as: alive at 24 months post-infusion; had not developed any of the MFDs by 24 months post-infusion; had not received rescue cell administration or allo-HSCT by 24 months post-infusion; and had not withdrawn from the study or had not been lost to follow-up by 24 months post-infusion. Percentage of participants who were alive and have none of the 6 major functional disabilities (MFDs) at Month 24 were reported.
Time Frame
At Month 24
Title
Proportion of Participants Who Had Experienced Either Acute ([>or=] Grade II) or Chronic Graft Versus Host Disease (GVHD) by Month 24
Description
Acute GVHD graded on the Acute GVHD Grading Scale (I-IV): Grade I is characterized as mild disease, Grade II as moderate, Grade III as severe (involvement of any organ system), and Grade IV as life-threatening; chronic GVHD was determined by the Investigator. Percentage of participants who experienced with either acute (>= Grade II) or chronic GVHD at Month 24 were reported.
Time Frame
By Month 24
Secondary Outcome Measure Information:
Title
Percentage of Participants Who Demonstrated Resolution of Gadolinium Positivity on Magnetic Resonance Imaging (MRI) at Month 24
Description
Percentage of participants who demonstrated resolution of gadolinium positivity (i.e., GdE-) on MRI at Month 24 were reported.
Time Frame
At Month 24
Title
Time to Sustained Resolution of Gadolinium Positivity on MRI
Description
Sustained resolution of gadolinium positivity was defined as having at least two consecutive GdE- results by MRI without a subsequent evaluation indicating GdE+.
Time Frame
Up to Month 24
Title
Number of Participants With Change in Total Neurologic Function Score (NFS) From Baseline up to Month 24
Description
NFS was 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" denoted absence of clinical signs of cerebral disease. Maximal signs within a domain score the total of all grades within that domain. Number of participants with change in total NFS from baseline up to Month 24 were reported.
Time Frame
Baseline up to Month 24
Title
Major Functional Disability (MFD)-Free Survival Rate
Description
MFD-free survival rate was defined as percentage of participants from drug product infusion to either second transplant, MFD, or death due to any cause, whichever occurs first. MFD-free survival rate was analyzed using Kaplan-Meier Analysis. Kaplan-Meier estimated MFD-free survival rate at 24 months after Lenti-D drug infusion was reported.
Time Frame
At 24 months after Lenti-D drug infusion
Title
Overall Survival Rate
Description
Overall survival rate was defined as percentage of participants alive from date of Lenti-D drug product infusion (Day 0) to date of death of all causes. Overall survival rate was censored at the date of last visit if the participant were alive. Participants who are alive were censored at the date of last contact. Overall survival rate was analyzed using Kaplan-Meier Analysis. Kaplan-Meier estimated overall survival rate at 24 months after Lenti-D drug infusion was reported.
Time Frame
At 24 months after Lenti-D drug infusion
Title
Proportion of Participants With Neutrophil Engraftment by 42 Days Post-drug Product Infusion
Description
Neutrophil engraftment (NE) was defined as achieving 3 consecutive absolute neutrophil count (ANC) laboratory values of >= 0.5×10^9 cells/Liter (L) (after initial post-infusion nadir) obtained on different days by 42 days post-infusion of Lenti-D Drug Product (Relative Day 43). Percentage of participants with neutrophil engraftment by 42 Days post-drug product infusion were reported.
Time Frame
By 42 days post-drug infusion
Title
Time to Neutrophil Engraftment Post-drug Product Infusion
Description
Neutrophil Engraftment was defined as achieving 3 consecutive ANC laboratory values of >= 0.5×10^9 cells/L (after initial post-infusion nadir) obtained on different days by 42 days post-infusion of Lenti-D Drug Product (Relative Day 43). Time to neutrophil engraftment post-drug product infusion was reported.
Time Frame
By 42 days post-drug infusion
Title
Proportion of Participants With Platelet Engraftment by Month 24
Description
Platelet Engraftment was defined as achieving 3 consecutive unsupported platelet counts of >=20 × 10^9 cells/L (after initial post-infusion nadir) obtained on different days while no platelet transfusions were administered for 7 days immediately preceding and during the evaluation period. The first day of 3 consecutive platelet counts >=20 × 10^9 cells/L was the day of PE. Percentage of participants with Platelet Engraftment by Month 24 (Rel Day 730) were reported.
Time Frame
By Month 24
Title
Time to Platelet Engraftment Post-drug Product Infusion
Description
Platelet Engraftment was defined as achieving 3 consecutive unsupported platelet counts of > or =20 × 10^9 cells/L (after initial post-infusion nadir) obtained on different days while no platelet transfusions were administered for 7 days immediately preceding and during the evaluation period. The first day of 3 consecutive platelet counts >=20 × 10^9 cells/L was the day of PE. Time to Platelet Engraftment post-drug product infusion up to Month 24 was reported.
Time Frame
By Month 24
Title
Proportion of Participants With Engraftment Failure By Month 24
Description
Participants were considered to have primary engraftment failure if they did not achieve NE by Relative Day 43. A participant was considered to have secondary engraftment failure if they achieved and then subsequently lost NE by the Month 24, i.e., if they met both the conditions; Achieved NE by Relative Day 43 as defined above and had sustained decline in ANC to < 0.5×10^9 cells/L for 3 consecutive measurements on different days after Relative Day 43, without alternate etiology. First day of the 3 consecutive ANC decline to < 0.5×10^9 cells/L was considered the day of secondary engraftment failure. Percentage of participants with both primary and secondary engraftment failure at Month 24 were reported.
Time Frame
By Month 24
Title
Proportion of Participants Who Underwent a Subsequent Allo-Hematopoietic Stem Cell (HSC) Infusion by Month 24
Description
Percentage of Participants who have undergone a subsequent allo-HSC infusion at Month 24 were reported.
Time Frame
By Month 24
Title
Percentage of Participants With Transplant-related Mortality Through 100 and 365 Days Post-drug Product Infusion
Description
Transplant-related mortality was determined by the Investigator in participants who had died from transplant-related causes by 100 days post-drug product infusion (Rel Day 101) or 365 days post-drug product infusion (Rel Day 366) respectively or had been followed to at least Rel Day 101 or 366 respectively if no events yet. Percentage of participants with transplant-related mortality through 100 and 365 days post-drug product infusion were reported.
Time Frame
From time of drug product infusion through 100 and 365 days post-drug product infusion
Title
Percentage of Participants With Adverse Events (AEs), Serious AEs, Grade >=3 AE, Related AEs, Related SAEs and Related Grade >=3 AEs
Description
Adverse event was defined as any untoward medical occurrence associated with the use of a drug product in participants, whether or not considered drug related. SAE was any AE, occurring at any dose and regardless of causality, that resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or was considered an important medical event that may jeopardize the participant and may require medical or surgical intervention to prevent an outcome listed previously. Percentage of participants with all AEs, all SAEs, all drug-product related AEs and SAEs Grade >=3 (severe or medically significant but not immediately life threatening AE) and related Grade >=3 AEs were reported.
Time Frame
From date of informed consent up to Month 24
Title
Percentage of Participants With Potentially Clinical Significant Changes in Laboratory Parameters by Month 24
Description
Laboratory parameters included hematology (Leukocytes [with a threshold (TS) range <4.0 x 10^9/L, >=18 x 10^9/L], Neutrophils [<1.0 x 10^9/L], Erythrocytes [<=3.0 x 10^12/L], Platelets [<=75 x 10^9/L]); clinical chemistry (Sodium [<=126 millimoles per liter (mmol/L), >=156 mmol/L], Potassium [<=3 mmol/L, >=6 mmol/L], Glucose [<=3.0 mmol/L], Urea Nitrogen [>=10.7 mmol/L], Creatinine [>=150 umol/L]) and liver function tests (LFT) (Alanine Aminotransferase [ALA]. Aspartate Aminotransferase [ASA], Alkaline Phosphatase [AP] with TS range of >=3 x upper limit of normal (ULN), Bilirubin [>=34.2 micromoles per liter (umol/L)]). Clinical significance was decided by investigator.
Time Frame
From time of drug product infusion up to Month 24
Title
Number of Emergency Room Visits (Post-Neutrophil Engraftment) By Month 24
Description
Number of emergency room visits (post-neutrophil engraftment) up to Month 24 were reported.
Time Frame
From Post-Neutrophil Engraftment up to Month 24
Title
Number of In-patient Hospitalizations (Post-Neutrophil Engraftment) By Month 24
Description
Number of In-patient hospitalizations (post-neutrophil engraftment) by Month 24 were reported.
Time Frame
From post-neutrophil engraftment up to Month 24
Title
Duration of In-patient Hospitalizations (Post-Neutrophil Engraftment) up to Month 24
Description
Duration of in-patient hospitalizations was calculated as: Duration = (Date of hospital discharge) - (Date of hospital admission before NE) + 1. Duration of In-patient hospitalizations (post-neutrophil engraftment) up to Month 24 was reported.
Time Frame
From post-neutrophil engraftment up to Month 24
Title
Number of Intensive Care Units (ICU) Stays (Post-neutrophil Engraftment) By Month 24
Description
Number of ICU Stays (Post-neutrophil Engraftment) By Month 24 were reported.
Time Frame
From post-neutrophil engraftment up to Month 24
Title
Duration of ICU Stays (Post-neutrophil Engraftment) By Month 24
Description
Duration of ICU Stays was calculated as: Duration = (Date of hospital discharge) - (Date of hospital admission before NE) + 1. Duration of ICU Stays (Post-neutrophil Engraftment) by Month 24 was reported.
Time Frame
From post-neutrophil engraftment up to Month 24
Title
Number of Participants With Vector-Derived Replication Competent Lentivirus (RCL) Detected by Month 24
Description
Number of Participants with Vector-derived RCL detected at Month 24 were reported. Screening participants blood samples for RCL at month 24 following Lenti-D Drug infusion was performed, with the more rigorous co-culture assays used to distinguish any false positives as applicable.
Time Frame
By Month 24
Title
Number of Participants With Insertional Oncogenesis By Month 24
Description
Insertional oncogenesis including myelodysplasia, leukemia, lymphoma. Number of participants with insertional oncogenesis at Month 24 were reported.
Time Frame
By Month 24

10. Eligibility

Sex
Male
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Informed consent was 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 adrenoleukodystrophy (ALD) as defined by: Elevated very long chain fatty acids (VLCFA) values, and Active CNS disease established by central radiographic review of brain magnetic resonance imaging (MRI) demonstrating: Loes score between 0.5 and 9 (inclusive) on the 34-point scale, and Gadolinium enhancement on MRI of demyelinating lesions. NFS less than or equal to (<or=) 1. Exclusion Criteria: Receipt of an allogeneic transplant or gene therapy. Availability of a willing 10/10 HLA-matched sibling donor (excluding female heterozygotes). 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. 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 milli meter (mm3), Platelet count < 100,000 cells/mm3, or Hemoglobin < 10 gram per deciliter (g/dL). Uncorrected bleeding disorder. 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 Renal compromise as evidenced by abnormal renal function (actual or calculated creatinine clearance < 50 milliliter per minute [mL/min]) Cardiac compromise as evidenced by left ventricular ejection fraction <40 percent (%) 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). Clinically significant active bacterial, viral, fungal, parasitic, or prion-associated infection 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. Any clinically significant cardiovascular 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. 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. If subjects are truly sexually abstinent (where true sexual abstinence is defined as being in line with the preferred and usual lifestyle of the subject), no second method is required. 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jakob Sieker, MD.
Organizational Affiliation
bluebird bio, Inc.
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
David Williams, MD
Organizational Affiliation
Boston Children's Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Christine Duncan, MD
Organizational Affiliation
Boston Children's Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Florian Eichler, MD
Organizational Affiliation
Massachusetts General Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Satiro de Oliveira, MD
Organizational Affiliation
University of California, Los Angeles
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Paul Orchard, MD
Organizational Affiliation
University of Minnesota
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Adrian Thrasher, MD, PhD
Organizational Affiliation
Great Ormond Street Hospital for Chidren NHS Foundation Trust
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Patrick Aubourg, MD, PhD
Organizational Affiliation
Hôpital Bicêtre
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jorn-Sven Kuhl, MD
Organizational Affiliation
University of Leipzig
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Nicholas Smith, MD
Organizational Affiliation
Women and Children's Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Hernan Amartino, MD
Organizational Affiliation
Medeos SRL
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mattel Children's Hospital UCLA/Ronald Reagan UCLA Medical Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Boston Children's Hospital/Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Medeos SRL
City
Buenos Aires
ZIP/Postal Code
C1022
Country
Argentina
Facility Name
Women and Children's Hospital
City
North Adelaide
State/Province
South Australia
ZIP/Postal Code
5006
Country
Australia
Facility Name
Hôpital Bicêtre
City
Le Kremlin-Bicêtre Cedex
ZIP/Postal Code
94275
Country
France
Facility Name
University of Leipzig
City
Leipzig
ZIP/Postal Code
04103
Country
Germany
Facility Name
Great Ormond Street Hospital for Children NHS Foundation Trust
City
London
ZIP/Postal Code
WC1N3JH
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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. Note that given the rarity of the disease and the identifiable nature of the participants in this study, it is anticipated that the sharing of data from this study may be limited. For enquiries, please contact us at datasharing@bluebirdbio.com.
Citations:
PubMed Identifier
28976817
Citation
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.
Results Reference
derived
Links:
URL
https://clinicaltrials.gov/show/NCT02698579
Description
ALD-102 is parent study for LTF-304 study

Learn more about this trial

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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