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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT01896102
Registration number
NCT01896102
Ethics application status
Date submitted
22/03/2013
Date registered
11/07/2013
Date last updated
25/04/2022
Titles & IDs
Public 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)
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Scientific 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)
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Secondary ID [1]
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2011-001953-10
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Secondary ID [2]
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ALD-102
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Cerebral Adrenoleukodystrophy (CALD)
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Condition category
Condition code
Human Genetics and Inherited Disorders
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Other human genetics and inherited disorders
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Neurological
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Other neurological disorders
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Metabolic and Endocrine
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Metabolic disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Other interventions - Lenti-D Drug Product (eli-cel)
Experimental: Lenti-D Drug Product - 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.
Other interventions: Lenti-D Drug Product (eli-cel)
Participants received a single IV infusion of Lenti-D Drug Product.
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Intervention code [1]
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Other interventions
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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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
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Assessment method [1]
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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.
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Timepoint [1]
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At Month 24
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Primary outcome [2]
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Proportion of Participants Who Had Experienced Either Acute ([>or=] Grade II) or Chronic Graft Versus Host Disease (GVHD) by Month 24
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Assessment method [2]
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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.
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Timepoint [2]
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By Month 24
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Secondary outcome [1]
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Percentage of Participants Who Demonstrated Resolution of Gadolinium Positivity on Magnetic Resonance Imaging (MRI) at Month 24
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Assessment method [1]
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Percentage of participants who demonstrated resolution of gadolinium positivity (i.e., GdE-) on MRI at Month 24 were reported.
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Timepoint [1]
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At Month 24
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Secondary outcome [2]
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Time to Sustained Resolution of Gadolinium Positivity on MRI
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Assessment method [2]
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Sustained resolution of gadolinium positivity was defined as having at least two consecutive GdE- results by MRI without a subsequent evaluation indicating GdE+.
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Timepoint [2]
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Up to Month 24
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Secondary outcome [3]
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Number of Participants With Change in Total Neurologic Function Score (NFS) From Baseline up to Month 24
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Assessment method [3]
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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.
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Timepoint [3]
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Baseline up to Month 24
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Secondary outcome [4]
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Major Functional Disability (MFD)-Free Survival Rate
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Assessment method [4]
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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.
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Timepoint [4]
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At 24 months after Lenti-D drug infusion
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Secondary outcome [5]
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Overall Survival Rate
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Assessment method [5]
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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.
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Timepoint [5]
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At 24 months after Lenti-D drug infusion
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Secondary outcome [6]
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Proportion of Participants With Neutrophil Engraftment by 42 Days Post-drug Product Infusion
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Assessment method [6]
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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.
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Timepoint [6]
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By 42 days post-drug infusion
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Secondary outcome [7]
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Time to Neutrophil Engraftment Post-drug Product Infusion
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Assessment method [7]
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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.
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Timepoint [7]
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By 42 days post-drug infusion
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Secondary outcome [8]
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Proportion of Participants With Platelet Engraftment by Month 24
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Assessment method [8]
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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.
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Timepoint [8]
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By Month 24
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Secondary outcome [9]
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Time to Platelet Engraftment Post-drug Product Infusion
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Assessment method [9]
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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.
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Timepoint [9]
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By Month 24
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Secondary outcome [10]
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Proportion of Participants With Engraftment Failure By Month 24
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Assessment method [10]
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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.
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Timepoint [10]
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By Month 24
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Secondary outcome [11]
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Proportion of Participants Who Underwent a Subsequent Allo-Hematopoietic Stem Cell (HSC) Infusion by Month 24
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Assessment method [11]
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Percentage of Participants who have undergone a subsequent allo-HSC infusion at Month 24 were reported.
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Timepoint [11]
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By Month 24
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Secondary outcome [12]
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Percentage of Participants With Transplant-related Mortality Through 100 and 365 Days Post-drug Product Infusion
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Assessment method [12]
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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.
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Timepoint [12]
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From time of drug product infusion through 100 and 365 days post-drug product infusion
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Secondary outcome [13]
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Percentage of Participants With Adverse Events (AEs), Serious AEs, Grade >=3 AE, Related AEs, Related SAEs and Related Grade >=3 AEs
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Assessment method [13]
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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.
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Timepoint [13]
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From date of informed consent up to Month 24
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Secondary outcome [14]
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Percentage of Participants With Potentially Clinical Significant Changes in Laboratory Parameters by Month 24
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Assessment method [14]
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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.
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Timepoint [14]
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From time of drug product infusion up to Month 24
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Secondary outcome [15]
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Number of Emergency Room Visits (Post-Neutrophil Engraftment) By Month 24
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Assessment method [15]
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Number of emergency room visits (post-neutrophil engraftment) up to Month 24 were reported.
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Timepoint [15]
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From Post-Neutrophil Engraftment up to Month 24
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Secondary outcome [16]
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Number of In-patient Hospitalizations (Post-Neutrophil Engraftment) By Month 24
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Assessment method [16]
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Number of In-patient hospitalizations (post-neutrophil engraftment) by Month 24 were reported.
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Timepoint [16]
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From post-neutrophil engraftment up to Month 24
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Secondary outcome [17]
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Duration of In-patient Hospitalizations (Post-Neutrophil Engraftment) up to Month 24
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Assessment method [17]
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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.
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Timepoint [17]
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From post-neutrophil engraftment up to Month 24
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Secondary outcome [18]
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Number of Intensive Care Units (ICU) Stays (Post-neutrophil Engraftment) By Month 24
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Assessment method [18]
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Number of ICU Stays (Post-neutrophil Engraftment) By Month 24 were reported.
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Timepoint [18]
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From post-neutrophil engraftment up to Month 24
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Secondary outcome [19]
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Duration of ICU Stays (Post-neutrophil Engraftment) By Month 24
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Assessment method [19]
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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.
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Timepoint [19]
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From post-neutrophil engraftment up to Month 24
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Secondary outcome [20]
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Number of Participants With Vector-Derived Replication Competent Lentivirus (RCL) Detected by Month 24
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Assessment method [20]
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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.
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Timepoint [20]
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By Month 24
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Secondary outcome [21]
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Number of Participants With Insertional Oncogenesis By Month 24
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Assessment method [21]
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Insertional oncogenesis including myelodysplasia, leukemia, lymphoma. Number of participants with insertional oncogenesis at Month 24 were reported.
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Timepoint [21]
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By Month 24
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Eligibility
Key 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.
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Minimum age
No limit
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Maximum age
17
Years
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Sex
Males
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Can healthy volunteers participate?
No
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Key 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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
N/A
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 2/Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
21/08/2013
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
26/03/2021
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Sample size
Target
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Accrual to date
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Final
32
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Recruitment in Australia
Recruitment state(s)
SA
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Recruitment hospital [1]
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Women and Children's Hospital - North Adelaide
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Recruitment postcode(s) [1]
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5006 - North Adelaide
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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California
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Country [2]
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United States of America
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State/province [2]
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Massachusetts
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Country [3]
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United States of America
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State/province [3]
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Minnesota
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Country [4]
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Argentina
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State/province [4]
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Buenos Aires
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Country [5]
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France
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State/province [5]
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Le Kremlin-Bicêtre Cedex
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Country [6]
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Germany
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State/province [6]
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Leipzig
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Country [7]
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United Kingdom
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State/province [7]
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London
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
bluebird bio
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Address
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Country
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT01896102
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Jakob Sieker, MD.
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Address
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bluebird bio, Inc.
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT01896102
Download to PDF