Clinical Trial Results:
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)
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Summary
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EudraCT number |
2018-001145-14 |
Trial protocol |
GB FR DE NL IT |
Global end of trial date |
24 Jul 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
09 Feb 2024
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First version publication date |
09 Feb 2024
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ALD-104
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03852498 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
bluebird bio, Inc
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Sponsor organisation address |
455 Grand Union Blvd, Somerville, Massachusetts, United States, 02145
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Public contact |
Clinical Trials Operations, Voisin Consulting, clinicaltrialinformation@voisinconsulting.com
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Scientific contact |
Clinical Trials Operations, Voisin Consulting, clinicaltrialinformation@voisinconsulting.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
24 Jul 2023
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
24 Jul 2023
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Global end of trial reached? |
Yes
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Global end of trial date |
24 Jul 2023
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary purpose of the study was to evaluate the efficacy and safety of Lenti-D Drug Product after myeloablative conditioning with busulfan and fludarabine in subjects with CALD.
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Protection of trial subjects |
This study was performed in accordance with Title 21, United States (US) Code of Federal Regulations (CFR) Parts 50, 54, 56 and 312 Subpart D; the International Council for Harmonisation (ICH) Guideline on Good Clinical Practice (GCP; E6); and the ethical principles outlined in the Declaration of Helsinki; and/or, where applicable, the European Directive 2001/20/EC relating to the implementation of GCP in the conduct of clinical trials on medicinal products for human use and Directive 2005/28/EC on GCP for investigational medicinal products for human use.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
24 Jan 2019
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
13 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 1
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Country: Number of subjects enrolled |
United Kingdom: 1
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Country: Number of subjects enrolled |
France: 5
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Country: Number of subjects enrolled |
Germany: 3
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Country: Number of subjects enrolled |
Italy: 1
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Country: Number of subjects enrolled |
United States: 24
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Worldwide total number of subjects |
35
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EEA total number of subjects |
10
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
33
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Adolescents (12-17 years) |
2
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
This study was conducted at 8 study centers in France, Italy, Germany, the Netherlands, United Kingdom, and United States of America from 24 January 2019 to 24 July 2023. | ||||||
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Pre-assignment
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Screening details |
A total of 35 male subjects were enrolled, underwent mobilization and infused with Lenti-D Drug Product (eli-cel). | ||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
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Arms
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Arm title
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Lenti-D Drug Product | ||||||
Arm description |
On Day 1, subjects received a single intravenous (IV) infusion of Lenti-D Drug Product at a dose of greater than or equal to (>=) 5.0 x 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). All subjects received myeloablative conditioning with busulfan and fludarabine over a number of days prior to drug product infusion. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Lenti-D Drug Product
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Investigational medicinal product code |
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Other name |
Elivaldogene autotemcel; Eli-cel; Autologous CD34+ cells transduced with Lenti -D LVV (lentiviral vector) encoding ABCD1 cDNA
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Pharmaceutical forms |
Dispersion for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received a single IV infusion of Lenti-D Drug Product on Day 1.
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Baseline characteristics reporting groups
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Reporting group title |
Lenti-D Drug Product
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Reporting group description |
On Day 1, subjects received a single intravenous (IV) infusion of Lenti-D Drug Product at a dose of greater than or equal to (>=) 5.0 x 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). All subjects received myeloablative conditioning with busulfan and fludarabine over a number of days prior to drug product infusion. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Lenti-D Drug Product
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Reporting group description |
On Day 1, subjects received a single intravenous (IV) infusion of Lenti-D Drug Product at a dose of greater than or equal to (>=) 5.0 x 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). All subjects received myeloablative conditioning with busulfan and fludarabine over a number of days prior to drug product infusion. | ||
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End point title |
Percentage of Subjects Who Were Alive and Have None of the 6 Major Functional Disabilities (MFDs) at Month 24 [1] | ||||||||
End point 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 defined as: alive at 24 months post infusion; have not developed any of the MFDs by 24 months post infusion; have not received rescue cell administration or allo-HSCT by 24 months post infusion; and have not withdrawn from the study or have not been lost to follow-up by 24 months post infusion. Transplant Population (TP) consisted of subjects who received Lenti-D Drug Product infusion. Evaluable subjects are defined as subjects who have been followed for 24 months (i.e. Rel Day of last contact >=730) or have completed the Month 24 Visit, or discontinued from the study but would have been followed for 24 months if still on the study (i.e. Rel Day of data cut >=730), at the time of the data cut.
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End point type |
Primary
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End point timeframe |
At Month 24
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were performed; no inferential statistical analyses were performed. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects who Achieved Neutrophil Engraftment After Drug Product Infusion [2] | ||||||||
End point description |
Neutrophil engraftment is defined as achieving 3 consecutive absolute neutrophil count (ANC) laboratory values of >= 0.5x10^9 cells/liter (L) (after initial post-infusion nadir) obtained on different days by 42 days post‑infusion of eli-cel (Rel Day 43). TP consisted of subjects who received Lenti-D Drug Product infusion. Evaluable subjects for NE if they achieved neutrophil engraftment by Rel Day 43, or had discontinued or were lost to follow-up before Rel Day 43 without achieving NE, or had been followed to at least Rel Day 43 but had not achieved NE. Subjects who discontinued or were lost to follow-up before Rel Day 43 without achieving NE were considered failures for NE.
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End point type |
Primary
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End point timeframe |
By 42 days post-drug infusion
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were performed; no inferential statistical analyses were performed. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects Without Gadolinium Enhancement (i.e. GdE-) on Magnetic Resonance Imaging (MRI) at Month 24 | ||||||||
End point description |
Percentage of subjects without Gadolinium Enhancement (i.e. GdE-) on MRI at Month 24 were reported. TP consisted of subjects who received Lenti-D Drug Product infusion. Evaluable subjects are defined as subjects who have completed the Month 24 GdE assessment.
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End point type |
Secondary
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End point timeframe |
At Month 24
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Subjects With Change in Neurologic Function Score (NFS) From Baseline to Month 24 | ||||||
End point 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"= absence of clinical signs of cerebral disease. TP population. Evaluable subjects are defined as subjects who have non-missing Baseline and have completed the Month 24 NFS assessment.
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End point type |
Secondary
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End point timeframe |
Baseline up to Month 24
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| No statistical analyses for this end point | |||||||
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End point title |
Major Functional Disability (MFD)-Free Survival Rate | ||||||||
End point description |
MFD-free survival rate was defined as percentage of subjects 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. TP consisted of subjects who received Lenti-D Drug Product infusion. Deaths, MFDs, and rescue cell administration or allo-HSCT are considered events. If a subject did not experience any event, he was to be censored at the Date of Last Contact.
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End point type |
Secondary
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End point timeframe |
At 24 months after Lenti-D drug infusion
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall Survival Rate | ||||||||
End point description |
Overall survival rate was defined as percentage of subjects alive from date of Lenti-D drug product infusion (Day 1) to date of death of all causes. Overall survival rate was censored at the date of last visit if the subject were alive. Subjects who are alive were censored at the date of last contact. Overall survival rate was analyzed using Kaplan-Meier Analysis. TP consisted of subjects who received Lenti-D Drug Product infusion.
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End point type |
Secondary
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End point timeframe |
At 24 months after Lenti-D drug infusion
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| No statistical analyses for this end point | |||||||||
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End point title |
Median Detectable Vector Copy Number (VCN) in Peripheral Blood Cells by Month 6 | ||||||||
End point description |
Presence of vector sequences in the genome of cells derived from the originally transduced HSC indicates the presence of transduced cells amongst the HSC precursors. The presence of vector sequences was evaluated throughout the study in whole blood, in selected subpopulations of blood cells (including CD14+ cells), and in bone marrow when indicated. The presence of vector sequences in the genomic DNA of cells was detected using quantitative polymerase chain reaction (qPCR), and results were expressed as vector copy number (VCN; vector copies per diploid genome, c/dg). TP consisted of subjects who received Lenti-D Drug Product infusion. Here, "number of subjects analysed" signifies those subjects who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
At Month 6 post-transplant
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects Who Experienced Either Acute (>= Grade 2) or Chronic Graft Versus Host Disease (GVHD) at Month 24 | ||||||||
End point description |
Acute GVHD graded on the Acute GVHD Grading Scale (1-4): Grade 1 is characterized as mild disease, Grade 2 as moderate, Grade 3 as severe (involvement of any organ system), and Grade 4 as life-threatening; chronic GVHD was determined by the Investigator. GVHD was seen after an eli-cel subject received a subsequent allogeneic hematopoietic stem cell transplant. No GVHD was seen in subjects who did not receive allogeneic stem cell transplants. Grade 2 nonserious GVHD was reported in a subject who received allogeneic transplant post eli-cel infusion. Percentage of subjects who experienced either acute (>= Grade 2) or chronic GVHD at Month 24 were reported. TP consisted of subjects who received Lenti-D Drug Product infusion. Evaluable subjects are defined as those who have either experienced the event by Month 24 (Rel Day 730) or have been followed for at least 12 months (Rel Day of last contact >= 365) if no events yet.
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End point type |
Secondary
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End point timeframe |
At Month 24
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to Neutrophil Engraftment After Drug Product Infusion | ||||||||
End point description |
Neutrophil engraftment is defined as achieving 3 consecutive absolute neutrophil count (ANC) laboratory values of >= 0.5 x 10^9 cells/liter (L) (after initial post-infusion nadir) obtained on different days by 42 days post‑infusion of eli-cel (Rel Day 43). TP consisted of subjects who received Lenti-D Drug Product infusion. Time to neutrophil engraftment after drug product infusion was reported. TP consisted of subjects who received Lenti-D Drug Product infusion
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End point type |
Secondary
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End point timeframe |
By 42 days post-drug infusion
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects With Platelet Engraftment by Month 24 | ||||||||
End point description |
Platelet engraftment was defined as achieving 3 consecutive unsupported platelet counts of >=20 x 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 x 10^9 cells/L was considered the Day of platelet engraftment. TP consisted of subjects who received Lenti-D Drug Product infusion. Subjects are evaluable for platelet engraftment if they achieved PE by Month 24, or have been followed for at least 24 months if no platelet engraftment.
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End point type |
Secondary
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End point timeframe |
At Month 24
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to Platelet Engraftment Post-drug Product Infusion | ||||||||
End point description |
Platelet Engraftment was defined as achieving 3 consecutive unsupported platelet counts of > or =20 x 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 x 10^9 cells/L was the day of PE. Time to platelet engraftment post-drug product infusion by Month 24 was reported. TP consisted of subjects who received Lenti-D Drug Product infusion.
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End point type |
Secondary
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End point timeframe |
At Month 24
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects with Loss of Neutrophil Engraftment Post-drug Product Infusion by Month 24 | ||||||||
End point description |
Subjects were considered to have primary engraftment failure if they did not achieve NE by Relative Day 43. A subject 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 x 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 x 10^9 cells/L was considered the day of secondary engraftment failure. Percentage of subjects with both primary or secondary loss of neutrophil engraftment at Month 24 were reported. TP consisted of subjects who received Lenti-D Drug Product infusion. Evaluable subjects include subjects who, had either primary engraftment failure or secondary engraftment failure by Month 24, or have been followed for at least 24 months if no events.
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End point type |
Secondary
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End point timeframe |
At Month 24
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects Who Underwent a Subsequent Allo-Hematopoietic Stem Cell Transplantation (HSCT) Infusion by Month 24 | ||||||||
End point description |
Percentage of subjects who have undergone a subsequent allo-HSCT infusion by Month 24 were reported. TP consisted of subjects who received Lenti-D Drug Product infusion. Evaluable subjects are defined as those who received subsequent allo-HSCT, or subjects who have been followed for at least 24 months (Rel Day of last contact >= 730 or completed Month 24 visit) if no events.
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End point type |
Secondary
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End point timeframe |
By Month 24
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects who Experienced Transplant-related Mortality Through 100 and 365 Days Post-drug Product Infusion | ||||||||||||
End point description |
Transplant-related mortality was determined by the investigator and summarized for the following intervals: from Rel Day 1 through 100 days post-drug product infusion (Rel Day 101) and from Rel Day 1 through 365 days post-drug product infusion (Rel Day 366). Percentage of subjects who experienced transplant-related mortality through 100 and 365 days post-drug product infusion were reported. TP consisted of subjects who received Lenti-D Drug Product infusion. Evaluable subjects include subjects who have died from transplant-related causes by Rel Day 101 or 366 respectively or have been followed to at least Rel Day 101 or 366 respectively if no events yet.
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End point type |
Secondary
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End point timeframe |
From time of drug product infusion through 100 and 365 days post-drug product infusion
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Subjects with Clinical >= Grade 3 AEs, All Investigational Medicinal Product-related AEs, all Serious Adverse Events (SAEs), and >= Grade 3 Infections | ||||||||||||||||
End point description |
Adverse event was defined as any untoward medical occurrence associated with the use of a drug product in subjects, 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 subject and may require medical or surgical intervention to prevent an outcome listed previously. Percentage of subjects with clinical >= Grade 3 AEs, all investigational medicinal product-related AEs, all serious adverse events (SAEs), and >= Grade 3 infections were reported. Intent-to-treat (ITT) population consisted of subjects who initiated any study procedures, beginning with mobilization by granulocyte colony stimulating factor (G-CSF).
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End point type |
Secondary
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End point timeframe |
From date of informed consent up to Month 24
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Percentage of Subjects With Potentially Clinically Significant Changes in Laboratory Parameters by Month 24 | ||||||||||||||||||||||||||||||||||||||||||
End point description |
Laboratory parameters included Hematology (Leukocytes [with a threshold 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]), Renal (Urea Nitrogen [>=10.7 mmol/L], Creatinine [>=150 umol/L]) and liver (Alanine Aminotransferase [ALA]. Aspartate Aminotransferase [ASA], Alkaline Phosphatase [AP] with threshold range of >=3 x upper limit of normal (ULN), Bilirubin [>=34.2 micromoles per liter (umol/L)]). Clinical significance was decided by investigator. ITT population consisted of subjects who initiated any study procedures, beginning with mobilization by G-CSF.
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End point type |
Secondary
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End point timeframe |
From Day 1 to Month 24
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||
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End point title |
Percentage of Subjects Who Experienced >= Grade 2 Acute Graft Versus Host Disease (GVHD) by Month 24 | ||||||||
End point description |
Acute GVHD graded on the Acute GVHD Grading Scale (1-4): Grade 1 is characterized as mild disease, Grade 2 as moderate, Grade 3 as severe (involvement of any organ system), and Grade 4 as life-threatening; Acute GVHD was determined by the Investigator. Grade 2 nonserious GVHD was reported in a patient who received allogeneic transplant post eli-cel infusion. TP consisted of subjects who received Lenti-D Drug Product infusion. Evaluable subjects are defined as those who had >= Grade 2 acute GVHD by Month 24 (Rel Day 730), or have been followed for at least 12 months (Rel Day of last contact >= 365) if no events yet. The case of GVHD was experienced by a subject after receiving allo-HSCT.
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End point type |
Secondary
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End point timeframe |
By Month 24
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects who Experienced Chronic GVHD by Month 24 | ||||||||
End point description |
Chronic GVHD graded on the Chronic GVHD Grading Scale as limited or extensive. Chronic GVHD was determined by the Investigator. Percentage of subjects who experienced chronic GVHD by Month 24 were reported. Evaluable subjects are defined as those who had chronic GVHD by Month 24 (Rel Day 730), or have been followed for at least 12 months (Rel Day of last contact >= 365) if no events yet.
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End point type |
Secondary
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End point timeframe |
By Month 24
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Emergency Room Visits (Post-Neutrophil Engraftment) By Month 24 | ||||||||
End point description |
Number of emergency room visits (post-neutrophil engraftment) up to Month 24 were reported. Successful Neutrophil Engraftment Population (NEP) consisted of subjects who achieved neutrophil engraftment defined as having 3 consecutive ANC laboratory values of >= 0.5×10^9 cells/L (after initial post-infusion nadir) obtained on different days by Rel Day 43.
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End point type |
Secondary
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End point timeframe |
From Post-Neutrophil Engraftment up to Month 24
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of In-patient Hospitalizations (Post-Neutrophil Engraftment) By Month 24 | ||||||||
End point description |
Number of In-patient hospitalizations (post-neutrophil engraftment) by Month 24 were reported. Successful NEP consisted of subjects who achieved neutrophil engraftment defined as having 3 consecutive ANC laboratory values of >= 0.5×10^9 cells/L (after initial post-infusion nadir) obtained on different days by Rel Day 43.
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End point type |
Secondary
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End point timeframe |
From post-neutrophil engraftment up to Month 24
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Duration of In-patient Hospitalizations (Post-Neutrophil Engraftment) up to Month 24 | ||||||||
End point 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. Successful NEP consisted of subjects who achieved neutrophil engraftment defined as having 3 consecutive ANC laboratory values of >= 0.5×10^9 cells/L (after initial post-infusion nadir) obtained on different days by Rel Day 43. Here, "number of subjects analysed" signified those subjects who were evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From post-neutrophil engraftment up to Month 24
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Number of Intensive Care Units (ICU) Stays (Post-neutrophil Engraftment) By Month 24 | ||||||||
End point description |
Number of ICU Stays (Post-neutrophil Engraftment) By Month 24 were reported. Successful NEP consisted of subjects who achieved neutrophil engraftment defined as having 3 consecutive ANC laboratory values of >= 0.5×10^9 cells/L (after initial post-infusion nadir) obtained on different days by Rel Day 43.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From post-neutrophil engraftment up to Month 24
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Duration of ICU Stays (Post-neutrophil Engraftment) By Month 24 | ||||||||
End point 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. Successful NEP consisted of subjects who achieved neutrophil engraftment defined as having 3 consecutive ANC laboratory values of >= 0.5×10^9 cells/L (after initial post-infusion nadir) obtained on different days by Rel Day 43.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From post-neutrophil engraftment up to Month 24
|
||||||||
|
|||||||||
| Notes [3] - No subjects had ICU stay and median was not estimable. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||
End point title |
Number of Subjects who Tested Positive and Negative for Vector-Derived Replication Competent Lentivirus (RCL) Detected by Month 24 | ||||||||||
End point description |
Number of subjects who tested positive and negative for vector-derived RCL detected at Month 24 were reported. Screening of subject's 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. TP consisted of subjects who received Lenti-D Drug Product infusion. Subjects were evaluable if they have at least 1 RCL assessment
|
||||||||||
End point type |
Secondary
|
||||||||||
End point timeframe |
By Month 24
|
||||||||||
|
|||||||||||
| No statistical analyses for this end point | |||||||||||
|
|||||||
End point title |
Number of Subjects With Insertional Oncogenesis By Month 24 | ||||||
End point description |
Insertional oncogenesis included myelodysplastic syndrome, leukemia, lymphoma. Number of subjects with insertional oncogenesis at Month 24 were reported. TP consisted of subjects who received Lenti-D Drug Product infusion.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
By Month 24
|
||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||||||
End point title |
Number of Subjects With >= Grade 3 Prolonged Cytopenia on or After Rel Day 60 And Rel Day 100 | ||||||||||
End point description |
Number of subjects with >= Grade 3 prolonged cytopenia (i.e., decreased platelet counts, decreased neutrophil counts, and/or decreased hemoglobin counts) on or after Rel Day 60 and Rel Day 100 were reported. TP consisted of subjects who received Lenti-D Drug Product infusion.
|
||||||||||
End point type |
Secondary
|
||||||||||
End point timeframe |
Prolonged cytopenias occurring on or after Rel Day 60 and Rel Day 100 following drug product infusion
|
||||||||||
|
|||||||||||
| No statistical analyses for this end point | |||||||||||
|
|||||||||
End point title |
Median Number of Emergency Room Visits (Post-Neutrophil Engraftment) By Month 24 | ||||||||
End point description |
Median number of emergency room visits (post-neutrophil engraftment) up to Month 24 were reported. Successful Neutrophil Engraftment Population (NEP) consisted of subjects who achieved neutrophil engraftment defined as having 3 consecutive ANC laboratory values of >= 0.5×10^9 cells/L (after initial post-infusion nadir) obtained on different days by Rel Day 43. Here, "number of subjects analysed" signified those subjects who were evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From Post-Neutrophil Engraftment up to Month 24
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Median Number of In-patient Hospitalizations (Post-Neutrophil Engraftment) By Month 24 | ||||||||
End point description |
Median number of In-patient hospitalizations (post-neutrophil engraftment) by Month 24 were reported. Successful NEP consisted of subjects who achieved neutrophil engraftment defined as having 3 consecutive ANC laboratory values of >= 0.5×10^9 cells/L (after initial post-infusion nadir) obtained on different days by Rel Day 43. Here, "number of subjects analysed" signified those subjects who were evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From post-neutrophil engraftment up to Month 24
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
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Adverse events information
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Timeframe for reporting adverse events |
From date of informed consent up to Month 24
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.0
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Reporting groups
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Reporting group title |
Lenti-D Drug Product
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Reporting group description |
On Day 1, subjects received a single IV infusion of Lenti-D Drug Product at a dose of >= 5.0 x 10^6 CD34+ cells/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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
|||||||
| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
||||||
13 Mar 2019 |
Protocol Amendment 2:
• Addition of G-CSF on apheresis days to optimize cell collection
• Added guidelines for administration of G-CSF after infusion of drug product to improve engraftment and align with standard study center practices
• Clarified that the semi-quantitative linear amplification mediated PCR (LAMPCR) or equivalent method will be used as a screening tool for identifying integration sites (IS) of interest, but that the frequencies used to determine whether a clinical work-up is required are to be based on quantitative IS-specific methodology. |
||||||
09 May 2019 |
Protocol Amendment 3:
• Added exclusion criterion for known hypersensitivity to protamine sulfate, as there may be residual amount of protamine sulfate in eli-cel. |
||||||
29 Jan 2020 |
Protocol Amendment 4:
• Increased the subject number to 35, expanding the cohort in order to accrue additional efficacy and safety information. In addition, updated statistical measures in the text to reflect the change in subject number.
• Revised the definition of hematological compromise in exclusion criterion #5 such that subjects are only excluded if both ANC count is < 1500 cell/mm^3 and either platelet count is < 100,000 cells/mm^3 or hemoglobin < 10g/dl. This change will allow inclusion of subjects who have only benign ethnic neutropenia and are not at risk of hematological complications. The removal of uncorrected bleeding disorder is now covered in exclusion criteria #12, as described in the list of non-substantial changes.
• Revised the language around enrollment and infusion of drug product suspension criteria to allow for individualization of benefit: risk assessment.
• Removed visits Month 9, Month 15, and Month 21 to decrease visit frequency to every 6 months, thereby decreasing patient burden without affecting patient safety by matching standard practice of maintenance visits every 6 months.
• Removed “uncorrected bleeding disorder” from exclusion criteria #5 and added contraindicated hematological disease to exclusion criteria #12 to increase specificity and remove redundancy of each criterion.
• Removed the neurological exam, NFS assessment, and MFD assessment from the Week 2 Visit to relieve patient burden in the acute post-transplantation period.
• Added text in Section 6.5.10 to reflect that MRIs will also be used to determine white matter lesion progression using volumetric analysis.
• Clarified in the text that mutational analysis of the ABCD1 gene is required before commencing conditioning. |
||||||
11 Sep 2020 |
Protocol Amendment 5:
• Revised algorithm for assessing clonal predominance.
• A change to drug product release guidelines.
• Clarifications around enrollment and drug product infusion suspension criteria.
• Clarifications around safety endpoints and exploratory endpoints.
• New guidelines around the impact of the COVID-19 pandemic, the use of antiretroviral medications, and the follow-up of newborns.
• Additional non-substantial changes. |
||||||
28 Jun 2021 |
Protocol Amendment 6:
• Provided considerations for vaccines as concomitant medications per guidance from a regulatory agency.
• In line with FDA Guidance on Long Term Follow-Up After Administration of Human Gene Therapy Product and to align protocols across regions, clarified that a sample for repeat ISA will be collected within 3 months of detection of a predominant clone. The figure was updated to indicate that ISA will be done yearly after Year 5 in Study LTF-304.
• Given the severity of the disease and limited treatment options, the clinical work-up for potential malignancy has been updated to allow for a safety review to be convened rather than immediate suspension of enrollment, allowing for individual benefit:risk assessment.
|
||||||
22 Nov 2022 |
Protocol Amendment 8:
• Protocol updated to reflect that parent study ALD-102 was completed and follow-up study LTF-304 was ongoing, where applicable.
• Added reference to Skysona U.S. product package insert and IB, where applicable.
• Updated exploratory endpoints relating to percent of cells expressing ALDP and VCN in cells to include both peripheral blood cells and CD14+ cells.
• A new section was added to describe characterization of protocol deviations.
• Impact of force of nature text updated to include war due to the impact on subject visits of the Russo-Ukrainian War.
• Text was revised to increase the number/frequency of collection timepoints for CBC with differential to occur monthly during the first year after eli-cel infusion, and thereafter every 4 months until Month 24. Text also edited to note that unscheduled visits may be performed for enhanced CBC and BM abnormality monitoring.
• Table row in Schedule of Events relating to bone marrow assessments updated to clarify that it included core needle biopsy and aspirate sampling and that samples were used for ISA, VCN and storage purposes. Several related footnotes were also updated.
• New section added to provide more detail on sample collection for RCL Testing, Integration Site Analysis, and VCN in Blood.
• Text updated to clarify that immunological studies should be conducted locally.
• Updates were made to refine order of priority of sample collection and to include bone marrow collection details and prioritization.
• Peripheral blood smears added to table of laboratory parameters and removed from prior section relating to performance of additional test at the Investigator’s discretion.
• Clarified general statistical methods relating to analyses pertaining to subjects who undergo allo-HSCT.
• A new safety analysis was added to provide the statistical definition of current oligoclonality and current persistent oligoclonality. |
||||||
Interruptions (globally) |
|||||||
| Were there any global interruptions to the trial? Yes | |||||||
|
|||||||
Limitations and caveats |
|||||||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| None reported | |||||||
