Clinical Trial Results:
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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Summary
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EudraCT number |
2011-001953-10 |
Trial protocol |
GB FR DE Outside EU/EEA |
Global end of trial date |
26 Mar 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
10 Oct 2021
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First version publication date |
10 Oct 2021
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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-102
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01896102 | ||
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 |
60 Binney Street, Cambridge, Massachusetts, United States, 02142
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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) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001244-PIP01-11 | ||
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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
26 Mar 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
26 Mar 2021
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Global end of trial reached? |
Yes
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Global end of trial date |
26 Mar 2021
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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 (eli-cel) 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 |
21 Aug 2013
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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 |
15 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 |
United Kingdom: 2
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Country: Number of subjects enrolled |
France: 1
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Country: Number of subjects enrolled |
Germany: 1
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Country: Number of subjects enrolled |
United States: 28
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Worldwide total number of subjects |
32
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EEA total number of subjects |
2
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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) |
31
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Adolescents (12-17 years) |
1
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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 in France, Germany, the United Kingdom and the United States from 21 August 2013 (First subject signed informed consent) to 26 March 2021 (Last subject last visit). | ||||||||||||
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Pre-assignment
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Screening details |
A total of 32 subjects were enrolled and treated in this study. All male subjects with CALD were treated 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 |
Subjects 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 contains cells transduced with lentiviral vector encoding ABCD1 cDNA for human adrenoleukodystrophy protein, suspended in a cryopreservative solution) on Day 0. | ||||||||||||
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 |
Autologous CD34+ cells transduced with Lenti -D LVV (lentiviral vector) encoding ABCD1 cDNA, elivaldogene autotemcel, eli-cel
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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 0.
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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 |
Subjects 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 contains cells transduced with lentiviral vector encoding ABCD1 cDNA for human adrenoleukodystrophy protein, suspended in a cryopreservative solution) on Day 0. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 |
Subjects 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 contains cells transduced with lentiviral vector encoding ABCD1 cDNA for human adrenoleukodystrophy protein, suspended in a cryopreservative solution) on Day 0. | ||
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End point title |
Proportion of Subjects Who are 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 was 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. The proportion of subjects was calculated by dividing that subjects who are alive by the number of evaluable subjects and multiplying by 100%.
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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 |
Proportion of Subjects Who Experienced Either Acute (>= Grade II) or Chronic Graft Versus Host Disease (GVHD) at Month 24 [2] | ||||||||
End point description |
Proportion of subjects who experienced with either acute (>= Grade II) or chronic GVHD at Month 24 was reported. 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. TP consisted of subjects who received Lenti-D Drug Product infusion. The proportion of subjects was calculated by dividing that subjects who experienced with either acute (>= Grade II) or chronic GVHD by the number of evaluable subjects and multiplying by 100%.
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End point type |
Primary
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End point timeframe |
At Month 24
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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 |
Proportion of Subjects Who Demonstrated Resolution of Gadolinium Positivity on MRI at Month 24 | ||||||||
End point description |
Proportion of subjects who demonstrated resolution of gadolinium positivity (i.e., GdE-) on Magnetic Resonance Imaging (MRI) at Month 24 were reported. 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. The proportion of subjects was calculated by dividing that subjects who demonstrated resolution of gadolinium positivity by the number of evaluable subjects and multiplying by 100%.
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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 Sustained Resolution of Gadolinium Positivity on MRI up to Month 24 | ||||||||
End point description |
Sustained resolution of gadolinium positivity was defined as having at least two consecutive GdE- results by MRI without a subsequent evaluation indicating GdE+. 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 |
Up to 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 Total Neurologic Function Score (NFS) from Baseline up to Month 24 | ||||||||||||||
End point description |
NFS was a 25-point composite scale used to evaluate the severity of gross neurologic dysfunction in CALD by scoring 15 symptoms across 6 categories: Hearing/auditory processing problems-1; Aphasia/apraxia-1; Loss of communication-3; Vision impairment/field cut-1; Cortical blindness-2; Swallowing/other central nervous system dysfunctions-2; Tube feeding-2; Running difficulties/hyperreflexia-1; Walking difficulties/spasticity/spastic gait (no assistance)-1; Spastic gait (needs assistance)-2; Wheelchair dependence-2; Complete loss of voluntary movement-3; Episodes of incontinence -1; Total incontinence-2; Nonfebrile seizures-1. A score of "0" denotes absence of clinical signs of cerebral disease. TP analysis set was used. 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 |
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 at 24 Months | ||||||||
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 analysed using Kaplan-Meier Analysis. Kaplan-Meier estimated MFD-free survival rate at 24 months after eli-cel 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 |
At 24 months after eli-cel infusion
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall Survival Rate at 24 Months | ||||||||
End point description |
Overall survival rate was defined as percentage of subjects 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 subject was still alive. Subjects who are alive were censored at the date of last contact. Overall survival rate was analysed using Kaplan-Meier Analysis. Kaplan-Meier estimated overall survival rate at 24 months after eli-cel infusion was reported. TP consisted of subjects who received Lenti-D Drug Product infusion. Percentage of subjects who survived till Month 24 were reported.
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End point type |
Secondary
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End point timeframe |
At 24 months after eli-cel infusion
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| No statistical analyses for this end point | |||||||||
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End point title |
Proportion of Subjects With Neutrophil Engraftment at 42 Days Post-drug Product Infusion | ||||||||
End point 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 at 42 days post-infusion of Lenti-D Drug Product (Relative Day 43). Proportion of subjects with neutrophil engraftment at 42 Days post-drug product infusion were reported. TP consisted of subjects who received Lenti-D Drug Product infusion. The proportion of subjects was calculated by dividing that subjects with neutrophil engraftment by the number of evaluable subjects and multiplying by 100%.
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End point type |
Secondary
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End point timeframe |
At 42 days post-drug infusion
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to Neutrophil Engraftment Post-drug Product Infusion | ||||||||
End point 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). 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 42 days post-drug infusion
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| No statistical analyses for this end point | |||||||||
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End point title |
Proportion of Subjects With Platelet Engraftment at Month 24 | ||||||||
End point 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. Proportion of subjects with platelet engraftment at Month 24 were reported. TP consisted of subjects who received Lenti-D Drug Product infusion. The proportion of subjects was calculated by dividing that subjects with platelet engraftment by the number of evaluable subjects and multiplying by 100%.
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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 × 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. 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 |
Up to Month 24
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| No statistical analyses for this end point | |||||||||
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End point title |
Proportion of Subjects With Engraftment failure at Month 24 | ||||||||
End point description |
Subject was considered to have primary engraftment failure if he did not achieve NE by Relative Day 43. A subject was considered to have secondary engraftment failure if he achieved and then subsequently lost NE by the Month 24, i.e., if he met both the conditions:- Achieved NE by Relative Day 43 as defined above;- 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. Proportion of subjects with primary or secondary engraftment failure at Month 24 were reported. TP population. Number of subjects analysed signifies those subjects who were evaluable for this endpoint. The proportion of subjects was calculated by dividing that subjects with engraftment failure by the number of evaluable subjects and multiplying by 100%.
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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 |
Proportion of Subjects Who Undergone a Subsequent Hematopoietic Stem Cell (HSC) Infusion at Month 24 | ||||||||
End point description |
Proportion of subjects who undergone a HSC infusion at Month 24 were reported. 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. The proportion of subjects was calculated by dividing that subjects who undergone a HSC infusion by the number of evaluable subjects and multiplying by 100%.
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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 |
Proportion of Subjects With Transplant-related Mortality Through 100 and 365 Days Post-drug Product Infusion | ||||||||||||
End point description |
Transplant-related mortality was determined by the Investigator. Proportion of subjects with 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. The proportion of subjects was calculated by dividing that subjects with transplant-related mortality by the number of evaluable subjects and multiplying by 100%.
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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 |
Proportion of Subjects With Adverse Events (AEs), Serious AEs, Grade >=3 AE, Related AEs, Related SAEs and Related Grade >=3 AEs | ||||||||||||||||||||
End point description |
AE: any untoward medical occurrence associated with the use of a drug 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. Proportion of subjects with all AEs, all SAEs, all drug-product related AEs, clinical AEs > or = Grade 3 AEs, AEs > or = Grade 3 infections were reported. Intent-to-treat (ITT) population: subjects who initiated any study procedures, beginning with mobilization by G-CSF. Proportion of subjects was calculated by dividing that subjects with AEs by the number of evaluable subjects and multiplying by 100%.
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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 |
Proportion of Subjects With Potentially Clinical Significant Changes in Laboratory Parameters up to Month 24 | ||||||||||||||||||||||||||||||||||||||||
End point 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. ITT population consisted of subjects who initiated any study procedures, beginning with mobilization by G-CSF. Proportion of subjects was calculated by dividing that subjects with potentially clinical significant changes in laboratory parameters by the number of evaluable subjects and multiplying by 100%.
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End point type |
Secondary
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End point timeframe |
From time of drug product infusion up to Month 24
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||
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End point title |
Proportion of Subjects With >= Grade II Acute GVHD at Month 24 | ||||||||
End point description |
Proportion of subjects with >= Grade II acute GVHD at Month 24 were reported. 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. TP consisted of subjects who received Lenti-D Drug Product infusion. The proportion of subjects was calculated by dividing that subjects with >= Grade II acute GVHD by the number of evaluable subjects and multiplying by 100%.
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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 |
Proportion of Subjects With Chronic GVHD at Month 24 | ||||||||
End point description |
Proportion of subjects with chronic GVHD at Month 24 were reported. Chronic GVHD was determined by the Investigator. TP consisted of subjects who received Lenti-D Drug Product infusion. The proportion of subjects was calculated by dividing that subjects with chronic GVHD by the number of evaluable subjects and multiplying by 100%.
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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 Emergency Room Visits (Post-Neutrophil Engraftment) up to Month 24 | ||||||||
End point description |
Number of emergency room visits (post-neutrophil engraftment) up to Month 24 were reported. The successful Neutrophil Engraftment Population (NEP) consisted of subjects who achieved NE 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 42 days post‑infusion of Lenti-D Drug Product.
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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) up to Month 24 | ||||||||
End point description |
Number of In-patient hospitalizations (post-neutrophil engraftment) up to Month 24 were reported. The successful NEP consisted of subjects who achieved NE 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 42 days post‑infusion of Lenti-D Drug Product.
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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 |
Duration of In-patient Hospitalizations (Post-Neutrophil Engraftment) up to Month 24 | ||||||||
End point description |
Duration of In-patient hospitalizations (post-neutrophil engraftment) up to Month 24 was reported. The successful NEP consisted of subjects who achieved NE 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 42 days post‑infusion of Lenti-D Drug Product. 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 |
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 Intensive Care Units (ICU) Stays (Post-neutrophil Engraftment) up to Month 24 | ||||||||
End point description |
Number of ICU Stays (Post-neutrophil Engraftment) up to Month 24 were reported. The successful NEP consisted of subjects who achieved NE 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 42 days post‑infusion of Lenti-D Drug Product.
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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 |
Duration of ICU Stays (Post-neutrophil Engraftment) up to Month 24 | ||||||||
End point description |
Duration of ICU Stays (Post-neutrophil Engraftment) up to Month 24 was reported. The successful NEP consisted of subjects who achieved NE 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 42 days post‑infusion of Lenti-D Drug Product. 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 |
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 Subjects With Vector-derived Replication Competent Lentivirus (RCL) Detected at Month 24 | ||||||
End point description |
Number of subjects with Vector-derived RCL detected at Month 24 were 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 |
Number of Subjects With Insertional Oncogenesis at Month 24 | ||||||
End point description |
Insertional oncogenesis included myelodysplasia, leukemia, lymphoma malignancies. Number of subjects with insertional oncogenesis at Month 24 were 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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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 |
Subjects received a single IV infusion of Lenti-D Drug Product at a dose of >= 5.0 × 10^6 CD34+ cells/kg (autologous CD34+ cell-enriched population that contains cells transduced with Lenti-D lentiviral vector encoding human adrenoleukodystrophy protein, suspended in a cryopreservative solution) on Day 0. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 |
||||||
03 Mar 2013 |
Protocol Amendment 2:
- Original protocol to enroll subjects. |
||||||
19 Jun 2013 |
Protocol Amendment 3:
- Changed inclusion criteria from boys <= 15 years of age to boys <= 17 years of age.
- Loosened the exclusion criteria from [12 months before D-60 to 3 months before D-60] of receiving an investigational study drug or procedure.
- Subjects who experience engraftment failure changed from being terminated from the study to continue to be followed for safety and efficacy after engraftment failure.
- Added discontinuation criteria:
* Vector copy number (VCN) is undetectable (< 0.002 copies per cell)
* neurological decline between Screening and Day -11, as evidence by NFS > 1 or Loes Score > 9
- Added plerixafor as a potential mobilizing agent if filgrastim alone is not sufficient.
- Reduced the number of rounds of apheresis (5 to 3) per mobilization cycle.
- Removed 6 neuropsychological tests that are not universally performed; added 4 neuropsychological tests that are more suitable for a global, multicenter study.
|
||||||
04 Oct 2013 |
Protocol Amendment 4:
- Removed requirement of a positive replication competent lentivirus reverse transcriptase-polymerase chain reaction (RCL RT-PCR) test before p24 protein enzyme-linked immunosorbent assay (ELISA) testing. |
||||||
09 Jul 2014 |
Protocol Amendment 5.1:
- To align with current standards, changed VCN discontinuation criterion from < 0.002 to < 0.0003 copies per cell.
- Clarified that enrollment will be temporarily held if any death occurs on the study.
- To align with current standards, changed criterion of work-up for clonal dominance from greater than (>) 20 percent (%) of cells to > 10% of total PBLs with gene marking derived from a single clone.
- Removed very long-chain fatty acids (VLCFA) testing at Month 3 Visit to allow time for engrafted cells to promote metabolism of VLCFA.
- Clarify that filgrastim may be used at the Investigator’s discretion after infusion of eli-cel.
- Clarified that Grade 3 and Grade 4 lab values related to myeloablative conditioning will not be reported as an SAE unless they meet the requirement of being immediately life threatening. |
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04 Jun 2016 |
Protocol Amendment 6.2:
- Increased the number of subjects to be infused with drug product from 15 to 17.
- Allowed for the use of lenograstim in addition to filgrastim for G-CSF use during mobilization.
- Added collection and analysis of GVHD (GVHD not expected in ALD 102 but important in comparing eli-cel with allo-HSCT).
- Removed integration site analysis (ISA) from Month 3 Visit; Added ISA back into Month 18.
- Month 24 Visit window changed from +/= 60 days to +/= 30 days to align with previous visit windows. |
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01 Nov 2016 |
Protocol Amendment 7:
- Increased the number of subjects to be infused with drug product from 17 to 25.
- Added assessments to Screening, Month 12, and Month 24 visits to confirm reconstitution of immune system post-drug product infusion.
- Specified that discontinuation due to disease progression or an SAE related to drug product, or who develop an MFD or die prior to Month 24 will be considered treatment failures in the primary efficacy analysis.
- Added that subjects who are evaluated after Month 24 and are MFD free will be considered successful in primary analysis.
- Expanded comparison population for safety endpoints to include allo HSCT-treated population in Study ALD-103. |
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06 Oct 2017 |
Protocol Amendment 8:
- Increased the number of subjects to be infused with drug product from 25 to approximately 30.
- Clarified that the assessment of MFDs does not require an NFS assessment .
- Clarified secondary efficacy endpoint for time to sustained resolution of gadolinium positivity on MRI, where sustained is defined as resolution without a subsequent evaluation indicating gadolinium positivity.
- Increased the dose for the eli-cel to >= 5.0 × 10^6 CD34+ cells/kg based on data from first 21 patients showing that doses of >= 6 ×10^6 were well tolerated.
- Increased the target cell collection during apheresis to 12 × 10^6 CD34+ cells/kg.
- Increased volume range to between 20 and 80 milliliter (mL) for infusion to allow for infusion of two drug product lots of 2 bags each.
- Based on regulatory recommendations, adjusted guideline on blood sample volume limits to not exceed 3% of total blood volume during a period of four weeks and to not exceed 1% at any single time.
- Added possibility to screen for human immunodeficiency virus-1 (HIV-1) if the replication competent lentivirus (RCL) screening assay has a positive result.
- Added that additional analyses can be performed for regulatory purposes any time after the first 17 subjects complete the study.
- Clarified that occurrence of a second transplant is considered a treatment failure.
- Adjusted point estimates based on the number of subjects planned for enrollment.
- Indicated that the all transplant population of ALD-101 and ALD-103 would be used for safety endpoints as a more appropriate comparator. |
||||||
24 Aug 2018 |
Protocol Amendment 9:
- Changed “incidence” to “proportion of subjects” in several endpoints, which is considered more accurate from a statistical standpoint. This change in terminology does not change the interpretation or analyses of the concerned endpoints.
- Clarified definitions for neutrophil engraftment, neutrophil engraftment failure, platelet engraftment, and platelet engraftment failure.
- Immunological Testing was added to Month 3 and Month 6 Visits to allow assessment of the rapidity of immune reconstitution after transplant.
- Added that the primary efficacy endpoint will also be analyzed for the ITT population if it is different than the TP, in response to Regulatory Agencies' recommendation during scientific advice.
- Updated the Baseline definitions for safety and efficacy analyses to reflect most recent value not impacted by a study procedure.
|
||||||
23 Sep 2020 |
Protocol Amendment 10:
- Separated the safety endpoint for insertional oncogenesis and clonal predominance into two endpoints, with insertional oncogenesis as a secondary endpoint and clonal predominance as an exploratory endpoint.
- Revised exploratory efficacy endpoints to provide individual outputs rather than change over time, as absolute values are a more informative parameter for analysis.
- Added text to provide guidelines around study procedures and assessments impacted by the COVID-19 pandemic.
- Added text to indicate that clinical work-up for unexpected blood test results may be performed.
- Updated the assessment of clonal predominance to be based on frequency of clones with lentiviral vector (LVV) insertions rather than on frequency of individual LVV insertion sites.
|
||||||
Interruptions (globally) |
|||||||
| Were there any global interruptions to the trial? Yes | |||||||
|
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Limitations and caveats |
|||||||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| None reported | |||||||
