Clinical Trial Results:
Phase I/II clinical trial of haematopoietic stem cell gene therapy for the Wiskott-Aldrich Syndrome
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Summary
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EudraCT number |
2009-011152-22 |
Trial protocol |
FR |
Global end of trial date |
09 Jan 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
30 Jun 2019
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First version publication date |
30 Jun 2019
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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 |
GTG003.08
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01347346 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
GENETHON
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Sponsor organisation address |
1 bis rue de l'Internationale, EVRY, France, 91002
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Public contact |
GERALDINE HONNET, GENETHON, 0033 169472868, clinical_development@genethon.fr
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Scientific contact |
GERALDINE HONNET, GENETHON, 0033 169472868, clinical_development@genethon.fr
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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-000786-PIP01-09 | ||
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 |
20 Jan 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
20 Jan 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
09 Jan 2017
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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 |
To assess the efficacy of haematopoietic stem-cell gene therapy in Wiskott-Aldrich syndrome (WAS) patients based on the clinical improvement in at least one of the following clinical parameters depending on the patient's symptomatology at study entry: eczema status, frequency and severity of infections, of bruising and bleeding episodes and of autoimmune disorders and consequently to assess the number of disease-related days of hospitalization.
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Protection of trial subjects |
Only male patients with WAS confirmed by DNA sequencing and with a severity score of 3 to 5 who had no suitable donor for an allogeneic HSCT were enrolled.
The cell/product target dose consisted of at least 3 x 10^6 but not more than 15 x 10^6 CD34+ cells per kg body weight transduced ex vivo with 1 x 10^8 i.g./mL of vector to achieve an average of 1 copy integrated per cell in 30-60% of cells. CD34+ cells were purified from bone marrow cells harvested under general anaesthesia, or from PBMCs mobilised through the use of G-CSF and plerixafor and recovered by leukapheresis, depending on the patient’s body weight and clinical status. Patient conditioning was to be initiated immediately after bone marrow or PBMC collection and consisted of busulfan (4 mg/kg) and fludarabine (40 mg/m2) for 3 days.
If the number of CD34+ was less than 1 x 10^6/kg, the cells were not to be infused, and the patient was to receive a haploidentical bone-marrow graft and to be withdrawn
from the study.
If there was no bone marrow recovery within 6 weeks, the patient was to receive a haploidentical bone marrow graft.
Follow-up of patients including physical examinations and blood tests were to take place at 1 month, 6 weeks, and 3, 6, 9, 12, 18, and 24 months after infusion of transduced cells. After completion of this 2-year follow-up period, patients could participate in a long-term follow-up study for another 8 years.
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Background therapy |
The only known cure for WAS is allogeneic haematopoietic stem cell transplantation (HSCT), using bone marrow, peripheral blood, or umbilical cord blood from a human leukocyte antigen (HLA)-matched donor. HLA-mismatched transplantation carries an increased risk for complications, in particular for graft vs. host disease, causing increased morbidity and mortality. In a cohort of 137 WAS patients treated in Europe, overall survival was 83% for matched family donor transplants, 75% for matched unrelated donor transplants, and 50% for related HLA-mismatched donors. It is estimated that a fully matched donor can be found for about a third to one half of the patients with WAS. As a result of existing therapeutic interventions, some patients with WAS survive into adulthood, however a significant number of patients die in their infancy from haemorrhage, infection, malignancy, or complications of HSCT. Despite the established role of allogeneic HSCT for patients with a suitable donor, there is still a need for novel, effective, well-tolerated treatments for WAS, particularly in patients with severe disease and those who lack an HLA-matched allogeneic donor. The knowledge of the defective gene causing WAS has prompted the development of new treatment options, focusing on the infusion of autologous hematopoietic stem cells modified ex vivo by gene therapy. | ||
Evidence for comparator |
The choice of a design with no control group was considered to be appropriate to establish a proof of concept and to investigate the safety of the investigational product in patients with severe WAS. Given the rarity and severity of the disease as well as the lack of therapeutic alternatives, apart from an allogeneic Haemotopoietic Stem Cell Transplantation, a controlled design was considered to be neither feasible nor ethically justifiable. | ||
Actual start date of recruitment |
04 May 2011
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy, Ethical reason, Regulatory reason, Scientific research | ||
Long term follow-up duration |
10 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 |
France: 5
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Worldwide total number of subjects |
5
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EEA total number of subjects |
5
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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) |
1
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Children (2-11 years) |
3
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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 |
Patients were all enrolled in one center at Necker-Enfants Malades Hospital, Paris, France from May the 4th, 2011 (patient # FR01) to January the 6th, 2014 (FR05). | ||||||||||
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Pre-assignment
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Screening details |
Male patients with WAS confirmed by DNA sequencing and with a severity score of 3 to 5 who had no suitable donor for an allogeneic Haematopoietic stem cell transplantation | ||||||||||
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Pre-assignment period milestones
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Number of subjects started |
5 | ||||||||||
Number of subjects completed |
5 | ||||||||||
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Period 1
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Period 1 title |
overall trial (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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Treatment | ||||||||||
Arm description |
Single infusion of patient-specific test product, followed by a 2-year follow-up period | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
Autologous CD34+ cells transduced with w1.6_hWASP_WPRE lentiviral vector
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Suspension for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Patient-specific test product, corresponding to autologous CD34+ cells transduced ex vivo with the w1.6_hWASP_WPRE (VSVg) lentiviral vector containing the human WAS gene in final formulation and container closure system, ready for intended medical use
Intravenous administration
Single infusion, cell/product target dose consisting of at least 3 x 10^6 but not more than 15 x 10^6 CD34+ cells per kg bodyweight transduced ex vivo with 1 x 10^8 i.g./ml of vector to achieve an average of 1 copy integrated per cell in 30-60% of cells
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Baseline characteristics reporting groups
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Reporting group title |
overall trial
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Reporting group description |
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End points reporting groups
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Reporting group title |
Treatment
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Reporting group description |
Single infusion of patient-specific test product, followed by a 2-year follow-up period | ||
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End point title |
Improvement in at least one of the following clinical conditions: eczema, infection, bruising/bleeding, autoimmune disorders, disease-related days of hospitalisation [1] | ||||||||||
End point description |
Improvement at 24 months in at least one of the following clinical conditions depending on the patient’s clinical symptomatology at study entry:
- Improvement in the eczema status at 24 months as compared with the baseline status at study entry.
- Reduction in the frequency and severity of infection episodes at 24 months as compared with the baseline status and the patient’s historical data collected over the 24 months prior to study entry.
- Reduction in the frequency and severity of bruising and bleeding episodes at 24 months evaluated by clinical examination as compared with the baseline status at study entry and the patient’s historical data collected over the 24 months prior to study entry.
- Reduction in the frequency and severity of autoimmune disorders at 24 months as compared with the baseline status at study entry.
- Reduction in the number of disease-related days of hospitalisation as compared with the patient’s historical data collected over the 24 months prior.
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End point type |
Primary
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End point timeframe |
24 months
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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 statistical analyses only, small sample size (n=5). |
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| Notes [2] - One patient died before completing the 2-year follow-up period |
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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 26 April 2011 to 20 January 2016
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.0
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Reporting groups
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Reporting group title |
Treatment
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Reporting group description |
Single infusion of patient-specific test product, followed by a 2-year follow-up period | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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11 Jan 2010 |
Modification of the clinical study protocol further to the deletion of the freezing and cryopreservation of transduced cells in the manufacturing process of the IMP:
- clarification of the inclusion and exclusion criteria
- modification of the conditioning regimen
- modification of the final total cell number required for engraftment
- adaptation of the primary Endpoint
Modification of the requirements for collecting and storing patient serum samples for RCL analysis
Addition of criteria for assessing the severity of AEs |
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09 Apr 2014 |
Adaptation of the clinical study protocol to comply with the Paediatric Investigation Plan approved by the Paediatric Committee of the EMA on 17 Sep 2013:
- modification of the primary and secondary objectives
- modification of inclusion criteria
- modification of the clinical monitoring during post-infusion period
- clarifications regarding the collection and analysis of AE data
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| Small sample size (n=5), One arm non comparative study, Descriptive statistical analyses only | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/25898053 http://www.ncbi.nlm.nih.gov/pubmed/28716862 http://www.ncbi.nlm.nih.gov/pubmed/26672655 |
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