Clinical Trial Results:
Gene therapy for SCID-X1 using a self-inactivating (SIN) gammaretroviral vector.
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Summary
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EudraCT number |
2007-000684-16 |
Trial protocol |
GB |
Global end of trial date |
14 Jan 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
26 Jul 2019
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First version publication date |
26 Jul 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 |
06MI10
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01175239 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Great Ormond Street Hospital NHS Foundation Trust
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Sponsor organisation address |
Great Ormond Street, London, United Kingdom, WC1N 3JH
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Public contact |
Professor Adrian Thrasher, UCL Great Ormond Street Institute of Child Health, +44 (0)2079052660, a.thrasher@ucl.ac.uk
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Scientific contact |
Professor Adrian Thrasher, UCL Great Ormond Street Institute of Child Health, +44 (0)2079052660, a.thrasher@ucl.ac.uk
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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 |
14 Jan 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
14 Jan 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
14 Jan 2019
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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 |
1. Treatment of SCID-X1 patients by somatic gene therapy when HLA-matched family or unrelated bone marrow donors are unavailable.
2. Successful ex vivo transduction of CD34+ haematopoietic cells from SCID-X1 patients by ex vivo gammaretrovirus-mediated gene transfer.
3. Evaluation of immunological and functional reconstitution in progeny of engrafted cells.
4. Longitudinal evaluation of clinical effect in terms of augmented immunity.
5. Evaluation of the functional performance of novel SIN gammaretroviral configuration.
6. Evaluation of the molecular characteristics of vector integration.
7. Evaluation of safety.
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
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Background therapy |
Bone marrow transplantation can often cure SCID-X1 particularly when an exact donor match from a brother or sister is available. However, only a third of children have a fully matched donor and the chances of success from other donor sources are not so good. For example, if a parent is used as a donor, the bone marrow is only half-matched, and more than 10% of patients will not survive beyond a year after transplant. Other survivors may also suffer from long term problems related to the toxic effect of the chemotherapy which is sometimes used to help the new bone marrow establish, and also graft versus host disease (GvHD), a condition where donor lymphocytes in the transplant recognise parts of the patient including the skin and gut as foreign and cause severe damage. Over the past decade new treatments have been developed based on our knowledge of the defective gene causing SCID-X1. We can now use genes as a type of medicine that will correct the problem in the patient’s own bone marrow cells to allow the development of a new immune system. This has been carried out effectively in over 30 patients with different forms of SCID including SCID-X1, and most of these children are living healthy lives. In some patients the gene therapy vector that carries the new gene has unfortunately caused leukaemia a few years after treatment because it has accidentally altered the way in which the growth of lymphocytes is normally controlled. Due to scientific advances, the technology now exists to reduce the risk of this side effect by changing the design of the vector. In this trial we aim to evaluate the treatment of patients with SCID-X1 with a new and safer gene therapy vector. In this study retroviral vector is designated as a critical raw material and retroviral vector transduced cells are designated as an Investigational Medicinal Product (IMP). | ||
Evidence for comparator |
N/A | ||
Actual start date of recruitment |
12 Mar 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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: 1
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Worldwide total number of subjects |
1
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EEA total number of subjects |
1
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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) |
1
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Adolescents (12-17 years) |
0
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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 |
The study was conducted at Great Ormond Street Hospital Foundation Trust in London between April 2011 and January 2019. | ||||||
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Pre-assignment
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Screening details |
This is an open labelled, non-randomised, single centre, phase I/II, cohort study involving a single infusion of autologous CD34+ cells transduced with the self-inactivating (SIN) gammaretroviral vector pSRS11.EFS.IL2RG.pre* in up to 10 patients with SCID-X1 aged 0 - 16 years old. | ||||||
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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 |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||
Blinding implementation details |
N/A
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Arms
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Arm title
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Single cohort | ||||||
Arm description |
Treatment of patients with SCID-X1 by gene therapy in whom HLA-matched family or unrelated donors are unavailable. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
pSRS11.EFS.IL2RG.pre* retroviral vector transduced cells
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
The gammaretroviral vector pSRS11.EFS.IL2RG.pre* is used to modify autologous CD34+ cells. The transduction protocol has been optimised to achieve a gene transfer efficiency of 30-60% in starting cells, which is predicted to give a mean transgene copy number of 1 in developing T-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 |
Somatic gene therapy for boys aged 0-16 years with X-linked Severe Combined Immunodeficiency (X-SCID) in whom HLA-matched family or unrelated donors are unavailable. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Single cohort
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Reporting group description |
Treatment of patients with SCID-X1 by gene therapy in whom HLA-matched family or unrelated donors are unavailable. | ||
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End point title |
Immunological reconstitution [1] | ||||||||
End point description |
- The gene therapy gamma chain (GTGC) lymphocyte subsets (LSS) immunophenotyping panel was carried out to show the distribution of cells and was used to detect an increase in naïve CD3+ T lymphocyte cell numbers and assess the development of normal distribution of CD4,CD8, TCRαβ, TCRγδ, CD16+CD56+ NK & c surface expression. TCR excision circles (TRECs) may be enumerated as a surrogate marker for new thymic emigrants following gene therapy.
- Whole blood Lymphocyte proliferation assays was be carried out to test function of T cells.
- Representation of TCR families by flow cytometric analysis (Vβ phenotyping), combined with CDR3 PCR spectratyping (Vβ spectratyping) also forms an important part of monitoring for both physiological and potentially pathological clonal expansions.
- Restoration of antibody production (IgA, IgM, IgG), and serological responses to vaccinations and natural infections (such as varicella) was assessed.
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End point type |
Primary
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End point timeframe |
From consent to end of trial
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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: Statistical analysis was not performed for study endpoints. No data available. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Incidence of adverse reactions | ||||||||
End point description |
Adverse reactions observed by the investigator or reported by the patient/parent/guardian during the study period recorded for evaluation
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End point type |
Secondary
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End point timeframe |
5 years post Genetherapy
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End point title |
Molecular characterisation of gene transfer | ||||||
End point description |
Molecular characterisation of gene transfer in patient cells is also an important parameter for assessment of efficiency, and potentially for assessment of safety:
- Quantification of transgene copy numbers is determined on sorted cell populations by real-time PCR methodology. Detailed integration analysis maybe used to investigate specific clonal expansions.
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End point type |
Secondary
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End point timeframe |
From treatment to end of trial
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End point title |
Normalisation of nutritional status, growth, and development | ||||||
End point description |
Efficacy and safety of the gene therapy procedure will be further assessed though clinical examinations, clinical laboratory assessments. Adverse reactions observed by the investigator or reported by the patient/parent/guardian during the study period will be recorded for evaluation
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End point type |
Secondary
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End point timeframe |
From consent to 5 years post genetherapy
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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 consent to 5 years post genetherapy
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Adverse event reporting additional description |
At each scheduled visit, adverse events that might have occurred since the previous visit or assessment will be elicited from the patient/parent/guardian. The investigators will maintain a record of all adverse events/occurrences in patients participating in the clinical trial. This record will be noted in the patient’s medical notes.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
CTCAE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
4
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Reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
Single cohort - Gene therapy for SCID-X1 using a self-inactivating (SIN) gammaretroviral vector for patients ages 0-16 years old. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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10 Sep 2010 |
The vector label previously approved by the MHRA with the initial CTA has been amended. Since the initial submission to the MHRA on the 16th March 2009, it was noted that an incorrect version of the vector labelling was submitted, therefore the final primary, secondary and tertiary container labels were sent for approval. These amended labels were approved by our QP. With this submission, we provided the labels on our IMP Label Approval Form, showing approval by the QP.
Investigator Brochure version 2 amended. The substantial change was to section 8 (‘guidance on risks and recognition of adverse reactions’). This section was amended to expand the information previously provided. The new text provided more detailed information on the specific risks associated with the procedure, including those associated with venepuncture, bone marrow harvest, retrovirus-mediated gene transfer, ex vivo manipulation of cells, infusion, generation of RCR and graft versus host
disease. |
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28 Sep 2010 |
Amendment to include study-specific GP letter (version 1, dated 9th August 2010). As no GP letter was submitted for approval for
this study previously, the amendment constituted implementation of a new document and was not an amendment to a previously submitted GP letter.
Amendment also included non-substantial amendments to the patient information sheet and consent form. |
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09 Feb 2011 |
As part of the amendment the CTA was amended to remove the vector as an IMP following notification from, Dr. Elaine Godfrey that the vector was no longer classified as an IMP when used for ex vivo transduction. Subsequently, the vector was removed as a listed IMP in section D. As a result of this few minor changes were made to protocol, Investigator Brochure and Investigational Medicinal
Product Dossier. |
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20 Aug 2014 |
This protocol was amended to incorporate the storage of a back-up graft for patients receiving conditioning. The option to condition patients prior to infusion has been included. Leukapheresis was included as an option for harvesting stem cells. Patient Information Sheets amended to reflect the changes to the treatment protocol. New back-up bone marrow harvest created for parent/guardian to consent for harvest and storage of child’s bone marrow as a back-up approximately 3 months prior to gene therapy. Transduction protocol amended following in-house optimisation and validation.
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27 Jun 2016 |
CD34+ cell harvest and transduction protocol amended in the IMPD. AE reporting section in the protocol updated as per updated sponsor’s SOP. All AEs are recorded in both patient’s notes & CRF. |
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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. | |||
| The recruitment target for this study was not met due to lack of patients meeting the study’s eligibility criteria and the rarity of the disease. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/25295500 |
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