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Gene Therapy for X-linked Severe Combined Immunodeficiency (SCID-X1)

Primary Purpose

X-linked Severe Combined Immunodeficiency

Status
Unknown status
Phase
Not Applicable
Locations
United Kingdom
Study Type
Interventional
Intervention
Single infusion of autologous CD34+ cells transduced with the self-inactivating (SIN) gammaretroviral vector pSRS11.EFS.IL2RG.pre
Sponsored by
Great Ormond Street Hospital for Children NHS Foundation Trust
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for X-linked Severe Combined Immunodeficiency focused on measuring X-linked severe combined immunodeficiency, gene therapy, Patients will be enrolled following diagnosis and referral to Great Ormond Street Immunology Service.

Eligibility Criteria

undefined - 16 Years (Child)MaleDoes not accept healthy volunteers

Inclusion Criteria:

  1. No HLA identical (A,B,C,DR,DQ) family donor and no HLA identical unrelated donor available within 3 months of diagnosis or patients whose underlying clinical problems and prognosis would be significantly compromised by chemotherapy conditioning (including persisting pneumonitis, protracted diarrhoea requiring parental nutrition, ongoing visceral viral infection (herpes viruses, HSV,VZV,CMV, EBV or adenovirus), systemic BCG infection, virus-induced lymphoproliferation.
  2. Diagnosis of classical SCID-X1 based on immunophenotype (absent, or reduced numbers of non-functional T lymphocytes) and confirmed by DNA sequencing
  3. Parental/guardian voluntary consent
  4. Boys between the ages of 0 and 16

Sites / Locations

  • Great Ormond Street Hospital for Children NHS Trust

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Single infusion of autologous CD34+ cells

Arm Description

Outcomes

Primary Outcome Measures

Immunological reconstitution
Immunophenotyping: detection of naïve CD3+ T-cell numbers, CD4, CD8, TCRαβ, TCRγδ, CD16+CD56+ NK & gamma chain expression. TRECs may be enumerated as surrogate marker for new thymic emigrants post-gene therapy Lymphocyte proliferation assays to test function of T cells Representation of TCR families by flow cytometry (Vβ phenotyping), & CDR3 PCR spectratyping (Vβ spectratyping) to monitor physiological & potentially pathological clonal expansions Restoration of antibody production (IgA, IgM, IgG) & serological responses to vaccinations & natural infections.

Secondary Outcome Measures

Incidence of adverse reactions
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. Adverse events that have a causal relationship to the IMP (ARs) and SAEs will be recorded on the AE reporting section of the CRF.
Molecular characterisation of gene transfer
Quantification of transgene copy numbers is determined on sorted cell populations by real-time PCR methodology. Detailed integration analysis may be used to investigate specific clonal expansions.
Normalisation of nutritional status, growth, and development
Normalisation of nutritional status, growth, and development will be assessed at each follow-up visit by the investigator through clinical examinations.

Full Information

First Posted
July 29, 2010
Last Updated
July 31, 2017
Sponsor
Great Ormond Street Hospital for Children NHS Foundation Trust
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1. Study Identification

Unique Protocol Identification Number
NCT01175239
Brief Title
Gene Therapy for X-linked Severe Combined Immunodeficiency (SCID-X1)
Official Title
Gene Therapy for SCID-X1 Using a Self-inactivating (SIN) Gammaretroviral Vector
Study Type
Interventional

2. Study Status

Record Verification Date
October 2016
Overall Recruitment Status
Unknown status
Study Start Date
April 2011 (undefined)
Primary Completion Date
December 2018 (Anticipated)
Study Completion Date
December 2018 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Great Ormond Street Hospital for Children NHS Foundation Trust

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
X-linked severe combined immunodeficiency (SCID-X1) is an inherited disorder that results in failure of development of the immune system in boys. This trial aims to treat SCID-X1 patients using gene therapy to replace the defective gene.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
X-linked Severe Combined Immunodeficiency
Keywords
X-linked severe combined immunodeficiency, gene therapy, Patients will be enrolled following diagnosis and referral to Great Ormond Street Immunology Service.

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
1 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Single infusion of autologous CD34+ cells
Arm Type
Experimental
Intervention Type
Genetic
Intervention Name(s)
Single infusion of autologous CD34+ cells transduced with the self-inactivating (SIN) gammaretroviral vector pSRS11.EFS.IL2RG.pre
Intervention Description
Single infusion of autologous CD34+ cells transduced with the self-inactivating (SIN) gammaretroviral vector pSRS11.EFS.IL2RG.pre
Primary Outcome Measure Information:
Title
Immunological reconstitution
Description
Immunophenotyping: detection of naïve CD3+ T-cell numbers, CD4, CD8, TCRαβ, TCRγδ, CD16+CD56+ NK & gamma chain expression. TRECs may be enumerated as surrogate marker for new thymic emigrants post-gene therapy Lymphocyte proliferation assays to test function of T cells Representation of TCR families by flow cytometry (Vβ phenotyping), & CDR3 PCR spectratyping (Vβ spectratyping) to monitor physiological & potentially pathological clonal expansions Restoration of antibody production (IgA, IgM, IgG) & serological responses to vaccinations & natural infections.
Time Frame
1-18 months post-infusion,then annually
Secondary Outcome Measure Information:
Title
Incidence of adverse reactions
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. Adverse events that have a causal relationship to the IMP (ARs) and SAEs will be recorded on the AE reporting section of the CRF.
Time Frame
from consent until 5 years post-infusion of gene-modified cells
Title
Molecular characterisation of gene transfer
Description
Quantification of transgene copy numbers is determined on sorted cell populations by real-time PCR methodology. Detailed integration analysis may be used to investigate specific clonal expansions.
Time Frame
until 5 years post-infusion of gene-modified cells
Title
Normalisation of nutritional status, growth, and development
Description
Normalisation of nutritional status, growth, and development will be assessed at each follow-up visit by the investigator through clinical examinations.
Time Frame
until 5 years post-infusion of gene-modified cells

10. Eligibility

Sex
Male
Maximum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: No HLA identical (A,B,C,DR,DQ) family donor and no HLA identical unrelated donor available within 3 months of diagnosis or patients whose underlying clinical problems and prognosis would be significantly compromised by chemotherapy conditioning (including persisting pneumonitis, protracted diarrhoea requiring parental nutrition, ongoing visceral viral infection (herpes viruses, HSV,VZV,CMV, EBV or adenovirus), systemic BCG infection, virus-induced lymphoproliferation. Diagnosis of classical SCID-X1 based on immunophenotype (absent, or reduced numbers of non-functional T lymphocytes) and confirmed by DNA sequencing Parental/guardian voluntary consent Boys between the ages of 0 and 16
Facility Information:
Facility Name
Great Ormond Street Hospital for Children NHS Trust
City
London
ZIP/Postal Code
WC1N 3JH
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
18180772
Citation
Thornhill SI, Schambach A, Howe SJ, Ulaganathan M, Grassman E, Williams D, Schiedlmeier B, Sebire NJ, Gaspar HB, Kinnon C, Baum C, Thrasher AJ. Self-inactivating gammaretroviral vectors for gene therapy of X-linked severe combined immunodeficiency. Mol Ther. 2008 Mar;16(3):590-8. doi: 10.1038/sj.mt.6300393. Epub 2008 Jan 8.
Results Reference
background
PubMed Identifier
10784449
Citation
Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P, Selz F, Hue C, Certain S, Casanova JL, Bousso P, Deist FL, Fischer A. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science. 2000 Apr 28;288(5466):669-72. doi: 10.1126/science.288.5466.669.
Results Reference
background
PubMed Identifier
11961146
Citation
Hacein-Bey-Abina S, Le Deist F, Carlier F, Bouneaud C, Hue C, De Villartay JP, Thrasher AJ, Wulffraat N, Sorensen R, Dupuis-Girod S, Fischer A, Davies EG, Kuis W, Leiva L, Cavazzana-Calvo M. Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N Engl J Med. 2002 Apr 18;346(16):1185-93. doi: 10.1056/NEJMoa012616.
Results Reference
background
PubMed Identifier
30261899
Citation
Clarke EL, Connell AJ, Six E, Kadry NA, Abbas AA, Hwang Y, Everett JK, Hofstaedter CE, Marsh R, Armant M, Kelsen J, Notarangelo LD, Collman RG, Hacein-Bey-Abina S, Kohn DB, Cavazzana M, Fischer A, Williams DA, Pai SY, Bushman FD. T cell dynamics and response of the microbiota after gene therapy to treat X-linked severe combined immunodeficiency. Genome Med. 2018 Sep 28;10(1):70. doi: 10.1186/s13073-018-0580-z.
Results Reference
derived
PubMed Identifier
25295500
Citation
Hacein-Bey-Abina S, Pai SY, Gaspar HB, Armant M, Berry CC, Blanche S, Bleesing J, Blondeau J, de Boer H, Buckland KF, Caccavelli L, Cros G, De Oliveira S, Fernandez KS, Guo D, Harris CE, Hopkins G, Lehmann LE, Lim A, London WB, van der Loo JC, Malani N, Male F, Malik P, Marinovic MA, McNicol AM, Moshous D, Neven B, Oleastro M, Picard C, Ritz J, Rivat C, Schambach A, Shaw KL, Sherman EA, Silberstein LE, Six E, Touzot F, Tsytsykova A, Xu-Bayford J, Baum C, Bushman FD, Fischer A, Kohn DB, Filipovich AH, Notarangelo LD, Cavazzana M, Williams DA, Thrasher AJ. A modified gamma-retrovirus vector for X-linked severe combined immunodeficiency. N Engl J Med. 2014 Oct 9;371(15):1407-17. doi: 10.1056/NEJMoa1404588.
Results Reference
derived

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Gene Therapy for X-linked Severe Combined Immunodeficiency (SCID-X1)

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