Back to resultsLentiviral (LV) Gene Therapy for Adenosine Deaminase (ADA) Deficiency
Primary Purpose
Adenosine Deaminase Deficiency, Severe Combined Immunodeficiencies (SCID)
Status
Completed
Phase
Phase 1
Locations
United Kingdom
Study Type
Interventional
Intervention
Infusion of autologous EFS-ADA LV CD34+ cells
Haematopoietic Stem Cell Transplantation (HSCT)
Busulfan
Peg-Ada
Sponsored by
About this trial
This is an interventional treatment trial for Adenosine Deaminase Deficiency focused on measuring Gene therapy, Hematopoietic stem and progenitor cells, Lentiviral vector, ADA-SCID
Eligibility Criteria
Gene Therapy (On Trial)
Inclusion Criteria:
- Diagnosis of ADA-SCID confirmed by DNA sequencing or by confirmed absence of <3% of ADA enzymatic activity in peripheral blood (or for neonates) in umbilical cord blood erythrocytes and/or leukocytes or in cultured fetal cells derived from either chorionic villus biopsy or amniocentesis, prior to institution of Polyethylene glycol-modified ADA (PEG-ADA) replacement therapy
- Patients who lack a fully Human leukocyte antigen (HLA)-matched family donor
- Patients (male or female) <5 years of age OR Patients (male or female) ≥ 5 years to 15 years of age who have preserved thymic function as evidenced by presence of >10 % naïve T cells (CD4+45RA+27+ cells)
- Parental/guardian signed informed consent
Exclusion Criteria:
- Cytogenetic abnormalities on peripheral blood
- Evidence of active malignant disease
- Known sensitivity to busulfan
- If applicable, confirmed pregnancy (to be tested in patients above 12 years old)
Gene Therapy (CUP)
A group of patients were treated under CUP (GOSH special license) either because the study was not yet open and patients needed urgent treatment, or because they were outside of the inclusion/exclusion criteria or received Investigational Medicinal Product (IMP) followed a different process (ie, received in two infusions). Patients followed the same protocol steps and study visits.
Historical Control Group
Inclusion Criteria:
- Diagnosis of ADA-SCID confirmed by DNA sequencing OR by confirmed absence of <3% of ADA enzymatic activity in peripheral blood or (for neonates) in umbilical cord blood erythrocytes and/or leucocytes or in cultured foetal cells derived from either chorionic villus biopsy or amniocentesis, prior to institution of PEG-ADA replacement therapy
- Patients (male or female) between 0-18 years at time of treatment
- Patient treated with allogeneic haematopoietic stem cell transplantation since 2000
Sites / Locations
- Great Ormond Street Hospital for Children NHS Foundation Trust
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Other
Arm Label
Gene Therapy
Historical Control Group
Arm Description
Infusion of autologous EFS-ADA LV CD34+ cells
Historical data from ADA-SCID patients who were treated with Hematopoietic Stem Cell Transplantation (HSCT)
Outcomes
Primary Outcome Measures
Overall Survival (OS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year)
Overall survival is defined as the percentage of subjects alive at 12 months post- treatment with OTL-101* or HSCT
Event-free Survival (EvFS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year)
Event-free survival is defined as the percentage of subjects alive with no "event", an "event" being the resumption of PEG-ADA ERT or the need for a rescue allogenic Hematopoietic Stem Cell Transplant (HSCT), or death.
Vector Copy Number (VCN) in Granulocytes Fraction (Neutrophils)
Engraftment of transduced cells was assessed using vector gene marking in granulocytes (neutrophils)
VCN in Peripheral Blood Mononuclear Cells (PBMCs)
Engraftment of transduced cells was assessed using vector gene marking in PBMCs
VCN in CD3+ T Cells
Engraftment of transduced cells was assessed using vector gene marking
VCN in CD19+ B Cells
Engraftment of transduced cells was assessed using vector gene marking in CD19+ B Cells
Change From Baseline in CD3+ T Cell Counts (1 Year)
Immune reconstitution was assessed by change in CD3+ T Cell counts over time.
Change From Baseline in CD3+ T Cell Counts (3 Years)
Immune reconstitution was assessed by change in CD3+ T Cell counts over time.
ADA Activity in Erythrocytes
ADA enzyme activity was assessed as a measure of successful engraftment of genetically modified Hematopoietic stem progenitor cells (HSPCs), as it marks sustained gene expression from the normal ADA transgene.
Reduction in Deoxyadenosine Triphosphate (dATP) in Erythrocytes
Decreased dATP levels coincide with increased ADA enzyme activity, detoxification was used as a marker of correction of the defective ADA gene. The threshold for detoxification was <100 μmol/L.
Frequency of Vector Integration Into Known Protooncogenes (3 Years)
Vector Integration Site Analysis (VISA) allowed determination of the distribution of vector integration sites in each subject's genome, as well as the relative clonal abundance. VISA was to be considered abnormal for a subject if, in 2 or more instances during the course of follow-up, a single integration site was found to represent >30% of the total integration sites detected.
There were no instances of clonal proliferation in the course of the 36 month follow-up for on-study and CUP subjects; hence, a detailed analysis of the frequency of clonal expansion associated with vector integration near proto-oncogenes was not generated.
Secondary Outcome Measures
OS of Subjects Treated With IMP With Those of Patients Treated With Allogeneic HSCT (3 Years)
Overall survival (OS) is defined as the percentage of subjects alive at 36 months post- treatment with OTL-101* or HSCT
EvFS of Subjects Treated With IMP With Those of Patients Treated With Allogeneic HSCT (3 Years)
Event-free survival is defined as the percentage of subjects alive with no "event", an "event" being the resumption of PEG-ADA ERT or the need for a rescue allogenic Hematopoietic Stem Cell Transplant (HSCT), or death.
Infection Rate
The infections of interest in this study were severe infections or opportunistic infectious episodes, defined as infections requiring hospitalization or prolonging hospitalization and/or documented infections by opportunistic pathogens.
Full Information
NCT ID
NCT01380990
First Posted
June 23, 2011
Last Updated
August 20, 2021
Sponsor
Great Ormond Street Hospital for Children NHS Foundation Trust
Collaborators
Orchard Therapeutics
1. Study Identification
Unique Protocol Identification Number
NCT01380990
Brief Title
Lentiviral (LV) Gene Therapy for Adenosine Deaminase (ADA) Deficiency
Official Title
Phase I/II, Historical Controlled, Open-label, Non-randomised, Single-centre Trial to Assess the Safety and Efficacy of EF1αS-ADA Lentiviral Vector Mediated Gene Modification of Autologous CD34+ Cells From ADA-deficient Individuals
Study Type
Interventional
2. Study Status
Record Verification Date
August 2021
Overall Recruitment Status
Completed
Study Start Date
November 15, 2012 (Actual)
Primary Completion Date
December 23, 2019 (Actual)
Study Completion Date
December 23, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Great Ormond Street Hospital for Children NHS Foundation Trust
Collaborators
Orchard Therapeutics
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
This is a historically controlled, non-randomized Phase I/II clinical trial to assess the safety and efficacy of autologous transplantation of CD34+ hematopoietic stem/progenitor cells (HSPCs), obtained from infants affected by ADA-SCID, following transduction of the HSPCs with a lentiviral vector (LV) carrying the human ADA complementary DNA (cDNA) under the control of the elongation factor 1 alpha shortened (EFS) promoter. Subjects treated in the trial receive the infusion of autologous, transduced cells following marrow cytoreduction with busulfan. The outcomes are compared to those observed in a historical control group of patients who received an allogeneic hematopoietic stem cell transplant (HSCT).
This Phase I/II clinical trial will be performed at Great Ormond Street Hospital (GOSH), London, United Kingdom.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adenosine Deaminase Deficiency, Severe Combined Immunodeficiencies (SCID)
Keywords
Gene therapy, Hematopoietic stem and progenitor cells, Lentiviral vector, ADA-SCID
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
36 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Gene Therapy
Arm Type
Experimental
Arm Description
Infusion of autologous EFS-ADA LV CD34+ cells
Arm Title
Historical Control Group
Arm Type
Other
Arm Description
Historical data from ADA-SCID patients who were treated with Hematopoietic Stem Cell Transplantation (HSCT)
Intervention Type
Genetic
Intervention Name(s)
Infusion of autologous EFS-ADA LV CD34+ cells
Other Intervention Name(s)
OTL-101*
Intervention Description
Autologous EFS-ADA LV CD34+ cells (OTL-101*) are infused intravenously
Intervention Type
Other
Intervention Name(s)
Haematopoietic Stem Cell Transplantation (HSCT)
Intervention Description
Historical data from a database of ADA-SCID patients treated with allogeneic HSCT from GOSH will be collected as comparator group.
Intervention Type
Drug
Intervention Name(s)
Busulfan
Intervention Description
Busulfan is used for non-myeloablative conditioning
Intervention Type
Drug
Intervention Name(s)
Peg-Ada
Intervention Description
Peg-Ada enzyme replacement therapy is discontinued at Day +3- (-3/+15 days) after successful engraftment
Primary Outcome Measure Information:
Title
Overall Survival (OS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year)
Description
Overall survival is defined as the percentage of subjects alive at 12 months post- treatment with OTL-101* or HSCT
Time Frame
12 months
Title
Event-free Survival (EvFS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year)
Description
Event-free survival is defined as the percentage of subjects alive with no "event", an "event" being the resumption of PEG-ADA ERT or the need for a rescue allogenic Hematopoietic Stem Cell Transplant (HSCT), or death.
Time Frame
12 months
Title
Vector Copy Number (VCN) in Granulocytes Fraction (Neutrophils)
Description
Engraftment of transduced cells was assessed using vector gene marking in granulocytes (neutrophils)
Time Frame
36 months
Title
VCN in Peripheral Blood Mononuclear Cells (PBMCs)
Description
Engraftment of transduced cells was assessed using vector gene marking in PBMCs
Time Frame
36 months
Title
VCN in CD3+ T Cells
Description
Engraftment of transduced cells was assessed using vector gene marking
Time Frame
36 months
Title
VCN in CD19+ B Cells
Description
Engraftment of transduced cells was assessed using vector gene marking in CD19+ B Cells
Time Frame
36 months
Title
Change From Baseline in CD3+ T Cell Counts (1 Year)
Description
Immune reconstitution was assessed by change in CD3+ T Cell counts over time.
Time Frame
12 months
Title
Change From Baseline in CD3+ T Cell Counts (3 Years)
Description
Immune reconstitution was assessed by change in CD3+ T Cell counts over time.
Time Frame
36 months
Title
ADA Activity in Erythrocytes
Description
ADA enzyme activity was assessed as a measure of successful engraftment of genetically modified Hematopoietic stem progenitor cells (HSPCs), as it marks sustained gene expression from the normal ADA transgene.
Time Frame
36 months
Title
Reduction in Deoxyadenosine Triphosphate (dATP) in Erythrocytes
Description
Decreased dATP levels coincide with increased ADA enzyme activity, detoxification was used as a marker of correction of the defective ADA gene. The threshold for detoxification was <100 μmol/L.
Time Frame
36 months
Title
Frequency of Vector Integration Into Known Protooncogenes (3 Years)
Description
Vector Integration Site Analysis (VISA) allowed determination of the distribution of vector integration sites in each subject's genome, as well as the relative clonal abundance. VISA was to be considered abnormal for a subject if, in 2 or more instances during the course of follow-up, a single integration site was found to represent >30% of the total integration sites detected.
There were no instances of clonal proliferation in the course of the 36 month follow-up for on-study and CUP subjects; hence, a detailed analysis of the frequency of clonal expansion associated with vector integration near proto-oncogenes was not generated.
Time Frame
36 months
Secondary Outcome Measure Information:
Title
OS of Subjects Treated With IMP With Those of Patients Treated With Allogeneic HSCT (3 Years)
Description
Overall survival (OS) is defined as the percentage of subjects alive at 36 months post- treatment with OTL-101* or HSCT
Time Frame
36 months
Title
EvFS of Subjects Treated With IMP With Those of Patients Treated With Allogeneic HSCT (3 Years)
Description
Event-free survival is defined as the percentage of subjects alive with no "event", an "event" being the resumption of PEG-ADA ERT or the need for a rescue allogenic Hematopoietic Stem Cell Transplant (HSCT), or death.
Time Frame
36 months
Title
Infection Rate
Description
The infections of interest in this study were severe infections or opportunistic infectious episodes, defined as infections requiring hospitalization or prolonging hospitalization and/or documented infections by opportunistic pathogens.
Time Frame
36 months
10. Eligibility
Sex
All
Maximum Age & Unit of Time
15 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Gene Therapy (On Trial)
Inclusion Criteria:
Diagnosis of ADA-SCID confirmed by DNA sequencing or by confirmed absence of <3% of ADA enzymatic activity in peripheral blood (or for neonates) in umbilical cord blood erythrocytes and/or leukocytes or in cultured fetal cells derived from either chorionic villus biopsy or amniocentesis, prior to institution of Polyethylene glycol-modified ADA (PEG-ADA) replacement therapy
Patients who lack a fully Human leukocyte antigen (HLA)-matched family donor
Patients (male or female) <5 years of age OR Patients (male or female) ≥ 5 years to 15 years of age who have preserved thymic function as evidenced by presence of >10 % naïve T cells (CD4+45RA+27+ cells)
Parental/guardian signed informed consent
Exclusion Criteria:
Cytogenetic abnormalities on peripheral blood
Evidence of active malignant disease
Known sensitivity to busulfan
If applicable, confirmed pregnancy (to be tested in patients above 12 years old)
Gene Therapy (CUP)
A group of patients were treated under CUP (GOSH special license) either because the study was not yet open and patients needed urgent treatment, or because they were outside of the inclusion/exclusion criteria or received Investigational Medicinal Product (IMP) followed a different process (ie, received in two infusions). Patients followed the same protocol steps and study visits.
Historical Control Group
Inclusion Criteria:
Diagnosis of ADA-SCID confirmed by DNA sequencing OR by confirmed absence of <3% of ADA enzymatic activity in peripheral blood or (for neonates) in umbilical cord blood erythrocytes and/or leucocytes or in cultured foetal cells derived from either chorionic villus biopsy or amniocentesis, prior to institution of PEG-ADA replacement therapy
Patients (male or female) between 0-18 years at time of treatment
Patient treated with allogeneic haematopoietic stem cell transplantation since 2000
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Claire Booth, Dr
Organizational Affiliation
Great Ormond Street Hospital NHS Foundation Trust
Official's Role
Principal Investigator
Facility Information:
Facility Name
Great Ormond Street Hospital for Children NHS Foundation Trust
City
London
ZIP/Postal Code
WC1N 3JH
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
33974366
Citation
Kohn DB, Booth C, Shaw KL, Xu-Bayford J, Garabedian E, Trevisan V, Carbonaro-Sarracino DA, Soni K, Terrazas D, Snell K, Ikeda A, Leon-Rico D, Moore TB, Buckland KF, Shah AJ, Gilmour KC, De Oliveira S, Rivat C, Crooks GM, Izotova N, Tse J, Adams S, Shupien S, Ricketts H, Davila A, Uzowuru C, Icreverzi A, Barman P, Campo Fernandez B, Hollis RP, Coronel M, Yu A, Chun KM, Casas CE, Zhang R, Arduini S, Lynn F, Kudari M, Spezzi A, Zahn M, Heimke R, Labik I, Parrott R, Buckley RH, Reeves L, Cornetta K, Sokolic R, Hershfield M, Schmidt M, Candotti F, Malech HL, Thrasher AJ, Gaspar HB. Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency. N Engl J Med. 2021 May 27;384(21):2002-2013. doi: 10.1056/NEJMoa2027675. Epub 2021 May 11.
Results Reference
derived
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Lentiviral (LV) Gene Therapy for Adenosine Deaminase (ADA) Deficiency
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