Autologous CD34+ Hematopoietic Stem Cells Transduced ex Vivo With Elongation Factor 1 Alpha Shortened (EFS) Lentiviral Vector Encoding for the Human ADA Gene
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|ClinicalTrials.gov Identifier: NCT01852071|
Recruitment Status : Completed
First Posted : May 13, 2013
Results First Posted : September 20, 2021
Last Update Posted : August 3, 2022
|Condition or disease||Intervention/treatment||Phase|
|ADA-SCID||Genetic: Infusion of autologous EFS-ADA LV CD34+ (OTL-101) Drug: busulfan Drug: PEG-ADA ERT||Phase 1 Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||46 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Autologous Transplantation of Bone Marrow CD34+ Stem/Progenitor Cells After Addition of a Normal Human ADA Complementary DNA (cDNA) by the EFS-ADA Lentiviral Vector for Severe Combined Immunodeficiency Due to Adenosine Deaminase Deficiency (ADA-SCID)|
|Actual Study Start Date :||August 2, 2013|
|Actual Primary Completion Date :||August 27, 2018|
|Actual Study Completion Date :||August 27, 2018|
Experimental: Gene Therapy
Infusion of autologous EFS-ADA Lentiviral (LV) CD34+ cells
Genetic: Infusion of autologous EFS-ADA LV CD34+ (OTL-101)
autologous EFS-ADA LV CD34+ cells (OTL-101) are infused intravenously
Other Name: OTL-101
Busulfan is used for non-myeloablative conditioning
Drug: PEG-ADA ERT
PEG-ADA ERT is discontinued at Day +30 (-3/+15 days) after successful engraftment
- Overall Survival (OS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year) [ Time Frame: 12 months ]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) [ Time Frame: 12 months ]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 allogeneic Hematopoietic Stem Cell Transplant (HSCT), or death.
- OS of Subjects Treated With Investigational Medicinal Product (IMP) (2 Years) [ Time Frame: 24 months ]OS is defined as the percentage of subjects alive at 24 months post- treatment with OTL-101 or HSCT
- EvFS of Subjects Treated With Investigational Medicinal Product (IMP) (2 Years) [ Time Frame: 24 months ]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 Peripheral Blood (PB) Granulocytes. [ Time Frame: 24 months ]Vector copy number in the PB granulocyte fraction that was T cell depleted, is a surrogate for amount of engrafted genetically modified Hematopoietic stem cell (HSC) that are producing granulocytes every 3-5 days. VCN analysis was performed by Droplet Digital PCR (ddPCR) on DNA extracted from peripheral blood granulocytes.
- VCN in Peripheral Blood Mononuclear Cells (PBMCs) [ Time Frame: 24 months ]PBMC VCN is a measure of the accumulation of peripheral blood leukocytes arising from engrafted, genetically modified HSC. VCN analysis was performed by ddPCR on DNA extracted from PBMC.
- ADA Activity in Erythrocytes [ Time Frame: 24 months ]ADA enzyme activity measured to assess the amount of functional gene product produced from the normal ADA transgene delivered by EFS-ADA LV; persistence of ADA enzyme activity over time demonstrates successful engraftment and differentiation of genetically modified HSC.
- Reduction in Deoxyadenosine Nucleotide (dAXP) in Erythrocytes [ Time Frame: 24 months ]Decreased dAXP levels coincide with increased ADA enzyme activity, detoxification was used to demonstrate functional ADA enzyme production from the introduced ADA transgene. The threshold for detoxification was <100 μmol/L.
- Change From Baseline in CD3+ T Cell Counts (2 Years) [ Time Frame: 24 months ]Immune reconstitution was assessed by change in CD3+ T Cell counts at baseline to Month 24.
- Number of Single Integration Sites Representing >30% of the Total Integration Sites (2 Years) [ Time Frame: 24 months ]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.
- Severe Infection Rate Excluding the First Three Months After Treatment [ Time Frame: 24 months ]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. Infections that took place in the first 3 months of follow-up post treatment were excluded from calculations to avoid possible bias introduced in the data by the effects of conditioning.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01852071
|United States, California|
|Mattel Children's Hospital, UCLA|
|Los Angeles, California, United States, 90095|
|United States, Maryland|
|Mark O. Hatfield Clinical Research Center, NIH|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Donald B Kohn, MD||University of California, Los Angeles|