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Completed

NCT Number: NCT01380990

Lentiviral (LV) Gene Therapy for Adenosine Deaminase (ADA) Deficiency

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.

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Key information

Conditions

Adenosine Deaminase Deficiency Congenital, Hereditary, and Neonatal Diseases and Abnormalities DNA Repair-Deficiency Disorders Genetic Diseases, Inborn Immune System Diseases Immunologic Deficiency Syndromes Infant, Newborn, Diseases Metabolic Diseases Nutritional and Metabolic Diseases Primary Immunodeficiency Diseases Severe Combined Immunodeficiencies (SCID) Severe Combined Immunodeficiency Severe combined immunodeficiency due to adenosine deaminase deficiency

Age range

Up to 15 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Great Ormond Street Hospital for Children NHS Foundation Trust

London, WC1N 3JH, United Kingdom

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Infusion of autologous EFS-ADA LV CD34+ cells

Genetic

Autologous EFS-ADA LV CD34+ cells (OTL-101*) are infused intravenously

Other names: OTL-101*

Haematopoietic Stem Cell Transplantation (HSCT)

Other

Historical data from a database of ADA-SCID patients treated with allogeneic HSCT from GOSH will be collected as comparator group.

busulfan

Drug

Busulfan is used for non-myeloablative conditioning

Peg-Ada

Drug

Peg-Ada enzyme replacement therapy is discontinued at Day +3- (-3/+15 days) after successful engraftment

Primary outcomes

  1. 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

  2. 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 allogenic Hematopoietic Stem Cell Transplant (HSCT), or death.

  3. Vector Copy Number (VCN) in Granulocytes Fraction (Neutrophils)

    Time frame: 36 months

    Engraftment of transduced cells was assessed using vector gene marking in granulocytes (neutrophils)

  4. VCN in Peripheral Blood Mononuclear Cells (PBMCs)

    Time frame: 36 months

    Engraftment of transduced cells was assessed using vector gene marking in PBMCs

  5. VCN in CD3+ T Cells

    Time frame: 36 months

    Engraftment of transduced cells was assessed using vector gene marking

  6. VCN in CD19+ B Cells

    Time frame: 36 months

    Engraftment of transduced cells was assessed using vector gene marking in CD19+ B Cells

  7. Change From Baseline in CD3+ T Cell Counts (1 Year)

    Time frame: 12 months

    Immune reconstitution was assessed by change in CD3+ T Cell counts over time.

  8. Change From Baseline in CD3+ T Cell Counts (3 Years)

    Time frame: 36 months

    Immune reconstitution was assessed by change in CD3+ T Cell counts over time.

  9. ADA Activity in Erythrocytes

    Time frame: 36 months

    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.

  10. Reduction in Deoxyadenosine Triphosphate (dATP) in Erythrocytes

    Time frame: 36 months

    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.

  11. Frequency of Vector Integration Into Known Protooncogenes (3 Years)

    Time frame: 36 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.

    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 outcomes

  1. OS of Subjects Treated With IMP With Those of Patients Treated With Allogeneic HSCT (3 Years)

    Time frame: 36 months

    Overall survival (OS) is defined as the percentage of subjects alive at 36 months post- treatment with OTL-101* or HSCT

  2. EvFS of Subjects Treated With IMP With Those of Patients Treated With Allogeneic HSCT (3 Years)

    Time frame: 36 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.

  3. Infection Rate

    Time frame: 36 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.

Sponsors and collaborators

Lead sponsor

Great Ormond Street Hospital for Children NHS Foundation Trust

Other

Collaborators

  • Orchard Therapeutics

Registry information

Official study 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

Important dates

Study start
2012
Primary completion
2019
Study completion
2019
First posted
Jun 27, 2011
Registry last updated
Sep 16, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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