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

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ClinicalTrials.gov Identifier: NCT01380990
Recruitment Status : Completed
First Posted : June 27, 2011
Last Update Posted : April 16, 2020
Sponsor:
Collaborator:
Orchard Therapeutics
Information provided by (Responsible Party):
Great Ormond Street Hospital for Children NHS Foundation Trust

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.


Condition or disease Intervention/treatment Phase
Adenosine Deaminase Deficiency Severe Combined Immunodeficiencies (SCID) Genetic: Infusion of autologous EFS-ADA LV CD34+ cells Other: Haematopoietic Stem Cell Transplantation (HSCT) Drug: Busulfan Drug: Peg-Ada Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : November 15, 2012
Actual Primary Completion Date : December 23, 2019
Actual Study Completion Date : December 23, 2019


Arm Intervention/treatment
Experimental: Gene Therapy
Infusion of autologous EFS-ADA LV CD34+ cells
Genetic: Infusion of autologous EFS-ADA LV CD34+ cells
Autologous EFS-ADA LV CD34+ cells (OTL-101) are infused intravenously
Other Name: OTL-101

Drug: Busulfan
Busulfan is used for non-myeloablative conditioning

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

Historical Control Group
Historical data from ADA-SCID patients who were treated with Hematopoietic Stem Cell Transplantation (HSCT)
Other: Haematopoietic Stem Cell Transplantation (HSCT)
Historical data from a database of ADA-SCID patients treated with allogeneic HSCT from GOSH will be collected as comparator group.




Primary Outcome Measures :
  1. Clinical progress of patients [ Time Frame: 3 years ]
    Assessed by evaluating adverse events (AEs), serious adverse events (SAEs) and the results of physical examination

  2. Hematological, and immunological progress of patients [ Time Frame: 3 years ]
    Assessed by evaluating laboratory values (biochemistry and hematology)

  3. Analysis of the frequency of vector integration into known proto-oncogenes [ Time Frame: 3 years ]
  4. Analysis of the frequency of clonal expansion associated with vector integration near proto-oncogenes [ Time Frame: 3 years ]
  5. Overall Survival (OS) of subjects treated with Investigational Medicinal Product (IMP) [ Time Frame: 1 year ]
  6. Event Free Survival (EvFS) of subjects treated with IMP [ Time Frame: 1 year ]
  7. Comparison of OS and EvFS of subjects treated with IMP with those of patients treated with allogeneic HSCT [ Time Frame: 1 year ]
  8. Success of engraftment and resulting immunological and metabolic effects in subjects who received the IMP [ Time Frame: 3 years ]

Secondary Outcome Measures :
  1. Comparison of OS and EvFS outcomes at 2 and 3 years in subjects treated with IMP and patients who received allogeneic HSCT allogeneic Hematopoietic Stem Cell Transplantation (HSCT) [ Time Frame: 2 and 3 years ]
  2. Reduction in the frequency of infections, evaluated at 1, 2, and 3 years post treatment on the basis of clinical history and examination [ Time Frame: 1, 2 and 3 years ]


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Ages Eligible for Study:   up to 15 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Gene Therapy (On Trial)

Inclusion Criteria:

  1. 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 PEG-ADA replacement therapy
  2. Patients who lack a fully Human leukocyte antigen (HLA)-matched family donor
  3. 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)
  4. Parental/guardian signed informed consent

Exclusion Criteria:

  1. Cytogenetic abnormalities on peripheral blood
  2. Evidence of active malignant disease
  3. Known sensitivity to busulfan
  4. 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 IMP followed a different process (ie, received in two infusions). Patients followed the same protocol steps and study visits.

Historical Control Group

Inclusion Criteria:

  1. 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
  2. Patients (male or female) between 0-18 years at time of treatment
  3. Patient treated with allogeneic haematopoietic stem cell transplantation since 2000

Information from the National Library of Medicine

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): NCT01380990


Locations
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United Kingdom
Great Ormond Street Hospital for Children NHS Foundation Trust
London, United Kingdom, WC1N 3JH
Sponsors and Collaborators
Great Ormond Street Hospital for Children NHS Foundation Trust
Orchard Therapeutics
Investigators
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Principal Investigator: Claire Booth, Dr Great Ormond Street Hospital NHS Foundation Trust
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Great Ormond Street Hospital for Children NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT01380990    
Other Study ID Numbers: 10-MI-29
First Posted: June 27, 2011    Key Record Dates
Last Update Posted: April 16, 2020
Last Verified: April 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Great Ormond Street Hospital for Children NHS Foundation Trust:
Gene therapy
Hematopoietic stem and progenitor cells
Lentiviral vector
ADA-SCID
Additional relevant MeSH terms:
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Severe Combined Immunodeficiency
Immunologic Deficiency Syndromes
Immune System Diseases
Infant, Newborn, Diseases
DNA Repair-Deficiency Disorders
Metabolic Diseases
Busulfan
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Antineoplastic Agents
Myeloablative Agonists