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Gene Therapy for Patients With ADA Adenosine Deaminase (ADA) Deficiency

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03765632
Recruitment Status : Recruiting
First Posted : December 5, 2018
Last Update Posted : December 6, 2018
Information provided by (Responsible Party):
Great Ormond Street Hospital for Children NHS Foundation Trust

Brief Summary:

Adenosine Deaminase (ADA) is an enzyme, needed by body to develop lymphocytes of the immune system. Children who are born in mutations with mutations in ADA gene have severe combined immunodeficiency (SCID). Children with ADA-deficient SCID generally die in the first year of life from severe infections because they do not have immune system that can fight against infections. ADA deficient individuals can be cured by bone marrow transplant, but the best results are obtained when there is fully matched family donor is available. In the absence of a matched related donor, transplants from unrelated or mismatched donors have a much worse outcome. There is a form of enzyme therapy (PEG-ADA) for ADA-deficient SCID, in which children receive injections of purified ADA enzyme 1-2 times each week. These injections can allow the immune system to recover to a level that protects children from infections.

However, these injections have to be given weekly and are very expensive (£ 125,000 - 200,000 annually) and the recovery of the immune system is not sustained over time.

Gene therapy for ADA-deficient SCID could be performed by introducing a normal copy of the human ADA gene into the blood forming stem cells of the patient's bone marrow by using a new type of gene delivery system (in this trial called a lentiviral vector). The gene corrected cells are then transplanted back into the patient after small dose of chemotherapy. These gene corrected stem cells can survive into the body and make lymphocytes. In this trial, the investigator will determine whether gene therapy for ADA-deficient SCID using a cryopreserved lentiviral vector is safe, feasible and effective

Condition or disease Intervention/treatment Phase
Ada-Scid Drug: Lentiviral transduced CD34+ cells Phase 1 Phase 2

Detailed Description:

This is a prospective, non-randomized, single-cohort, longitudinal, single-center, clinical study designed to assess the efficacy and safety of a cryopreserved formulation of OTL-101 (autologous CD34+ hematopoietic stem cells transduced ex vivo with EFS LV encoding for the human ADA gene) administered to ADA-SCID patients between the ages of 30 days and 17 years, who are not eligible for an HLA-matched sibling/family donor and meeting the inclusion/exclusion criteria.

The aim of this study is to assess the success of treatment for overall survival and event free survival.

Eligible patients will be hospitalised to undergo the harvesting of autologous CD34+ cells. To enable the release of the cell product for infusion, the product must meet various quality control criteria for safety, identity, viability, purity and potency. If OTL-101 meets the acceptance criteria and is released, the patients will be readmitted for conditioning prior to infusion of OTL-101.

For patients who have successfully received the OTL-101 product, PEG-ADA ERT will be discontinued at Day+30 (+/-3) after the transplant. After the patients discharge from hospital, the patients will be seen at regular intervals to review their history, perform examinations and draw blood samples at Months 1, 3, 6, 9, 12, 18, and 24. Any medically-indicated interventions will be determined at these visits. After Month 24 visit, the patients will have completed the study and may enter a long term registry.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Cryopreserved Lentivirus Gene Therapy for Adenosine Deaminase (ADA) Deficiency
Actual Study Start Date : January 2, 2018
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : March 2021

Arm Intervention/treatment
Experimental: Lentiviral transduced CD34+ cells
OTL-101, a cryopreserved formulation of autologous CD34+ haematopoietic stem cells transduced ex vivo with Elongation Factor 1α Short form (EFS) lentiviral vector (LV) encoding for the human adenosine deaminase deficiency (ADA) gene
Drug: Lentiviral transduced CD34+ cells
Biological: Infusion of autologous cryopreserved EFS-ADA LV CD34+ cells
Other Name: OTL-101

Primary Outcome Measures :
  1. Overall survival at 12 months post OTL-101 infusion [ Time Frame: 12 Months ]
    Overall survival is defined as the proportion of subjects alive. as the proportion of subjects alive with no "event", an "event" being the resumption of PEG-ADA ERT or the need for a rescue SCT, or death free survival in ADA-SCID patients treated with a cryopreserved formulation of OTL-101.

  2. Event free survival at 12 months post OTL-101 infusion defined as Death, returning to PEG-ADA Enzyme Replacement Therapy (ERT) or Need of rescue Stem Cell Transplant (SCT) [ Time Frame: 12 Months ]
    Event-free survival is defined as the time-to event from the OTL-101 infusion if an event occurred, or to the date of the last evaluation without an event if no event occurred.

Secondary Outcome Measures :
  1. Overall survival at 24 months post OTL-101 infusion [ Time Frame: 24 months ]

    Overall survival is defined as the proportion of subject's alive post OTL-101 infusion.

    Safety evaluation includes frequency of severe infections or opportunistic infectious episodes (defined as infections or severe infections requiring hospitalisation or prolonging hospitalisation and/or documented infections by opportunistic pathogens (i.e. interstitial pneumonia, intractable diarrhoea), performance outcomes and immune response.

  2. 3. Event free survival at 24 months and safety evaluation as assessed by number of patients with Grade 3 through Grade 5 adverse events that are related to the intervention, graded according to NCI CTCAE Version 3.0 [ Time Frame: 24 Months ]

    Event-free survival is defined as the proportion of subjects alive with no "event", an "event" being the resumption of PEG-ADA ERT or the need for a rescue SCT, or death. Safety evaluations are event free survival.

    Safety evaluation and will be assessed throughout the study by evaluating adverse events including infections, clinical laboratory test results, vital signs measurements, physical examination results, and concomitant medication usage.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Provision of written informed consent prior to any study related procedures. In this study consent must be provided by the parents/legal guardians and, where applicable according to local laws, a signed assent from the child,
  2. Subjects ≥30 days and <18 years of age,
  3. With a diagnosis of ADA-SCID based on:

    1. . Evidence of ADA deficiency, defined as: i. Decreased ADA enzymatic activity in erythrocytes, leukocytes, skin fibroblasts, or in cultured foetal cells to levels consistent with ADA-SCID as determined by the reference laboratory, or ii. Identified mutations in ADA alleles consistent with a severe reduction in ADA activity,
    2. . Evidence of ADA-SCID based on either: i. Family history of a first order relative with ADA deficiency and clinical and laboratory evidence of severe immunologic deficiency, or ii. Evidence of severe immunologic deficiency in subjects prior to the institution of immune restorative therapy, based on

    Lymphopenia (absolute lymphocyte count <400 cells/mL) OR absence or low number of T-cells (absolute CD3+ count < 300 cells/mL), or

    Severely decreased T lymphocyte blastogenic responses to phytohemagglutinin (either <10% of lower limit of normal controls for the diagnostic laboratory, or <10% of the response of the normal control of the day, or stimulation index <10), or

    Identification of SCID by neonatal screening revealing low TREC levels.

  4. Ineligible for or with no available matched family donor for allogeneic BM transplantation, defined as the absence of a medically eligible HLA-identical sibling or family donor, with normal immune function, who could serve as an allogeneic bone marrow donor.
  5. Females of child-bearing age will be required to provide a negative pregnancy test 30 days prior to Visit 2.
  6. Subjects and their parents/legal guardians must be willing and able to comply with study restrictions and to remain at the clinic for the required duration during the study period and willing to return to the clinic for the follow up evaluation as specified in the protocol.

Exclusion Criteria:

  1. Ineligible for autologous hematopoietic stem cell (HSC) procedure.
  2. Other conditions which in the opinion of the Principal Investigator and/or Co-Investigators, contraindicate the harvest of bone marrow, the administration of Busulfan and the infusion of transduced cells, or which indicate an inability of the subject or subject's parent/legal guardian to comply with the protocol.
  3. Haematologic abnormality, defined as:

    Anaemia (Hb <8.0 g/dl). Evidence of bi/trilineage cytopaenia (haemoglobin <8 g/dl, neutrophils <0.5 x 109/L, platelets 50 x 109/L). Thrombocytopaenia (platelet count <50,000/mm3). Prothrombin time or partial thromboplastin time (PTT) >2 x upper limit of normal (ULN) (subjects with a correctable deficiency controlled on medication will not be excluded).

    • Cytogenetic abnormalities of PB, BM or amniotic fluid (if available). If cytogenetic testing has not been performed on cells from amniocentesis, assessment should be by karyotype, CGH, and or WES.
    • Prior allogeneic HSCT with cytoreductive conditioning.
  4. Pulmonary abnormality, defined as:

    • Resting O2 saturation by pulse oximetry <90% on room air.
    • Chest X-ray indicating active or progressive pulmonary disease. Note: Chest X-ray indicating residual signs of treated pneumonitis is acceptable for eligibility.
  5. Cardiac abnormality, defined as:

    • Abnormal ECG indicating cardiac pathology.
    • Uncorrected congenital cardiac malformation with clinical symptoms.
    • Active cardiac disease, including clinical evidence of congestive heart failure, cyanosis, hypotension.
    • Poor cardiac function as evidenced by left ventricular ejection fraction <40% on echocardiogram.
  6. Neurologic abnormality, defined as:

    • Significant neurologic abnormality revealed by examination.
    • Uncontrolled seizure disorder.
  7. Known history of significant renal abnormality.
  8. Known history of significant hepatic or gastrointestinal abnormality.
  9. Oncologic disease, defined as:

    • Evidence of active malignant disease other than DFSP2..
    • Evidence of DFSP expected to require anti-neoplastic therapy within the 5 years following the infusion of genetically corrected cells (if anti-neoplastic therapy has been completed, a subject with a history of DFSP can be included).
    • Evidence of DFSP expected to be life-limiting within the 5 years following the infusion of genetically corrected cells.
  10. Known sensitivity to Busulfan.
  11. Confirmation of an infectious disease by deoxyribonucleic acid (DNA) polymerase chain reactions (PCR) positive at time of screening assessment according to local protocols/procedures (including HIV-1 and hepatitis B).
  12. The subject is pregnant or has a major congenital anomaly.
  13. Is likely to require treatment during the study with drugs that are not permitted by the study protocol (see Section 0).
  14. The subject has previously received another form of gene therapy.

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 identifier (NCT number): NCT03765632

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Contact: Claire Booth, Dr +44 (0)207 905 2198

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United Kingdom
Great Ormond Street Hospital for Children NHS Trust Recruiting
London, United Kingdom, WC1N 3JH
Contact: Claire Booth, Dr    +44(0)207 905 2198   
Contact: Kajal Soni, Miss    0207 762 6056   
Principal Investigator: Claire Booth, Dr         
Sponsors and Collaborators
Great Ormond Street Hospital for Children NHS Foundation Trust
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Principal Investigator: Claire Booth, Dr UCL Great Ormond Street Institute of Child Health

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Responsible Party: Great Ormond Street Hospital for Children NHS Foundation Trust Identifier: NCT03765632    
Other Study ID Numbers: 17IC04
First Posted: December 5, 2018    Key Record Dates
Last Update Posted: December 6, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Vasodilator Agents
Purinergic P1 Receptor Agonists
Purinergic Agonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action