Immunologic Deficiency Syndromes
Conditions
Keywords
SCID, gene therapy, Adenosine deaminase, retroviral vector
Brief summary
This is a phase I/II protocol to evaluate the safety and efficacy of ADA gene transfer into hematopoietic stem/progenitor cells for the treatment of adenosine deaminase (ADA)-deficiency. This condition is an autosomal recessive form of Severe Combined Immunodeficiency (SCID) characterized by impaired immune responses, recurrent infections, failure to thrive and systemic toxicity due to accumulation of purine metabolites. Transplants from an human leukocyte-antigen (HLA)-identical sibling donor is the treatment of choice, but available for a minority of patients. The use of alternative bone marrow donors or enzyme replacement therapy is associated with important drawbacks. The drug product studied in this protocol consists of autologous cluster of differentiation (CD)34+ hematopoietic stem/progenitor cells engineered ex vivo with a retroviral vector encoding the therapeutic gene ADA. The engineered CD34+ cells are infused following a nonmyeloablative conditioning with busulfan to make space in the bone marrow. The study objectives are: a) to evaluate the safety and the clinical efficacy of gene therapy, in the absence of enzyme replacement therapy; b) to evaluate the biological activity (engraftment, ADA expression) of ADA transduced CD34+ cells and their hematopoietic progeny. c) to evaluate the immunological reconstitution and purine metabolism after gene therapy.
Detailed description
The safety of the study will be evaluated by description of all adverse events and adverse drug reactions. The study is aimed at reaching the minimum sample size of ten patients.
Interventions
GENETICGene Therapy
Infusion of autologous CD34+ cells transduced with retroviral vector encoding ADA after non-myeloablative conditioning with busulfan
DRUGBusulfan
Busulfan is used for non-myeloablative conditioning
Sponsors
Fondazione Telethon
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 17 Years
Healthy volunteers
No
Inclusion criteria
* ADA-SCID with no HLA-identical sibling donor available * pediatric age and at least one of the following criteria: * inadequate immune response after PEG-ADA for \> 6 months * patients who discontinued PEG-ADA due to intolerance, allergy or auto-immunity * patients for whom enzyme replacement therapy is not a life long therapeutic option
Exclusion criteria
* HIV infection * history or current malignancy * Patients who received a previous gene therapy treatment in the 12 months prior to receiving Strimvelis * any other conditions dangerous for the patients according to the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Survival | baseline to 3 years post gene therapy | From post-treatment to up to 3 years |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Severe Infections | Before Treatment and 3-months post-treatment up to 3 years | Severe infections were defined as those that required hospitalization or those that prolonged hospitalization. The rate of infection was estimated as number of severe infections over person-years of observation (free from severe infections) before and after treatment administration. The first 3 months after gene therapy were not considered in the post-gene therapy analysis, because all subjects were hospitalized during this period. |
| CD3+ Cell Counts | baseline up to 3 years post gene therapy | T-lymphocyte counts (CD3+): mean T-lymphocyte at Baseline and 3 years post gene therapy. Samples were taken from peripheral venous whole blood and tested by cytofluorometry; values are means (10\^6/L). |
Countries
Israel, Italy
Participant flow
Recruitment details
The Pivotal study enrolled 12 participants.
Participants by arm
| Arm | Count |
|---|---|
| Gene Therapy (Pivotal) Infusion of autologous cluster of differentiation (CD)34+ cells transduced with retroviral vector encoding ADA after non-myeloablative conditioning with busulfan | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Treatment | Physician Decision | 1 |
Baseline characteristics
| Characteristic | Gene Therapy (Pivotal) |
|---|---|
| Age, Categorical <=18 years | 12 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 2.38 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 12 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Region of Enrollment Italy | 12 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 12 |
| other Total, other adverse events | 12 / 12 |
| serious Total, serious adverse events | 10 / 12 |
Outcome results
Primary
Survival
From post-treatment to up to 3 years
Time frame: baseline to 3 years post gene therapy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Gene Therapy (Pivotal) | Survival | 12 Participants |
Secondary
CD3+ Cell Counts
T-lymphocyte counts (CD3+): mean T-lymphocyte at Baseline and 3 years post gene therapy. Samples were taken from peripheral venous whole blood and tested by cytofluorometry; values are means (10\^6/L).
Time frame: baseline up to 3 years post gene therapy
Population: Only subjects with available data at each visit were included in the analysis
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Gene Therapy (Pivotal) | CD3+ Cell Counts | Year 2 | 633 10^6 cells/L |
| Gene Therapy (Pivotal) | CD3+ Cell Counts | Year 3 | 831.1 10^6 cells/L |
| Gene Therapy (Pivotal) | CD3+ Cell Counts | Year 1 | 348.3 10^6 cells/L |
| Gene Therapy (Pivotal) | CD3+ Cell Counts | Baseline | 112.5 10^6 cells/L |
p-value: 0.00395% CI: [1.45, 6.19]Mixed Model Repeated Measures
p-value: <0.00195% CI: [2.63, 11.25]Mixed Model Repeated Measures
p-value: <0.00195% CI: [3.08, 13.64]Mixed Model Repeated Measures
Secondary
Rate of Severe Infections
Severe infections were defined as those that required hospitalization or those that prolonged hospitalization. The rate of infection was estimated as number of severe infections over person-years of observation (free from severe infections) before and after treatment administration. The first 3 months after gene therapy were not considered in the post-gene therapy analysis, because all subjects were hospitalized during this period.
Time frame: Before Treatment and 3-months post-treatment up to 3 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gene Therapy (Pivotal) | Rate of Severe Infections | 1.1 Severe Infections per person year |
| Severe Infections (After Gene Therapy) | Rate of Severe Infections | 0.429 Severe Infections per person year |
p-value: 0.005One-sided Poisson-regression