| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Severe combined immunodeficiency disorder (SCID) is a heterogeneous group of inherited disorders characterized by a profound reduction or absence of T lymphocyte function, resulting in lack of both cellular and humoral immunity. The most common form of SCID is an X-linked form (SCID-X1), which accounts for 30-50% of all cases. Children with SCID lack virtually all immune protection from pathogens. They are prone to repeated and persistent infections that can be very serious or life threatening. |
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| E.1.1.1 | Medical condition in easily understood language |
| Children who are born with mutations in the IL2RG gene which is located on the X chromosome have severe combined immunodeficiency (SCID). |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10069566 |
| E.1.2 | Term | Severe combined immunodeficiency syndrome |
| E.1.2 | System Organ Class | 100000004850 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the research is to measure event-free survival and T cell immune reconstitution one year after gene therapy. Events include death, infusion of the patient's back-up cells (collected prior to gene therapy) for failure of blood cell recovery and bone marrow transplant from a donor due to poor immune system recovery. T cell reconstitution recovery 1 year after gene therapy will be evaluated by assessment of the patient's T cells and gene marking. |
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| E.2.2 | Secondary objectives of the trial |
| Secondary objectives are to measure overall survival, event-free survival, safety related to the procedure, clinical and laboratory measures of efficacy including blood immune reconstitution and gene marking after gene transfer. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
All subjects must fulfill the following criteria to be included in the study:
1. Diagnosis of SCID-X1 based on immunophenotype and lack of T cell function (proliferation to PHA <10% of the lower limit of normal for the laboratory) AND confirmed by a mutation in IL2RG
2. Lack of an HLA identical (A, B, C, DR, DQ) related donor
3. Age <5 years
4. Signed informed consent
5. Documentation of willingness to follow up for 15 years post-infusion
6. If the patient has previously undergone allogeneic transplant, lack of donor T cell engraftment must be documented.
7. Age at least 8 weeks of age by the time of busulfan administration
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| E.4 | Principal exclusion criteria |
Subjects will not be eligible for the study if any of the following criteria is fulfilled:
1. Patients with an active, therapy-resistant infection. Infections that are known to be highly morbid in SCID patients will be considered active and therapy-resistant if the infectious agent is repeatedly isolated despite a minimum of 2 weeks of appropriate therapy and is associated with significant organ dysfunction (including but not limited to abnormalities listed below).
a. Mechanical ventilation including continuous positive airway pressure
b. Abnormal liver function defined by AST and ALT >10 times the upper range of normal OR Bilirubin >2 mg/dL
c. Shortening fraction on echocardiogram <25% or ejection fraction <50%
d. Renal failure defined as glomerular filtration rate <30 ml/min/1.73 m2 or dialysis dependence
2. Uncontrolled seizure disorder
3. Encephalopathy
4. Documented coexistence of any disorder known to affect DNA repair
5. Diagnosis of active malignant disease other than EBV-associated lymphoproliferative disease
6. Patients with evidence of infection with HIV-1
7. Previous allogeneic transplant with cytoreductive chemotherapy
8. Major (life-threatening) congenital anomalies. Examples of “major (life-threatening) congenital anomalies” include, but are not limited to: unrepaired cyanotic heart disease, hypoplastic lungs, anencephaly or other major central nervous system malformations, other severe non-repairable malformations of the gastrointestinal or genitourinary tracts that significantly impair organ function.
9. Other conditions which in the opinion of the P.I. or Co-investigators, contra-indicate collection and/or infusion of transduced cells or indicate patient’s inability to follow the protocol. These may include for example clinical ineligibility to receive anaesthesia, severe deterioration of clinical condition of the patient after collection of bone marrow but before infusion of transduced cells, or documented refusal or inability of the family to return for scheduled visits. There may be other unforeseen rare circumstances that would result in exclusion of the patient, such as sudden loss of legal guardianship.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Measure event-free survival and T cell immune reconstitution 1 year after gene transfer. Event-free Survival is defined as the time from the infusion to the first event, if an event occurred, or to the date of the last evaluation without an event if no event occurred. If no event occurred, the subject’s data will be considered censored at the last evaluation. An event is any of the following:
• Death
• Infusion of back-up product due to failure of haematopoietic recovery, or
• Allogeneic transplant performed for poor immune reconstitution
T cell reconstitution is defined as both:
• CD3+ T cell count ≥300 cells/microliter in peripheral blood, and
• Gene marking ≥0.1 copies/cell in sorted CD3+ T cells
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Secondary endpoints are enumeration of events related to survival, safety and measuring laboratory correlates of efficacy.
1) Overall survival at 2 years post-infusion
2) Event-free survival at 2 years post-infusion
Events will include death, allogeneic transplant and development of insertional oncogenesis requiring treatment. Descriptive statistics and graphical techniques will be used to summarize overall and event-free survival. Given the trial’s nature with small numbers of infant and child subjects who require close medical supervision, and stringent screening requirements, loss to follow-up is not anticipated. Cumulative events will be reported and recorded into a database in real time. At scheduled investigations, absolute numbers of specific events will be tallied and, after several events have transpired, exact (binomial) confidence intervals of proportions will be computed. Over the 2-year period, monitoring will be continuous and individual patient timelines will be plotted (noting specific events and times), and a cumulative probability of the composite endpoint will be estimated.
3) Incidence of adverse events related to gene therapy including:
a. Detection of replication competent lentivirus (RCL)
b. Clonal dominance
c. Life-threatening adverse reactions related to the gene therapy procedure i.e. insertional oncogenesis
Samples will be collected according to the monitoring schedule. RCL will be performed by the National Gene Vector Biorepository. Monitoring of clonal dominance will be performed in the laboratory of Frederic Bushman, University of Pennsylvania
4) Clinical and laboratory correlates of efficacy including:
a. Immune reconstitution
This will include
• enumeration of absolute lymphocyte count determined by routine complete blood counts (CBC)
• absolute numbers of T, B and NK lymphocytes
• percentage of naïve and memory T and B cell subsets
• freedom from immunoglobulin substitution for at least 9 months measured at 2 years post-infusion
• serum immunoglobulin levels (IgA, IgM and IgG at least 12 weeks without exogenous substitution)
• antigen specific antibody titers to tetanus toxoid
• proliferation of lymphocytes to phytohemagglutinin determined by tritiated thymidine incorporation
• T cell receptor excision circles (TREC)
• T cell receptor Vb family usage
b. Frequency of gene marking in peripheral blood cells
• To assess the efficacy of stem cell transduction/engraftment, we will obtain serial samples of peripheral blood and sort specific lineages including CD3+, CD19+, CD3- CD56+ and CD15+ cells. Genomic DNA isolated from each population will be assayed for vector copy number by quantitative PCR (qPCR).
c. Clonal diversity of vector integrants
• Clonal diversity will be quantitated and used to estimate the number of transduced HSC that have engrafted in the subjects. Number of sequence reads and unique integration sites will be assessed to quantify population clone diversity, distribution of integration sites and relative abundance.
5) Haematopoietic recovery after receipt of busulfan
Haematopoietic recovery is defined as absolute neutrophil count (ANC) above 0.5 x 109 /l for three consecutive days, achieved within 6 weeks following infusion.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The secondary endpoints will be measured over a series of timepoints throughout the study. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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