E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with severe combined immunodeficiency (SCID) based on a genetic defect in the Recombinase Activating Gene 1 (RAG1) |
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E.1.1.1 | Medical condition in easily understood language |
Children with a severe combined immunodeficiency due to a mutation in the RAG1 gene |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
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 objectives of the study are to demonstrate feasibility and safety of gene corrected autologous CD34+-selected hematopoietic stem cell therapy using a lentiviral SIN vector encoding codon-optimized human RAG1 cDNA in patients with RAG1-deficient SCID. |
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E.2.2 | Secondary objectives of the trial |
To demonstrate efficacy of this therapeutic intervention based on a) T and B cell reconstitution at one year after infusion of the investigational medicinal product, b) event free survival of the patient, and c) persistence of gene marking in myeloid and lymphoid cell lineages in blood and marrow |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. RAG1 deficient SCID as confirmed by genetic analysis 2. Peripheral blood T cells < 300/µL and/or naïve T cells < 1/µL 3. Age < 2 years 4. Age at least 8 weeks by the time of busulfan administration 5. lack of an available HLA-matched donor (HLA-identical sibling or 10/10 (A, B, C, DR, DQ) allele-matched (un)related donor) 6. signed informed consent (parental or guardian) 7. able to return to the local HSCT centre for follow-up (per protocol) during the 2-year study and the 15-year long-term off study review
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E.4 | Principal exclusion criteria |
1. availability of a HLA-matched donor (HLA-identical sibling or 10/10 (A, B, C, DR, DQ) allele-matched (un)related donor) 2. RAG 1 deficiency with peripheral blood T cells > 300/µL and/or naïve T cells > 1/µL 3. Omenn syndrome 4. Previous allogeneic HSCT 5. Significant organ dysfunction/co-morbidity (including but not limited to the ones listed below) a. Mechanical ventilation b. Shortening fraction on echocardiogram <25% c. Renal failure defined as dialysis dependence d. Uncontrolled seizure disorder 6. Any other condition that the investigator considers is a contraindication to collection and/or infusion of transduced cells for that individual or indicate patient's inability to follow the protocol, for example contraindication to busulfan, major congenital abnormalities, ineligible to receive anesthesia, or documented refusal or inability of the family to return for scheduled visits 7. HIV infection or HTLV infection
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Feasibility of successful generation of an IMP (RAG1 LV CD34+ cells) for RAG1 deficient SCID patients that meets the release criteria as defined in the IMPD. 2. Event free survival (EFS) after infusion of the IMP with events defined as a) failure of engraftment (neutrophils > 500/µL on three consecutive timepoints) within six weeks requiring infusion of the autologous unmanipulated backup stem cell product b) insufficient immune reconstitution within one year after RAG1 LV CD34+ cells infusion requiring allo-SCT c) occurrence of insertional mutagenesis presenting as malignant disease.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
ad 1. After producing the first three and after all five IMPs ad2. At one year after IMP infusion in the first three and at one after infusion of the fifth patient |
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E.5.2 | Secondary end point(s) |
- Overall survival (at 2 years) - T cell reconstitution (CD3 T cells > 300/μL blood) at 1 year - CD4 reconstitution (CD4 > 200/μL) at 1 year - Thymic function (presence of naïve CD4 T cells) at 1 year - T and B cell receptor molecular repertoire at 1 year - immunoglobulin substitution independence at 2 years - Persistence of gene marking in myeloid and lymphoid lineages in blood and mar-row at six months and one year (> 0.1 VCN) - Frequency of serious/invasive infections - Recovery from failure to thrive - Quality of life at 2 years (assessed using PedQual by proxy).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
see time points in 5.2 per item |
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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) | Yes |
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 | Yes |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Israel |
United Kingdom |
Germany |
Italy |
Netherlands |
Poland |
Spain |
Türkiye |
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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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The trial ends 5 years after administration of the IMP to the last subject in the trial. The 5 years timepoint is the last study visit of the last subject included in 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 | 6 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 17 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 30 |