E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
This study will enroll subjects with transfusion-dependent beta-thalassemia, who have a beta0/beta0 genotype, defined by a history of at least 100 mL/kg/year of packed red blood cells (pRBCs) or ≥ 8 transfusions of pRBCs per year in the 2 years preceding enrollment. |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054660 |
E.1.2 | Term | Thalassemia beta |
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 |
To evaluate the efficacy of treatment with LentiGlobin BB305 Drug Product in subjects ≤50 years of age with transfusion-dependent beta-thalassemia, who have a beta0/beta0 genotype. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety of treatment with LentiGlobin BB305 Drug Product in subjects ≤50 years of age with transfusion-dependent beta-thalassemia, who have a beta0/beta0 genotype. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subjects ≤50 years of age at the time of consent or assent (as applicable), and able to provide written consent (adults, or legal guardians, as applicable) or assent (adolescents or children). Provided that the DMC has approved enrolling subjects younger than 5 years of age, subjects younger than 5 years of age may be enrolled if they weigh a minimum of 6 kg and are reasonably anticipated to be able to provide at least the minimum number of cells required to initiate the manufacturing process. 2. Diagnosis of TDT with a history of at least 100 mL/kg/year of pRBCs in the 2 years preceding enrollment (all subjects), or be managed under standard thalassemia guidelines (e.g.,Thalassemia International Federation, 2014) with ≥8 transfusions of pRBCs per year in the 2 years preceding enrollment (subjects ≥12 years). 3. Clinically stable. 4. Treated and followed for at least the past 2 years in a specialized center that maintained detailed medical records on RBC transfusions, inpatient hospitalization, and iron chelation history. |
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E.4 | Principal exclusion criteria |
1. Presence of a mutation characterized as other than beta0 (e.g., beta+, betaE, betaC) on at least one HBB allele. For the purpose of this study, the HBB mutation IVS I-110 (G -> A) will be considered equivalent to a beta0 mutation. 2. Positive for presence of HIV-1 or HIV-2, HBV, or HCV. 3. Clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the clinical investigator. 4. A white blood cell (WBC) count <3×10^9/L, and/or platelet count <100×10^9/L not related to hypersplenism. 5. Uncorrected bleeding disorder. 6. Any prior or current malignancy or myeloproliferative or significant immunodeficiency disorder. 7. Immediate family member (i.e. parent or siblings) with a known Familial Cancer Syndrome. 8. Prior HSCT. 9. Advanced liver disease. 10. Baseline estimated glomerular filtration rate <70 mL/min/1.73 m^2. 11. Uncontrolled seizure disorder. 12. Diffusion capacity of carbon monoxide (DLco) <50% of predicted (corrected for Hb and/or alveolar volume, as clinically indicated). 13. A cardiac T2* <10 ms by MRI. 14. Any other evidence of severe iron overload that, in the investigator's opinion, warrants exclusion. 15. Participation in another clinical study with an investigational drug within 30 days of Screening. 16. Any other condition that would render the subject ineligible for HSCT, as determined by the attending transplant physician or investigator. 17. Prior receipt of gene therapy. 18. Diagnosis of significant psychiatric disorder of the subject that could seriously impede the ability to participate in the study. 19. Pregnancy or breastfeeding in a postpartum female or absence of adequate contraception for fertile subjects. 20. An assessment by the investigator that the subject would not comply with the study procedures outlined in the protocol. 21. A known and available human leukocyte antigen (HLA)-matched family donor. Ifrequired by regional authority, patients with a known and available matched unrelated donor will be excluded from the study. 22. Any contraindications to the use of G-CSF and plerixafor during the mobilization of hematopoietic stem cells and any contraindications to the use of busulfan and any other medicinal products used during the myeloablative conditioning, including hypersensitivity to the active substances or to any of the excipients. |
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E.5 End points |
E.5.1 | Primary end point(s) |
EFFICACY ENDPOINT -The proportion of subjects who meet the definition of "transfusion reduction" (TR), defined as demonstration of a ≥60% reduction in volume of pRBC transfusion requirements (in mL/kg) in the post-treatment time period of Months 12 to 24, compared to the average annual transfusion requirements in the 24 months prior to study enrollment. |
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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) |
EFFICACY ENDPOINTS - Characterization of subjects achieving transfusion independence (TI) - Characterization of transfusion reduction (TR) - Average pre-transfusion Hb (i.e. last value recorded prior to each pRBC transfusion) during 24 months prior to enrollment compared to average pre-transfusion Hb from Month 12 through 24 (in subjects who are not transfusion independent) or to average bi-monthly Hb from Month 12 through Month 24 (in subjects who are transfusion independent) - Characterization of use of iron chelation among all subjects - Evaluation of the change in iron burden over time
PHARMACODYNAMIC ENDPOINTS - βA-T87Q-globin expression - Correlation of βA-T87Q-globin expression at early time points post drug product infusion to βA-T87Q-globin expression at later time points, as well as clinical outcomes - VCN in cell populations from peripheral blood
SAFETY ENDPOINTS - Success and kinetics of HSC engraftment - Incidence of transplant-related mortality through 100 days post-drug product infusion and through 1 year post-drug product infusion - Overall survival - Detection of vector-derived replication competent lentivirus (RCL) in any subject - Characterization of events of insertional mutagenesis leading to clonal dominance or leukemia - Monitoring of laboratory parameters and frequency and severity of clinical adverse events |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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) | No |
E.7.1.1 | First administration to humans | No |
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) | Yes |
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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
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 |
France |
Germany |
Greece |
Italy |
United Kingdom |
United States |
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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 study will end when the last subject completes the Month 24 visit or discontinues from the study. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |