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 do not have 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 | 19.1 |
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 ≥12 and ≤50 of age with transfusion-dependent beta-thalassemia, who do not have 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 ≥12 and ≤50 of age with transfusion-dependent beta-thalassemia, who do not have beta0/beta0 genotype. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subjects between 12 and 50 years of age at the time of consent or assent.
2. Diagnosis of TDT with a history of at least 100 mL/kg/year of pRBCs in the 2 years preceding enrollment, or be managed under standard thalassemia guidelines, with ≥8 transfusions of pRBCs per year in the 2 years preceding enrollment.
3. Clinically stable, and eligible to undergo HSCT.
4. Treated and followed for at least the past 2 years in a specialized center that maintained detailed medical records on RBC transfusions, in-patient hospitalization, and iron chelation history.
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E.4 | Principal exclusion criteria |
1. Presence of a mutation characterized as beta0 on both HBB alleles. For the purpose of this study, 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.
4. A 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 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.
13. A cardiac T2* < 10 ms by MRI.
14. Any other evidence of severe iron overload that 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 HLA-matched family donor. If required by regional regulatory 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 independence” (TI). TI is defined as a weighted average Hb ≥9 g/dL without any RBC transfusions for a continuous period of ≥12 months at any time during the study after drug product infusion. |
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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
- Characterization of transfusion reduction (TR) among subjects not achieving TI
- Trend in hemoglobin pre- and post-treatment
- Characterization of use of iron chelation among all subjects
- Evaluation of the change in iron burden over time
EXPLORATORY EFFICACY ENDPOINTS
- Evaluation of health-related quality of life (HRQoL) over time
- Assessment of growth and puberty parameters (age appropriate), bone density, diabetes, endocrine evaluations, and neurocognitive development (pediatric subjects < 18 years of age)
- Assessment of improvement in ineffective erythropoiesis
- Correlations of pre-treatment variables with response
- Measures of health resource utilization
PHARMACODYNAMIC ENDPOINTS
- βA-T87Q globin expression
- VCN in cell populations from peripheral blood
EXPLORATORY PHARMACODYNAMIC ENDPOINT
- Relationship between measures of myeloablation and pharmacodynamic and clinical outcomes
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 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.8.5 | 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 |
Thailand |
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 |