| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Beta talassemia trasfusione dipendente |
| Beta talassemia trasfusione dipendente |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Not possible to specify |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10043391 |
| E.1.2 | Term | Thalassaemia beta |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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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 |
1. To evaluate the safety and tolerability of autologous CD34+ cell enriched fraction that contains Hematopoietic Stem Cells (HSC) transduced with Lentiviral Vector (LV) encoding the beta-globin gene in pediatric and adult patients with transfusion dependent beta-thalassemia following a reduced toxicity conditioning regimen.
2. To evaluate the efficacy of autologous CD34+ cell enriched fraction that contains Hematopoietic Stem Cells (HSC) transduced with Lentiviral Vector (LV) encoding the beta-globin gene in pediatric and adult patients with transfusion dependent beta-thalassemia following a reduced toxicity conditioning regimen.
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Written informed consent
• Transfusion-dependent beta-thalassemia (any genotype). Transfusion dependence is defined as receiving ≥ 8 transfusions of blood per year over a minimum of 2 years.
• Karnofsky Index or Lansky > 80%
• Age ≥ 3 years and < 65 years
• Adequate cardiac, renal, hepatic and pulmonary functions as evidenced by:
Left ventricular ejection fraction (LVEF) greater than 45% by echo and normal ECG or presence of abnormalities not significant for cardiac disease. Absence of severe pulmonary hypertension
Diffusing capacity of the lung for carbon monoxide (DLCO) > 50% and forced expiratory volume in 1 sec (FEV1) and forced expiratory vital capacity (FVC) > 60% predicted
(if non cooperative: pulse oximetry > 95 % in room air)
Serum creatinine < 1.5 upper limit of normal
Absent-mild-moderate liver iron overload on T2*MRI (less than 12 months before enrolment)
Absent-mild-moderate cardiac iron overload T2*MRI (less than 12 months before enrolment)
Absence of severe liver fibrosis or cirrhosis on fibroscan or liver biopsy (less than 12 months before enrolment)
• Low risk thrombophilic screen and negative history of significant previous thrombotic events
• For all patients in reproductive age, agreement to use highly effective and adequate method of contraception while receiving treatment phase and for at least 12 months following drugs administration (including both females of child bearing potential and males with partners of child bearing potential)
• Good adherence to transfusion and chelation programme as indirect evidence of good adherence to treatment and follow-up evaluations for current trial
• Availability of an adequate and well documented transfusion history (at least previous 6 months) or availability to follow a regular transfusion regimen according to guidelines and provide a detailed transfusion record of the 6 months prior to intervention phase
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| E.4 | Principal exclusion criteria |
• Use of other investigational agents within 4 weeks prior to study enrolment (within 6 weeks if use of long-acting agents)
• Severe, active viral, bacterial, or fungal infection at eligibility evaluation
• Malignant neoplasia (except local skin cancer or cervical intraepithelial neoplasia) or exceptional family history of familial cancer syndromes
• Myelodysplasia, cytogenetic alterations associated with neoplasia, or other serious haematological disorder than thalassemia
• History of uncontrolled seizures
• Other clinical conditions judged non compatible with the procedure and/or the treatment
• Positivity for HIV (serology or RNA), and/or HbsAg and/or HBV DNA and/or HCV RNA (or negative HCV RNA but on antiviral treatment) and/or Treponema Pallidum or Mycoplasma active infection
• Active alcohol or substance abuse within 6 months of the study
• Pregnancy or lactation
• Previous allogeneic bone marrow transplantation or gene therapy
• For paediatric patients only: availability of an HLA-matched donor (sibling or of a suitable 10/10 matched unrelated donor).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
End point primario:
1) Overall survival
E.5.1.1 Tempo/i di rilevazione di questo end point:
• 2 years from gene therapy
E.5.1 End point primario (ripetere se necessario):
2) Achievement of hematological engraftment defined as:
• first day of neutrophil count >500/mm3
• platelets >20,000/mm3 on 3 consecutive blood counts ≤ day +60 from gene therapy.
E.5.1.1 Tempo/i di rilevazione di questo end point:
• neutrophil count (0-24h)
• platelets count ≤ day +60 from gene therapy
E.5.1 End point primario (ripetere se necessario):
3) Safety of the administration of autologous HSC transduced with LV-GLOBE measured as:
• short-term tolerability;
• absence of Replication Competent Lentivirus (RCL);
• absence of abnormal clonal proliferation.
E.5.1.1 Tempo/i di rilevazione di questo end point:
• short-term tolerability (0-24 hours from gene therapy);
• absence of Replication Competent Lentivirus (RCL) (0-24 months)
• absence of abnormal clonal proliferation (0-24 months).
E.5.1 End point primario (ripetere se necessario):
4) Short-term safety and tolerability of the different conditioning regimens.
E.5.1.1 Tempo/i di rilevazione di questo end point:
• from day -5 to day 100 after ATIMP Injection by clinical and laboratory surveillance
E.5.1 End point primario (ripetere se necessario):
5) Overall safety and tolerability
E.5.1.1 Tempo/i di rilevazione di questo end point:
• from treatment phase to 2 years after gene therapy
E.5.1 End point primario (ripetere se necessario):
6) Polyclonal engraftment
E.5.1.1 Tempo/i di rilevazione di questo end point:
• integration analysis at 6, 12, 18, 24 months after ATIMP Injection.
E.5.1 End point primario (ripetere se necessario):
7) Reduction in transfusion frequency up to transfusion independence.
E.5.1.1 Tempo/i di rilevazione di questo end point:
• from 6 months after ATIMP injection and compared to baseline (recorded from -7 to -1 months).
E.5.1 End point secondario (ripetere se necessario):
8) Transfusion independence
E.5.1.1 Tempo/i di rilevazione di questo end point:
• 9, 12, 18, 24 months from ATIMP injection
E.5.1 End point secondario (ripetere se necessario):
9) Adequate Hb level (Hb > 9 gr/dL in adults and Hb > 10 gr/dL in children)
E.5.1.1 Tempo/i di rilevazione di questo end point:
• 9, 12, 18 and 24 months of follow-up in patients who reach transfusion independence
E.5.1 End point secondario (ripetere se necessario):
10) Adequate engraftment of genetically corrected cells (expressed as VCN ≥ 0.15 on bone marrow erythroid cells)
E.5.1.1 Tempo/i di rilevazione di questo end point:
• 6, 12 and 24 months from ATIMP injection
E.5.1 End point secondario (ripetere se necessario):
11) Presence (for homozygous and compound heterozygous beta-zero globin mutations) of transgene expression or at least 2-fold increase (for mutations including beta+ alleles) of transgene expression
E.5.1.1 Tempo/i di rilevazione di questo end point:
• 6, 12 and 24 months year from ATIMP injection.
E.5.1 End point secondario (ripetere se necessario):
12) Improvement of health-related quality of life (HRQoL)
E.5.1.1 Tempo/i di rilevazione di questo end point:
• 12 and 24 months of follow-up compared to baseline.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1)2 years from gene therapy
2.1)0-24h/
2.2)≤ day +60 from gene therapy.
3.1) 0-24 hours from gene therapy.
3.2) 0-24 months.
3.3) 0-24 months
4)from day -5 to day 100 after ATIMP Injection by clinical and laboratory surveillance
5)from treatment phase to 2 years after gene therapy
6)integration analysis at 6, 12, 18, 24 months after ATIMP Injection.
7)from 6 months after ATIMP injection and compared to baseline (recorded from -7 to -1 months).
8) 9, 12, 18, 24 months from ATIMP injection
9) 9, 12, 18 and 24 months of follow-up in patients who reach transfusion independence
10) 6, 12 and 24 months from ATIMP injection
11) 6, 12 and 24 months year from ATIMP injection
12) 12 and 24 months of follow-up compared to baseline
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| E.5.2 | Secondary end point(s) |
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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 | No |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
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