E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Transfusion-Dependent β Thalassemia |
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E.1.1.1 | Medical condition in easily understood language |
Transfusion-Dependent β Thalassemia |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
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 |
To evaluate the safety and efficacy of a single dose of autologous CRISPR-Cas9 modified CD34+ hHSPCs (CTX001) in subjects with transfusion-dependent β-thalassemia (TDT) |
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E.2.2 | Secondary objectives of the trial |
• To quantify percentage of edited alleles in peripheral blood leukocytes and bone marrow cells
• To assess the production of HbF post-CTX001 infusion
• To assess the effects of infusion of CTX001 on disease-specific events and clinical status
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age ≥18 and ≤35 years of age.
2. Able to provide written informed consent.
3. Diagnosis of transfusion-dependent β-thalassemia (TDT) as defined by:
a. Documented homozygous β-thalassemia (with the exception of the β0/β0 genotype) or compound heterozygous β-thalassemia including β-thalassemia/hemoglobin E (HbE). Subjects can be enrolled based on historical data, but a confirmation of the genotype using the study central laboratory will be required before busulfan conditioning. The β0/β0 genotypes are defined using the HbVar Database.
b. A history of at least 100 mL/kg/year or 10 units/year of packed Red Blood Cell (RBC) transfusions in the prior 2 years before signing the consent.
4. Karnofsky performance status of ≥80%.
5. Eligible for autologous stem cell transplant as per investigator’s judgment.
6. Access to detailed medical records on packed RBC transfusions, including volume or units of packed RBCs and associated pre-transfusion Hb values, and in-patient hospitalizations, for at least the 2 years prior to consent.
7. Female subjects of childbearing potential (postmenarcheal, has an intact uterus and at least 1 ovary, and is less than 1 year postmenopausal) must agree to use acceptable method(s) of contraception from consent through at least 6 months after CTX001 infusion.
8. Male subjects must agree to use effective contraception (including condoms) from start of busulfan conditioning through at least 6 months after CTX001 infusion.
9. Willing to participate in an additional long-term follow-up study or registry after completion of this study. |
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E.4 | Principal exclusion criteria |
1. An available 10/10 Human Leukocyte Antigen (HLA)-matched related donor.
2. Prior allo-hematopoietic stem cell transplant (HSCT).
3. Subjects with associated α-thalassemia and >1 alpha chain deletion.
4. Subjects with a β0/β0 thalassemia genotype or sickle cell beta thalassemia variant
5. Clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the investigator.
6. White blood cell (WBC) count <3 × 10^9/L or platelet count <50 × 10^9/L not related to hypersplenism.
7. History of a significant bleeding disorder.
8. History of any illness or any clinical condition that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject. This may include, but is not limited to: history of relevant drug allergies; history of cardiovascular or central nervous system disease; history or presence of clinically significant pathology; or history of mental disease.
9. Any prior or current malignancy or myeloproliferative disorder or a significant immunodeficiency disorder.
10. Advanced liver disease, defined as:
a. Aspartate transaminase (AST), alanine transaminase (ALT) >3 x the upper limit of normal (ULN), or direct bilirubin value >2 x the ULN, or:
b. Baseline prothrombin time (International Normalized Ratio; INR) >1.5 x ULN, or
c. History of cirrhosis or any evidence of bridging fibrosis, or active hepatitis on liver biopsy. Liver biopsy is required when liver iron concentration (LIC) is ≥15 mg/g on T2* MRI of liver. If a liver biopsy has been performed less than 6 months prior to consent, it does not need to be repeated.
11. A cardiac T2* <10 ms by MRI or left ventricular ejection fraction (LVEF) <45% by echocardiogram.
12. Baseline estimated glomerular filtration rate <60 mL/min/1.73 m^2.
13. Diffusing capacity of the lungs for carbon monoxide (DLco) <50% of predicted (corrected for hemoglobin and/or alveolar volume).
14. Prior treatment with gene therapy.
15. Intolerance or known sensitivity to plerixafor, granulocyte colony stimulating factor (G-CSF) products (e.g., filgrastim), or busulfan. Prior anaphylaxis with excipients of CTX001 product (Dimethyl sulfoxide [DMSO], Dextran).
16. Positive serology for human immunodeficiency virus-1 (HIV-1) or human immunodeficiency virus-2 (HIV-2), hepatitis B virus (HBV; hepatitis B core antibody [HBcAb] and positive HBV polymerase chain reaction [PCR]), or hepatitis C virus (HCV) (positive HCV PCR). Positive serology for syphilis, toxoplasmosis or any other infectious disease marker as required by local testing for cellular processing.
17. Participation in another clinical study with an investigational drug within 30 days of screening or fewer than 5 half-lives of the investigational agent, whichever is longer from screening.
18. An assessment by the investigator that the subject would not comply with the study procedures outlined in the protocol.
19. Pregnant or breastfeeding females. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety:
• Proportion of subjects with engraftment. Engraftment is defined as ANC ≥500/µL for three consecutive days. Engraftment failure is defined as any subject not achieving neutrophil engraftment by Day +42 following CTX001 infusion or if backup unmodified CD34+ cells are utilized.
• Time to engraftment.
• Frequency and severity of collected AEs from signing of informed consent through Month 24 visit as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03.
• Incidence of transplant related mortality (TRM) at 100 days and 1 year post-CTX001 infusion. TRM is defined as death possibly related to the transplantation procedure as assessed by the investigator.
• All-cause mortality.
Primary Efficacy:
• Proportion of subjects achieving transfusion reduction for at least 6 months (TR6).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Safety: see above
• Proportion of subjects achieving TR6: 3 months post-CTX001 infusion for at least 6 months at the time of analysis |
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E.5.2 | Secondary end point(s) |
Key Secondary Efficacy:
• Proportion of subjects achieving transfusion independence for at least 6 months (TI6).
Secondary Endpoints:
• Proportion of subjects achieving transfusion reduction for at least 12 months (TR12).
• Proportion of subjects achieving transfusion independence for at least 12 months (TI12).
• Proportion of alleles with intended genetic modification present in peripheral blood leukocytes.
• Proportion of alleles with intended genetic modification present in bone marrow cells.
• Change in fetal hemoglobin concentration (pre-transfusion) over time.
• Change in health-related quality of life (HRQoL) from baseline over time using EQ-5D-5L and FACT-BMT.
• Change in parameters of iron overload, including:
o Liver iron concentration (LIC) and cardiac iron content (CIC) from baseline as assessed by T2* MRI.
o Change in serum ferritin level from baseline over time.
• Proportion of subjects receiving iron chelation therapy over time. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Proportion of subjects achieving TI6: 3 months post-CTX001 infusion for at least 6 months at the time of analysis
• Proportion of subjects achieving TR12: 3 months post-CTX001 infusion for at least 12 months at the time of analysis
• Proportion of subjects achieving TI12: 3 months post-CTX001 infusion for at least 12 months at the time of analysis
• Proportion of alleles with intended genetic modification present in peripheral blood leukocytes and bone marrow cells, change in HbF levels (pre-transfusion): at Months 1, 2, 3, 4, 5, 6, 9, 12, 18, 24
• Change in HRQoL: at Months 3, 6, 12, 18, 24
• Change in parameters of iron overload:
o Change in serum ferritin level: continuous variable over time.
o Change in LIC: at Months 12 and 24
o Change in Cardiac T2*: at Months 12 and 24 |
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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 | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
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 |
Canada |
Germany |
Italy |
United Kingdom |
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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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End of study will be defined as the date the last subject completes the 24-month follow-up period. The Sponsor will notify all applicable regulatory agencies in accordance with local requirements when the study has ended. |
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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 | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |