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 CD34+ cells of the bone marrow
• 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. Subjects 12 to 35 years of age, inclusive on the date of informed consent
2. Subject (or their legally authorized representative or guardian) will sign and date an informed consent form (ICF) and, where applicable, an assent form
3. Diagnosis of transfusion-dependent β-thalassemia (TDT) as defined by:
a. Documented homozygous β-thalassemia 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 β^0 and non β^0 genotypes are defined using the HbVar Database.
b. A history of at least 100 mL/kg/year or 10 units/year of packed RBC transfusions in the prior 2 years before signing the consent or the last rescreening for patients going through repeat screening.
4. Karnofsky performance status of ≥80% for subjects ≥16 years of age.
Lansky performance status of ≥80% for subjects <16 years of age.
5. Eligible for autologous stem cell transplant as per investigator's judgment.
6. Access to detailed medical records on packed RBC transfusions, including units and estimated volumes (latter if available) of packed RBCs and associated pre-transfusion Hb values, weight, and in-patient hospitalizations, for at least the 2 years prior to consent. Pre-transfusion body weight and Hb values should be collected (if available) for every transfusion.
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 of reproductive capacity must agree to use effective contraception from start of mobilization through at least 6 months after CTX001 infusion (Section 3.6 of the protocol).
9. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, contraceptive guidelines, and other study procedures.
10. Willing to participate in an additional long-term follow-up study (Study VX18-CTX001-131) after completion of this study. |
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E.4 | Principal exclusion criteria |
1. A willing and healthy 10/10 human leukocyte antigen (HLA)-matched related donor is available per investigator's judgement.
2. Prior allogeneic HSCT.
3. Subjects with associated α-thalassemia and >1 alpha deletion or alpha multiplications.
4. Subjects with 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 count <3 × 10^9/L or platelet count <50 × 10^9/L not related to hypersplenism per investigator judgment.
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: immediate family member with a known family cancer syndrome, history of relevant drug allergies; history of cardiovascular or central nervous system disease; history or presence of clinically significant pathology; history of uncontrolled seizure disorders, or history of psychiatric disorders.
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 >2.5 x 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 on a prior liver biopsy, if available
d. Subjects with active hepatitis infection (see criterion 16).
e. Subjects with history of chronic hepatitis infection are also excluded unless liver biopsy within 3 months prior to or at screening shows no evidence of bridging fibrosis or cirrhosis
f. Liver iron content (LIC) ≥15 mg/g on R2* MRI of liver, unless liver biopsy within 3 months prior to or at screening shows no evidence of bridging fibrosis or cirrhosis.
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 m2.
13. Diffusion capacity of the lungs for carbon monoxide (DLco) <50% of predicted (corrected for hemoglobin and/or alveolar volume).
14. Prior treatment with gene therapy/editing product.
15. Intolerance, contraindication, or known sensitivity to plerixafor, GCSF products (e.g., filgrastim), or busulfan. Prior anaphylaxis with excipients of CTX001 product (dimethyl sulfoxide [DMSO], Dextran).
16. Positive serology for the presence of human immunodeficiency virus-1 (HIV-1) or human immunodeficiency virus-2 (HIV-2) (positive for both antigen/antibody AND nucleic acid tests [NAT]), hepatitis B virus (HBV) (positive for Hepatitis B core antibody [HBcAb] or positive hepatitis B surface antigen (HBsAg) AND for NAT tests), syphilis [positive screening AND positive confirmatory tests (RPR or treponemal specific test)], or hepatitis C virus (HCV positive for both antibody [HCAb] and for NAT tests). Additional infectious disease markers should be obtained and tested as required by the local authority for the collection and processing of cellular therapy products. These additional tests (e.g., HTLV-1, HTLV-2, malaria, tuberculosis, toxoplasmosis, Trypanosoma cruzi, or West Nile virus) will be evaluated to determine overall impact to the patient and manufacturing of CTX001.
17. Participation in another clinical study with an investigational drug/product 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 Endpoints:
• Successful neutrophil engraftment.
• Time to neutrophil engraftment.
• Time to platelet engraftment
• Safety and tolerability assessments based on adverse events (AEs),
clinical laboratory values, and vital signs
• Incidence of transplant related mortality (TRM) within 100 days and
within 1 year post-CTX001 infusion.
• All-cause mortality.
Primary Efficacy Endpoint:
• Proportion of subjects achieving TI12, defined as maintaining weighted average Hb ≥9 g/dL without RBC transfusions for at least 12 consecutive months any time after CTX001 infusion. The evaluation of TI12 starts 60 days after last RBC transfusion for post-transplant support or TDT disease management. |
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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) |
Key Secondary Efficacy Endpoint:
• Proportion of subjects achieving TI6, defined as maintaining weighted average Hb ≥9 g/dL without RBC transfusions for at least 6 consecutive months any time after CTX001 infusion. The evaluation of TI6 starts 60 days after last RBC transfusion for post-transplant support or TDT disease management.
Secondary Endpoints:
• Proportion of subjects achieving at least 95%, 90%, 85%, 75%, 50% reduction from baseline in annualized transfusions up to 24 months starting 60 days after CTX001 infusion.
• Relative change from baseline in transfusions up to 24 months starting 60 days after CTX001 infusion
• Duration of transfusion free in subjects who have achieved TI12
• Proportion of alleles with intended genetic modification present in peripheral blood leukocytes over time. Intended genetic modifications are indels that modify the sequence of the erythrocyte-specific enhancer in intron 2 of BCL11A
• Proportion of alleles with intended genetic modification present in CD34+ cells of the bone marrow over time
• Fetal hemoglobin concentration (pre-transfusion) over time
• Total hemoglobin concentration (pre-transfusion) over time
• Change in patient reported outcomes (PROs) over time using EuroQol
Quality of Life Scale (EQ 5D 5L) for subjects ≥18 years old, EQ 5D-Y for subjects <18 years old), functional assessment of cancer therapy bone marrow transplant (FACT-BMT) for subjects ≥18 years old, and Pediatric Quality of Life Inventory (PedsQL) for subjects <18 years old
• Change in parameters of iron overload, including:
o Liver iron concentration (LIC) from baseline as assessed by R2* magnetic resonance imaging (MRI) 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 |
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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) | 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.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 |
United States |
Germany |
Greece |
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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The end of study is defined as the last scheduled visit (or contact) of the last subject.
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 | 4 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |