E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cerebral Adrenoleukodystrophy (CALD) |
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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] - Nutritional and Metabolic Diseases [C18] |
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 | 10051260 |
E.1.2 | Term | Adrenoleukodystrophy |
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 |
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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 |
1. Informed consent is obtained from a competent custodial parent or guardian with legal capacity to execute a local IRB/Independent Ethics Committee (IEC) approved consent (informed assent will be sought from capable subjects, in accordance with the directive of the IRB/IEC and with local requirements). 2. Males aged 17 years and younger, at the time of parental/guardian consent and, where appropriate, subject assent. 3. Active cerebral ALD as defined by: -Elevated VLCFA values, and -Active CNS disease established by central radiographic review of brain MRI demonstrating: i. Loes score between 0.5 and 9 (inclusive) on the 34-point scale, and ii. Gadolinium enhancement on MRI of demyelinating lesions. 4. Neurological Function Score (NFS) ≤ 1. |
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E.4 | Principal exclusion criteria |
1. Receipt of an allogeneic transplant or gene therapy. 2. Availability of a willing 10/10 HLA-matched sibling donor (excluding female heterozygotes). 3. Use of statins, Lorenzo's Oil, or dietary regimens used to lower VLCFA of consent. 4. Receipt of an investigational study drug or procedure within 3 months before Screening that might confound study outcomes. Use of investigational study drugs is prohibited throughout the course of the study. 5. Any conditions that make it impossible to perform MRI studies (including allergies to anesthetics or contrast agents). 6. Hematological compromise as evidenced by: - Peripheral blood ANC count < 1500 cells/mm3, - Platelet count < 100,000 cells/mm3, or - Hemoglobin < 10 g/dL. - Uncorrected bleeding disorder. 7. Hepatic compromise as evidenced by: - Aspartate transaminase (AST) value > 2.5×ULN - Alanine transaminase (ALT) value > 2.5×ULN - Total bilirubin value > 3.0 mg/dL, except if there is a diagnosis of Gilbert's Syndrome and the subject is otherwise stable 8. Renal compromise as evidenced by abnormal renal function (actual or calculated creatinine clearance < 50 mL/min) 9. Cardiac compromise as evidenced by left ventricular ejection fraction <40% 10. Immediate family member with a known or suspected familial cancer syndrome (including but not limited to hereditary breast and ovarian cancer syndrome, hereditary non-polyposis colorectal cancer syndrome, and familial adenomatous polyposis). 11. Clinically significant active bacterial, viral, fungal, parasitic, or prionassociated infection 12. Positive for human immunodeficiency virus type 1 or 2 (HIV-1, HIV-2); hepatitis B; hepatitis C; human T lymphotrophic virus 1 (HTLV-1). (Note that subjects who have been vaccinated against hepatitis B [hepatitis B surface antibody-positive] who are negative for other markers of prior hepatitis B infection [eg, negative for hepatitis B core antibody (Ab)] are eligible. Subjects with past exposure to HBV [HBcAb positive and/or HBeAb positive] are also eligible for the study provided they have a negative test for HBV DNA. Also note that subjects who are positive for anti-hepatitis C antibody are eligible as long as they have a negative hepatitis C viral load). 13. Any clinically significant cardiovascular or pulmonary disease, or other disease or condition that would be contraindicated for any of the other study procedures. 14. Absence of adequate contraception for fertile subjects. Male subjects and their female partners are required to use two different effective methods of contraception from Screening through at least 6 months after drug product infusion. 15. Any contraindications to the use of G-CSF during the mobilization of hematopoietic stem cells and any contraindications to the use of busulfan and cyclophosphamide, including known 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) |
The primary efficacy endpoint is: • Proportion of subjects who are alive and have none of the 6 MFDs at Month 24 (i.e. Month 24 MFD-free survival). MFDs are: o loss of communication o cortical blindness o tube feeding o total incontinence o wheelchair dependence o complete loss of voluntary movement
The primary safety endpoint is: • The proportion of subjects who experience either acute (≥ Grade II) or chronic GVHD by Month 24. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
24 months post-transplant |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints include: • Proportion of subjects who demonstrate resolution of gadolinium positivity on MRI (i.e., GdE-) at Month 24 • Time to sustained resolution of gadolinium positivity on MRI (i.e., GdE -). • Change in total NFS from Baseline to Month 24 • MFD-free survival over time • Overall survival
The secondary safety endpoints : • Proportion of subjects with neutrophil engraftment by 42 days post-drug product infusion • Time to neutrophil engraftment post-drug product infusion • Proportion of subjects with platelet engraftment by Month 24 • Time to platelet engraftment post-drug product infusion • Proportion of subjects with loss of engraftment post-drug product infusion by Month 24 • Proportion of subjects who undergo a subsequent HSC infusion by Month 24 • Proportion of subjects with transplant-related mortality through 100 and 365 days post-drug product infusion • Proportion of subjects with and severity of clinical ≥ Grade 3 AEs, all drug-product related AEs, all SAEs, ≥ Grade 3 infections, and changes in laboratory parameters by Month 24 • Proportion of subjects with ≥ Grade II acute GVHD by Month 24 • Proportion of subjects with chronic GVHD by Month 24 • Number of emergency room visits (post-neutrophil engraftment) by Month 24 • Number and duration of in-patient hospitalizations (post-neutrophil engraftment) by Month 24 • Number and duration of ICU stays (post-neutrophil engraftment) by Month 24 • Incidence of vector-derived RCL at Month 24 • The number of subjects with insertional oncogenesis (myelodysplasia, leukemia, lymphoma, etc.) by Month 24
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
24 months post-transplant |
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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 | Yes |
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) | 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
| Yes |
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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
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 |
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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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 | 8 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |