Clinical study to assess the efficacy and safety of gene therapy for the treatment of cerebral adrenoleukodystrophy

Phase 1

• Conditions: Cerebral Adrenoleukodystrophy (CALD); MedDRA version: 20.0Level: PTClassification code 10051260Term: AdrenoleukodystrophySystem Organ Class: 10010331 - Congenital, familial and genetic disorders; Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]

• Registration Number: EUCTR2011-001953-10-DE
• Lead Sponsor: bluebird bio, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2017-12-11
• Last Update Posted: 3 May 2021

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: Male
• Target Recruitment: 32

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.
Are the trial subjects under 18? yes
Number of subjects for this age range: 32
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: • Efficacy<br>• Safety;Secondary Objective: Not applicable;Primary end point(s): The primary efficacy endpoint is:<br>• 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: <br>o loss of communication <br>o cortical blindness <br>o tube feeding <br>o total incontinence <br>o wheelchair dependence <br>o complete loss of voluntary movement <br><br>The primary safety endpoint is:<br>• The proportion of subjects who experience either acute (= Grade II) or chronic GVHD by Month 24. ;Timepoint(s) of evaluation of this end point: 24 months post-transplant