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

• Register: EUCTR
• Last refreshed on: 30 April 2019
• Main ID: EUCTR2018-001145-14-FR
• Date of registration: 23/10/2018
• Prospective Registration: Yes
• Primary sponsor: bluebird bio, Inc.
• Public title: Clinical study to assess the efficacy and safety of gene therapy for the treatment of cerebral adrenoleukodystrophy.
• Scientific title: A Phase 3 Study of Lenti-D Drug Product After Myeloablative Conditioning Using Busulfan and Fludarabine in Subjects =17 Years of Age With Cerebral Adrenoleukodystrophy (CALD)
• Date of first enrolment: 27/03/2019
• Target sample size: 20
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-001145-14
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: no; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

France, Germany, Italy, Netherlands, United Kingdom, United States

Contacts

• Name: Clinical Trials Operations
• Affiliation: Voisin Consulting

• Name: Clinical Trials Operations
• Affiliation: Voisin Consulting

Key inclusion & exclusion criteria

Inclusion criteria:
1. Informed consent is obtained from a competent custodial parent or guardian with legal capacity to execute a local IRB/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:
a. Elevated VLCFA values, and
b. Active central nervous system (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. Neurologic Function Score (NFS) =1.
Are the trial subjects under 18? yes
Number of subjects for this age range: 20
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. Prior receipt of an allogeneic transplant or gene therapy.
2. Use of statins, Lorenzo’s Oil, or dietary regimens used to lower VLCFA levels.
3. 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.
4. Any conditions that make it impossible to perform MRI studies (including allergies to anesthetics or contrast agents).
5. Hematological compromise as evidenced by:
a. Peripheral blood ANC count <1500 cells/mm3,
b. Platelet count <100,000 cells/mm3, or
c. Hemoglobin <10 g/dL.
d. Uncorrected bleeding disorder.
6. Hepatic compromise as evidenced by:
a. Aspartate transaminase (AST) value >2.5 × ULN,
b. Alanine transaminase (ALT) value >2.5 × ULN,
c. Total bilirubin value >3.0 mg/dL, except if there is a diagnosis of Gilbert’s Syndrome and the subject is otherwise stable.
7. Baseline estimated glomerular filtration rate <70 mL/min/1.73 m2.
8. Cardiac compromise as evidenced by left ventricular ejection fraction <40%.
9. Immediate family member with a known or suspected Familial Cancer Syndrome.
10. Clinically significant uncontrolled, active bacterial, viral, fungal, parasitic, or prion associated infection.
11. Positive for HIV, hepatitis B or C virus, or human T lymphotrophic virus 1 (HTLV-1).
12. Absence of adequate contraception for fertile subjects.
13. Any contraindications to the use of G-CSF or plerixafor during the mobilization of hematopoietic stem cells, and any contraindications to the use of busulfan or fludarabine, including known hypersensitivity to the active substances or to any of the excipients in their formulations.


Age minimum:
Age maximum:
Gender:
Female: no
Male: yes

Health Condition(s) or Problem(s) studied

Cerebral Adrenoleukodystrophy (CALD)
MedDRA version: 20.0 Level: PT Classification code 10051260 Term: Adrenoleukodystrophy System Organ Class: 10010331 - Congenital, familial and genetic disorders

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Intervention(s)

Product Name: Lenti-D Drug Product
Pharmaceutical Form: Dispersion for infusion
Other descriptive name: Autologous haematopoietic stem cells transduced with lentiviral vector Lenti-D encoding the human ABCD1 cDNA
Concentration unit: Other
Concentration type: not less then
Concentration number: 5000000-

Primary Outcome(s)

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 with neutrophil engraftment after drug product infusion.

Main Objective: To evaluate the efficacy and safety of Lenti-D Drug Product after myeloablative conditioning with busulfan and fludarabine in subjects with CALD

Secondary Objective: N/A

Timepoint(s) of evaluation of this end point: Month 24

Secondary Outcome(s)

Secondary end point(s): Secondary efficacy endpoints are the following:
• Proportion of subjects without gadolinium enhancement on MRI (i.e., GdE-) at Month 24.
• Value and change in total NFS from Baseline to protocol scheduled visits.
• MFD-free survival over time.
• Overall survival.
• Detectable vector copy number (VCN) in peripheral blood cells by Month 6.

The secondary safety endpoints are the following:
• The proportion of subjects who experience either acute (=Grade II) or chronic GVHD at Month 24.
• Time to neutrophil engraftment after drug product infusion.
• The proportion of subjects with platelet engraftment by Month 24.
• Time to platelet engraftment post-drug product infusion.
• The proportion of subjects with loss of neutrophil engraftment post-drug product infusion by Month 24.
• The proportion of subjects who undergo a subsequent HSC infusion by Month 24.
• The proportion of subjects who experience transplant-related mortality through 100 and 365 days post-drug product infusion.
• The proportion of subjects who experience =Grade II acute GVHD by Month 24.
• The proportion of subjects who experience 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.
• The number of subjects in which vector-derived RCL is detected by Month 24.
• The number of subjects with insertional mutagenesis leading to clonal dominance by Month 24.
• The number of subjects with insertional mutagenesis leading to leukemia by Month 24.

Timepoint(s) of evaluation of this end point: Month 24

Secondary ID(s)

2018-001145-14-GB

ALD-104

Source(s) of Monetary Support

bluebird bio, Inc.

Ethics review

Status: Approved
Approval date:
Contact: