A Phase I/II clinical trial of hematopoietic stem cell gene therapy for the treatment of Metachromatic Leukodystrophy - TIGET-MLD

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2009-017349-77-IT
• Date of registration: 26/04/2010
• Prospective Registration: No
• Primary sponsor: FONDAZIONE CENTRO S. RAFFAELE DEL MONTE TABOR
• Public title: A Phase I/II clinical trial of hematopoietic stem cell gene therapy for the treatment of Metachromatic Leukodystrophy - TIGET-MLD
• Scientific title: A Phase I/II clinical trial of hematopoietic stem cell gene therapy for the treatment of Metachromatic Leukodystrophy - TIGET-MLD
• Date of first enrolment: 15/03/2010
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-017349-77
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes 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: Placebo: Other:

Countries of recruitment

Italy

Key inclusion & exclusion criteria

Inclusion criteria:
Pre-symptomatic late infantile patients; Pre- or early-symptomatic early juvenile patients; Parental/guardian/patient signed informed consent.
Are the trial subjects under 18? yes
Number of subjects for this age range:
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:
Patients will be excluded from the present study according to the following crite-ria: HIV-positive patients; Patients affected by neoplastic diseases; Patients with cytogenetic alterations typical of MDS/AML; Patients with end-organ functions or any other severe disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study; Patients enrolled in other trials; Patients who underwent allogeneic hematopoietic stem cell transplantation in the previous 6 months; Patients who underwent allogeneic hematopoietic stem cell transplantation with evidence of residual cells of donor origin.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

metachromatic leukodystrophy
MedDRA version: 9.1 Level: PT Classification code 10024381

Intervention(s)

Product Name: autologous CD34+ cells transduced with a lentiviral vector encoding the ARSA cDNA
Pharmaceutical Form: Suspension for injection
Current Sponsor code: autologous CD34+ cells transduced with a lentiviral vector encoding the ARSA cDNA
Concentration unit: % percent
Concentration type: equal
Concentration number: 100-

Trade Name: BUSILVEX
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: Busulfan
Concentration unit: mg/kg milligram(s)/kilogram
Concentration type: equal
Concentration number: 1-

Primary Outcome(s)

Primary end point(s): Safety Primary endpoints ; Conditioning regimen related safety, consisting in the absence of engraftment failure or delayed hematological reconstitution (prolonged aplasia) and surveillance of non-hematological regimen related toxicity (for clinical toxicity NCI Common Toxicity Criteria > 2; for laboratory toxicity NCI Common Toxicity Criteria > 3). Safety of LV-transduced cell infusion, defined as: a)short-term safety and tolerability of lentiviral-transduced cell infusion; b)long-term safety of lentiviral-transduced cell infusion (absence of Replication Competent Lentivirus (RCL) and abnormal clonal proliferations). Efficacy Primary endpoints : An improvement of 10% of the total score at gross motor function measure (GMFM) at comparison with the GMFM scores obtained by aged matched untreated MLD patients, evaluated 24 months after treatment; A significant (2 SD) increase of Arylsulfatase A (ARSA) activity as com-pared to pre-treatment values, measured in hematopoietic cells 24 months after treatment.

Secondary Objective: Evaluation of the efficacy of the procedure in reducing the progression of demyelination (and atrophy) in the central and peripheral nervous system in comparison with that documented in our historical controls, as assessed by validated instrumental parameters brain MR score and NCV Index at ENG recordings (see secondary efficacy end-points). Evaluation of the biological efficacy of the procedure in treated patients, which consists in the sustained engraftment of the transduced cells, essential prerequisite for achieving clinical benefit. Long-term transduced cell engraftment will prove that i) ARSA LV transduced HSC with long-term repopulation potential and ii) the conditioning regimen was adequate for allowing transduced cell engraftment.

Main Objective: Evaluation of the safety of gene therapy in MLD patients, considering both the conditioning regimen safety and the safety of LV-transduced cell infusion, short and long-term after the treatment. Evaluation of the efficacy of gene therapy, assessed as reduction in the progression of the clinical motor impairment in treated patients as compared to the progression measured in untreated MLD patients in our disease natural history study, accompanied by a significant increase of residual ARSA activity as compared to pre-treatment patients values. Motor functions will be measured by the clinically relevant GMFM scoring system. Indeed, there is a clear causal relationship between the potential beneficial outcome meas-ured with the GMFM and the treatment, being motor impairment consequent to the involvement of both central and peripheral nervous system, and less influenced by other variables. Residual ARSA activity will be measured on hematopoietic cells (PBMC and BM cells).

Secondary ID(s)

TIGET-MLD