Gene therapy with autologous genetically-modified CD34+ cells for X-linked Chronic Granulomatous Disease

• Register: EUCTR
• Last refreshed on: 14 November 2016
• Main ID: EUCTR2012-000242-35-GB
• Date of registration: 19/07/2012
• Prospective Registration: Yes
• Primary sponsor: Genethon
• Public title: Gene therapy with autologous genetically-modified CD34+ cells for X-linked Chronic Granulomatous Disease
• Scientific title: A phase I/II, non randomized, multicenter, open-label study of autologous CD34+ cells transduced with the G1XCGD Lentiviral vector in patients with X-Linked Chronic Granulomatous Disease - Phase I/II G1XCGD.01 study : an ex-vivo gene therapy for X-CGD patients
• Date of first enrolment: 10/01/2013
• Target sample size: 11
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-000242-35
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: Placebo: Other:
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

France, Germany, Switzerland, United Kingdom

Contacts

• Name: Delphine AGATHON
• Affiliation: GENETHON

• Name: Delphine AGATHON
• Affiliation: GENETHON

Key inclusion & exclusion criteria

Inclusion criteria:
- Male X-CGD patients > 6 months of age
-Molecular diagnosis confirmed by DNA sequencing and supported by laboratory evidence for absent or significantly reduced biochemical activity of the NADPH-oxidase
-At least one prior, ongoing or resistant severe infection and/or inflammatory complications requiring hospitalisation despite conventional therapy
- No HLA-matched donor available after 3 months search unless the risk of waiting for a potential match or for performing an allogeneic transplant is considered unacceptable
-No co-infection with Human Immunodeficiency Virus (HIV) or hepatitis B virus (HBsAg positive) or hepatitis C virus (HCV RNA positive)
-Written informed consent for adult patient
-Parental/guardian and where appropriate child’s signed consent/assent
- If applicable, patients must agree to use appropriate medically approved contraception during the trial and for 1 month afterwards
Are the trial subjects under 18? yes
Number of subjects for this age range: 8
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 2
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 0

Exclusion criteria:
-10/10 HLA identical (A,B,C,DR,DQ) family or unrelated or cord blood donor unless there is deemed to be an unacceptable risk associated with an allogeneic procedure
-Contraindication for leukapheresis (anaemia Hb <8g/dl, cardiovascular instability, severe coagulopathy)
-Contraindication for administration of conditioning medication and any component of the Investigational Medicinal Product (IMP) preparation
-Administration of gammainterferon within 30 days before the infusion of transduced autologous CD34+ cells
-Participation in another experimental therapeutic protocol within 6 months prior to baseline and during the study period
-Any other condition that, in the opinion of the Investigator, may compromise the safety or compliance of the patient or would preclude the patient from successful completion of the study
-Patient/Parent/Guardian unable or unwilling to comply with the protocol requirements


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

Health Condition(s) or Problem(s) studied

X-linked Chronic Granulomatous Disease
MedDRA version: 19.0 Level: PT Classification code 10008906 Term: Chronic granulomatous disease System Organ Class: 10010331 - Congenital, familial and genetic disorders

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Intervention(s)

Product Name: Suspension of autologous CD34+cells transduced with the G1XCGD viral vector
Product Code: G1XCGD transduced CD34+ cells
Pharmaceutical Form: Dispersion for infusion
Other descriptive name: AUTOLOGOUS CD34+ CELLS TRANSDUCED EX-VIVO WITH THE PCCLCHIMGP91/VSVG LENTIVIRAL VECTOR
Concentration unit: Other
Concentration number: >4x10e6 CD34+viab-cells/kg

Primary Outcome(s)

Primary end point(s): - Safety of the procedure as measured by the incidence of adverse events
- Restoration and stability over time of the NADPH functioning granulocytes assessed by a DHR test (= 5% of expressing cells at 12 months)

Timepoint(s) of evaluation of this end point: The assessment of the safety of the IMP by the measurement of the safety parameters, e.g. adverse events. This will include clinical adverse events, as well as any clinically significant laboratory abnormality which will have to be reported as an AE. Overall incidence of adverse events will be evaluated for the study as a whole. Similarly the incidence of serious adverse events will be monitored.
The determination of the efficacy of the IMP. It will be evaluated by the measurement of the percentage of oxidase positive granulocytes at month 12 by DHR test.

Main Objective: -Evaluation of safety
-Evaluation of biochemical and functional reconstitution in progeny of engrafted cells and transgene expression stability at 12 months

Secondary Objective: -Clinical efficacy and longitudinal evaluation of clinical effect in terms of augmented immunity against bacterial and fungal infection
-Transduction of CD34+ haematopoietic cells from X-CGD patients by ex vivo lentivirus-mediated gene transfer
-Evaluation of engraftment kinetics and stability

Secondary Outcome(s)

Secondary end point(s): -Normalisation of nutritional status, growth, development (as measured by clinical evaluation), severe infection and/or inflammatory complication which recommended patient’s inclusion
-Percentage of transduced CD34+ haematopoietic cells infused and of blood cells over time (at month 1, 2, 3, 6, 9, 12, 18 and 24 months)
-Immunological reconstitution as measured by evidence of restored neutrophil functionality and immunity against bacterial and fungal infections over time

Timepoint(s) of evaluation of this end point: As a secondary efficacy endpoint, the evolution of the nutritional status, the growth and the development will be evaluated by the regular clinical examination during the study visit.
Similarly, the evolution of the severe infection and inflammation will be evaluated by the clinical exam but also by the imaging and the laboratory results.
For the immmunological reconstitution, the restoration of the neutrophil functionality and immunity will be measured by the NADPH oxidase activity (NBC and DHR) and the percentage of transduced CD34+ haematopoietic cells infused and of blood cells at month 1, 2, 3, 6, 9, 12, 18 and 24 to be validated with the Investigators).

Secondary ID(s)

NCT01855685

G1XCGD.01

Source(s) of Monetary Support

GENETHON

Net 4CGD