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Gene Therapy for X-linked Chronic Granulomatous Disease

Primary Purpose

X-Linked Chronic Granulomatous Disease

Status

Active

Phase

Phase 1

Locations

France

Study Type

Interventional

Intervention

X vivo gene therapy

About this trial

This is an interventional treatment trial for X-Linked Chronic Granulomatous Disease focused on measuring XCGD

Eligibility Criteria

24 Months - undefined (Child, Adult, Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

Male X-CGD patients >23 months of age. Youngest patients (>1 month and ≤ 23 months) may be enrolled at physician's appreciation; in this case mobilization of peripheral HSC may be replaced by two bone marrow harvests.
Molecular diagnosis confirmed by DNA sequencing and supported by laboratory evidence for absent or reduction > 70% of the biochemical activity of the NAHPD-oxidase.
At least one ongoing or resistant or at high risk of relapse 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 (HBs Ag positive) or hepatitis C virus (anti-HCV Ab positive).
Written informed consent for adult patient.
Parental/guardian and where appropriate child's signed consent/assent.

Exclusion Criteria:

10/10 HLA identical (A, B, C, DR, DQ) family or unrelated.
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 gamma interferon 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.

Sites / Locations

Hôpital Necker Enfants Malades

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

open label

Arm Description

X vivo gene therapy

Outcomes

Primary Outcome Measures

Safety as measured by the incidence of adverse events

Restoration and stability over time of the NADPH functioning granulocytes assessed by a Dihydrorhodamine (DHR) flow cytometry test

Secondary Outcome Measures

Clinical improvement

Assessed by: complete physical examination to assess the normalisation of nutritional status, the growth, the development, the decrease in the severity of the infection and/or inflammatory complication at inclusion.

Percentage of transduced CD34+ haematopoietic cells infused and of blood cells over time

Immunological reconstitution

Assessed by: evidence of restored neutrophil functionality (DRH test), expression of gp91phox protein by flow cytometry and immunity against bacterial and fungal infections over time.

Full Information

NCT ID

NCT02757911

First Posted

April 20, 2016

Last Updated

April 5, 2023

Sponsor

Genethon

1. Study Identification

Unique Protocol Identification Number

NCT02757911

Brief Title

Gene Therapy for X-linked Chronic Granulomatous Disease

Official Title

A Phase I/II, Non Randomized, Monocentric Open-label Study of Autologous CD34+ Cells Transduced With the G1XCGD Lentiviral Vector in Patients With X-Linked Chronic Granulomatous Disease

Study Type

Interventional

2. Study Status

Record Verification Date

April 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

March 2016 (Actual)

Primary Completion Date

June 2034 (Anticipated)

Study Completion Date

June 2034 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Genethon

4. Oversight

5. Study Description

Brief Summary

X-linked chronic granulomatous disease (X-CGD) is a rare genetic disorder, which affects boys. It is a primary immunodeficiency disorder which results from an inability of the white blood cells called phagocytic cells (or phagocytes) to kill invading bacteria and fungi. These cells have difficulty forming the free radicals (most importantly the superoxide radical due to defective phagocyte NADPH oxidase complex) which are important in the killing of ingested pathogens. In X-CGD (which accounts for two thirds of CGD patients), the defect lies in a gene which makes up a critical part of the NADPH-oxidase complex (the catalytic subunit; gp91-phox protein). Therefore they kill bacteria and fungi poorly, and the patients suffer from severe and recurrent infections. This also results in inflammation which can damage parts of the body such as the lung and gut. In many cases, patients can be adequately protected from infection by constant intake of antibiotics. However, in others, severe life-threatening infections break through. In some cases, inflammation in the bowel or urinary systems results in blockages which cannot be treated with antibiotics, and which may require the use of other drugs such as steroids. Development of curative treatments for CGD is therefore of great importance.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

X-Linked Chronic Granulomatous Disease

Keywords

XCGD

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

3 (Actual)

8. Arms, Groups, and Interventions

Arm Title

open label

Arm Type

Experimental

Arm Description

X vivo gene therapy

Intervention Type

Genetic

Intervention Name(s)

X vivo gene therapy

Intervention Description

Transplantation of patient's autologous CD34+ cells transduced with lentiviral vector containing XCGD gene. The investigational product is patient-specific and corresponds to autologous CD34+ cells transduced ex vivo with the G1XCGD vector. These transduced cells will be cryopreserved until safety testing and infusion into the patient.

Primary Outcome Measure Information:

Title

Safety as measured by the incidence of adverse events

Time Frame

60 months

Title

Restoration and stability over time of the NADPH functioning granulocytes assessed by a Dihydrorhodamine (DHR) flow cytometry test

Time Frame

12 months

Secondary Outcome Measure Information:

Title

Clinical improvement

Description

Time Frame

60 months

Title

Percentage of transduced CD34+ haematopoietic cells infused and of blood cells over time

Time Frame

60 months

Title

Immunological reconstitution

Description

Assessed by: evidence of restored neutrophil functionality (DRH test), expression of gp91phox protein by flow cytometry and immunity against bacterial and fungal infections over time.

Time Frame

60 months

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

24 Months

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male X-CGD patients >23 months of age. Youngest patients (>1 month and ≤ 23 months) may be enrolled at physician's appreciation; in this case mobilization of peripheral HSC may be replaced by two bone marrow harvests. Molecular diagnosis confirmed by DNA sequencing and supported by laboratory evidence for absent or reduction > 70% of the biochemical activity of the NAHPD-oxidase. At least one ongoing or resistant or at high risk of relapse 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 (HBs Ag positive) or hepatitis C virus (anti-HCV Ab positive). Written informed consent for adult patient. Parental/guardian and where appropriate child's signed consent/assent. Exclusion Criteria: 10/10 HLA identical (A, B, C, DR, DQ) family or unrelated. 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 gamma interferon 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Stéphane BLANCHE, MD, PHD

Organizational Affiliation

Hôpital Necker-Enfants Malades

Official's Role

Principal Investigator

Facility Information:

Facility Name

Hôpital Necker Enfants Malades

City

Paris

ZIP/Postal Code

75015

Country

France

12. IPD Sharing Statement

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Gene Therapy for X-linked Chronic Granulomatous Disease

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