Chronic granulomatous disease (CGD) is a congenital immunodeficiency, in which neutrophil granulocytes and monocytes are not capable of producing reactive oxygen species and therefore are unable to kill phagocytized bacteria or fungi. MedDRA version: 14.1 Level: PT Classification code 10008906 Term: Chronic granulomatous disease System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Interventions
Product Name: genetically modified autologous blood stem cells
Product Code: somatic gene-therapy by X-CGD
Pharmaceutical Form: Suspension for infusion
INN or Proposed INN: G1XCG
Other descriptive nam
Sponsors
Johann Wolfgang Goethe-University
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Verified diagnosis of the X-linked form of chronic granulomatous disease, with loss of gp91phox expression (Western Blot). Evidence of less than 5% of normal oxidase production in circulating neutrophil granulocytes as measured by DHR- and NBT-assay. 2. History of severe chronic infections with life-threatening course or severe steroid- sensitive or steroid insensitive granulomatous disease, with necessity of inpatient treatment, without sustained improvement even under maximum conservative treatment measures. 3. 18 years old or older 4. No HLA identical (10/10 match) sibling- or unrelated donor, or contraindications for allogenic stem cell transplantation in presence of a suitable donor. The lack of an HLA-identical (10/10 match) sibling- or unrelated donor has to be confirmed by an unsuccessful search in national and international donor registers for at leat 3 months. 5. Normal organ-function: GFR = 60ml/min., Bilirubin = 1,5-fold upper reference-level, normal parameters for liver enzymes and clotting (TPZ 75-100%, PTT 30-38sec, Fibrinogen 200-400mg/dl), Leukocytes > 3 x 109/l, Granulocytes > 1.5 x 109/l, Thrombocytes >100 x 109/l 6. Contraception from start of G-CF application until 1 year after retransfusion of the gene-corrected cells. Women with childbearing potential or partners with childebearing potential of male patients with have to apply safe contraceptive measures (Pearlindex 70% 9. Signed informed consent Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 5 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Patients with non-controlled acute infections 2. Severe cardiac or pulmonary malfuctions: ejection fraction II°, arrhythmia requiring therapy, FEV1/VC 1,5-fold upper reference-level 4. Creatinine-clearance <60ml/min 5. HIV-, Hepatitis B- or C - infection 6. Contraindications for G-CSF administration, as autoimmune vasculitis. 7. Contraindications for stem cell apheresis, as low hemoglobin <8g/dl, cardiovascular instability or severe coagulapathy 8. Pregnacy or breast-feeding 9. Drug- or alcohol-abuse 10. Lack of search for an unrelated donor 11. Patients with an available HLA 9/10 MMUD will be excluded from the study if SCT is considered to be beneficial according to thorough risk-benefit-assessment
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1. Investigation of the clinical feasibility of a therapy with genetically modified autologous peripheral CD34+ cells for genetic correction of the NADPH oxidase in CGD patients with gp91phox defect. 2. Investigation of the efficacy of the somatic gene-therapy by monitoring oxidase function in circulating granulocytes in long-term course.;Secondary Objective: Only main objectives were defined.;Primary end point(s): 1. The transduction rate of G-CSF mobilized periperal CD34+ cells from CGD patients with a SIN-gammaretroviral vector. 2. Engraftment rate of the transduced CD34+ cells in the patients. 3 Long-term expression of the transgene (gp91phox) and functional reconstitution of the NADPH oxidase in circulating cells of the peripheral blood. 4. Frequency and severity of unexpected toxic adverse events during and after infusion of the genetically modified CD34+ cells.;Timepoint(s) of evaluation of this end point: Monthly for the first 6 month after treatment, thereafter quarterly for 5 years. Completion of follow-up: 01.04.2020 Final report: 01.11.2020 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Frequency of infections as indicator for clinical benefit for CGD patients 2. Proliferation, differentiation and transduction-efficiency of CD34+ cells in ex-vivo culture under serum-free conditions. ;Timepoint(s) of evaluation of this end point: Monthly for the first 6 month after treatment, thereafter quarterly for 5 years. Completion of follow-up: 01.04.2020 Final report: 01.11.2020 | — |
Countries
Germany
Contacts
Public ContactStudy Center
Study Center
Outcome results
None listed