A Phase I/II Gene Therapy trial for X-CGD with a SIN gamma retroviral vector

• Register: EUCTR
• Last refreshed on: 16 December 2019
• Main ID: EUCTR2012-001725-26-DE
• Date of registration: 18/12/2012
• Prospective Registration: Yes
• Primary sponsor: Johann Wolfgang Goethe-University
• Public title: A Phase I/II Gene Therapy trial for X-CGD with a SIN gamma retroviral vector
• Scientific title: A Phase I/II Gene Therapy trial for X-CGD with a SIN gamma retroviral vector - gene therapy for X-CGD
• Date of first enrolment: 12/03/2013
• Target sample size: 5
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-001725-26
• 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 Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Germany

Contacts

• Name: Study Center
• Affiliation: Study Center

• Name: Study Center
• Affiliation: Study Center

Key inclusion & exclusion 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 <1%), as sexual abstinence, combination of an oral contraceptive, IUS, vaginal ring with drug delivery, contraceptive pad, implanted contraceptive, injected depot-contraceptive; in combination with a second contraceptive method, in terms os a barrier-method, such as condom, diaphragm /cervical cap with spermicide or sterilization in male patients or partners.
a. A woman of childbearing potential is defined, as sexually mature woman without hysterectomy or surgical sterilization, who has not been postmenopausal for at least 12 months (no menstruation within the last 12 months).
7. No interferon-gamma injection within two weeks prior to hematopoietic stem cell mobilization
8. Karnofsky-Index > 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:
1. Patients with non-controlled acute infections
2. Severe cardiac or pulmonary malfuctions: ejection fraction < 60%, valvular heart disease > II°, arrhythmia requiring therapy, FEV1/VC < 75% , DLCO <60%
3. Bilirubin > 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



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

Health Condition(s) or Problem(s) studied

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

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

Intervention(s)

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 name: Genetically modified autologous blood stem cells
Concentration unit: Other
Concentration type: range
Concentration number: 100-500

Primary Outcome(s)

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

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.

Secondary Objective: Only main objectives were defined.

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 Outcome(s)

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 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.

Secondary ID(s)

X-CGD-Version2

Source(s) of Monetary Support

LOEWE

Ethics review

Status: Approved
Approval date:
Contact: