Gene Therapy for X-CGD

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2013 by Johann Wolfgang Goethe University Hospitals
Sponsor:
Information provided by (Responsible Party):
Hubert Serve, Prof., MD, Johann Wolfgang Goethe University Hospitals
ClinicalTrials.gov Identifier:
NCT01906541
First received: July 15, 2013
Last updated: August 1, 2013
Last verified: August 2013

July 15, 2013
August 1, 2013
July 2013
December 2013   (final data collection date for primary outcome measure)
  • Transduction rate of granulocyte colony-stimulating factor (G-CSF) mobilized peripheral CD34+ cells from CGD patients with a SIN gamma retroviral vector [ Time Frame: 1 week ] [ Designated as safety issue: No ]
  • Engraftment rate of the transduced CD34+ cells in the patients [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Long-term expression of the transgene (rate of gp91phox positive cells) in circulating cells in the peripheral blood [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Functional reconstitution of the NADPH oxidase in circulating cells of the peripheral blood (% DHR positive cells) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Frequency and severity of unexpected toxic adverse events during and after infusion of the genetically modified CD34+ cells [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
Same as current
Complete list of historical versions of study NCT01906541 on ClinicalTrials.gov Archive Site
  • Frequency of infections as indicator for the clinical benefit for the patients [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Proliferation rate of CD34+ cells in ex-vivo culture under serum-free conditions [ Time Frame: up to 3 weeks ] [ Designated as safety issue: No ]
  • Differentiation rate of CD34+ cells (as measured by flow cytometry) in ex-vivo culture under serum-free conditions [ Time Frame: up to 3 weeks ] [ Designated as safety issue: No ]
  • Transduction rate of CD34+ cells in ex-vivo culture under serum-free conditions [ Time Frame: up to 12 weeks ] [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
Gene Therapy for X-CGD
A Phase I/II Gene Therapy Trial for X-CGD With a SIN Gammaretroviral Vector

X-linked chronic granulomatous disease (X-CGD) is a rare inherited immune defect, which is caused by the inability of phagocytic cells to produce reactive oxygen species due to a defect in the gp91phox subunit of the NADPH oxidase complex. X-CGD patients suffer from recurrent and life-threatening infections and severe hyperinflammatory complications.

The only curative treatment for X-CGD is allogenic hematopoietic stem cell transplantation, but this procedure implies severe risks and many patients lack an appropriate donor. Therefore alternative curative approaches are urgently needed. In this study, patients will be treated with gene-corrected autologous CD34+ cells, using a SIN gammaretroviral vector for ex-vivo gene-therapy.

Not Provided
Interventional
Phase 1
Phase 2
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
X-linked Chronic Granulomatous Disease
Genetic: ex-vivo gene-therapy
transplantation autologous CD34+ cells, transduced with a SIN gammaretroviral vector
Experimental: ex-vivo gene-therapy
transplantation of genetically modified autologous CD34+ cells
Intervention: Genetic: ex-vivo gene-therapy
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
5
December 2019
December 2013   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • 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 dihydrorhodamine- (DHR-) and nitro blue tetrazolium- (NBT-) assay
  • 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
  • No Human Leukocyte Antigen (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
  • Normal organ-function: glomerular filtration rate (GFR) ≥ 60ml/min., Bilirubin ≤ 1.5-fold upper reference-level, normal parameters for liver enzymes and clotting (TPZ 75-100%, partial thromboplastin time (PTT) 30-38sec, Fibrinogen 200-400mg/dl), Leukocytes > 3 x 10^9/l, Granulocytes > 1.5 x 10^9/l, Thrombocytes >100 x 10^9/l
  • Contraception from start of G-CSF application until 1 year after retransfusion of the gene-corrected cells
  • No interferon-gamma injection within two weeks prior to hematopoietic stem cell mobilization
  • Karnofsky-Index > 70%
  • Signed informed consent

Exclusion Criteria:

  • Patients with non-controlled acute infections
  • Severe cardiac or pulmonary malfunctions: ejection fraction < 60%, valvular heart disease > II°, arrhythmia requiring therapy, forced expiratory volume at one second/vital capacity (FEV1/VC) < 75% , diffusion capacity of lung for carbon monoxide (DLCO) <60%
  • Bilirubin > 1.5-fold upper reference-level
  • HIV-, Hepatitis B- or C - infection
  • Contraindications for G-CSF administration, as autoimmune vasculitis.
  • Contraindications for stem cell apheresis, as low hemoglobin < 8g/dl, cardiovascular instability or severe coagulopathy
  • Pregnancy or breast-feeding
  • Drug- or alcohol-abuse
  • Lack of search for an unrelated donor
  • Patients with a HLA 9/10 mismatched unrelated donor (MMUD) will be excluded, if a thorough risk-benefit analysis favors allogenic hematopoietic stem cell transplantation (HSCT)
Both
18 Years and older
No
Contact: Hubert Serve, Prof., MD 0049/69/6301 ext 4634 serve@em.uni-frankfurt.de
Contact: Joachim Schwäble, MD 0049/69/67824900 schwaeble@em.uni-frankfurt.de
Germany
 
NCT01906541
X-CGD
Yes
Hubert Serve, Prof., MD, Johann Wolfgang Goethe University Hospitals
Hubert Serve, Prof., MD
Not Provided
Not Provided
Johann Wolfgang Goethe University Hospitals
August 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP