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Gene Therapy for X-CGD

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01906541
Recruitment Status : Unknown
Verified August 2013 by Hubert Serve, Prof., MD, Johann Wolfgang Goethe University Hospital.
Recruitment status was:  Recruiting
First Posted : July 24, 2013
Last Update Posted : August 2, 2013
Information provided by (Responsible Party):
Hubert Serve, Prof., MD, Johann Wolfgang Goethe University Hospital

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
X-linked Chronic Granulomatous Disease Genetic: ex-vivo gene-therapy Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 5 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Gene Therapy Trial for X-CGD With a SIN Gammaretroviral Vector
Study Start Date : July 2013
Estimated Primary Completion Date : December 2013
Estimated Study Completion Date : December 2019

Arm Intervention/treatment
Experimental: ex-vivo gene-therapy
transplantation of genetically modified autologous CD34+ cells
Genetic: ex-vivo gene-therapy
transplantation autologous CD34+ cells, transduced with a SIN gammaretroviral vector

Primary Outcome Measures :
  1. 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 ]
  2. Engraftment rate of the transduced CD34+ cells in the patients [ Time Frame: 5 years ]
  3. Long-term expression of the transgene (rate of gp91phox positive cells) in circulating cells in the peripheral blood [ Time Frame: 5 years ]
  4. Functional reconstitution of the NADPH oxidase in circulating cells of the peripheral blood (% DHR positive cells) [ Time Frame: 5 years ]
  5. Frequency and severity of unexpected toxic adverse events during and after infusion of the genetically modified CD34+ cells [ Time Frame: 5 years ]

Secondary Outcome Measures :
  1. Frequency of infections as indicator for the clinical benefit for the patients [ Time Frame: 5 years ]
  2. Proliferation rate of CD34+ cells in ex-vivo culture under serum-free conditions [ Time Frame: up to 3 weeks ]
  3. Differentiation rate of CD34+ cells (as measured by flow cytometry) in ex-vivo culture under serum-free conditions [ Time Frame: up to 3 weeks ]
  4. Transduction rate of CD34+ cells in ex-vivo culture under serum-free conditions [ Time Frame: up to 12 weeks ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01906541

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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

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University Hospital Frankfurt Recruiting
Frankfurt am Main, Germany, 60595
Contact: Joachim Schwäble, MD    0049/69 /67824900    schwaeble@em.uni-frankfurt.de   
Sponsors and Collaborators
Hubert Serve, Prof., MD
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Responsible Party: Hubert Serve, Prof., MD, Head of Medical Department II, Johann Wolfgang Goethe University Hospital
ClinicalTrials.gov Identifier: NCT01906541    
Other Study ID Numbers: X-CGD
First Posted: July 24, 2013    Key Record Dates
Last Update Posted: August 2, 2013
Last Verified: August 2013
Keywords provided by Hubert Serve, Prof., MD, Johann Wolfgang Goethe University Hospital:
chronic granulomatous disease
Additional relevant MeSH terms:
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Granulomatous Disease, Chronic
Pathologic Processes
Phagocyte Bactericidal Dysfunction
Leukocyte Disorders
Hematologic Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Immunologic Deficiency Syndromes
Immune System Diseases
Chronic Disease
Disease Attributes