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Autologous Hematopoietic Stem Cell Gene Therapy for Metachromatic Leukodystrophy and Adrenoleukodystrophy

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ClinicalTrials.gov Identifier: NCT02559830
Recruitment Status : Recruiting
First Posted : September 24, 2015
Last Update Posted : September 24, 2015
Sponsor:
Collaborators:
Shenzhen University
Guangzhou Women and Children's Medical Center
Information provided by (Responsible Party):
Shenzhen Second People's Hospital

Tracking Information
First Submitted Date  ICMJE August 12, 2015
First Posted Date  ICMJE September 24, 2015
Last Update Posted Date September 24, 2015
Study Start Date  ICMJE January 2015
Estimated Primary Completion Date October 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 23, 2015)
  • The short-term safety and tolerability after hematopoietic stem cell transplanation [ Time Frame: 2 months ]
    The absence of engraftment failure or delayed hematopoietic reconstitution (prolonged aplasia), defined as Absolute Neutrophil Count (ANC)<500/μl with no evidence of Bone Marrow recovery, requiring cellular back-up administration.
  • Incidence of Treatment-Emergent Adverse Events(For MLD) [ Time Frame: 72 hours ]
    It will be evaluated on the basis of adverse events reporting and monitoring of the systemic reactions to cell infusion (fever, tachycardia, nausea and vomiting, joint pain, skin rash).
  • Incidence of Treatment-Emergent Adverse Events(For ALD) [ Time Frame: 72 hours ]
    It will be evaluated on the basis of adverse events reporting and monitoring of the systemic reactions to cell infusion (fever, tachycardia, nausea and vomiting, joint pain, skin rash).
  • Neurologic deficit [ Time Frame: up to 5 years ]
    Before and after transplanation 1/2 year, 1 year, 3 years,and 5 years,Neurologic deficit will be scored according to previous publication from Peters et al. (2004) Blood 104(3):881-888 for patients
  • Neuropsychological testing [ Time Frame: up to 5 years ]
    Before and after transplanation 1/2 year , 1 year, 3 years,and 5 years, the patients will be subjected to neuropsychologic testing by using age-matched Wechsler Intelligence Scale for Children(WISC-III score )system between 6-16 years. above 16 -90 years, patients will be scored by Wechsler Adult Intelligence Scale (WAIS).
  • ARSA activity for MLD [ Time Frame: up to 5 years ]
    Before and after transplantation 1/2 year, 1 year, 3 years and 5 years, residual ARSA activity( nmol/mg Prot/hr) measured in peripheral blood mononuclear cell (PBMC) and/or bone marrow progenitors will be tested (For MLD).
  • VLCFA level for ALD [ Time Frame: up to 5 years ]
    Before and after transplantation 1/2 year, 1 year, 3 years and 5 years, very long chain fatty acid(VLCFA) level ( C22,C24,C26 ,nmol/ml; C24/C22; C26/C22) in plasma will be measured (For ALD).
  • The long-term safety of lentiviral-transduced cell infusion [ Time Frame: up to 5 years ]
    Before and after transplanation 1/2 year, 1 year, 3 years,and 5 years, following tests willbe performed : Replication Competent Lentivirus (RCL): ELISA for HIV p24 antigen (plasma) and DNA Polymerase Chain Reaction (PCR) for vesicular stomatitis virus G (VSV-G) (cells). Reverse Transcription-Polymerase Chain Reaction(RT-PCR) for HIV-pol RNA.
  • Improvement in the nerve conduction velocity (NCV) Index [ Time Frame: up to 5 years ]
    Before and after transplantation 1/2 year , 1 year, 3 years and 5 years , nerve conduction velocity (NCV) Index for electromyography (ENG) will be scored .
  • Magnetic Resonance imaging (MRI) score [ Time Frame: up to 5 years ]
    Before and after transplantation 1/2 year , 1 year, 3 years and 5 years , a detailed demerit scoring (0-34 points) developed by Dr. Loes will be performed in determining the extent of myelin injury in brain (eg, very early stage = MRI score 1-3; early stage = MRI score 4-8; late stage = MRI score 9-13; very late stage = MRI score greater than 13).
  • Genomic lentiviral integration sites [ Time Frame: up to 5 years ]
    Before and after transplantation 1/2 year , 1 year, 3 years and 5 years , CD34+ cells , Myeloid cells (CD14 cells ) , Lymph B cells (CD19 cells) , lymph T cells (CD3 cells) from periheral blood will be seperated and DNA will be extracted, genomic lentiviral integration sites will be investigated according to previosu publications by Biffi etal (Science,2013) .
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: September 23, 2015)
  • immune responses against the transgene(For MLD) [ Time Frame: 5 years ]
    Before and after transplantation 1/2 year , 1 year, 3 years and 5 years ,treated patients will be monitored if generation of ARSA antiboy (MLD) by immunoblot analyses.
  • immune responses against the transgene(For ALD) [ Time Frame: 5 years ]
    Before and after transplantation 1/2 year , 1 year, 3 years and 5 years ,treated patients will be monitored if generation of or ABCD1 antibody by immunoblot analyses.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Autologous Hematopoietic Stem Cell Gene Therapy for Metachromatic Leukodystrophy and Adrenoleukodystrophy
Official Title  ICMJE A Phase I/II Clinical Trial of Lentiviral Hematopoietic Stem Cell Gene Therapy for Treatment of Developed Metachromatic Leukodystrophy and Adrenoleukodystrophy
Brief Summary Evaluating the safety and efficacy of Lentiviral Hematopoietic Stem Cell Gene Therapy for advanced stage of Metachromatic Leukodystrophy and adrenoleukodystrophy.
Detailed Description

This is a phase I/II protocol aiming at the assessment of the safety and efficacy of arylsulfatase A(ARSA) / adenosine-triphosphate-binding cassette, sub-family D (ABCD1) gene transfer into hematopoietic stem/progenitor cells for the treatment of metachromatic leukodystrophy/adrenoleukodystrophy.

Metachromatic Leukodystrophy (MLD) is an autosomal recessive Lysosomal Storage Disorder (LSD) characterized by severe and progressive dysmyelination affecting the central and peripheral nervous system. Adrenoleukodystrophy (also known as X-linked adrenoleukodystrophy, ALD, X-ALD), a disorder of peroxisomal fatty acid beta oxidation which results in the accumulation of very-long chain fatty acids (VLCFA) in tissues throughout the body, is caused by mutations in ABCD1.Both diseases are characterized by progressive neurodegenerative decline, leading to a devastating state without treatment.

Hematopoietic cell transplantation (HCT) is ineffective in ameliorating patients' phenotype or delaying disease evolution in many patients. No evidences of efficacy of enzyme replacement strategies are available at the moment. Transplantation of genetically corrected autologous hematopoietic stem cells (HSC) could represent a novel and potentially efficacious treatment for MLD/ALD patients.

Recently, an Italian group conducted a gene therapy clinical trial based on autologous HSC and advanced generation lentiviral vectors (LV) for patients affected by the most severe, early onset forms of the disease (ClinicalTrials.gov Identifier:

NCT01560182).The safety and efficacy of this gene therapy approach in MLD patients was evaluated.During 3 years of follow-up, they reported multilineage ARSA expression and ability to prevent and correct neurological disease manifestations.However, only pre-symptomatic late infantile/Pre- or early-symptomatic early juvenile patients were recruited into the trial. In most cases, MLD/ALD patients tend to be diagnosed at an advanced stage, missing the best timing of curable HSC intervention. In our study, we intend to recruit symptomatic patients for transduced cluster of differentiation 34 positive (CD34+) HSC treatment. In the treated patients, we will study the short-term and long-term safety of the administration of the autologous transduced HSC, their long-term engraftment, the expression of vector-derived ARSA/ABCD1, and the ability of the transduced cells to provide a clinical benefit to the patients. The treated patients will be followed for 3 years and thereafter monitored for the safety of gene therapy for additional 5 years. If successful, this study will provide key results on the safety and efficacy of gene therapy for MLD/ALD patients.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Metachromatic Leukodystrophy
  • Adrenoleukodystrophy
Intervention  ICMJE Genetic: transduced CD34+ hematopoietic stem cell
Autologous hematopoietic stem cells (HSCs) collected from the mobilized peripheral blood and transduced ex vivo with a Lentiviral vector encoding the human ARSA(for MLD)/ABCD1(for ALD) cDNA(complementary DNA). Dose: ≥ 2x10^6 transduced CD34+ cells/Kg (maximum 20x10^6) at bedside for infusion.
Study Arms  ICMJE Experimental: transduced CD34+ hematopoietic stem cell
Transplantation of autologous CD34+ hematopoietic stem cells transduced with ARSA/ABCD1 encoding lentiviral vector. Dosage: 2x10^6/Kg (Minimum)to 20x10^6/Kg (Maximum) transduced CD34+ cells at bedside for infusion
Intervention: Genetic: transduced CD34+ hematopoietic stem cell
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 23, 2015)
50
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 2025
Estimated Primary Completion Date October 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Inclusion Criteria For MLD:

  1. Confirmed diagnosis as MLD by ARSA genetic diagnosis, MRI(Magnetic Resonance Imaging)and low ARSA A activity (below 20% of normal level);
  2. The patient' symptoms and lesions have not been developed to the end stage of MLD.

Inclusion Criteria For ALD:

  1. Confirmed diagnosis as ALD by ABCD1 genetic diagnosis, abnormal MRI imaging, abnormal high level of very long chain fatty acid (VLCFA) and adrenocorticotropic hormone (ACTH);
  2. The patient' symptoms and lesions have not been developed to the end stage of ALD.

Exclusion Criteria:

Exclusion Criteria For MLD:

  1. No clinical symptoms of MLD;
  2. ARSA activity >50% compared to healthy individuals;
  3. End stage of MLD;
  4. Other complications, ie. Cancer;
  5. human immunodeficiency virus(HIV) RNA and/or hepatitis C virus RNA and/or hepatitis B virus DNA positive patients;
  6. Patients who underwent allogenic hematopoietic stem cell transplantation with evidence of residual cells of donor origin.

Exclusion Criteria For ALD:

  1. No evidence of brain lesions;
  2. Normal level of VLCFAs in blood;
  3. End stage of ALD;
  4. Other complications, ie. Cancer;
  5. human immunodeficiency virus(HIV) RNA and/or hepatitis C virus RNA and/or hepatitis B virus DNA positive patients;
  6. Patients who underwent allogenic hematopoietic stem cell transplantation with evidence of residual cells of donor origin.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 45 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: JiaCai zhou, M.D.,Ph.D +8613923406652 jiacai8199@163.com
Contact: Qizhou Lian, M.D.,Ph.D. dalilian2000@aliyun.com
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02559830
Other Study ID Numbers  ICMJE ChiCTR-OPC-15005802
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Shenzhen Second People's Hospital
Study Sponsor  ICMJE Shenzhen Second People's Hospital
Collaborators  ICMJE
  • Shenzhen University
  • Guangzhou Women and Children's Medical Center
Investigators  ICMJE
Principal Investigator: Qizhou Lian, M.D.,Ph.D. The University of Hong Kong
Principal Investigator: Jiacai Zhuo Shenzhen Second People's Hospital
Principal Investigator: Xin Du, M.D.,Ph.D. Shenzhen Second People's Hospital
Principal Investigator: Hua Jiang, M.D,Ph.D Guangzhou Women and Children's Medical Center
Principal Investigator: GuangFu Chen, M.D.,Ph.D Shenzhen Second People's Hospital
PRS Account Shenzhen Second People's Hospital
Verification Date September 2015

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