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Gene Therapy in Patients With Mucopolysaccharidosis Disease

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ClinicalTrials.gov Identifier: NCT03173521
Recruitment Status : Recruiting
First Posted : June 2, 2017
Last Update Posted : January 25, 2019
Sponsor:
Information provided by (Responsible Party):
Nicola Brunetti-Pierri, Fondazione Telethon

Brief Summary:
This study investigated the safety and efficacy of gene therapy approaches for Mucopolysaccharidosis type VI disease caused by the deficiency of arylsulfatase B (ARSB) enzyme. The aim of the study is to evaluate the safety and efficacy of the treatment.

Condition or disease Intervention/treatment Phase
Mucopolysaccharidosis Type VI Biological: AAV2/8.TBG.hARSB Phase 1 Phase 2

Detailed Description:
Mucopolysaccharidosis type VI disease is involved in Lysosomal Storage Disorder. The MPS VI disease is characterized by growth retardation, corneal clouding, cardiac valve disease, organomegaly, skeletal dysplasia, without central nervous system involvement.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Open Label
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Open Label, Dose Escalation, Safety Study in Subjects With Mucopolysaccharidosis Type VI (MPS VI) Using Adeno-Associated Viral Vector 8 to Deliver the Human ARSB Gene to Liver
Actual Study Start Date : July 17, 2017
Estimated Primary Completion Date : April 30, 2020
Estimated Study Completion Date : June 1, 2022


Arm Intervention/treatment
Experimental: open label Biological: AAV2/8.TBG.hARSB

Adeno-associated viral vector serotype 8 with liver-specific thyroxinebinding globulin (TBG) promoter driving the expression of the human ARSB gene. Three dose levels are available:

  • Starting dose is 6x1011 gc of vector per kg of body weight.
  • High dose is 2x1012 gc of vector per kg of body weight and will be administered after at least two subjects at the starting dose have experienced no DLT
  • Low dose is 2x1011 gc of vector per kg of body weight. Intermediate doses are also possible. The administration of the IMP will be performed into a peripheral vein. The IMP final volume to be injected is calculated based on the patient's weight (determined on the day of hospital admission), as 3 mL/kg.




Primary Outcome Measures :
  1. Safety and tolerability:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: from gene therapy until fourteen weeks ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  2. Safety and tolerability:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 4 months post gene therapy ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  3. Safety and tolerability:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 9 months post gene therapy ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  4. Safety and tolerability:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 12 months post gene therapy ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  5. Safety and tolerability:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 18 months post gene therapy ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  6. Safety and tolerability:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 24 months post gene therapy ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  7. Safety and tolerability:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 30 months post gene therapy ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  8. Safety and tolerability:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 36 months post gene therapy ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  9. efficacy urinary GAG [ Time Frame: 4 months post gene therapy ]
    ug GAG/mg creatinine

  10. efficacy urinary GAG [ Time Frame: 9 months post gene therapy ]
    ug GAG/mg creatinine

  11. efficacy urinary GAG [ Time Frame: 12 months post gene therapy ]
    ug GAG/mg creatinine

  12. efficacy urinary GAG [ Time Frame: 18 months post gene therapy ]
    ug GAG/mg creatinine

  13. efficacy urinary GAG [ Time Frame: 24 months post gene therapy ]
    ug GAG/mg creatinine

  14. efficacy urinary GAG [ Time Frame: 30 months post gene therapy ]
    ug GAG/mg creatinine

  15. efficacy urinary GAG [ Time Frame: 36 months post gene therapy ]
    ug GAG/mg creatinine


Secondary Outcome Measures :
  1. efficacy Forced vital capacity [ Time Frame: 4 months post gene therapy ]
    percentage

  2. efficacy Forced vital capacity [ Time Frame: 9 months post gene therapy ]
    percentage

  3. efficacy Forced vital capacity [ Time Frame: 12 months post gene therapy ]
    percentage

  4. efficacy Forced vital capacity [ Time Frame: 18 months post gene therapy ]
    percentage

  5. efficacy Forced vital capacity [ Time Frame: 24 months post gene therapy ]
    percentage

  6. efficacy Forced vital capacity [ Time Frame: 30 months post gene therapy ]
    percentage

  7. efficacy Forced vital capacity [ Time Frame: 36 months post gene therapy ]
    percentage

  8. efficacy forced expiratory volume at 1 second [ Time Frame: 4 months post gene therapy ]
    percentage

  9. efficacy forced expiratory volume at 1 second [ Time Frame: 9 months post gene therapy ]
    percentage

  10. efficacy forced expiratory volume at 1 second [ Time Frame: 12 months post gene therapy ]
    percentage

  11. efficacy forced expiratory volume at 1 second [ Time Frame: 18 months post gene therapy ]
    percentage

  12. efficacy forced expiratory volume at 1 second [ Time Frame: 24 months post gene therapy ]
    percentage

  13. efficacy forced expiratory volume at 1 second [ Time Frame: 30 months post gene therapy ]
    percentage

  14. efficacy forced expiratory volume at 1 second [ Time Frame: 36 months post gene therapy ]
    percentage

  15. efficacy 6 minute walking test [ Time Frame: 4 months post gene therapy ]
    meter

  16. efficacy 6 minute walking test [ Time Frame: 9 months post gene therapy ]
    meter

  17. efficacy 6 minute walking test [ Time Frame: 12 months post gene therapy ]
    meter

  18. efficacy 6 minute walking test [ Time Frame: 18 months post gene therapy ]
    meter

  19. efficacy 6 minute walking test [ Time Frame: 24 months post gene therapy ]
    meter

  20. efficacy 6 minute walking test [ Time Frame: 30 months post gene therapy ]
    meter

  21. efficacy 6 minute walking test [ Time Frame: 36 monthspost gene therapy ]
    meter

  22. efficacy 3 minute stair climb test [ Time Frame: 4 months post gene therapy ]
    number of stair climbed

  23. efficacy 3 minute stair climb test [ Time Frame: 9 months post gene therapy ]
    number of stair climbed

  24. efficacy 3 minute stair climb test [ Time Frame: 12 months post gene therapy ]
    number of stair climbed

  25. efficacy 3 minute stair climb test [ Time Frame: 18 months post gene therapy ]
    number of stair climbed

  26. efficacy 3 minute stair climb test [ Time Frame: 24 months post gene therapy ]
    number of stair climbed

  27. efficacy 3 minute stair climb test [ Time Frame: 30 months post gene therapy ]
    number of stair climbed

  28. efficacy 3 minute stair climb test [ Time Frame: 36 months post gene therapy ]
    number of stair climbed



Information from the National Library of Medicine

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Ages Eligible for Study:   4 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Subjects must have a documented biochemical and molecular diagnosis of MPS VI.
  2. Subjects must be 4 years old or older.
  3. Subjects should have received Enzyme Replacement Therapy (ERT) for at least 12 months before enrolment, and should continue to receive treatment until 7-14 days before IMP administration.
  4. Documented informed consent; willingness to adhere to protocol and required long-term follow-up as evidenced by written informed consent.

Exclusion Criteria:

  1. Subjects unable or unwilling to meet requirements of the study.
  2. Participation in a clinical study with an investigational drug in the 6 months prior to enrolment in this trial.
  3. Subjects who are unable to perform the 6MWT.
  4. History of severe anaphylactoid reaction to Naglazyme in subjects receiving ERT that could affect the safety (severe reaction is meant to be an event with respiratory impairment that is life-threatening).
  5. Presence of tracheostomy or need of ventilatory assistance.
  6. Subjects with evidence of progressive severe myelomalacia that is predicted to require neck surgery in the first six months after enrolment.
  7. Serum AST or ALT above the upper limit of normal range at the baseline evaluations (Baseline 2, -5 days).
  8. Co-existence of chronic diseases or clinically relevant abnormal baseline laboratory values; infections with hepatitis B, C, or HIV (Baseline 1).
  9. Systemic corticosteroid therapy or other immunosuppressive/immunomodulating drugs within 2 weeks prior to IMP administration.
  10. Female individuals of childbearing age who are pregnant or nursing or unwilling to use effective contraception for at least one year post- IMP administration.
  11. Fertile male individuals who are unwilling to use male barrier contraceptives such as condom.
  12. Any other condition that would not allow the subject to complete follow-up examinations during the course of the study and that, in the opinion of the Investigator, would make the subject unsuitable for the study.
  13. Detectable serum neutralizing antibodies (NAB) against AAV8 vector (Baseline 1).

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): NCT03173521


Contacts
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Contact: Nicola Brunetti-Pierri +390817463288 nicola.brunetti@unina.it

Locations
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Italy
Federico II University Recruiting
Napoli, Naples, Italy, 80131
Contact: Nicola Brunetti-Pierri    +390817463288    brunetti@tigem.it   
Netherlands
Erasmus Medical Center, Rotterdam Center for Lysosomal and Metabolic disease Recruiting
Rotterdam, Netherlands
Contact: Ans van der Ploeg       a.vanderploeg@erasmusmc.nl   
Turkey
Children's Hospital Hacettepe University Recruiting
Ankara, Turkey
Contact: Serap Sivri       ssivri@hacettepe.edu.tr   
Sponsors and Collaborators
Fondazione Telethon
Investigators
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Principal Investigator: Nicola Brunetti-Pierri Fondazione Telethon

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Responsible Party: Nicola Brunetti-Pierri, Principal Investigator, Fondazione Telethon
ClinicalTrials.gov Identifier: NCT03173521     History of Changes
Other Study ID Numbers: TIGEM1-MPS VI
First Posted: June 2, 2017    Key Record Dates
Last Update Posted: January 25, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Mucopolysaccharidoses
Mucopolysaccharidosis VI
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Mucinoses
Connective Tissue Diseases
Metabolic Diseases