Clinical Trial: Safety and Efficacy in LPL-Deficient Subjects of AMT-011, an Adeno-Associated Viral Vector Expressing Human Lipoprotein Lipase [S447X]

Study Status: Not yet recruiting
Recruit Status: Unknown status
Study Type: Interventional

Official Title: A Study to Determine the Safety and Efficacy in Lipoprotein Lipase-Deficient Subjects After Intramuscular Administration of AMT-011, an Adeno-Associated Viral Vector Expressing Human Lipoprotein Lipas

Brief Summary:

LPLD is a rare autosomal recessive disorder, characterized by the presence of marked chylomicronemia and hence hypertriglyceridemia. Clinically the most severe manifestation of chylomicronemia, is acute pancreatitis, which can be lethal. There is no effective therapy available to modulate the course of the illness and prevent complications for these patients. The current clinical management consists of severe reduction of dietary fat that is hard if not almost impossible to comply with. LPLD subjects continue to experience pancreatitis attacks, and are admitted to intensive care units on several occasions.

Alipogene tiparvovec corrects or restores lipoprotein lipase (LPL) function long term, and hence reverses some symptoms, halts the disease progression and prevents further complications. Alipogene tiparvovec gene therapy ensures that a catabolically beneficial variant of the human LPL gene, LPL[S447X] is expressed and active in the relevant tissues in humans. Delivery of the gene is realized via intramuscular injection of an adeno-associated viral vector, pseudotyped with AAV1 capsids.


Detailed Summary: The CT-AMT-011-01 study is an open-label, dose-escalating study evaluating the safety and efficacy of a single intramuscular administration of AMT-011 (at multiple sites). The study will be performed in the Community Genomic medicineCenter (CGMC) Chicoutimi, Canada, under the supervision of their medical ethical committee and according to the local biosafety procedures. The study participants will be treated under the responsibility of a Principal Investigator specialised in the treatment of lipid disorders. A total number of 14 subjects will be administered. Participants will be screened 3 weeks prior to administration of AMT-011 and will be evaluated for 12 weeks post administration in this study. After the study, subjects will be followed up long term with particular emphasis on the safety and efficacy aspects of LPL gene therapy using AMT-011. Subjects will be evaluated at the clinical site at 19 weeks, 26 weeks, 39 weeks, 1 year, 1.5 years, 2 years, 3 years, 4 years and 5 years after administration of AMT-011. The TG values that are obtained at week 26 will be used for secondary efficacy analysis.
Sponsor: Amsterdam Molecular Therapeutics

Current Primary Outcome:

  • Reduction of fasting triglyceride (TG) concentrations [ Time Frame: 12 weeks ]
    To achieve a reduction in fasting plasma TG such that the difference in median plasma TG observed before administration and up to 12 weeks after administration represents approximately 40% reduction, on top of a low-fat diet.
  • safety profile of AMT-011 [ Time Frame: 15 years ]
    Between 6 and 15 years after administration of AMT-011, patients will be annually contacted by phone to monitor delayed adverse events related to administration of AMT-011.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Reduction of TG concentrations [ Time Frame: 26 weeks ]
    To achieve sustained efficacy, defined as approximately 40% reduction in fasting plasma TG up to 26 weeks after administration, on top of a low-fat diet.
  • Reduction of TG concentrations [ Time Frame: 12 weeks ]
    To achieve a reduction in fasting plasma TG to a level equal to or less than 10.00 mmol/L on top of a low-fat diet at 12 weeks after administration.
  • Reduction of TG concentrations [ Time Frame: 26 weeks ]
    To achieve sustained efficacy, defined as a reduction in fasting plasma TG at 26 weeks after administration to a level equal to or less than 10.00 mmol/L on top of a low-fat diet.
  • Biological activity and expression of the transgene product. [ Time Frame: 1 year ]
    To determine the biological activity and expression of the lipoprotein lipase (LPLS447X) transgene product.
  • Evaluation immune respons [ Time Frame: 5 years ]
    To evaluate potential immune responses against the lipoprotein lipase (LPLS447X) transgene product and the adeno-associated viral (AAV) vector.
  • To assess the shedding of the viral vector [ Time Frame: 1 year ]
    To assess shedding of AMT-011


Original Secondary Outcome: Same as current

Information By: Amsterdam Molecular Therapeutics

Dates:
Date Received: April 22, 2010
Date Started: August 2007
Date Completion: June 2013
Last Updated: September 29, 2011
Last Verified: April 2010