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

Brief Title

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

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 LipaseS447X

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 Description

      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.

Study Phase

Phase 2/Phase 3

Study Type


Primary Outcome

Reduction of fasting triglyceride (TG) concentrations

Secondary Outcome

 Reduction of TG concentrations


Familial Lipoprotein Lipase Deficiency


Alipogene Tiparvovec (AMT-011), Human LPL [S447X]

Study Arms / Comparison Groups

 Dose cohort 3 x 10^11gc/kg
Description:  intra muscular, 3 x E11 gc per kg body weight, injected in a single series of intramuscular injections


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

August 2007

Completion Date

June 2013

Primary Completion Date

June 2013

Eligibility Criteria

        Inclusion Criteria:

          -  Eligible Population Study participants must have participated in the preceding
             observation study (Prep-02: Appendix III) and be diagnosed with lipoprotein lipase
             deficiency, meeting the following criteria: (I) Their lipoprotein lipase activity
             levels in post-heparin plasma should be ≤20 % of normal; (II) Confirmed homozygocity
             or compound heterozygocity for mutations in the LPL gene; (III) Post-heparin plasma
             LPL mass should be >5% of normal; (IV) Median fasting plasma TG concentrations
             >10.00mmol/L, as determined on the basis of 5 consecutive time points in the preceding
             observation study with a history of pancreatitis.

          -  General Health The participant must be in good general physical health with, in the
             opinion of the investigator, no other clinically significant and relevant
             abnormalities of medical history, and no abnormalities at the physical examination and
             routine laboratory evaluation performed prior to the trial.

          -  Age Age ≥18 years old.

          -  Sex Male or female. Females must be of non-child bearing potential or with a negative
             pregnancy test and not breast feeding. Female subjects must use appropriate
             contraception (if relevant) and their spouse must use barrier contraception for the
             duration of the study (12 weeks). Males must practice barrier birth control and their
             spouse should use appropriate contraception until three consecutive semen samples,
             taken at least 75 days after administration, are negative for AMT-011 vector DNA.

          -  Compliance The participant is willing to fully comply with all study procedures and
             requirements of the trial such as restrictions to a low-fat diet (see section 8.1).

          -  Consent The participant has the mental ability to give voluntary written informed
             consent to participate in the study.

        Exclusion Criteria:

          -  Disease

          -  Apolipoprotein CII deficiency.

          -  Inflammatory muscle disease (e.g. myositis, myopathies or rhabdomolysis).

          -  Any current or relevant previous history of serious, severe or unstable physical or
             psychiatric illness, any medical disorder that may make the participant unlikely to
             fully complete the study, or any condition that presents undue risk from the study
             medication or procedures (e.g. malignant neoplasia).

          -  Active infectious disease of any nature, including clinically active viral infections.

          -  Laboratory Parameters

        The following blood screening tests will result in exclusion from participation:

          -  Platelet count < 100 x 109 /L.

          -  Hemoglobin < 7.0 mmol/L.

          -  Liver function disturbances (bilirubin >2.50 x normal, transaminases >3 x ULN).

          -  CPK > 3 x ULN.

          -  Creatinine > 3 x ULN.




18 Years - N/A

Accepts Healthy Volunteers



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Location Countries


Location Countries


Administrative Informations



Organization ID


Responsible Party


Study Sponsor

Amsterdam Molecular Therapeutics


 International Antiviral Therapy Evaluation Center

Study Sponsor

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Verification Date

April 2010