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Efficacy and Safety of Human Lipoprotein Lipase (LPL)[S447X] Expressed by an Adeno-Associated Viral Vector in LPL-deficient Subjects

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. Identifier: NCT00891306
Recruitment Status : Completed
First Posted : May 1, 2009
Last Update Posted : September 29, 2011
The Clinical Trial Company
Information provided by (Responsible Party):
Amsterdam Molecular Therapeutics

Brief Summary:
This trial is designed to expand the currently available data on the safety and efficacy of alipogene tiparvovec treatment in lipoprotein lipase deficiency (LPLD) and to further the understanding of possible mechanisms of action of the therapy.

Condition or disease Intervention/treatment Phase
Familial Lipoprotein Lipase Deficiency Genetic: Alipogene Tiparvovec (AMT-011), Human LPL [S447X] Drug: mycophenolate mofetil Drug: cyclosporine Drug: methylprednisolone Phase 2 Phase 3

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label Study to Assess the Efficacy and Safety of Alipogene Tiparvovec (AMT-011), Human LPL [S447X], Expressed by an Adeno-Associated Viral Vector After Intramuscular Administration in LPL-deficient Adult Subjects
Study Start Date : February 2009
Actual Primary Completion Date : August 2010
Actual Study Completion Date : April 2011

Arm Intervention/treatment
Experimental: Treatment arm
Gene Therapy
Genetic: Alipogene Tiparvovec (AMT-011), Human LPL [S447X]
intra muscular, 1 x E12 gc per kg body weight, injected in a single series of intramuscular injections
Other Names:
  • Glybera
  • AMT-011

Drug: mycophenolate mofetil
oral, 2 g/day, day -3 till week 12
Other Name: CellCept

Drug: cyclosporine
oral, 3 mg/kg/day, day -3 till week 12
Other Name: Neoral

Drug: methylprednisolone
single intravenous bolus of methylprednisolone (1 mg/kg bodyweight)
Other Name: Solumedrol®

Primary Outcome Measures :
  1. Reduction of triglyceride (TG) concentrations [ Time Frame: 12 weeks ]

Secondary Outcome Measures :
  1. Reduction of chylomicrons and/or chylomicron-TG ratio [ Time Frame: 12 weeks ]
  2. To determine the biological activity and expression of the lipoprotein lipase [LPLS447X] transgene product [ Time Frame: 14 weeks ]
  3. To assess the safety profile [ Time Frame: 14 weeks ]
  4. To assess shedding of viral vector [ Time Frame: 14 weeks ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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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:

  • Being diagnosed with LPLD defined as:

    • Confirmed homozygosity or compound heterozygosity for the mutations in the LPL gene, resulting in LPL deficiency
    • Having a post heparin plasma LPL activity of ≤ 20% of normal or a well defined mutation for which it is documented that the LPL mass and activity are within the limits described above
    • Having a history of pancreatitis
    • Having fluctuating TG concentrations with median fasting plasma TG concentrations > 10.00 mmol/L
  • Being in good general physical health with, in the opinion of the investigator:

    • No other clinically significant and relevant abnormalities in the medical history which could interfere with the participation to the study
    • No clinically significant abnormalities at the physical examination which could interfere with the participation to the study
    • No clinically significant abnormalities at the routine laboratory evaluation performed prior to the trial
  • Women of non-child bearing potential or with a negative pregnancy test.
  • Non breast feeding women
  • Women using appropriate contraceptive (if relevant) and their partner using barrier contraception 2 weeks before starting immunosuppressive therapy
  • Men practicing barrier birth control and their partner using appropriate contraception.
  • Willing to fully comply with all study procedures and requirements of the trial such as restrictions to a low-fat diet.

Exclusion Criteria:

  • Having a chronic inflammatory muscle disease.
  • Any current or relevant previous history of serious, severe or unstable physical or psychiatric illness, any medical disorder that may make the subject unlikely to fully complete the study, or any condition that presents undue risk from the study medication or procedures based on the investigator's opinion(eg. malignant neoplasia)
  • Active infectious disease of any nature, including clinically active viral infections
  • Having one of the following outcomes from the blood screening tests after appropriate correction due to the presence of chylomicronemia:

    • Platelet count < 100 x 109 /L
    • Hemoglobin < 6.2 mmol/L
    • Liver function disturbances (bilirubin ≥1.5 x normal, ALT > 2 x ULN (upper limit of normal)
    • CPK > 2 x ULN
    • Cockcroft-Gault estimated creatinine clearance < 50cc/min
    • PT and PTT outside normal range or not determinable unless judged as acceptable for the subjects by the investigator
    • Having a positive test for HIV, Hepatitis B, Hepatitis C or being positive for tuberculosis
  • Obesity defined as body mass index (BMI) > 30 kg/m2
  • Having a recent history of alcohol or drug abuse e.g. barbiturates, cannabinoids and amphetamines, and the subject is positive in a urine screen for drugs of abuse
  • Using anti-coagulants
  • Participation in another clinical trial or receipt of any other investigational drug within 30 days of screening or planning to participate in another clinical trial during the course of the study, except observational studies
  • Subjects which cannot be treated with immunosuppressive medication or steroids
  • Known to be allergic to any constituent of the therapy (including the immune suppressors) or a having a condition that prohibits the use of therapy
  • Received previous treatment with AMT-010, Alipogene tiparvovec or other gene therapy investigational product
  • Requiring a post heparin plasma LPL activity test for diagnostic confirmation and having a history of heparin induced thrombocytopenia or other heparin related complications

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 identifier (NCT number): NCT00891306

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Canada, Quebec
ECOGENE-21 Clinical Trial Center / Centre de santé et de services sociaux de Chicoutimi
Chicoutimi, Quebec, Canada, G7H 5H6
Centre des Maladies Lipidiques de Québec
Quebec, Canada, G1V 4M6
Sponsors and Collaborators
Amsterdam Molecular Therapeutics
The Clinical Trial Company
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Principal Investigator: Daniel Gaudet, MD, Ph.D. ECOGENE-21 Clinical Trial Center / Centre de santé et de services sociaux de Chicoutimi, Chicoutimi Hospital, Quebec, Canada
Additional Information:

Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Amsterdam Molecular Therapeutics Identifier: NCT00891306    
Other Study ID Numbers: CT-AMT-011-02
First Posted: May 1, 2009    Key Record Dates
Last Update Posted: September 29, 2011
Last Verified: September 2011
Keywords provided by Amsterdam Molecular Therapeutics:
LPLD, Lipoprotein Lipase Deficiency
Gene therapy
Lipoprotein Lipase
Alipogene tiparvovec
Additional relevant MeSH terms:
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Hyperlipoproteinemia Type I
Lipid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lipid Metabolism Disorders
Metabolic Diseases
Mycophenolic Acid
Methylprednisolone Hemisuccinate
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Dermatologic Agents
Antirheumatic Agents
Calcineurin Inhibitors
Antibiotics, Antineoplastic
Antineoplastic Agents
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Inflammatory Agents