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

September 28, 2011 updated by: Amsterdam Molecular Therapeutics

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

5

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
      • Quebec, Canada, G1V 4M6
        • Centre des Maladies Lipidiques de Québec
    • Quebec
      • Chicoutimi, Quebec, Canada, G7H 5H6
        • ECOGENE-21 Clinical Trial Center / Centre de santé et de services sociaux de Chicoutimi

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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 Names:
  • CellCept
Drug: cyclosporine
oral, 3 mg/kg/day, day -3 till week 12
Other Names:
  • Neoral
Drug: methylprednisolone
single intravenous bolus of methylprednisolone (1 mg/kg bodyweight)
Other Names:
  • Solumedrol®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Reduction of triglyceride (TG) concentrations
Time Frame: 12 weeks
12 weeks

Secondary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Amsterdam Molecular Therapeutics

Collaborators

The Clinical Trial Company

Investigators

  • 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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2009

Primary Completion (Actual)

August 1, 2010

Study Completion (Actual)

April 1, 2011

Study Registration Dates

First Submitted

April 30, 2009

First Submitted That Met QC Criteria

April 30, 2009

First Posted (Estimate)

May 1, 2009

Study Record Updates

Last Update Posted (Estimate)

September 29, 2011

Last Update Submitted That Met QC Criteria

September 28, 2011

Last Verified

September 1, 2011

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CT-AMT-011-02

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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