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

September 29, 2011 updated by: Amsterdam Molecular Therapeutics

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

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 Overview

Status

Unknown

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

14

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
      • Chicoutimi, Quebec, Canada
        • 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:

  • 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.

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: Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Dose cohort 3 x 10^11gc/kg
intra muscular, 3 x E11 gc per kg body weight, injected in a single series of intramuscular injections
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
Genetic: Alipogene Tiparvovec (AMT-011), Human LPL [S447X]
intra muscular, 3 x E11 gc per kg body weight, injected in a single series of intramuscular injections
Other Names:
  • Glybera, AMT 011
Experimental: Alipogene Tiparvovec, Human LPL [S447X]
intra muscular, 3 x E11 gc per kg body weight, injected in a single series of intramuscular injections with immunosuppressants
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: cyclosporine
oral, 3 mg/kg/day, day -3 till week 12
Other Names:
  • Neoral
Genetic: Alipogene Tiparvovec (AMT-011), Human LPL [S447X]
intra muscular, 3 x E11 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
Experimental: Alipogene Tiparvovec, Human LPL [S447X], 1xE12 gc/kg
intra muscular, 1 x E12 gc per kg body weight, injected in a single series of intramuscular injections with immunosuppressants
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
Genetic: Alipogene Tiparvovec (AMT-011), Human LPL [S447X]
intra muscular, 3 x E11 gc per kg body weight, injected in a single series of intramuscular injections
Other Names:
  • Glybera, AMT 011

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
12 weeks
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.
15 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
26 weeks
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.
12 weeks
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.
26 weeks
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.
1 year
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.
5 years
To assess the shedding of the viral vector
Time Frame: 1 year
To assess shedding of AMT-011
1 year

Collaborators and Investigators

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

Sponsor

Amsterdam Molecular Therapeutics

Collaborators

International Antiviral Therapy Evaluation Center

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

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

August 1, 2007

Primary Completion (Anticipated)

June 1, 2013

Study Completion (Anticipated)

June 1, 2013

Study Registration Dates

First Submitted

April 22, 2010

First Submitted That Met QC Criteria

April 22, 2010

First Posted (Estimate)

April 23, 2010

Study Record Updates

Last Update Posted (Estimate)

September 30, 2011

Last Update Submitted That Met QC Criteria

September 29, 2011

Last Verified

April 1, 2010

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CT-AMT-011-01

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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