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Familial Lipoprotein Lipase DeficiencyPhase 2/3NCT00891306

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

A Phase 2/3 study testing Alipogene Tiparvovec (AMT-011), Human LPL [S447X], mycophenolate mofetil and cyclosporine in people with Familial Lipoprotein Lipase Deficiency, run by Amsterdam Molecular Therapeutics at 2 sites in Canada.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Familial Lipoprotein Lipase Deficiency
What is being tested?
Alipogene Tiparvovec (AMT-011), Human LPL [S447X], mycophenolate mofetil and cyclosporine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
5 participants
Where
2 sitesCanada
Study dates
Feb 2009to Apr 2011
Phase
Phase 2/3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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:
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  • 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.

Who cannot join

  • 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
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  • 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

Trial locations and contacts

2 sites in 1 country.

Canada2 sites

  • ECOGENE-21 Clinical Trial Center / Centre de santé et de services sociaux de Chicoutimi

    Chicoutimi, Quebec, G7H 5H6

  • Centre des Maladies Lipidiques de Québec

    Québec, Quebec, G1V 4M6

Other trials in Canada

About this study

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

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.

Read the 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.

Being tested
Alipogene Tiparvovec (AMT-011), Human LPL [S447X], mycophenolate mofetil, cyclosporine, methylprednisolone
Keywords
LPLD, Lipoprotein Lipase Deficiency, Chylomicronemia, Gene therapy, AAV, Lipoprotein Lipase, Alipogene tiparvovec, AMT-011
Medical subject headings
Hyperlipoproteinemia Type I

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

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

    Also called Glybera, AMT-011

    intra muscular, 1 x E12 gc per kg body weight, injected in a single series of intramuscular injections

  • mycophenolate mofetilDrug

    Also called CellCept

    oral, 2 g/day, day -3 till week 12

  • cyclosporineDrug

    Also called Neoral

    oral, 3 mg/kg/day, day -3 till week 12

  • methylprednisoloneDrug

    Also called Solumedrol®

    single intravenous bolus of methylprednisolone (1 mg/kg bodyweight)

Study groups in NCT00891306
Study groupRoleWhat they receive
Treatment armExperimentalGene Therapy
Receives: Genetic: Alipogene Tiparvovec (AMT-011), Human LPL [S447X]; Drug: mycophenolate mofetil; Drug: cyclosporine; Drug: methylprednisolone

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Reduction of triglyceride (TG) concentrations

    Measured: 12 weeks

Secondary outcomes (4)

  1. Reduction of chylomicrons and/or chylomicron-TG ratio

    Measured: 12 weeks

  2. To determine the biological activity and expression of the lipoprotein lipase [LPLS447X] transgene product

    Measured: 14 weeks

  3. To assess the safety profile

    Measured: 14 weeks

  4. To assess shedding of viral vector

    Measured: 14 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 May 2009 (estimated)
  2. Study startFeb 2009
  3. Primary completionAug 2010
  4. Study completionApr 2011

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
5 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00891306
Sponsor's protocol ID
CT-AMT-011-02
Status last verified
Sep 2011
First submitted
30 Apr 2009
Last updated
29 Sep 2011
Results posted
No
Data monitoring committee
Yes

Publications

  • Rip J, Nierman MC, Sierts JA, Petersen W, Van den Oever K, Van Raalte D, Ross CJ, Hayden MR, Bakker AC, Dijkhuizen P, Hermens WT, Twisk J, Stroes E, Kastelein JJ, Kuivenhoven JA, Meulenberg JM. Gene therapy for lipoprotein lipase deficiency: working toward clinical application. Hum Gene Ther. 2005 Nov;16(11):1276-86. doi: 10.1089/hum.2005.16.1276.

    PubMed 16259561

  • Ross CJ, Twisk J, Meulenberg JM, Liu G, van den Oever K, Moraal E, Hermens WT, Rip J, Kastelein JJ, Kuivenhoven JA, Hayden MR. Long-term correction of murine lipoprotein lipase deficiency with AAV1-mediated gene transfer of the naturally occurring LPL(S447X) beneficial mutation. Hum Gene Ther. 2004 Sep;15(9):906-19. doi: 10.1089/hum.2004.15.906.

    PubMed 15353045

  • Ross CJ, Liu G, Kuivenhoven JA, Twisk J, Rip J, van Dop W, Excoffon KJ, Lewis SM, Kastelein JJ, Hayden MR. Complete rescue of lipoprotein lipase-deficient mice by somatic gene transfer of the naturally occurring LPLS447X beneficial mutation. Arterioscler Thromb Vasc Biol. 2005 Oct;25(10):2143-50. doi: 10.1161/01.ATV.0000176971.27302.b0. Epub 2005 Jul 7.

    PubMed 16002740

  • Ross CJ, Twisk J, Bakker AC, Miao F, Verbart D, Rip J, Godbey T, Dijkhuizen P, Hermens WT, Kastelein JJ, Kuivenhoven JA, Meulenberg JM, Hayden MR. Correction of feline lipoprotein lipase deficiency with adeno-associated virus serotype 1-mediated gene transfer of the lipoprotein lipase S447X beneficial mutation. Hum Gene Ther. 2006 May;17(5):487-99. doi: 10.1089/hum.2006.17.487.

    PubMed 16716106

  • Stroes ES, Nierman MC, Meulenberg JJ, Franssen R, Twisk J, Henny CP, Maas MM, Zwinderman AH, Ross C, Aronica E, High KA, Levi MM, Hayden MR, Kastelein JJ, Kuivenhoven JA. Intramuscular administration of AAV1-lipoprotein lipase S447X lowers triglycerides in lipoprotein lipase-deficient patients. Arterioscler Thromb Vasc Biol. 2008 Dec;28(12):2303-4. doi: 10.1161/ATVBAHA.108.175620. Epub 2008 Sep 18. No abstract available.

    PubMed 18802015

  • Carpentier AC, Frisch F, Labbe SM, Gagnon R, de Wal J, Greentree S, Petry H, Twisk J, Brisson D, Gaudet D. Effect of alipogene tiparvovec (AAV1-LPL(S447X)) on postprandial chylomicron metabolism in lipoprotein lipase-deficient patients. J Clin Endocrinol Metab. 2012 May;97(5):1635-44. doi: 10.1210/jc.2011-3002. Epub 2012 Mar 21.

    PubMed 22438229

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Alipogene Tiparvovec (AMT-011), Human LPL [S447X], mycophenolate mofetil and cyclosporine in people with Familial Lipoprotein Lipase Deficiency, run by Amsterdam Molecular Therapeutics at 2 sites in Canada.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 29 Sep 2011. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Reduction of triglyceride (TG) concentrations (time frame: 12 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00891306, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Sep 2011.

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