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HypercholesterolemiaPhase 3NCT00263081

Efficacy of Lapaquistat Acetate Co-Administered With Current Lipid-Lowering Treatment on Blood Cholesterol Levels in Subjects With Homozygous Familial Hypercholesterolemia

A Phase 3 study testing Lapaquistat acetate and current lipid-lowering treatment and Current lipid-lowering treatment in people with Hypercholesterolemia, run by Takeda at 10 sites in 6 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

The purpose of the study is to determine the efficacy of lapaquistat acetate, once daily (QD), to lower cholesterol in subjects with homozygous familial hypercholesterolemia undergoing lipid-lowering treatment. Read more about this study

Who is it for?
Ages 8 years and older
Conditions the study is for
Hypercholesterolemia
What is being tested?
Lapaquistat acetate and current lipid-lowering treatment and Current lipid-lowering treatment
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
44 participants
Where
10 sitesin 6 countries
Study dates
Nov 2005to Mar 2007
Phase
Phase 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 8 years and older
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • Must be at least 8 years of age (12 years of age in Poland) and weigh greater than or equal to 30 kg.
  • Must have homozygous FH, as documented by genetic testing that confirmed 2 mutated alleles at the LDL-receptor locus, or by the following clinical criteria:
  • documented history of untreated fasting serum LDL-C >460 mg/dL (11.91 mmol/L).
  • tendinous or cutaneous xanthomas and/or corneal arcus before age 10 and/or premature coronary heart disease before age 20.
  • Must be taking a stable, approved lipid-lowering drug regimen for a minimum of 8 weeks prior to Screening Visit 1 and were to continue that treatment for the duration of the study.
  • Female participants can not be pregnant, not lactating, not planning on becoming pregnant and agree to use adequate contraception throughout the course of the study.

Who cannot join

  • Has alanine aminotransferase or aspartate aminotransferase levels greater than 2 times the upper limit of normal, active liver disease, jaundice, or serum creatinine >135 μmol/L (1.5 mg/dL) at screening.
  • Has a creatine kinase greater than 3 times the upper limit of normal
  • Has a positive hepatitis B surface antigen, or hepatitis C virus antibody, as determined by medical history.
  • Has a positive human immunodeficiency virus status or was taking antiretroviral medications, as determined by medical history and/or subject's verbal report.
  • Is unable or unwilling to discontinue excluded medications or to continue stable doses of 'stable dose' medications or would require treatment with any excluded medication during the study.
  • Is currently participating in another investigational study or had participated in an investigational study within the past 30 days or, for drugs with a long half-life, within a period of less than 5 times the drug's half-life.
Show all 14Show fewer
  • Has a previous history of cancer that had been in remission for less than 5 years prior to the first dose of study drug. This criterion was not to include those subjects with basal cell or Stage 1 squamous cell carcinoma of the skin.
  • Has known hypersensitivity or history of adverse reaction to lapaquistat acetate.
  • Has a history of fibromyalgia, myopathy, rhabdomyolysis, or unexplained muscle pain.
  • Has an endocrine disorder, such as Cushing Syndrome, hyperthyroidism, or inappropriately treated hypothyroidism, affecting lipid metabolism. Subjects with hypothyroidism on appropriate replacement therapy.
  • Has uncontrolled hypertension despite medical treatment.
  • Has inflammatory bowel disease or any other malabsorption syndrome or had gastric bypass or any other surgical procedure for weight loss.
  • Has a history of drug abuse or a history of alcohol abuse within the past 2 years.
  • Has any other serious disease or condition at screening or at randomization that might have reduced life expectancy, impaired successful management according to the protocol, or made the subject an unsuitable candidate to receive study drug.

Trial locations and contacts

10 sites in 6 countries.

10 sites in 6 countries

Poland3 sites
  • Study site

    Bialystok

  • Study site

    Warsaw

  • Study site

    Zabrze

Other trials in Poland

United States2 sites
  • Study site

    Cincinnati, Ohio

  • Study site

    Columbus, Ohio

Other trials in United States

France2 sites
  • Study site

    Paris

  • Study site

    Strasbourg

Other trials in France

Canada1 site
  • Study site

    Québec

Other trials in Canada

Israel1 site
  • Study site

    Jerusalem

Other trials in Israel

United Kingdom1 site
  • Study site

    Manchester

Other trials in United Kingdom

About this study

Official title: A Double-blind, Placebo-controlled, Randomized Study to Evaluate the Efficacy and Safety of TAK-475 or Placebo When Co-administered With Current Lipid-lowering Therapy in Subjects With Homozygous Familial Hypercholesterolemia.

The purpose of the study is to determine the efficacy of lapaquistat acetate, once daily (QD), to lower cholesterol in subjects with homozygous familial hypercholesterolemia undergoing lipid-lowering treatment.

Read the detailed description

According to the World Health Organization, CHD is now the leading cause of death worldwide. In 2001, CHD caused 7.2 million deaths and estimates for 2020 indicate that annual CHD deaths will increase to 11.1 million. These statistics suggest that improved options are needed to treat hypercholesterolemia and dyslipidemia.

The balance among cholesterol synthesis, dietary intake, and degradation is normally adequate to maintain healthy cholesterol plasma levels. However, in patients with hypercholesterolemia, elevated low-density lipoprotein cholesterol leads to atherosclerotic deposition of cholesterol in the arterial walls. Consequently, in this population it has been established that lowering low-density lipoprotein cholesterol plasma concentrations effectively reduces cardiovascular morbidity and mortality. The National Cholesterol Education Program Adult Treatment Panel III has therefore identified control of low-density lipoprotein cholesterol as essential in the prevention and management of CHD. Additional lipid risk factors designated by National Cholesterol Education Program Adult Treatment Panel III include elevated triglycerides, elevated non-high-density lipoprotein cholesterol (atherogenic lipoproteins), and low levels of high-density lipoprotein cholesterol. Lipoproteins rich in triglycerides, such as very-low-density lipoprotein cholesterol, appear to contribute to atherosclerosis, whereas the apparent protective effect of high-density lipoprotein cholesterol, which is likely related to high-density lipoprotein cholesterol-facilitated transport of cholesterol away from atherosclerotic deposits, may be limited at low high-density lipoprotein cholesterol concentrations.

Initial dietary and lifestyle measures taken to control dyslipidemia are often inadequate, and most patients require pharmacologic intervention. Currently, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the first-line monotherapies most often prescribed to reduce low-density lipoprotein cholesterol, after diet and therapeutic lifestyle change. However, with statin monotherapy, many patients fail to reach National Cholesterol Education Program Adult Treatment Panel III recommended levels of low-density lipoprotein cholesterol reduction. As a result, the statin dosage must be increased or an additional treatment added to achieve treatment goals. Increasing the statin dosage may result in decreased tolerability and potential safety concerns, contributing to the high discontinuation rates of statins and their prescription at low and often ineffective doses. Further, although the effectiveness of increasing the dose varies among the statins, in general, doubling of the dose above the minimum effective dose has been found to decrease serum low-density lipoprotein cholesterol by only an additional 6 percent.

Takeda Global Research and Development Center, Inc. is developing an orally active squalene synthase inhibitor, TAK-475 (lapaquistat acetate) for the treatment of dyslipidemia. Lapaquistat acetate inhibits the biosynthesis of cholesterol by inhibiting the enzyme squalene synthase, which catalyzes the conversion of farnesyl diphosphate to squalene-a precursor in the final steps of cholesterol production.

This study will evaluate the efficacy of lapaquistat acetate coadministered with ongoing lipid-lowering therapy in treating subjects with homozygous familial hypercholesterolemia. The effect on LDL-C and other lipid parameters, as well as the safety and tolerability of lapaquistat acetate compared to a placebo will be evaluated during a 12-week double-blind treatment period. The long-term safety of lapaquistat acetate treatment in this population will be evaluated during an open-label extension period. Study Participation is anticipated to be up to 3 years.

Being tested
Lapaquistat acetate and current lipid-lowering treatment, Current lipid-lowering treatment
Keywords
Hyperlipidemia, Dyslipidemia, Drug Therapy
Medical subject headings
Hypercholesterolemia, Hyperlipidemias, Dyslipidemias

What participants receive

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

  • Lapaquistat acetate and current lipid-lowering treatmentDrug

    Also called Lapaquistat, TAK-475

    Cohort 1: Weight is less than 50 kg:

    Lapaquistat acetate 50 mg, tablets, orally, once daily and current lipid-lowering treatment for up to 12 weeks.

    Cohort 2: Weight is more than 50 kg:

    Lapaquistat acetate 100 mg, tablets, orally, once daily and current lipid-lowering treatment for up to 12 weeks.

  • Current lipid-lowering treatmentDrug

    Lapaquistat acetate placebo-matching tablets, orally, once daily and current lipid-lowering treatment for up to 12 weeks.

Study groups in NCT00263081
Study groupRoleWhat they receive
Lapaquistat Acetate QDExperimental(and current lipid-lowering treatment)
Receives: Drug: Lapaquistat acetate and current lipid-lowering treatment
Current lipid-lowering treatmentPlacebo comparatorNot described
Receives: Drug: Current lipid-lowering treatment

What is being measured

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

  1. Change from Baseline in Low Density Lipoprotein cholesterol

    Measured: Week 12 or Final Visit

Secondary outcomes (12)
  1. Change from Baseline in calculated Low Density Lipoprotein cholesterol

    Measured: Week 12 or Final Visit

  2. Change from Baseline in non- High Density Lipoprotein cholesterol

    Measured: Week 12 or Final Visit

  3. Change from Baseline in Triglycerides

    Measured: Week 12 or Final Visit

  4. Change from Baseline in Total Cholesterol

    Measured: Week 12 or Final Visit

  5. Change from Baseline in High Density Lipoprotein cholesterol

    Measured: Week 12 or Final Visit

  6. Change from Baseline in Very Low Density Lipoprotein cholesterol

    Measured: Week 12 or Final Visit

  7. Change from Baseline in apolipoprotein A1

    Measured: Week 12 or Final Visit

  8. Change from Baseline in apolipoprotein B

    Measured: Week 12 or Final Visit

  9. Lipoprotein cholesterol/High Density Lipoprotein cholesterol

    Measured: Week 12 or Final Visit

  10. Change from Baseline in the ratio of Total Cholesterol/High Density Lipoprotein cholesterol

    Measured: Week 12 or Final Visit

  11. Change from Baseline in the ratio of apolipoprotein A1/apolipoprotein B

    Measured: Week 12 or Final Visit

  12. Change from Baseline in high-sensitivity C-reactive protein

    Measured: Week 12 or Final Visit

Timeline

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

  1. First posted7 Dec 2005 (estimated)
  2. Study startNov 2005
  3. Primary completionMar 2007
  4. Study completionMar 2007

Why it stopped: Overall profile of the compound does not offer significant clinical advantage to patients over currently available lipid lowering agents

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 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
44 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00263081
Sponsor's protocol ID
01-05-TL-475-016
Other IDs
2005-003626-26, U1111-1122-7919, 2005
Status last verified
May 2012
First submitted
6 Dec 2005
Last updated
24 May 2012
Results posted
No
Data monitoring committee
No

Publications

  • Stein EA, Bays H, O'Brien D, Pedicano J, Piper E, Spezzi A. Lapaquistat acetate: development of a squalene synthase inhibitor for the treatment of hypercholesterolemia. Circulation. 2011 May 10;123(18):1974-85. doi: 10.1161/CIRCULATIONAHA.110.975284. Epub 2011 Apr 25.

    PubMed 21518985

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Lapaquistat acetate and current lipid-lowering treatment and Current lipid-lowering treatment in people with Hypercholesterolemia, run by Takeda at 10 sites in 6 countries.

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 6 inclusion and 14 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: stopped early, as of the sponsor's last update on 24 May 2012. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 10 sites in Poland, United States, France, Canada, Israel and 1 more country. 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. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

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 was stopped early (reason given: Overall profile of the compound does not offer significant clinical advantage to patients over currently available lipid lowering agents). Results are not available in the source record.

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?

Change from Baseline in Low Density Lipoprotein cholesterol (time frame: Week 12 or Final Visit). 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 NCT00263081, which also lists 1 linked publication.

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 24 May 2012.

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