The main objective of this study is to further determine the efficacy of lapaquistat acetate 50mg compared to placebo during a period of 12 weeks. This period is followed by an optional 48 week open label extension to be able to study the long term…
Source
Brief title
Condition
- Lipid metabolism disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy variable for this study is fasting plasma LDL-C
Secondary outcome
The secondary efficacy variables are other lipid parameters including:
TC.
Apolipoprotein B.
TG.
HDL-C.
Apolipoprotein A1.
VLDL-C.
Non-HDL-C (TC-HDL-C).
LDL-C/HDL-C, TC/HDLC, Apo B/Apo A1 ratios.
Other:
hs-CRP.
The percentage of subjects reaching LDL-C levels of <160 mg/dL (4.1 mmol/L),
<130 mg/dL (3.37 mmol/L) and <100 mg/dL (2.59 mmol/L) at Week 12 (or ET) during
the double-blind will be evaluated.
Safety Variables
The safety assessments include the following variables:
AEs.
Safety laboratory tests.
Physical examination.
Vital signs.
12-Lead ECG.
Background summary
Despite lifestyle changes and the availability of effective lipid lowering
agents, cardiovascular disease continues to be the major cause of death in
Western Europe and North America. International guidelines are increasingly
stringent with respect to control of lipid levels and there is a general
increases in awareness on the on the appropriate use of lipid lowering agents
in subject populations of varying degrees of cardiovascular risk. Also there
are patients that are statin intolerant.
Therefore there remains a clinical need for new effective lipid-lowering
therapies.
Lapaquistat acetate is a novel lipid lowering agent that inhibits the
cholesterol synthesis pathway at a different level than statins. In phase 2/3
studies 50 mg doses of lapaquistat acetate have been shown to significantly
reduce LDL-cholesterol and to be well tolerated. Therefore this investigational
drug may help in meeting the clinical needs.
Study objective
The main objective of this study is to further determine the efficacy of
lapaquistat acetate 50mg compared to placebo during a period of 12 weeks. This
period is followed by an optional 48 week open label extension to be able to
study the long term safety and lipid variables.
Study design
See fig 6a and 6b on page 24 of the protocol.
Double blind period
The study will consist of a screening Visit (V1) to assess eligibility,
followed by a 6-week dietary run-in period. If after the run-in period the
subject*s lipid level have been satisfactorily controlled as described in the
inclusion criteria at V2 and V3 they will return for randomization (V4).
After randomization, the subjects will enter the 12 week double blind treatment
period in which they will receive either lapaquistat acetate 50 mg or placebo
once daily. 75% of the patients will receive active treatment and 25 % will
receive placebo.
For the double blind study, patients will be asked to visit the clinic a
maximum of 9 times (8 times when visit 3.1. is not necessary), which includes
the screening visit V1, the visits during the run-in period (V2,3 and 3.1 if
needed), randomization visit (V4), Visits 5-7 (week 2,4,8 of treatment period)
and visit 8 either at the end of the treatment period (week 12) or at early
termination. Subjects will be followed up by phone for routine AEs 14 days
after last dose.
Open label-extension period.
All subjects who complete the double-blind portion of the study and wish to
continue treatment will be included in the 48-week open-label extension period.
All subjects enrolled into the open label extension period will receive active
treatment.
For subjects continuing in the open label extension; the visit at the end of
the double-blind period (V8) will be considered the first visit of the
extension. Furthermore the subjects will visit the clinic for V9-14 (week 14,
16, 20, 24, 36 and 48 after start of treatment) and V15 at the end of the
extension period or in case of early termination. Subjects will be followed up
by phone for routine AEs 14 days after last dose (week 62).
Intervention
In the double blind phase subjects are being treated either with lapaquistat
acetate 50 mg or placebo once daily for 12 weeks. 75% of the subjects will
receive active treatment and 25% will receive placebo.
In the open label extension phase, all subjects will receive active treatment
for a period of 48 weeks.
Study burden and risks
Burden:
The patient will visit the clinic a maximum of 17 times in the study (a maximum
of 9 times when the patient does not participate in the extension study).
During the study the patient will be on a therapeutic lifestyle change diet
(see appendix E, page 77-78 of the protocol) or equivalent.
At visits 1-15 blood and urine will be collected for safety laboratory tests as
well as lipid tests and pregnancy test (if applicable). In addition, vital
signs and weight is taken and dietary guidance is provided.
At visit 1 (screening), 4 (randomization), 8 (end of double blind study/start
of extension) and 15 (end of extension study) a physical examination and
12-lead ECG is done in addition to the procedures described above.
If required for lipid evaluation there is an optional visit 3.1 in between
visits 3 and 4. During this visit the same procedures as described for visits
1-15 are performed.
In case the patient does not continue in the open-label phase; visit 8 will be
the final visit to the clinic.
Risks:
The side effects that have been reported during clinical trials with
lapaquistat acetate include fatigue, headache, dyspepsia (indigestion),
abdominal pain, nausea, dizziness, diarrhea, sore throat, insomnia, back pain,
muscle cramps, flu-like illness, somnolence and lethargy. These side effects
were all mild or moderate.
Lipid-lowering drugs like lapaquistat acetate may affect the lens of the eye
and the testes. However, no conclusive evidence of damage to the eye or the
testes has been seen in completed studies of lapaquistat acetate given to
humans. A study of the effect of lapaquistat acetate taken for two years is
nearly finished. The data from this study has been regularly reviewed by a
safety committee. So far the study has been allowed to continue. A clinical
study on the effect of lapaquistat acetate on the testes has been completed.
No changes were found in the sperm or in the hormones of any of the men who
participated in the study.
Additionally, there is a very small risk that lapaquistat acetate or other
lipid-lowering medicines may provoke inflammation of muscles, or may affect the
liver in a small percentage of subjects.
Arundel Great court, 2 Arundel Street
London, WC2R 3DA
United Kingdom
Arundel Great court, 2 Arundel Street
London, WC2R 3DA
United Kingdom
Listed location countries
Age
Inclusion criteria
1. The subject is a male or female and at least 18 years of age.
2. A female subject of childbearing potential who is sexually active agrees to use adequate contraception from screening throughout the duration of the study and for 30 days following the last dose. Women NOT of child bearing potential are defined as those who have been surgically sterilized (hysterectomy, oophorectomy, tubal ligation) or who are postmenopausal (defined as at least 2 years since last regular menses). Acceptable methods of contraception are defined in Section 9.1.10 Contraception and Pregnancy Avoidance Procedure.
3. The subject is capable of understanding and complying with protocol requirements.
4. The subject or the subject*s legally acceptable representative signs a written informed consent form prior to the initiation of any study procedures.
5. Prior to Randomization, the subject has a mean LDL-C *130 mg/dL (3.36 mmol/L) and *190 mg/dL (4.92 mmol/L) for 2 consecutive samples (at least 1 week apart). The difference between the 2 individual LDL-C values must not exceed 15% of the higher value.
6. Prior to Randomization, the subject has mean TG <400 mg/dL (4.52 mmol/L) for 2 consecutive samples (at least 1 week apart). The upper value for either sample must be *450 mg/dL (5.08 mmol/L).
7. The subject is willing and able to comply with a standardized diet (TLC or equivalent).
Exclusion criteria
1. The subject has an ALT or AST level >2 times the upper limit of normal (ULN), identified during screening (eg, from the V1 blood sample). If a repeat test is *2 times ULN then contact the Medical Monitor for consideration of inclusion - See Section 9.3.1
2. The subject has a serum creatinine >133 mmol/L (>1.5mg/dL), identified during screening (eg, from the V1 blood sample).
3. The subject has a CK >3 times the upper limit of normal (ULN), identified during screening (eg, from the V1 blood sample). If a repeat test is *3 times the ULN then contact the Medical Monitor for consideration of inclusion - See Section 9.3.1
4. The subject has active liver disease or jaundice.
5. The subject has taken any fibrates within 42 days of Visit 1 or any lipid-lowering therapy for at least 30 days prior to Screening (Visit 1). (See Excluded Medications 7.3)
1. The subject has an ALT or AST level >2 times the upper limit of normal (ULN), identified during screening (eg, from the V1 blood sample). If a repeat test is *2 times ULN then contact the Medical Monitor for consideration of inclusion - See Section 9.3.1
2. The subject has a serum creatinine >133 mmol/L (>1.5mg/dL), identified during screening (eg, from the V1 blood sample).
3. The subject has a CK >3 times the upper limit of normal (ULN), identified during screening (eg, from the V1 blood sample). If a repeat test is *3 times the ULN then contact the Medical Monitor for consideration of inclusion - See Section 9.3.1
4. The subject has active liver disease or jaundice.
5. The subject has taken any fibrates within 42 days of Visit 1 or any lipid-lowering therapy for at least 30 days prior to Screening (Visit 1). (See Excluded Medications 7.3)
6. The subject has a previous history of cancer that has been in remission for less than 5 years prior to the first dose of study medication. This criterion does not include those subjects with basal cell or stage 1 squamous cell carcinoma of the skin.
7. The subject has an endocrine disorder, such as Cushing*s syndrome, hyperthyroidism, or inappropriately treated hypothyroidism affecting lipid metabolism. Subjects with hypothyroidism on appropriate replacement therapy (defined as stable thyroid hormone replacement at least 3 months prior to Screening and TSH levels *1.5 times ULN) will be eligible for enrollment.
8. The subject has a history of myocardial infarction, angina pectoris, unstable angina, transient ischemic attacks, cerebrovascular accident, peripheral vascular disease, abdominal aortic aneurysm, coronary angioplasty, coronary or peripheral arterial surgery (bypass graft surgery), or multiple risk factors that confer a 10-year risk for cardiovascular heart disease (CHD) >20% based on Framingham risk scoring.
9. The subject has a positive hepatitis B surface antigen or hepatitis C virus antibody test, as determined by medical history and/or subject*s verbal report.
10. The subject has a positive human immunodeficiency virus (HIV) status or is taking antiretroviral medications, as determined by medical history and/or subject*s verbal report.
11. The subject is unable or unwilling to discontinue excluded medications or to continue stable doses of *stable dose* medications. (See Excluded Medications and Concomitant Medications.)
12. The subject has received any investigational medication 30 days prior to screening, (for drugs with a long half-life, within a period of less than 5 times the drug*s half-life) or has participated in an investigational study
13. The subject has received lapaquistat acetate in a previous clinical study or as a therapeutic agent
14. The subject has a history or presence of clinically significant food allergy that would prevent adherence to the specialized diet.
15. The subject has a known heterozygous or homozygous familial hypercholesterolemia or known type III hyperlipoproteinemia (familial dysbetalipoproteinemia).
16. The subject has fibromyalgia, myopathy, rhabdomyolysis, or unexplained muscle pain.
17. The subject has uncontrolled hypertension (defined as resting diastolic blood pressure >100 mmHg and/or a resting systolic blood pressure >160 mmHg) at Screening.
18. The subject has had inflammatory bowel disease or any other malabsorption syndrome, or has had gastric bypass or any other surgical procedure for weight loss.
19. The subject is unwilling or unable, in the opinion of the investigator, to comply with the protocol or scheduled appointments.
20. The subject is unable to understand verbal or written English or any other language for which a certified translation of the approved informed consent is available.
21. The subject has a history of drug abuse (defined as illicit drug use) or a history of high alcohol intake (defined as regular or daily consumption of more than 3 alcoholic drinks per day by men and 2 by women) within the previous 2 years.
22. The subject has type 1 or 2 diabetes mellitus.
23. The subject is a study site employee, or is an immediate family member (ie, spouse, parent, child, sibling) of a study site employee who is involved in conduct of this study.
24. If female, the subject is pregnant or lactating.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
EudraCT | EUCTR2007-001489-34-NL |
CCMO | NL17957.018.07 |
Other | nummer nog niet bekend |