Primary Objectives:1. To evaluate the efficacy of anacetrapib 100 mg for 24 weeks relative to placeboon plasma concentrations of LDL-C (BQ method).2. To evaluate the efficacy of anacetrapib 100 mg for 24 weeks relative to placeboon plasma…
ID
Source
Brief title
Condition
- Lipid metabolism disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The co-primary efficacy endpoints are the percent change from baseline in LDL-C
(BQ
method) and HDL-C at Week 24. Non-HDL-C, apoB, apoA-I, Lp(a) at Week 24 and
HDL-C at Week 24 among patients with low HDL-C at LDL-C goal are efficacy
variables addressing the secondary hypotheses.
Safety and tolerability endpoints such as blood chemistry, hematology, and
vital signs
will be monitored. Clinical adverse experiences, select safety endpoints of
interest and
laboratory values exceeding predefined limits of change will be evaluated.
Secondary outcome
Some other endpoints of interest are percent change from baseline at Week 24
are TC, TG, apoE, VLDL-C, VLDL-TG, LDLC/HDL-C, apoB/apoA-I, LDL-C/apoB,
TC/HDL-C, LDL-C estimated by direct and Friedewald methods, CETP activity and
CETP concentration.
Background summary
This study supports the use of anacetrapib as an add-on to statin therapy with
or without
other lipid-modifying medication(s) in high, moderate and low CHD-risk patients
with
hypercholesterolemia who are not at LDL-C goal (as per NCEP ATP III guidelines)
and
in patients with low HDL-C who are at LDL-C goal. Moreover, since patients will
be
allowed to enter the study on a high efficacy statin ± other lipid-modifying
therapies, the
data will be used to support the use of anacetrapib with any high efficacy dose
of
commonly used statins or with ezetimibe, niacin or fibrates + statin.
Additionally, this
study will provide efficacy and tolerability data for a lower (25 mg) dose of
anacetrapib.
Study objective
Primary Objectives:
1. To evaluate the efficacy of anacetrapib 100 mg for 24 weeks relative to
placebo
on plasma concentrations of LDL-C (BQ method).
2. To evaluate the efficacy of anacetrapib 100 mg for 24 weeks relative to
placebo
on plasma concentrations of HDL-C.
3. To evaluate the safety and tolerability of anacetrapib 100 mg for 24 weeks.
Hypotheses;
1. Treatment with anacetrapib 100 mg for 24 weeks will lower LDL-C (BQ method)
to a greater extent than treatment with placebo.
2. Treatment with anacetrapib 100 mg for 24 weeks will raise HDL-C to a greater
extent than treatment with placebo.
Secondary Objectives:
1. To evaluate the efficacy of adding anacetrapib 100mg for 24 weeks relative to
placebo on plasma concentrations of non-HDL-C.
2. To evaluate the efficacy of adding anacetrapib 100mg for 24 weeks relative to
placebo on plasma concentrations of apoB.
3. To evaluate the efficacy of adding anacetrapib 100mg for 24 weeks relative to
placebo on plasma concentrations of apoA-1.
4. To evaluate the efficacy of adding anacetrapib 100mg for 24 weeks relative to
placebo on plasma concentrations of Lp(a).
5. To evaluate the effect of anacetrapib 100 mg on HDL-C in patients with low
HDL-C at LDL-C goal after 24 weeks of treatment.
6. To evaluate the LDL-C-decreasing efficacy of anacetrapib 25 mg vs. placebo
after
24 weeks of treatment.
7. To evaluate the HDL-C-increasing efficacy of anacetrapib 25 mg vs. placebo
after
24 weeks of treatment.
8. To evaluate the efficacy of adding anacetrapib 25mg for 24 weeks relative to
placebo on plasma concentrations of non-HDL-C.
9. To evaluate the efficacy of adding anacetrapib 25mg for 24 weeks relative to
placebo on plasma concentrations of apoB.
10. To evaluate the efficacy of adding anacetrapib 25mg for 24 weeks relative to
placebo on plasma concentrations of apoA-1.
11. To evaluate the efficacy of adding anacetrapib 25mg for 24 weeks relative to
placebo on plasma concentrations of Lp(a).
12. To evaluate the effect of anacetrapib 25 mg on HDL-C in patients with low
HDLC
at LDL-C goal after 24 weeks of treatment.
13. To evaluate the safety and tolerability of anacetrapib 25 mg for 24 weeks.
Hypotheses:
1. Treatment with anacetrapib 100mg for 24 weeks will lower non-HDL-C to a
greater extent than treatment with placebo.
2. Treatment with anacetrapib 100mg for 24 weeks will lower apoB to a greater
extent than treatment with placebo.
3. Treatment with anacetrapib 100mg for 24weeks will raise apoA-1 to a greater
extent than treatment with placebo.
4. Treatment with anacetrapib 100mg for 24 weeks will lower Lp(a) to a greater
extent than treatment with placebo.
5. Treatment with anacetrapib 100 mg for 24 weeks in patients with low HDL-C at
LDL-C goal will raise HDL-C to a greater extent than treatment with placebo.
6. Treatment with anacetrapib 25 mg for 24 weeks will lower LDL-C to a greater
extent than treatment with placebo.
7. Treatment with anacetrapib 25 mg for 24 weeks will raise HDL-C to a greater
extent than treatment with placebo.
8. Treatment with anacetrapib 25mg for 24 weeks will lower non-HDL-C to a
greater extent than treatment with placebo.
9. Treatment with anacetrapib 25mg for 24 weeks will lower apoB to a greater
extent than treatment with placebo.
10. Treatment with anacetrapib 25mg for 24 weeks will raise apoA-1 to a greater
extent than treatment with placebo.
11. Treatment with anacetrapib 25mg for 24 weeks will lower Lp(a)to a greater
extent
than treatment with placebo.
12. Treatment with anacetrapib 25 mg for 24 weeks in patients with low HDL-C at
LDL-C goal will raise HDL-C to a greater extent than treatment with placebo.
Exploratory
1. To evaluate the LDL-C-decreasing efficacy of anacetrapib 100 mg vs. 25 mg
after
24 weeks of treatment.
2. To evaluate the HDL-C-increasing efficacy of anacetrapib 100 mg vs. 25 mg
after
24 weeks of treatment.
3. To evaluate the proportion of patients reaching LDL-C goal relative to
placebo
after 24 weeks of treatment in patients not at LDL-C goal at baseline.
4. To evaluate the lipid-modifying efficacy of anacetrapib (25mg, 100mg) added
to
different background statins (i.e. simvastatin, atorvastatin, rosuvastatin)
with or
without other LMTs compared to placebo after 24 weeks of treatment.
5. To evaluate the effects of anacetrapib (25mg, 100 mg) relative to placebo on
TG,
TC, TC/HDL-C, LDL-C/HDL-C, apoB/apoA-I, LDL-C/apoB, apoE, VLDL-C,
VLDL-TG, CETP activity and CETP concentration after 24 weeks of treatment.
6. To evaluate the proportion of patients reaching HDL-C >=*60mg/dL (1.55 mmol/L)
relative to placebo after 24 weeks of treatment with anacetrapib (100mg, 25mg)
in
patients with HDL below 40 mg/dL (1.03 mmol/L) at baseline.
7. To evaluate the LDL-C lowering and HDL-C raising effect of anacetrapib by
baseline CETP activity and CETP concentration.
8. To evaluate the effects of anacetrapib (25mg, 100mg) on lipid endpoints in
patients with diabetes after 24 weeks of treatment.
9. To evaluate the effect of anacetrapib (25mg, 100mg) on fasting plasma
glucose,
fasting plasma insulin, HbA1c and HOMA-IR (homeostatic model assessment of
insulin resistance) after 24 weeks of treatment.
10. To evaluate the effects of cessation of anacetrapib (25mg, 100mg) for 12
weeks
on lipid endpoints and PK.
11. To evaluate the safety and tolerability of anacetrapib (25mg, 100mg) 12
weeks
after cessation of treatment.
Study design
This is a multicenter, double-blind, placebo-controlled study in patients with
hypercholesterolemia or low HDL-C on a stable dose of statin ± other
lipid-modifying
therapies (LMTs) e.g. ezetimibe, niacin, fibrate.
Patients should be on treatment with a stable dose-regimen of statin ± other
lipidmodifying
therapies for at least 6 weeks prior to Visit 1, and are required to remain on
the
same regimen for the duration of the study. Approximately 450 patients will be
randomized in a 1:1:1 ratio to treatment with anacetrapib 100 mg, anacetrapib
25 mg or
placebo for 24 weeks.
As shown in the study flow chart the total duration of the study will be 40
weeks; which
will include a 2-week screening period (visits 1 to 2), 2-week placebo run-in
period
(visits 2 to 3) and a 24-week treatment period (visits 3-6), followed by a
post-study
follow-up visit 12 weeks after early discontinuation or completion of study drug
treatment. All patients discontinuing will also be contacted at their intended
Week 36
date to assess for serious cardiovascular adverse events, all-cause death or
pregnancy in
women of child-bearing potential.
Consistent with the adjudication SOP, selected adverse cardiovascular events
and allcause
mortality will be adjudicated by an expert committee independent of the
SPONSOR.
Intervention
Patients will take once a day two tablets during the meal. Patients will take
daily one tablet of anacetrapib 100 mg or corresponding placebo and one tablet
of anacetrapib 25 mg or corresponding placebo for 24 weeks.
The clinical safety will be evaluated during every visit.
Controles can be physical examination, measurement of the vital signs and
clinical lab measurements, such as lipid tests, biomarkers for cardiovascular
risk and lab tests of safety.
All patients will undergo an ECG at visit 2.
Study burden and risks
Please refer to the details of the study flowchart on page 11 to 13 of the
protocol. See also section E4, E6 and E9 for risks and burden.
One Merck Drive NA
Whitehouse Station 08889-0100, NJ
US
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Whitehouse Station 08889-0100, NJ
US
Listed location countries
Age
Inclusion criteria
Patients will be eligible to continue to Visit 2 if they meet the following criteria at
Visit 1:
1. Patient is male or female and >=18 and <=80 (or maximum age less than 80; per local
regulation) years of age on day of signing informed consent.
2. A female patient should NOT be of reproductive potential. A female patient not of reproductive potential is defined as: one who has either 1) reached natural menopause defined as age 46 or older with a) 12 months of spontaneous amenorrhea or b) 6 months of spontaneous amenorrhea with serum FSH levels in the postmenopausal range as determined by the central laboratory, 2) 6 weeks post-surgical bilateral oophorectomy with or without hysterectomy, or 3) bilateral tubal ligation.
3. Patient is not pregnant or breast-feeding and does not plan to become pregnant any time in the future.
4. As per NCEP ATP III CHD risk category at screening, patients are required to meet
ONE of the following criteria (detailed definitions of risk categories are in
Appendix 6.7):
a. Very high risk patients (presence of established CHD or other forms of
atherosclerotic vascular disease plus multiple major risk factors [e.g. diabetes],
severe and poorly controlled risk factors [e.g. cigarette smoking], multiple risk
factors of the metabolic syndrome [e.g. high triglycerides >=200mg/dL (2.26
mmol/L) plus non-HDL-C >=130 mg/dL (3.36 mmol/L) with low HDL-C
<40mg/dL (1.03 mmol/L)] or acute coronary syndrome.) with LDL-C >=70 to
<115 mg/dL (>=1.81 to <2.97 mmol/L)
b. High risk patients (CHD or CHD risk equivalent, DM, 10-yr risk>20%) with
LDL-C >=100 to <145 mg/dL (>=2.59 to <3.75 mmol/L);c. Moderate risk patients(>=2 risk factors; 10-yr risk <=20%) with LDL-C >= 130
mg/dL (>= 3.36 mmol/L)
d. Lower risk patients (0 to 1 risk factor) with LDL-C >= 160 mg/dL (>=4.14 mmol/L)
e. Patients at LDL-C goal (as per CHD- risk category) and with low HDL-C, <40
mg/dL (1.03 mmol/L)
5. Patient has been treated with an appropriate dose of statin as assessed by the
investigator (i.e. one of the following) for at least 6 weeks prior to Visit 1:
simvastatin 40 mg or 80 mg
atorvastatin 20 mg, 40 mg or 80 mg
rosuvastatin 5 mg, 10 mg, 20 mg or 40 mg
pitavastatin 4 mg
lovastatin 80 mg
pravastatin 80 mg
Note: Lipid modifying therapy must be stable for at least 6 weeks prior to
Visit 1. Patients are expected to take statin under supervision of their
treating physician in accordance with statin product circular in that region.
6. Patients provide written informed consent/assent for the trial. The patient may also
provide consent/assent for Future Biomedical Research. However, the subject may
participate in the main trial without participating in Future Biomedical Research.
Note: Patient with laboratory values outside ranges described in the protocol may, at
the discretion of the investigator, have ONLY ONE repeat determination performed
and if the repeat value satisfies the criterion patient may continue.
Visit 3
Patients are eligible for randomization if they meet the following criteria at Visit 3.
7. Patient is greater than 75% compliant with study medication during the single-blind
placebo run-in phase or in the opinion of the investigator, compliance will improve
following additional counseling.
Exclusion criteria
Visit 1
1. Patient has previously participated in a study with a CETP inhibitor.
2. Patient has homozygous familial hypercholesterolemia.
3. Patient has a TG > 600 mg/dL (6.78 mmol/L)
4. Patient has creatine phosphokinase (CPK) >2 x upper limit of normal (ULN) [per
central laboratory reference ranges].
5. Patient has alanine aminotransferase (ALT) or aspartate aminotransferase (AST)
>2 x upper limit of normal (ULN) [per central laboratory reference ranges].
6. Patient has severe chronic heart failure defined by New York Heart Association
(NYHA) Classes III or IV.
7. Patient has uncontrolled cardiac arrhythmias, MI, PCI, CABG, unstable angina, or
stroke within three months prior to Visit 1.
8. Patient has uncontrolled hypertension defined as follows:
Sitting diastolic blood pressure >=100 mmHg, or sitting systolic blood pressure
>=160 mm Hg (non-diabetic patients).
OR
Sitting diastolic blood pressure >=90 mmHg, or sitting systolic blood pressure
>=150 mm Hg (diabetic patients).
9. Patient has uncontrolled endocrine or metabolic disease known to influence serum
lipids or lipoproteins (i.e., secondary causes of hyperlipidemia).
Note: Patients with thyroid stimulating hormone (TSH) values outside the central
laboratory normal range who are determined to be without symptoms of either
hypo- or hyperthyroidism may be allowed in the study if, after review by the
Investigator and Project Physician, the patient is deemed not to have clinically
significant thyroid hormone excess or deficiency.
10. Patient has active or chronic hepatobiliary, hepatic or gall bladder disease. Note:
Patients with chronic hepatitis B or C or non-alcoholic steatosis are allowed in the
study if ALT and AST are within protocol-specified range
11. Patient has eGFR <30 mL/min/1.73m2 based on the 4-variable MDRD
(Modification of Diet in Renal Disease) equation, nephrotic syndrome or other
clinically significant renal disease.
12. Patient has history of mental instability, drug/alcohol abuse within the past five
years or major psychiatric illness inadequately controlled and unstable.
13. Patient has history of ileal bypass, gastric bypass, or other significant condition
associated with malabsorption.
14. Patient is human immunodeficiency virus (HIV) positive (as assessed by medical
history).
15. Patient has a history of malignancy <=5 years prior to signing informed consent,
except for adequately treated basal cell or squamous cell skin cancer or in situ
cervical cancer.
16. Patient has donated blood products or has had phlebotomy of >300 mL within
eight weeks of signing informed consent, or intends to donate 250 mL of blood
products or receive blood products within the projected duration of the study.
17. Patient has a history or current evidence of any condition, therapy, lab
abnormality or other circumstance that might confound the results of the study, or
interfere with the patient*s participation for the full duration of the study, such that
it is not in the best interest of the patient to participate.
18. Patient is currently taking medications that are potent inhibitors or inducers of
CYP3A4 (including but not limited to cyclosporine, systemic itraconazole or
ketoconazole, erythromycin, clarithromycin, or telithromycin, nefazodone,
protease inhibitors, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin,
St John*s wort) or has discontinued treatment <3 weeks prior to Visit 1.
Consumption of >1 liter of grapefruit juice per/day is also prohibited.
19. Patient is currently participating or has participated in a study with an
investigational compound or device within three months of signing informed
consent.
20. Patient consumes more than two alcoholic drinks per day.
21. Patient is receiving treatment with systemic corticosteroids.
Note: Treatment with corticosteroids used as replacement therapy for
pituitary/adrenal disease is acceptable; however, the patient must have been on a
stable regimen for at least six weeks prior to Visit 1.
22. Patient is taking systemic anabolic agents.
Additional details regarding excluded concomitant medications can be found in
Appendix 6.10.
Note: Patient with laboratory values outside ranges described in the protocol
may, at the discretion of the investigator, have ONLY ONE repeat determination
performed and if the repeat value satisfies the criterion patient may continue.
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 | EUCTR2012-003110-14-NL |
| CCMO | NL42135.056.12 |