To evaluate the efficacy and safety of extended release (ER) Niacin/Laropiprant when added to ongoing lipid-modifying therapy in patients with primary hypercholesterolemia or mixed dyslipidemia.
ID
Source
Brief title
Condition
- Lipid metabolism disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
In patients with primary hypercholesterolemia or mixed dyslipidemia on stable
LMT and with elevated LDL-C: To evaluate the efficacy of ERN/LRPT 2 g relative
to placebo on plasma LDL-C at Week 12 of treatment.
Secondary outcome
In patients with primary hypercholesterolemia or mixed dyslipidemia on stable
LMT and with elevated LDL-C:
1. To evaluate the efficacy of ERN/LRPT 2 g relative to placebo on plasma
concentrations of LDL-C:HDL-C, HDL-C, TG, non-HDL-C, Apo B, ApoB:ApoA-I,
TC:HDL-C, Lp(a), Apo A-I, and TC at Week 12 of treatment.
2. To evaluate the efficacy of ERN/LRPT 2 g relative to placebo on plasma
concentrations of LDL-C, LDL-C:HDL-C, HDL-C, TG, non-HDL-C, Apo B, ApoB:ApoA-I,
TC:HDL-C, Lp(a), Apo A-I, and TC in the following five LMT subgroups and four
other key subgroups at Week-12 of treatment:
a. The LMT subgroup of patients on simvastatin alone
b. The LMT subgroup of patients on ezetimibe/simvastatin combination tablet
c. The LMT subgroup of patients on rosuvastatin alone
d. The LMT subgroup of patients on atorvastatin alone
e. The LMT subgroup of patients on simvastatin, rosuvastatin, or atorvastatin
combined or coadministered with ezetimibe
f. Subgroup of patients with low baseline HDL-C per NCEP ATP III [<40 mg/dL
(men), <50 mg/dL (women)]
g. Subgroup of patients with low baseline HDL-C per ESC [<40 mg/dL (men), <45
mg/dL (women)] guidelines
h. Subgroup of patients with metabolic syndrome (including patients with
diabetes)
i. Subgroup of patients with metabolic syndrome (excluding patients with
diabetes)
3. To evaluate the efficacy of ERN/LRPT 2 g relative to placebo on plasma
concentrations of LDL-C, LDL-C:HDL-C, HDL-C, TG, non-HDL-C, Apo B, ApoB:ApoA-I,
TC:HDL-C, Lp(a), Apo A-I, and TC in the following four other key subgroups at
Week 12 of treatment:
a. Patients at combined (very high/high) CHD risk per NCEP ATP III
b. Patients at very high CHD risk per NCEP ATP III
c. Patients at high CHD risk per NCEP ATP III
d. Patients at moderate CHD risk per NCEP ATP III
4. To assess:
a. The proportion of patients who achieve NCEP ATP III LDL-C target levels
after the addition of ERN/LPRT 2 g relative to placebo at Week 12 of treatment.
b. The proportion of patients who achieve ESC LDL-C target levels after the
addition of ERN/LPRT 2 g relative to placebo at Week 12 of treatment.
5.To evaluate the efficacy of ERN/LRPT 1 g relative to placebo on plasma
concentrations of LDL-C, LDL-C:HDL-C, HDL-C, TG, non-HDL-C, Apo B, ApoB:ApoA-I,
TC:HDL-C, Lp(a), Apo A-I, and TC in all patients at Week 4 of treatment.
6. To evaluate lipid efficacy of ERN/LRPT 2g relative to placebo on plasma
concentrations of LDL-C, LDL-C:HDL-C, HDL-C, TG, non-HDL-C, Apo B, ApoB:ApoA,
TC:HDL-C, Lp(a), Apo A-I, and TC in subgroups defined by age, gender, race,
region, CV risk status, diabetes status, metabolic syndrome status (including
and excluding patients with diabetes), type of hyperlipidemia, low/otherwise
baseline HDL-C (per NCEP ATP III and, separately, per ESC) and baseline LDL-C,
HDL-C and TG levels at Week 12 of treatment.
7. To evaluate the safety and tolerability of ERN/LRPT 2 g across 12 weeks of
treatment.
Background summary
LDL-C has been well established as a risk factor for cardiovascular disease,
and a linear relationship exists between reductions in LDL-C and cardiovascular
risk reduction. I addition, epidemiological and clinical studies suggest that
low levels of HDL-C and high levels of triglycerides are also positively
associated with increased cardiovascular disease risk. Statins are the gold
standard therapy to lower LDL-C; however, a significant number of
statin-treated patients remain at risk. Combination therapy to target LDL-C as
well as other potentially atherogenic lipid parameters may result in
incremental clinical benefit beyond that possible with statin therapy alone. In
controlled trials only 30% of CV events are prevented by statin monotherapy.
Niacin is the most effective approved agent for raising HDL-C and is also
efficacious in lowering LDL-C and triglycerides. A major impediment to the
optimal use of niacin is the flushing experienced by most patients. Bothersome
side effects, such as flushing of the face and trunk have been reported in over
90% of patients receiving niacin, even at a commonly prescribed dose of 500 mg
t.i.d. However, lipid efficacy minimally requires doses of 1 g/day with the
greatest lipid efficacy seen at the 2-g/day dose. Thus, an agent that can
reduce niacininduced flushing (NIF) will facilitate more widespread use of
niacin in the treatment of lipid disorders and may allow dosing at therapeutic
levels within a shorter period of time after initiation of therapy. The ability
to escalate to therapeutic doses quickly is likely to improve the acceptance of
niacin for the treatment of lipid abnormalities and allow more patients to
reach target goals.
Study objective
To evaluate the efficacy and safety of extended release (ER) Niacin/Laropiprant
when added to ongoing lipid-modifying therapy in patients with primary
hypercholesterolemia or mixed dyslipidemia.
Study design
Multicenter, randomized, double-blind, placebo-controlled.
Study duration is 19 weeks which includes the 2-week poststudy telephone
follow-up and screening period. There will be 6 visites plus telephone call.
A minimum of 306 patients will be randomized to each of the following LMT
groups: simvastatin monotherapy, atorvastatin monotherapy, rosuvastatin
monotherapy and ezetimibe/simvastatin combination therapy (same tablet). In
addition, a maximum of 200 patients taking ezetimibe coadministered with
simvastatin or atorvastatin or rosuvastatin will be randomized.
Patients who have been on a stable dose of protocol-specified LMT for at least
6 weeks prior to Visit 1 may enter Visit 1/Week-5 for screening and to have
laboratory samples drawn for screening (TSH, FSH, HbA1c), and Framingham Risk
Score calculation.
The central laboratory*s LDL-C and TG values obtained at Visit 1 will be used
to determine if the patient is likely to meet the lipid criteria needed for
eligibility at Visit 2.
The central lab values obtained at Visit 2 will be used to determine if the
patient meets the lipid and other lab criteria (ALT, AST, CK, eGFR) needed for
randomization.
At Visit 3/Day 1, eligible patients completing the LMT stabilization/placebo
run-in period will be randomized to one of the 2 blinded treatment groups
(Table 2-3) in a 1:1 ratio: ERN/LRPT or placebo, using central randomization
stratified by LMT via Interactive Voice Response System (IVRS). Patients in
Treatment Group 1 will receive 1 g of ERN/LRPT (one 1-g tablet) for 4 weeks.
After 4 weeks (Visit 4) of blinded treatment, Treatment Group 1 will be
advanced to ERN/LRPT 2 g (two 1-g tablets) and remain on this treatment for the
remainder of the study, an additional 8 weeks. Patients in Treatment Group 2
will receive 1 placebo tablet daily and will be advanced to 2 placebo tablets
daily after 4 weeks (Visit 4) for the remainder of the study.
Intervention
At Visit 3/Day 1, eligible patients completing the LMT stabilization/placebo
run-in period will be randomized to one of the 2 blinded treatment groups
(Table 2-3) in a 1:1 ratio: ERN/LRPT or placebo, using central randomization
stratified by LMT via Interactive Voice Response System (IVRS). Patients in
Treatment Group 1 will receive 1 g of ERN/LRPT (one 1-g tablet) for 4 weeks.
After 4 weeks (Visit 4) of blinded treatment, Treatment Group 1 will be
advanced to ERN/LRPT 2 g (two 1-g tablets) and remain on this treatment for the
remainder of the study, an additional 8 weeks. Patients in Treatment Group 2
will receive 1 placebo tablet daily and will be advanced to 2 placebo tablets
daily after 4 weeks (Visit 4) for the remainder of the study.
Study burden and risks
A small, incremental increase in fasting serum glucose (FSG) is an expected
effect of niacin therapy in some patients. This increase may be transient.
Niacine Induced Flushing (NIF) may occur in patients taking the study drug.
Patients should be instructed not to drink alcoholic beverages around the time
of study drug dosing, as alcohol may intensify flushing symptoms.
Beginning at Visit 1, patients must be encouraged to follow the local dietary
guidelines of the country or region. At each subsequent study visit, patients
will be reminded to maintain this diet throughout the study. Refer to Appendix
6.3 of the study protocol for currently recommended NCEP TLC Diet (from the
NCEP ATP III Guidelines).
GCTM, K15-2310, 2000 Galloping Hill Road
Kenilworth, NJ 07033
US
GCTM, K15-2310, 2000 Galloping Hill Road
Kenilworth, NJ 07033
US
Listed location countries
Age
Inclusion criteria
- Patient has a history of primary hypercholesterolemia or mixed dyslipidemia
- Patient must meet one of the folowing risk categories and corresponding LDL-C criteria at visit 2: Very high risk, High Risk or Moderate Risk (see table at page 16 of protocol)
- Patient has been on a stable dose of one of the following LMT's for at least 6 weeks prior to Visit 1, and agrees to remain on the same type and dose of LMT for the duration of the study: Monotherapy:simvastatin or rosuvastatin or atorvastatin; Combination Therapy: ezetimibe/simvastatin in the same tablet; Co-administration Therapy: simvastatin or rosuvastatin or atorvastatin coadministered with ezetimibe
- Patient has TG levels <500mg/dL (<5.65 mmol/L)
- Patient is male or female and ><= 18 years of age on day of signing informed consent
Exclusion criteria
- Patient has taken a prohibited Lipid Modifying Therapy within 6 weeks of Visit 1
- Patient has had a change to the type or dose of acceptable LMT regimen within 6 weeks prior to Visit 1
- Patient is pregnant, breastfeeding, or expecting to conceive during the study including the 14-day post study follow-up
- Patient has a history of malignancy <= 5 years prior to signing informed consent
- Patient has had prohibited medical conditions like: poorly controlled Diabetes Type 1 or 2, an uncontrolled endocrine or metabolic disease, nephrotic syndrome or renal disease, active peptic ulcer disease (within 3 months of visit 1), cardiac disease, arterial bleeding, hepatic disease, malabsorption etc.
- Patient is on prohibited concomitant medication, e.g.: systemic steroids or systemic anabolic agents. antioxidant vitamins (certain vitamins at certain dosages) or patient is Chinese and is on simvastatin 80mg.
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 | EUCTR2010-021627-27-NL |
| ClinicalTrials.gov | NCT01274559 |
| CCMO | NL36288.018.11 |