Dyslipidemia
Conditions
Brief summary
This study will evaluate the efficacy of laropiprant (LRPT) to reduce flushing symptoms beyond 6 months and will measure the impact of withdrawal of laropiprant in patients following 20 weeks of stable maintenance therapy.
Interventions
DRUGER niacin (+) laropiprant (ERN/LRPT)
One 1g/20 mg tablet ERN/LRPT once daily for 4 weeks, then two 1g/20 mg tablets daily (2g/40 mg total) for 28 weeks
DRUGExtended-release niacin (ERN)
Two 1g tablets ERN (2g total) once daily for 12 weeks.
DRUGPlacebo to ERN/LRPT
One tablet placebo to ERN/LRPT once daily for 4 weeks, then two tablets placebo to ERN/LRPT daily for 28 weeks
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Patient is a male, or a female who is unlikely to conceive, as indicated by meeting at least one of the following conditions: (a) Patient is a male.(b) Patient is a female of reproductive potential and either agrees to remain abstinent (if this form of birth control is accepted by local regulatory agencies and review committees as the sole method of birth control) or use (or have their partner use) 2 acceptable methods of birth control within the projected duration of the study.(c) Patient is a female who is not of reproductive potential and therefore eligible to participate in this study without requiring the use of contraception. * Lipid-modifying therapy (LMT) is appropriate for the patient * Patient meets one of the following criteria based on the National Cholesterol Education Program Adult Treatment Panel III guidelines : 1) High risk and is on a statin with LDL-cholesterol (LDL-C) \<100 mg/dL or intolerant to statins with LDL-C \<120 mg/dL; 2) Multiple risk with LDL-C \<130 mg/dL; 3) Low risk with LDL-C \<190 mg/dL * Patient has triglyceride levels \<500 mg/dL
Exclusion criteria
* Patient is pregnant, breast-feeding, or expecting to conceive * Patient has a history of cancer within 5 years of screening (except certain skin and cervical cancers) * Female patient plans to donate eggs during the study * Male patient plans to donate sperm during the study * Patient has or has a history of any condition, therapy, or lab abnormality that might confound the study results, interfere with participation for the full duration of the study, or make participation in the study not in the patient's best interest * Patient has donated or received blood within 8 weeks of screening or plans to donate/receive blood during and 8 weeks after the study * Patient is experiencing menopausal hot flashes * Patient has chronic heart failure, uncontrolled cardiac arrhythmias, or poorly controlled hypertension * Patient has type 1 or 2 diabetes and is poorly-controlled, newly diagnosed, has recently had repeated hypoglycemia, or is taking new or recently adjusted antidiabetic medication * Patient has uncontrolled metabolic or endocrine disease that influences serum lipids or lipoproteins * Patient has kidney disease * Patient had active peptic ulcers within 3 months of screening * Patient has a history of heart attack, stroke, heart bypass surgery, angina, or angioplasty within 3 months of screening * Patient is human immunodeficiency virus (HIV) positive * Patient is taking or has taken niacin \>50 mg daily within 6 weeks of screening * Patient has had a change to type or dose of LMT regimen within 6 weeks of Visit 1 * Patient is taking a statin and a fibrate at screening * Patient is taking a long acting non-steroidal anti-inflammatory drug (NSAID), such as naproxen or aspirin \>100 mg per day at screening * Patient has arterial bleeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number Participants With Days Per Week With Global Flushing Severity Score (GFSS) ≥4 Partitioned Into 6 Categories During the Postwithdrawal Period | Week 21 to Week 32 | Flushing symptoms were recorded using participant's response to the Global Flushing Severity Score (GFSS), which assessed the overall severity of the flushing experience, using a scale of 0 (no symptom) to 10 (extreme). The number of days/week was derived as: 7\*(total number of days with GFSS ≥4 across Weeks 21-32 divided by the total number of days with nonmissing GFSS across the same period). The number of days/week with a GFSS ≥4 for each participant was listed in 1 of the following 6 categories: 0, \>0 to 0.5, \>0.5 to 1, \>1 to 2, \>2 to 3, and \>3 days per week. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Maximum GFSS ≥4 During the Post-withdrawal Period | Week 21 to Week 32 | Flushing symptoms were recorded using participant's response to the Global Flushing Severity Score (GFSS), which assesses the overall severity of the flushing experience (including redness, warmth, tingling, or itching) using a scale with response categories of None, Mild, Moderate, Severe, and Extreme. The categories were supplemented with numbers 0 to 10 to allow for greater precision within each category (None=0, Mild=1-3, Moderate=4-6, Severe=7-9, Extreme=10). The daily response was recorded in the morning, and reflected the symptoms experienced during the previous 24 hours. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ERN/LRPT One 1g/20 mg tablet ERN/LRPT once daily for 4 weeks, then two 1g/20 mg tablets daily (2g/40 mg total) for 28 weeks | 463 |
| ERN/LRPT Then ERN One 1g/20mg tablet ERN/LRPT once daily for 4 weeks, then two 1g/20 mg tablets daily (2g/40 mg total) for 16 weeks then Two 1g tablets ERN (2g total) once daily for 12 weeks. | 456 |
| Placebo One tablet placebo to ERN/LRPT once daily for 4 weeks, then two tablets placebo to ERN/LRPT daily for 28 weeks. | 233 |
| Total | 1,152 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 35 | 54 | 13 |
| Overall Study | Flushing Symptoms | 29 | 46 | 3 |
| Overall Study | Lost to Follow-up | 2 | 3 | 1 |
| Overall Study | Physician Decision | 3 | 1 | 1 |
| Overall Study | Protocol Violation | 9 | 5 | 1 |
| Overall Study | Withdrawal by Subject | 29 | 22 | 13 |
Baseline characteristics
| Characteristic | ERN/LRPT | ERN/LRPT Then ERN | Placebo | Total |
|---|---|---|---|---|
| Age, Customized < 65 years | 334 Participants | 328 Participants | 166 Participants | 828 Participants |
| Age, Customized >=65 years | 129 Participants | 128 Participants | 67 Participants | 324 Participants |
| Sex: Female, Male Female | 184 Participants | 144 Participants | 87 Participants | 415 Participants |
| Sex: Female, Male Male | 279 Participants | 312 Participants | 146 Participants | 737 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 136 / 461 | 162 / 455 | 37 / 232 |
| serious Total, serious adverse events | 17 / 461 | 34 / 455 | 13 / 232 |
Outcome results
Primary
Number Participants With Days Per Week With Global Flushing Severity Score (GFSS) ≥4 Partitioned Into 6 Categories During the Postwithdrawal Period
Flushing symptoms were recorded using participant's response to the Global Flushing Severity Score (GFSS), which assessed the overall severity of the flushing experience, using a scale of 0 (no symptom) to 10 (extreme). The number of days/week was derived as: 7\*(total number of days with GFSS ≥4 across Weeks 21-32 divided by the total number of days with nonmissing GFSS across the same period). The number of days/week with a GFSS ≥4 for each participant was listed in 1 of the following 6 categories: 0, \>0 to 0.5, \>0.5 to 1, \>1 to 2, \>2 to 3, and \>3 days per week.
Time frame: Week 21 to Week 32
Population: Analysis performed using the Full Analysis Set (FAS) population which included all randomized participants that did not have a withdrawal visit and/or did not have at least 1 GFSS score during the post-withdrawal period (Weeks 21 to 32).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ERN/LRPT | Number Participants With Days Per Week With Global Flushing Severity Score (GFSS) ≥4 Partitioned Into 6 Categories During the Postwithdrawal Period | 0 Days per week | 291 Participants |
| ERN/LRPT | Number Participants With Days Per Week With Global Flushing Severity Score (GFSS) ≥4 Partitioned Into 6 Categories During the Postwithdrawal Period | >0 to ≤ 0.5 Days per week | 43 Participants |
| ERN/LRPT | Number Participants With Days Per Week With Global Flushing Severity Score (GFSS) ≥4 Partitioned Into 6 Categories During the Postwithdrawal Period | >0.5 to ≤1 Days per week | 3 Participants |
| ERN/LRPT | Number Participants With Days Per Week With Global Flushing Severity Score (GFSS) ≥4 Partitioned Into 6 Categories During the Postwithdrawal Period | >1.0 to ≤2 Days per week | 8 Participants |
| ERN/LRPT | Number Participants With Days Per Week With Global Flushing Severity Score (GFSS) ≥4 Partitioned Into 6 Categories During the Postwithdrawal Period | >2 to ≤3 Days per week | 1 Participants |
| ERN/LRPT | Number Participants With Days Per Week With Global Flushing Severity Score (GFSS) ≥4 Partitioned Into 6 Categories During the Postwithdrawal Period | >3 Days per week | 16 Participants |
| ERN/LRPT Then ERN | Number Participants With Days Per Week With Global Flushing Severity Score (GFSS) ≥4 Partitioned Into 6 Categories During the Postwithdrawal Period | >3 Days per week | 20 Participants |
| ERN/LRPT Then ERN | Number Participants With Days Per Week With Global Flushing Severity Score (GFSS) ≥4 Partitioned Into 6 Categories During the Postwithdrawal Period | 0 Days per week | 181 Participants |
| ERN/LRPT Then ERN | Number Participants With Days Per Week With Global Flushing Severity Score (GFSS) ≥4 Partitioned Into 6 Categories During the Postwithdrawal Period | >1.0 to ≤2 Days per week | 30 Participants |
| ERN/LRPT Then ERN | Number Participants With Days Per Week With Global Flushing Severity Score (GFSS) ≥4 Partitioned Into 6 Categories During the Postwithdrawal Period | >2 to ≤3 Days per week | 17 Participants |
| ERN/LRPT Then ERN | Number Participants With Days Per Week With Global Flushing Severity Score (GFSS) ≥4 Partitioned Into 6 Categories During the Postwithdrawal Period | >0 to ≤ 0.5 Days per week | 74 Participants |
| ERN/LRPT Then ERN | Number Participants With Days Per Week With Global Flushing Severity Score (GFSS) ≥4 Partitioned Into 6 Categories During the Postwithdrawal Period | >0.5 to ≤1 Days per week | 32 Participants |
| Placebo | Number Participants With Days Per Week With Global Flushing Severity Score (GFSS) ≥4 Partitioned Into 6 Categories During the Postwithdrawal Period | >0 to ≤ 0.5 Days per week | 7 Participants |
| Placebo | Number Participants With Days Per Week With Global Flushing Severity Score (GFSS) ≥4 Partitioned Into 6 Categories During the Postwithdrawal Period | >0.5 to ≤1 Days per week | 4 Participants |
| Placebo | Number Participants With Days Per Week With Global Flushing Severity Score (GFSS) ≥4 Partitioned Into 6 Categories During the Postwithdrawal Period | >3 Days per week | 4 Participants |
| Placebo | Number Participants With Days Per Week With Global Flushing Severity Score (GFSS) ≥4 Partitioned Into 6 Categories During the Postwithdrawal Period | >1.0 to ≤2 Days per week | 3 Participants |
| Placebo | Number Participants With Days Per Week With Global Flushing Severity Score (GFSS) ≥4 Partitioned Into 6 Categories During the Postwithdrawal Period | 0 Days per week | 188 Participants |
| Placebo | Number Participants With Days Per Week With Global Flushing Severity Score (GFSS) ≥4 Partitioned Into 6 Categories During the Postwithdrawal Period | >2 to ≤3 Days per week | 1 Participants |
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Number of Participants With Maximum GFSS ≥4 During the Post-withdrawal Period
Flushing symptoms were recorded using participant's response to the Global Flushing Severity Score (GFSS), which assesses the overall severity of the flushing experience (including redness, warmth, tingling, or itching) using a scale with response categories of None, Mild, Moderate, Severe, and Extreme. The categories were supplemented with numbers 0 to 10 to allow for greater precision within each category (None=0, Mild=1-3, Moderate=4-6, Severe=7-9, Extreme=10). The daily response was recorded in the morning, and reflected the symptoms experienced during the previous 24 hours.
Time frame: Week 21 to Week 32
Population: Analysis performed using the Full Analysis Set (FAS) population which included all randomized participants that did not have a withdrawal visit and/or did not have at least 1 GFSS score during the post-withdrawal period (Weeks 21 to 32).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ERN/LRPT | Number of Participants With Maximum GFSS ≥4 During the Post-withdrawal Period | 71 Participants |
| ERN/LRPT Then ERN | Number of Participants With Maximum GFSS ≥4 During the Post-withdrawal Period | 173 Participants |
| Placebo | Number of Participants With Maximum GFSS ≥4 During the Post-withdrawal Period | 19 Participants |
p-value: <0.001Unconditional Miettinen and Nurminen