Hypercholesterolemia
Conditions
Brief summary
The purpose of this study is to evaluate the potential effects of ER niacin/laropiprant, ER niacin, laropiprant, and placebo over the course of seven days on urinary levels of a metabolite of thromboxane A2 (TxA2), as a marker of in vivo platelet reactivity.
Interventions
DRUGComparator: niacin + laropiprant
ER niacin 2 g/laropiprant 40 mg tablet once daily for 7 days
DRUGComparator: niacin
ER niacin 2 g tablet once daily for 7 days
laropiprant 40 mg once daily for 7 days
DRUGComparator: placebo
matching placebo tablets for each of the interventions once daily for 7 days
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Female subjects may not be pregnant and/or will agree to use appropriate method of contraception beginning at least 2 weeks prior to administration of the first dose of study drug in the first treatment period, throughout the study and until at least 2 weeks after administration of the last dose of study drug in the last treatment period. * Subject is judged to be in good health based on medical history, physical examination, vital sign measurements, and laboratory safety tests performed at the prestudy (screening) visit and/or prior to administration of the initial dose of study drug. * Subject has no clinically significant abnormality on electrocardiogram (ECG) performed at the prestudy (screening) visit and/or prior to administration of the initial dose of study drug. * Subject has been a nonsmoker and/or has not used nicotine or nicotine-containing products for at least approximately 6 months; subjects who have discontinued smoking or the use of nicotine/nicotine containing products for at least approximately 3 months may be enrolled in the study at the discretion of the investigator
Exclusion criteria
* Subject is mentally or legally incapacitated, has significant emotional problems at the time of prestudy (screening) visit or expected during the conduct of the study or has a history of a clinically significant psychiatric disorder over the last 5 to 10 years. - Subjects who have had situational depression may be enrolled in the study at the discretion of the investigator. * Subject has a history of stroke, chronic seizures, or major neurological disorder. * Subject has a history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases. * Subject has a history of neoplastic disease (including leukemia, lymphoma, malignant melanoma), or myeloproliferative disease, regardless of the time since treatment. * Subject has history of a thrombotic or platelet related disorder including prior deep venous thrombosis. Subject is being treated with coumadin, heparin, clopidogrel has used these agents within 2 weeks of screening. Subject is being treated with aspirin or has used this agent within 3 weeks prior to administration of screening. * Subject is unable to refrain from or anticipates the use of any medication, including prescription and non- prescription drugs or herbal remedies beginning approximately 2 weeks prior to administration of the initial dose of study drug, throughout the study until the poststudy visit. * Subject consumes excessive amounts of alcohol, defined as greater than 3 glasses, of alcoholic beverages or distilled spirits per day. * Subject consumes excessive amounts, defined as greater than 6 servings, of coffee, tea, cola, or other caffeinated beverages per day. * Subject has had major surgery, donated or lost 1 unit of blood (approximately 500 mL) or participated in another investigational study within 4 weeks prior to the prestudy (screening) visit. * Subject has a history of significant multiple and/or severe allergies, or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food. * Subject is currently a regular user of any illicit drugs or has a history of drug (including alcohol) abuse within approximately 6 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Urinary 11-dehydrothromboxane B2 (11-dTxB2) | On Day 7 across the 24-hour urinary collection period. | The creatinine-normalized urine levels of 11-dTxB2 on Day 7 following a 7 day course of daily dosing in the overall 24 hour collection interval. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Prostaglandin I Metabolite (PGI-M) | On Day 7 across the 24-hour urinary collection period. | The creatinine-normalized urine levels of PGI-M in the overall 24 hour collection interval following administration on Day 7. |
Participant flow
Recruitment details
Phase I First Patient Entered 16 Aug 2007. Study conducted at Comprehensive Phase One, Miramar, FL. and Cedra Clinical Research LLC, San Antonio, TX.
Participants by arm
| Arm | Count |
|---|---|
| Totals for Study All participants in the study. | 26 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Period 1 | Adverse Event | 1 | 0 | 0 | 1 |
| Period 2 | Withdrawal by Subject | 0 | 0 | 0 | 1 |
| Period 3 | Withdrawal by Subject | 1 | 0 | 0 | 0 |
| Period 4 | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Totals for Study |
|---|---|
| Age, Continuous | 48.1 years STANDARD_DEVIATION 11.6 |
| Height | 165.5 cm |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 12 Participants |
| urinary 11-dTxB2 | 418.5 pg/mg creatinine |
| urinary PGI2-Metabolite | 89.7 pg/mg creatinine |
| Weight | 78.4 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 15 / 25 | 21 / 24 | 4 / 25 | 5 / 25 |
| serious Total, serious adverse events | 0 / 25 | 0 / 24 | 0 / 25 | 0 / 25 |
Outcome results
Primary
Urinary 11-dehydrothromboxane B2 (11-dTxB2)
The creatinine-normalized urine levels of 11-dTxB2 on Day 7 following a 7 day course of daily dosing in the overall 24 hour collection interval.
Time frame: On Day 7 across the 24-hour urinary collection period.
Population: Twenty-six (26) subjects (including replacements) were enrolled in this study. All available subjects (besides the 4 that were excluded due suspected NSAID/Aspirin use) and had partial data (at least one available period) were included in the statistical analysis models/comparisons.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ER Niacin 2 g / Laropiprant 40 mg | Urinary 11-dehydrothromboxane B2 (11-dTxB2) | 414.6 pg/mg creatinine |
| ER Niacin 2 g | Urinary 11-dehydrothromboxane B2 (11-dTxB2) | 371.6 pg/mg creatinine |
| Laropiprant 40 mg | Urinary 11-dehydrothromboxane B2 (11-dTxB2) | 407.3 pg/mg creatinine |
| Placebo | Urinary 11-dehydrothromboxane B2 (11-dTxB2) | 466.1 pg/mg creatinine |
Comparison: The endpoint is the urine levels of 11-dTxB2 on Day 7 following a 7 day course of daily dosing in the overall 24 hour collection interval. The point estimate and 90% confidence intervals (CIs) were calculated for the geometric mean ratio (GMR) \[Treatment A/B\] of the urine levels of 11-dTxB2 on Day 7.90% CI: [0.9, 1.38]
90% CI: [0.71, 1.07]
90% CI: [0.65, 0.98]
90% CI: [0.72, 1.09]
90% CI: [0.74, 1.12]
90% CI: [0.83, 1.25]
Secondary
Prostaglandin I Metabolite (PGI-M)
The creatinine-normalized urine levels of PGI-M in the overall 24 hour collection interval following administration on Day 7.
Time frame: On Day 7 across the 24-hour urinary collection period.
Population: Twenty-six (26) subjects (including replacements) were enrolled in this study. All available subjects (besides the 4 that were excluded due suspected NSAID/Aspirin use) and had partial data (at least one available period) were included in the statistical analysis models/comparisons.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ER Niacin 2 g / Laropiprant 40 mg | Prostaglandin I Metabolite (PGI-M) | 73.5 pg/mg creatinine |
| ER Niacin 2 g | Prostaglandin I Metabolite (PGI-M) | 70.9 pg/mg creatinine |
| Laropiprant 40 mg | Prostaglandin I Metabolite (PGI-M) | 114.5 pg/mg creatinine |
| Placebo | Prostaglandin I Metabolite (PGI-M) | 127.5 pg/mg creatinine |
90% CI: [0.92, 1.17]
90% CI: [0.8, 1.01]
90% CI: [0.49, 0.63]
90% CI: [0.51, 0.65]
90% CI: [0.55, 0.7]
90% CI: [0.57, 0.72]