Type 2 Diabetes Mellitus
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 specific metabolite (which is a marker of in vivo platelet reactivity).
Detailed description
Subjects will receive 1 of 4 treatments per period and will eventually receive all 4 treatments: Treatment A: ER niacin 2g/laropiprant 40 mg daily + Placebo to laropiprant for 7 days Treatment B: ER niacin 2 g daily + Placebo to laropiprant for 7 days Treatment C: laropiprant 40 mg daily + Placebo to ER niacin/laropiprant for 7 days Treatment D: placebo daily for 7 days. There will be at least a 7-day interval between dosing on Day 7 of a period and dosing on Day 1 of the subsequent period
Interventions
DRUGComparator: ER niacin (+) laropiprant
ER niacin 2 g/ laropiprant 40 mg daily for 7 days.
DRUGComparator: ER niacin
ER niacin 2 g daily for 7 days.
laropiprant 40 mg 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 has a history of T2DM either treated with diet and exercise alone or with metformin or a sulfonylurea * Subject is judged to be in good health (other than history of Type 2 diabetes mellitus) 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 * Subject has a history of stroke, chronic seizures, or major neurological disorder * Subject has a history of clinically significant endocrine (except for Type 2 diabetes mellitus), 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 blood or platelet related disorder including prior deep venous thrombosis. Subject is being treated with coumadin, heparin, clopidogrel or 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 (with the exception of metformin or sulfonylurea agents), including prescription and nonprescription drugs or herbal remedies beginning approximately 2 weeks until the post-study visit. No concomitant medications may be taken during the study * Subject consumes excessive amounts of alcohol, defined as greater than 3 glasses of alcoholic beverages, per day * Subject consumes excessive amounts, defined as greater than 6, 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 uses insulin, PPAR gamma agonists (rosiglitazone or pioglitazone), exenatide (Byetta), acarbose (Prandase, Precose) or dipeptidyl-peptidase 4 (DPP-4) inhibitors (JANUVIA™1)
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. | PGI-M in the Overall 24 Hour Collection Interval Following Administration on Day 7 |
Participant flow
Recruitment details
Phase I First Patient Enrolled 21 Aug 2007, First Patient Treated 7 Sept 2007. Study conducted at 3 centers: Arkansas Research Medical Testing, LLC, Little Rock, AR; Healthcare Discoveries Inc., San Antonio, TX; and Comprehensive Phase One, Fort Myers, FL. Merck's ER Niacin was used.
Pre-assignment details
Subjects were treated either w/diet and exercise alone, or with metformin, or a sulfonylurea, and had to be on stable meds for \>= 8 wks pre-study.
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 | 0 | 0 | 1 | 0 |
| Period 1 | Protocol Violation | 0 | 1 | 1 | 0 |
| Period 2 | Protocol Violation | 0 | 0 | 1 | 0 |
| Period 4 | Adverse Event | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Totals For Study |
|---|---|
| Age, Continuous | 55.3 years STANDARD_DEVIATION 6.7 |
| Height | 163.9 cm |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 12 Participants |
| urinary 11-dTxB2 | 639.1 pg/mg creatinine |
| urinary PGI2-Metabolite | 167.5 pg/mg creatinine |
| Weight | 85.9 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 | 17 / 23 | 23 / 25 | 12 / 23 | 11 / 22 |
| serious Total, serious adverse events | 0 / 23 | 1 / 25 | 0 / 23 | 0 / 22 |
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 2 that were excluded due to suspected NSAID/Aspirin use) who complied with the protocol and had partial data were included in the subsequent statistical analysis models/comparisons.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ER Niacin/Laropiprant | Urinary 11-Dehydrothromboxane B2 (11-dTxB2) | 525.3 pg/mg creatinine |
| ER Niacin | Urinary 11-Dehydrothromboxane B2 (11-dTxB2) | 540.8 pg/mg creatinine |
| Laropiprant | Urinary 11-Dehydrothromboxane B2 (11-dTxB2) | 585.3 pg/mg creatinine |
| Placebo | Urinary 11-Dehydrothromboxane B2 (11-dTxB2) | 625.1 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: [0.8, 1.18]
90% CI: [0.77, 1.14]
90% CI: [0.71, 1.05]
90% CI: [0.69, 1.02]
90% CI: [0.76, 1.13]
90% CI: [0.74, 1.09]
Secondary
Prostaglandin I Metabolite (PGI-M)
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 2 that were excluded due to suspected NSAID/Aspirin use) who complied with the protocol and had partial data were included in the subsequent statistical analysis models/comparisons.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ER Niacin/Laropiprant | Prostaglandin I Metabolite (PGI-M) | 90.1 pg/mg creatinine |
| ER Niacin | Prostaglandin I Metabolite (PGI-M) | 95.4 pg/mg creatinine |
| Laropiprant | Prostaglandin I Metabolite (PGI-M) | 158.5 pg/mg creatinine |
| Placebo | Prostaglandin I Metabolite (PGI-M) | 168.1 pg/mg creatinine |
90% CI: [0.84, 1.06]
90% CI: [0.84, 1.05]
90% CI: [0.51, 0.64]
90% CI: [0.48, 0.6]
90% CI: [0.54, 0.67]
90% CI: [0.51, 0.64]