Carotid Atherosclerosis
Conditions
Brief summary
This study will examine the effect of statin and niacin therapy on carotid plaque biomarkers
Interventions
DRUGAtorvastatin/niacin extended-release
80 mg tablet atorvastatin once daily, 10 mg tablet placebo to atorvastatin once daily, and niacin extended-release tablet starting at 500 mg daily and titrating to 2g daily. Treatment will be from 4 to 12 weeks.
DRUGAtorvastatin
10 mg tablet atorvastatin once daily, 80 mg tablet placebo to atorvastatin once daily, and placebo to niacin extended-release tablet starting at 500 mg daily and titrating to 2g daily. Treatment will be from 4 to 12 weeks.
DRUGSimvastatin
(Russia and Brazil) 80 mg tablet simvastatin once daily, 10 mg tablet placebo to simvastatin once daily, and niacin extended-release tablet starting at 500 mg daily and titrating to 2g daily. Treatment will be from 4 to 12 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 90 Years
Healthy volunteers
No
Inclusion criteria
* Patient is diagnosed with carotid stenosis AND is scheduled to undergo carotid endarterectomy * Female patients of reproductive potential must abstain from sex or use an acceptable method of birth control through out the study
Exclusion criteria
* Patient must undergo CEA less than 4 weeks after entering study * Patient has recent history of acute coronary syndrome * Patient has has coronary artery bypass graft surgery within 30 days of study start * Patient has thyroid disease that has not been treated for more than 6 weeks * Patient has donated blood within 8 weeks of study start * Patient has poorly controlled diabetes mellitis * Patient has human immunodeficiency virus (HIV) or Hepatitis B or C * Patient is taking warfarin or other anticoagulants * Patient is taking hormone replacement therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite Score of Plaque Inflammation/Stability Gene Expression as Assayed by Ribonucleic Acid (RNA) Taqman Analysis | At time of carotid endarterectomy (after 4 to 12 weeks of dosing) | Excised carotid plaques were evaluated for the gene expression of 60 biomarkers associated with inflammation (Hot biomarkers) & 25 biomarkers associated with stability (Cold biomarkers). Each biomarker was assayed using a quantitative polymerase chain reaction method and results were reported as a Cycle Threshold, (Ct). A Composite Score was calculated by averaging the Ct for each of the 25 cold genes, and subtracting the average Ct for the 60 hot genes. A higher composite score was associated with greater inflammation and a lower score was associated with stability (non-inflamed). |
| Plaque Instability Protein Composite Score | At time of carotid endarterectomy (after 4 to 12 weeks of dosing) | Each excised plaque was analyzed using an assay of 20 proteins that reflect plaque composition and inflammation. Each protein was assigned scaled signs, with a lower (negative) sign associated with plaque stability and a higher (positive) sign associated with plaque inflammation/instability. The Composite Score was the average amounts of all the 20 proteins with their associated signs. A higher Composite Score is associated with more plaque instability. |
| Total Cholesterol and Free Cholesterol Measured by Enzymatic Chromogenic Assay | At time of carotid endarterectomy (after 4 to 12 weeks of dosing) | Cholesterol ester was to be calculated by the following formula: Cholesterol Ester = Total Cholesterol - Free Cholesterol. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Statin 80 mg + Niacin ER Participants in Russia and Brasil will receive 80 mg Simvastatin + niacin. All other participants will receive 80 mg Atorvastatin + niacin. | 50 |
| Statin 10 mg Participants in Russia and Brasil will receive 10 mg Simvastatin. All other participants will receive 10 mg Atorvastatin. | 50 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 5 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Statin 80 mg + Niacin ER | Statin 10 mg | Total |
|---|---|---|---|
| Age, Continuous | 69.68 years STANDARD_DEVIATION 9.42 | 69.20 years STANDARD_DEVIATION 8.63 | 69.47 years STANDARD_DEVIATION 8.99 |
| Sex: Female, Male Female | 15 Participants | 17 Participants | 32 Participants |
| Sex: Female, Male Male | 35 Participants | 33 Participants | 68 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 50 | 2 / 50 |
| serious Total, serious adverse events | 9 / 50 | 7 / 50 |
Outcome results
Primary
Composite Score of Plaque Inflammation/Stability Gene Expression as Assayed by Ribonucleic Acid (RNA) Taqman Analysis
Excised carotid plaques were evaluated for the gene expression of 60 biomarkers associated with inflammation (Hot biomarkers) & 25 biomarkers associated with stability (Cold biomarkers). Each biomarker was assayed using a quantitative polymerase chain reaction method and results were reported as a Cycle Threshold, (Ct). A Composite Score was calculated by averaging the Ct for each of the 25 cold genes, and subtracting the average Ct for the 60 hot genes. A higher composite score was associated with greater inflammation and a lower score was associated with stability (non-inflamed).
Time frame: At time of carotid endarterectomy (after 4 to 12 weeks of dosing)
Population: Only participants who completed the study, had evaluable plaque samples and were at least 80% compliant with dosing schedule were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Statin 80 mg + Niacin Extended-release (ER) | Composite Score of Plaque Inflammation/Stability Gene Expression as Assayed by Ribonucleic Acid (RNA) Taqman Analysis | 1.36 Cycle threshold (Ct) | Standard Deviation 1.17 |
| Statin 10 mg | Composite Score of Plaque Inflammation/Stability Gene Expression as Assayed by Ribonucleic Acid (RNA) Taqman Analysis | 0.82 Cycle threshold (Ct) | Standard Deviation 1.33 |
p-value: 0.81190% CI: [-0.24, 0.78]ANOVA
Primary
Plaque Instability Protein Composite Score
Each excised plaque was analyzed using an assay of 20 proteins that reflect plaque composition and inflammation. Each protein was assigned scaled signs, with a lower (negative) sign associated with plaque stability and a higher (positive) sign associated with plaque inflammation/instability. The Composite Score was the average amounts of all the 20 proteins with their associated signs. A higher Composite Score is associated with more plaque instability.
Time frame: At time of carotid endarterectomy (after 4 to 12 weeks of dosing)
Population: Only participants who completed the study, had evaluable plaque samples and were at least 80% compliant with dosing schedule were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Statin 80 mg + Niacin Extended-release (ER) | Plaque Instability Protein Composite Score | -7.19 Score | Standard Deviation 10.45 |
| Statin 10 mg | Plaque Instability Protein Composite Score | -10.48 Score | Standard Deviation 11.7 |
p-value: 0.89890% CI: [-1.09, 8.36]ANOVA
Primary
Total Cholesterol and Free Cholesterol Measured by Enzymatic Chromogenic Assay
Cholesterol ester was to be calculated by the following formula: Cholesterol Ester = Total Cholesterol - Free Cholesterol.
Time frame: At time of carotid endarterectomy (after 4 to 12 weeks of dosing)
Population: Only participants who completed the study, had evaluable plaque samples and were at least 80% compliant with dosing schedule were to be included in the analysis. This was not performed due to technical concerns. Instead, the cholesterol content determination, if performed, will use mass spectrometry approach and would be an exploratory objective.