Lipoprotein-associated Phospholipase A2 (Lp-PLA2) Progenitor Cells and Coronary Atherosclerosis in Humans
Condition: Endothelial Dysfunction
MeSH terms: Atherosclerosis
Intervention: darapladib; placebo
Intervention description: darapladib, tablet, 160 mg, by mouth, one time daily, 6 month duration; placebo, by mouth, once daily for six months
Intervention MeSH terms: Darapladib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 70.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: coronary endothelial dysfunction; coronary vasospasm

Summary:

      AIM III is a prospective, randomized, double-blinded, placebo controlled trial. The study is
      directly connected to IRB 08-008161 as a specific aim of the National Institute of Health
      (NIH) grant. Participants may either consent to and qualify for AIM I and AIM II (IRB
      08-008161) or have a cardiac catheterization with acetylcholine testing in the Cardiac
      Catheterization Laboratory at Mayo Clinic in Rochester, Minnesota to be considered for this
      study.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients undergoing coronary angiography including endothelial function testing with
             the medication acetylcholine in the cardiac catheterization laboratory at Mayo Clinic.
             Patients may be enrolled in AIM I and AIM II IRB 08-008161 :Lp-PLA2, Progenitor Cells
             and Atherosclerosis in Humans".

          2. Male or female aged at least 18 years, inclusive, at screening. Female subjects must
             be post-menopausal or using a highly effective method for avoidance of pregnancy. The
             decision to include or exclude women of childbearing potential may be made at the
             discretion of the investigator in accordance with local practice in relation to
             adequate contraception.

          3. Age greater than 18 up to age 85

        Exclusion Criteria:

          1. Current severe heart failure New York Heart Association class III or IV with ejection
             fraction less than 40%

          2. Unstable angina

          3. Myocardial infarction or angioplasty within 6 months prior to entry into the study

          4. Planned coronary revascularization (PCI or CABG)

          5. Planned major surgical procedure

          6. Patients with segments with endothelial dysfunction of less than 10 mm in length or
             complete occlusion will be excluded.

          7. Angiographic exclusion criteria include left main disease with greater than 30%
             stenosis on angiogram, luminal diameter of the study vessel less than 2.5 mm, severe
             tortuousity of the study vessel, or any other relevant anatomical reasons that the
             investigator deems inappropriate for the study.

          8. Current liver disease, known hepatic or biliary abnormalities (with the exception of
             Gilbert's syndrome or asymptomatic gallstones) or evidence of abnormal liver function
             tests (total bilirubin or alkaline phosphatase > 1.5 x upper limit of normal (UNL); or
             alanine transaminase (ALT) or aspartate amino transferase (AST) > 2.5 x UNL or other
             hepatic abnormalities that in the opinion of the investigator would preclude the
             subject from participation in the study.

          9. Chronic or acute kidney disease with serum creatinine greater than or equal to 2 mg/dL
             or estimated glomerular filtration rate <40 mL/min/1.73m2, renal transplant status,
             history of contrast nephropathy,

         10. Poorly controlled hypertension despite lifestyle modifications and pharmacotherapy.
             (systolic BP >160 mm Hg and/or diastolic BP >110 mm Hg),

         11. Poorly controlled diabetes mellitus (HbA1c >10%),

         12. Current or within 1 month use of any form of corticosteroids,

         13. Severe asthma that is poorly controlled on pharmacotherapy

         14. History of anaphylaxis, anaphylactoid (resembling anaphylaxis) reactions

         15. Current life-threatening conditions other than vascular disease, alcohol or drug abuse
             within the last 6 months

         16. Malignancy within the past 5 years,

         17. Positive pregnancy test (all female subjects of childbearing potential must have a
             urine β-human chorionic gonadotropin (hCG) pregnancy test performed at Screening
             and/or within 7 days prior to randomization) or is known to be pregnant or lactating.

         18. Current or planned chronic administration of strong oral or injectable cytochrome
             P-450 isoenzyme 3A4 (CYP3A4) inhibitors.

         19. Subjects with both parents of Japanese, Chinese, or Korean ancestry must have a blood
             sample collected for assessment of Lp-PLA2 activity by the central laboratory prior to
             randomization. Those with Lp-PLA2 activity ≤10 nmol/min/mL will be excluded from
             participation in the study.

         20. Previous exposure to darapladib (SB-480848).

         21. Use of an investigational device or investigational drug within 30 days or 5
             half-lives (whichever is longer) preceding the first dose of the study medication, or
             any subject the investigator deems unsuitable for the study

         22. Patients who require treatment with positive inotropic agents other than digoxin
             during the study

         23. Patients with cerebrovascular accident within 6 months prior to entry into the study

         24. Significant endocrine, hepatic or renal disorders

         25. Local or systemic infectious disease within 4 weeks prior to entry into study

         26. Mental instability

         27. Federal Medical Center inmates

         28. Hemoglobin less than 12 mg/dL