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Lipoprotein-associated Phospholipase A2 (Lp-PLA2) Progenitor Cells and Coronary Atherosclerosis in Humans

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ClinicalTrials.gov Identifier: NCT01067339
Recruitment Status : Completed
First Posted : February 11, 2010
Results First Posted : March 15, 2017
Last Update Posted : April 18, 2017
Information provided by (Responsible Party):

Study Description
Brief 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.

Condition or disease Intervention/treatment Phase
Endothelial Dysfunction Drug: darapladib Drug: placebo Phase 3

Detailed Description:
The main goal of AIM III is to assess and quantify the effect of long-term administration of darapladib 160 mg once a day, a selective, reversible, orally active inhibitor of plasma and vascular Lp-PLA2, on coronary endothelial function, progression of coronary atherosclerosis as determined by intravascular ultrasound (IVUS), and atherosclerosis in patients with early atherosclerosis. Patients with evidence of coronary endothelial dysfunction, as determined by intracoronary administration of acetylcholine during angiography and IVUS, will be followed for 6 months during once daily dosing of darapladib. Coronary endothelial function is determined by the changes in coronary artery diameter and coronary blood flow response to the intracoronary administration of acetylcholine and adenosine. The patients will be followed in clinic 6 months. They will have follow-up angiography, assessment of endothelial function, and IVUS during the six month visit.

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Lp-PLA2, Progenitor Cells and Coronary Atherosclerosis in Humans AIM III
Study Start Date : February 4, 2010
Primary Completion Date : November 2015
Study Completion Date : November 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Atherosclerosis
U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: Darapladib
Subjects randomized to this arm will receive a darapladib tablet, 160 mg, by mouth, once per day for 6 months.
Drug: darapladib
darapladib, tablet, 160 mg, by mouth, one time daily, 6 month duration
Placebo Comparator: Placebo
Subjects randomized to this arm will receive a placebo tablet matching the study drug, once per day for 6 months.
Drug: placebo
placebo, by mouth, once daily for six months

Outcome Measures

Primary Outcome Measures :
  1. Percentage Change in Coronary Artery Diameter [ Time Frame: baseline, six months ]
    The change of coronary artery diameter was measured in response to a maximal dose of acetylcholine administered intracoronary during an invasive coronary endothelial function assessment. Percentage change in coronary artery diameter provides a measure of endothelium dependent epicardial function.

  2. Percentage Change in Coronary Blood Flow (CBF) [ Time Frame: baseline, six months ]
    The change in coronary blood flow was measured in response to maximal dose of acetylcholine administered intracoronary during an invasive coronary endothelial function assessment. Percentage change in coronary blood flow provides a measure of endothelium dependent microvascular function.

Eligibility Criteria

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01067339

United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
National Heart, Lung, and Blood Institute (NHLBI)
National Institute on Aging (NIA)
Principal Investigator: Amir Lerman, MD Mayo Clinic
More Information

Responsible Party: Amir Lerman, Professor of Medicine, Mayo Clinic
ClinicalTrials.gov Identifier: NCT01067339     History of Changes
Other Study ID Numbers: 10-000044
5R01HL092954 ( U.S. NIH Grant/Contract )
5R01AG031750 ( U.S. NIH Grant/Contract )
First Posted: February 11, 2010    Key Record Dates
Results First Posted: March 15, 2017
Last Update Posted: April 18, 2017
Last Verified: March 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Amir Lerman, Mayo Clinic:
coronary endothelial dysfunction
coronary vasospasm

Additional relevant MeSH terms:
Arterial Occlusive Diseases
Vascular Diseases
Cardiovascular Diseases
Phospholipase A2 Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action