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

Lp-PLA2, Progenitor Cells and Coronary Atherosclerosis in Humans AIM III

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.

Study Overview

• Status: Completed
• Conditions: Endothelial Dysfunction
• Intervention / Treatment: Drug: darapladib; Drug: placebo

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 Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change in Coronary Artery Diameter	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.	baseline, six months
Percentage Change in Coronary Blood Flow (CBF)	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.	baseline, six months

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); GlaxoSmithKline; National Institute on Aging (NIA)

Publications and helpful links

General Publications

• Prasad M, Lennon R, Barsness GW, Prasad A, Gulati R, Lerman LO, Lerman A. Chronic inhibition of lipoprotein-associated phospholipase A2 does not improve coronary endothelial function: A prospective, randomized-controlled trial. Int J Cardiol. 2018 Feb 15;253:7-13. doi: 10.1016/j.ijcard.2017.09.171.

Study record dates

Study Major Dates

• Study Start: February 4, 2010
• Primary Completion (Actual): November 1, 2015
• Study Completion (Actual): November 1, 2015

Study Registration Dates

• First Submitted: February 9, 2010
• First Submitted That Met QC Criteria: February 10, 2010
• First Posted (Estimate): February 11, 2010

Study Record Updates

• Last Update Posted (Actual): April 18, 2017
• Last Update Submitted That Met QC Criteria: March 22, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: coronary endothelial dysfunction; coronary vasospasm
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Phospholipase A2 Inhibitors; Darapladib
• Other Study ID Numbers: 10-000044; 5R01HL092954 (U.S. NIH Grant/Contract); 5R01AG031750 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No