Plasma and Platelet microRNAs in Clopidogrel Low Response Patients

Coronary Artery Disease Clinical Trial

— PPRC  

Official title:

The Association Between Plasma or Platelet microRNAs and Clopidogrel Low Response and Its Mechanism

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02447809
• Other study ID #: 004
• Status: Recruiting
• Phase: Phase 4
• First received: May 5, 2015
• Last updated: February 11, 2016
• Start date: January 2015
• Est. completion date: December 2016

Study information

• Verified date: February 2016
• Source: The First Affiliated Hospital with Nanjing Medical University
• Contact: Chunjian Li, Ph.D
• Phone: +86-25-83718836
• Email: lijay[@]njmu.edu.cn
• Is FDA regulated: No
• Health authority: China: Ethics CommitteeChina: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

Clopidogrel is an important anti-platelet agent.However, about 30% of the coronary artery disease patients presented clopidogrel low response (CLR).Previous studies showed that the cardiovascular event ratio of the CLR patients was 4.4 times of the normal responders.

It is known that the plasma and platelet miRNAs are determined by different disease status when platelets are released from the megakaryocyte, and the platelet miRNAs can adjust the expressions of the platelet's receptors and proteins.The purpose of this study is to find multiple platelet miRNAs involved in the development of CLR, and platelet miRNAs cause CLR through adjusting the expressions of the key receptors and proteins in the ADP activating pathway and consequently reducing their responses to clopidogrel.

The CLR will be detected by light transmission aggregometry (LTA) and vasodilator-stimulated phosphoprotein phosphorylation (VASP-P). Differential expressions of plasma and platelet miRNAs profile in CLR patients will be screened by deep sequencing and validated to investigate the association between plasma and platelet miRNAs profile and CLR as well as the patients' prognosis.The study results would serve as markers for individualized anti-platelet treatment, and supply new targets for the treatment of coronary artery disease.

Description:

A multiphase, case-control study was designed to identify plasma and platelet miRNAs as surrogate markers for CLR .

All patients take 300mg loading dose clopidogrel plus 100mg daily ASA and 75mg daily clopidogrel after admission. Patients are recruited after percutaneous coronary intervention (PCI). Light transmittancy aggregation (LTA) in response to 5μM ADP is to measured 5 days after taking the loading dose clopidogrel.Than CLR patients were selected.

In the initial biomarker-screening stage, plasma and platelet samples from 20 CLR patients and 20 controls underwent Solexa sequencing to identify miRNAs that showed significant differences between the CLR cases and matched controls.

Subsequently,we performed a biomarker confirmation analysis with a hydrolysis probe-based RT-qPCR assay to refine the number of plasma and platelet miRNAs in the CLR signature. This analysis was carried out in 2 phases: (a) the biomarker-selection phase, in which plasma and platelet samples from 20 CLR patients and 20 control individuals formed the training set, and (b) the biomarker-validation phase, in which plasma and platelet samples from an additional 80 CLR patients and 80 controls formed the validation set.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. completion date: December 2016
• Est. primary completion date: December 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Patients who receive stent implantation;

• Patients who take 100mg daily ASA and 75mg daily clopidogrel

• Patient age >18 years and <80 years old;

• Signed inform consent

Exclusion Criteria:

• Allergy or intolerance to ASA,clopidogrel;

• Patients who are planning to take warfarin or drugs that potentially could interfere with the anti-platelet effects of ASA,clopidogrel.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Single Blind (Subject), Primary Purpose: Diagnostic

Related Conditions & MeSH terms

• Coronary Artery Disease
• Coronary Disease
• Myocardial Ischemia

Intervention

Drug:
• Clopidogrel
(ASA 100mg daily and Clopidogre 75mg daily)* 12 month.
• acetylsalicylic acid (ASA)

Locations

Country	Name	City	State
China	First Affiliated Hospital of Nanjing Medical University	Nanjing	Jiangsu

Sponsors (2)

Lead Sponsor	Collaborator
The First Affiliated Hospital with Nanjing Medical University	National Natural Science Foundation of China

Country where clinical trial is conducted

China, 

References & Publications (12)

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Clancy L, Freedman JE. New paradigms in thrombosis: novel mediators and biomarkers platelet RNA transfer. J Thromb Thrombolysis. 2014 Jan;37(1):12-6. doi: 10.1007/s11239-013-1001-1. Review. — View Citation

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Hu Z, Chen X, Zhao Y, Tian T, Jin G, Shu Y, Chen Y, Xu L, Zen K, Zhang C, Shen H. Serum microRNA signatures identified in a genome-wide serum microRNA expression profiling predict survival of non-small-cell lung cancer. J Clin Oncol. 2010 Apr 1;28(10):1721-6. doi: 10.1200/JCO.2009.24.9342. Epub 2010 Mar 1. — View Citation

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Li C, Fang Z, Jiang T, Zhang Q, Liu C, Zhang C, Xiang Y. Serum microRNAs profile from genome-wide serves as a fingerprint for diagnosis of acute myocardial infarction and angina pectoris. BMC Med Genomics. 2013 May 4;6:16. doi: 10.1186/1755-8794-6-16. — View Citation

Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O'Briant KC, Allen A, Lin DW, Urban N, Drescher CW, Knudsen BS, Stirewalt DL, Gentleman R, Vessella RL, Nelson PS, Martin DB, Tewari M. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10513-8. doi: 10.1073/pnas.0804549105. Epub 2008 Jul 28. — View Citation

Nagalla S, Shaw C, Kong X, Kondkar AA, Edelstein LC, Ma L, Chen J, McKnight GS, López JA, Yang L, Jin Y, Bray MS, Leal SM, Dong JF, Bray PF. Platelet microRNA-mRNA coexpression profiles correlate with platelet reactivity. Blood. 2011 May 12;117(19):5189-97. doi: 10.1182/blood-2010-09-299719. Epub 2011 Mar 17. — View Citation

Siller-Matula JM, Trenk D, Schrör K, Gawaz M, Kristensen SD, Storey RF, Huber K; EPA (European Platelet Academy). Response variability to P2Y12 receptor inhibitors: expectations and reality. JACC Cardiovasc Interv. 2013 Nov;6(11):1111-28. doi: 10.1016/j.jcin.2013.06.011. Review. — View Citation

Song MA, Paradis AN, Gay MS, Shin J, Zhang L. Differential expression of microRNAs in ischemic heart disease. Drug Discov Today. 2015 Feb;20(2):223-35. doi: 10.1016/j.drudis.2014.10.004. Epub 2014 Oct 23. Review. — View Citation

Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001 Aug 16;345(7):494-502. Erratum in: N Engl J Med 2001 Nov 15;345(20):1506. N Engl J Med 2001 Dec 6;345(23):1716. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Bleeding	1-month and 1-year minor,moderate and major bleeding	1-month and 1-year after recruited	Yes
Primary	The expressions of miRNAs profile	Two pools of plasma and platelet were collected from participants separately. The total RNA of each pool was extracted by using Trizol Reagent. An initial screening of miRNAs expression was performed by Solexa sequencing. And differential expression was validated using RT-qPCR in individuals samples.	5-days After recruited	No
Secondary	Clinical efficacy	1-month and 1-year death,non-fatal myocardial infarction,ischemic stroke,revascularization and stent thrombosis(ARC definition)	1-month and 1-year after recruited	No