Coronary Artery DiseasePhase 4PPRCNCT02447809
Plasma and Platelet microRNAs in Clopidogrel Low Response Patients
A Phase 4 study testing Clopidogrel and acetylsalicylic acid (ASA) in people with Coronary Artery Disease, run by The First Affiliated Hospital with Nanjing Medical University at 1 site in China.
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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Coronary Artery Disease
- What is being tested?
- Clopidogrel and acetylsalicylic acid (ASA)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 400 participants
- Where
- 1 siteChina
- Study dates
- Jan 2015to Dec 2016
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
China1 site, 1 recruiting
- Recruiting
First Affiliated Hospital of Nanjing Medical University
Nanjing, Jiangsu, 210029
Fuming Zhang, M.D., +86-25-83718836 ext. 6360, jsphkj@163.com
Yi Chai, M.D., +86-25-83718836 ext. 6360, jsphkj@163.com
About this study
Official title: The Association Between Plasma or Platelet microRNAs and Clopidogrel Low Response and Its Mechanism
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.
Read the detailed 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.
- Conditions
- Coronary Artery Disease
- Being tested
- Clopidogrel, acetylsalicylic acid (ASA)
- Keywords
- microRNA, Platelet, Clopidogrel low response
- Medical subject headings
- Coronary Artery Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ClopidogrelDrug
Also called Plavix
(ASA 100mg daily and Clopidogre 75mg daily)* 12 month.
acetylsalicylic acid (ASA)Drug
| Study group | Role | What they receive |
|---|---|---|
| Regular DAPT(IPA≤60%) | Experimental | ASA and Clopidogrel Receives: Drug: Clopidogrel; Drug: acetylsalicylic acid (ASA) |
| Regular DAPT(IPA>60%) | Active comparator | ASA and Clopidogrel Receives: Drug: Clopidogrel; Drug: acetylsalicylic acid (ASA) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 5-days After recruited
Secondary outcomes (1)
Clinical efficacy
1-month and 1-year death,non-fatal myocardial infarction,ischemic stroke,revascularization and stent thrombosis(ARC definition)
Measured: 1-month and 1-year after recruited
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 May 2015 (estimated)
- Study startJan 2015
- Primary completionDec 2016 (estimated)
- Study completionDec 2016 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Coronary Artery DiseaseStudies of the same condition, open and under way.
- More trials run by The First Affiliated Hospital with Nanjing Medical UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 400 participants (estimated)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Collaborators
- National Natural Science Foundation of China
- Responsible party
- Principal investigator, Chunjian Li, The First Affiliated Hospital with Nanjing Medical University
- Investigators
- Chunjian Li, Principal investigator, The First Affiliated Hospital with Nanjing Medical University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02447809
- Sponsor's protocol ID
- 004
- Acronym
- PPRC
- Status last verified
- Feb 2016
- First submitted
- 5 May 2015
- Last updated
- 15 Feb 2016
- Results posted
- No
- Data monitoring committee
- No
Publications
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. doi: 10.1056/NEJMoa010746.
PubMed 11519503Siller-Matula JM, Trenk D, Schror 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.
PubMed 24262612Calin GA, Croce CM. MicroRNA-cancer connection: the beginning of a new tale. Cancer Res. 2006 Aug 1;66(15):7390-4. doi: 10.1158/0008-5472.CAN-06-0800.
PubMed 16885332Hu 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.
PubMed 20194856Clancy 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.
PubMed 24163053Landry P, Plante I, Ouellet DL, Perron MP, Rousseau G, Provost P. Existence of a microRNA pathway in anucleate platelets. Nat Struct Mol Biol. 2009 Sep;16(9):961-6. doi: 10.1038/nsmb.1651. Epub 2009 Aug 9.
PubMed 19668211Dangelmaier C, Jin J, Smith JB, Kunapuli SP. Potentiation of thromboxane A2-induced platelet secretion by Gi signaling through the phosphoinositide-3 kinase pathway. Thromb Haemost. 2001 Feb;85(2):341-8.
PubMed 11246558Li 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.
PubMed 23641832Nagalla S, Shaw C, Kong X, Kondkar AA, Edelstein LC, Ma L, Chen J, McKnight GS, Lopez 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.
PubMed 21415270Katz MG, Fargnoli AS, Williams RD, Kendle AP, Steuerwald NM, Bridges CR. MiRNAs as potential molecular targets in heart failure. Future Cardiol. 2014 Nov;10(6):789-800. doi: 10.2217/fca.14.64.
PubMed 25495820Song 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.
PubMed 25461956Mitchell 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.
PubMed 18663219
Study at a glance
From the registry record, last updated by the sponsor on 15 Feb 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Association Between Plasma or Platelet microRNAs and Clopidogrel Low Response and Its Mechanism
- ClinicalTrials.gov ID
- NCT02447809
- Acronym / sponsor ID
- PPRC / 004
- Conditions
- Coronary Artery Disease
- Keywords
- microRNA, Platelet, Clopidogrel low response
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 400 participants (estimated)
- Lead sponsor
- The First Affiliated Hospital with Nanjing Medical UniversityUniversity, hospital or other
- Collaborators
- National Natural Science Foundation of China
- Study start
- Jan 2015
- Primary completion
- Dec 2016 (estimated)
- Study completion
- Dec 2016 (estimated)
- First posted
- 19 May 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed 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.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- Single blind (participant)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Regular DAPT(IPA≤60%) | Experimental | Drug: Clopidogrel, Drug: acetylsalicylic acid (ASA)ASA and Clopidogrel |
| Regular DAPT(IPA>60%) | Active comparator | Drug: Clopidogrel, Drug: acetylsalicylic acid (ASA)ASA and Clopidogrel |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (2 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ClopidogrelAlso: Plavix(ASA 100mg daily and Clopidogre 75mg daily)* 12 month. | Drug | Regular DAPT(IPA>60%), Regular DAPT(IPA≤60%) |
| acetylsalicylic acid (ASA) | Drug | Regular DAPT(IPA>60%), Regular DAPT(IPA≤60%) |
Primary outcome
The expressions of miRNAs profile
Time frame: 5-days After recruited
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.
1 secondary outcome
Clinical efficacy
Time frame: 1-month and 1-year after recruited
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Feb 2016.
- Background: PubMed 11519503Yusuf 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. doi: 10.1056/NEJMoa010746.
- Background: PubMed 24262612Siller-Matula JM, Trenk D, Schror 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.
- Background: PubMed 16885332Calin GA, Croce CM. MicroRNA-cancer connection: the beginning of a new tale. Cancer Res. 2006 Aug 1;66(15):7390-4. doi: 10.1158/0008-5472.CAN-06-0800.
- Background: PubMed 20194856Hu 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.
- Background: PubMed 24163053Clancy 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.
- Background: PubMed 19668211Landry P, Plante I, Ouellet DL, Perron MP, Rousseau G, Provost P. Existence of a microRNA pathway in anucleate platelets. Nat Struct Mol Biol. 2009 Sep;16(9):961-6. doi: 10.1038/nsmb.1651. Epub 2009 Aug 9.
- Background: PubMed 11246558Dangelmaier C, Jin J, Smith JB, Kunapuli SP. Potentiation of thromboxane A2-induced platelet secretion by Gi signaling through the phosphoinositide-3 kinase pathway. Thromb Haemost. 2001 Feb;85(2):341-8.
- Background: PubMed 23641832Li 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.
- Background: PubMed 21415270Nagalla S, Shaw C, Kong X, Kondkar AA, Edelstein LC, Ma L, Chen J, McKnight GS, Lopez 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.
- Background: PubMed 25495820Katz MG, Fargnoli AS, Williams RD, Kendle AP, Steuerwald NM, Bridges CR. MiRNAs as potential molecular targets in heart failure. Future Cardiol. 2014 Nov;10(6):789-800. doi: 10.2217/fca.14.64.
- Background: PubMed 25461956Song 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.
- Background: PubMed 18663219Mitchell 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Chunjian Li principal investigator
The First Affiliated Hospital with Nanjing Medical University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Clopidogrel and acetylsalicylic acid (ASA) in people with Coronary Artery Disease, run by The First Affiliated Hospital with Nanjing Medical University at 1 site in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 15 Feb 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Chunjian Li, Ph.D (+86-25-83718836 ext. 6018, lijay@njmu.edu.cn), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The expressions of miRNAs profile (time frame: 5-days After recruited). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02447809, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Feb 2016.