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Trial registered on ANZCTR


Registration number
ACTRN12615000709549
Ethics application status
Approved
Date submitted
18/06/2015
Date registered
9/07/2015
Date last updated
9/07/2015
Type of registration
Retrospectively registered

Titles & IDs
Public title
Double blind, placebo controlled randomised trial assessing the efficacy of endothelin-1 receptor antagonism in the prevention of microvascular injury in patients with non-ST elevation acute coronary syndrome (NSTEACS) undergoing percutaneous coronary intervention: the ENDORA-PCI trial
Scientific title
Double blind, placebo controlled randomised trial assessing the efficacy of endothelin-1 receptor antagonism against placebo in the prevention of microvascular injury in patients with non-ST elevation acute coronary syndrome (NSTEACS) undergoing percutaneous coronary intervention: the ENDORA-PCI trial
Secondary ID [1] 286934 0
Nil
Universal Trial Number (UTN)
U1111-1171-3407
Trial acronym
ENDORA-PCI
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Peri-procedural myocardial injury/infarction
 295360 0
Non-ST elevation acute coronary syndrome (NSTEACS) 295452 0
Condition category
Condition code
Cardiovascular 295627 295627 0 0
Coronary heart disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Ambrisentan, endothelin receptor antagonist, oral tablet, 10mg daily

Patients randomised to the ambrisentan arm will be given 10mg of ambrisentan along with standard medical therapy immediately after randomisation. Further doses of ambrisentan will be administered if the standard dosing interval (24 hours) is exceeded between the preceding dose and planned PCI. The total dose of medications given to the patients will be dictated by the number of days between patients' initial presentation and their PCI procedure. There is no set maximum of total dose.
Intervention code [1] 292128 0
Prevention
Intervention code [2] 292197 0
Treatment: Drugs
Comparator / control treatment
Lactose tablet

The tablets will be packaged into generic size 00 gelatin capsule acquired from the pharmacy such that the treatment and placebo will appear the same.
Control group
Placebo

Outcomes
Primary outcome [1] 295344 0
The primary outcome is the peri-procedural change in index of microvascular resistance (IMR) as measured by thermodiluation curves.

Measurement of IMR will be carried out before and after PCI. Before commencement of PCI, patients will receive an intracoronary injection of 200 mcg of glyceryl trinitrate and intra-venous adenosine infusion (140mcg/kg/min) to induce hyperaemia. This is a necessary condition for the accurate measurement of IMR and other physiological parameters as described.

A Pressurewire-Certus 4 (Radi medical systems) guide-wire will be advanced down the target coronary artery so that the microsensor (3 centimetres from the tip) is well beyond the culprit stenosis and in the distal third of the target artery. Pressures at the guide catheter tip (Pa) and distal artery (Pd) will be recorded, and three thermodilution curves will be performed to measure the thermodilution-derived mean transit time (Tmn). These measurements will be used to calculate the index of microvascular resistance (IMR). The principles of IMR calculation are described below. The stenting procedure will then proceed as per usual practice. During the first balloon inflation, the coronary wedge pressure (Pw) will be recorded.

Calculation of the IMR requires the use of pressure wire technology which allows the measurement of both flow and temperature in the distal coronary artery. Pressures are measured in both the proximal (Pa) and distal (Pd) artery through the guide catheter and pressure wire respectively. Thermodilution techniques are used to determine the thermodilution-derived mean transit time (Tmn), which is an inverse correlate of coronary blood flow. The IMR is adjusted for the presence of collateral flow using the coronary wedge pressure (Pw) which is the pressure in the distal vessel during balloon inflation proximal to the microsensor. The index of microcirculatory resistance is calculated using the following equation:


IMR = Pa x Tmn x (Pd-Pw)/(Pa-Pw)
Timepoint [1] 295344 0
Measurement of IMR will be carried out immediately before and 5 minutes after the end of procedure.
Secondary outcome [1] 315394 0
Change in myocardial strain.
Myocardial strain will be measured echocardiographically and analysed offline with Philips QLAB software version 10.
Timepoint [1] 315394 0
The strain measurement will be made at the time of randomisation, immediately (<2 hours) after the procedure and within 1 day following the end of the procedure.
Secondary outcome [2] 315537 0
Changes in neutrophil function

Myeloperoxidase and elastase activity will be used as measures of neutrophil function.

Plasma will be collected and frozen at -80 degrees Celsius. The analyses will be performed in batch to ensure consistency.
Timepoint [2] 315537 0
Patients' bloods will be collected peripherally and from the culprit coronary artery immediately before and after the PCI, transported in ice to the laboratory, centrifuged at 4 degrees Celsius, and frozen at -80 degrees Celsius.
Secondary outcome [3] 315538 0
Change in platelet function

Platelet aggregation will be measured using Multiplate (Registered Trademark) Impedance aggregometry. Platelet activation and platelet-derived microparticle formation will be measured using flow cytometry and XACT, a phospholipid specific procoagulant test.

Plasma will be collected and frozen at -80 degrees Celsius. The analyses will be performed in batch to ensure consistency.
Timepoint [3] 315538 0
Patients' bloods will be collected peripherally and from the culprit coronary artery immediately before and after the PCI, transported and centrifuged (double spun) at room temperature and frozen at -80 degrees Celsius.

Eligibility
Key inclusion criteria
1) Age > 18 years
2) Typical ischaemic chest pain lasting > 20 minutes
3) Either
*Electrocardiographic changes: new ST segment depression of > 0.1mV in >2 contiguous leads; or
*New transient T wave inversion of > 0.2mV in > 2 contiguous leads or
*Troponin T > 100 ng/L; or a 30% rise in a 6-hour troponin when the initial troponin T is 14 – 100 ng/L.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) complete occlusion of the culprit artery
2) ST-elevation myocardial infarction
3) prior history of a thrombotic disorder
4) pregnant women or women of child bearing potential who are planning to become pregnant within the next 3 months
5) haemodynamic instability
6) acute heart failure during the index admission
7) significant hepatic impairment (history or cirrhosis or abnormal serum ALT or AST 3-fold greater than the upper limit of normal)
8) Patients with idiopathic pulmonary fibrosis (IPF) with or without secondary pulmonary hypertension.
9) Patients who exhibit or may exhibit hypersensitivity to ambrisentan or to any of the excipients
10) significant renal impairment
11) failure to advance either the guide-wire or the angioplasty balloon beyond the stenosis
12) “proximal type” procedural complication

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The principle investigators will review all new cardiology admissions on a daily basis to identify potential participants for this study. The patients will then be screened based on the inclusion and exclusion criteria, and consented for the study if they fulfil the requirement. Patients with pre-existing therapeutic relationships with a principle investigator will be screened and consented by an alternate principle investigator to maintain neutrality of the recruitment process.

The participant will be enrolled into the study after the informed consent process has been completed and the participant has met all inclusion criteria and none of the exclusion criteria. The participant will receive a study enrolment number and this will be documented in the participant’s medical record and on all study documents.

Patients will be randomised in a 1:1 ratio to receive oral doses of ambrisentan or placebo at time of recruitment, with minimisation based on acute coronary syndrome (ACS) subtypes and history of diabetes. This will take place during the index hospital admission using the MINIM randomisation software and performed by a neutral research co-ordinator who will not be involved in any aspects of the research project. Participants will be assigned a randomisation number, which will correspond to the treatment allocated.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Patients will be randomised in a 1:1 ratio to receive oral doses of ambrisentan or placebo at time of recruitment, with minimisation based on acute coronary syndrome (ACS) subtypes and history of diabetes. This will take place during the index hospital admission using the MINIM randomisation software and performed by a neutral research co-ordinator who will not be involved in any aspects of the research project. Participants will be assigned a randomisation number, which will correspond to the treatment allocated.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Peri-procedural changes in IMR (delta IMR) has not been extensively studied to date. A recent study observed an overall increase in IMR by 20.6 +/- 6.0% following PCI for patients with NSTEMI (Akdeniz et al, EuroIntervension 2013), with a greater delta IMR observed (86.8 +/- 110.5%) in those with PMI than those without (-5 +/- 21%). A less dramatic trend has been observed in another study looking at patients with stable coronary artery disease, reporting a delta IMR of 22.1% following PCI in the PMI group as compared with 3.2% in patients who did not suffer PMI (absolute difference of 19.0%)(Layland et al, Heart, 2012). No studies have been performed to investigate the effect on Ambrisentan on IMR, although with every 20% incremental increase in IMR, there appears to be an adverse correlation with infarct size, myocardial haemorrhage, microvasular obstruction on cardiac MRI in the acute setting following primary PCI for STEMI, and infarct size and left ventricular function and remodelling in the intermediate term(Payne et al, JAHA, 2012).


The primary endpoint is the difference in the peri-procedural change in IMR (ie post-PCI IMR - pre-PCI IMR, or delta IMR), between patients who receive Ambrisentan and placebo. Assuming normal distribution, sample size was calculated based on a hypothesized absolute difference of 20% between the two study arms, with an estimated standard deviation of 25%. With an overall sample size of 52 patients, the study will be able to achieve a power of 80% at a significance level of 5%.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
16/02/2015
Date of last participant enrolment
Anticipated
1/12/2016
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
52
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 3940 0
Prince of Wales Hospital - Randwick
Recruitment postcode(s) [1] 9857 0
2031 - Randwick

Funding & Sponsors
Funding source category [1] 291498 0
Charities/Societies/Foundations
Name [1] 291498 0
Prince of wales Hospital Foundation
Country [1] 291498 0
Australia
Primary sponsor type
Hospital
Name
Prince of Wales Hospital
Address
Barker Street, Randwick, NSW, 2031
Country
Australia
Secondary sponsor category [1] 290177 0
Hospital
Name [1] 290177 0
Eastern Heart Clinic
Address [1] 290177 0
Prince of Wales Hospital, Barker Street, Randwick, NSW, 2031
Country [1] 290177 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293038 0
South Eastern Sydney Local Health District
Ethics committee address [1] 293038 0
Ethics committee country [1] 293038 0
Australia
Date submitted for ethics approval [1] 293038 0
Approval date [1] 293038 0
31/10/2013
Ethics approval number [1] 293038 0
13/049

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 58182 0
Dr Kevin Liou
Address 58182 0
Eastern Heart Clinic
Prince of Wales Hospital
Barker Street
Randwick, 2031
NSW
Country 58182 0
Australia
Phone 58182 0
+61 2 93820700
Fax 58182 0
Email 58182 0
kevin.liou@sesiahs.health.gov.nsw.au
Contact person for public queries
Name 58183 0
Kevin Liou
Address 58183 0
Eastern Heart Clinic
Prince of Wales Hospital
Barker Street
Randwick, 2031
NSW
Country 58183 0
Australia
Phone 58183 0
+61 2 93820700
Fax 58183 0
Email 58183 0
kevin.liou@sesiahs.health.gov.nsw.au
Contact person for scientific queries
Name 58184 0
Kevin Liou
Address 58184 0
Eastern Heart Clinic
Prince of Wales Hospital
Barker Street
Randwick, 2031
NSW
Country 58184 0
Australia
Phone 58184 0
+61 2 93820700
Fax 58184 0
Email 58184 0
kevin.liou@sesiahs.health.gov.nsw.au

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseDesign and Rationale for the Endothelin-1 Receptor Antagonism in the Prevention of Microvascular Injury in Patients with non-ST Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention (ENDORA-PCI) Trial.2016https://dx.doi.org/10.1007/s10557-016-6641-x
N.B. These documents automatically identified may not have been verified by the study sponsor.