Oxford Acute Myocardial Infarction - Pressure-controlled Intermittent Coronary Sinus Occlusion
Phase: NA
Conditions: ST Elevation Myocardial Infarction
Sponsor: Oxford University Hospitals NHS Trust

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Trial Title:  Oxford Acute Myocardial Infarction - Pressure-controlled Intermittent 
Coronary Sinus Occlusion in STEMI  (OxAMI-PICSO study)  
 
NCT03473015 
Ethics Ref: 15/SC0167 
Date and Version No: 26 February 2018 Version 5.0 
 
Chief Investigator: 
Prof. Adrian Banning (Oxford University Hospital) 
Investigators:  
Prof. Keith Channon (University of Oxford) 
Dr. Raj Kharbanda (Oxford University Hospitals) 
Dr. Colin Forfar (Oxford University Hospitals) 
Prof. Stefan Neubauer (University of Oxford) 
Prof. Robin Choudhury (University of Oxford) 
  Dr. Giovanni Luigi De Maria (University of Oxford) 
  Dr. Erica Dall’Armellina (University of Oxford) 
  Dr. Vanessa Ferreira (University of Oxford) 
 
Sponsor:  
Oxford University Hospitals NHS Trust 
 
Funders:  
Miracor Medical Systems 
BRC ACS theme 
 
Chief Investigator Signature:  
No potential conflicts of interest to declare 
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the 
Sponsor, the Investigator Team, host organisation, and members of the Research Ethics Committee, unless 
authorised to do so. 
 

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TABLE OF CONTENTS 
1. 
KEY TRIAL CONTACTS ..................................................................................................................... 4 
2. 
SYNOPSIS ....................................................................................................................................... 4 
3. 
ABBREVIATIONS ............................................................................................................................. 6 
4. 
BACKGROUND AND RATIONALE .................................................................................................... 7 
5. 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS ................................................................ 11 
6. 
TRIAL DESIGN .............................................................................................................................. 12 
7. 
PARTICIPANT IDENTIFICATION .................................................................................................... 13 
7.1. 
Trial Participants .......................................................................................................................... 13 
7.2. 
Inclusion Criteria .......................................................................................................................... 14 
7.3. 
Exclusion Criteria ......................................................................................................................... 14 
8. 
TRIAL PROCEDURES ..................................................................................................................... 15 
8.1. 
Informed Consent ........................................................................................................................ 15 
8.2. 
Discontinuation/Withdrawal of Participants from Trial Treatment ............................................ 19 
8.2.1 Study Withdrawal ....................................................................................................................... 19 
8.2.2 
Participant death: ................................................................................................................... 19 
8.3 
Study timeline (see “Integrated flowchart for OxAMI-PICSO study” as below) ........................... 19 
8.3.1 
Stage 1: Pre-Stenting .............................................................................................................. 20 
8.3.2 
Stage 2: PICSO treatment ....................................................................................................... 21 
8.3.3 
Stage 3: Stenting ..................................................................................................................... 21 
8.3.4 
Stage 4: 24-48 hours post PCI ................................................................................................. 22 
8.3.5 
Stage 5: 6 months post PCI ..................................................................................................... 22 
8.4 
Definition of End of Trial ............................................................................................................... 23 
9. 
STUDY ASSESSMENT .................................................................................................................... 23 
9.1 
Data Collection, Patient Reported Outcomes and Cardiovascular Outcomes .............................. 23 
9.2 
PICSO device ................................................................................................................................. 23 
9.3 Analysis of CMR ................................................................................................................................ 23 
9.4 Analysis of cardiac physiological measurements ............................................................................. 23 
10. 
IDENTIFICATION & DESCRIPTION OF THE INVESTIGATIONAL DEVICE ......................................... 25 
10.1   Device description ........................................................................................................................ 25 
10.2 
Device Safety .............................................................................................................................. 27 
10.3 
Device Accountability ................................................................................................................. 29 
11 
SAFETY REPORTING ....................................................................................................................... 29 
11.1 
Definitions .................................................................................................................................. 29 

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11.2 
Causality ..................................................................................................................................... 32 
11.3 
Procedures for Recording Adverse Events ................................................................................. 33 
11.4 
Reporting Procedures for Serious Adverse Events ..................................................................... 34 
11.5 
Expectedness .............................................................................................................................. 34 
11.6 
Safety Monitoring Committee .................................................................................................... 34 
11.7 
Safety for PICSO .......................................................................................................................... 35 
11.8 
Safety for CMR ............................................................................................................................ 35 
11.9 
Safety of cardiac physiological measurements .......................................................................... 35 
11.10 Safety of blood sampling ............................................................................................................ 36 
12 
STATISTICS ................................................................................................................................... 36 
12.1  Number of Participants ................................................................................................................. 36 
12.2 Analysis of Endpoints ..................................................................................................................... 37 
13 
DATA MANAGEMENT .................................................................................................................. 38 
13.1 
Source Data ................................................................................................................................ 38 
13.2 
Access to Data ............................................................................................................................ 38 
13.3 
Data Recording and Record Keeping .......................................................................................... 39 
14 
QUALITY ASSURANCE PROCEDURES ............................................................................................ 39 
15 
SERIOUS BREACHES ..................................................................................................................... 39 
16 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................................................... 40 
16.1 Specific Ethical Considerations for participants in emergency situations ...................................... 40 
16.2 Possible risks and/or discomfort for patient .................................................................................. 40 
16.3 Collaboration and Partnership with Commercial Companies ........................................................ 40 
16.4 Feasibility ....................................................................................................................................... 41 
16.4.1 Facility ...................................................................................................................................... 41 
16.5 
Declaration of Helsinki ............................................................................................................... 41 
16.6 
ICH Guidelines for Good Clinical Practice ................................................................................... 41 
16.7 
Medical Device regulations ........................................................................................................ 41 
16.8 
Approvals .................................................................................................................................... 41 
16.9 
Reporting .................................................................................................................................... 42 
16.10 Participant Confidentiality .......................................................................................................... 42 
16.11 Potential Benefits ....................................................................................................................... 42 
17 
FINANCE AND INSURANCE .......................................................................................................... 43 
17.1 
Funding ....................................................................................................................................... 43 
17.2 
Insurance .................................................................................................................................... 43 
18 
PUBLICATION POLICY .................................................................................................................. 43 

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19 
REFERENCES ................................................................................................................................ 43 
20       APPENDIX A …………………………………………………………………………………………………………………………….46 
21     APPENDIX B…………..…………………………………………………………………………………………………………………47 
 
1. KEY TRIAL CONTACTS 
 
Chief Investigator 
Prof Adrian P. Banning 
Department of Cardiology 
John Radcliffe Hospital 
Headington, Oxford, OX39DU 
Adrian.Banning@ouh.nhs.uk 
Tel:  01865 228934 
 
Fax: 01865 220585 
Sponsor 
Oxford University Hospitals NHS Trust 
 
Statistician 
Roger Kessels 
Miracor Medical System 
Gumpendorferstrasse 109, top1.05 
Austria 
rkessels@miricormedical.com 
Tel: 0031 6117175890 
 
2. SYNOPSIS 
Trial Title 
Oxford Acute Myocardial Infarction - Pressure-controlled Intermittent 
Coronary Sinus Occlusion in STEMI   
Internal ref. no. (or 
short title) 
OxAMI-PICSO 
Clinical Phase  
II 
Trial Design 
Prospective single centre observational cohort study 

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Trial Participants 
Patients admitted for primary percutaneous coronary intervention for ST 
elevation myocardial infarction 
Planned Sample Size 
75 patients 
Treatment duration 
Maximum of 90 minutes  
Follow up duration 
6 months 
Planned Trial Period 
18 months 
 
Objectives 
Outcome Measures/Endpoints 
Primary 
 
To evaluate the effect of pressure 
intermittent controlled coronary 
sinus occlusion on the indexes of 
coronary 
physiology 
and 
on 
infarct size in STEMI patients at 
short and mid term follow up. 
To evaluate the effect of pressure 
intermittent controlled coronary 
sinus occlusion on infarct size 
measured at cardiac magnetic 
resonance after 24-48 hours from 
revascularization. 
Secondary 
 
To evaluate the utility of individual 
biomarkers (blood components 
derived substances from cells, 
DNA, 
plasma 
etc) 
in 
the 
assessment of coronary artery 
disease and myocardial infarction 
investigating also how these 
individual biomarkers may be 
modified by PICSO treatment. 
To evaluate the effect of pressure 
intermittent controlled coronary 
sinus 
occlusion 
on 
humoral 
biomarkers and on the evolution of 
parameters of coronary physiology 
at 24 hours and infarct size, 
microvascular 
obstruction 
at 
cardiac magnetic resonance after 6 
months from revascularization. 
Safety Endpoint 
To evaluate the rate of PICSO failure deployment, coronary sinus 
complications, and additional time and radiation exposure associated to 
for PICSO deployment 
Device name 
Pressure intermittent controlled coronary sinus occlusion (PICSO) 
Device Manufacturer 
Miracor Medical System 
Device Classification 
Interventional Cardiology 
 
Protocol version 
no. 
Effective 
Date 
Significant Changes 
Previous 
protocol 
version no. 
2.0 
01.04.2015 
- Clarification of follow up duration 
- Clarification for what group of 
patient CMR follow up is meant  
v1.0 13.02.2015 
3.0 
20.06.2016 
- Extension of sample size to 75 
patients to achieve a minimum of 
25 patients with complete dataset 
v2.0 01.04.2015 

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Protocol version 
no. 
Effective 
Date 
Significant Changes 
Previous 
protocol 
version no. 
4.0 
06.05.2016 
- Change in information about 
regulatory status of PICSO 
technology from CE-marked to 
non non-CE mark 
- Extension of recruitment beyond 
the period specified in the IRAS 
application form 
V3.0 20.06.2016 
5.0  
26.02.2018 
- Extension of recruitment beyond 
the period specified in the IRAS 
application form 
- Extension of inclusion criteria to 
allow enrolment of all patients 
with ST elevation myocardial 
infarction, irrespectively of the 
coronary location of the culprit 
lesion 
V4.0 06.05.2016 
 
3. ABBREVIATIONS 
 
AE 
Adverse event 
AR  
Adverse reaction 
CFR 
Coronary flow reserve 
CI 
Chief Investigator 
CMR 
Cardiac magnetic resonance 
CRA 
Clinical Research Associate (Monitor) 
CRF 
Case Report Form 
CRO  
Contract Research Organisation 
CT 
Clinical Trials 
 
 
DMC/DMSC 
Data Monitoring Committee / Data Monitoring and Safety Committee 
FFR 
Fractional flow reserve 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonisation 
IMR 
Index microrcirculatory resistance 
IRB 
Independent Review Board 

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MI 
Myocardial infarction 
NHS 
National Health Service 
NRES 
National Research Ethics Service  
PCI  
Percutaneous coronary intervention 
PI 
Principal Investigator 
PICSO 
Pressure controlled intermittent coronary sinus occlsuion 
PIL 
Participant/ Patient Information Leaflet 
R&D 
NHS Trust R&D Department 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SDV 
Source Data Verification 
 
 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TMF 
Trial Master File 
TSG 
Oxford University Hospitals Trust / University of Oxford Trials Safety Group 
 
4. BACKGROUND AND RATIONALE 
Restoration of blood flow in the infarct related artery (IRA) is the cornerstone for the current treatment of 
ST elevation myocardial infarction (STEMI) [1]. However in a variable proportion of patients, ranging from 
30 to 40%, myocardial reperfusion is impaired, despite the apparent successful achievement of epicardial 
coronary artery patency [2]. This condition, known as no reflow, is due to microvasculature dysfunction 
and/or obstruction and it is the result of the interaction of several pathophysiological mechanisms 
including ischemia injury, reperfusion injury, distal embolization and tissue oedema [3].  
4.1 
Diagnosis of no reflow 
Identification of no reflow and microvascular obstruction can be obtained by application of different 
diagnostic tools. So far cardiac magnetic resonance (CMR) represents the gold standard for detection and 
quantification of myocardial damage and microvascular impairment [4]. Parameters easily derived from 

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CMR such as infarct size, area at risk, myocardial salvage and microvascular obstruction have been shown 
to be related to long term outcome. 
A major limitation of CMR is the time-delay from percutaneous coronary intervention (PCI), being applied 
at the earliest at the end of the revascularization procedure [4]. Early identification of patients at higher 
risk of no reflow, during the PCI procedure, would be extremely useful and in such regard parameters of 
coronary physiology may have a role.  Indeed, measurements of blood flow and coronary microcirculation 
function are now used in the catheter lab during routine PCI, using standard techniques (a pressure wire) 
that are incorporated into the PCI procedure itself (by replacing the PCI procedure wire with a pressure 
wire). An example of this is the measurement of the index of microcirculatory resistance (IMR), defined as 
distal coronary pressure divided by the inverse of the hyperaemic mean transit time (a correlate to 
absolute flow). It is measured simultaneously with the coronary pressure wire and it evaluates 
microvascular resistance, independently of epicardial stenosis [5]. IMR has become the catheter-based 
method of choice to independently assess coronary microcirculation [5-6]. Recent data suggest that IMR, 
measured acutely in patients with MI undergoing emergency PCI, provides useful prognostic information 
[7]. Specifically, a postprocedure IMR> 40 has been shown to be significantly associated with a worst long 
term prognosis in terms of cardiac death and re-hospitalization for heart failure [8].  
We have conducted a preliminary study, in the setting of the Oxford Acute Myocardial Infarction (OxAMI) 
project, to understand the procedural aspects at PCI that may directly influence the microcirculation. The 
key findings are that:  
1. 
Coronary stenting itself reduces IMR and is thus beneficial in terms of the microcirculation.  
2. 
Patients with a low pre-stenting IMR tend to do have little change in IMR. 
3. 
Conversely the reduction in IMR is largest in those with a higher IMR (> 40) before stenting 
4. 
However, a proportion of patients with high IMR can continue to have a still high (> 40) or even 
further increased poststenting IMR. 
  

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This suggests that patients with a high pre-stenting IMR are at especially higher risk and may benefit from 
additional interventions.  
 
4.2 Retroperfusion strategy and PICSO 
So far many strategies have been proposed in order to prevent and/or to treat no reflow, but none have 
demonstrated a consistent beneficial effect. A new proposed approach being investigated is the 
retroreperfusion strategy [9] based on the principle that it is possible to reduce the ongoing ischemia by 
perfusing the myocardium through the coronary sinus. 
The concept of retroperfusion is 100 years old it has been initially discarded after the advent of coronary 
artery bypass grafting and PCI. Different techniques of retroperfusion are available: intermittent coronary 
sinus occlusion (ICSO), synchronized retrograde perfusion (SRP) and simplified retroperfusion (SR) [10-13]. 
The common denominator is the temporal increase in coronary sinus pressure through the coronary sinus 
occlusion (ICSO) or retroperfusion with arterial blood (SRP and SR). 
PICSO is a modification of the original time-dependent ICSO and it is applied through a dedicated catheter 
(PICSO Impulse catheter, Mirarcor Medical System GmbH, Vienna, Austria). 
The catheter presents a balloon at the distal end. The balloon inflates and deflates cyclically once deployed 
in the coronary sinus, leading to intermitted coronary sinus pressure increase. This intermittent increase 
in coronary sinus pressure leads to an improved perfusion of the ischemic area with potential benefit in 
terms of myocardial salvage through 3 mechanisms: 1) redistribution of blood flow from the remote 
myocardium to the border zone of the ischemic myocardium [14]; 2) enhanced wash out of noxious, 
inflammatory factors and embolic material across the microvascular bed (suction effect upon balloon 
release) [15]; 3) improvement in collaterals through release of vascular growth factors as consequence of 
venous pressure increase [16-17]. 

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The PICSO technology has revealed to be effective in several models by reducing infarct size (IS) [18] and 
a metanalysis on seven studies on animal models has confirmed a statistically significant -29% (CI95% -
40.9 – -17.7, p<0.001) reduction in IS compared to control group [19]. Moreover, it has also been shown 
that the benefit from PICSO treatment is directly proportional to the pressure reached in the coronary 
sinus during the balloon inflation and thus to the increase in coronary wedge (CW) pressure, which is the 
pressure associated to the blood flow provided to the ischemic region by collateral branches [20].  
The Prepare-PICSO study represents the first-in-man experience with the PICSO device [21]. On a small 
sample of 15 patients with stable angina the PICSO treatment showed to be firstly safe and, as observed 
in the animal models, was associated to a significantly increase in coronary sinus pressure as well in mean 
CW pressure in the distal left anterior descending (LAD) coronary artery [21].  
These findings have triggered the Prepare-RAMSES study in which PICSO treatment was investigated for 
the first time in man in patients with STEMI [22]. The results of the study have been recently published. 
The study was initially designed to include 30 patients with anterior STEMI with PICSO treatment for 90 
minutes after the completion of primary percutaneous coronary intervention (PPCI). The study enrolled 
only anterior STEMI since expected to be responsive to the PICSO device, being mainly the anterior wall of 
the myocardium drained by the coronary sinus. The device resulted to be safe, with a median implantation 
time of 12 minutes. The primary endpoint was the reduction in IS at cardiac magnetic resonance (CMR) at 
2-4 days and 4 months. The PICSO group was compared with a matched control group of patients.  
Although the study did not show an overall difference in the reduction in IS in the PICSO group [22], IS 
reduction appeared to be significantly related to the quantity of PICSO treatment (pressure achieved in 
the coronary sinus x time of treatment) and significantly higher in the small subgroup of patients receiving 
high PICSO quantity. 
It is possible that the study did not reach the primary endpoint due to some limitations in its design. First 
of all the small sample size has to be acknowledged, since the investigators managed to fully deliver the 
PICSO treatment only to 12 patients (63% of the initially intended sample size). Moreover, the study 

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presented a potential “selection bias” that drove the investigators to include in the study “relatively 
healthier” patients in which anticipated benefit was limited: 40% of patients enrolled presented with a 
Thrombolysis In Myocardial Infarction (TIMI) flow > 1, e.g. presented with an open coronary artery at the 
time of primary PCI. Moreover the application of PICSO treatment at the end of the PPCI may have blunted 
the expected benefit: the device was deployed after stenting, the stage the procedure known to be at 
higher risk of distal embolization of atherothrombotic debris downstream the coronary microvasculature 
[22]. 
Identification of “higher risk” STEMI patients is thus crucial in order to confirm a clear benefit associated 
to the PICSO device. 
4.3 
Study Hypothesis 
The Oxford Acute Myocardial Infarction - Pressure-controlled Intermittent Coronary Sinus Occlusion in 
STEMI (OxAMI-PICSO) study aims to analyze the potential benefit of PICSO in a selected population of 
STEMI patients. In patients with prestenting high IMR, and thus with larger infarct size and more 
compromised microvasculature status, PICSO treatment added to the conventional revascularization gold 
standard is expected to be associated to a better myocardial reperfusion. This will be assessed by 
measurement of indexes of coronary physiology and by CMR evaluation of indexes associated to infarct 
size, myocardial salvage and microvascular obstruction, and other biomarkers. The comparator group will 
be matched participants previously enrolled in the OxAMI study, with STEMI and with a prestenting IMR 
above 40. 
 
5. OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
 
Objectives 
Outcome Measures/Endpoints  

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Primary Objective 
To assess the impact of PICSO on coronary 
physiology parameters, on infarct size, on 
myocardial salvage and on microvascular 
obstruction at CMR in a selected population of 
STEMI patients at higher risk of no reflow and 
with the theoretical prerequisites that make 
more likely to respond to PICSO treatment. The 
control group will be represented by a highly 
matched group of patients from the ongoing Ox-
AMI (Oxford Acute Myocardial Infarction) project 
(Ethics Ref 11/SC/0397), who have undergone all 
other aspects of the study protocol, including 
assessment of coronary physiology at 24 hours 
post primary PCI, 24-48 hours and 6 months 
CMR, but who have not received PICSO 
treatment. 
Area at risk, Infarct size, Myocardial salvage and 
microvascular obstruction measured by cardiac 
magnetic resonance at 24-48 hours 
Secondary Objectives 
The OxAMI-PICSO study aims to evaluate the 
utility of individual biomarkers (blood 
components derived substances from cells, DNA, 
plasma etc) in the assessment of coronary artery 
disease and myocardial infarction. The OxAMI-
PICSO may show also how these individual 
biomarkers may be modified by PICSO 
treatment. 
Coronary flow reserve (CFR), Fractional Flow 
reserve (FFR), index of microcirculatory resistance 
(IMR) measured at 24 hours after PCI. 
Infarct size and microvascular obstruction extent 
measured by cardiac magnetic resonance at 6 
months  
Individual Biomarkers related to coronary artery 
disease/myocardial infarction at three time points 
(PCI, 24/48 hours after PCI and 6 months). These 
include: blood biomarkers of myocardial injury, 
metabolism and inflammation.  
Tertiary Objectives 
To evaluate the rate of PICSO failure 
deployment, coronary sinus complications, and 
additional time and radiation exposure 
associated to for PICSO deployment 
Rate of PICSO failure deployment 
Rate of coronary sinus complications: 
perforation, dissection, thrombosis 
Time for PICSO deployment / additional 
screening time and radiation dose 
 
6. TRIAL DESIGN 
The OxAMI-PICSO study is a prospective single centre observational cohort study of the use of PICSO in 
patients presenting for primary PCI for acute myocardial infarction. The OxAMI- PICSO study is based upon 
the established framework of the OxAMI study (Ethics Ref 11/SC/0397). 

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Patients, age 30-90, presenting with ST elevation myocardial infarction will be considered for inclusion in 
the study. Measurement of IMR before stenting is an essential prerequisite for the study: only patients 
with pre-stenting IMR > 40 will be considered eligible for the PICSO treatment. Patients with IMR≤ 40 will 
remain in the study but will not undergo PICSO treatment. The procedure for consent in patients 
undergoing emergency PCI will be as already established in the ongoing OxAMI study, and is discussed 
below in Section 8.1.2. 
The PCI procedure will be undertaken in a standard fashion, and include the use of pressure wire 
measurements before and after stent deployment. Aspiration or distal protection devices may be used if 
clinically indicated and where vessel anatomy is suitable. The devices used and the procedural techniques 
will be driven by clinical decision making at the patient and institutional level, and carried out in 
accordance with the Oxford University Hospitals NHS Trust (OUHT) departmental guidelines for PCI.  
PICSO treatment will be added on top of the conventional treatment.  
The protocol will constitute of 5 main stages described in details in the next sections (Section 8.3). 
Only patients with pre-stenting IMR > 40 and who assent to receive PICSO treatment will undergo 24 hours 
coronary angiogram with coronary physiology measurement, 24-48 hours CMR scan and 6 months CMR 
scan. Patients who assent to participate in the study but in whom the prestenting IMR ≤ 40, or those in 
whom the prestenting IMR > 40 but the participant declines PICSO treatment will remain in the study for 
blood sampling and clinical data collection at the same follow up time points (24 hours, 48 hours and 6 
months). A summary of the study design, indicating the time points and procedures, is shown in Section 
8.3. 
 
7. PARTICIPANT IDENTIFICATION 
7.1. Trial Participants 
 

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Participants aged 30-90 years old, referred for emergency diagnostic coronary angiography 
presenting with ST elevation myocardial infarction, with the intention to proceed to primary PCI with 
stenting.   
7.2. Inclusion Criteria 
 
Participants must satisfy the following conditions: 
- 
Male or Female, aged 30 to 90 years,  
- 
Clinical presentation with STEMI 
- 
Referred for coronary angiography with view to proceed to PCI with stenting.   
7.3. Exclusion Criteria 
 
The participant may not enter the study if ANY of the following are known to apply: 
- 
Patients in whom safety or clinical concerns preclude participation.  
- 
Known anaemia (Hb <9). 
- 
Pregnant or breast feeding females. 
- 
Revascularization by mean of balloon angioplasty without stenting 
- 
History of stroke, TIA or reversible ischemic neurological disease within last 6 months 
- 
Known severe renal failure (eGFR < 30 ml/min/1.73m2) or history of dialysis or renal transplant 
- 
Previous coronary bypass artery grafting  
- 
Known severe valvular abnormalities 
- 
Previous STEMI presentation 
- 
Presentation with cardiogenic shock 
- 
Severe bradycardia (Heart rate < 50 beats per minutes) 
- 
STEMI due to stent thrombosis 
- 
Unconscious on presentation 

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- 
Non-cardiac comorbidities and life expectancy < 1 year 
- 
Use of warfarin 
- 
Presence of pacemaker or other electrodes in the coronary sinus 
- 
Contraindications to adenosine 
- 
Additional exclusion criteria for participants undergoing CMR 
o claustrophobia which limits / prevents participants from remaining in CMR scanner. 
o patients who cannot lie flat on the scan table. 
o patients with metallic implants, pacemakers, implantable defibrillators etc, unless known to be 
CMR compatible. 
o patients with known allergy to medium of contrast (gadolinium) 
8. TRIAL PROCEDURES 
8.1. Informed Consent 
Informed consent will be obtained, with the recruitment approach to the patient, as described below. 
 
8.1.1 
Patients proceeding to emergency angiogram/PCI 
The clinical treatment of these patients is in the emergency context and delays to treatment are 
detrimental. It is necessary to administer prompt emergency treatment and it is not always 
possible to identify and approach a Consultee beforehand. Thus we would seek a waiver, as 
described in Section 32(9) of the Mental Capacity Act, since  
a) 
the treatment needs to be given urgently,  
b) 
it is necessary to take the action for the purpose of the research urgently,  
but  
c) 
it is not reasonably practicable to consult prior to enrolling the patient.  

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In this situation the Mental Capacity Act allows the participant to be enrolled with a agreement of a 
registered medical practitioner (RMP) not involved in the research or in accordance with a 
procedure agreed with the appropriate body (i.e. REC). Since this is only applicable for the duration 
of the emergency we will seek written informed consent as soon as reasonably practicable (see 
diagram and Section 8.1.1.2 below). This process includes an important role for a healthcare 
professional as a type of patient “advocate”. This is discussed in section 8.1.1.2 below.  We also seek 
approval from the REC for the waiver procedure. 
 
8.1.1.1 
Verbal assent 
Because of the urgency of the situation it is not feasible to obtain fully informed written consent. 
Fully informed consent requires that the potential participant have time to read and reflect on a 
patient information sheet which in this context is clinically inadvisable. We therefore propose to 
obtain verbal assent so as to optimize the amount of appropriate information conveyed to potential 
participants acutely and minimize the clinical risks involved with substantial delay. The research 
study will be discussed verbally with the patient and the risks and benefits explained.  
In detail the patient at the time of verbal assent process will be informed that as part of the research 
project he might undergo to some extra blood samples and to measurement of the index of 
microcirculatory resistance (IMR) which allows to have an indirect assessment of the entity of the 
ongoing heart attack. The patient will be also informed that in case IMR value will be greater than 
40, thus suggesting a possible significant damage to the heart muscle that may benefit from 
additional treatment, he might be asked to provide assent for PICSO treatment. Patients with pre-
stenting IMR ≤ 40 or those with prestenting IMR > 40 who elect not to receive PICSO treatment will 
be given the opportunity to continue to participate within the OxAMI-PICSO study, but without the 
use of the PICSO device. 
 

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Participants will be reminded that they have the right to withdraw from the study at any stage and 
that this will not affect their treatment or human rights. The research and clinical team have 
extensive experience of patient assent, and the role of a Patient Advocate (see below), through the 
recruitment of approximately 250 participants undergoing emergency PCI for STEMI in the OxAMI 
study. 
Only conscious patients, able to provide verbal assent will be enrolled in the study. 
 
8.1.1.2 
Patient Advocate  
Because of the urgency of the situation it is not feasible to consult prior to enrolment, a RMP or 
patient “advocate” will be identified to act in accordance with 32(9). The Patient Advocate will act 
as witness and documenter of the verbal consent process for all conscious potential participants 
and/or overseer of the waiver process (8.1.2.3) as a whole. This RMP will be present at the time of 
emergency treatment, but is not part of the research team. The Advocate will ensure that the verbal 
consent process is undertaken, that the patient does not object (i.e. the patient “assents” rather 
than “dissents”), and that the researcher has taken practical steps to explain the study, risks and 
benefits, within the context of the emergency clinical situation, and in accordance with the clinical 
status of the patient.  The Advocate in this situation will be a healthcare professional such as a 
specialist nurse. Assessment of patients in this context is within their professional capacity and the 
role here will be to witness verbal consent or assent.  
Most of the nursing staff attended a series of seminars to make them aware of their specific roles 
and responsibilities in this situation, and they have acted as patients’ advocates through the 
recruitment of approximately 250 participants undergoing emergency PCI for STEMI in the ongoing 
OxAMI study. These seminars have been directed by an ethicist who is not directly involved with the 
research project. We will continue to provide this training and draw on the extensive experience of 
the members of the clinical team currently acting as a Patient Advocate.  

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8.1.1.3 
Post-emergency phase 
Once the emergency phase is over and treatment has been delivered, we will seek full written 
informed consent as soon as practical. For most patients this means within 12 hours of admission. 
This consent will be a two parts process: 
a) We will seek consent to allow use of data and samples already acquired during the emergency 
phase  
b) We will seek consent for ongoing participation in the study.  
If the participant elects to withdraw from the study at this point then we will seek consent to use 
the data and samples already acquired. If this is not given, then all research data and samples 
acquired during the emergency treatment will be destroyed, otherwise only data acquired in the 
emergency situation will be retained in the study.  

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If a patient is unable to provide informed consent at this stage due to deterioration in clinical 
condition, we propose to keep the data and samples acquired under the assent phase. We would 
not seek further ‘consent’ from relatives at the risk of causing undue distress. 
8.2. Discontinuation/Withdrawal of Participants from Trial Treatment 
8.2.1 Study Withdrawal 
We anticipate and have made provision for withdrawal when the emergency exception period is 
complete; if a patient is assessed and has capacity then they may completely or partially withdraw at 
any time. This possibility will be made clear as a part of seeking of full written informed consent after 
the initial emergency procedure. 
8.2.2 Participant death:  
If the participant dies before giving full written consent then we propose to continue using the data 
and samples obtained. We would not seek further ‘consent’ from relatives at the risk of causing undue 
distress.  
8.3 Study timeline (see “Integrated flowchart for OxAMI-PICSO study” as below) 
The OxAMI-PICSO study will take place beside an ongoing large prospective observational study in 
STEMI patients (OxAMI study). Patients fulfilling the OxAMI-PICSO criteria will be invited to participate 
in the study. OxAMI-PICSO study will constitute of 5 main stages: 

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8.3.1 Stage 1: Pre-Stenting 
1. Diagnostic angiography will be performed in the standard manner using appropriate catheters.  
2. Bivalirudin will be administered (0.75mg/kg bolus followed by an infusion of 1.75 mg/kg/min for 
up 4 hours after the procedure as clinically warranted), as routinely used for PCI. The lesion will be 

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crossed with a coronary guide wire in the usual manner for PCI. Normal blood flow will be rapidly 
achieved by thrombus aspiration and/or predilation 
3. Pre-stenting coronary physiology parameters, namely FFR, CFR and IMR, will be measured, using 
a pressure wire, as used for routine clinical measurements in patients undergoing PCI.  
4. If pre-stenting IMR is > 40, patients will be invited to receive the PICSO device. If pre-stenting IMR 
is ≤ 40 PICSO device will not be proposed, but the patient will be invited to remain in the study for 
serial blood sampling (procedural-6 hours-24 hours and 48 hours) and routine clinical data 
collection.   
8.3.2 Stage 2: PICSO treatment 
1. In patients with IMR >40 who assent to PICSO treatment, the PICSO device will be deployed as 
already previously described in the literature [22] (Section 9.2). The overall duration of PICSO will 
be no less of 60 minutes up to a maximum of 90 minutes in order to ensure a PICSO delivery dose 
of 800 mmHg.  
 
8.3.3 Stage 3: Stenting 
1. Stenting is performed as usual clinical practice. 
2. Post-dilation is left to operator’s discretion, as in clinical routine. 
3. At the end of the procedure a final reassessment of coronary physiology parameters is performed 
again as previously described. 
 
Blood samples may be taken, (by 5 or 10 ml syringes), at the following time-points, from both 
peripheral vein (V), using the venous cannula, from the coronary sinus (CS) using a CS sampling 
catheter, or the PICSO delivery sheath, and from the coronary artery (C) either via the guide catheter 
used for the procedure or an aspiration catheter placed through the guide catheter: 
 

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Sampling point (1): beginning of procedure 
 
 
 
V, C 
Sampling point (2): placement of PICSO device  
 
              V, CS, C                               
Sampling point (3): end of procedure 
 
  
 
 
V, CS, C 
Sampling point (4): end of PICSO treatment period 
 
 
V, CS,  
Sampling point (5): 6 hours after 1st stent deployment                                  V 
 
For patients in whom an aspiration catheter or protection device is used during PCI, blood, 
thrombus and/or atheromatous plaque material may be retrieved during the procedure. These 
materials, which are usually discarded, will be retained for analysis. Data on the PCI procedure 
and any device or technology used will be collected.  
 
8.3.4 Stage 4: 24-48 hours post PCI 
Full written consent to take part to the OxAMI-PICSO study is obtained as soon as practicable. The 
following study assessments may be carried out: 
1. Repeat coronary angiogram for assessment of coronary physiology parameters assessment – 
for participants who receive the PICSO device only 
2. Cardiac magnetic resonance - for participants who receive the PICSO device only 
3. Venous blood sampling for biomarker measurement 
4. Data Collection, Patient Reported Outcomes and Cardiovascular Outcomes 
 
8.3.5 Stage 5: 6 months post PCI 
Participants will be invited to attend the hospital as an outpatient at approximately 6 months post-
PPCI for the following research assessments 
1. 
Cardiovascular MRI - for participants who receive the PICSO device only 
2. 
Blood sampling for biomarker measurement  
3. 
Data Collection, Patient Reported Outcomes and Cardiovascular Outcomes 

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8.4 Definition of End of Trial 
Recruitment to the study will cease as soon as 25 participants have undergone PICSO treatment and have 
completed follow-up at 6 months. The study will end on the date of the last CMR at 6 months follow up of 
the last participant recruited.  
9. STUDY ASSESSMENT 
9.1 Data Collection, Patient Reported Outcomes and Cardiovascular Outcomes 
Data on the clinical procedures and any devices and/or imaging technologies used will be collected. 
Medical history will be taken from the patient once informed consent has been given and relevant sections 
of the medical notes may be accessed by the study team. Clinical outcomes and MACE will be ascertained 
during the follow-up appointment with the patient, by accessing relevant sections of the medical notes, 
ONS database and existing databases of cardiac outcomes and treatment (such as the CCAD and MINAP 
databases), or by contacting the GP if appropriate.  
9.2 PICSO device 
See Section 10 
9.3 Analysis of CMR 
Cardiac related parameters will be derived for further analysis. Analyses will be performed according to 
published methods and will be focused on the assessment of different cardiac components including 
anatomy, function, tissue, flow and metabolism (i.e. ventricular volumes, wall motion, infarct size, area at 
risk, myocardial salvage and microvascular obstruction) [23]. These parameters are partly used both 
clinically and in research settings (e.g. heart volumes, myocardial mass).  
9.4 Analysis of cardiac physiological measurements 
Cardiac and/or coronary flow and pressures will be measured, before and after stenting and during the 
repeat coronary angiogram at 24 hours post-PPCI, using commercially available measurement guidewires 

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according to standard techniques that are in routine use in current PCI practice. The guidewire contains a 
pressure-temperature sensor to allow for calculation of the physiological parameters. The guide wire is 
calibrated at the beginning of the PCI and then advanced into the distal third of the culprit artery. 
Calculations will be based on measurements of proximal and distal coronary pressure(s) and mean transit 
time (in seconds) during maximal hyperemia, as previously described.  Briefly a pressure wire (Radi; St Jude 
Medical, St Paul, MN, USA) is placed in the LAD distal to the lesion. Baseline mean aortic pressure (Pa), 
mean distal pressure (Pd) and Pd/Pa ratio will be recorded. Thermodilution-based measurement of CFR 
and IMR will be performed by injecting in the IRA 5 ml of room temperature saline solution and recording 
mean transit time (meanTt) at baseline and after induction of maximal hyperaemia by intravenous infusion 
at a rate of at a rate of 140 mg/kg/min. Once hyperaemia is achieved the following parameters will be 
obtained: FFR (Pd/Pa during hyperemia), CFR (meanTtbaseline/meanTthyperaemia) and IMR 
(Pdhyperaemia* meanTthyperaemia). 
9.5 Analysis of blood samples 
Blood samples collected at the respective time points will be prepared under standard laboratory 
protocols, blood and its derived components will be aliquoted and stored, as necessary, in appropriate 
conditions for further analyses.  The samples will be analysed for known and novel biomarkers related to 
coronary artery disease and myocardial infarction, using techniques such as enzyme immunoassay, flow 
cytometry etc. Samples may be assayed using novel platforms to investigate the potential utility against 
the existing techniques. Samples may be stored and sent to other centres, outside the UK, for specific 
analyses, according to the availability of specialist techniques.  Depending on specific informed consent 
being given by participants, blood will be stored for DNA extraction and future genetic analysis, including 
typing of SNPs and for whole genome analysis. Specific genetic variants may be used to guide invitations 
to participate in future studies. 
9.6 Analysis of particulate debris 

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Intracoronary thrombus / plaque material obtained with the use of thrombus aspiration at any stage of 
the procedure will be prepared under standard laboratory protocols and stored at -80ºC for further 
analyses.  Snap frozen debris may be analysed using immunohistochemical stains, including antibodies to 
CD68, smooth muscle actin, CD3, and CD20, Tissue Factor [24], Vascular Endothelial Growth Factor (VEGF) 
[25], MMPs 2 and 9 [26], cellular proliferation and apoptosis [27-29]. Samples may also be analysed by 
extraction of mRNA for RT-PCR, or for levels of proteins/lipids using proteomics/lipidomics approach or 
other molecular markers using novel technologies. 
10. IDENTIFICATION & DESCRIPTION OF THE INVESTIGATIONAL DEVICE 
10.1   Device description 
 
The PICSO Impulse System consists of the PICSO Impulse console (101.100.000.000) and PICSO 
impulse catheter (300.100.000.010) by Miracor Medical Systems (Gumpendorferstrasse 139, Top1.05 
Vienna, A-1060).  
                
 
                        PICSO Impulse Console                                        PICSO Impulse Catheter 
Each PICSO Impulse catheter will have a serial number, which will be recorded for traceability during 
and after completion of the study.  
The PICSO Impulse catheter presents a balloon at the distal end. The balloon inflates and deflates 
cyclically once deployed in the coronary sinus, leading to intermitted coronary sinus pressure increase. 
This intermittent increase in coronary sinus pressure leads to an improved perfusion of the ischemic 

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area with potential benefit in terms of myocardial salvage through 3 mechanisms: 1) redistribution of 
blood flow from the remote myocardium to the border zone of the ischemic myocardium [14]; 2) 
enhanced wash out of noxious, inflammatory factors and embolic material across the microvascular 
bed (suction effect upon balloon release) [15]; 3) improvement in collaterals through release of vascular 
growth factors as consequence of venous pressure increase [16-17].  
The PICSO Impulse catheter is a 8F double lumen catheter with a 15.5x20mm long balloon at the distal 
end. The catheter is connected to the console through two pneumatic tubes in which helium is shuttled 
to and from the balloon. In addition, the coronary sinus pressure is monitored through the center lumen 
of the catheter. The catheter is placed in the coronary sinus over a 0.025’ wire by a 8.5Fr pre-shaped 
delivery long steerable sheath (Oscor Destino Steerable Sheath DS856750/22) inserted in the femoral 
vein. Femoral vein access is obtained as routine practice according to Seldinger technique. Once the 
catheter is placed, the guidewire is removed and the steerable sheath is retracted in the right atrium 
for support. PICSO deployment median time has been estimated to be of 12 minutes (Interquartile 
Range 9-18 minutes) 
The PICSO Impulse Catheter is then connected to the PICSO Impulse console. The PICSO Impulse 
Console automatically operates the PICSO Impulse Catheter. The balloon is intermittently inflated and 
deflated using helium, based on coronary sinus pressure and synchronized with the ECG. The monitor 
displays the inflation/ deflation state of the balloon, as well as trend graphs and time counters; Live 
graphs display curves and numeric values of ECG, coronary sinus pressure, aortic pressure and auxiliary 
input. It is easy to use and provides direct feedback on the patient’s individual therapy using the ‘PICSO 
Dose’, which is defined as the sum of the coronary sinus pressure modulation for all PICSO cycles 
applied. All data are automatically stored and can be retrieved for later analysis for each patient. The 
unit is transportable and runs on battery supply if needed during patient transportation. 
Once the PICSO Impulse catheter is connected to the consoled, by activating the “START” button, the 
distal balloon will be cyclically inflated. Each cycle starts with a balloon inflation triggered by QRS 

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complex on ECG monitoring. During balloon inflation coronary sinus pressure will progressively increase 
till reaching a plateau, then coronary sinus occlusion is stopped by balloon deflation. For security, each 
balloon inflation has a maximum limit of 30 seconds in duration. The deflation interval between two 
cycles has a minimum duration of 3 seconds. 
In the OxAMI-PICSO the PICSO Impulse system will be adopted in a highly selected population of 
patients with ST elevation myocardial infarction, characterized by a possibly impaired microvasculature 
impairment at the time of the PCI, as expressed by a prestenting elevated index of microcirculatory 
resistance (> 40). The aim is to assess the extent of infarct size after 24-48 hours in such specific group 
of patients. Propensity-score matched historical patients from the ongoing OxAMI study will be controls 
in the OxAMI-PICSO study. 
All the investigators using the PICSO device will undergo a specialist training programme completion, 
including the performance of the first cases under the supervision of a proctor expert. Educational 
training sessions for use of the PICSO will be provided to all clinical staff (nurses, radiographers, 
physiologists) involved in the care of patients who have received PICSO. 
10.2 Device Safety 
PICSO treatment is safe. Potential complications associated to PICSO may include: 
a) 
Bleeding due to damage to the coronary sinus where the PICSO catheter is placed 
b) 
Bleeding in the groin from the femoral vein access. 
c) 
Long term blockage of the coronary sinus where the PICSO catheter sits. 
d) 
Helium leak from the catheter into the blood. A leak of helium into the patient could occur with a 
balloon rupture or hole. However the risk is significantly mitigated since the system can automatically 
detect any leakage and stop the procedure. The maximum helium volume that could enter the patient 
using the PICSO system is less than 10 ml. This volume is approximately 1/3 of the volume that could 
leak from a bursting intra-aortic balloon pump (IABP) catheter, that are used in routine clinical practice 
in the aorta (i.e arterial circulation), whereas the PICSO catheter is used exclusively in the venous 

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circulation.. A helium leak from the PICSO system is therefore regarded to constitute a low risk to the 
patient. 
Data about PICSO are continuously increasing and in the two main studies performed in man so far 
(PREPARE-PICSO and PREPARE-RAMSES) only one procedure adverse event (tamponade secondary to 
coronary sinus perforation) has been described. This rate (<3%) of complication is further lower than 
that associated to the routine elective electrophysiological procedures to the coronary sinus in the 
context of tachycardia ablation or cardiac resynchronization therapy. 
It is possible that the PICSO balloon may be dislodged from the coronary sinus into the right atrium. 
This event has no known safety implications for the patients, but it may affect the efficacy of the PICSO 
treatment. The PICSO console will detect the occurrence of such event and alert the clinical team. In 
such a scenario balloon repositioning will only be considered if the treatment time-interval is less than 
60 minutes. In order to minimize the risk for the patient, repositioning will be performed under 
fluoroscopic guidance in the catheterization laboratory. Once the balloon is repositioned, the PICSO 
treatment will be continued to achieve a minimum total treatment time of 60 minutes to a maximum 
of 90 minutes from the time of stent deployment. 
All the investigators using the PICSO device will undergo a specialist training programme completion, 
including the performance of the first cases under the supervision of a proctor expert. Educational 
training sessions for use of the PICSO will be provided to all clinical staff (nurses, radiographers, 
physiologists) involved in the care of patients who have received PICSO. Patients undergoing PICSO 
treatment will be strictly monitored, according to the standard clinical care guidelines, during and after 
the PICSO treatment in order to minimize or to early detect possible issues associated to the treatment. 
After the procedure, when the PICSO treatment is still ongoing, the patients will be monitored in the 
Recovery Assessment Area in order to guarantee a rapid access to the Catheterization Laboratory, if 
required. 
The additional x-rays used for the placing of the device is extremely low in the context of the exposure 
associated to the standard primary PCI procedure. The radiation dose associated with the placement 

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of the device is estimated to be 4.3 mSv, which is approximately equivalent to 22 months exposure to 
UK background radiation.  This may theoretically be associated with an increased lifetime risk of 
developing a cancer of 0.06%. This compares with the risk of developing a cancer in the general 
population of around 30% to 40%. So overall this represents a very small addition to the underlying 
cancer risk from all causes.  
The radiation exposure in case of repositioning the PICSO balloon is estimated to be less than that 
associated with the device implantation. Therefore patients undergoing repositioning would have a 
global radiation dose associated to the PICSO device of no more of 8 mSv. 
 
10.3 Device Accountability  
 
PICSO Impulse console and PICSO Impulse catheter will be provided by Miracor Medical Systems. We 
will be documenting the number of devices, with their lot numbers, that will be shipped to the John 
Radcliffe Hospital. PICSO Impulse console will be placed in the Catheterization Laboratory of the John 
Radcliffe Hospital, connected to electric supply in order to assure full charge of the battery. After their 
delivery, the PICSO Impulse catheters will be stored in the storage room of the Catheterization 
Laboratory f the John Radcliffe Hospitals and kept in a cool, dry place.  
We will document on the CRF the LOT number and expiry date for each balloon for each patient. 
11 SAFETY REPORTING  
11.1 Definitions 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury or any 
untoward clinical signs (including an abnormal laboratory findings) in 
participants, users or other persons whether or not related to the 
investigational medical device. This includes events related to the 

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investigational device or comparator, events related to the procedures 
involved (any procedure in the protocol). For users or other persons this 
is restricted to events related to the investigational medical device. 
Adverse 
Device 
effect 
(ADE) 
 
An adverse event related to the use of an investigational medical device. 
This definition includes any events resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, 
or operation, or any malfunction of the investigational device. This 
definition also includes any event resulting from user error or form 
intentional misuse of the investigational device. 
 
Serious 
Adverse 
Event 
(SAE) 
An adverse event that: 
• 
Led to death 
• 
Resulted in serious deterioration in the health of the subject 
that: 
o resulted in a life-threatening illness or injury 
o resulted in a permanent impairment of a body structure 
or a body function 
o required 
in-patient 
care 
or 
prolongation 
of 
hospitalisation 
o resulted in medical or surgical intervention to prevent 
life-threatening illness or injury or permanent 
impairment to a body structure or a body function. 

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This includes device deficiencies that might have led to a serious adverse 
event if: 
a) suitable action had not been taken or 
b) intervention had not been made or 
c) circumstances had been less fortunate.  
These are handled under the SAE reporting system. 
Planned hospitalisation for a pre-existing condition, or a procedure 
required by the trial protocol, without serious deterioration in health, is 
not considered a serious adverse event. 
Serious Adverse Device 
Effect (SADE) 
Any untoward medical occurrence that can be attributed wholly or 
partly to the device, which resulted in any of the characteristics of a 
serious adverse event as described above. 
Unanticipated Serious Adverse Device Effects (USADE) 
Any serious adverse device effect which, by its nature, incidence, 
severity or outcome, has not been identified  
Device deficiency 
Inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance.  Device deficiencies include 
malfunctions, use errors and inadequate labeling. 
Device deficiencies that did not lead to an adverse event, but could have 
led to a medical occurrence if suitable action had not been taken, or 
intervention had not been made or if circumstances had been less 
fortunate 

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User error 
Act or omission of an act that results in a different medical device 
response than intended by the manufacturer or expected by the user.  
Use error includes slips, lapses and mistakes.  An unexpected 
physiological response of the subject does not itself constitute a use 
error. 
 
Severity definitions 
The following definitions will be used to determine the severity rating for all adverse events: 
Mild: awareness of signs or symptoms, that does not interfere with the subject’s usual activity or is 
transient that resolved without treatment and with no sequelae. 
Moderate: a sign or symptom, which interferes with the subject’s usual activity. 
Severe: incapacity with inability to do work or perform usual activities. 
11.2 Causality 
The relationship of each adverse event to the trial device may be determined by the manufacturer and/or 
a medically qualified Investigator according to the following definitions:  
Not related: The event is clearly related to other factors such as the patients/participants clinical condition, 
therapeutic intervention, concomitant medication. 
Unlikely: The event is probably produced by other factors such as the patients/participants clinical 
condition, therapeutic intervention, concomitant medication and does not follow a known response 
pattern to the device 

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Possibly: The event follows a reasonable temporal relationship form the time of placement/administration 
and/or follows a known response pattern to the device but could have been caused by other factors such 
as the patients/participants clinical condition, therapeutic intervention, concomitant medication. 
Most probable: The event follows a reasonable temporal relationship form the time of 
placement/administration and/or follows a known response pattern to the device and could not have been 
caused by other factors such as the patients/participants clinical condition, therapeutic intervention, 
concomitant medication. Further the event immediately follows the administration/placement of the 
device and improves on stopping or removing the device. 
11.3 Procedures for Recording Adverse Events 
All adverse events (including ADEs) and device deficiencies occurring during the course of the study will be 
recorded on the CRF whether or not attributed to the trial device. The information recorded will include 
but not be limited to: 
• 
A description of the event 
• 
The dates of the onset and resolution 
• 
Action taken 
• 
Outcome 
• 
Assessment of relatedness to the device 
• 
Whether the AE is serious or not 
• 
Whether the AE arises from device deficiency 
• 
Whether the AE arises from user error 
The severity of events will be assessed on the following scale:  1 = mild, 2 = moderate, 3 = severe. 
AEs/ADEs considered related to the device as judged by a medically qualified investigator or the Sponsor 
will be followed either until resolution, or the event is considered stable. 

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It will be left to the Investigator’s clinical judgment to decide whether or not an AE/ADE is of sufficient 
severity to require the participant’s removal from treatment.  A participant may also voluntarily withdraw 
from treatment due to what he or she perceives as an intolerable AE/ADE.  If either of these occurs, the 
participant must undergo an end of trial assessment and be given appropriate care under medical 
supervision until symptoms cease, or the condition becomes stable. 
11.4 Reporting Procedures for Serious Adverse Events 
Reporting of all Serious Adverse Events will be done in accordance with the European Commission 
Guidelines on Medical Devices Serious Adverse Event Reporting (MEDDEV 2.7/3; December 2010). 
SAEs/SADEs that pose an immediate risk to patient health or safety, will be reported to the trial 
DSMC/Sponsor immediately or no later than 24 hours after the Investigator is aware and to the device 
manufacturer, competent authority and the REC within 2 calendar days of the Chief Investigator becoming 
aware of the event.   
All other reported SAEs/SADEs will be reported to the trial DSMC and Sponsor competent authority within 
7 calendar days of notification, if appropriate. This will not include SAEs that may be expected as part of 
the risks of routine care. Adverse device events (SADEs, USADEs) and device deficiencies will also be 
reported to the device manufacturer.  All SAEs will be followed up to resolution.   
SAEs/SADEs will be recorded for a time period going from verbal assent/PICSO device adoption to 30 days 
following the use of the device.  
11.5 Expectedness 
Expectedness will be determined according to the Manufacturers risk analysis report 
11.6 Safety Monitoring Committee 

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The Oxford University Hospitals Trust will conduct a review of all SAEs/SADEs for the trial reported during 
the quarter and cumulatively. The aims of this committee include: 
• 
To pick up any trends, such as increases in un/expected events, and take appropriate action 
• 
To seek additional advice or information from investigators where required 
• 
To evaluate the risk of the trial continuing and take appropriate action where necessary 
11.7 Safety for PICSO 
See 10.2 
11.8 Safety for CMR  
CMR is a safe and non-invasive technique with no known risk when appropriately supervised. It does not 
involve ionising radiation. Potential participants with ferromagnetic objects in their bodies or with 
implanted devices which can be damaged by the CMR magnet will be excluded. All participants entering 
the scanner room are screened for such objects. Gadolinium contrast is widely used for clinical indications 
in CMR and is safe. Occasionally it may cause a mild headache, nausea, itching and very rarely (< 1 in 1000) 
a more severe allergic reaction. It is cleared within hours by the body. Gadolinium has recently been 
associated with nephrogenic systemic fibrosis in patients with severe renal dysfunction; hence, as per 
departmental guidelines based on Food and Drug Administration guidelines, all patients with glomerular 
filtration rate (GFR) < 30 ml/min (stage 3-5 renal disease) should be not be given gadolinium. Participants 
for whom there is a possible history of metal in the eye and we are unable to find documented clinical 
evidence that the metal has been removed, will be offered an orbital (eye) x-ray prior to their cardiac CMR 
scan to confirm or negate presence of metal in the eye. This will add 0.1 mSv additional radiation exposure; 
this is 1/260 of that incurred during a standard coronary angiogram procedure. There are no 
contraindications to short periods of supplementary oxygen in appropriately selected patients.  
11.9  Safety of cardiac physiological measurements 

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Coronary pressure wire studies are routinely performed during PCI procedures. The repeat 
catheterizations 24-48 hours after PCI are not part of routine practice and special attention will be paid to 
minimize radiation and use of contrast agent. The risk of repeating cardiac catheterization is low; a 
commonly occurring consequence is bruising at the site of vascular access which can be treated with 
simple analgesia. Based on local audit data, the average radiation exposure for a patient during routine 
angiography is 5 mSv. The additional IMR measurement adds on average only 1.6 mSv to the procedure. 
The follow up visits for IMR measurement also allows a valuable clinical opportunity to assess the result of 
initial PCI, which not otherwise be performed.  
11.10 
 Safety of blood sampling 
Blood sampling performed during the procedure will be performed through either the femoral venous 
sheath, coronary sinus catheter or coronary artery catheter. The femoral artery sheath and coronary artery 
catheter are required for and routinely used for PCI to be carried out. Some discomfort and possible 
complications are associated with placement of the femoral arterial sheath, but this is already clinically 
indicated as a necessary part of the PCI. The femoral venous sheath is not routinely placed for all PCI 
procedures, but is used whenever additional venous access during PCI is required clinically, for example to 
place catheters in to the venous system, or catheters or pacing electrodes in to the right side of the heart, 
or infusion of drugs during the PCI procedure. Potential risks and complications associated with venous 
sheath placement are much less than arterial sheath placement, because blood is not under arterial 
pressure and because other potential risks are intrinsically lower in the venous circulation. Placement of a 
coronary sinus catheter is not routinely used during PCI, but is used routinely using during other commonly 
performed cardiac interventions. The risk of additional complications is very low. The average volume of 
blood samples for research analyses taken at each sampling point would not exceed 40 ml. 
12 STATISTICS 
12.1  Number of Participants 

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The OxAMI-PICSO study aims to investigate the potential benefit of PICSO in a highly selected population 
of STEMI patients. In line with the data reported by Sayeed et al in a previous metanalysis on 7 studies 
about PICSO application in animal models, the recently published Prepare-RAMSES study also observed a 
30% reduction in IS in the treatment arm, however such reduction was not statistically significant in 
comparison to the control arm [19]. The study, however could still show a benefit of PICSO in terms of IS 
reduction at six months follow up in the subgroup of patients receiving high PICSO quantity. The study, 
however, was significantly hampered by the inclusion of relative low risk patients and by a small sample 
size. The author managed indeed to deliver full PICSO treatment only in 63% of the initial planned cohort 
(12 patients, of the 30 planned, received a prolonged treatment with PICSO) [22].  
In order to address the first limitation of the Prepare-RAMSES study, OxAMI-PICSO study will select 
patients with a prestenting higher IMR. In this way PICSO is meant to be applied only in a population at 
higher risk and highly likely to get benefit from its application.  
In this regard assuming that the stricter inclusion criteria may allow to detect a substantial benefit from 
PICSO compared to the control group and expecting that this will allow to achieve a significant 29% 
reduction in IS as shown in Sayeed’s metanalysis [19], we initially calculated a final sample size of 12 
patients with complete final data per each group with an interval of confidence at 95% and a 80% power. 
However considering that this was the final same sample size enrolled in the Prepare-RAMSES study, 
initially meant to recruit 30 patients per arm, we propose to double the actual sample size from 12 to 25 
per arm. 
Allowing for participants who do not wish to undergo repeat cardiac catheterisation, or cardiac MRI, we 
anticipate that approximately 75 patients may be recruited to the study in order to achieve full 
participation and complete follow up in 25 subjects. 
12.2 Analysis of Endpoints  
In keeping with our usual practice we will obtain expert statistical advice from the Centre for Statistics in 
Medicine (or equivalent) for each specific task.  Summary statistics, including means, medians, and 

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variances, will be calculated at each time point and for each type of data (e.g. parameters derived from 
coronary physiology and CMR). The distribution of the levels will be described. It may be necessary to log 
transform the data before further statistical analysis. For each parameter an analysis of variance will be 
carried out at each time point.  
Control group in OxAMI-PICSO study is represented by a highly matched group of patients underwent to 
primary PCI, with a prestenting IMR > 40 and with available 24 hours recath and 24-48 hours/6 months 
CMR data. Matching will be performed by application of a propensity score matching analysis including 
the following predictors in the model: age, sex, pain to wire time, thrombotic burden (assessed as 
angiographic thrombus score), thrombus aspiration performance, stent volume, glycoprotein IIbIIIa 
inhibitors adoption.  
13 DATA MANAGEMENT 
13.1 Source Data 
Source documents are where data are first recorded, and from which participants’ CRF data are obtained. 
These include, but are not limited to, hospital records (from which medical history and previous and 
concurrent medication may be summarised into the CRF), clinical and office charts, laboratory and 
pharmacy records, diaries, microfiches, radiographs, and correspondence. 
CRF entries will be considered source data if the CRF is the site of the original recording (e.g. there is no 
other written or electronic record of data).  All documents will be stored safely in confidential conditions. 
On all trial-specific documents, other than the signed consent, the participant will be referred to by the 
trial participant number/code, not by name. 
13.2 Access to Data 
Direct access will be granted to authorised representatives from the Sponsor, host institution and the 
regulatory authorities to permit trial-related monitoring, audits and inspections. 

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13.3 Data Recording and Record Keeping 
Study data will be entered on case record forms (CRF). The department SOP on database design will be 
followed. Data will be uploaded into SPSS or equivalent statistical software for statistical analysis. The 
participants will be identified by a study specific participant number in any database.  The name and any 
other identifying detail will NOT be included in any study data electronic file. All data will be made non 
patient-identifiable as soon as is practical to do so via the participant ID.  
14 QUALITY ASSURANCE PROCEDURES 
The trial will be conducted in accordance with the current approved protocol, ICH GCP, relevant 
regulations and standard operating procedures. 
Regular monitoring will be performed by the sponsor according to ICH GCP. Data will be evaluated for 
compliance with the protocol and accuracy in relation to source documents. Following written standard 
operating procedures, the monitors will verify that the clinical trial is conducted and data are generated, 
documented and reported in compliance with the protocol, GCP and the applicable regulatory 
requirements. 
15 SERIOUS BREACHES 
A serious breach is defined as “A breach of GCP or the trial protocol which is likely to affect to a significant 
degree –  
(a) the safety or physical or mental integrity of the subjects of the trial; or 
(b) the scientific value of the trial”. 
In the event that a serious breach is suspected the Sponsor must be contacted within 1 working day. In 
collaboration with the C.I., the serious breach will be reviewed by the Sponsor and, if appropriate, the 
Sponsor will report it to the REC committee, Regulatory authority and the NHS host organisation within 
seven calendar days. 

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16 ETHICAL AND REGULATORY CONSIDERATIONS 
16.1 Specific Ethical Considerations for participants in emergency situations 
Research in emergency situations is ethically complex because of the urgent nature of the interventions 
and the often severely compromised capacity of the patient. The processes of enrolment and consent 
described above, including verbal consent and assent, the involvement of the Advocate represents our 
attempt to develop a thorough, ethically justified process that both protects patients’ rights and interests 
and enables important research to be done. These processes have been developed in the light of and 
guided by the provisions laid out in the Mental Capacity Act with special reference to Section 32(9). 
16.2 Possible risks and/or discomfort for patient 
Patients referred for cardiac catheterization and PCI will undergo this procedure as would routinely be 
performed. Patients will therefore be consented for the standard of care procedure and its associated 
risks. 
Overall the PCI procedure time may be lengthened by around 20 minutes to complete the selected study 
procedures (cardiac physiological measurements + PICSO catheter placement).   In the context of a PCI 
procedure that typically last approximately 60 minutes; the additional time taken should not result in any 
clinically significant difference to the participants. Very occasionally this additional time can result in some 
back discomfort for patients having to lie on the angiography bed for the additional time period. 
CMR is an established cardiac imaging technique in our institution and is generally very well tolerated. 
Specific considerations for safety are reflected by the additional exclusion criteria listed in section 7.3. All 
local protocols will be adhered to and only fully trained staff will carry out procedure according to 
departmental SOPs. 
16.3 Collaboration and Partnership with Commercial Companies 
The University of Oxford, the Oxford University Hospitals NHS Trust (OUHT) and the OxAMI-PICSO study 
may work in partnership with, and receive support from, commercial companies who provide the devices 

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and technologies related to PCI and other research investigations. As part of this partnership we may make 
available research data to the company specifically related to the use of their device or technology. All data 
will be supplied in a fully anonymised format and participants would not be identifiable from this.    
16.4 Feasibility 
16.4.1 Facility 
The Oxford Heart Centre is a state-of-the-art facility which incorporated services in cardiology and cardiac 
surgery. The cardiac catheter laboratories are fully equipped to support these studies.  
16.5 Declaration of Helsinki 
The Investigator will ensure that this trial is conducted in accordance with the principles of the Declaration 
of Helsinki.  
16.6 
ICH Guidelines for Good Clinical Practice 
The Investigator will ensure that this trial is conducted in full conformity with relevant regulations and with 
the ICH Guidelines for Good Clinical Practice (CPMP/ICH/135/95) July 1996. 
16.7 
Medical Device regulations 
The Investigator will ensure that this trial is conducted in full conformity with: 
• 
European Commission Medical Device Guidelines relating to the application of the EU Directives 
on Medical Devices 
• 
Guide to European Medical Device Trials and BS EN ISO 14155 
16.8 
Approvals 

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The protocol, informed consent form, participant information sheet and any proposed advertising material 
will be submitted to an appropriate Research Ethics Committee (REC), and host institution(s) for written 
approval. 
The Investigator will submit and, where necessary, obtain approval from the above parties for all 
substantial amendments to the original approved documents. 
16.9 
Reporting 
The CI shall submit once a year throughout the clinical trial, or on request, an Annual Progress Report to 
the REC, host organisation and Sponsor.  In addition, an End of Trial notification and final report will be 
submitted to the REC, host organisation and Sponsor. 
16.10 Participant Confidentiality 
The trial staff will ensure that the participants’ anonymity is maintained.  The participants will be identified 
only by initials and a participants ID number on the CRF and any electronic database.  All documents will 
be stored securely and only accessible by trial staff and authorised personnel. The trial will comply with 
the Data Protection Act, which requires data to be anonymised as soon as it is practical to do so. 
16.11 Potential Benefits 
The information derived from coronary pressure/flow measurements is often very useful to the 
interventional cardiologist in optimising PCI strategy, and the use of vasodilators (e.g. adenosine) as part 
of the coronary pressure/flow measurements often results in useful clinical improvements in coronary 
flow.  
Finally PICSO treatment, according to pre-clinical literature evidences, is expected to provide a benefit in 
terms of infarct size reduction. According to animal models this advantage should amount around a 29% 
in reduction of the infarcted area. The application of PICSO treatment in a highly selected, high risk 
population of STEMI patients should amplify the potential benefits of this therapy.  

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17 FINANCE AND INSURANCE 
17.1 
Funding 
The study will be supported by British Heart Foundation, NIHR Biomedical Research Centre 
programme. Miracor Medical Systems will support the study by providing PICSO catheters, PICSO 
Impulse Console and an unrestricted grant. 
17.2 
Insurance 
NHS bodies are legally liable for the negligent acts and omissions of their employees. If the patient is  
harmed whilst taking part in a clinical trial as a result of negligence on the part of a member of the 
study team a liability cover would apply. Non-negligent harm is not covered by the NHS indemnity 
scheme. The Oxford University Hospitals NHS Trust, therefore, cannot agree in advance to pay 
compensation in these circumstances. In exceptional circumstances an ex-gratia payment may be 
offered. 
18 PUBLICATION POLICY 
Data will be owned and supervised by the trust. The Investigators will be involved in reviewing drafts 
of the manuscripts, abstracts, press releases and any other publications arising from the study.  
Authors will acknowledge that the study was Funded by British Heart Foundation, NIHR Biomedical 
Research Centre programme and Miracor Medical Systems. Authorship will be determined in 
accordance with the ICMJE guidelines and other contributors will be acknowledged. Copies of any 
publications connected to this study are available on request from the OXAMI-PICSO investigators. 
19 REFERENCES 
 
 
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20. APPENDIX A:  SCHEDULE OF PROCEDURES IN PICSO GROUP 
 
 
 
PICSO group 
Procedures 
Pre-PCI 
 During PCI 
6 
hours 
24 
hours 
48 
hours 
6 
months 
Start of 
procedure 
PICSO start 
End of PCI 
PICSO stop 
Verbal assent 
X 
 
 
 
 
 
 
 
 
Blood samples 
 
X 
X 
X 
X 
X 
X 
X 
X 
PICSO 
 
 
X 
X 
X 
 
 
 
 
Coronary physiology 
measurements (IMR, CFR, FFR) 
 
X 
 
X 
 
X 
 
 
 
Informed written consent 
 
 
 
 
 
X 
 
 
 
Coronary angiogram with 
coronary physiology 
measurements (IMR, CFR, FFR) 
 
 
 
 
 
 
X 
 
 
CMR 
 
 
 
 
 
 
 
X 
X 
ECG 
X 
 
 
X 
 
X 
 
 
 
Echocardiography 
 
 
 
 
 
 
X 
 
 
Medical history   
Demographic data collection  
 
 
 
 
 
 
 
X 
 

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21. APPENDIX B:  SCHEDULE OF PROCEDURES IN NON-PICSO GROUP 
 
 
 
NON-PICSO group 
Procedures 
Pre-PCI 
 During PCI 
6 hours 
24 hours 
48 hours 
6 months 
Start of 
procedure 
End of PCI 
Verbal assent 
X 
 
 
 
 
 
 
Blood samples 
 
X 
X 
X 
X 
X 
X 
Coronary physiology 
measurements (IMR, CFR, FFR) 
 
X 
X 
 
 
 
 
Informed written consent 
 
 
 
X 
 
 
 
ECG 
X 
 
X 
X 
 
 
 
Echocardiography 
 
 
 
 
X 
 
 
Medical history   
Demographic data collection  
 
 
 
 
 
X