Non-inferiority of Angiography-derived Physiology Guidance Versus Usual Care in an All-comers PCI Population Treated With Unrestricted Use of the Healing-Targeted Supreme (HT Supreme) Drug-eluting Stent and P2Y12 Inhibitor Monotherapy After 1-month of Dual-antiplatelet Therapy: the PIONEER IV trial

The CE-marked Healing-Target Supreme (HT SupremeTM) Sirolimus eluting stent or
any next generation of the HT SupremeTM stent family will be used in line with
their indications. The rationale for the use of HT Supreme is following:
- long drug-elution delays the healing process and may lead to incompetent
healing;
- targeting a quicker return of a functional, protective endothelial layer
could lead to better short-term prevention of stent thrombosis and at long-term
could prevent neoatherosclerosis;
- HT Supreme has been specifically designed to allow the vessel to heal and
return to its natural protective defences against thrombosis and restenosis
allowing for short dual-antiplatelet therapy followed by P2Y12 inhibitor
monotherapy;

Recently the sub analysis of the Global Leaders trial demonstrated that in
complex procedures ticagrelor monotherapy after one month of DAPT with aspirin
reduces the occurrence of death from all causes without reducing bleeding,
compared to standard DAPT for one year followed by aspirin monotherapy.

QFR has been validated as an accurate alternative for iFR and FFR in several
reports and has obtained Conformité Européenne (CE) mark 18-23. In the FAVOR I
study, the diagnostic accuracy of QFR has been demonstrated without the need
for pharmacologic hyperemia18. Thereafter, the FAVOR II China and the FAVOR II
Europe-Japan study demonstrated the diagnostic accuracy of QFR for detection of
functional significant lesions in comparison with 2D-QCA using FFR as reference
standard 19, 23. In a systematic review and Bayesian meta-analysis, Collet et
al confirmed the high sensitivity and specificity of QFR against pressure wire
derived physiological assessment21. Both FAVOR III China and Europe-Japan are
ongoing randomized controlled trials in stable and unstable angina. FAVOR III
China study aims to demonstrate the superiority of QFR-guided PCI in terms of
clinical outcome and cost-effectiveness compared to angiography-guided PCI in
which no other functional tests such as FFR/iFR can be used for further
assessment of the lesion before PCI. The FAVOR III China study is not able to
answer the question whether QFR can replace FFR or not. On the other hand, the
objective of the FAVOR III Europe-Japan study is to investigate whether a
QFR-based diagnostic strategy will result in non-inferior clinical outcome
after 12 months compared to an FFR-based diagnostic strategy. The FAVOR III
Europe-Japan study could bring an answer to the question whether QFR as a tool
for physiological assessment can replace FFR or not. However, the use of FFR in
daily practice is still low, and whether routine QFR-guided PCI could improve
clinical outcomes in daily practice will remain unanswered.

The computational pressure-flow dynamics derived FFR (caFFR) (RainMed Ltd,
Suzhou, China) is another well validated alternative to traditional FFR and
iFR. This method is based on computational pressure-fluid dynamics, in
conjunction with thrombolysis in myocardial infarction (TIMI) frame count,
applied to coronary angiography simulated three-dimensional (3D) mesh
reconstruction of the coronary artery, without using pressure wire or hyperemia
state The calculation of caFFR requires a specialized pressure transducer
(FlashPressure, RainMed Ltd, Suzhou, China) to extract the aortic pressure.
CaFFR was first validated in 323 patients of the FLASH FFR study which showed
the diagnostic accuracy of 95.7% as compared with invasive FFR. Ai et al.
further showed the high level of agreement between caFFR and invasive FFR in
both pre-PCI and post-PCI stages. In addition, multiple studies have
demonstrated the independent prognostic value of post-PCI caFFR for clinical
outcomes in ACS and CCS populations and several trials are ongoing with the
technology. The cut-off value for higher target vessel failure was caFFR<0.90
in a cohort of 136 patients, while the cut-off value of post-PCI caFFR was
<=0.83 in 65 patients for predicting VOCE.Thus, the cut off value of caFFR still
requires further research.

This PIONEER IV trial aims to demonstrate a non-inferiority of QFR-guidance PCI
to usual care PCI
with respect to Patient oriented Composite Endpoint (PoCE) at 1 year with the
unrestricted use of
HT Supreme-SES in an all-comers population (including HBR patients) treated
post PCI with one month
DAPT followed by 11-month of P2Y12 inhibitor monotherapy.

Patients with blocked or narrowed blood vessels will be treated with the
Healing-Targeted Supreme stent (HT-SupremeTM). This stent is covered with a
drug layer (Sirolimus) which reduces the chances of narrowing or blockage in
that part of the vessel again. This drug layer is biodegradable and is slowly
absorbed by your body and disappears completely from the stent. It has been
approved by the authorities to treat a narrowing of the coronary artery. This
study aims to study the efficacy and performance of the HT supreme in all
patients treated.

This clinical trial will also compare two diagnostic techniques. The first
technique uses imaging software QFR (Quantitative Flow Ratio) from Medis or
caFFR from RainMed in providing information on the blockage/narrowing in your
blood vessel(s) and provides guidance on how to best treat your vessels. The
Medis and RainMed assessment software is non-invasive, which means nothing will
enter your body, and has been approved by the authorities. The other technique
are local routine diagnostic procedures (LRDP) already used at your hospital
(e.g. visual assessment and/or invasive wire-based techniques (iFR and FFR),
which have also been approved by the authorities.

In this trial two anticoagulants (antiplatelet inhibitors) are prescribed for
the duration of one month. This is shorter than usual, but treatment guidelines
are currently moving towards this recommendation, based on new clinical data.
The anticoagulant medication reduces the risk of blood clots forming in the
doped blood vessel after your PCI procedure. The risk of blood clotting
decreases, but this increases the risk of heavier bleeding if you cut yourself,
for example.
After this month, only ticagrelor is prescribed for the duration of another 11
months.

The PIONEER IV study is a prospective, single-blind (patient), randomized, 1:1,
controlled, multi-centre trial comparing clinical outcomes between
angiography-derived physiology guidance to usual care in an all-comers patient
population undergoing PCI with unrestrictive use of HT Supreme
sirolimus-eluting stent.
All patients should receive dual anti-platelet therapy (DAPT), being aspirin
(ASA) and ticagrelor for 1 month, followed by 11 months of ticagrelor
monotherapy only. After that, ticagrelor monotherapy is replaced by aspirin
monotherapy at 1 year or according to standard of care.
Of note: ticagrelor is the default P2Y12 (highly recommended) in Acute Coronary
Syndromes (ACS) and chronic coronary syndromes (CCS). For additional
information/recommendation refer to section 11.12.
Patient will be randomized either to angio-based physiology guidance or usual
care.
Angio-based physiology guidance cohort Preprocedural guidance:
* Patient undergo PCI using HT Supreme stent in all flow limiting lesions
(QFR<0.80) due to significant stenosis/occlusion;
* on-line assessment of QFR is performed to evaluate the functional severity of
the lesion(s). If QFR is <=0.80, PCI is performed with the HT Supreme stent. If
QFR is >0.80, the treatment of the lesion is deferred.
Post-stenting assessment:
After stenting, QFR is repeated in the stented vessel(s). In case distal QFR is
<0.91 or delta QFR (across the stent is >0.05), post-dilatation of stented
segment or additional stenting is recommended. Post-stent IVUS/OCT assessment
and guidance for further treatment (to elucidate the cause of non-normalisation
of QFR and to guide the treatment) are optional at the discretion of the
investigator.
Usual care cohort Presence of one or more coronary artery stenosis (*50%) by
visual assessment in a native coronary artery or coronary artery bypass graft
(venous or arterial) suitable for coronary stent implantation.

HT Supreme stent will be implanted in all lesions. Non-invasive and invasive
assessment of the
physiological severity of the lesion, prior or at the time of the treatment, is
left at the discretion of
the operator.
All patients will be (at minimum) contacted via visit at 30 days (±7 days) and
12 months (±30 days)
and by phone contact at 6 months (±14 days), 24 months (±30 days) and 36 months
(±45 days) post
index procedure to assess clinical status and adverse events.

a. If randomized to QFR guidance:
perform QFR on the diagnostic angiogram from referral site (if analysable* and
in the absence of positive non-invasive test). In case the clinical
presentation changed since the diagnostic angiography (e.g. CCS to ACS), the
diagnostic angiography should be repeated to document the intercurrent change
in anatomy/QFR.
1 if QFR of all lesions -on the referral angio- are negative and in the absence
of a prior positive non-invasive test, the patient will not be admitted to the
cathlab/will not undergo PCI. The patient will stay in the study (deferred PCI
for all lesions) with a clear explanation to the patient and to the referring
physician
2 if QFR of all lesions -on the referral angio- are negative but in presence of
a prior positive non-invasive test, the negative QFR should be challenged by
wire-derived FFR/iFR during the procedure.
*if QFR on diagnostic angio is not analysable, patient will be admitted to the
cathlab and will undergo QFR.
b. If randomized to usual care: -> patient will be admitted to the cathlab for
the PCI (as requested by the referral site).

Coronary stenting with both BMS and DES has been performed successfully for
several decades and is considered a standard treatment for coronary artery
disease. Furthermore, there is extensive clinical and commercial experience
worldwide with cardiac catheterisation and interventional procedures and it is
expected that the procedural risks in this study and existing stenting
procedure will not be significantly different. Possible benefits may be found
for future patients treated with HT SupremeTM. PCI and functional guidance
(QFR) based upon results of this study.