Use of Physiology to Evaluate Procedural Result After PCI CTO
Phase: NA
Conditions: Percutaneous Coronary Revascularisation, Complex Coronary Lesion
Sponsor: Isala

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ULTRA-CTO, V2.0, 04 December 2023 
 
 
 
 
 
 
ULTRA-CTO STUDY 
 
USE OF PHYSIOLOGY TO EVALUATE PROCEDURAL  
 
RESULT AFTER PCI CTO 
 
 
04 December 2023 
Version 2.0 
 
 
 
 

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PROTOCOL TITLE ‘Use of physiology to evaluate procedural result after PCI CTO’ 
 
Protocol ID 
NL 76172.075.21 
Short title 
ULTRA-CTO 
Version 
2.0 
Date 
December 04, 2023 
Principal and coordinating 
investigator 
M.A.H. van Leeuwen, MD, PhD 
Department of Cardiology, Isala Zwolle,  
The Netherlands 
Co-principal investigator 
R.J. van Geuns, MD, PhD 
Department of Cardiology, Radboudumc,  
The Netherlands 
Sub-investigator 
T.A. Meijers, MD 
Department of Cardiology, Isala Zwolle,  
The Netherlands 
Sponsor  
Board of Directors, Isala hospital, Zwolle,  
The Netherlands 
Subsidizing party 
Abbott Vascular international BVBA, 
Brussel, Belgium 
Independent expert  
Prof. M.R. Meijerink, MD, PhD 
CRO 
Radboudumc Technology Center 
Clinical Studies 
Geert Grooteplein Zuid 10,  
6525 GA Nijmegen, The Netherlands 
Time schedule 
FPI: 31-08-2021 
LPI: 01-04-2024 
LPO: 01-05-2024 

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PROTOCOL SIGNATURE SHEET 
 
I have read the protocol and agree to conduct this trial in accordance with all stipulations of 
the protocol, with applicable laws and regulations and in accordance with the ethical 
principles outlined in the Declaration of Helsinki. 
 
 
Name 
Signature 
Date 
Principal Investigator: 
 
 
 
 
 
 
 
 
 

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HISTORY OF CHANGES 
 
Revision 
Release date 
Change 
1.0 
31-12-2020 
Initial release 
1.1 
10-03-2021 
Additional information 
objectives, endpoints, co-
investigator and sample size 
calculation 
2.0 
04 December 2023 
Adjustments: 
- Sponsor 
- CRO 
- Co-principal investigator 
- Secondary objectives 
- Inclusion criteria: deletion 
of inclusion criterion 
‘Presence of at least one 
intermediate 
(angiographically 30-90%) 
stenosis in the non-CTO 
vessel or major side branch 
of the CTO vessel with 
diameter ≥ 2mm, for which 
FFR is clinically indicated’. 
- Study design and study 
procedures: 
• 
Staged OCT vs direct 
OCT (based on clinical 
judgement and local 
practice) 
• 
Repeat post-PCI 
FFR and RFR after 
additional PCI is now 
compulsory instead of 
recommended. 
 
 
 

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TABLE OF CONTENTS 
 
1. 
LIST OF ABBREVIATIONS .............................................................................................. 7 
2. 
SUMMARY ....................................................................................................................... 8 
3. 
INTRODUCTION AND RATIONALE .............................................................................. 10 
4. 
OBJECTIVES ................................................................................................................. 12 
4.1 
Primary objective .................................................................................................... 12 
4.2 
Secondary objectives ............................................................................................. 12 
5. 
STUDY DESIGN ............................................................................................................. 12 
6. 
STUDY POPULATION ................................................................................................... 14 
6.1 
Inclusion criteria ..................................................................................................... 14 
6.2 
Exclusion criteria .................................................................................................... 14 
6.3 
Screen failures ....................................................................................................... 14 
6.4 
Sample size calculation .......................................................................................... 15 
7. 
TREATMENT OF SUBJECTS ........................................................................................ 16 
7.1 
Overall treatment .................................................................................................... 16 
7.1.1 
Index procedure ............................................................................................... 16 
7.1.2 
Staged procedure (4 weeks) ............................................................................ 17 
7.2 
Data transfer and analysis ..................................................................................... 18 
8. 
METHODS ...................................................................................................................... 19 
8.1 
Study endpoints ..................................................................................................... 19 
8.1.1 
Primary study endpoint ..................................................................................... 19 
8.1.2 
Secondary study endpoints (definitions in appendix I) ..................................... 19 
8.2 
Randomisation, blinding and treatment allocation ................................................. 20 
8.3 
Study procedures ................................................................................................... 20 
8.3.1 
Baseline (pre procedure) .................................................................................. 20 
8.3.2 
Index Procedure ............................................................................................... 20 
8.3.3 
Discharge ......................................................................................................... 20 
8.3.4 
Staged procedure ............................................................................................. 21 
8.4 
Withdrawal of individual subjects ........................................................................... 22 
8.5 
Replacement of individual subjects after withdrawal .............................................. 22 
8.6 
Premature termination of the study ........................................................................ 22 
9. 
SAFETY REPORTING ................................................................................................... 23 
9.1 
Temporary halt for reasons of subject safety ......................................................... 23 
9.2 
AEs and SAEs ........................................................................................................ 23 
9.2.1 
Adverse events (AEs) ....................................................................................... 23 
9.2.2 
Serious adverse events (SAEs) ....................................................................... 23 
9.3 
Follow-up of adverse events .................................................................................. 24 
9.4 
Adverse event reporting ......................................................................................... 24 
10. STATISTICAL ANALYSIS .............................................................................................. 25 
10.1 
General methods .................................................................................................... 25 
10.2 
Analysis primary outcome ...................................................................................... 25 
10.3 
Analysis of secondary outcomes ............................................................................ 25 

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10.4 
Safety analysis ....................................................................................................... 26 
11. ETHICAL CONSIDERATIONS ....................................................................................... 27 
11.1 
Regulation statement ............................................................................................. 27 
11.2 
Recruitment and consent ....................................................................................... 27 
11.3 
Benefits and risks assessment and group relatedness .......................................... 27 
11.4 
Compensation for injury ......................................................................................... 27 
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ............................. 28 
12.1 
Handling and storage of data and documents ....................................................... 28 
12.2 
Monitoring and Quality Assurance ......................................................................... 28 
12.3 
Amendments .......................................................................................................... 29 
12.4 
Annual progress report ........................................................................................... 29 
12.5 
Temporary halt and (prematurely) end of study report ........................................... 29 
12.6 
Publication policy ................................................................................................... 30 
13. REFERENCES ............................................................................................................... 31 
14. APPENDIX I: RELEVANT DEFINITIONS ....................................................................... 33 

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1. LIST OF ABBREVIATIONS  
 
CCS 
Canadian Cardiovascular Society 
CFR  
Coronary flow reserve 
CTO  
Chronic total occlusion 
FFR 
Fractional flow reserve 
IMR 
Index of microcirculatory resistance 
IVUS 
Intravascular ultrasound 
MACE  
Major adverse cardiovascular events 
NYHA 
New York Heart Association 
OCT 
Optical coherence tomography 
PCI  
Percutaneous coronary intervention 
Pd/Pa 
Pressure-distal / pressure-aorta = ratio of mean resting distal coronary 
pressure to aortic pressure 
POBA 
Plain old balloon angioplasty 
RFR 
Resting full-cycle ratio 
SSR 
Suboptimal stent result 
ST 
Stent thrombosis 
TLR 
Target lesion revascularization 
TVF 
Target vessel failure 
 
 
 

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2. SUMMARY 
 
Rationale: 
Post-percutaneous coronary intervention (PCI) intra-coronary physiology emerges as a useful 
tool to assess acute stent results. After  PCI of  non-chronic total occlusions (CTOs), several 
previous studies suggested a relationship between low post-PCI fractional flow reserve (FFR) 
and future adverse cardiac events 1, 2. Non-hyperemic pressure ratio is a new category of 
resting indices, such as resting full-cycle ratio (RFR), that is calculated by measuring a resting 
pressure gradient across a coronary lesion under resting conditions (i.e. without pharmacologic 
hyperemia, as opposed to FFR) to assess the hemodynamic significance of a stenosis 3. A 
non-hyperemic pressure ratio, such as RFR, is theoretically less subject to the factors 
influencing FFR after PCI of a CTO, such as total stent length or acutely smaller diameters of 
the newly reperfused CTO vessel. However, the usefulness of post-PCI RFR in these patients 
remains to be elucidated. The ULTRA-CTO study will primarily evaluate both the value of post-
PCI RFR and post-PCI FFR for detecting suboptimal stent result (SSR) in the acute phase. 
The components of SSR are depicted in figure 1. 
Hypothesis: The hypothesis is that the area under the curve (AUC) of post-PCI RFR is non-
inferior to the AUC of post-PCI FFR in CTO patients with regard to prediction of suboptimal 
stent result (SSR). 
Primary objective: To assess the predictive value of post-PCI RFR and FFR with regard to 
SSR in CTO patients.  
Secondary objectives: 
To assess: 
- The predictive value with regard to SSR of the RFR and FFR gradient across the stented 
segment.  
- The correlation between post-PCI physiology (RFR, FFR, CFR, IMR) and SSR with anginal 
complaints (SAQ score), cardiovascular events and clinical (CCS and NYHA) classification 
- The impact on physician-decision making based on OCT and physiology findings. 
 
Study design: Prospective, multicentre, non-randomised investigator-initiated trial with a 
non-inferiority design 
 
 

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Study population: All patients of 18 years and older who are accepted for and successfully 
treated by PCI CTO in whom physiology measurements and OCT recordings are possible.  
Main study endpoint: The AUC of post-PCI RFR compared to the AUC of post-PCI FFR 
with regard to SSR. 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: The anticipated benefit is improvement of our knowledge on how to 
optimize stent results in CTO PCI. Because the pressure wires and OCT camera that are 
used for the study-related measurements are commonly used interventional tools, this poses 
no study-related additional risk for participating patients. International guidelines recommend 
the use of intravascular imaging for PCI guidance, especially in complex cases leading to 
lower myocardial infarction, TVR and cardiac mortality. Pressure wires are clinically indicated 
to identify hemodynamic significant (remaining) lesions that needs to be revascularized. Due 
to study-related measurements the procedures will be moderately prolonged, most likely by 
approximately 15 minutes.  
With minimal effort and risk, subjects included in this trial are able to contribute to research to 
that may improve the treatment of CTOs, which may have large impact on clinical practice 
and guidelines. 
 
 

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3. INTRODUCTION AND RATIONALE 
 
Post-PCI intra-coronary physiology emerges as a useful tool to assess acute stent results. 
Several previous studies suggested a relationship between low post-PCI FFR and future 
adverse cardiac events 1, 2, although an optimal cutoff value has not been reported. Non-
hyperemic pressure ratio (NHPR) is a new category of resting indices, such as resting full-
cycle ratio (RFR), among others, that is calculated by measuring a resting pressure gradient 
across a coronary lesion under resting conditions (i.e., without pharmacologic hyperemia) to 
assess the hemodynamic significance of a stenosis 3. The use of RFR instead of hyperemic 
physiology omits the use of a vasodilator, allowing the physician to perform multiple physiology 
assessments in less time and improving patient experience. In addition, RFR is potentially 
useful in the assessment of tandem lesions with minimal interaction between individual 
coronary stenoses. Currently, no data are available regarding post-PCI RFR or other non-
hyperemic pressure ratios with regard to clinical outcome and stent result.  
 
In the FFR-Search registry 4, 50% of all patients had a suboptimal FFR (≤ 0.90) after PCI with 
good angiographic result. Complex lesion characteristics, use of multiple stents and smaller 
reference vessel diameter were associated with a suboptimal FFR. This may explain an even 
higher rate of suboptimal FFR in chronic total occlusion (CTO) patients despite satisfactory 
angiographic results (65%) in the FFR-Search registry, but CTO lesions were present in only 
5% of the total patient cohort. Karamasis et al. 5 also showed that post-PCI FFR ≤0.90 was 
present in 69% and ≤0.80 in one-third of patient after successful CTO PCI (n=26). The high 
incidence of low post-intervention FFR might be present in this particular group of patients 
because of longer stented segments and suboptimal stent results, including stent 
underexpansion, strut malapposition, stent edge dissection/hematoma, in-stent tissue 
protrusion 6, 7, or acutely smaller diameters of the newly reperfused CTO vessel.  
 
Of note, studies including patients with an increased complexity (i.e., CTO or lesion length >28 
mm) demonstrated a consistent benefit of intravascular ultrasound (IVUS)-guided PCI as 
compared with angiography only, mainly driven by a reduction of repeat revascularization for 
restenosis (MACE at 1 year: CTO-IVUS, 2.6% vs. 7.1%, P=0.035; IVUS-XPL, 2.9% vs. 5.8%, 
P=0.007) 8, 9. Optical coherence tomography (OCT) guidance has been shown to be equivalent 
to IVUS guidance, but OCT might be more suitable to assess stent edge dissections and stent 
malapposition 10. Thus, OCT may play an important role in the CTO treatment algorithm, 
determining the need for adjunctive therapies as well as adequate stent sizing and optimizing 
stent placement.  

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This suggests that intra-coronary physiology and intra-coronary imaging might be very useful 
to guide post-procedure decision-making and optimization of CTO PCI. Karamasis et al. 5 
showed a significant 4 month recovery of post-PCI FFR in CTO (mean increase of 0.07 from 
0.82 to 0.89). Previously, Werner et al. used a Doppler wire to measure coronary flow reserve 
immediately after CTO PCI and at 5 months follow-up. Their study showed an increase of 
coronary flow reserve (2.01±0.58 to 2.50±0.79) because of a decrease in the baseline (resting) 
average peak velocity 11. Although the investigators interpreted these findings as the result of 
the resolution of the microvascular dysfunction caused by the CTO, they did not confirm this 
with specific parameters that address microvascular resistance, such the index of 
microcirculatory resistance (IMR). Distal luminal enlargement of the recanalized CTO vessels 
might be the most important explanation for increasing FFR at follow-up, due to restoration of 
flow, shear stress, and vasomotor properties of the distal vessel after the CTO recanalization.  
 
These combined findings question the reliability of FFR in the acute stage and suggest that 
FFR may not be the optimal physiologic tool to assess PCI-result in the acute stage. Also,  
further effort is warranted to understand the pathophysiological substrate of low post-PCI FFR 
in CTO patients. Coronary physiology measurements, including RFR, FFR, IMR and coronary 
flow reserve (CFR) and the addition of OCT, will lead to a better understanding of the functional 
and anatomical aspects of CTO PCI to guide further optimization of procedural results. 
Although non-hyperemic pressure ratio, such as RFR, is theoretically less subject to the factors 
influencing FFR, the usefulness of post-PCI RFR remains to be elucidated. 
The ULTRA-CTO study will primarily evaluate both the value of post-PCI RFR and post-PCI 
FFR for detecting suboptimal stent result (SSR) in the acute phase, and the stability of these 
measurements over time in a subset of patients with a staged procedure and repeated 
physiologic assessment. 
 
 

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4. OBJECTIVES 
 
4.1 Primary objective  
To assess the predictive value of post-PCI RFR and FFR with regard to SSR in CTO patients. 
 
4.2 Secondary objectives 
- To assess the predictive value with regard to SSR of the RFR and FFR gradient across the 
stented segment  
- To evaluate the correlation between positive RFR (≤0.89) and positive FFR (≤0.80) with 
regard to SSR following angiographically satisfactory CTO PCI.  
- To evaluate the correlation between post-PCI physiology (RFR, FFR, CFR, IMR) and SSR 
with anginal complaints (measured using the Seattle Angina Questionnaire [SAQ] 12), 
cardiovascular events and other clinical classifications (CCS and NYHA) 
- To assess the impact on physician-decision making based on OCT and physiology findings.  
 
4.3 Exploratory objectives 
-   To assess the change in RFR, FFR and other physiologic parameters over time (subset of 
patients) 
 
5. STUDY DESIGN 
ULTRA-CTO is a prospective multicentre non-randomised investigator-initiated trial designed 
to enrol 200 subjects with an indication for PCI CTO.  
After angiographically successful CTO PCI, intra-coronary physiologic assessment (RFR, 
FFR, CFR and IMR) and subsequent OCT of the CTO vessel will be performed. OCT may also 
be performed during a staged procedure when indicated (i.e. high contrast use, procedural 
duration, major dissection or other safety reasons according to the operator)..   
When intra-coronary physiologic assessment or OCT is not possible at all, the patients will not 
be included in the study (6.1).   
When the operator decides to optimize the stent result (post-dilation or additional stenting), 
based on the OCT and/or physiology, post-PCI RFR and FFR should be repeated.  
For patients with a remaining intermediate stenosis (angiographically 30-90%) in a non-CTO 
vessel or major side branch of the CTO vessel with diameter ³ 2mm, clinically indicated FFR 
guided PCI will be planned within 4 ± 2 weeks. During this staged procedure, intra-coronary 
physiologic assessment (RFR, FFR, CFR and IMR) will be repeated in the CTO vessel for 
exploratory objectives (before additional PCI).   

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At 4 ± 2 weeks follow-up, the occurrence of cardiovascular events and clinical classification 
will be assessed for secondary objectives.  See figure 2 for the study flow chart. A description 
of the primary and secondary endpoint(s) is included in paragraph 8.1. 
 
Figure 2. Flowchart ULTRA-CTO 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Indication for CTO PCI  
Exclusion study participation: 
PCI CTO not succesful 
Impossible to perform post-PCI physiology or 
Informed consent 
Index procedure /hospitalisation 
Succesful PCI CTO 
Not meeting in-/exclusion criteria  
Follow-up ( 4 ± 2 weeks):   
Clinical Classification (SAQ, NYHA), 
Post-PCI physiology (index) 
Additional PCI performed ? 
(based on OCT/physiology) 
Staged FFR 
guided PCI 
Post-PCI OCT  
(index or staged within 4 weeks ) 
Repeat post-PCI 
physiology CTO 
Repeat post-PCI 
FFR and RFR  

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6. STUDY POPULATION 
6.1 Inclusion criteria 
In order to be eligible to participate in this trial, a subject must meet all of the following 
criteria: 
 
1) Age 18 years and older. 
2) Angiographically successful PCI CTO, which is considered acceptable and final by the 
operator, without any remaining lesion ³ 30% proximal to the stented segment. 
3) Possibility to perform physiologic measurements and OCT of sufficient quality.  
4) Patients willing and capable to provide written informed consent. 
 
6.2 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from participation 
in this trial: 
 
1) Contra-indication for adenosine. 
 
6.3 Screen failures 
Subjects will be screened in hospital based on the information available. Subjects fulfilling 
the eligibility criteria and who have provided informed consent (IC) will be enrolled in the 
trial. Subjects who do not meet these criteria will be considered screen failures. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
subjects and will be captured on trial electronic case report forms (eCRFs). No further 
clinical follow-up will be performed on these subjects.  
 
 

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6.4 Sample size calculation 
This study is aimed at assessing a difference in the AUCs of paired data where each subject 
(with and without SSR) is subjected to FFR and RFR measurement post-PCI. This 
procedure compares two ROC curves for the paired sample case where in each subject 
has a known condition value (SSR) and test values from two diagnostic tests (RFR and 
FFR). The test values are paired because they are measured on the same subject.  
Researchers wish to show that a new classification method works at least as well as the 
current method. The trial is powered for non-inferiority. 
Based on previous studies the area under the curve of FFR in relation to SSR is assumed 
to be 0.90 and the incidence of SSR is assumed to be 40% 6, 7, 13. 
Assuming an AUC of 0.90 for FFR, with a significance level a of 5%, and a non-inferiority 
limit margin 0.10 and an estimated prevalence of SSR of 40%, a total of 190 patients are 
needed to obtain a power of 80%. To account for a drop out of 5%, the sample size will be 
increased to 200 patients.  
 

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7. TREATMENT OF SUBJECTS 
7.1 Overall treatment 
Patients will be medically treated according to the international guidelines. Screening of 
eligible patients will be performed by the researchers. Eligible patients meeting the inclusion 
criteria will be asked for informed consent by one of the researchers. The PCI procedure, 
intra-coronary physiologic assessment and OCT will be performed according to local 
guidelines and common practice. The study-related measurements at index - and staged 
procedure are described below and more detailed in a designated Standard Operating 
Procedure (SOP). 
7.1.1 
Index procedure 
1. After angiographically successful PCI of the CTO target vessel (no remaining lesion 
proximal or in-stent ³ 30%, confirmed in two orthogonal projections with an angle ³25 
degrees apart), physiologic measurements must be performed in this vessel before 
additional OCT. 
 
2. Physiologic assessment 
- Physiologic measurements must be performed using the Coroflow system 
(Coroventis) in combination with the PressureWire X (Abbott). 
- Physiologic measurements must be performed using intravenous adenosine and 
in the following order: 
1) Ensure adequate guide catheter position and adequate proximal venous access 
2) Administration of intracoronary nitrate (100 or 200 mcg) 
3) RFR 10 mm proximal to proximal stent edge. 
4) Pd/Pa (proximal arterial pressure/proximal aortic pressure without adenosine)  
5) RFR 10 mm distal to distal stent edge (without adenosine) 
6) Pd/Pa (distal arterial pressure/proximal aortic pressure without adenosine)  
7) Go to CFR/IMR mode: follow the steps and potential troubleshooting steps as 
indicated by the Coroventis software 
- Obtain the required hyperemia by infusion of intravenous adenosine with a dosage 
of 140 mcg/kg/min  
 
- CFR and IMR are calculated automatically. 
- Maintain hyperemia by continuing the infusion of adenosine 
8) Go to FFR mode:  

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- 10 mm distal to distal stent edge: FFR measurement after 20 heart beats during 
stable maximal hyperemia 
-  10 mm proximal to proximal stent edge: FFR measurement after 20 heart beats 
during stable maximal hyperemia 
- Stop infusion of adenosine 
- Check drift: if drift >0.03 repeat physiologic measurements (description “drift”) 
- Additional OCT will be performed during the index procedure or staged when 
indicated..  
 
 
3. OCT 
-  OCT imaging of the stented segment in the CTO target vessel; starting and 
visualizing 10 mm distal from the stent edge and ending/visualizing 10 mm proximal 
of the stent edge.   
- Based on the OCT findings and/or physiologic assessment, stent optimization 
(postdilation or additional stent placement) to eliminate treatable components of 
SSR (as defined in appendix I) is left to the operator’s discretion. 
- Distal RFR and distal FFR should be repeated after stent optimization 
- It must be noted on the designated form which component(s) of SSR were seen 
and treated by the operator. 
- In case the operator decides to perform one or more additional interventions or 
decides to refrain from additional interventions, it will be noted on the designated 
form what motivated the operator to do so  
- End of procedure. 
 
7.1.2 
Staged procedure (within 4 ± 2 weeks) 
1) 1) OCT may be performed during a staged procedure when indicated (i.e. high contrast 
use, procedural duration, major dissection or other safety reasons according to the 
operator).  See details for OCT at 7.1.1, section 3. 
2) For patients with a remaining intermediate stenosis (angiographically 30-90%) in a non-
CTO vessel or major side branch of the CTO vessel with diameter ³ 2mm, clinically 
indicated FFR guided PCI will be planned within 4 ± 2 weeks. During this staged 
procedure, intra-coronary physiologic assessment (RFR, FFR, CFR and IMR) will be 
repeated in the CTO vessel for exploratory objectives (before additional PCI). 
3) When the operator decides to optimize the CTO stent result (post-dilation or additional 
stenting), post-PCI RFR and FFR should be repeated.  

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7.2 Data transfer and analysis 
All physiologic measurements and OCT recordings at index – and staged procedure for 
exploratory purposes (see paragraph 7.1.1 and 7.1.2) must be stored and the anonymized 
raw data must be send to Radboudumc Technology Center. Physiologic data will be 
checked and analysed by the researchers. The specific OCT analyses will be performed by 
the researchers. 
 
 
 
 

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8. METHODS 
8.1 Study endpoints 
8.1.1 
Primary study endpoint 
Primary endpoint is defined as:  
The AUC of post-PCI RFR compared to the AUC of post-PCI FFR with regard to 
SSR.  
 
 
 
 
 
 
 
 
  
Components of combined endpoint of SSR: Geographical miss (A), stent mal-
apposition (B), stent mal-expansion (C) and intra-stent plaque protrusion/thrombus 
(D), edge dissection (E), as depicted in Figure 1. Definitions are described in 
appendix I. 
 
 
8.1.2 
Secondary study endpoints (definitions in appendix I) 
Secondary endpoints are defined as : 
- The predictive value of the RFR and FFR gradient across the stented segment with 
regard to SSR in CTO patients. 
- The correlation between positive RFR (≤0.89) and positive FFR (≤0.80) with regard 
to SSR following angiographically satisfactory CTO PCI.  
- The correlation between post-PCI physiology (RFR, FFR, CFR, IMR) and SSR with 
anginal complaints (SAQ score), NYHA and CCS classification and MACE at follow-
up. 

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- The correlation between OCT and/or physiology findings and physician-decision 
making (perform or refrain from additional PCI) 
 
8.1.3 Exploratory study endpoints 
Exploratory endpoints are defined as: 
- The change in RFR, FFR, Pd/Pa, IMR and CFR over time after CTO PCI in a subset 
of patients undergoing repeated physiologic assessment during a staged procedure     
 
 
 
8.2 Randomisation, blinding and treatment allocation 
There will be no randomisation and thus no blinding of the randomisation assignment. 
 
8.3 Study procedures 
The following study phases and procedures can be distinguished. See figure 3 for a 
schematic overview of all study procedures. 
 
8.3.1 Baseline (pre procedure)  
Screening of eligible patients will be performed by the researchers. Eligible patients 
meeting the inclusion criteria will be asked for informed consent by one of the 
researchers. The operator will be informed about participation in the trial.  
Accordingly the following baseline characteristics will be obtained before start of the 
procedure: patient characteristics, medical history, risk factors, blood sampling 
(creatinine clearance), the indication for the CTO PCI and specific characteristics of the 
CTO.  
8.3.2 Index Procedure 
 Several variables regarding procedure-related technical characteristics and the study-
related measurements will be collected during the index procedure. 
 
8.3.3 Discharge  
Occurrence of (S)AEs including MACE and other complications will be registered at 
discharge.  
 

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8.3.1  Staged procedure 
At 4 weeks, prior to the staged procedure, clinical classification, occurrence of (S)AEs 
including MACE and other events will be registered.  
 
Similar to the index procedure, several variables regarding procedure-related technical 
characteristics and the study-related physiologic measurements will be collected 
during the staged procedure. 
 
 
 
Figure 3. Study procedures 
 
1. 
This study will be conducted in subjects fulfilling all inclusion criteria and none of the exclusion criteria (see 
paragraph 6.1 and 6.2). 
2. 
Written informed consent will be obtained before enrollment in the trial.  
3. 
Blood sampling (creatinine clearance) will be performed according to standard care. No more than 20 ml of 
blood will be obtained during each sample. 
4. 
CCS classification, NYHA classification and at staged procedure also SAQ score, TLR, ST, MACE, TVF. 
 
 
Study procedure 
Baseline  
(pre procedure) 
Index procedure / 
hospitalization 
Staged procedure 
(subset of patients) 
Follow-up 
4 ± 2 weeks 
Patient eligibility: 
Inclusion/exclusion  
 
X1 
 
 
 
Patient informed consent 
X2 
 
 
 
Baseline characteristics: 
- Patient characteristics 
- Blood sample (creatinine clearance) 
- Use of medication 
- Medical history 
- Risk factors 
- Indication for CTO PCI 
- CTO characteristics 
 
X 
X3 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
PCI procedure variables 
 - Technical characteristics  
 - Physiology parameters 
 - OCT  
 
 
X 
X 
X 
 
(X) 
(X) 
(X) 
 
Clinical classification4 
X 
 
 
X 
Adverse events and complications 
 
X 
(X) 
X 

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8.4 Withdrawal of individual subjects 
Subjects can leave the trial at any time for any reason if they wish to do so without any 
consequences. The sponsor can decide to withdraw a subject from the trial for urgent 
medical reasons. 
 
8.5 Replacement of individual subjects after withdrawal 
Subjects will not be replaced after withdrawal from the trial unless a subject withdraw his or 
her consent before the start of procedure. 
 
8.6  Premature termination of the study 
A possible reason to prematurely end the study could be based on a decision of the 
sponsor. In that case a written statement will be prepared for the Medical Ethics Committee 
(MEC).  
 
 

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9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the Medical Research involving Human 
Subjects Act (WMO), the sponsor will suspend the trial if there is sufficient ground that 
continuation of the trial will jeopardise subject health or safety.  The sponsor will notify the 
accredited MEC without undue delay of a temporary halt including the reason for such an 
action. The trial will be suspended pending a further positive decision by the accredited 
MEC. The investigator will take care that all subjects are kept informed. 
  
9.2 AEs and SAEs  
9.2.1 
Adverse events (AEs) 
Adverse events (AEs) are defined as any undesirable experience occurring to a subject 
during the trial, whether or not considered related to coronary procedures. All AEs 
reported spontaneously by the subject or observed by the investigator or his staff will 
be recorded starting from enrolment onwards until follow-up or the staged procedure in 
a subset at 4 ± 2 weeks. Unchanged chronic conditions are not AEs and should not be 
recorded on the AE sheet.  
9.2.2 
Serious adverse events (SAEs) 
A serious adverse event (SAE) is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalization or prolongation of existing inpatients’ hospitalization*; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
 
*Hospitalization:  
Any AE leading to hospitalization or prolongation of hospitalization will be considered 
as serious, unless the admission is:  
• planned before subject’s inclusion in the trial (i.e. elective or scheduled surgery) or 
• ambulant (shorter than 12 hours) or 
• part of the normal treatment or monitoring of the studied disease (i.e. not due to a 
worsening of the disease) 

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9.3 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. AEs will not be 
followed up on once patients finish the study after 4 weeks. 
SAEs will be collected and monitored throughout the entire course of the trial.  
 
9.4 Adverse event reporting 
Each AE or complication meeting the definition for SAE will be reported by site upon 
discovery to the Clinical Research Organization (CRO)/sponsor, within 24 hours of the site 
investigator’s knowledge of the event. The accredited MEC will receive an overview of all 
SAEs annually.  
 
 
 

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10. STATISTICAL ANALYSIS 
The principal features of the statistical analysis of the data are described in this chapter. A 
more technical and detailed elaboration will be written in a separate statistical analysis plan 
(SAP). 
 
10.1 General methods 
In general, statistics for continuous variables will include mean, median, standard deviation, 
minimum, maximum, 25th  and 75th  percentile. Binary variables will be described with 
frequencies, percentages. 
 
10.2 Analysis primary outcome 
Primary objective of the study is to evaluate non-inferiority of with a pre-specified non-
inferiority margin of 0.10 and AUC of 0.90. The hypothesis for testing non-inferiority is 
 
 
 
H0: AUCRFR – AUCFFR ≤ -0.10 
 
 
H1: AUCRFR – AUCFFR > -0.10 
 
 
Non-inferiority is established if the lower limit of a (1–2α) × 100% confidence interval of the 
difference between AUCRFR and AUCFFR is above -0.10 rather than the usual (1 − α) × 100% 
confidence interval. We will construct a 90% 2-sided confidence interval and use the lower 
bound to determine non-inferiority. If the lower boundary of the 90%CI of the difference is 
above -0.10 than RFR is non-inferior to FFR. If the lower boundary of the 90%CI of the 
difference is below -0.10 than RFR is inconclusive or inferior to FFR. 
 
10.3 Analysis of secondary outcomes 
Pearson r correlation and Spearman correlation coefficient rho (r) will be used to evaluate 
the degree of relationship between variables. For normally distributed variables, we will use 
the Pearson r correlation, while in case of skewed, ordinal data, the degree of association 
between variables will be quantified using Spearman correlation coefficient rho (r).  
For repeated measurements (RFR, FFR, and other physiological parameters) we will use 
the paired t test for normally distributed variables and the Wilcoxon signed-rank test for 
skewed continuous data. 
 
 

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10.4 Safety analysis 
 
The number, nature, frequency, severity and treatments will be described. 
 
 

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11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
The trial will be conducted in compliance with the protocol, principles of the Declaration of 
Helsinki (2013), WMO, ICH-Good Clinical Practice, as well as local regulations and 
applicable regulatory requirements.  
 
11.2 Recruitment and consent 
Eligible patients meeting the inclusion criteria will be asked for IC by one of the cardiologists. 
Written IC will be obtained before the index PCI procedure. The information is intended to 
give each participant a thorough understanding of the purpose and the nature of the trial, 
the cooperation required, anticipated benefits, and potential hazards of the trial. The 
cardiologist also explains that the patient is completely free to refuse or to withdraw from 
the trial and that if he does so he receives standard treatment with the same degree of care.  
 
11.3 Benefits and risks assessment and group relatedness 
The anticipated benefit is improvement of our knowledge on how to optimize stent results 
in CTO PCI.  
Because the pressure wires and OCT camera that are used for the study-related 
measurements are commonly used interventional tools, this poses no study-related 
additional risk for participating patients. International guidelines recommend the use of 
intravascular imaging for PCI guidance, especially in complex cases leading to lower 
myocardial infarction, TVR and cardiac mortality. Pressure wires are clinically indicated to 
identify hemodynamic significant (remaining) lesions that needs to be revascularized. Due 
to study-related measurements the procedures will be moderately prolonged, most likely by 
approximately 15 minutes. With minimal effort and risk, subjects included in this trial are 
able to contribute to research to that may improve the treatment of CTOs, which may have 
large impact on clinical practice and guidelines. 
 
11.4 Compensation for injury 
The investigator has a liability insurance which is in accordance with article 7 of the WMO.  
The sponsor will arrange an insurance which is in accordance with the legal requirements 
in the Netherlands (Article 7 WMO). This insurance provides cover for damage to research 
subjects through injury or death caused by the trial.  
 
 
 

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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
Electronic Case Report Forms (eCRFs) have been developed to capture the trial 
information outlined in this protocol. Data from these eCRFs will be used in the analysis of 
trial results. Modification of the eCRFs will only be made if deemed necessary by the 
sponsor. 
Data entered in to the eCRFs will be taken from source documentation, such as hospital 
procedure reports, admission and discharge summaries and other hospital or physician 
office/clinic documents. If no standard hospital or office document exists to capture some 
of the information that may be unique to this trial, a worksheet may be developed to record 
this information and be used as a source document. This worksheet needs to be signed by 
the person responsible for the registered data on the worksheet at the given site. These 
source documents will serve as the basis for monitoring the eCRFs. Electronic patient 
records will be considered as source documents on the condition that the hospital’s 
database is a validated system. If this is not the case, electronic records will have to be 
printed and added to the paper patient file. A print-out of the eCRF cannot be used as source 
documentation. 
The investigator will maintain all records pertaining to this trial for fifteen years following 
trial completion, or as otherwise instructed by the CRO, or per local requirements whichever 
is longer. Published data will not be traceable to the individual patient. 
 
12.2 Monitoring and Quality Assurance  
CRO and/or designee will monitor the trial over its duration according to the pre-specified 
monitoring plan. This will be done by means of personal visits to the site’s facilities, 
telephone contacts to the investigator or designee, and/or remotely through the internet-
based database with verification of the source data. The trial monitor may inspect all 
documents and required documents that are maintained by the investigator/site, including 
medical records (office, clinic or hospital) for the subjects in this trial. The investigator/site 
will permit access to such records.  
 
Source documentation must be available to substantiate proper IC procedures, adherence 
to protocol procedures, adequate reporting and follow-up of adverse event and accuracy of 
data collected on case report forms. A monitoring visit log will be maintained at the site. The 
investigator and/or research coordinator will be available for monitoring visits. It is expected 
that the investigator will provide the trial monitor with a suitable working environment for 
review of trial-related document.  

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A comprehensive, integrated data management plan, including on-line queries and (remote) 
data cleaning will be implemented to ensure the integrity of the data. All changes to the 
database will be tracked by an audit trail. 
 
All site personnel will be trained on the protocol and internet-based database prior to the 
initiation of the trial at each respective site. Only trained (site) personnel will receive access 
to the internet-based database by means of a personalized username and password. 
 
12.3 Amendments  
Amendments are changes made to the research after a favourable opinion by the 
accredited MEC has been given. All amendments will be notified to the MEC that gave a 
favorable opinion.  
 
12.4 Annual progress report 
A summary of the progress of the trial will be submitted to the accredited MEC once a year. 
Information will be provided on the date of inclusion of the first subject, numbers of subjects 
included and numbers of subjects that have completed the trial, serious adverse events, 
other problems, and amendments.  
 
12.5 Temporary halt and (prematurely) end of study report 
The sponsor will notify the accredited MEC of the end of the trial within a period of 8 weeks. 
The end of the trial is defined as the last patient’s last visit.  
 
The sponsor will notify the MEC immediately of a temporary halt of the trial, including the 
reason of such an action.  
In case the trial is ended prematurely, the sponsor will notify the accredited MEC within 15 
days, including the reasons for the premature termination. 
 
Within one year after the end of the trial, the sponsor will submit a final trial report with the 
results of the trial, including any publications/abstracts of the trial, to the accredited MEC.  
 
 
 

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12.6 Publication policy 
This trial will be registered at www.clinicaltrials.gov. The results of this prospective, 
multicentre, non-randomised investigator-initiated trial with a non-inferiority design are 
intended to be published in a peer-reviewed journal and as abstracts/presentations at 
medical congresses. The publication rights in regard to the main results of the trial, i.e., 
regarding the primary and secondary objectives, belong to the sponsor. No individual 
investigator may publish on the results of this trial, or their own patients, without prior 
approval from the sponsor. A minimum number of subjects per site needs to be included in 
the trial by the investigator in order to be considered as co-author for publication. This is 
further defined in a separate clinical trial agreement with each participating site. 
 
 
 

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13. REFERENCES 
 
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van Bommel RJ, Masdjedi K, Diletti R, Lemmert ME, van Zandvoort L, Wilschut J, 
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Bezerra H and Holmes D. Optical coherence tomography imaging during percutaneous 
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Maehara A, Ben-Yehuda O, Ali Z, Wijns W, Bezerra HG, Shite J, Genereux P, 
Nichols M, Jenkins P, Witzenbichler B, Mintz GS and Stone GW. Comparison of Stent 
Expansion Guided by Optical Coherence Tomography Versus Intravascular Ultrasound: The 
ILUMIEN II Study (Observational Study of Optical Coherence Tomography [OCT] in Patients 
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Cardiovasc Interv. 2015;8:1704-14. 
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Hong SJ, Kim BK, Shin DH, Nam CM, Kim JS, Ko YG, Choi D, Kang TS, Kang WC, 
Her AY, Kim YH, Hur SH, Hong BK, Kwon H, Jang Y, Hong MK and Investigators I-X. Effect 
of Intravascular Ultrasound-Guided vs Angiography-Guided Everolimus-Eluting Stent 
Implantation: The IVUS-XPL Randomized Clinical Trial. JAMA. 2015;314:2155-63. 
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Kim BK, Shin DH, Hong MK, Park HS, Rha SW, Mintz GS, Kim JS, Kim JS, Lee SJ, 
Kim HY, Hong BK, Kang WC, Choi JH, Jang Y and Investigators C-IS. Clinical Impact of 
Intravascular Ultrasound-Guided Chronic Total Occlusion Intervention With Zotarolimus-
Eluting Versus Biolimus-Eluting Stent Implantation: Randomized Study. Circ Cardiovasc 
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Raber L and Ueki Y. Optical coherence tomography- vs. intravascular ultrasound-
guided percutaneous coronary intervention. J Thorac Dis. 2017;9:1403-1408. 
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Werner GS, Emig U, Bahrmann P, Ferrari M and Figulla HR. Recovery of impaired 
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Spertus JA, Winder JA, Dewhurst TA, Deyo RA, Prodzinski J, McDonell M and Fihn 
SD. Development and evaluation of the Seattle Angina Questionnaire: a new functional 
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Hanekamp CE, Koolen JJ, Pijls NH, Michels HR and Bonnier HJ. Comparison of 
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Rathore S, Hakeem A, Pauriah M, Roberts E, Beaumont A and Morris JL. A 
comparison of the transradial and the transfemoral approach in chronic total occlusion 
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Di Vito L, Yoon JH, Kato K, Yonetsu T, Vergallo R, Costa M, Bezerra HG, Arbustini E, 
Narula J, Crea F, Prati F, Jang IK and group C. Comprehensive overview of definitions for 
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Executive Group on behalf of the Joint European Society of Cardiology /American College of 
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Universal Definition of Myocardial I. Fourth Universal Definition of Myocardial Infarction 
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Bruining N, Cho JM, Chowdhary S, Costa MA, de Silva R, Dijkstra J, Di Mario C, Dudek D, 
Falk E, Feldman MD, Fitzgerald P, Garcia-Garcia HM, Gonzalo N, Granada JF, Guagliumi G, 
Holm NR, Honda Y, Ikeno F, Kawasaki M, Kochman J, Koltowski L, Kubo T, Kume T, Kyono 
H, Lam CC, Lamouche G, Lee DP, Leon MB, Maehara A, Manfrini O, Mintz GS, Mizuno K, 
Morel MA, Nadkarni S, Okura H, Otake H, Pietrasik A, Prati F, Raber L, Radu MD, Rieber J, 
Riga M, Rollins A, Rosenberg M, Sirbu V, Serruys PW, Shimada K, Shinke T, Shite J, Siegel 
E, Sonoda S, Suter M, Takarada S, Tanaka A, Terashima M, Thim T, Uemura S, Ughi GJ, 
van Beusekom HM, van der Steen AF, van Es GA, van Soest G, Virmani R, Waxman S, 
Weissman NJ, Weisz G and International Working Group for Intravascular Optical 
Coherence T. Consensus standards for acquisition, measurement, and reporting of 
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Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG, Morel 
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14. APPENDIX I: RELEVANT DEFINITIONS 
 
Angiographic success 
Successful PCI of the target lesion with a residual stenosis of less 
than 30% angiographically. 
 
CCS 
Canadian Cardiovascular Society. 
Clinical classification 
CCS classification, NYHA classification and at staged procedure 
also SAQ score, TLR, ST, MACE, TVF. 
CTO  
Lesion exhibiting TIMI 0-1 flow in a native coronary artery with an 
occlusion duration > 3 months14. 
 
Geographical miss  
Incomplete stent coverage of plaques within 10 mm distal or 
proximal to the stent edges with residual stenosis on OCT of ≥ 
50% cross-sectional area (CSA) as compared to the reference 
lumen area.  
 
Intrastent plaque-
protrusion 
Distance between strut surface and the greatest extent of 
protrusion >100 µm15. 
 
Intrastent thrombus-
protrusion 
Irregular mass protruding into lumen >250 µm at the thickest 
point; thrombus may not be connected to the vessel wall15. 
 
MACE 
Composite endpoint of all-cause mortality, myocardial infarction 
and any coronary revascularization. 
 
Microvascular 
dysfunction 
IMR > 25. 
Myocardial infarction 
Defined according to the expert consensus document16. 
 
NYHA 
New York Heart Association. 
Pd/Pa  
Pressure-distal / pressure-aorta = ratio of mean resting distal 
coronary pressure to aortic pressure 
Reference lumen area 
 
The average of the two largest lumen areas proximal and distal 
to a stenosis but within the same segment (usually within 10 
mm)17. 

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Repeat revascularization 
 
PCI 
or 
CABG 
(with 
specification 
of 
target 
vessel 
revascularization). 
 
SAQ 
Seattle Angina Questionnaire12. 
Sponsor 
The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or 
investigator. A party that provides funding for a study but does 
not commission it is not regarded as the sponsor, but referred to 
as a subsidising party. 
 
Stent edge dissection 
(clinically relevant) 
 
Dissection width ≥ 200 µm, and/or dissection angle ≥ 60°, and/or 
dissection length > 0.67 mm15. Stent edge dissections meeting 
these criteria are considered components of SSR. 
 
Stent edge dissection 
(other) 
 
Stent edge dissections not meeting the criteria of clinically 
relevant stent edge dissections.  
Stent malapposition 
 
Distance from the center of the stent blooming artifact to the 
vessel wall of ≥ 200 µm15 and present in at least 5 consecutive 
OCT frames6.  
 
Stent thrombosis 
 
Presence of a thrombus that originates in the stent or in the 
segment 5 mm proximal or distal to the stent18. 
 
Stent underexpansion 
 
In-stent minimal lumen area less than 90% of the average 
reference lumen area15.  
 
TLR 
 
Re-intervention of the treated segment within 5 mm proximal or 
distal to the stent18. 
 
TVF 
 
Composite endpoint of cardiac death, target-vessel myocardial 
infarction and clinically driven target-vessel revascularization.