The NOrdic-Baltic Randomized Registry Study for Long-term Clinical Evaluation of Adjunction of PCI to Optimal Medical Therapy in Chronic Total Coronary Occlusion
Phase: NA
Conditions: Chronic Total Occlusion of Coronary Artery, Heart Failure, Angina Pectoris
Sponsor: Leif Thuesen

Protocol 
 
 
 
 
The NOrdic‐Baltic randomized registry 
study for Long‐term clinical Evaluation of 
adjunction of PCI to optimal medical 
therapy in Chronic Total coronary 
Occlusion 
 
NOBLE CTO 
 
 
The Nordic‐Baltic CTO study group 
 
 
 
 
 
 
 
 
 
Correspondence:  
Martin Kirk Christensen, Department of Cardiology, Aalborg University Hospital, 
Aalborg, Denmark. 
Mail: m.kirk@rn.dk 

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Table of contents 
1. 
ABBREVIATIONS .............................................................................................................. 6 
2. 
SYNOPSIS ........................................................................................................................ 8 
3. 
PURPOSE ....................................................................................................................... 13 
4. 
HYPOTHESIS .................................................................................................................. 13 
5. 
BACKGROUND .............................................................................................................. 13 
5.1 
Fejl! Bogmærke er ikke defineret. 
5.2 
Fejl! Bogmærke er ikke defineret. 
5.3 
Fejl! Bogmærke er ikke defineret. 
6. 
THE RANDOMIZED REGISTRY ........................................................................................ 14 
7. 
MATERIAL AND METHODS ............................................................................................ 15 
7.1 
The index lesion vessel 
15 
7.2 
Non‐CTO lesions 
15 
7.3 
CTO PCI 
15 
7.4 
Patients 
16 
7.5 
Inclusion criteria 16 
7.6 
Exclusion criteria 17 
8. 
SCHEDULE OF EVENT REGISTRATION ............................................................................. 17 
9. 
ENDPOINTS ................................................................................................................... 17 
9.1 
Primary endpoint 17 

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9.2 
Primary co‐endpoint 
18 
9.3 
First Published endpoints 
18 
9.4 
Secondary endpoints 
18 
10. ECHOCARDIOGRAPHY ................................................................................................... 18 
11. CMR  FEJL! BOGMÆRKE ER IKKE DEFINERET. 
11.1 Health economy and socio‐economic aspects 
19 
11.2 Evaluation of endpoints 
19 
11.3 Definition of endpoints 
19 
11.3.1 All-cause death ................................................................................................................................................................................. 19 
11.3.2 Stroke 19 
11.3.3 Cardiac death .................................................................................................................................................................................... 20 
11.3.4 Procedure related myocardial infarction ............................................................................................................................. 20 
11.3.5 Spontaneous myocardial infarction ........................................................................................................................................ 20 
11.3.6 Target lesion revascularization ................................................................................................................................................ 21 
11.3.7 Target vessel revascularization ................................................................................................................................................ 21 
11.3.8 Stent thrombosis ............................................................................................................................................................................. 21 
11.4 Recommendations for index lesion re‐revascularization 
21 
11.5 Study stents 
21 
11.6 PCI procedure; antithrombotic treatment 
22 
11.7 Measurement of biomarkers 
22 
12. STATISTICS AND SAMPLE SIZE ....................................................................................... 22 
12.1 Primary endpoint 22 
12.2 Primary co‐endpoint 
22 
12.3 Secondary endpoints and other variables 
22 
12.4 Sample size calculation (primary endpoint) 
22 

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12.5 Sample size calculation (primary co‐endpoint) 23 
12.6 Analysis of the population 
23 
13. RANDOMIZATION AND DATA MANAGEMENT ............................................................... 23 
13.1 Randomization 
23 
13.2 Data management 23 
13.3 Monitoring of the study 
24 
13.4 Data Safety Monitoring Board (DSMB) 
24 
13.5 Direct access to source documentation 
24 
13.6 Source data verification 
24 
14. ETHICAL ASPECTS .......................................................................................................... 25 
14.1 Ethical conduct of the study 
25 
14.2 Risks, side effects, advantages and disadvantages in study participation 
25 
14.3 Ethical considerations 
26 
14.4 Informed consent 26 
14.5 Patient information and informed consent 
27 
14.6 Withdrawal 
27 
14.7 Biological material 28 
15. STUDY PLAN .................................................................................................................. 28 
15.1 Participating centres and operators 
28 
15.2 Steering committee 
28 
15.3 Progress of the study 
28 

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16. ECONOMY ..................................................................................................................... 28 
17. PUBLICATION ................................................................................................................ 29 
18. REFERENCES .................................................................................................................. 29 

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1. Abbreviations 
AMI 
 
Acute Myocardial Infarction 
AP 
 
Angina Pectoris 
ASA 
 
Acetylsalicylic Acid 
CABG 
 
Coronary Artery Bypass Grafting 
CCS 
 
Canadian Cardiovascular Society Angina Grading System 
CK-MB mass 
Creatinine Kinase MB 
CMR 
 
Cardiac magnetic resonance 
CRF 
 
Case Report Form 
CTO 
 
Chronic total occlusion 
CV 
 
Curriculum Vitae 
DAPT 
 
Dual antiplatelet therapy 
DES 
 
Drug Eluting Stents 
ECG 
 
Electrocardiogram 
EC 
 
Ethical Committee 
GCP 
 
Good Clinical Practice  
IHD 
 
Ischemic Heart Disease 
LAD 
 
Anterior descendant coronary artery 
LVEF 
 
Left ventricular ejection fraction 
LBBB 
 
Left bundle branch block 
MACE 
 
Death, myocardial infarction and revascularization 
 
MACCE 
 
Death, myocardial infarction, stroke and revascularization 
PCI 
 
Percutaneous Coronary Intervention 
PET 
 
Positron emission tomography 
SAQ 
 
Seattle Angina Questionaire 
SF-12v2  
12-Item Short Form Survey Instrument 
SPECT 
 
Single-photon emission computed tomography 
TIMI 
 
Thrombolysis In Myocardial Infarction 
TNI 
 
Troponin I 
TNT 
 
Troponin T 
TLR 
 
Target Lesion Revascularization 
TVR 
 
Target Vessel Revascularization 

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2. Synopsis 
 
The NOrdic-Baltic randomized registry study for Long-term clinical Evaluation of 
adjunction of PCI to optimal medical therapy in Chronic Total coronary Occlusion 
 
NOBLE CTO 
The Nordic-Baltic PCI study group 
 
 
Version Number 
1.3 
Date 
27. 04. 2018. 
National Coordinating 
investigator 
Martin Kirk Christensen, Department of 
Cardiology, Aalborg University Hospital, 
Denmark. 
Sponsor 
Leif Thuesen, Department of Cardiology, 
Aalborg University Hospital, Denmark. 
Investigators 
Dedicated Nordic-Baltic chronic total 
coronary occlusion (CTO) operators. At 
each site one coordinating investigator. 
Protocol authors 
Martin Kirk Christensen and Leif Thuesen, 
Department of Cardiology, Aalborg 
University Hospital, Denmark.  
Study cohort 
Patients with CTO-related symptoms or 
reversible myocardial dysfunction. 
CTO lesions for inclusion 
Coronary artery supplying a major 
myocardial territory  
Purpose 
To assess quality of life, symptoms, 
cardiac function, cardiac events and 
survival of adjunction of PCI to optimal 
medical therapy (OMT) in CTO patients.  

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Trial Type; randomized registry 
In the context of CTO treatment 
evaluation, the conventional randomized 
clinical trial is associated with a number of 
shortcomings: 
 Unreliable power calculation concerning 
long-term mortality. 
 Unknown crossing over rate. 
 Unknown optimal follow-up time. 
 Sub-group results problematic. 
Therefore, we have designed the present 
study as a randomized registry. 
Consequently, results will be hypothesis 
generating. However, the randomization 
to OMT vs. OMT + PCI will yield an 
unbiased and clinical relevant evaluation 
of a relatively conservative therapy vs. a 
more aggressive CTO approach. 
 
The randomization will be 1:1. The OMT-
group participants are offered PCI after 6 
months.  
After inclusion of 2000 patients, there will 
be a decision of continuation of patient 
inclusion according to clinical results and 
patient inclusion rate. 
Background 
 Short and long-term effects of CTO 
treatment are poorly investigated. 
 The high procedural success rate of 
CTO-PCI at dedicated centers permits a 
randomized comparison of OMT + PCI 
vs. OMT. 

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 In recently published randomized studies 
CTO PCI did not improve clinical 
outcomes. 
Definitions 
 CTO lesion; TIMI 0 antegrade flow for 
estimated >3 months. 
Inclusion criteria 
 ≥1 CTO lesion amenable to PCI. 
 Stable or stabilized coronary artery 
disease  
 Symptoms (angina pectoris or shortness 
of breath) and/or signs of reversible 
perfusion defect by SPECT, PET or MR 
and/or angiographic/echocardiographic 
signs of reversible ischemia.  
 CTO lesion in a major coronary vessel 
supplying a significant myocardial 
territory (vessel diameter usually ≥3mm). 
Exclusion criteria 
 Expected survival <1 year. 
 Renal failure on dialysis. 
 Relative or absolute contraindication to 
dual antiplatelet therapy 
 Stable non-CTO lesions treated within 
one month. 
 Declined informed consent. 
 Regarding CMR: allergy to contrast 
medium, severe obesity, claustrophobia 
and certain metallic implants 
Primary endpoint 
 
 3-year all-cause mortality 
 6-month quality of life (SF-12v2 and 
SAQ) 
Secondary endpoints 
 All-cause mortality, cardiac mortality, 
non-cardiac mortality. 

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 Minor and major stroke. 
 Myocardial infarction (all, type 1-4). 
 Target vessel and non-target vessel 
revascularization. 
 ARC-defined stent thrombosis. 
 Bleeding (Bleeding Academic Research 
Consortium Definition for Bleeding; 3a, 
3b, 3c, 5a, 5b).  
 Secondary endpoints will be assessed 
after inclusion of 100, 250, 500, 1000, 
1500 and 2000 patients. 
Clinical follow-up 
Clinical follow-up as needed to achieve 
OMT and symptomatic relief.  
Out-patient clinical control after 6 months. 
Follow-up by telephone call after 1, 2, 3, 
5, 10, 15 and 20 years. 
Statistical analysis 
Continuous variables will be compared 
with the two-sample t-test or the Mann-
Whitney U-test. Categorical variables will 
be analysed with the χ²-test. Endpoints 
will be analysed until occurrence of and 
endpoint event or loss to follow-up using 
Kaplan-Meier time-to-event curves. A two-
sided p-value of less than 5% will indicate 
significance.  
Sample size calculation for 3-
year all-cause mortality and first 
published endpoint (6-months 
quality of life) 
There are no randomized clinical trials 
powered to compare all-cause mortality or 
symptomatic improvement of OMT vs. 
OMT and PCI in patients with ≥1 CTO 
lesion amenable to PCI. 
 

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We expect a 3-year all-cause mortality 
rate of 4.5% in the PCI group vs. 6.0% in 
the OMT group. With alpha of 5% and 
power (1-beta) 80%, a total of 1966 
patients will be needed to detect this 
treatment effect difference. To account for 
loss-to follow-up 2000 patients will be 
randomized. 
 
We expect symptomatic improvement in 
45% of patients after OMT and in 75% of 
patients after PCI. With alpha of 5% and 
power (1-beta) 80%, a total of 82 patients 
will be needed to detect this treatment 
effect difference. To count for loss to 
follow-up, a total of 100 patients will be 
included (50 in each group).  
Analysis of the population 
 
The results will be analysed according to 
the intention-to-treat principle. 
Pre-specified subgroups 
 
 Successful/unsuccessful PCI. 
 6-month cross-over group. 
 Permanent OMT group (non-cross-over 
group) 
 Female/male gender. 
 Diabetes/non-diabetes. 
 Symptomatic/asymptomatic. 
 Angina/myocardial dysfunction 
 CTO coronary segment location. 
 Age ≥/≤ 80 years. 
Sub-studies (optional) 
 
 Socio-economic status 

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 6-month CMR evaluation of reversible 
perfusion defects compared to index 
CMR before CTO PCI. 
 6-month echocardiographic evaluation of 
systolic and diastolic left ventricular 
function compared to index 
echocardiography before CTO PCI. 
 Evaluation of ventricular arrhythmias by 
implantation of cardiac monitor  
 
3. Purpose 
To assess all-cause mortality and to monitor continuously short- and long-term clinical 
and socio-economic effects of CTO PCI as adjunction to optimal medical therapy. 
4. Hypothesis 
In patients with ≥1 CTO lesion amenable to PCI, restoring normal blood flow in the 
occluded artery will improve short and long-term quality of life, improve and preserve 
myocardial function, reduce risk of extensive myocardial infarction, reduce cardiac and 
all-cause death and positively influence socio-economic status.1,2 At the same time, 
successful CTO treatment may increase risk of non-extensive myocardial infarction, 
stent thrombosis and new revascularization.3,4  
5. Background 
Opening of a chronic total coronary occlusion by PCI used to be associated with low 
procedural successrate and increased risk of procedural complications. Consequently, 
these patients were primarily medically treated or referred to coronary bypass 
operation.1,5,6 Improvements in CTO PCI techniques, devices and operator skills in 
recent years has changed the CTO treatment scenario.7 CTO treatments may now be 
characterized by high success rates and acceptable low risk of complications.5 
However, short and long-term effects of CTO treatment in non-selected CTO patients 
are poorly investigated and adequately powered randomized clinical trials on symptoms, 

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quality of life, adverse cardiac events and longevity are non-existent. Consequently, a 
large-scale randomized clinical CTO vs. OMT trial is a realistic and clinically relevant 
initiative. 
 
 
Unfortunately, slow patient inclusion rate and reluctance to include patients have been 
difficult to overcome in two recent conventional randomized clinical trials on PCI vs. 
OMT; the EUROCTO8 and the DECISION9 trials. Both studies were terminated 
prematurely. The recently published DECISION trial documented no benefit of PCI as 
adjunct to OMT in CTO patients. In the present randomized registry, the OMT patients 
are offered PCI after a 6-month period of optimal medical therapy. The design of the 
present study is expected to be acceptable to most CTO patients and clinicians. In an 
all-comers CTO-population it will enable randomized assessment of 6-month quality of 
life parameters, angina and NYHA scores and imaging indices of myocardial ischemia 
and function (optional). Furthermore, long-term clinical follow-up with registration of 
major adverse cardiac events will be possible in cohorts randomized to OMT and PCI 
vs. OMT, and in non-randomized comparisons of cohorts 1) randomized to PCI, 2) 
randomized to PCI with unsuccessful/successful procedural results, 3) randomized to 
OMT without crossover to PCI and 4) randomized to OMT with crossover to PCI.  
 
6. The randomized registry 
In the context of CTO treatment evaluation, the conventional randomized clinical trial is 
associated with a number of shortcomings: 
 Unreliable power calculation concerning long-term mortality. 
 Unknown cross-over rate. 
 Unknown optimal follow-up time. 
 Sub-group analyses problematic. 
Therefore, we have designed the present study as a randomized registry. 
Consequently, results will be hypothesis generating. Still, the randomization to OMT vs. 
OMT + PCI will yield an unbiased and clinical relevant evaluation of a relatively 
conservative therapy vs. a more aggressive CTO approach. Further, the prospective 

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and CTO-focused parameter registration will provide high data quality for sub-group 
analyses.  
 
7. Material and methods 
7.1 The index lesion vessel 
The present study will focus on CTO lesions in major epicardial vessels that supply a 
significant myocardial territory (vessel diameter usually ≥3mm). 
7.2 Non-CTO lesions 
Concomitant non-CTO lesion treatment may invalidate assessment of the clinical effects 
and paraclinical findings related to a CTO lesion and treatment thereof. Consequently, 
stable non-CTO lesions should not be treated within one month of the index procedure. 
7.3 CTO PCI 
A CTO PCI is indicated in patients with angina pectoris/shortness of breath and normal 
left ventricular function or with demonstrated reversible myocardial perfusion defect by 
either single-photon emission computed tomography (SPECT), positron emission 
tomography (PET) or cardiac magnetic resonance (CMR).10  
 
Antegrade, retrograde and combined approaches may be used at the discretion of the 
operator. Coronary stent implantation using 3rd generation DES will be preferred. In 
case of procedural failure, more attempts should be considered to achieve as high 
success rate as possible without compromising patient safety. The operators should pay 
attention to the use of contrast, minimize focal radiation and prioritize patient safety in 
complex antegrade and retrograde procedures.1,10  
 
Bilateral injections should be used routinely. Usually, the initial procedure is carried out 
by antegrade approach using over-the-wire balloons or dedicated catheters for support 
and wire exchange. Retrograde wiring through contralateral or ipsilateral collaterals is 
reserved failed primary attempts and performed either as a secondary procedure or as 

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a hybrid procedure usually starting by antegrade approach. Antegrade sub-intimal 
tracking or variants of this procedure may be used in some cases.11  
 
Patients will be pre-treated with guideline based dual antiplatelet therapy. Procedural 
anticoagulation after local standards. Post PCI, lifelong aspirin (75 mg/day) and 6-12 
months DAPT.2  
 
Uncomplicated cases may be discharged the same or the next day.  
 
7.4 Patients 
Consecutive CTO-patients participating in the study will be randomized 1:1 to optimal 
medical therapy (OMT) vs. OMT and CTO PCI. After inclusion of 2000 patients, it will be 
decided whether to continue the study considering clinical results and patient inclusion 
rate.  
 
The patients will be identified after a clinically indicated coronary angiogram. A CTO 
lesion is defined as absence of antegrade flow (Trombolysis in Myocardial Infarction 
(TIMI) grade flow 0) and a history suggesting occlusion of the vessel for >3 months. The 
investigators will not advertise for participants, and the participants will not receive 
honorarium for participation. 
7.5 Inclusion criteria 
 ≥1 CTO lesion amenable to PCI. 
 Stable or stabilized coronary artery disease. 
 Symptoms (angina pectoris or shortness of breath) and/or signs of reversible perfusion 
defect by SPECT, PET or MR and/or angiographic/echocardiographic signs of 
reversible ischemia.   
 CTO lesion in a major coronary vessel supplying a significant myocardial territory 
(vessel diameter usually ≥3mm). 

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7.6 Exclusion criteria 
 Expected survival <1 year. 
 Renal failure on dialysis.  
 Relative or absolute contraindication to dual antiplatelet therapy. 
 Allergy relevant to the study treatments. 
 Age <18 years. 
 Declined informed consent. 
 Inability to understand or provide informed consent 
 Non-CTO revascularization less than one month prior to the index treatment. 
 Regarding CMR: allergy to the contrast medium, severe obesity, claustrophobia and 
certain metallic implants 
8. Schedule of event registration 
After 6 months, the routine pre-study assessment of clinical status, quality of life by 12-
Item Short Form Survey Instrument (SF-12v2)1212 and Seattle Angina Questionaire 
(SAQ)13, echocardiography (optional) and CMR (optional) will be repeated as an out-
patient visit. SF-12v2 and Seattle Angina Questionnaire will be performed as interview. 
The participants will be contacted by phone after 1, 2, 3, 5, 10, 15 and 20 years. 
Possible cardiac problems (significant angina, myocardial infarction, new 
revascularization or death) will be investigated by requisition of relevant hospital files, 
ECG recordings, angiograms or death certificates. The 15- and 20-year follow-up may 
be substituted by registry-based event detection.10 There will be an optional registry-
based assessment of socioeconomic status after a relevant follow-up period. 
9. Endpoints  
9.1 Primary endpoint  
All-cause mortality after inclusion of 2000 patients with a minimal follow-up of 6 months. 

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9.2 Primary co-endpoint 
Quality of life assessment by Seattle Angina questionnaire and 12-Item Short Form 
Survey Instrument (SF-12v2)12,14 after 6 months. The questionnaires will be performed 
as interview during an out-patient visit. 
9.3 First Published endpoints 
After 6 months: 
 Quality of life. 
 CCS/NYHA status. 
 MACCE. 
 Echocardiographic parameters (optional). 
 Magnetic resonance imaging (CMR) parameters (optional). 
 Health economy (optional). 
 Socio-economic status (optional). 
 
9.4 Secondary endpoints 
After 1, 2, 3, 5, 10, 15 and 20 year’s registration of: 
 All-cause mortality, cardiac mortality, non-cardiac mortality. 
 Minor and major stroke. 
 Myocardial infarction (all, type 1-4). 
 Target vessel and non-target vessel revascularization. 
 ARC-defined stent thrombosis. 
 Bleeding (Bleeding Academic Research Consortium Definition for Bleeding; 3a, 3b, 3c, 
5a, 5b). 
10. 
Echocardiography 
The registration is optional and performed by centre decision. 
Endpoints will be  
 Systolic function evaluated by left ventricular ejection fraction. 
 Systolic longitudinal function evaluated by global longitudinal strain.  
 Diastolic and systolic function by tissue Doppler indices. 

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 Left ventricular and left atrium volume. 
11. 
Cardiac magnetic resonance 
The registration is optional and performed by centre decision. 
Endpoints will be 
 Reduction of inducible myocardial perfusion defect evaluated by CMR perfusion. 
 Improvement of left ventricular ejection fraction/regional hypokinesia. 
 Correlation of angina and myocardial perfusion defect. 
 
11.1 Health economy and socio-economic aspects 
Health economy and socio-economic aspects of the investigation will be assessed and 
described in a dedicated protocol. The registration is optional and performed by 
participating countries. 
11.2 Evaluation of endpoints 
Primary and secondary endpoints will be assessed by an independent endpoint 
committee. The endpoint committee will consist of experienced clinical and 
interventional cardiologists. 
11.3 Definition of endpoints 
11.3.1 All-cause death 
All-cause death encompasses cardiac death and other fatal categories, which include 
cerebrovascular death, death from other cardiovascular diseases (i.e. pulmonary 
embolism, aortic dissection will be included in this category), death from malignant 
disease, death from suicide, violence or accident, or death from other causes.15 
11.3.2 Stroke 
 Stroke: duration of a focal or global neurological deficit >24 h; OR <24 h if available 
neuro-imaging documents a new haemorrhage or infarct; or the neurological deficit 
results in death.  

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 Non-disabling stroke: a mRS score of <2 at 90 days or one that does not result in an 
increase of at least one mRS category from an individual’s pre-stroke baseline.  
 Disabling stroke: a mRS score of 2 or more at 90 days and an increase of at least one 
mRS category from an individual’s pre-stroke baseline.16  
11.3.3 Cardiac death 
Cardiac death encompasses coronary heart disease death including fatal myocardial 
infarction, sudden cardiac death including fatal arrhythmias and cardiac arrest without 
successful resuscitation, death from heart failure including cardiogenic shock, and death 
related to a cardiac procedure or surgery within 28 days from the procedure.15 
11.3.4  Procedure related myocardial infarction 
Patients with normal (>99th percentile URL) baseline biomarker concentrations, 
elevations of cTn >5 x 99th percentile URL occurring within 72 h of the procedure – plus 
evidence of prolonged ischemia (one of the following): 
 Prolonged chest pain (>20 min). 
 Ischemic ST changes or new pathological Q waves. 
 Angiographic evidence of a flow limiting complication, such as loss of patency of a side 
branch, persistent slow-flow or no-reflow, embolization. 
 Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality (MI type 4a). 
If the baseline cTn values are elevated and are stable or falling, then a rise of >20% is 
required for the diagnosis of MI type 4a.17  
11.3.5  Spontaneous myocardial infarction 
Evidence of myocardial necrosis in a clinical setting consistent with myocardial 
ischemia. Under these conditions any one of the following criteria meets the diagnosis 
for myocardial infarction: 
1) Rise and/or fall of cardiac biomarkers (preferably troponin) >72 hours after a 
revascularization procedure with at least one value above the 99th percentile of the 
upper reference limit (URL) together with evidence of myocardial ischemia with at least 
one of the following (MI types 1 or 2); 
 Symptoms of ischemia;  

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 ECG changes indicative of new ischemia (new ST-T changes or new left bundle branch 
block. 
 Development of pathological Q waves in the ECG 
 Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality. 
2) Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms 
suggestive of myocardial ischemia, and accompanied by presumably new ST elevation, 
or new LBBB, and/or evidence of fresh thrombus by coronary angiography and/or at 
autopsy, but death occurring before blood samples could be obtained, or at a time 
before the appearance of cardiac biomarkers in the blood.  
3) Pathological findings of an acute myocardial infarction.17  
11.3.6 Target lesion revascularization 
Coronary artery bypass grafting or PCI of index lesion.15  
11.3.7 Target vessel revascularization 
Coronary artery bypass grafting or PCI of index vessel.15  
11.3.8 Stent thrombosis 
Stent thrombosis is recognized when documented by angiography and/or autopsy and 
when meeting the criteria for spontaneous myocardial infarction occurring in the territory 
of the treated vessel. Stent thrombosis is categorized as acute, sub-acute, late and very 
late and as definite, probable and possible according to the ARC-criteria.15 
11.4 Recommendations for index lesion re-revascularization 
Angina pectoris, CCS >1, related to index lesion, and fractional flow reserve (FFR) ≤ 
0.80. 
11.5 Study stents 
CE-marked 3rd generation drug eluting stent. 

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11.6 PCI procedure; antithrombotic treatment 
Unfractionated Heparin, low-molecular weight Heparin or Bivalirudin and GPIIbIIIa 
inhibitors are used according to local hospital routine. Dual antiplatelet therapy is 
administered as recommended by treatment guidelines; usually Acetylsalicylic Acid 
(ASA) lifelong and an ADP receptor/P2Y12 inhibitor for 1 to 12 months according to 
clinical presentation and stent characteristics. 
11.7 Measurement of biomarkers 
After the PCI procedure, Creatinine Kinase MB (CK-MB) and Troponin-T/I will be 
measured if there is clinical indication; suspicion of procedure-related myocardial 
infarction. 
12. 
Statistics and sample size 
12.1 Primary endpoint 
The primary endpoint (all-cause mortality after inclusion of 2000 patients with a median 
follow-up of 3 years will be analysed for superiority using Kaplan-Meier survival  
analysis. A p-value ≤5% will indicate significance. 
12.2 Primary co-endpoint 
The primary co-endpoint of 6-month quality of life by SF36 questionnaire will be 
analysed for superiority using Kaplan-Meier survival analysis. A p-value ≤5% will 
indicate significance. 
12.3 Secondary endpoints and other variables 
For continuous variables, differences between the treatment groups will be evaluated by 
Wilcoxon's rank-sum test. For discrete variables, differences will be expressed as 
counts and in percent and will be analysed with the chi-square or Fisher's exact test. 
Two-sided tests are used and the p-value indicating significance will be ≤5%. 
12.4 Sample size calculation (primary endpoint) 
There are no randomized data on CTO treatment by PCI vs. OMT. A meta-analysis 
including 13 studies with 1-10 years of follow-up, found all-cause mortality rates of 

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14.3% after successful PCI and 17.5% after a failed intervention.1 Jones DA et al. found 
a mortality of 4.5% and 17.2% after successful vs. unsuccessful CTO PCI; 836 patients 
with 2.0 to 5.4 years of follow-up.18 Jang et al. demonstrated improved survival in CTO 
patients treated with attempted revascularization and OMT (including CABG and PCI 
failures) compared to OMT alone even in the presence of well developed collateral 
circulation. They found a mortality of 3.4% in the combined group compared to 9.7% in 
OMT during median 40 months of follow up.19 In the present study, we anticipate a 3-
year all-cause mortality rate of 4.5% in the PCI group vs. 6.0% in the OMT group. With 
alpha of 5% and power (1-beta) 80%, a total of 1966 patients will be needed to detect 
this treatment effect difference. To count for loss-to follow-up 2000 patients will be 
randomized (1000 patients in each group). 
12.5 Sample size calculation (primary co-endpoint) 
We expect symptomatic improvement in 45% of unselected patients after OMT and in 
75% of patients after PCI. With alpha of 5% and power (1-beta) 80%, a total of 82 
patients will be needed to detect this treatment effect difference. To count for loss to 
follow-up, a total of 100 patients will be included (50 in each group). 
 
12.6 Analysis of the population 
The results will be analysed according to the intention-to-treat principle. 
13. 
Randomization and data management 
13.1 Randomization 
The patients will be randomized after written informed consent. Randomization by block 
randomization according to center. Randomization will be performed using REDCap 
electronic data capture tools hosted at Aalborg University Hospital. 
13.2 Data management 
The study is reported to The Danish Data Protection Agency (Datatilsynet) through the 
joint report of the North Denmark Region, and the agency's guidelines for data 
management will be followed.  

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Data will be collected and reported using a web-based case report form (CRF) using 
REDCap20 hosted at Aalborg University Hospital. 
13.3 Monitoring of the study 
The study will be monitored according to the good clinical practice (GCP) rules. Study 
coordinators will have regular contact to the participating departments to ensure that the 
trial is conducted in compliance with the protocol, GCP and applicable regulatory 
requirements. The study coordinators will review source documents for verification of 
consistency with the data recorded in the CRF and provide information and support to 
the investigator(s). 
 
The investigators must provide a CV or equivalent documentation of suitability to be 
participate in the trial. All investigators and other responsible personnel will be listed 
together with their function in the trial on the signature list. 
13.4 Data Safety Monitoring Board (DSMB) 
The DSMB will receive monthly information on rates of all-cause death, major stroke, 
procedure related myocardial infarction, spontaneous myocardial infarction, definite 
stent thrombosis and TLR. The DSMB will have unlimited access to the study database 
and will independently make decision on continuation or ending the study.  
13.5 Direct access to source documentation 
The investigators/institutions will permit study-related monitoring, audits, IEC review and 
regulatory inspections, providing direct access to source data/hospital records. The 
investigators are responsible and verify that each patient has consented in writing to 
direct access to the original source data/hospital records by the use of written patient 
information and signed informed consent.  
13.6 Source data verification 
The data recorded in the CRF by the investigator will be controlled for consistency and 
correctness. Any discrepancies of source data/hospital records and CRF data will be 
described and corrected if possible. 

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14. 
Ethical aspects 
14.1 Ethical conduct of the study 
The study will be conducted in accordance with the protocol, applicable regulatory 
requirements and the ethical principles of the Declaration of Helsinki as adopted by the 
18th World Medical Assembly in Helsinki, Finland in 1964 and subsequent versions. 
 
It is the responsibility of the coordinating investigator to obtain approval of the study 
protocol/protocol amendments, the patient information and the informed consent form 
from the Ethical Committee for all patients included in the study. The written approval 
from the Ethical Committee should be dated and have an attached list of those persons 
present at the IEC meeting. 
14.2 Risks, side effects, advantages and disadvantages in study 
participation 
The treatment strategies investigated in the present study, OMT vs. PCI are well known 
and widely used in routine treatment of CTO lesions. Both treatments may be used 
according to the international guidelines. 
 
The medical therapy will be based on international standard treatment for angina 
pectoris. No experimental study drugs will be used. 
 
The PCI treatment is performed in local anaesthesia and may be associated with some 
discomfort and a less than 5% risk of severe complications, including death, myocardial 
infarction, stroke, perforation, renal failure and radiation dermatitis.21,22 After the PCI 
procedure, the patients will be discharged the same or the following day. 
 
Available data suggest that a successful CTO procedure may be associated with 
improved quality of life and increased life length. Consequently, study participants 
randomized to OMT will be offered a PCI procedure after 6 months of OMT. 
 

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Before discharge all patients will be seen by a non-invasive cardiologist to optimize 
medical treatment. Thereafter, study participants will be followed individually according 
to clinical status to achieve OMT and for the patient acceptable symptomatic relief. In 
case of failure to achieve acceptable symptomatic relief on OMT or in case of 
unacceptable side-effects, it will – according to patient wish – be acceptable to change 
strategy to CTO PCI.   
 
14.3 Ethical considerations 
As outlined in earlier, there is considerable uncertainty regarding the optimal treatment 
of patients with CTO, especially regarding the effect of CTO PCI on mortality, symptom 
severity and quality of life. Therefore, it is of major clinical interest to examine this 
problem in a randomized setting. There are no certain advantages related to 
participating in the study, but participants may appreciate the close contact to the 
hospital during study period. We perceive a clear advantage for future patients due to 
the results of this study. There are no disadvantages to participation, but participants 
may expect spending time for scheduled follow-up visits and examinations. CMR and 
echocardiography are already used as routine investigations before CTO PCI. The 
patients will not be exposed to risks beyond that of current standard treatment.  
 
14.4 Informed consent 
Patients will only be included in the study only after signing an informed consent form.  
Written information will be given in sufficient time for the patient to prepare before the 
oral information provided by either project coordinator or investigator in a quiet 
environment without disturbances. If the patient so wishes, study participation may be 
discussed with a third person and a third person may be present during the process of 
oral information. Amble time for consideration (at least 24 hours is allowed) after initial 
written and oral information will be provided before signing the consent form.  Follow up 
regarding participation can with the patient’s permission be scheduled as either out of 
hospital visit or by telephone, but consent form must be signed prior to first study visit.  

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14.5 Patient information and informed consent 
It is the responsibility of the investigator to provide each patient with full and adequate 
verbal and written information about the objectives, procedures and possible risks and 
benefits of study participation. The written patient information must not be changed 
without prior discussion with the coordinating investigator. 
 
The patients will be notified of their voluntary participation and of their right to withdraw 
from the study at any time and without giving any particular reason. The patients will 
also be informed that withdrawing from the study does not influence their future 
treatment. The investigator is responsible for obtaining written informed consent from all 
patients prior to enrolment in the study. 
14.6 Withdrawal 
A patient can be withdrawn from the study at any time, if it is the wish of the patient, or if 
it is medically indicated. If a patient does not show up for a scheduled visit every effort 
will be made to contact the patient. In any circumstance, every effort will be made to 
document patient outcome. 
 
A patient's participation in the study will be discontinued if any of the following criteria 
applies: 
 By patient request 
 The patient's general condition contraindicates continuing in the study, as judged by 
the investigator. 
 Protocol violation. 
If the patient decides to withdraw from the study, he/she will be contacted, if he/she 
agrees, to obtain information about the reason(s) for discontinuation. The date and 
reason for the withdrawal will be recorded in the CRF. 
14.7 Study termination 
Active enrollment in this study will be terminated in case of a statistically significant 
difference (p<0.001) in all-cause mortality by a data and safety monitoring board 
requested interim analysis after inclusion of 100, 250, 500, 1000, 1500 or 2000 patients. 

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14.8 Biological material 
Biological material will not harvested or stored in relation to the study. 
 
15. 
Study plan 
15.1 Participating centres and operators 
Danish/Nordic/Baltic interventional centres with documented interest and experience in 
treatment of CTO lesions by PCI according to the study protocol may participate. The 
participating centres should each include ≥10 patients per year. 
15.2 Steering committee 
The steering committee members will be selected on basis of participation in the study. 
All steering committee members will have full access to the database and will 
participate in interpretation of data. 
15.3 Progress of the study 
The progress of the study will be checked on a monthly basis by the steering 
committee. The steering committee will receive and evaluate data on inclusion rates 
and the overall primary endpoint event rate. Further, the steering committee will receive 
the DSMB assessments and recommendations. The steering committee will receive 
data by e-mail and answer by e-mail with copy to all members. On basis on comments 
from the steering committee members, the coordinating investigators will draw 
preliminary conclusions on study progress. Before decisions on study related issues 
may be implemented, there should be acceptance from the majority of coordinating 
investigators. 
 
16. 
Economy 
The NOBLE CTO study is an academic conceived study and conducted by 
interventional and non-interventional cardiologists in the Nordic/Baltic countries. The 
study is independent of commercial interests. The study is supported by an unrestricted 

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grant from the Novo Nordisk Foundation and coordinating investigators will apply for 
further grants from local and national funds and unrestricted grants from relevant health 
care companies. All relevant trial documents will be updated with received grants or 
other changes to funding and the Ethical Committee of Northern Jutland notified. The 
PCI Research Account, Aalborg University Hospital, will administer the study grants. 
The participants will not receive any fee for participation. Patients’ additional 
transportation expenses related to the study visits will be covered by the study. 
 
17. 
Publication 
Results, positive as well as negative, will be sought published in an international 
cardiovascular journal and the protocol is registered online (www.clinicaltrials.gov ID: 
“NCT03392415”). Publication and author issues will be decided by the steering 
committee on basis of general involvement in the study, number of included patients, 
drafting of protocol, core laboratory function, etc. 
 
18. 
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