Bifurcations Bad Krozingen (BBK) 3 - Trial Randomised Comparison of Culotte-stenting Versus DK-Crush--stenting for the Treatment of de Novo Non-left Main Coronary Bifurcation Lesions With Everolimus-eluting Stents
Phase: NA
Conditions: Coronary Stenosis, Stent Stenosis
Sponsor: University Heart Center Freiburg - Bad Krozingen

  
 
Clinical Investigation Plan 
 
Randomized comparison of Culotte Technique versus “Double Kissing” – Crush 
technique (DK-Crush) for the percutaneous treatment of de novo non-left main 
coronary bifurcation lesions with modern everolimus-eluting stents (EES) –  
The BBK 3 Study 
 
 
Study Type: 
 
 
Open, multi-center, randomized trial 
 
  
Study Registration:   
NCT04192760 
 
 
Principal Investigator:  
PD Dr. med. Miroslaw Ferenc  
  
 
 
 
University Heart Center Freiburg • Bad Krozingen 
  
 
 
 
Bad Krozingen, Germany 
  
 
 
 
Phone:  +49 7633 402 2400 
  
 
 
 
Fax: 
  +49 7633 402 2409 
  
 
 
 
e-mail: miroslaw.ferenc@universitaets-herzzentrum.de 
 
 
Steering committee:  
Prof. Dr. med. Franz-Josef Neumann (Chair) 
Prof. Dr. med. Adnan Kastrati 
Prof. Dr. med. Gerd Richardt 
Dr. med. Kambis Mashayekhi                                          
 
Dr. med. Miroslaw Ferenc 
 
    
Data Management: 
 
PD Dr. med. Miroslaw Ferenc  
  
 
 
 
Dr. med. Thomas Nührenberg 
 
 
 
 
Prof. Dr. med. Willibald Hochholzer 
 
 
 
 
University Heart Center Freiburg • Bad Krozingen 
  
 
 
 
Bad Krozingen, Germany 
  
 
 
 
Phone:  +49 7633 402 0 
  
 
 
 
Fax:       +49 7633 402 2409 
  
 
 
 
 
 
 
 
 
Investigation plan  
Version and Date: 
 
Version 4.0, 01-Dec-2020 
 

    
 
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SIGNATURE PAGES 
 
Study Number 
NCT04192760 
 
Study Title 
Randomized comparison of Culotte technique versus “Double Kissing” 
– Crush technique (DK-Crush) for the percutaneous treatment of  
de novo non-left main coronary bifurcation lesions with modern 
everolimus-eluting stents (EES) –multicenter study – The BBK-3 study 
 
 
 
 
Principal Investigator  
 
The Principal Investigator  has approved the investigation plan version 4.0 dated 01 Dec 
2020 and confirms hereby to conduct the study according to the investigation plan, current 
version of the World Medical Declaration of Helsinki, ISO 14155 norm and the local legally 
applicable requirements. 
 
 
Miroslaw Ferenc 
 
Principal Investigator 
 
 
 
__________________________ 
 
___________________________ 
Place / Date  
 
 
 
Signature 
 
 
 
 
 
 

    
 
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SIGNATURE PAGES 
 
Study Number 
NCT04192760 
 
Study Title 
Randomized comparison of Culotte technique versus “Double Kissing” 
– Crush technique (DK-Crush) for the percutaneous treatment of de 
novo non-left main coronary bifurcation lesions with modern 
everolimus-eluting stents (EES) –multicenter study – The BBK-3 study 
 
 
Local Principal Investigator Signature 
 
I have read and fully understand the amended protocol version and agree hereby to conduct 
the study according to the investigation plan version 4.0 dated 01 Dec 2020, the current 
version of the World Medical Declaration of Helsinki, ISO 14155 norm and the local legally 
applicable requirements. 
 
 
______________________   _______________________    _____________ 
Investigator 
 
 
      Signature  
 
 
  Date             
 
 
 
Center name and address: 
 
 
 
 
 
 
 
 
 
 
 
 

    
 
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TABLE OF CONTENTS 
 
SIGNATURE PAGES .................................................................................................... 2 
SIGNATURE PAGES .................................................................................................... 3 
STUDY SUMMARY ....................................................................................................... 6 
1.   
STUDY BACKGROUND........................................................................................ 7 
2.   
STUDY DESIGN .................................................................................................. 8 
3.  
HYPOTHESIS .................................................................................................... 10 
4. STUDY ENDPOINTS ............................................................................................... 10 
4.1  
 Primary study endpoint ...................................................................................10 
4.2   
Secondary endpoints .......................................................................................11 
5. 
PATIENT SELECTION ........................................................................................ 13 
5.1   
Inclusion Criteria ..............................................................................................13 
5.2   
Exclusion Criteria .............................................................................................14 
5.3     Randomization .................................................................................................14 
6.   
STUDY ASSESSMENTS .................................................................................... 15 
6.1 
Patient Enrollment............................................................................................15 
6.2   
Laboratory Assessments..................................................................................15 
6.3   
Concomitant Medications .................................................................................15 
6.4   
Coronary Angiography and Intervention ...........................................................16 
6.4.1  Angiography ......................................................................................16 
6.4.2 
Lesion / Vessel Pre-treatment............................................................16 
6.4.3 
Stenting Procedure and Stenting Technique ......................................17 
6.4.4 
Stent type ..........................................................................................18 
6.5   
Follow-up .........................................................................................................18 
6.5.1 Angiographic Follow-Up ........................................................................18 
6.5.2  Clinical Follow-up .................................................................................19 
7.  
DATA COLLECTION AND DATA MANAGEMENT ................................................. 20 
8.  
SAFETY ............................................................................................................ 20 
9.  
SAMPLE SIZE ESTIMATION ............................................................................... 21 
10.  QUALITIY ASSURANCE ..................................................................................... 22 
10.1  Monitoring Procedure .......................................................................................22 
10.2  Source Data Verification (SDV) ........................................................................22 
11.  ETHICAL AND LEGAL PRINCIPLES ................................................................... 23 
        11.1     Regulatory and ethical compliance ............................................................ 23 

    
 
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         11.2       Responsibilities of the investigator .......................................................... 23 
         11.3       Confidentiality of trial documents and patient records ............................... 24 
12.  TRIAL DOCUMENTS AND ARCHIVING ............................................................... 24 
         12.1       Trial documents/investigator site file ........................................................ 24 
         12.2       Archiving .............................................................................................. 25 
13.  PROTOCOL ADHERENCE AND AMENDMENTS ................................................. 25 
         13.1       Protocol adherence ............................................................................... 25 
         13.2      Amendments to the protocol .................................................................... 26 
14.  FUNDING AND SUPPORT.................................................................................. 26 
REFERENCES ........................................................................................................... 27 
 
 

    
 
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STUDY SUMMARY 
 
Background: In percutaneous coronary intervention (PCI) of bifurcation lesions, the need for 
stenting of both, the main and side branch (double stenting), depends on lesion complexity. 
With high complexity (Medina classification 1,1,1 or 0,1,1), double stenting may be the 
treatment of choice. When double stenting is required, there are three major technical 
approaches: T-stenting (T- and Protrusion = TAP) technique, Culotte-stenting or “double 
kissing” Crush – technique (DK-Crush). Thus far, there is only limited evidence on the 
optimal double stenting technique. In the BBK 2 study, Culotte stenting demonstrated benefit 
over TAP stenting 1. The DK-Crush 3 study  2 showed superiority for DK-crush technique as 
compared to Culotte technique, however only patients with distal left main stenosis were 
treated in this study. Thus, no randomized study directly compared the Culotte with the DK 
crush technique in non-left main coronary bifurcation lesions.  
Aim: This prospective randomized multicenter study will compare the long-term safety and 
efficacy of Culotte stenting versus DK-Crush stenting in the treatment of the de-novo non-left 
main coronary bifurcation lesions with new generation everolimus-eluting stents.   
Methods: Four-hundred patients, in whom a double-stenting technique is intended for the 
treatment of a non-left main de-novo coronary bifurcation lesion will be randomly assigned to 
Culotte stenting or to DK-crush stenting with an approved contemporary everolimus-eluting 
stent. As a part of usual care, patients will undergo 9-month angiographic follow-up with 
quantitative coronary angiography. Clinical follow-up is planned at 9-12 months. The primary 
study endpoint is the maximal percent diameter stenosis in the bifurcation lesion at 9 months. 
Secondary endpoints include binary restenosis (estimated by Quantitative Coronary 
Angiography (QCA) analysis), Target Lesion Revascularization (TLR), Freedom from Major 
Adverse Cardiac Events (MACE) and the rate of stent thrombosis according to the definition 
of the Academic Research Consortium (ARC definition). The study will have 80% power to 
detect a 25% decrease in the primary endpoint at p < 0.05 by Culotte stenting as compared 
with DK-Crush.  
 
 

    
 
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1.   
STUDY BACKGROUND 
Provisional side branch stenting is the most frequently used type of treatment in coronary 
bifurcation lesions. When stenting of both the side branch and the main branch (double 
stenting) is needed - because of complex anatomy, dissection occurring during lesion 
preparation, TIMI flow < 2 or high residual stenosis > 75% -  there is a variety of established 
technical approaches. The most common double stenting techniques in daily routine are TAP 
stenting, Culotte stenting and “double kissing “-Crush stenting.  
 
Our recently published BBK 2 - study 1 demonstrated a benefit of the Culotte technique as 
compared to TAP technique during PCI of de-novo coronary bifurcation lesions, with a 
significant reduction in in-stent restenosis (primary study endpoint). Moreover, the BBK 2 - 
study showed a trend to better clinical outcomes after Culotte stenting during the first year of 
the clinical follow-up (secondary study endpoints). The difference was mainly driven by 
significant reduction for in-stent restenosis of the side branch stent.  
 
In China, Dr. Chen and his colleagues 2 modified the initially introduced classic crush 
technique to the “double kissing“-crush technique. The DK-Crush technique is technically 
more challenging due to more procedural steps. The use of the DK-crush technique was 
assessed in several randomized trials: comparison with classic crush technique 3, with 
provisional T-stenting 4 and with Culotte 2 (only for patients treated for distal left main 
stenosis). The DK-Crush technique was associated with a lower angiographic restenosis rate 
and as well as with lower reintervention rates during long-term clinical follow-up.  
 
In Europe, the randomized multicenter Nordic II study 7 addressed the question whether 
classic Crush-stenting or Culotte-stenting achieves better angiographic and clinical outcome 
after PCI in bifurcation lesions. The results demonstrated no significant difference in respect 
to the primary study endpoint. Major adverse cardiac events (MACE) as primary study 
endpoint occurred in 3.7 % in the Culotte study arm as compared to 4.3 % in the Crush study 
arm (p = 0.87).  
 
All previous studies on the DK-Crush technique were performed using first generation drug-
eluting stents (DES), which are no longer in use. Currently, no randomized study compared 
DK-crush with Culotte techniques in patients with non-left main bifurcation lesions using 
contemporary DES. However, recent data showed that the use of new-generation DES is 
associated with better clinical outcomes as compared to first-generation DES 5, 6. 

    
 
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2.   
STUDY DESIGN 
This study is a prospective, randomized, multicenter evaluation of the treatment of de-novo 
coronary bifurcation lesions comparing DK-crush stenting with Culotte stenting using 
approved modern third-generation DES. 
 
The primary endpoint of this study is the maximal percent diameter stenosis within the 
bifurcation at 9 months, assessed by quantitative coronary angiography. In addition, the 
study will assess various safety parameters. 
 
Four-hundred patients will be enrolled and randomly assigned to DK-crush stenting or to 
Culotte stenting of non-left main bifurcation lesions. Only CE-certified everolimus-eluting 
Synergy™ and Synergy Megatron™ stents must be used.  
 
This study is an investigator-initiated trial, designed and conducted by the University Heart 
Center Freiburg ∙ Bad Krozingen. Partial financial support is obtained by a scientific grant 
from Boston Scientific (BSI). Data from patients enrolled at participating study sites will be 
transferred after pseudonymization to a central database at the University Heart Center 
Freiburg • Bad Krozingen to perform final data analysis and to publish the results of the 
study.  
 
 
 
 
 

    
 
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Trial randomisation scheme: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bifurcations Bad Krozingen (BBK) 3 - randomized multicenter study 
400 patients  
with de-novo non-left main bifurcation stenosis with indication for PCI of the main and the side 
branch using everolimus–eluting stents  
1:1 - randomization to “double kissing” Crush (DK-Crush) stenting or Culotte stenting 
n = 200  
 
Culotte stenting 
n = 200  
DK-Crush stenting 
Primary study endpoint:  
Maximal % diameter stenosis in the bifurcation lesion (QCA) 
Secondary study endpoints:   
Binary restenosis; TLR; MACE/ Death/ MI / Stent-Thrombosis 
Clinical Follow-up:  
 
9 - 12 months 
 
 
Re-Angiography:  
 
 
All patients 9 months post index PCI with QCA - analysis 

    
 
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Assessment Schedule 
 
 
Assessment 
 
 
 
Screening 
 
 
 
PCI 
 
 
 
Pre-
discharge 
 
 
9 months 
± 30 days 
 
 
If no 
Re – Angiography: 
12 months ± 30 days 
Inclusion/Exclusion criteria  
X 
 
 
 
 
Informed consent signed 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Angina pectoris and NYHA 
status 
X 
 
 
X 
X 
Creatine kinase (CK) and 
hs-troponin 
X 
 
X 
 
 
12 lead ECG 
X 
 
X 
 
 
Medication History 
X 
X 
 
X 
X 
Adverse Event Monitoring 
 
X 
X 
X 
X 
Index Procedure 
 
X 
 
 
 
Re – Angiography 
 
 
 
X 
 
 
 
3.  
HYPOTHESIS 
 
The hypothesis of this study is as follows: 
 
In non left-main coronary bifurcation lesions (main vessel > 2.5mm, side branch > 2.25mm) 
including significant ostial side branch disease, Culotte stenting compared with DK-crush 
stenting reduces maximal percent diameter stenosis at the bifurcation at 9-month follow-up 
by 25 %.  
 
4. STUDY ENDPOINTS 
 
4.1  
 Primary study endpoint 
 
The primary study endpoint is: 
 
-  Maximal percent diameter stenosis at the bifurcation at 9 months.  
 

    
 
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4.2   
Secondary endpoints 
 
The following secondary endpoints will be evaluated in this study:  
 
-  Binary restenosis (≥ 50% diameter stenosis) rate at any segment of the bifurcation at  
 
9 months post procedure 
 
-   Binary restenosis (≥ 50% diameter stenosis) in the main and side branch at 9 months 
post procedure. 
 
-   TLR of the main and side branch at 9-12 months post procedure. Intervening target-
lesion revascularization is defined as any repeated percutaneous revascularization of the 
stented segment, including the 5-mm proximal and distal margins. 
 
-  MACE defined as death, myocardial infarction (according to the fourth universal definition 
of myocardial infarction, 2018), emergent cardiac bypass surgery, or TLR at 9-12 months. 
 
-   Device success defined as attainment of < 30% residual stenosis of the target lesion 
using drug-eluting stent (DES) in the main and side branch  
 
-   Procedure time, radiation time and volume of used contrast medium  
 
-   Post-procedure thrombotic stent occlusion at 9-12 months according to the  Academic 
Research Consortium-criteria: Stent thrombosis is classified by the ARC definition as 
definite, probable, or possible and as early (0 to 30 days), late (31 to 360 days), or very 
late (>360 days). The definition of definite stent thrombosis requires the presence of an 
acute coronary syndrome with angiographic or autopsy evidence of thrombus or 
occlusion. Probable stent thrombosis includes unexplained deaths within 30 days after 
the procedure or acute myocardial infarction involving the target-vessel territory without 
angiographic confirmation. Possible stent thrombosis includes all unexplained deaths 
occurring at least 30 days after the procedure.  
 
-  Disabling stroke defined as stroke requiring inpatient rehabilitation or skilled nursing care. 
 
-  Bleeding classified as type 3-5 according to the BARC classification as follows: 

    
 
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Type 0:  
No bleeding 
 
Type 1: Bleeding that is not actionable and does not cause the patient to seek 
unscheduled performance of studies, hospitalization, or treatment by a health-care 
professional; may include episodes leading to self-discontinuation of medical therapy by 
the patient without consulting a health-care professional. 
 
Type 2: Any overt, actionable sign of hemorrhage (e.g., more bleeding than would be 
expected for a clinical circumstance, including bleeding found by imaging alone) that 
does not fit the criteria for type 3, 4, or 5 but does meet at least one of the following 
criteria: requiring nonsurgical, medical intervention by a health-care professional, leading 
to hospitalization or increased level of care, or prompting evaluation 
 
Type 3: 
 
Type 3a: Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL* (provided hemoglobin 
drop is related to bleed), any transfusion with overt bleeding 
 
Type 3b: Overt bleeding plus hemoglobin drop ≥5 g/dL* (provided hemoglobin drop is 
related to bleed), Cardiac tamponade, Bleeding requiring surgical intervention for control 
(excluding dental/nasal/skin/hemorrhoid), Bleeding requiring intravenous vasoactive 
agents 
 
Type 3c: Intracranial hemorrhage (does not include microbleeds or hemorrhagic 
transformation, does include intraspinal), subcategories confirmed by autopsy or imaging 
or lumbar puncture, intraocular bleed compromising vision 
 
Type 4: 
 
CABG-related bleeding, perioperative intracranial bleeding within 48 h, reoperation after 
closure of sternotomy for the purpose of controlling bleeding, transfusion of ≥ 5 U whole 
blood or packed red blood cells within a 48-h period, chest tube output more than or 
equal to 2L within a 24-h period 
 
Type 5: 
 
Fatal bleeding 
 
Type 5a: 
 
Probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious 
 
Type 5b: 
 
Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation 
 

    
 
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5. 
PATIENT SELECTION 
 
This trial will include 400 symptomatic patients with a de novo bifurcation lesion of a native 
coronary artery who meet eligibility criteria and provide written informed consent for 
participation in the study.  
Eligible subjects will be informed about the scope and potential risks of the study verbally 
and in written form (ICF) the day before PCI. Informed consent will be obtained at the 
subsequent day before any study-related procedure and before start of the PCI.  
 
 
5.1   
Inclusion Criteria 
 
Patients will be enrolled only, if all the following conditions are met: 
 
1.  
Clinical indication, evidenced by angina/angina-equivalent symptoms or documented 
ischemia (non-invasive imaging such as scintigraphy, stress-MRI or stress-echo; FFR 
or iwFR) or patients with acute coronary syndromes (NST-ACS). 
 
2.   
Clinical indication to perform double stenting only with Synergy™ stents for a clinically 
significant bifurcation stenosis as judged by the operator. 
 
3. 
De-novo non-left main coronary bifurcation lesions - 1,1,1  or 0,1,1 according to the 
Medina classification - of a native coronary artery with the following reference vessel 
diameters: main branch > 2,5 mm; side branch > 2,25 mm. The difference between 
vessel diameter of the main and side branch is ≤ 1 mm.  
 
4. 
The target lesion has not been previously treated with any interventional  procedure. 
 
5. 
The target vessel (main branch and side branch) must appear feasible for stent 
implantation. 
 
6. 
Patient has no other coronary intervention planned within 30 days of the procedure. 
 
7. 
Patient has been informed of the nature of the study and agrees to its provisions and 
has written informed consent as approved by the Ethics Committee. 

    
 
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8. 
Patient is willing to comply with all required post-procedure follow-up. 
 
 
5.2   
Exclusion Criteria 
 
Patients are not eligible for enrollment into the study if any of the following conditions apply: 
 
1.   
Patient had an acute ST-elevation myocardial infarction or target vessel contains 
intraluminal thrombus. 
 
2.   
Use of any other coronary stent than Synergy™ and Synergy Megatron™ except for 
bail-out situations. 
 
3. 
Patient with a known hypersensitivity or contraindication to the needed antithrombotic 
therapy, stent type or contrast media that cannot be adequately pre-medicated. 
 
4.   
Non successful treatment of other lesion during the same procedure. 
 
5. 
Patient with a severe bleeding diathesis, history of recent major bleeding or stroke 
 
 (≤ 6 months), coagulopathy or severe liver disease. 
 
6.  
Patient has a co-morbidity (i.e. cancer) that may cause the patient to be non-
compliant with the protocol, or is associated with limited life-expectancy  
 
(less than 1 year). 
 
7.  
Patient is participating in any other clinical study with an investigational product. 
   
 
8. 
Patient is known to be pregnant or lactating at time of inclusion.  
 
 
 
5.3     Randomization 
 

    
 
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Patients who fulfill inclusion and have no exclusion criteria and provided written informed 
consent to the study will be randomized to DK-Crush stenting or to Culotte-stenting using 
computer-generated random sequences stratified by investigation sites. The random 
sequence and block sizes per site will be selected by the statistician and will be unknown to 
the investigators and medical staff caring for the patients. Randomization will be performed 
immediately before catheter treatment of the bifurcation lesion.  
 
6.   
STUDY ASSESSMENTS 
 
6.1 
Patient Enrollment 
 
All potential subjects must be consented prior to performing any study related procedures. 
The investigator or representative will explain the nature and scope of the study, potential 
risks and benefits of participation, and answer questions for the patient. If the patient agrees 
to participate, informed consent must be signed and dated; a copy must be provided to the 
patient  
 
Baseline data to be collected will include demographics, angiographic and clinical 
parameters.  
 
6.2   
Laboratory Assessments 
 
-   12-lead ECG prior to procedure and between 12 hours and 24 hours post-procedure or 
before hospital discharge 
-  CK and CKMB and Troponin T prior to procedure and at least once prior to discharge. If 
several pre- and post-procedure assessments are available, highest levels are reported. 
 
6.3   
Concomitant Medications 
 
All subjects receive the medication regimen listed below. All medications administered 
should be recorded in the subject`s medical record. 
 
Prior to Procedure 
 
Aspirin  
 
At least 400 mg per os 
  
 
 
 
Clopidogrel 
 
600 mg loading dose or 
                                       
Prasugrel 
 
60 mg loading dose or 

    
 
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Ticagrelor 
 
180 mg loading dose 
 
 
 
 
for all: if not on chronic treatment 
 
During Procedure 
 
IV Heparin 
 
For angioplasty bolus 100 I.U./ kg/ KG 
 
 
 
 
IC Glyceryl trinitrate 100 – 200 mcg prior to baseline and 
 
 
 
 
 
 
 
post intervention angiograms 
 
Post-Procedure 
 
Aspirin  
 
At least 100 mg per day indefinitely 
  
 
 
 
Clopidogrel 
 
75 mg per day for at least 6 months or 
Prasugrel 
10 mg or 5 mg/day for at least 6 months 
as per drug label 
Ticagrelor 
2 x 90 mg /day for at least 6 months as 
per drug label 
 
Glycoprotein IIb/IIIa inhibitors can be used for bail out.  
 
 
6.4   
Coronary Angiography and Intervention 
 
6.4.1  Angiography 
 
Using standard procedures for angioplasty, an introducer sheath of at least 6 French will be 
introduced and the heparin bolus will be administered. After introduction of the guiding 
catheter and following intra-coronary injection of nitroglycerin, baseline angiography of the 
vessel will be performed in at least two best views that show the target lesion free of 
foreshortening or vessel overlap. 
 
 
6.4.2 Lesion / Vessel Pre-treatment 
 
For any patients with multiple lesions requiring treatment at the time of the index procedure, 
lesions outside the target vessel must be treated first successfully. 
 
The target lesion in the main branch will be crossed with an intracoronary guide wire of  
0.014 inch diameter and a second guide wire is passed into the side branch to protect the 
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successful passage with the guide wires the lesion in the main branch should be pre-dilated 
with an appropriately sized balloon. Pre-dilatation of the side branch before stenting of the 
main branch is up to the discretion of the operator. 
 
6.4.3 Stenting Procedure and Stenting Technique 
 
Both the DK-Crush as well the Culotte technique provide complete coverage of the side 
branch ostium, avoiding non-stented gaps at the orifice of the side branch with minimal stent 
distortion or stent overlap in the carina region or the proximal segment of the main branch.  
 
Stents should be selected long enough to cover the lesions completely. If more than one 
stent is needed to cover the lesion in the main or side branch completely, it is recommended 
to overlap the stents 1 – 2 mm. The aim should be to reach a diameter stenosis < 10% 
without proximal and distal dissections. Post dilatation may be performed at the discretion of 
the operator. Pre or post dilatation technique should avoid balloon injury to any segment of 
the vessel that will not be entirely covered by the drug-eluting stent. Further treatment to 
proximal or distal aspects of the main vessel or side branch can be continued at the 
discretion of the operator. At any stage, proximal or distal dissections may be treated as 
required with further stent implantations. At any stage, post-dilatations may be undertaken to 
optimize stent expansion.  
 
Irrespective of the assigned treatment, glyceryl trinitrate is injected intra-coronary at the 
completion of the procedure and final angiography of the vessel is performed in the two 
optimal views that were chosen at baseline. 
The additional use of intracoronary imaging techniques is up to the discretion of the operator. 
 
Final ‘kissing balloon’ dilatation must be performed in all patients irrespective of whether they 
were assigned to DK-Crush or Culotte-stenting.  
 
DK-Crush stenting technique: 
Lesion preparation in the main vessel and side branch may be undertaken according to 
operator preference (including rotablation). After lesion preparation, the side branch is 
stented first. Side branch stent should have a small protrusion into the main branch. Before 
stent implantation in the side branch, an adequately sized balloon should be placed in the 
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branch, stent balloon and wire are removed and the balloon in the main branch must be 
inflated, to crush the struts into the vessel wall. In next step, the new wire should be crossed 
into the ostium of the side branch and first kissing balloon dilatation will follow. The next step 
is to implant the second stent into the main branch, followed by second re-wiring, a second 
kissing balloon-dilatation and final proximal optimization (POT) procedure (single short 
balloon inflation in proximal segment). 
 
Culotte stent technique: 
Lesion preparation in the main vessel and side branch may be undertaken according to 
operator preference. After lesion preparation, the side branch has to be stented first.  The 
first stent is placed from main branch into the side branch, covering the entire diseased 
segment with a wire jailed in the main vessel. The main vessel is rewired through the stent 
struts, and after removal of the jailed wire, is dilated with a balloon to separate stent struts. 
The side branch wire is then removed (to prevent metal-to-metal jail) and the main vessel is 
stented covering the proximal and distal segment. The side-branch is re-wired and high 
pressure (e.g. 20 atm) individual inflations are made in each vessel at the bifurcation point to 
ensure good stent strut separation. Afterwards, a lower pressure kissing inflation is made. 
For both the high pressure individual and lower pressure kissing inflations, balloon sizing 
should be in accordance with the diameter of the vessel itself. Finally, a proximal optimization 
(POT) procedure (single short balloon inflation in proximal segment) is performed. 
 
6.4.4 Stent type 
 
Approved modern everolimus-eluting stents will be used as study stents: Only use of 
Synergy™ and Synergy Megatron™ stents from Boston Scientific is allowed. 
 
6.5   
Follow-up  
 
All patients enrolled in the study will be required to complete the follow-up to evaluate long-
term results. 
 
6.5.1 Angiographic Follow-Up  
 
Irrespective of symptoms, current guidelines recommend considering routine follow-up 
angiography after treatment of complex lesions (such as bifurcation lesions). This is routine 

    
 
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practice at our institution. Thus, as part of our clinical routine, all patients will undergo repeat 
angiography at 9 months (± 30 days) after the index procedure. Angiographies will be 
performed as described in Section 6.4.1. 
 
All angiographies, including unscheduled angiograms, will be analyzed by the angiographic 
core laboratory:  
Dr. med. Ulrich Beschorner 
coreLab Black Forest GmbH  
Bad Krozingen, Germany 
  
Phone:   
+49 7633 4024975 
  
Fax:     
+49 7633 4024999 
 
For quantitative coronary angiography, angiograms obtained at baseline, at completion of the 
intervention and at 9 months follow-up or  in case of an unplanned coronary angiography 
before 9 month will be analyzed using a computer based system dedicated to bifurcation 
analysis (Qangio XA, version7.0, Medis, Leiden, Netherlands), according to the standard 
operating procedure of the angiographic core laboratory.  
Quantitative angiographic measurements will be obtained of the three segments of the 
bifurcation lesion: the proximal and distal segment of the main branch and the side branch. 
Measurements in the stented portion of the vessel (in-stent) and in the distal or proximal  
5 mm margin (edge) will be performed. In-segment analyses will comprise the in-stent and 
the edge area.  In addition, the bifurcation angle from the analysis system will be estimated. 
 
6.5.2  Clinical Follow-up 
 
At 9-12 months post procedure (at time of angiographic follow-up or telephone contact or 
contact with general practitioner). 
 
The assessment will include angina status (according to the Canadian Cardiovascular 
Society Classification of angina), all adverse events, all concomitant medications and any 
interventional treatment that occurred since the index procedure. 
 
 
 
 

    
 
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7.  
DATA COLLECTION AND DATA MANAGEMENT 
 
Study data will be entered in pseudonymized form in a study database by authorized and 
trained members of the study team via electronic case report forms (eCRF). The electronic 
data capture system REDCap™ is used for data acquisition. This system uses built-in 
security features to prevent unauthorized access to patient data, including an encrypted 
transport protocol for data transmission from the participating sites to the study database. An 
audit trail provides a history of the data entered, changed or deleted, indicating the processor 
and date. 
Employees of the Clinical Trials Unit charged with hosting the eCRF and the study database 
are obliged to maintain data confidentiality and to comply with data protection regulation. 
Before any data entry is performed, the trial eCRF will be validated. The technical 
specifications of the database will be described in the codebook delivered automatically by 
the REDCap™ system. 
Access will be granted to authorized personnel only, and only if they have received 
appropriate training. The study database is located on a server of the IT facility 
(Klinikrechenzentrum, KRZ) of Medical Center - University of Freiburg. 
 
 
8.  
SAFETY  
 
Adverse Events are any untoward occurrence in the patient, which does not necessarily have 
a causal relationship with study treatment. A Serious Adverse Event is defined as any 
untoward medical occurrence that meets at least 1 of the following serious criteria: 
 
- 
led to a death  
- 
led to a serious deterioration in the health of the patient that either resulted in:  
a. 
life-threatening illness or injury, or  
b. 
a permanent impairment of a body structure or a body function, or 
c. 
in-patient or prolonged hospitalization, or 
d. 
medical or surgical intervention to prevent life threatening illness or injury or 
permanent impairment to a body structure or a body function. 
- 
led to fetal distress, fetal death or a congenital abnormality or birth defect. 
 
 

    
 
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For the BBK3 clinical investigation, the following Serious Adverse Events are considered 
Serious Adverse Events of Special Interest (SAESI) and will be reported as outcome. SAESI 
include myocardial infarction, all forms of revascularization, stent thrombosis, disabling 
stroke as well as bleeding as defined by BARC criteria 3-5. For all these events, the causal 
relationship with the investigational procedure should be established as detailed as follows:  
- Unrelated: the event is definitely not related associated with the procedure 
- Possible:  
the temporal sequence between the procedure and the event is such that 
the relationship is likely or patient’s condition or concomitant therapy could 
have caused the SAESI. 
- Probable: 
the temporal sequence between the procedure and the event is relevant or 
the event subsides upon procedure completion (dechallenge) or the event 
cannot be reasonably explained by the patient`s condition.    
 
- Definite:  
the temporal sequence is relevant and the event subsides upon procedure 
completion (dechallenge).  
 
During the complete duration of the study, all SAESIs are collected, examined by the use of 
source documents and documented in the CRF. Study duration comprises the time from 
when the informed consent is signed until the last study assessment has been completed. 
No specific safety assessment is planned. All follow-up visits are part of routine clinical 
practice. SAESI’s will be assessed at 9 months or at latest at 1 year (in accordance with 
study assessments). SAESI information will be obtained from the treating physician and a 
copy of the reports will be sent to the representative of the sponsor of the study within 5 
working days: University Heart Center Freiburg – Bad Krozingen (PD Dr. M. Ferenc; PI of the 
BBK 3 study).  
 
9.  
SAMPLE SIZE ESTIMATION 
 
 
The study is designed to have a 80% power to detect a 25% relative reduction of the primary 
endpoint by Culotte technique as compared with DK-crush stenting at a significance level of 
0.05.  
Based on our previous study we assume a maximum percent diameter stenosis of 20 % in 
the Culotte arm and a common standard deviation of 22%. We, thus, obtain a sample size of 
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diameter stenosis from 26.7 % to 20 % by Culotte stenting as compared with DK- Crush 
stenting. The study will include 200 patients in each study arm, to allow for losses to 
angiographic follow-up. 
 
10.  
QUALITIY ASSURANCE 
 
 
The sponsor is responsible for implementing and maintaining quality assurance to ensure 
that trials are conducted, data are generated, documented, and reported in compliance with 
the protocol, ICH-GCP, and the applicable regulatory requirement(s). 
 
10.1 
 Monitoring Procedure 
 
The investigator will accept monitoring visits before, during and after the clinical trial. Prior to 
patient recruitment, a site initiation visit at each site is conducted in order to train and 
introduce the investigators and their staff to the trial protocol, related trial specific procedures, 
ISO 14155 norm and national/local regulatory requirements.  
The initiation visit is conducted by the sponsor of this trial.  
During the trial, a monitor will visit each site once for the whole study depending on the 
recruitment rate and quality of data. During these on-site visits, the monitor verifies that the 
trial is conducted according to the trial protocol, trial specific procedures, ISO 14155 norm 
and national/local regulatory requirements.  
The 
presence 
of 
signed 
informed 
consents, 
eligibility 
of 
patients, 
and 
documentation/reporting of safety data (SAESIs) will be verified by the monitor.  
The monitor performs also source data verification (SDV) and source data review (SDR).The 
investigator must maintain source documents for each patient in the trial. The investigator 
must also keep the original signed ICFs. The investigator must give the monitor access to all 
relevant source documents to confirm their consistency with the eCRF entries.  
 
10.2  Source Data Verification (SDV)  
 
Source data include original documents, data, and records such as hospital records, clinical 
and office charts, laboratory notes, memoranda, or evaluation checklists,  recorded data from 
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copies, microfilm or magnetic media, X-rays, at the laboratories and at medico-technical 
departments involved in the clinical trial. 
In addition to source data review source data verification will be performed in order to verify 
the accuracy and completeness of the entries on the case report form (CRF) by comparing 
them with the source data, and to ensure and increase the quality of the data. All data which 
are subject to SDV must have been entered in the medical record or, in the case of source 
documents, enclosed with the medical record. The investigators will afford the CRA access 
to the medical records for the performance of SDV.  
 
11.  
ETHICAL AND LEGAL PRINCIPLES 
 
This clinical trial was designed, shall be implemented and reported in accordance with the 
ICH- GCP, with applicable local regulations (including European Directive 2001/20/EC), and 
with the ethical principles laid down in the Declaration of Helsinki. 
Before initiating the clinical trial, the sponsor/coordinating investigator should submit the CTP 
and any required application(s) to the appropriate competent authority for review, 
acceptance, and/or permission, as required by the applicable regulatory requirements. 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Independent Ethics Committee (IEC) before trial start. A signed and 
dated statement that the protocol and informed consent have been approved by the IEC 
must be available prior to initiation of the trial.  
 
11.1  Regulatory and ethical compliance 
 
Before the start of the trial, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the trial in accordance with these documents and all 
of the instructions and procedures found in this protocol and to give access to all relevant 
data and records to sponsor CRAs, auditors, sponsor Clinical Quality Assurance 
representatives, designated agents of sponsor, IECs and CA(s) as required. 
 
11.2 
 Responsibilities of the investigator 
 
Before enrolment in the clinical trial, the patient will be informed that participation in the 
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without having to give reasons and without penalty or loss of benefits to which the patient is 
otherwise entitled. 
The treating physician will provide the patient with information about the treatment methods 
to be compared and the possible risks involved. At the same time, the nature, significance, 
implications, expected benefits and potential risks of the clinical trial and alternative 
treatment will be explained to the patient. The patient will be given ample time and 
opportunity to obtain answers to any open questions. All questions relating to the clinical trial 
should be answered to the satisfaction of the patient.  
In addition, the patient will be given a patient information sheet which contains all the 
important information in writing. The patient’s written consent must be obtained before any 
trial-specific tests/treatments. For this purpose, the written consent form will be personally 
dated and signed by the trial patient and the investigator conducting the informed consent 
discussion.  
By signing the consent form, the patient agrees to voluntarily participate in the clinical trial 
and declares his/her intention to comply with the requirements of the clinical trial and the 
investigator’s instructions during the clinical trial. By signing the form, the patient also 
declares that he/she agrees to the recording of personal data, particularly medical data, for 
the trial, to their storage and codified (“pseudonymized”) transmission to the sponsor, CA(s), 
and further agrees that authorized representatives of the sponsor, who are bound to 
confidentiality.  
After signing, the patient will be given one copy of the signed and dated written consent form 
and any other written information to be provided to the patients. 
11.3 
Confidentiality of trial documents and patient records 
 
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to sponsor. Signed informed consent forms and patient 
enrolment log must be kept strictly confidential to enable patient identification at the site. 
All study-related information will be stored securely at the study site. All participant 
information will be stored in locked file cabinets in areas with limited access. All laboratory 
specimens, reports, data collection, process, and administrative forms will be identified by a 
coded identification number only to maintain participant confidentiality. 
12.  
TRIAL DOCUMENTS AND ARCHIVING 
12.1  Trial documents/investigator site file 
 

    
 
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The investigator will be given an investigator site file containing all the necessary essential 
trial documents for the initiation of the trial at his/her site. The essential documents include a 
list on which the investigator will enter all appropriately qualified persons to whom he/she has 
delegated important trial-related tasks. 
The investigator, or an individual who is designated by the investigator, will be responsible 
for the maintenance and completeness of the trial documents during the clinical trial. At the 
request of the monitor, auditor, IEC the investigator shall make available all the requested 
trial-related records for direct access. Essential documents must not be removed 
permanently. 
12.2  Archiving 
 
After completion of the clinical trial, the essential trial documents - as defined by ICH-GCP 
E6 section - will be retained at the trial site for a sufficient period so that they will be available 
for audits and inspections by the CA(s). 
The investigator will be responsible for the storage. The following retention periods will apply 
after the completion/termination of the clinical trial: 
The above-mentioned essential documents must be retained for at least 10 years (section 
13, subsection 10 GCP-V). 
The medical records and other source documents must be retained for the longest possible 
period allowed by the hospital, the institution or the private practice. 
The investigator/the institution should take measures to prevent accidental or premature 
destruction of these documents. The sponsor will notify the investigator in writing when the 
trial-related essential documents are no longer required. 
 
13.  
PROTOCOL ADHERENCE AND AMENDMENTS 
13.1  Protocol adherence 
 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact sponsor or its agents, if any, monitoring the 
trial to request approval of a protocol deviation, as no authorised deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the trial this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
sponsor and approved by the IEC it cannot be implemented. 
 

    
 
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13.2  Amendments to the protocol 
 
Any change or addition to the protocol can only be made in a written protocol amendment 
that must be approved by sponsor, CA where required, and the IEC. 
Only changes of the protocol that are required for patient safety may be implemented prior to 
IEC approval.  
Regardless of the need for approval of formal protocol amendments, the investigator is 
expected to take immediate action required for the safety of any patient included in this trial, 
even if this action represents a deviation from the protocol. In such cases, the sponsor has to 
be notified as soon as possible of this action; the IEC should be informed correspondingly. 
Information regarding important protocol modifications will be provided in due time to further 
relevant parties (e.g. investigators, trial participants, trial registries, journals). 
 
14.  
FUNDING AND SUPPORT  
 
This is an investigator-initiated trial of the University Heart Center Freiburg • Bad Krozingen, 
Bad Krozingen, Germany. Financial support will be provided by Boston Scientific 
International S.A., Parc d`Affaires Le Val Saint-Quentin, 2 Rue René Caudron, 78960 
Voisins-le Bretonneux, France.  
 
 

    
 
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