Bifurcation lesions are frequent and account for about 15_ of all

The Nordic Bifurcation Study 23.09.2004 Protocol How to use drug eluting stents (DES) in bifurcation lesions? A strategy of routine stenting of both main vessel and side branch versus a strategy of routine main vessel stenting and optional treatment of side branch A randomized Nordic multicenter study “THE NORDIC PCI STUDY GROUP” Leif Thuesen, Department of Cardiology, Skejby Hospital, University of Aarhus. Denmark. Fax: +45 89496002. Tel: +45 89496105. Mail: leif.thuesen@iekf.au.dk 2004-09-23 Amendment No 1 incorporated in the protocol The Nordic Bifurcation Study 1. 2. ABBREVIATIONS ................................................................................................................................................... 1 BACKGROUND ....................................................................................................................................................... 2 2.1 2.2 2.3 BALLOON ANGIOPLASTY (POBA) AND BARE METAL STENTS (BMS)................................................................... 2 DRUG ELUTING STENTS (DES) ............................................................................................................................. 2 CLASSIFICATION OF BIFURCATION LESIONS ......................................................................................................... 2 Y- and T-shape lesions ................................................................................................................................ 2 Y-shape lesion: .........................................................................................................................................................2 T-shape lesion: ..........................................................................................................................................................2 2.3.1 2.3.1.1 2.3.1.2 2.3.2 2.3.2.1 2.3.2.2 2.3.2.3 2.3.2.4 2.3.2.5 2.3.2.6 Type 1-4 lesions .......................................................................................................................................... 2 Type 1 lesion: ...........................................................................................................................................................2 Type 2 lesion: ...........................................................................................................................................................3 Type 3 lesion: ...........................................................................................................................................................3 Type 4 lesion: ...........................................................................................................................................................3 Type 4a lesion: ..........................................................................................................................................................3 Type 4b lesion: .........................................................................................................................................................3 2.4 TREATMENT STRATEGIES ..................................................................................................................................... 3 Stenting of main vessel and optional treatment of side branch ................................................................... 3 Stenting of both main vessel and side branch ............................................................................................. 4 2.4.1 2.4.2 3. PURPOSE.................................................................................................................................................................. 4 3.1 3.2 PRIMARY OBJECTIVE............................................................................................................................................ 4 SECONDARY OBJECTIVE ....................................................................................................................................... 4 4. ETHICAL ASPECTS ............................................................................................................................................... 5 4.1 4.2 4.3 ETHICAL CONDUCT OF THE STUDY ....................................................................................................................... 5 INDEPENDENT ETHICS COMMITTEE (IEC) ........................................................................................................... 5 PATIENT INFORMATION AND THE INFORMED CONSENT ....................................................................................... 5 5. STUDY PLAN ........................................................................................................................................................... 5 5.1 5.2 5.3 PARTICIPATING CENTERS ..................................................................................................................................... 5 MATERIAL AND METHODS ................................................................................................................................... 5 PCI PROCEDURE .................................................................................................................................................. 6 DES-PCI principles .................................................................................................................................... 6 5.3.1 5.4 5.5 STUDY STENTS ..................................................................................................................................................... 6 SCHEDULE OF EVENTS ......................................................................................................................................... 7 Admission .................................................................................................................................................... 7 PCI procedure............................................................................................................................................. 7 12-18 hours ................................................................................................................................................. 7 Hospital period ........................................................................................................................................... 7 5.5.1 5.5.2 5.5.3 5.5.4 2004-09-23 Amendment No 1 incorporated in the protocol The Nordic Bifurcation Study 5.5.5 5.5.6 5.5.7 5.6 5.7 5.8 After one month ........................................................................................................................................... 8 After 6 months ............................................................................................................................................. 8 After 8 months ............................................................................................................................................. 8 ADVERSE EVENT ................................................................................................................................................. 9 WITHDRAWALS ................................................................................................................................................... 9 PATIENTS ........................................................................................................................................................... 10 Inclusion criteria....................................................................................................................................... 10 Exclusion criteria ...................................................................................................................................... 10 5.8.1 5.8.2 5.9 END POINT ......................................................................................................................................................... 10 Primary end point ..................................................................................................................................... 10 Secondary end points ................................................................................................................................ 10 Clinical ...................................................................................................................................................................10 Angiographic ..........................................................................................................................................................11 5.9.1 5.9.2 5.9.2.1 5.9.2.2 5.9.3 5.9.3.1 5.9.3.2 5.9.3.3 5.9.3.4 5.9.3.5 5.9.3.6 5.9.3.7 5.9.3.8 End point evaluation ................................................................................................................................. 11 Q wave myocardial infarction .................................................................................................................................11 Non Q wave myocardial infarction .........................................................................................................................11 Procedure related myocardial infarction .................................................................................................................11 Target lesion revascularization ...............................................................................................................................11 Target vessel revascularization ...............................................................................................................................11 Stent thrombosis .....................................................................................................................................................11 Vessel measurement ...............................................................................................................................................12 Angiographic restenosis ..........................................................................................................................................12 5.9.4 5.9.4.1 5.9.4.2 Angiographic core lab .............................................................................................................................. 12 Definition of Index angiography .............................................................................................................................12 Follow-up angiography ...........................................................................................................................................12 5.10 STEERING COMMITTEE ....................................................................................................................................... 12 Progress of the study ................................................................................................................................. 13 5.10.1 6. STATISTICS AND DATA MANAGEMENT ...................................................................................................... 13 6.1 6.2 6.3 6.4 6.5 6.6 6.7 PRIMARY END POINT .......................................................................................................................................... 13 SECONDARY END POINTS AND OTHER PARAMETERS .......................................................................................... 13 SAFETY .............................................................................................................................................................. 13 ANALYSIS POPULATION ..................................................................................................................................... 13 SAMPLE SIZE CALCULATION .............................................................................................................................. 13 RANDOMIZATION PROCEDURE ........................................................................................................................... 14 DATA MANAGEMENT ......................................................................................................................................... 14 CRF ........................................................................................................................................................... 14 6.7.1 7. MONITORING OF THE STUDY ........................................................................................................................ 14 7.1 7.2 DIRECT ACCESS TO SOURCE DOCUMENTATION .................................................................................................. 15 SOURCE DATA VERIFICATION ............................................................................................................................. 15 2004-09-23 Amendment No 1 incorporated in the protocol The Nordic Bifurcation Study 8. ADMINISTRATION .............................................................................................................................................. 15 8.1 8.2 8.3 ECONOMY.......................................................................................................................................................... 15 ORGANIZATION ................................................................................................................................................. 15 PUBLICATION..................................................................................................................................................... 16 9. SIGNED AGREEMENT OF THE STUDY PROTOCOL .................................................................................. 17 9.1 9.2 COORDINATING AND PRINCIPAL INVESTIGATOR ................................................................................................ 17 INVESTIGATOR ................................................................................................................................................... 18 REFERENCES ................................................................................................................................................... 19 10. 2004-09-23 Amendment No 1 incorporated in the protocol The Nordic Bifurcation Study 1 1. Abbreviations AMI AP ASA BMS CABG CCS CK-MB CRF CV DES ECG GCP IEC IHD MACE PCI POBA TLR TVR Acute Myocardial Infarction Angina Pectoris Acetylsalicylic Acid Bare Metal Stents Coronary Artery By-pass Grafting Canadian Cardiovascular Society Angina Grading System Creatine Kinase MB Case Report Form Curriculum Vitae Drug Eluting Stents Electrocardiogram Good Clinical Practice Independent Ethics Committee Ischemic Heart Diseases Cardiac death, Myocardial Infarction, Stent trombosis or Target Vessel Revascularization Percutaneous Coronary Intervention Plain Old Balloon Angioplasty Target Lesion Revascularization Target Vessel Revascularization 2004-09-23 Amendment No 1 incorporated in the protocol The Nordic Bifurcation Study 2 2. Background 2.1 Balloon angioplasty (POBA) and bare metal stents (BMS) Bifurcation lesions are frequent and account for about 15% of all Percutan Coronary Intervention (PCI) cases (1). Initial results with balloon angioplasty were poor with high risk of acute closure of main vessel or side branch and with a high restenosis rate (2). Today, coronary stenting has become routine praxis in these lesions and problems with acute main vessel closure have been eliminated. However, bifurcation stenting is still associated with a high rate of restenosis, and acute side branch closure is not uncommon (3). The restenosis problem is especially pronounced, when multiple stents are used in these lesions (4). 2.2 Drug eluting stents (DES) The use of drug eluting stents in both main vessel and side branch may reduce the problems of acute side branch closure and high restenosis rates in these lesions (3). At present there are no randomized studies comparing DES and BMS in bifurcation lesions. However, preliminary data from the SCANSTENT study suggests, that the use of DES reduces problems with restenosis in bifurcation lesions, and that a technically correct use of these stents results in low restenosis rates, both of the main vessel and of the side branch (5,6). 2.3 Classification of bifurcation lesions 2.3.1 Y- and T-shape lesions 2.3.1.1 Y-shape lesion: The angulation between side branch and main vessel is <70 . Side branch access is usually easy, but plaque shift pronounced. o 2.3.1.2 T-shape lesion: The angulation between side branch and main vessel is >70 . Side branch access may be difficult, but plaque shift less pronounced (7). 2.3.2 Type 1-4 lesions o 2.3.2.1 Type 1 lesion: True bifurcation lesion involving main vessel, proximal and distal to the side branch, and the ostium of the side branch. 2004-09-23 Amendment No 1 incorporated in the protocol The Nordic Bifurcation Study 3 2.3.2.2 Type 2 lesion: Bifurcation lesion involving main vessel proximal and distal to the side branch, but no involvement of side branch ostium. 2.3.2.3 Type 3 lesion: Bifurcation lesion involving main vessel proximal, but not distal to the side branch and without involvement of side branch ostium. 2.3.2.4 Type 4 lesion: Bifurcation lesion involving the distal main vessel and the ostium of the side branch. 2.3.2.5 Type 4a lesion: Bifurcation lesion involving main vessel distal, but not proximal to the side branch and without involvement of side branch ostium. 2.3.2.6 Type 4b lesion: Bifurcation lesion involving the side branch ostium only. 2.4 Treatment strategies In clinical praxis it has been difficult to choose a treatment strategy based on the lesion types mentioned above because of difficulties in assessing the true plaque burden and localization by angiography alone, and because plaque shift during the PCI procedure may be pronounced and unpredictable. Also, the side branch angulation may be modified by the procedure (7). A number of different treatment strategies have been recommended by different centers or by opinion leaders in the field of PCI. So far, however, none of the proposed strategies have been evaluated in well conducted randomized clinical trials. Different treatment strategies may be summarized as two basic strategies: 2.4.1 Stenting of main vessel and optional treatment of side branch Stenting of both main vessel and side branch Stenting of main vessel and optional treatment of side branch This is the standard bifurcation treatment of many centers. This bifurcation technique may be carried out in different ways. Usually, both main vessel and side branch are wired and ballooned, preferentially with kissing balloon technique. The main vessel is stented with both wires in place. The side branch is rewired through the stent struts and the main vessel redilated after removal of the jailed wire. If the flow in the side branch is normal (TIMI 3 flow), the procedure is terminated. If the TIMI flow rate is <3 the side branch is dilated through 2004-09-23 Amendment No 1 incorporated in the protocol The Nordic Bifurcation Study 4 main vessel stent struts. The side branch is stented if the side branch TIMI flow rate is 0 after dilatation. Thus, side branch stenting is not indicated merely because of residual stenosis or dissection. This is a rather simple technique, but there may be significant residual stenosis and even occlusion of the side branch. However, the clinical significance of side branch stenosis or occlusion is not known. 2.4.2 Stenting of both main vessel and side branch This technique has gained increasing popularity in the DES era, as the problems by the use of multiple BMS in bifurcations may have been solved with the advent of DES. In this strategy, both vessels are wired and predilated. Thereafter, there are more treatment options, which are used at the discretion of the operator. 1. The side branch is stented with an uninflated balloon or a stent in the main vessel. The side branch stent is implanted with its proximal end protruding more than half the main vessel diameter into the main vessel. The side branch stent is crushed by the main vessel balloon/stent. – Crush technique (8). 2. The side branch or the main vessel is stented. The non-stented vessel is wired, dilated and stented through the implanted stent. Then the first vessel is rewired and redilated through the second stent. – Culotte technique (9). 3. The main vessel is stented, and the side branch stented through the stent struts of the main vessel stent. – Y technique (7). The above mentioned three procedures are finalized by kissing balloon inflation. This treatment strategy may be complex and technically demanding and may be associated with procedural complications as a result of longer procedures and more aggressive guiding and guide-wire techniques. Also, the rate of stent thrombosis remains to be determined in these procedures. 3. Purpose 3.1 Primary objective In a randomized study to compare: A strategy of main vessel stenting and optional side branch treatment versus a strategy of stenting main vessel and side branch by evaluation of cardiac death, myocardial infarction, stent thrombosis and target vessel revascularization (TVR) after 6 months. 3.2 Secondary objective 3.2.1 To compare and evaluate clinical signs after 1, 6 and 8 months after main vessel stenting and optional side branch treatment versus stenting main vessel and side branch. 3.2.2 To evaluate and compare angiography at PCI procedure and at 8 months after main vessel stenting and optional side branch treatment versus stenting main vessel and side branch. 2004-09-23 Amendment No 1 incorporated in the protocol The Nordic Bifurcation Study 5 4. Ethical aspects Both treatment strategies are well described and used in Nordic cardiac centers. The risk of an angiographic control is less than the potential benefits of such a control. 4.1 Ethical conduct of the study The trial will be conducted in accordance with the protocol, applicable regulatory requirements and the ethical principles of the Declaration of Helsinki as adopted by the 18 World Medical Assembly in Helsinki, Finland, in 1964 and subsequent versions. th 4.2 Independent Ethics Committee (IEC) It is the responsibility of the Coordinating Investigator to obtain approval of the trial protocol/protocol amendments, the patient information and the Informed Consent from the IEC before enrolment of any patient into the trial. The written approval from the IEC should be dated and have an attached list of those persons (with names and positions) present at the IEC meeting. 4.3 Patient information and the 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 the trial. All patients should be given the opportunity to ask questions about the trial and should be given sufficient time to decide whether or not to participate in the trial. 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 freedom to withdraw from the trial at any time and without giving any particular reason. Patients must also be informed that withdrawing from the trial will not affect their future medical care, treatment or benefits to which the patient is otherwise entitled. The Investigator is responsible for obtaining written Informed Consent from all patients (or their legally acceptable representatives and/or witnesses, where applicable) prior to enrolment in the trial. 5. Study Plan 5.1 Participating centers Nordic interventional centers with interest and experience in treatment of bifurcation lesions with the above mentioned techniques and who expect to include >10 patients with angiographic follow-up during an eight month period. 5.2 Material and methods Consecutive patients admitted for PCI treatment of one or more bifurcation lesions will be randomized 1:1 to the two bifurcation treatment strategies, described below: 2004-09-23 Amendment No 1 incorporated in the protocol The Nordic Bifurcation Study 6 A strategy of main vessel stenting and optional side branch treatment (optional side branch treatment group), and a strategy of stenting main vessel and side branch (stenting main vessel and side branch group). According to the determination of sample size, based on the primary objective, the enrolment will be stopped when 200 patients are randomized. However the secondary objective number two are of great importance, therefore the enrolment will be stopped when 200 patients with planned angiographic control at 8 months have been randomized. A maximum of 400 patients can be included in the study. 5.3 PCI procedure Main treatment principles of the “optional side branch treatment group”: 1. Stenting of main vessel. 2. Side branch dilatation if TIMI flow <3. 3. Side branch stenting if TIMI flow =0 after dilatation. 4. If the side branch is stented, the procedure is finalized by kissing balloon dilatation. Main treatment principles of the “stenting main vessel and side branch group”. 1. Stenting of both vessels by “crush”, “culotte”, “Y” or other techniques. 2. Procedure finalized by kissing balloon dilatation. 5.3.1 DES-PCI principles Based on data from the Sirius and the TAXUS studies (10,11) all possible effort should be exerted to avoid pre-treatment (conventional balloon, cutting balloon, mini rail balloon, rotablation, atherectomy) of segments, which will not be covered by stent, i.e. the main vessel segments in the “optional side branch treatment group”, and main vessel plus side branch segments in the “stenting main vessel and side branch group”. The radial or the femoral approach is used. Six F guiding is used routinely. Seven or eight F is used in “crush technique” procedures. Heparin or low-molecular weight heparin and GP IIbIIIa inhibitors are used according to local hospital routine. Life long Acetylsalicylic Acid (ASA) is given to all patients, and clopidogrel is used for 6-12 months. Ticlopidine can be used, if the patient does not tolerate clopidogrel. Creatine Kinase MB (CK-MB) and Troponin-T/I will be measured at the index procedure and 12-18 hours after the procedure. 5.4 Study stents The serolimus eluting stent “Cypher Select” (Cordis) will be used in the study. If the “Cypher Select” stent cannot be implanted, another drug eluting stent or bare metal stent may be used at the discretion of the operator, however different types of drug eluting stents cannot be use in the same vessel. The “Cypher Select” is a trademarked product launched worldwide. The product is CE marked. 2004-09-23 Amendment No 1 incorporated in the protocol The Nordic Bifurcation Study 7 5.5 Schedule of Events 5.5.1 Admission Before the patients are included to the study the inclusion and exclusion criteria will be checked and the Informed consent will be obtained. The following will also be recorded: Patients characteristics (weight, height, family history of IHD (Ischemic Heart Disease), treatment for hypercholesterolaemia, hypertension and active smoking) Cardiac data (history of PCI, history of CABG (Coronary Artery By-pass Grafting), number of diseased vessels, ejection fraction, number of treated vessels, number of treated lesioins and CCS-angina score (Canadian Cardiovascular Society Angina Grading System) patients will be asked if they accept a control angiography at 8 months. PCI procedure 5.5.2 After the initial coronary angiography the patient will be randomized and CKMB and Troponin-T/I will be taken. Thereafter the PCI procedure will be performed according to the randomized alternative. 5.5.3 12-18 hours CKMB and Troponin-T/I analyses will be repeated after 12-18 hours. 5.5.4 Hospital period Before discharge the following will be registered: Cardiac death Myocardial infarction Stent thrombosis TVR Total death Target Lesion Revascularization (TLR) Myocardial infarction related to index procedure Events during and after the PCI procedure until discharge or day 7 from admission (which ever comes first) will be recorded. 2004-09-23 Amendment No 1 incorporated in the protocol The Nordic Bifurcation Study 8 5.5.5 After one month For safety reasons, a telephone call will be made to all patients one month after the PCI procedure. The following will be registered: Cardiac death Myocardial infarction Stent thrombosis TVR Total death TLR The study nurse will review the patient’s hospital record and make the phone call. 5.5.6 After 6 months A clinical follow-up is done after six months in all patients. The patients will meet the responsible Investigator and the following will be investigated. Cardiac death Myocardial infarction Stent thrombosis TVR Total death TLR CCS angina score After 8 months 5.5.7 An eight months follow up angiography is carried out in patients, who have accepted a follow up angiography before randomization. Before the follow up angiography, it is decided, whether revascularization is indicated for clinical reasons or not. The following will also be registered: Cardiac death Myocardial infarction Stent thrombosis TVR Total death TLR CCS angina score 2004-09-23 Amendment No 1 incorporated in the protocol The Nordic Bifurcation Study 9 Flow chart for study procedures Admission PCI procedure Informed Consent Inclusion/Exclusion criteria Patient characteristics Cardiac Data Acceptance of Angiography at 8 months Randomization CKMB, Troponin-T/I Cardiac death Myocardial infarction Stent trombosis TVR Total death TLR Myocardial infarction related to index procedure CCS angina score Angiography X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X 12-18 hours Hospital period 1 month (phone call) 6 months (visit) 8 months (visit) 5.6 Adverse Event The “Cypher Select” is a trade marked product launched world wide therefore there will not be any adverse events associated with the use of “Cypher Select” 5.7 Withdrawals A patient can be withdrawn from the trial at any time, if it is the wish of the patient, or if it is medically necessary, as judged by the Investigator. If a patient does not return for a scheduled visit, every effort should be made to contact the patient. In any circumstance, every effort should be made to document patient outcome, if possible. A patient’s participation in the trial will be discontinued if any of the following criteria applies: 2004-09-23 Amendment No 1 incorporated in the protocol The Nordic Bifurcation Study 10 - Patient’s general condition contraindicates continuing the trial, as judged by the Investigator. Non-eligible patient. Protocol violation. If a patient decides to withdraw from the trial, he/she will be contacted in order to, if the patient agrees, obtain information about the reason(s) for discontinuation. The date and reason for the withdrawal will be recorded in the Case Report Form (CRF). 5.8 Patients 5.8.1      5.8.2       Inclusion criteria Stable or unstable Angina Pectoris (AP). Bifurcation lesion of “LAD/diagonal”, “Cx/obtuse marginal”, “RCA-PDA/posterolateral branch or LM/Cx/LAD in a right dominant system. Diameter of main vessel by visual estimate >2,5 mm. Diameter of side branch by visual estimate >2,0 mm. Signed Informed consent Exclusion criteria ST-elevation Acute Myocardial Infarction (AMI) within 24 hours. Expected survival <1year. S-creatinine >200 Umol/l. Allergy to Aspirin, Clopidogrel or Ticlopidine. Allergy to serolimus/paclitaxel. Left main bifurcation in a non-right dominant system. 5.9 End point 5.9.1 Primary end point Combined end point of: cardiac death, myocardial infarction, stent thrombosis or TVR after 6 months. 5.9.2 Secondary end points 5.9.2.1 Clinical MACE (cardiac death, myocardial infarction, stent trombosis or TVR during) hospital period, after 1 and 8 months Cardiac death during hospital period, after 1, 6 and 8 months Myocardial infarction during hospital period, after 1, 6 and 8 months 2004-09-23 Amendment No 1 incorporated in the protocol The Nordic Bifurcation Study 11 - Stent thrombosis during hospital period after 1, 6 and 8 months TVR during hospital period, after 1, 6 and 8 months Total death during hospital period, after 1, 6 and 8 months TLR during hospital period, after 1, 6 and 8 months Myocardial infarction related to index procedure CCS-angina score after 6 and 8 months 5.9.2.2 Angiographic Late loss of main vessel and side branch after 8 months. Percentual diameter stenosis of main vessel and side branch after 8 months. Angiographic restenosis (>50% diameter stenosis) rate of main vessel and side branch after 8 months. End point evaluation 5.9.3 Primary and secondary end points will be assessed by an independent end point committee The end point committee will consist of experienced interventional cardiologists. The detailed end point definitions are the following: 5.9.3.1 Q wave myocardial infarction Appearance of a new Q wave in two or more contiguous leads on Electrocardiogram (ECG) 5.9.3.2 Non Q wave myocardial infarction Infarction, which is considered present in a patient having clinical, angiographic, electrocardiographic, and/or laboratory evidence of myocardial necrosis with an ECG showing no new Q waves. 5.9.3.3 Procedure related myocardial infarction A >threefold increase of CK-MB /or Troponin-T/I. 5.9.3.4 Target lesion revascularization Coronary by-pass operation with grafting or PCI of index lesion. 5.9.3.5 Target vessel revascularization Coronary by-pass operation with grafting or PCI of index vessel. 5.9.3.6 Stent thrombosis Thrombotic occlusion of index stent/stents. 2004-09-23 Amendment No 1 incorporated in the protocol The Nordic Bifurcation Study 12 5.9.3.7 Vessel measurement Proximal reference diameter: Vesseldiameter proximal to lesion. Distal reference diameter: vessel diameter distal to lesion. Reference diameter: mean of proximal and distal vessel diameter. Percentual diameter stenosis: (Reference diameter – minimal luminal diameter) / reference diameter in percent. 5.9.3.8 Angiographic restenosis >50% diameter stenosis. 5.9.4 Angiographic core lab The index and the follow-up angiograms will be assessed blindly by one of the participating centers (by now Department of Cardiology, Skejby Hospital, 8200 Aarhus C, Denmark). 5.9.4.1 Definition of Index angiography The angiography obtained during the PCI procedure will be used as index angíography. There should be at least two cine-runs before the procedure and after the procedure with the same angulations and proceeded by 0,1 mg intracoronary nitroglycerine (documented on the angiogram). The diagnostic/guiding catheter should be well visible near the center of the angiogram with and without dye. The index lesion should be well visualized and located at the center of the angiogram. There should be an angulation difference between the two baseline angiograms of at least 30 degrees. Between the pre and post angiograms all balloon inflations and stent implantations should be documented by short cine-runs. 5.9.4.2 Follow-up angiography After 8 months conventional diagnostic angiography will be performed and the projections used at the index angiography will be repeated after 0.1 mg nitroglycerine intracoronary. Index angiograms and 8 months control-angiograms will be stored on CDs and sent by mail to the angiographic core lab. at Skejby Hospital. 5.10 Steering committee The steering committee will consist of one or two Investigators from each center. All steering committee members will have full access to the database and will participate in the interpretation of data. 2004-09-23 Amendment No 1 incorporated in the protocol The Nordic Bifurcation Study 13 5.10.1 Progress of the study The progress of the study will be checked on a weekly basis the steering committee. They will receive and evaluate data on inclusion rate and the primary end point event rate. Further the steering committee will receive and evaluate the weekly safety data on the rate of stent thrombosis in the two groups. 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 Investigator will draw preliminary conclusions, which will have to be approved by the steering committee members. 6. Statistics and Data Management The statistical analysis will be performed by UNI-C, University of Aarhus. 6.1 Primary end point The composite of the primary end points at six months follow-up will be analyzed by the Kaplan–Meier method. Differences between the event-free survival curves for the two groups will be compared with the use of the Wilcoxon and log-rank tests. Two-sided test are used, and the p-value considered to indicate significance will be 0,05. 6.2 Secondary end points and other parameters For continuous variables, differences between the treatment groups will be evaluated by analysis of variance or Wilcoxon's rank-sum test. For discrete variables, differences will be expressed as counts and percentages will be analyzed with Fisher's exact test. Secondary end-points will be assessed after 8 months. Two-sided test is used, and the p-value considered to indicate significance will be 0,05. 6.3 Safety For safety reasons stent thrombosis after one month will be monitored continuously. A stent thrombosis rate of >5% in any of the treatment groups will necessitate premature termination of the trial. 6.4 Analysis Population Results are analyzed according to the intention-to-treat principle i.e. patients randomized to a certain group will be followed and assessed irrespectively of the actual treatment. Protocol violations will be noted and the responsible centers notified. 6.5 Sample size calculation With an expected primary end point event rate of 30% in the “stenting main vessel and side branch group”, an alpha of 5% and a power of 80%, a reduction of primary end point event rate to 15% in the “optional side branch treatment group” can be detected with 100 patients in each group (5). 2004-09-23 Amendment No 1 incorporated in the protocol The Nordic Bifurcation Study 14 6.6 Randomization procedure The patient will be randomized at the beginning of the PCI procedure and before any insertion of wire or balloons. There will be a block randomization according to centre and a stratification according to sex, age >70 years, diabetes, use of GPIIbIIIa blocker and +/-angiographic follow up. The patients will be computer randomized by a 24 hour telephone service. The PARAVOX system will be used. PARAVOX is an automatic telephone randomization/voice response system. In this system the telephone push-buttons works as keyboard, while the computer communicates by pre-recorded messages. After the caller has been guided through all required entries, treatment and a unique patient number is allocated and announced in clear speech. The randomization is performed by well-reputed methods (stratified block-randomization). The system allows round-the-clock access. Only site-specific pass-codes are permitted access. The core of the system is a stand-alone PC – dedicated to receive and handle randomization calls. There are logging of all calls and all call attempts. 6.7 Data management Dedicated case record forms will be used and faxed to PCI research, Cardiac Cath. Lab., Skejby Hospital. Data will be stored in an Access database and double data entry will be used as quality control. There will be a log of accesses and attempt of access. Back-up data and original data will be cryptotized. 6.7.1 CRF A CRF is required and should be completed for each included patient. The patient’s identity must always remain confidential. All information in the CRFs should be in English. The Investigator is responsible for ensuring the accuracy, completeness, legibility and timeliness of the data recorded in the CRFs. The CRFs should be completed by using a black or blue ballpoint pen. Any corrections of data can only be made by using one single line through the incorrect data, leaving the incorrect data clearly visible (e.g. 352 325). Erasure by any method is not allowed. Corrections must be made both in original CRFs and in the Investigator’s copies. Corrections to the CRFs must be dated, initialed and explained (if necessary) by the Investigator or a designated representative. 7. Monitoring of the study Data will be monitored according to GCP rules by independent professionals. During the trial, the Monitor will have regular contacts with the trial site(s), including visits to ensure that the trial is conducted and documented properly in compliance with the protocol, Good Clinical Practice (GCP) and applicable regulatory requirements. 2004-09-23 Amendment No 1 incorporated in the protocol The Nordic Bifurcation Study 15 The Monitor will ensure that accountability of investigational products is performed and will review source documents for verification of consistency with the data recorded in the CRFs. The Monitor will also provide information and support to the Investigator(s). The Investigator and other responsible personnel must be available during the monitoring visits, audits and inspections and should devote sufficient time to these processes. The Investigator should provide a curriculum vita (CV) or equivalent documentation of suitability to be responsible for the trial. All Investigators and other responsible personnel should be listed together with their function in the trial on the signature list. 7.1 Direct access to source documentation The Investigator(s)/institution(s) will permit trial-related monitoring, audits, IEC review and regulatory inspection(s), providing direct access to source data/hospital records. The Investigator verifies 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. 7.2 Source data verification During the monitoring, the data recorded in the CRFs by the Investigator will be controlled for consistency with the source data/hospital records by the trial monitor (source data verification). Any discrepancies of data will be documented and explained in the monitoring reports. 8. Administration 8.1 Economy The Nordic Bifucation Study is an academic study conceived and conducted by cardiovascular interventionalists in the Nordic countries. The study is independent of commercial interests. An unrestricted grant of Dkr. 5,000 per patient is donated by Cordis. Study stents are provided by Cordis at a reduced price as agreed by Cordis and participating centers. 8.2 Organization Nordic centers with experience and interest in bifurcation techniques and with a potential of randomizing 10 angiographic follow-up patients during a one-year period can participate in the study. Each center will select one or two PCI operators for the Steering Committee of the study. Communication will primarily take place by E-mail. The Coordinating Investigator Leif Thuesen will have the responsibility as Sponsor. 2004-09-23 Amendment No 1 incorporated in the protocol The Nordic Bifurcation Study 16 8.3 Publication Results will be published in an international cardiovascular journal. Publication and author issues will be decided by the steering committee on basis general involvement in the study (core lab. function, end-point committee membership ect.) and of number of included patients. 2004-09-23 Amendment No 1 incorporated in the protocol The Nordic Bifurcation Study 17 9. Signed agreement of the study protocol 9.1 Coordinating and Principal Investigator Protocol Title “A strategy of routine stenting of both main vessel and side branch versus a strategy of routine main vessel stenting and optional treatment of side branch” We, the undersigned, have read and understand the protocol specified above and agree on the contents. The study protocol will serve as a basis for co-operation in this trial. Coordinating Investigator (Sponsor’s role in the Study) ______________________________________ Date Leif Thuesen Director Cardiac Cath. Lab., D.M.Sc. Skejby Hospital, Aarhus, Demmark ______________________________________ Signature Principal Investigator(s) (Main responsible for each country) ______________________________________ Name of Principal Investigator ______________________________________ Date ______________________________________ Title of Principal Investigator ______________________________________ Signature 2004-09-23 Amendment No 1 incorporated in the protocol The Nordic Bifurcation Study 18 9.2 Investigator To be signed by the participating Investigator. A separate page with each Investigators signature will be added to the protocol. Protocol Title “A strategy of routine stenting of both main vessel and side branch versus a strategy of routine main vessel stenting and optional treatment of side branch” I, the undersigned, have read and understand the protocol specified above and agree on the contents. The study protocol will serve as a basis for co-operation in this trial. Investigator(s) ______________________________________ Name of Investigator ______________________________________ Date ______________________________________ Title of Investigator ______________________________________ Signature 2004-09-23 Amendment No 1 incorporated in the protocol The Nordic Bifurcation Study 19 10. References 1. Meier B, Gruentzig AR, King SB 3rd, Douglas JS Jr, Hollman J, Ischinger T, Aueron F, Galan K. Risk of side branch occlusion during coronary angioplasty. Am J Cardiol 1984;53:10-4. 2. Pinkerton CA, Slack JD, Van Tassel JW, Orr CM. Angioplasty for dilatation of complex coronary artery bifurcation stenoses. Am J Cardiol 1985;55:1626-8. 3. Al Suwaidi J, Yeh W, Cohen HA, Detre KM, Williams DO, Holmes DR Jr. Immediate and one-year outcome in patients with coronary bifurcation lesions in the modern era (NHLBI dynamic registry). Am J Cardiol 2001;87:1139-44. 4. Yamashita T, Nishida T, Adamian MG, Briguori C, Vaghetti M, Corvaja N, Albiero R, Finci L, Di Mario C, Tobis JM, Colombo A. Bifurcation lesions: two stents versus one stent - immediate and follow-up results. J Am Coll Cardiol 2000; 35:1145-51 5. Colombo A, Moses JW, Morice MC, Ludwig J, Holmes DR Jr, Spanos V, Louvard Y, Desmedt B, Di Mario C, Leon MB. Randomized study to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions. Circulation 2004;109:1244-1249. 6. The Scandstent Study Group. Personal communication. 7. Lefevre T, Louvard Y, Morice MC, Dumas P, Loubeyre C, Benslimane A, Premchand RK, Guillard N, Piechaud JF. Stenting of bifurcation lesions: classification, treatments, and results. Catheter Cardiovasc Interv 2000; 49:274-83. 8. Colombo A, Stankovic G, Orlic D, Corvaja N, Liistro F, Airoldi F, Chieffo A, Spanos V, Montorfano M, Di Mario C. Modified T-stenting technique with crushing for bifurcation lesions: immediate results and 30-day outcome. Catheter Cardiovasc Interv 2003;60:145-51. 9. Chevalier B, Glatt B, Royer T, Guyon P. Placement of coronary stents in bifurcation lesions by the "culotte" technique. Am J Cardiol. 1998 Oct 15;82(8):943-9. 10. Stone GW, Ellis SG, Cox DA, Hermiller J, O'Shaughnessy C, Mann JT, Turco M, Caputo R, Bergin P, Greenberg J, Popma JJ, Russell ME; TAXUS-IV Investigators. A polymer-based, paclitaxeleluting stent in patients with coronary artery disease.N Engl J Med. 2004;350:221-31. 11. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O'Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, Jaeger JL, Kuntz RE; SIRIUS Investigators. Sirolimuseluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003;349:1315-23. 2004-09-23 Amendment No 1 incorporated in the protocol