Ignite Creation Date:
2024-05-05 @ 5:01 PM
Last Modification Date:
2024-10-26 @ 9:27 AM
Study NCT ID:
NCT00376870
Status:
UNKNOWN
Last Update Posted:
2008-08-01
First Post:
2006-09-13
Brief Title:
PIoglitazone for PrEvention of Restenosis in Diabetic Patients
Sponsor:
University of Rome Tor Vergata
Organization:
University of Rome Tor Vergata
Study Overview
Official Title:
Prevention of Coronary Artery in STENT Restenosis With the Combined Use of Pioglitazone and Sirolimus-Eluting Coronary Stent
Status:
UNKNOWN
Status Verified Date:
2008-06
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Restenosis requiring reintervention is still a limitation of percutaneous coronary angioplasty Despite the use of Drug eluting stent DES the rate of restenosis remains 7 to 16 in diabetic patients making it a challenging problem in interventional cardiology
Still in clinical trials most of these attempts did not successfully limit neointimal formation after coronary stenting
Thiazolidinediones TZDs like pioglitazone pio or rosiglitazone are a novel class of oral antidiabetic agents currently used to treat patients with type 2 diabetes mellitus
These agents increase insulin sensitivity and as such have favorable effects on blood glucose levels and the lipid profile in treated patients
Beyond their metabolic action TZDs have been shown to exhibit antiinflammatory and antiatherogenic effects in vascular cells in vitro and to limit lesion development in various animal models of arteriosclerosis
Moreover TZDs inhibit VSMC proliferation and migration 2 critical processes in neointimal formation after coronary stenting
Data from rodent models suggest that TZDs limit intimal proliferation after vascular injury and in clinical studies with type 2 diabetic coronary artery disease CAD patients TZDs have been shown to reduce neointimal formation as well as restenosis after coronary stent implantation
Still it remains unclear to what extend these effects depend on the metabolic action of these drugs and what might mainly be due to the improvement in glycemic control
Recently a few reports on prevention of restenosis in type 2 diabetic patients T2DM with the use of TZDs as been published All of them uses BMS as endoprosthetic devices None of these evaluated the use of TZDs in combination with DES
Aim of the study is to evaluate the efficacy of pioglitazone in prevention of in-stent restenosis after successful implantation of a sirolimus-eluting coronary stent for treatment of de-novo complex coronary vessel disease in patients with T2DM and stable coronary artery disease
Study primary end-point are late-loss at 9 monthsSecondary end-point include binary restenosis MACE at 1 9 and 12 month stent thrombosis at 12 months
Still in clinical trials most of these attempts did not successfully limit neointimal formation after coronary stenting
Thiazolidinediones TZDs like pioglitazone pio or rosiglitazone are a novel class of oral antidiabetic agents currently used to treat patients with type 2 diabetes mellitus
These agents increase insulin sensitivity and as such have favorable effects on blood glucose levels and the lipid profile in treated patients
Beyond their metabolic action TZDs have been shown to exhibit antiinflammatory and antiatherogenic effects in vascular cells in vitro and to limit lesion development in various animal models of arteriosclerosis
Moreover TZDs inhibit VSMC proliferation and migration 2 critical processes in neointimal formation after coronary stenting
Data from rodent models suggest that TZDs limit intimal proliferation after vascular injury and in clinical studies with type 2 diabetic coronary artery disease CAD patients TZDs have been shown to reduce neointimal formation as well as restenosis after coronary stent implantation
Still it remains unclear to what extend these effects depend on the metabolic action of these drugs and what might mainly be due to the improvement in glycemic control
Recently a few reports on prevention of restenosis in type 2 diabetic patients T2DM with the use of TZDs as been published All of them uses BMS as endoprosthetic devices None of these evaluated the use of TZDs in combination with DES
Aim of the study is to evaluate the efficacy of pioglitazone in prevention of in-stent restenosis after successful implantation of a sirolimus-eluting coronary stent for treatment of de-novo complex coronary vessel disease in patients with T2DM and stable coronary artery disease
Study primary end-point are late-loss at 9 monthsSecondary end-point include binary restenosis MACE at 1 9 and 12 month stent thrombosis at 12 months
Detailed Description:
2Design This is a randomised placebo-controlled double-blinded multicenter centre studyThe patients clinical data will be recorded on case report forms CRF
3Aim of the study To evaluate the efficacy of Pioglitazone 30 mgdaily therapy on in-stent late luminal loss in T2DM patients treated with sirolimus-eluting stent for a complex lesion Both Pioglitazone and matched Placebo will be provided by Takeda Global Research Development TGRD London UK
4Endpoints
41Primary Endpoint
The primary end-point is defined by
In-stent late luminal loss after 9 months of implant procedure
42Secondary Endpoint
The secondary end-points are defined by
Binary restenosis defined as in-segment stenosis of at least 50 percent on follow-up angiography
Incidence of major adverse cardiac events MACE within discharge 30 days 6 and 12 months after implant procedure The major adverse events are described as follows
Acute myocardial infarction
Cardiac death
Recurrent Myocardial infarction Q-wave and non-Q wave
Target Lesion Revascularization TLR
Target Vessel Revascularization TVR
Incidence of STENT Thrombosis classified by the ARC definition
definite probable or possible
Acute 0 to 24 hours after stent implantation Subacute 24 hours to 30 days or Late 30 to 360 days and Very Late 1 year afer stent implantation
Safety and tolerability
5Study population Sample size is calculated on the basis of results from previous trials that have examined the effect of TZDs on neointima formation in diabetic subjects with late luminal loss in the control group of 043045 mm and a pre-specified 40 reduction in the TZDs group expected late luminal loss of 026028 mm resulting in 86 lesions per group to achieve statistical significance alpha005 beta02 2 tailed Considering a 20 of patients lost in follow-up and a mean of 13 lesion for patients treated we will need 80 patients per group The patients to be enrolled have to fulfil the inclusion criteria listed below and none of the exclusion criteria and they have to be enrolled in a consecutive manner
6Conduct of the study
61Screening procedure and enrollment Patients with T2DM scheduled for angioplasty will be screened for eligibility If all inclusion criteria are met and no exclusion criteria are present the patients should be enrolled in the study
62 Randomisation procedure After informed written consent is obtained a randomisation number will be assigned to the patient A pre-packed blind-label study drug or placebo with a 3 months dose will be assigned to the patient The first dose will be administered before the implant procedure and continued for 9 months Randomisation code will be stored in a safe place
63 Stenting procedure Stents can be implanted after lesion predilatation or using direct stenting technique performed at the discretion of the operator After checking the correct position stent should be inflated and deployed with a single inflation Residual stenosis after the stent implant must be less than 10 If needed another stent should be placed overlapping with former Post dilatation of the overlapped segment with a non-compliant balloon is mandatory
64 Pharmacological treatment
Pre-procedure
Aspirin 75 mg
Clopidogrel loading dose of 600 mg
Intravenous GP IIbIIIa agents will be allowed at the discretion of the operator with the following doses
Abciximab 025 mgkg intravenous bolus 10-60 min before the procedure followed by a continuous infusion of 0125 mgkgmin for 12-18 hours
Tirofiban 10 mcgkg intravenous bolus followed by a continuous infusion of 0 15 mcgkgmin for 18-24 hours
Eptifibatide 180 mcgkg intravenous bolus immediately before the procedure followed by a continuous infusion of 2 mcgkgmin in patients with serum creatinine 2 mgdl the infusion should be of 1 mcgkgmin and a second bolus of 180 mcgkgmin 10 min after the first bolus Infusion should be maintained for 18-24 hours
Intra-procedure
Heparin will be given at the dose of 70-100 Ukg if no GP IIbIIIa are administered or at a dose of 5070 UKg if GP IIbIIIa are administered
Post-procedure
Aspirin 75 mgday indefinitely
Clopidogrel 75 mgday for 12 months All of the patients will receive standard medical therapy as judged by the reference cardiologist including beta-blockers angiotensin-converting enzyme inhibitors and statins
7In hospital and follow-up examination
Physical examination
A physical examination will be performed in all patients enrolled before hospital discharge and at 3 9 and 12 months The physical evaluation must include an assessment of the patients clinical status including evaluation of ischemia and angina status
The patient and primary care physicians will be strongly encouraged to keep an optimal control of the glycemia considering the following recommendation
Changes in life style with increment in physical activity will be suggested for all patients The diabetology centre will treat patients with stepwise approach to achieve a possible goal of HbA1c 7 and daily glycaemic levels reported in the following table
Glycemic goals ADA and AACE criteria 12 HbA1c 65 - 70 Fasting pre-prandial glucose levels 90 - 130 mgdl Post-prandial glucose levels 140 - 180 mgdl Bed time glucose levels 110 - 150 mgdl
1 American Diabetes Association Diabetes Care 2004 27 S15-S35
2 American Association of Clinical Endocrinologists Endocrine Pract 2002 suppl1 40-82
The approach will be
Type 2 diabetic patients on oral anti-diabetic OAD therapy
1 starting with OAD monotherapy
2 if failure after 2 months HbA1c70 OAD monotherapy uptitration
3 if failure HbA1c70 OAD combination
4 if failure HbA1c70 OAD basal insulin
5 if failure HbA1c70 OAD multiple daily insulin injections
6 if failure HbA1c70 multiple daily insulin injections Starting from point 3 diabetology centre will decide on the dosing and therapeutic regimens Type 2 diabetic patients on insulin therapy
7 Multiple daily insulin injections with increasing doses if HbA1c70 The number of diabetologic follow-up visits will be decided by the usual diabetology care policy of the centre according to plasma glucose and HbA1c levels
Blood samples cardiac enzymes Troponin CK and CK-MB should be evaluated before the procedure and before discharge CK-MB after 6 12 and 24 hour and continued if abnormal till normalization
Metabolic and inflammatory indices will be analysed before discharge and at 3 9 and 12 months follow-up Among them will be evaluated fasting glucose fasting insulin HbA1c triglyceride total cholesterol LDL cholesterol HDL cholesterol APO-aAPO-b Hs-CRP CD40L Adiponectin
8 Scheduled follow-up visit
Patients will be contacted by phone at 30 days and 6 months follow-up and they will undergo clinical evaluation after 3 9 and 12 months At 9 months follow-up patients will be scheduled for a repeat angiography
Pre procedure Post procedure Hospital discharge 30-day follow-up 3 month follow-up 6 month follow-up 9 month follow-up 12 month follow-up Physical examination Yes - Yes Phone call Yes Phone call Yes Yes Blood sampling Yes Ck-MB CK Tn - - Yes Yes Yes Coronary angiography Yes Yes - - - Yes -
9 Definitions
91 In segment late-luminal loss
Defined as difference between the minimal luminal diameter at the end of the procedure and the minimal luminal diameter at 9 months follow-up in the target lesion or either edge 5mm
92 Major Adverse Cardiac Events
Acute Myocardial infarction Chest pain persisting for 30 minutes associated with
ST segment elevation of at least 01 mV in two or more contiguous leads or true posterior MI with ST segment depression of at least 01 mV in leads V1 through V3 or new left bundle branch block and elevation of CK-MB or CK more than two times upper limit of normal Periprocedural myocardial infarction is defind by 3 times ULN rise in troponin or CK-MB
Cardiac death all deaths occurring during the study are considered cardiac related unless clinical assessment can establish an unequivocal non-cardiac cause
Re-infarction a diagnosis of a new myocardial infarction is clinically defined on the basis of ECG or enzymatic doses if one of the following criteria is met
1 Detection of new pathological Q-waves not present on baseline ECG according to the Minnesota Code
2 Enzyme changes defined by more than two times upper limit of normal CK and the presence of CK-MB If the CK-MB is not available the CK will be accepted as evidence of myocardial infarction
Target lesion revascularization repeat revascularization PCI or CABG in the follow-up period due to restenosis either in the target lesion or either edge 5mm
Target vessel revascularization repeat revascularization PCI or CABG in the follow-up period due to restenosis either within the target lesion or anywhere else in the same epicardial coronary artery includes proximal and distal lesions branches and left main
93 Binary restenosis
Defined as in-segment stenosis of at least 50 percent on follow-up angiography
94 Thrombosis
The definition of definite stent thrombosis required the presence of an acute coronary syndrome with angiographic or autopsy evidence of thrombus or occlusion
Probable stent thrombosis included unexplained deaths within 30 days after the procedure or acute myocardial infarction involving the target-vessel territory without angiographic confirmation
Possible stent thrombosis included all unexplained deaths occurring 30 days after the procedure
95 Complex Lesion definition
Total occlusions
Long lesions 28 mm Two long lesions in series necessitating overlapping stents are accepted
True bifurcation lesions with a side branch greater than or expected to be 25 mm by visual estimate
Patients requiring 4 or more stents in one procedure
Target lesions in a vessels with diameter 25 mm by visual estimate which are not secondary branches such as postero-laterals diagonals or obtuse marginals
10 Quantitative Coronary Angiography Baseline postprocedural and follow-up coronary angiograms will be digitally recorded and assessed off-line in the angiographic laboratory with an automated edge-detection system by experienced personnel unaware of the study drug allocation The complexity of the lesions will defined according to the modified grading system of the American College of Cardiology-American Heart Association16 The morphologic appearance of in-stent restenosis at follow-up angiography will be classified according to the system proposed by Mehran et al17 All measurements will be performed on cineangiograms recorded after the intracoronary administration of nitroglycerin The same single worst-view projection will be used at all times The contrast-filled nontapered catheter tip will be used for calibration The reference diameter will be determined by interpolation
The variables that will be measured include the reference diameter of the vessel the minimal diameter of the lumen the extent of stenosis the difference between the reference diameter and the minimal luminal diameter divided by the reference diameter and multiplied by 100 late luminal loss the difference between the minimal luminal diameter at the end of the procedure and the minimal luminal diameter at 9 follow-up and net luminal gain the difference between the minimal luminal diameter at 9 follow-up and the minimal luminal diameter before the procedure Quantitative analysis will be used to evaluate the stented area in stent and the area that included the stented segment as well as the 5-mm margins proximal and distal to the stent in segment
12 Safety and Tolerability
121 Definition of Adverse Events AE An AE is defined as any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product it does not necessarily have to have a causal relationship with this treatment
An AE can therefore be any unfavourable and unintended sign eg an abnormal laboratory finding symptom or disease temporally associated with the use of a medicinal product whether or not it is considered related to the medicinal product
122 Definition of Serious Adverse Events SAE
A serious adverse event SAE is defined as any untoward medical occurrence that at any dose
1 Results in DEATH
2 Is LIFE THREATENING
The term life threatening refers to an event in which the subject was at risk of death at the time of the event it does not refer to an event that hypothetically might have caused death if it were more severe
3 Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization
4 Results in persistent or significant DISABILITYINCAPACITY
5 Leads to a CONGENITAL ANOMALYBIRTH DEFECT
6 Is an IMPORTANT MEDICAL EVENT that satisfies any of the following
May require intervention to prevent items 1 through 5 above
May expose the subject to danger even though the event is not immediately life threatening or fatal or does not result in hospitalization
Includes any event or synonym described in the Takeda Medically Significant List Table A
Table A Takeda Medically Significant List Term Acute respiratory failureacute respiratory distress syndrome Hepatic necrosis Ventricular fibrillation Acute liver failure Torsade de pointes Anaphylactic shock Malignant hypertension Acute renal failure Convulsive seizures Pulmonary hypertension Agranulocytosis Pulmonary fibrosis Aplastic anemia Confirmed or suspected endotoxin shock Toxic epidermal necrolysis Confirmed or suspected transmission of infectious agent by products Stevens-Johnson syndrome
123 Severity of AEs
The different categories of intensity severity are characterized as follows
Mild The event is transient and easily tolerated by the subject Moderate The event causes the subject discomfort and interrupts the subjects usual activities
Severe The event causes considerable interference with the subjects usual activities
124 Causality of AEs
The relationship of each AE to study drug will be assessed using the following categories
Definite An AE that follows a reasonable temporal sequence from administration of the drug including the course after treatment withdrawal of the drug AND that satisfies any of the following
Reappearance of similar reaction upon readministration rechallenge
Positive results in a drug sensitivity test skin test etc
Toxic level of the drug revealed by measurement of drug concentrations in blood or another body fluid
Probable An AE that follows a reasonable temporal sequence from administration of the drug including the course after withdrawal of the drug AND for which involvement of factors other than the drug such as underlying diseases complications concomitant drugs and concurrent treatment can reasonably be excluded
Possible An AE that follows a reasonable temporal sequence from administration of the drug including the course after withdrawal of the drug AND for which possible involvement of the drug can be argued although factors other than the drug such as underlying diseases complications concomitant drugs and concurrent treatments also may be responsible For example there have been similar reports in the past including reports on its analogues or the occurrence of the event could be predicted from the pharmacologic actions or chemical structure of the drug
Not related An AE that does not follow a reasonable temporal sequence from administration of the drug or that can be reasonably explained by other factors such as underlying diseases complications concomitant drugs and concurrent treatments
125 Relationship to Study Procedures
Relationship causality to study procedures should be determined for AEs The relationship should be assessed as Yes if the investigator considers that there is reasonable possibility that an event is due to a study procedures Otherwise the relationship should be assessed as No
126 AE Reporting
At each study visit the investigator will assess whether any subjective AEs have occurred A neutral question such as How have you been feeling since your last visit may be asked Subjects may report AEs occurring at any other time during the study
All subjects experiencing AEs whether considered associated with the use of the study medication or not must be monitored until the symptoms subside and any clinically relevant changes in laboratory values have returned to baseline or until there is a satisfactory explanation for the changes observed All AEs will be documented in the AE page of the CRF whether or not the investigator concludes that the event is related to the drug treatment The following information will be documented for each event
Event term
Start and stop date and time
Severity
Investigators opinion of the causal relationship between the event and administration of study drugs not related possible probable or definite
Investigators opinion of the causal relationship to study procedures including the details of the suspected procedure
Action concerning study drug
Outcome of event
127 Collection and Reporting of SAEs
When an SAE occurs after informed consent through the AE collection period it should be reported according to the following procedure
A Takeda SAE form must be completed in English and signed by the investigator immediately or within 1 working day of first onset or notification of the event The information should be completed as fully as possible but contain at a minimum
A short description of the event and the reason why the event is categorized as serious
Subject identification number
Investigators name
Causality assessment
The SAE form should be transmitted within 1 working day to the attention of
Takeda Global Research Development TGRD Pharmacovigilance Dept Arundel Great Court 2 Arundel Street London WC2R 3DA Fax No 44 207 759 5272
Any SAE spontaneously reported to the investigator following the AE collection period should be reported to TGRD
128 Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date the investigator should add this to the initial SAE form or provide other written documentation and fax it immediately within 1 working day of receipt Copies of any relevant data from the hospital notes eg ECGs laboratory tests discharge summary postmortem results should be sent to the addressee if requested
All SAEs should be followed up until resolution or permanent outcome of the event The timelines and procedure for follow-up reports are the same as those for the initial report
13 Patient withdrawal
Patient may withdraw from the study at any time and for any reason without affecting their right to treatment by the Investigator Every patient should be encouraged to remain in the study until they have completed the 12 months follow-up If the patient prematurely discontinues from the study for any reason a final evaluation must be completed for that patient and the reason for withdrawal must be documented All documentation concerning the patients must be as complete as possible
3Aim of the study To evaluate the efficacy of Pioglitazone 30 mgdaily therapy on in-stent late luminal loss in T2DM patients treated with sirolimus-eluting stent for a complex lesion Both Pioglitazone and matched Placebo will be provided by Takeda Global Research Development TGRD London UK
4Endpoints
41Primary Endpoint
The primary end-point is defined by
In-stent late luminal loss after 9 months of implant procedure
42Secondary Endpoint
The secondary end-points are defined by
Binary restenosis defined as in-segment stenosis of at least 50 percent on follow-up angiography
Incidence of major adverse cardiac events MACE within discharge 30 days 6 and 12 months after implant procedure The major adverse events are described as follows
Acute myocardial infarction
Cardiac death
Recurrent Myocardial infarction Q-wave and non-Q wave
Target Lesion Revascularization TLR
Target Vessel Revascularization TVR
Incidence of STENT Thrombosis classified by the ARC definition
definite probable or possible
Acute 0 to 24 hours after stent implantation Subacute 24 hours to 30 days or Late 30 to 360 days and Very Late 1 year afer stent implantation
Safety and tolerability
5Study population Sample size is calculated on the basis of results from previous trials that have examined the effect of TZDs on neointima formation in diabetic subjects with late luminal loss in the control group of 043045 mm and a pre-specified 40 reduction in the TZDs group expected late luminal loss of 026028 mm resulting in 86 lesions per group to achieve statistical significance alpha005 beta02 2 tailed Considering a 20 of patients lost in follow-up and a mean of 13 lesion for patients treated we will need 80 patients per group The patients to be enrolled have to fulfil the inclusion criteria listed below and none of the exclusion criteria and they have to be enrolled in a consecutive manner
6Conduct of the study
61Screening procedure and enrollment Patients with T2DM scheduled for angioplasty will be screened for eligibility If all inclusion criteria are met and no exclusion criteria are present the patients should be enrolled in the study
62 Randomisation procedure After informed written consent is obtained a randomisation number will be assigned to the patient A pre-packed blind-label study drug or placebo with a 3 months dose will be assigned to the patient The first dose will be administered before the implant procedure and continued for 9 months Randomisation code will be stored in a safe place
63 Stenting procedure Stents can be implanted after lesion predilatation or using direct stenting technique performed at the discretion of the operator After checking the correct position stent should be inflated and deployed with a single inflation Residual stenosis after the stent implant must be less than 10 If needed another stent should be placed overlapping with former Post dilatation of the overlapped segment with a non-compliant balloon is mandatory
64 Pharmacological treatment
Pre-procedure
Aspirin 75 mg
Clopidogrel loading dose of 600 mg
Intravenous GP IIbIIIa agents will be allowed at the discretion of the operator with the following doses
Abciximab 025 mgkg intravenous bolus 10-60 min before the procedure followed by a continuous infusion of 0125 mgkgmin for 12-18 hours
Tirofiban 10 mcgkg intravenous bolus followed by a continuous infusion of 0 15 mcgkgmin for 18-24 hours
Eptifibatide 180 mcgkg intravenous bolus immediately before the procedure followed by a continuous infusion of 2 mcgkgmin in patients with serum creatinine 2 mgdl the infusion should be of 1 mcgkgmin and a second bolus of 180 mcgkgmin 10 min after the first bolus Infusion should be maintained for 18-24 hours
Intra-procedure
Heparin will be given at the dose of 70-100 Ukg if no GP IIbIIIa are administered or at a dose of 5070 UKg if GP IIbIIIa are administered
Post-procedure
Aspirin 75 mgday indefinitely
Clopidogrel 75 mgday for 12 months All of the patients will receive standard medical therapy as judged by the reference cardiologist including beta-blockers angiotensin-converting enzyme inhibitors and statins
7In hospital and follow-up examination
Physical examination
A physical examination will be performed in all patients enrolled before hospital discharge and at 3 9 and 12 months The physical evaluation must include an assessment of the patients clinical status including evaluation of ischemia and angina status
The patient and primary care physicians will be strongly encouraged to keep an optimal control of the glycemia considering the following recommendation
Changes in life style with increment in physical activity will be suggested for all patients The diabetology centre will treat patients with stepwise approach to achieve a possible goal of HbA1c 7 and daily glycaemic levels reported in the following table
Glycemic goals ADA and AACE criteria 12 HbA1c 65 - 70 Fasting pre-prandial glucose levels 90 - 130 mgdl Post-prandial glucose levels 140 - 180 mgdl Bed time glucose levels 110 - 150 mgdl
1 American Diabetes Association Diabetes Care 2004 27 S15-S35
2 American Association of Clinical Endocrinologists Endocrine Pract 2002 suppl1 40-82
The approach will be
Type 2 diabetic patients on oral anti-diabetic OAD therapy
1 starting with OAD monotherapy
2 if failure after 2 months HbA1c70 OAD monotherapy uptitration
3 if failure HbA1c70 OAD combination
4 if failure HbA1c70 OAD basal insulin
5 if failure HbA1c70 OAD multiple daily insulin injections
6 if failure HbA1c70 multiple daily insulin injections Starting from point 3 diabetology centre will decide on the dosing and therapeutic regimens Type 2 diabetic patients on insulin therapy
7 Multiple daily insulin injections with increasing doses if HbA1c70 The number of diabetologic follow-up visits will be decided by the usual diabetology care policy of the centre according to plasma glucose and HbA1c levels
Blood samples cardiac enzymes Troponin CK and CK-MB should be evaluated before the procedure and before discharge CK-MB after 6 12 and 24 hour and continued if abnormal till normalization
Metabolic and inflammatory indices will be analysed before discharge and at 3 9 and 12 months follow-up Among them will be evaluated fasting glucose fasting insulin HbA1c triglyceride total cholesterol LDL cholesterol HDL cholesterol APO-aAPO-b Hs-CRP CD40L Adiponectin
8 Scheduled follow-up visit
Patients will be contacted by phone at 30 days and 6 months follow-up and they will undergo clinical evaluation after 3 9 and 12 months At 9 months follow-up patients will be scheduled for a repeat angiography
Pre procedure Post procedure Hospital discharge 30-day follow-up 3 month follow-up 6 month follow-up 9 month follow-up 12 month follow-up Physical examination Yes - Yes Phone call Yes Phone call Yes Yes Blood sampling Yes Ck-MB CK Tn - - Yes Yes Yes Coronary angiography Yes Yes - - - Yes -
9 Definitions
91 In segment late-luminal loss
Defined as difference between the minimal luminal diameter at the end of the procedure and the minimal luminal diameter at 9 months follow-up in the target lesion or either edge 5mm
92 Major Adverse Cardiac Events
Acute Myocardial infarction Chest pain persisting for 30 minutes associated with
ST segment elevation of at least 01 mV in two or more contiguous leads or true posterior MI with ST segment depression of at least 01 mV in leads V1 through V3 or new left bundle branch block and elevation of CK-MB or CK more than two times upper limit of normal Periprocedural myocardial infarction is defind by 3 times ULN rise in troponin or CK-MB
Cardiac death all deaths occurring during the study are considered cardiac related unless clinical assessment can establish an unequivocal non-cardiac cause
Re-infarction a diagnosis of a new myocardial infarction is clinically defined on the basis of ECG or enzymatic doses if one of the following criteria is met
1 Detection of new pathological Q-waves not present on baseline ECG according to the Minnesota Code
2 Enzyme changes defined by more than two times upper limit of normal CK and the presence of CK-MB If the CK-MB is not available the CK will be accepted as evidence of myocardial infarction
Target lesion revascularization repeat revascularization PCI or CABG in the follow-up period due to restenosis either in the target lesion or either edge 5mm
Target vessel revascularization repeat revascularization PCI or CABG in the follow-up period due to restenosis either within the target lesion or anywhere else in the same epicardial coronary artery includes proximal and distal lesions branches and left main
93 Binary restenosis
Defined as in-segment stenosis of at least 50 percent on follow-up angiography
94 Thrombosis
The definition of definite stent thrombosis required the presence of an acute coronary syndrome with angiographic or autopsy evidence of thrombus or occlusion
Probable stent thrombosis included unexplained deaths within 30 days after the procedure or acute myocardial infarction involving the target-vessel territory without angiographic confirmation
Possible stent thrombosis included all unexplained deaths occurring 30 days after the procedure
95 Complex Lesion definition
Total occlusions
Long lesions 28 mm Two long lesions in series necessitating overlapping stents are accepted
True bifurcation lesions with a side branch greater than or expected to be 25 mm by visual estimate
Patients requiring 4 or more stents in one procedure
Target lesions in a vessels with diameter 25 mm by visual estimate which are not secondary branches such as postero-laterals diagonals or obtuse marginals
10 Quantitative Coronary Angiography Baseline postprocedural and follow-up coronary angiograms will be digitally recorded and assessed off-line in the angiographic laboratory with an automated edge-detection system by experienced personnel unaware of the study drug allocation The complexity of the lesions will defined according to the modified grading system of the American College of Cardiology-American Heart Association16 The morphologic appearance of in-stent restenosis at follow-up angiography will be classified according to the system proposed by Mehran et al17 All measurements will be performed on cineangiograms recorded after the intracoronary administration of nitroglycerin The same single worst-view projection will be used at all times The contrast-filled nontapered catheter tip will be used for calibration The reference diameter will be determined by interpolation
The variables that will be measured include the reference diameter of the vessel the minimal diameter of the lumen the extent of stenosis the difference between the reference diameter and the minimal luminal diameter divided by the reference diameter and multiplied by 100 late luminal loss the difference between the minimal luminal diameter at the end of the procedure and the minimal luminal diameter at 9 follow-up and net luminal gain the difference between the minimal luminal diameter at 9 follow-up and the minimal luminal diameter before the procedure Quantitative analysis will be used to evaluate the stented area in stent and the area that included the stented segment as well as the 5-mm margins proximal and distal to the stent in segment
12 Safety and Tolerability
121 Definition of Adverse Events AE An AE is defined as any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product it does not necessarily have to have a causal relationship with this treatment
An AE can therefore be any unfavourable and unintended sign eg an abnormal laboratory finding symptom or disease temporally associated with the use of a medicinal product whether or not it is considered related to the medicinal product
122 Definition of Serious Adverse Events SAE
A serious adverse event SAE is defined as any untoward medical occurrence that at any dose
1 Results in DEATH
2 Is LIFE THREATENING
The term life threatening refers to an event in which the subject was at risk of death at the time of the event it does not refer to an event that hypothetically might have caused death if it were more severe
3 Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization
4 Results in persistent or significant DISABILITYINCAPACITY
5 Leads to a CONGENITAL ANOMALYBIRTH DEFECT
6 Is an IMPORTANT MEDICAL EVENT that satisfies any of the following
May require intervention to prevent items 1 through 5 above
May expose the subject to danger even though the event is not immediately life threatening or fatal or does not result in hospitalization
Includes any event or synonym described in the Takeda Medically Significant List Table A
Table A Takeda Medically Significant List Term Acute respiratory failureacute respiratory distress syndrome Hepatic necrosis Ventricular fibrillation Acute liver failure Torsade de pointes Anaphylactic shock Malignant hypertension Acute renal failure Convulsive seizures Pulmonary hypertension Agranulocytosis Pulmonary fibrosis Aplastic anemia Confirmed or suspected endotoxin shock Toxic epidermal necrolysis Confirmed or suspected transmission of infectious agent by products Stevens-Johnson syndrome
123 Severity of AEs
The different categories of intensity severity are characterized as follows
Mild The event is transient and easily tolerated by the subject Moderate The event causes the subject discomfort and interrupts the subjects usual activities
Severe The event causes considerable interference with the subjects usual activities
124 Causality of AEs
The relationship of each AE to study drug will be assessed using the following categories
Definite An AE that follows a reasonable temporal sequence from administration of the drug including the course after treatment withdrawal of the drug AND that satisfies any of the following
Reappearance of similar reaction upon readministration rechallenge
Positive results in a drug sensitivity test skin test etc
Toxic level of the drug revealed by measurement of drug concentrations in blood or another body fluid
Probable An AE that follows a reasonable temporal sequence from administration of the drug including the course after withdrawal of the drug AND for which involvement of factors other than the drug such as underlying diseases complications concomitant drugs and concurrent treatment can reasonably be excluded
Possible An AE that follows a reasonable temporal sequence from administration of the drug including the course after withdrawal of the drug AND for which possible involvement of the drug can be argued although factors other than the drug such as underlying diseases complications concomitant drugs and concurrent treatments also may be responsible For example there have been similar reports in the past including reports on its analogues or the occurrence of the event could be predicted from the pharmacologic actions or chemical structure of the drug
Not related An AE that does not follow a reasonable temporal sequence from administration of the drug or that can be reasonably explained by other factors such as underlying diseases complications concomitant drugs and concurrent treatments
125 Relationship to Study Procedures
Relationship causality to study procedures should be determined for AEs The relationship should be assessed as Yes if the investigator considers that there is reasonable possibility that an event is due to a study procedures Otherwise the relationship should be assessed as No
126 AE Reporting
At each study visit the investigator will assess whether any subjective AEs have occurred A neutral question such as How have you been feeling since your last visit may be asked Subjects may report AEs occurring at any other time during the study
All subjects experiencing AEs whether considered associated with the use of the study medication or not must be monitored until the symptoms subside and any clinically relevant changes in laboratory values have returned to baseline or until there is a satisfactory explanation for the changes observed All AEs will be documented in the AE page of the CRF whether or not the investigator concludes that the event is related to the drug treatment The following information will be documented for each event
Event term
Start and stop date and time
Severity
Investigators opinion of the causal relationship between the event and administration of study drugs not related possible probable or definite
Investigators opinion of the causal relationship to study procedures including the details of the suspected procedure
Action concerning study drug
Outcome of event
127 Collection and Reporting of SAEs
When an SAE occurs after informed consent through the AE collection period it should be reported according to the following procedure
A Takeda SAE form must be completed in English and signed by the investigator immediately or within 1 working day of first onset or notification of the event The information should be completed as fully as possible but contain at a minimum
A short description of the event and the reason why the event is categorized as serious
Subject identification number
Investigators name
Causality assessment
The SAE form should be transmitted within 1 working day to the attention of
Takeda Global Research Development TGRD Pharmacovigilance Dept Arundel Great Court 2 Arundel Street London WC2R 3DA Fax No 44 207 759 5272
Any SAE spontaneously reported to the investigator following the AE collection period should be reported to TGRD
128 Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date the investigator should add this to the initial SAE form or provide other written documentation and fax it immediately within 1 working day of receipt Copies of any relevant data from the hospital notes eg ECGs laboratory tests discharge summary postmortem results should be sent to the addressee if requested
All SAEs should be followed up until resolution or permanent outcome of the event The timelines and procedure for follow-up reports are the same as those for the initial report
13 Patient withdrawal
Patient may withdraw from the study at any time and for any reason without affecting their right to treatment by the Investigator Every patient should be encouraged to remain in the study until they have completed the 12 months follow-up If the patient prematurely discontinues from the study for any reason a final evaluation must be completed for that patient and the reason for withdrawal must be documented All documentation concerning the patients must be as complete as possible
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None