PIoglitazone for PrEvention of Restenosis in Diabetic Patients
PIoglitazone for PrEvention of Restenosis in Diabetic Patients
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 months.Secondary end-point include binary
 restenosis MACE at 1, 9 and 12 month, stent thrombosis at 12 months.
2.Design This is a randomised, placebo-controlled, double-blinded, multicenter centre
 study.The patients' clinical data will be recorded on case report forms (CRF).

 3.Aim of the study To evaluate the efficacy of Pioglitazone (30 mg/daily) 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.

 4.Endpoints

 4.1.Primary Endpoint

 The primary end-point is defined by:

 -  In-stent late luminal loss after 9 months of implant procedure

 4.2.Secondary 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

 5.Study 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 0.43±0.45 mm and a
 pre-specified 40% reduction in the TZDs group (expected late luminal loss of 0.26±0.28
 mm) resulting in 86 lesions per group to achieve statistical significance ([alpha]=0.05,
 [beta]=0.2, 2 tailed). Considering a 20% of patients lost in follow-up and a mean of 1.3
 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.

 6.Conduct of the study

 6.1.Screening 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.

 6.2 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.

 6.3 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.

 6.4 Pharmacological treatment

 Pre-procedure:

 -  Aspirin 75 mg

 -  Clopidogrel loading dose of 600 mg

 Intravenous GP IIb/IIIa agents will be allowed at the discretion of the operator with the
 following doses:

 -  Abciximab 0,25 mg/kg intravenous bolus 10-60 min. before the procedure, followed by a
 continuous infusion of 0,125 mg/kg/min for 12-18 hours.

 -  Tirofiban 10 mcg/kg intravenous bolus, followed by a continuous infusion of 0, 15
 mcg/kg/min for 18-24 hours.

 -  Eptifibatide 180 mcg/kg intravenous bolus immediately before the procedure, followed by
 a continuous infusion of 2 mcg/kg/min (in patients with serum creatinine > 2 mg/dl the
 infusion should be of 1 mcg/kg/min) and a second bolus of 180 mcg/kg/min 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 U/kg if no GP IIb/IIIa are administered or at a
 dose of 50/70 U/Kg if GP IIb/IIIa are administered.

 Post-procedure:

 *Aspirin 75 mg/day indefinitely

 *Clopidogrel 75 mg/day 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.

 7.In 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
 patient's 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 (1,2) HbA1c 6.5 - 7.0% Fasting / pre-prandial glucose
 levels 90 - 130 mg/dl Post-prandial glucose levels 140 - 180 mg/dl Bed time glucose levels
 110 - 150 mg/dl

 1. American Diabetes Association, Diabetes Care 2004, 27: S15-S35

 2. American Association of Clinical Endocrinologists, Endocrine Pract 2002 (suppl.1):
 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 (HbA1c>7.0%), OAD monotherapy uptitration

 3. if failure (HbA1c>7.0%), OAD combination

 4. if failure (HbA1c>7.0%), OAD + basal insulin

 5. if failure (HbA1c>7.0%), OAD + multiple daily insulin injections

 6. if failure (HbA1c>7.0%), 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 HbA1c>7.0% 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-a/APO-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

 9.1 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).

 9.2 Major Adverse Cardiac Events

 Acute Myocardial infarction: Chest pain persisting for > 30 minutes associated with:

 ST segment elevation of at least 0.1 mV in two or more contiguous leads; or true posterior MI
 with ST segment depression of at least 0.1 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).

 9.3 Binary restenosis

 Defined as in-segment stenosis of at least 50 percent on follow-up angiography.

 9.4 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.

 9.5 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 ≥2.5 mm by
 visual estimate.

 -  Patients requiring 4 or more stents in one procedure.

 -  Target lesions in a vessels with diameter 2.5 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 al.17. 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

 12.1 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 (e.g., 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.

 12.2 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 DISABILITY/INCAPACITY.

 5. Leads to a CONGENITAL ANOMALY/BIRTH 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 failure/acute 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

 12.3 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 subject's usual activities.

 Severe: The event causes considerable interference with the subject's usual activities.

 12.4 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.

 12.5 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".

 12.6 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.

 -  Investigator's opinion of the causal relationship between the event and administration
 of study drug(s) (not related, possible, probable, or definite).

 -  Investigator's opinion of the causal relationship to study procedure(s), including the
 details of the suspected procedure.

 -  Action concerning study drug.

 -  Outcome of event.

 12.7 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.

 -  Investigator's 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.

 12.8 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.
I5.1 Inclusion criteria

 -  Patients must be previously diagnosed with type 2 diabetes with documented treatment
 with insulin, oral hypoglycemics, or diet controlled by medical history. (Undocumented
 or newly diagnosed diabetics must fulfill the American Diabetes Association
 Criteria-Report of the Expert Committee on the Diagnosis and Classification of
 Diabetes Mellitus (Diabetes Care 2003;26:S5-20)).

 -  Diagnosis of angina pectoris defined by Canadian Cardiovascular Society Classification
 (CCS I, II, III, IV) OR unstable angina pectoris (Braunwald Classification B&C,
 I-II-III) OR patients with documented silent ischemia;

 -  Patients with "de novo" coronary lesion (any length) who are eligible for coronary
 revascularization;

 -  Target lesion is ≥2.5 mm to ≤3.5mm in diameter (visual estimate);

 -  Target lesion stenosis is ≥50% (visual estimate);

 -  Male or Female age >18 years old;

 -  Patients with one or more lesions to be treated with a sirolimus eluting stent
 (Cypher, Cordis);

 -  Patient must provide written informed consent prior to the procedure using a form that
 is approved by the local Institutional Review Board.

 -  At least one lesion must be a complex lesion (see below for details)

 5.2 Exclusion criteria

 -  Patients under age 18 years old;

 -  Patient has experienced an ST-segment elevation myocardial infarction within the
 preceding 30 days;

 -  Active liver disease (ALT>2.5 times upper limit of normal);

 -  Impaired renal function (creatinine ≥2.5 mg/dL);

 -  Previous brachytherapy of target vessel;

 -  Lesion of the Left Main trunk > 50%;

 -  Target lesion is in a saphenous venous graft or internal mammary graft;

 -  Target lesion is due to restenosis ;

 -  Recipient of heart transplant;

 -  Women who are pregnant or who have the potential to become pregnant during the study;

 -  Patients with life expectancy of less than one year or factors making clinical
 follow-up difficult;

 -  Patients with bleeding diathesis in whom anticoagulant or antiplatelet drug is
 contraindicated;

 -  Patient with intolerance/contraindication to Aspirin or Ticlopidine/Clopidogrel or
 pioglitazone treatment;

 -  Currently participating in an investigational drug or another device study;

 -  Patients with leukopenia;

 -  Patients with neutropenia;

 -  Documented peptic ulcer or gastric/intestinal bleeding in the last 6 months;

 -  Patients with thrombocytopenia.