This clinical study synopsis is provided in line with Boehringer Ingelheim s Policy on Transparency and Publication of Clinical Study Data.

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1 abcd Clinical Study Synopsis for Public Disclosure This clinical study synopsis is provided in line with s Policy on Transparency and Publication of Clinical Study Data. The synopsis which is part of the clinical study report had been prepared in accordance with best practice and applicable legal and regulatory requirements at the time of study completion. The synopsis may include approved and non approved uses, doses, formulations, treatment regimens and/or age groups; it has not necessarily been submitted to regulatory authorities. A synopsis is not intended to provide a comprehensive analysis of all data currently available regarding a particular drug. More current information regarding a drug is available in the approved labeling information which may vary from country to country.. Additional information on this study and the drug concerned may be provided upon request based on s Policy on Transparency and Publication of Clinical Study Data. The synopsis is supplied for informational purposes only in the interests of scientific disclosure. It must not be used for any commercial purposes and must not be distributed, published, modified, reused, posted in any way, or used for any other purpose without the express written permission of.

2 Title of study: A phase IIIb IV, randomised, open label trial evaluating the efficacy and safety of tenecteplase together with unfractionated heparin prior to early PCI as compared to standard primary PCI in patients with acute myocardial infarction. ASSENT 4 PCI (Assessment of the Safety and Efficacy of a New Treatment Strategy for Acute Myocardial Infarction.) Investigator: M.D. (Principal Investigator) M.D. (Coinvestigator) Study center(s): 262 centers in 24 countries (ITT population) Publication (reference): No Clinical phase: IIIb IV Objectives: To compare the efficacy and safety of a strategy of prepci fibrinolytic treatment including full dose tenecteplase combined with ASA and unfractionated heparin (Group A) versus a strategy of standard primary PCI including ASA and unfractionated heparin (Group B) in patients with large acute myocardial infarcts. Methodology: An open, randomised, parallel clinical trial comparing two treatment strategies: standard PCI pretreated with tenecteplase versus standard primary PCI. No. of subjects: planned: actual: 4000 patients (ITT population) 1667 randomised patients (ITT population): + standard early PCI (Group A): 829 patients Early standard primary PCI (Group B): 838 patients Enrolment was discontinued prematurely as recommended by the DSMB due to a higher mortality in the facilitated treatment group (Group A).

3 Diagnosis and main criteria for inclusion: Diagnosis: Acute Myocardial Infarction (AMI) Inclusion criteria: Age > 18 years; Onset of symptoms of AMI within 6 hours prior to randomisation; Intention to perform a primary PCI as reperfusion treatment; Large infarct, as demonstrated on a 12lead ECG by ST segment elevation of a total of 6 mm across multiple leads (e.g., 2 mm in 3 leads, or 3 mm in 2 leads, or 2 mm in 2 leads with 1 mm in 2 more leads, etc.); or in patients with inferior M.I. a total of >6 mm ST deviation is a permissible entry criteria provided it includes >4 mm ST elevation coupled with concomitant ST depression; or left bundle branch block (LBBB) presumed to be new and with concordant ST segment elevation >1mm; Informed consent received. Exclusion criteria: Expected arrival at the catheterisation laboratory <1 h or >3 h after randomisation; Anticipated or obvious problems with vascular access; Previous enrolment in this study; The usual contraindications to fibrinolytic treatment as used in ASSENT 3 and 3 Plus,

4 Test treatment: (Group A) dose:, ASA and unfractionated heparin followed by standard PCI (facilitated PCI) ASA mg PO (alternatively IV) at study entry mg daily PO thereafter Weight adjusted Weight (kg) Dose in mg Dose in ml *) <60 30 mg 6 ml >60 to <70 35 mg 7 ml >70 to <80 40 mg 8 ml >80 to <90 45 mg 9 ml >90 50 mg 10 ml *) 50 mg reconstituted in 10 ml sterile water for injection Unfractionated heparin Single, weight adjusted IV bolus: 60 IU/kg, maximum 4000 IU Additional IV boluses in the cath lab according to ACT. Target ACT: seconds PCI mode of admin.: Standard procedure (no GP IIb/IIIa antagonists; if during the procedure, in the judgement of the operator, recurrent new clot formation or other events endanger the procedural success and clinical outcome (bail out situation), the use of appropriate medication according to standard hospital procedures is at the discretion of the operator/investigator; additional unfractionated heparin according to ACT) : Single IV bolus injection given over 5 10 seconds Unfractionated heparin: Single IV bolus injection ASA: PO

5 batch no.: : N9069A1, L83219, M22465, M27505, , M36482 SWFI (solvent): 95127DK, 08511DK, 15221DK, 17502DK Unfractionated heparin (LIQUEMIN ): G074021, G075311, G Unfractionated heparin (HEPARIN CHOAY ): 2059, 2049, 2064 ASA: Available commercial preparation (not in the study kit) Reference therapy: (Group B) dose: Standard primary PCI (ASA and unfractionated heparin followed by PCI) ASA mg PO (alternatively IV) at study entry mg daily PO thereafter Unfractionated heparin Single, weight adjusted IV bolus: 70 IU/kg (no maximum dose) Additional IV boluses in the cath lab according to ACT. PCI Target ACT: seconds ( seconds with a GP IIb/IIIa antagonist added) mode of admin.: batch no.: Standard primary procedure (GP IIb/IIIa antagonists at the investigator s discretion; additional unfractionated heparin according to ACT) Unfractionated heparin: Single IV bolus injection ASA: PO Unfractionated heparin (LIQUEMIN ): G074021, G075311, G Unfractionated heparin (HEPARIN CHOAY ): 2059, 2049, 2064 ASA: Available commercial preparation (not in the study kit) Duration of treatment: : single bolus injection (Group A) Unfractionated heparin: single bolus injection (followed by nonstudy unfractionated heparin according to ACT / Group A and B)) ASA: at least 90 days (Group A and B)

6 Duration of followup: Main study 90 days from randomisation for both groups for primary, secondary and tertiary endpoints. Followup study One year from randomisation for vital status (separate report) Criteria for evaluation: Efficacy: Primary endpoint: Death or cardiogenic shock or congestive heart failure within 90 days Secondary endpoints: 30day, composite endpoint Death or cardiogenic shock or congestive heart failure; 90day, composite endpoint Cardiogenic shock or congestive heart failure single endpoints Death; Congestive heart failure; Cardiogenic shock; Reinfarction; Repeat TVR; Rehospitalisation for congestive heart failure; Rehospitalisation for cardiogenic shock; Rehospitalisation for other cardiac reasons; NTproBNP (is reported separately)

7 Tertiary endpoints Inhospital composite endpoints Death or cardiogenic shock or congestive heart failure; Cardiogenic shock or congestive heart failure single endpoints Death; Congestive heart failure; Cardiogenic shock; Reinfarction; Refractory ischaemia; Repeat TVR; Aborted MI (at discharge; part of the ECG report); NTproBNP (at discharge or day 7) TIMI flow TIMI flow grade of IRA before and after PCI 30day composite endpoint Cardiogenic shock or congestive heart failure single endpoints Death; Congestive heart failure; Cardiogenic shock; Reinfarction; Repeat TVR; Rehospitalisation for congestive heart failure; Rehospitalisation for cardiogenic shock; Rehospitalisation for other cardiac reasons

8 Safety: Secondary endpoints: 90day Disabling stroke; Total stroke; Rehospitalisation for stroke or ICH Tertiary endpoints: Inhospital ICH; Total stroke; Major bleeds; Minor bleeds; Transfusions Substudies ECG: Angiogram: 30day Disabling stroke; Total stroke; Rehospitalisation for stroke or ICH ST segment resolution (reported separately) TIMI flow grades (reported separately) Statistical methods: An intenttotreat (ITT) superiority analysis of all patients randomised was carried out as the primary analysis. For all single and composite efficacy and/or safety endpoints the relative risks (with their twosided 95 %, confidence intervals) was calculated and the corresponding pvalues of the chisquare tests on proportions issued. Subgroup analyses were done for primary, secondary and tertiary endpoints using predefined common risk factors as covariates. The secondary analyses, based on the per protocol (PP) and the full set (FS) populations, were used for sensitivity testing only. SUMMARY CONCLUSIONS: (For the main study, 90day followup, only; 1year followup data are reported separately as not yet available when this report was written)

9 Efficacy results: Group A facilitated PCI (the experimental group) Group B primary PCI (reference group) The study was prematurely discontinued as recommended by the DSMB due to a higher mortality rate in group A than in group B, which was statistically significant at the time of the DSMB recommendation. The results presented are for the ITT population 1667 patients. Primary endpoint composite of death or cardiogenic shock or congestive heart failure within 90days; event rates: Group A 18.6% (151/810) Group B 13.4% (110/819) Relative risk (unadjusted) Pvalue After adjustment for predefined common risk factors, the analysis showed similar results without any relevant differences. The significant difference between the groups for the primary endpoint at 90 days was already present inhospital and at 30 days, and it tended to increase over time. The diverging was caused by congestive heart failure only. Single endpoints components of the primary endpoint did not show a significant difference between the study groups at 90days, but reinfarction and repeat target vessel revascularisation (TVR) did: Group A Group B Pvalue Death 6.7% 4.9% Cardiogenic shock 6.3% 4.8% Congestive heart failure 12.0% 9.2% Reinfarction 6.1% 3.7% Repeat TVR 6.6% 3.4% For the primary endpoint components, there was over time no significant difference between the study groups for cardiogenic shock and congestive heart failure at any time, only for death was there a statistically significant difference inhospital and at 30days, which became nonsignificant at 90days. In group A the majority of deaths occurred early after treatment, 58% within 48 hours, while in group B the death rate tended to be constant throughout the followup period. In the period 3090 days the occurrence of death was reversed between the study groups, 5 patients died in group A and 9 in group B. Totally 55 patients died within 90 days in group A and 41 in group B. The three most common causes of cardiac death in both study groups were: cardiogenic shock,

10 cardiac rupture/emd and major arrhythmias (asystole/cardiac arrest/sudden death). In group A 8 patients died of a stroke or ICH vs. none in group B. >50% of fatal strokes in group A occurred quite late, between 730 days after treatment. The only statistically significant difference in concomitant medication was an almost 5 fold higher use of GP IIb/IIIa antagonists during and after the PCI in group B: by app. 10% of patients in group A and app. 50% in group B. This discrepant use did not violate the study protocol, but probably had an antithrombotic effect favouring group B. Safety results: Overall the safety profile in both study groups were as expected. In group A stroke and ICH occurred significantly more often than in group B, but not more frequently than in previous ASSENT studies. Non intracranial bleeds were not of major concern and did not contribute to the premature discontinuation: only minor bleeds occurred significantly more often in group A, while for major bleeds the difference was not statistically significant. Inhospital adverse events the most important ones are summarized below: Group A Group B Pvalue % (n) % (n) ICH 1.0% (8) 0.0% (0) Total stroke 1.8% (15) 0.0% (0) < Major bleeds 5.6% (46) 4.4% (37) Minor bleeds 25.3% (210) 19.0% (159) Blood transfusions 6.2% (48) 4.2% (33) Abrupt vessel closure 1.9% (16) 0.1% (1) Between hospital discharge and day 90 one ICH occurred in each group and 6 additional strokes in group A and none in group B. Total number of strokes up to 90 days were: 22 in group A and 1 in group B.

11 Conclusions: Based on the results of this study, a strategy of fulldose tenecteplase routinely preceding PCI by 13 hours, and with antithrombotic cotherapy as used in this study, can not be recommended. Indeed, this combined therapy could be harmful. Whether such a strategy could be beneficial with an upfront loading dose of a thienopyridine, with better antithrombin cotherapy, in patients treated earlier (e.g. prehospital in ambulances within 23 hours of onset of symptoms), with longer delay to PCI or with a more selective performance of the PCI (e.g. only in case of failed fibrinolysis) is unknown and should be studied in future trials.