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 1 of NOV / 23 NOV JUN 2008 Title of trial: Telmisartan Randomized AssessmeNt Study in ace intolerant subjects with cardiovascular Disease (TRANSCEND) Coordinating Investigator: A large, simple, randomized, double-blind, multicentre, international trial comparing the effects of telmisartan with placebo on outcomes in patients at high risk for cardiovascular events and intolerant of ACE-I Trial sites: Multicentre study, cf. Appendix Publication (reference): Clinical phase: Objectives: Methodology: TRANSCEND Investigators. Lancet 2008;372: [P ] Department of error. Erratum for: 'TRANSCEND Investigators. Lancet 2008;372: '. Lancet 2008;372(9647): 1384 [P ] Sleight P. Acta Diabetol 2005;42:S50-S56 [P ] ONTARGET/TRANSCEND Investigators. Am Heart J 2004;148(1):52-61 [P ] III The objective of the TRANSCEND trial was to determine if telmisartan 80 mg daily is superior to placebo in reducing the composite endpoint of cardiovascular (CV) death, myocardial infarction (MI), stroke and hospitalisation for congestive heart failure (CHF) in patients who are intolerant to angiotensin converting enzyme-inhibitors (ACE-Is). Randomised (1:1 ratio), double-blind, parallel-group, placebo-controlled trial with a single-blind run-in phase of 3 to 4 weeks (starting with placebo for 1 week, continuing with telmisartan 80 mg for 2 to 3 weeks), and a planned randomised treatment phase of 3.5 to 6 years; patients were randomised to either monotherapy with telmisartan (80 mg) or to placebo. All patients in this trial received concomitant medication according to their medical needs.

3 2 of 12 No. of subjects: planned: entered: at least 5000 patients as per original trial protocol at least 6000 patients as per Amendment 2.1 (dated 17 April 2003) actual: Diagnosis and main criteria for inclusion: enrolled (run-in period): 6665 patients entered (randomised period): 5926 patients Telmisartan: entered: 2954 patients; analysed (for primary endpoint): 2954 patients Placebo: entered: 2972 patients; analysed (for primary endpoint): 2972 patients Male or female patients, 55 years of age or older, and at a high risk of CV events indicated by: 1. Coronary artery disease (CAD) defined as: a) Previous MI (>2 days post uncomplicated MI, prior to informed consent), or b) Stable or unstable angina (>30 days prior to informed consent) each with documented multi-vessel coronary disease, >50% stenosis in at least 2 major coronary arteries on coronary angiography, or positive stress test (ST depression 2 mm or a positive nuclear perfusion scintigram), or c) Multi-vessel percutaneous transluminal coronary angioplasty (PTCA) >30 days prior to informed consent, or d) Multi-vessel coronary artery bypass graft (CABG) surgery without angina (>4 years prior to informed consent), or with recurrent angina following surgery. 2. Peripheral arterial disease (PAD) defined as: a) Previous limb bypass surgery or percutaneous transluminal angioplasty, or b) Previous limb or foot amputation, or c) History of intermittent claudication, with an ankle/arm blood pressure (BP) ratio of 0.80 on at least one side, or d) Significant peripheral artery stenosis (>50%) documented by angiography on non-invasive testing. 3. Previous stroke (including definite or presumed cerebral infarction, intracerebral haemorrhage, stroke of uncertain subtype, but not subarachnoid haemorrhage).

4 3 of Transient ischaemic attack (TIA) >7 days and <1 year prior to informed consent (TIA defined as acute loss of focal cerebral or monocular function with symptoms lasting <24 hours, and thought to be due to inadequate cerebral or ocular blood supply as a result of arterial thrombosis or embolism). Test product: 5. High-risk diabetes (insulin-dependent or non-insulin-dependent) with evidence of end-organ damage (retinopathy, left ventricular hypertrophy, or any evidence of previous cardiac or vascular disease). Only patients with known intolerance to ACE-Is according to their medical history or as assessed during the run-in period of the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) were included into this trial. Telmisartan dose: Run-in period: 1 week telmisartan-matching placebo, followed by 2 to 3 weeks telmisartan 80 mg Randomised period: telmisartan 80 mg daily mode of admin.: Oral batch no.: Refer to Appendix Reference therapy: Telmisartan-matching placebo dose: Run-in period: 1 week telmisartan-matching placebo, followed by 2 to 3 weeks telmisartan 80 mg Randomised period: placebo matching telmisartan 80 mg mode of admin.: Oral batch no.: Refer to Appendix Duration of treatment: Run-in period: 1 week telmisartan-matching placebo, followed by 2 to 3 weeks telmisartan 80 mg Randomised period: planned: minimum of 3.5 years, maximum of 6 years actual median observation time: telmisartan: 1766 days placebo: 1772 days

5 4 of 12 Criteria for evaluation: Efficacy / clinical pharmacology: Primary endpoint: Composite of CV death, MI, stroke, or hospitalisation for CHF Secondary endpoints: - Composite of CV death, non-fatal MI, and non-fatal stroke - The individual components of the primary endpoint - Occurrence of nephropathy analysed based on the following 6 subcategories: Doubling of serum creatinine Progression to end-stage renal disease [ESRD] (i.e. initiation of dialysis, need for renal transplantation, or estimated glomerular filtration rate [egfr] <15 ml/min/1.73m 2 ) New microalbuminuria (urinary albumine creatinine ratio [UACR] 30 mg/g creatinine [Crea] in patients with a UACR <30 mg/g Crea at baseline) New macroalbuminuria (UACR 300 mg/g Crea in patients with a UACR <300 mg/g Crea at baseline) Combined endpoint of doubling of serum creatinine, progression to ESRD, new microalbuminuria, or new macroalbuminuria Normalisation from micro- or macroalbuminuria to normoalbuminuria (UACR <30 mg/g Crea in patients with a UACR 30 mg/g Crea at baseline) - Newly diagnosed CHF - CV revascularisation procedures - Newly diagnosed diabetes - Cognitive impairment and cognitive decline - New onset of atrial fibrillation Other endpoints: - All-cause mortality (= non-cv mortality + CV mortality) Non-CV death - Angina (unstable, new, and worsening) - TIA - Malignancy (fatal and non-fatal) - Laser therapy for diabetic retinopathy

6 5 of 12 Additionally, changes from baseline in BP, ankle/arm BP ratio, Mini Mental State Examination (MMSE), egfr, serum creatinine, and UACR were determined. Safety: Statistical methods: Serious adverse events (SAEs, coded using the Medical Dictionary for Regulatory Activities [MedDRA]), adverse events (AEs) leading to discontinuation of trial medication (coded using an internal coding system); clinical laboratory evaluations; vital signs (BP and pulse rate), electrocardiograms [ECGs]. Primary and secondary outcome events: time-to-event analysis (Kaplan Meier) and hazard ratios based on the intent-to-treat principle and using the proportional hazard model (Cox regression); χ 2 -test for cognitive impairment and cognitive decline Sensitivity analyses: Cox regression including covariates, χ 2 -test Descriptive statistics, analysis of covariance (ANCOVA) SUMMARY CONCLUSIONS: Efficacy / clinical pharmacology results: A total of 6665 patients were enrolled by 650 centres worldwide. After a singleblind run-in period of 3 to 4 weeks, a total of 5926 patients were randomised to either telmisartan 80 mg (2954 patients) or placebo (2972 patients). All patients received concomitant medication according to their medical needs. The most frequent reasons for non-randomisation were the patients' request to stop treatment (6.1%), insufficient compliance with study medication (5.1%), and the occurrence of AEs (2.6%). The majority of patients (99.7% of randomised patients) completed the trial with identical proportions in the 2 treatment groups; 'completed' was defined as final visit performed or vital status confirmed (including death) at the end of the trial. A total of 18.5% of all randomised patients permanently discontinued study medication (telmisartan: 17.7%; placebo: 19.4%) with a trend for fewer discontinuations in the telmisartan group (risk ratio for telmisartan vs. placebo: 0.91; 95% CI 0.82, 1.02; p=0.0969). Of those who permanently discontinued study medication, 42.9% stopped due to AEs (telmisartan: 47.2%; placebo: 39.1%). Demographics and baseline characteristics of the randomised patients were similar in the 2 treatment groups. The mean age of patients was 66.9 years;

7 6 of % of patients were male. Most patients were of white ethnicity (62.4%); 21.3% of patients were Asian, and 1.8% were black. For the majority of patients, CAD was the primary risk factor for inclusion in the trial (66.8%). At baseline, hypertension was present in 86.0% of patients and diabetes mellitus in 41.6%. The majority of patients received acetylsalicylic acid (74.7% at baseline, 71.2% at study end), beta blockers (58.3% at baseline, 57.8% at study end), and statins (55.2% at baseline, increasing to 63.5% at study end). After randomisation, differences between treatment groups in the use of concomitant medication were seen for diuretics (33.0% at baseline, 33.7% at study end in the telmisartan group, 40.0% at study end in the placebo group), calcium channel blockers excluding diltiazem/verapamil (31.1% at baseline, 30.8% vs. 39.2%, respectively, at study end), and beta blockers (58.3% at baseline, 56.6% vs. 59.0%, respectively, at study end). The mean systolic/diastolic blood pressure (SBP/DBP) at baseline was 141.0/81.9 mmhg and did not differ between treatment groups. During the runin period, patients received telmisartan-matching placebo for 1 week, followed by telmisartan 80 mg for 2 to 3 weeks. When patients were randomised following the run-in period, the mean SPB/DPB had decreased similarly in both treatment groups (telmisartan: 5.9/ 4.0 mmhg, placebo: 6.1/ 4.0 mmhg). At the 6 week visit, the BP in the telmisartan group had further decreased (mean change from baseline: 7.2/ 4.8 mmhg) while it had almost returned to baseline levels in the placebo group (mean change from baseline: 1.0/ 1.2 mmhg). These treatment differences in BP were generally maintained throughout the study. The weighted mean change from baseline post-randomisation was 6.5/ 4.9 mmhg with telmisartan and 2.3/ 2.6 mmhg with placebo. At baseline, no differences between treatment groups were observed for the mean egfr, mean serum creatinine, or geometric mean UACR. Patient compliance with study medication during the randomised period was high at all visits. At the final visit, 79.2% of patients in the telmisartan group and 77.1% in the placebo group were compliant with study medication. Primary endpoint The primary composite endpoint occurred in 465 patients (15.7%) in the telmisartan group and 504 patients (17.0%) in the placebo group; the event rates per 100 patient years were 3.58 and 3.87, respectively. The hazard ratio (HR) of telmisartan vs. placebo was 0.92 (95% CI 0.81, 1.05; p = ). The trial could not demonstrate superiority of telmisartan over placebo in the prevention of CV

8 7 of 12 death, non-fatal MI, non-fatal stroke, and hospitalisation for CHF. For non-fatal stroke and non-fatal MI, incidences were lower in the telmisartan group than in the placebo group (non-fatal MI: 3.6% vs. 4.6%, non-fatal stroke: 3.6% vs. 4.3%); no relevant differences were seen for hospitalisation for CHF and CV death. Baseline SBP and SBP changes over time did not substantially influence the results for the primary endpoint; the SBP-adjusted hazard ratio of telmisartan vs. placebo was 0.94 (95% CI 0.83, 1.07). The TRANSCEND trial had been planned based on the event rates observed in the previous Heart Outcomes Prevention Evaluation (HOPE) trial. Under these assumptions, a sample size of 3000 patients per treatment group to be recruited within 2 years and to be observed for a maximum of 5.5 years would have had a power of approximately 94% to establish the superiority of telmisartan over placebo. However, the observed yearly event rates in TRANSCEND were lower than expected. This was mainly due to the improved standard of medical care at the time the TRANSCEND trial was performed, which was reflected e.g. in the more frequent use of concomitant medications and of revascularisation procedures in patients in TRANSCEND. According to a retrospective power calculation with the number of patients randomised and the actual recruitment and observation periods and assuming that the observed event rates are real, the TRANSCEND study had a limited statistical power and as such only a 25% chance of demonstrating superiority of telmisartan over placebo. The Kaplan-Meier analysis suggested that the assumption of proportional hazards was not fulfilled for the primary composite endpoint as well as for the secondary composite endpoint of CV death, MI, and stroke. Hence, this was investigated using a Cox proportional hazards model with the categorised time to first event ( 6 months, >6 months) as covariate. No treatment difference was seen for the primary endpoint up to 6 months after randomisation. Thereafter (>6 months), the incidence of the primary endpoint was lower in the telmisartan group than in the placebo group (13.6% vs. 15.2%). However, the interaction between treatment and time period was not statistically significant (p = ). The per-protocol set (PPS) included all patients of the full analysis set (FAS) who were taking study medication according to the trial protocol for the majority of their time in the study. The per-protocol analysis showed the consistency and confirmed the results obtained for the FAS; the hazard ratio of telmisartan vs. placebo for the primary endpoint was 0.95 (95% CI 0.82, 1.08). The incidences observed with the PPS were slightly lower than in the FAS, suggesting that

9 8 of 12 persistent use of study medication had a beneficial effect. A total of 30 subgroup analyses were performed for the primary endpoint, e.g. for core subgroups such as age, intrinsic factors, extrinsic factors, medical history, and concomitant medication use. No significant subgroup-by-treatment interactions were observed for the primary endpoint. Secondary and other endpoints The incidence of the secondary 3-fold composite endpoint of CV death, nonfatal MI, and non-fatal stroke, which was the primary endpoint in the HOPE study, was significantly lower in the telmisartan group (13.0%) than in the placebo group (14.8%). The hazard ratio for this comparison was 0.87 (95% CI 0.76, 1.00; p = ). For the 3-fold composite endpoint, the treatment difference was not consistent over time (time period-by-treatment interaction: p = ). No treatment difference was seen up to 6 months after randomisation. Thereafter (<6 months), the incidences of the 3-fold composite endpoint were significantly lower with telmisartan (11.3%) than with placebo (13.6%); the hazard ratio was 0.82 (95% CI 0.71, 0.95). The SBP-adjusted hazard ratio of telmisartan vs. placebo was 0.88 (95% CI 0.77, 1.01). The incidences of the 3-fold composite endpoint for the PPS were slightly lower than for the FAS; the hazard ratio of telmisartan vs. placebo based on the PPS was 0.89 (95% CI 0.77, 1.03). The incidence of all-cause mortality was 12.3% in the telmisartan group and 11.7% in the placebo group. The hazard ratio of telmisartan vs. placebo was 1.05 (95% CI 0.91, 1.22). The predominant reasons for death were CV death and malignancies. Telmisartan significantly reduced the risk of new microalbuminuria (HR 0.76), new macroalbuminuria (HR vs. placebo 0.66), of the composite of doubling of serum creatinine, progression to ESRD, new microalbuminuria, or new macroalbuminuria (HR 0.80), and had a beneficial treatment effect on the normalisation from micro- or macro- to normoalbuminuria (HR 1.39). The incidences for the doubling of serum creatinine were 2.1% in the telmisartan group and 1.3% in the placebo group; the hazard ratio of telmisartan vs. placebo of 1.58 was statistically significant. No treatment difference was observed for progression to ESRD. The incidence of newly diagnosed diabetes did not differ between treatment groups. The incidence of confirmed newly diagnosed diabetes (as assessed by

10 9 of 12 the investigators) was significantly lower with telmisartan than with placebo (HR 0.75, 95% CI 0.60, 0.95). In this trial, a higher rate of malignancies (overall and in patients without cancer at baseline) was observed in patients treated with telmisartan than in those treated with placebo. No differences between treatment groups were seen for fatal malignancies. So far, there is no evidence that ARBs are associated with a higher risk of malignancies. Chance findings due to multiple testing cannot be excluded. Safety results: The mean observation time during the run-in period was 25.2 days. During the randomised period, the overall mean observation time was about 4.6 years and comparable between treatment groups. While receiving the study medication (on treatment), the mean observation time was 1527 days in the telmisartan group and 1515 days in the placebo group. All differences between treatment groups described below for AEs were also observed after adjustment for observation time. Since the safety profile of telmisartan is well established, reporting of AEs was limited to AEs leading to permanent treatment discontinuation and SAEs. During the run-in period, study drug-related AEs leading to permanent treatment discontinuation were reported for 2.54% of patients. The most frequent AE leading to permanent treatment discontinuation was dizziness / vertigo / lightheadedness (0.68%). Serious adverse events leading to permanent treatment discontinuation during the run-in period were reported for only 7 patients (0.11%), with hypotension (n=3) being the most frequently reported. Non-fatal SAEs were reported for 1.83% of patients during the run-in period; these were mainly cardiac disorders. During the randomised period, 12.03% of patients died. Mortality overall and mortality while on treatment were slightly higher in the telmisartan group than in the placebo group (overall: 12.32% vs %; on treatment: 9.61% vs. 8.95%). However, when all-cause mortality was analysed as a secondary efficacy endpoint, no statistically significant difference between telmisartan and placebo was observed (HR 1.05; 95% CI 0.91, 1.22). The most frequently reported SAEs on treatment in association with death were sudden cardiac death (telmisartan: 2.34%; placebo: 2.25%) and myocardial infarction (telmisartan: 1.18%; placebo: 1.18%). The frequencies of primary causes of death and of SAEs reported in association with death while on treatment were generally comparable between treatment groups. The incidence of cardiac failure reported as SAE in association

11 10 of 12 with death was higher in the telmisartan group (0.91%) than in the placebo group (0.64%). The incidence of ventricular tachyarrhythmia was higher in the telmisartan group (0.20%) than in the placebo group (0.03%). Post-treatment, primary causes of death and SAEs in association with death were observed at comparable frequencies in both treatment groups. The frequencies of patients with non-fatal SAEs reported while on treatment were comparable between the 2 treatment groups (telmisartan: 57.24%; placebo: 58.51%). The frequencies of SAEs were also generally comparable between treatment groups on the system organ class and preferred term levels. However, SAEs belonging to the system organ class cardiac disorders were reported in fewer patients in the telmisartan group (24.51%) than in the placebo group (26.62%). The following preferred terms were reported in slightly fewer patients in the telmisartan group than in the placebo group: diabetes mellitus (6.60% vs. 8.04%), angina pectoris (14.15% vs %), and myocardial infarction (4.67% vs. 5.42%). In contrast, the preferred term intermittent claudication was slightly more frequently reported in the telmisartan group than in the placebo group (6.70% vs. 5.65%). The frequency of SAEs considered drug-related by investigators was low. Serious adverse events considered study drug-related by investigators were reported for 0.44% of patients in the telmisartan group and in 0.13% of patients in the placebo group. Adverse events leading to permanent treatment discontinuation were slightly more frequent in the telmisartan group (8.36%) than in the placebo group (7.57%). The most frequently reported AE leading to permanent treatment discontinuation was hypertension / higher blood pressure / uncontrolled high BP; it was less frequently reported in the telmisartan group (0.61%) than in the placebo group (1.01%). In contrast, hypotension / low BP (telmisartan: 0.71%; placebo: 0.37%) and dizziness / vertigo / lightheadedness (telmisartan: 0.74%; placebo: 0.30%) were more frequently reported in the telmisartan group than in the placebo group. As expected, further differences between the treatment groups were observed for other known side effects of telmisartan: Gastrointestinal symptoms, renal diseases, and increases in creatinine or potassium values were more frequently reported as AEs leading to permanent treatment discontinuation in the telmisartan group than in the placebo group. Discontinuations of trial medication because of non-fatal SAEs were rare (telmisartan: 0.34%; placebo: 0.24%). Cough, angioedema, hypotensive symptoms, syncope, diarrhoea, renal failure, and signs of renal dysfunction were defined post hoc as AEs of special interest.

12 11 of 12 The differences between treatment groups were analysed using the χ 2 -test. For this analysis, patients were considered if a respective SAE was documented, a respective reason for temporary or permanent treatment discontinuation was given, or, in the case of signs of renal dysfunction, if relevant clinical laboratory values were above a pre-specified limit. Overall, this analysis confirmed the established safety profile of telmisartan: For cough, angioedema, and renal failure, no relevant differences between telmisartan and placebo were observed, whereas hypotensive symptoms, syncope, diarrhoea, and signs of renal dysfunction were more frequent in the telmisartan group than in the placebo group. The difference seen for signs of renal dysfunction was mainly due to higher frequencies of patients with potassium values >5.5 mmol/l, with doubling of serum creatinine, and with temporary or permanent discontinuation of study medication due to renal dysfunction in the telmisartan group; the frequency of patients with need for dialysis was comparable between treatment groups. Mean increases in serum creatinine from baseline to the end of the study were higher in the telmisartan group (0.06 mg/dl) than in the placebo group (0.01 mg/dl). The proportions of patients with transitions from low or normal to high creatinine values (telmisartan: 16.6%; placebo: 11.6%) and with possibly clinically significant increases ( 1.5 mg/dl) in creatinine (telmisartan: 13.8%; placebo: 11.2%) were higher in the telmisartan group than in the placebo group. For serum potassium, a small mean increase from baseline was observed in the telmisartan group (0.05 mmol/l), whereas a small mean decrease was observed in the placebo group ( 0.07 mmol/l). The frequency of patients with transitions from low or normal to high potassium values was higher in the telmisartan group (3.6%) than in the placebo group (2.0%). Likewise, possibly clinically significant increases of serum potassium (>5.8 mmol/l) at any time were more frequent in the telmisartan group (1.8%) than in the placebo group (0.5%). For the remaining laboratory parameters investigated (total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglycerides, glucose), no relevant differences were observed between treatment groups. The analyses of AEs and clinical laboratory parameters in subgroups did not reveal unexpected differences from the overall study population. The frequencies of patients with markedly low BP (evaluated as sitting SBP <100 mmhg, sitting DBP <60 mmhg, or both sitting SBP <100 and DBP

13 12 of 12 <60 mmhg) were higher in the telmisartan group than in the placebo group throughout the randomised period. Between treatment groups, no relevant differences in ECG data were noted. Conclusions: The TRANSCEND study could not demonstrate that telmisartan was superior to placebo in reducing the 4-fold composite endpoint of CV death, non-fatal MI, non-fatal stroke, and hospitalisations for CHF in patients at high risk and intolerant to ACE-Is who received concomitant medication according to their medical needs and current medical guidelines. Telmisartan was shown to be superior to placebo in reducing the secondary 3-fold composite endpoint of CV death, non-fatal MI, and non-fatal stroke, which was the primary endpoint in the HOPE study. The treatment benefit of telmisartan observed for the 3-fold composite endpoint was due to lower incidences of the components 'non-fatal stroke' and 'non-fatal MI' in the telmisartan group. The treatment effect of telmisartan on the 3-fold composite endpoint was time-dependent, with a significant treatment benefit of telmisartan from 6 months after randomisation onwards. Overall, the established safety profile of telmisartan was confirmed also in patients at high risk of cardiovascular disease.