ONgoing Telmisartan Alone and in combination with Ramipril

Global Endpoint TrialThe telmisartan trial in cardiovascular protection

Sponsored by Boehringer Ingelheim

ONgoing Telmisartan Alone and in combination with Ramipril

Global Endpoint TrialThe telmisartan trial in cardiovascular protection

Sponsored by Boehringer Ingelheim

®

ONgoing Telmisartan Alone and in combination with Ramipril

Global Endpoint TrialThe Micardis trial in cardiovascular protection

Sponsored by Boehringer Ingelheim

ONgoing Telmisartan Alone and in combination with Ramipril

Global Endpoint TrialThe Micardis trial in cardiovascular protection

Sponsored by Boehringer Ingelheim

Trial Programme

ONTARGETThe principal trial

23,400 patients

TRANSCENDThe parallel trial

5000 patients

ONTARGET Trial Programme28,400 patients

Background

Telmisartan is:

an angiotensin II AT1 receptor blocker (ARB)

approved for hypertension, alone or in combination with another antihypertensive agent

Background

Ramipril is: an angiotensin converting enzyme (ACE) inhibitor approved for

– hypertension

– congestive heart failure post myocardial infarction

– reduction of cardiovascular risk in high-risk patients aged 55 years

ONTARGET will be the largest ARB clinical trial ever conducted

It will build on the positive results from the landmark Heart Outcomes Prevention Evaluation (HOPE) trial, which investigated the effect of ramipril on cardiovascular risk

From HOPE to

The HOPE study

Double-blind, randomized, placebo-controlled trial Over 9500 patients at high risk of cardiovascular

disease 4.5-year treatment period Compared the risk of cardiovascular events with

the ACE inhibitor, ramipril (10 mg/day), vs placebo, both given as add-on to existing antihypertensive therapy

HOPE study results – primary endpointsCombined

cardiovascular endpoint

Cardiovascular mortality, myocardial

infarction, stroke

Cardiovascular mortality

Myocardial infarction

Stroke

-22% p<0.001

-26% p<0.001

-20% p<0.001

-32% p<0.001Ramipril n=4645, Placebo n=4652

The HOPE Study Investigators, 2000

HOPE study results – secondary endpoints

All-cause mortality

Need for revascularization

Hospitalization for heart failure

Complications relating to diabetes

-16% p=0.005 -15% p=0.002-12% p=0.25

-16% p=0.03

Ramipril n=4645, Placebo n=4652

The HOPE Study Investigators, 2000

AT1 RECEPTORVasoconstrictionSodium retentionWater retentionSNS activation

Growth-promoting effects

AT2 RECEPTORTissue regeneration

Inhibitor of inappropriate cell proliferation

SNS = Sympathetic Nervous System

ANGIOTENSIN I

ANGIOTENSIN II

Bradykinin

Inactive fragments

ACE inhibitor

ARB

Rationale

ANGIOTENSIN I

ANGIOTENSIN II

ARB

AT1 RECEPTORVasoconstrictionSodium retentionWater retentionSNS activation

Growth-promoting effects

AT2 RECEPTORTissue regeneration

Inhibitor of inappropriate cell proliferation

Angiotensin II escape

Bradykinin

Inactive fragments

ACE inhibitor

SNS = Sympathetic Nervous System

Rationale

Telmisartan and ramipril combination therapy should: avert the negative consequences of angiotensin II

escape associated with ramipril treatment

prevent any excess angiotensin II acting at AT1 receptors

retain potential tissue-protective benefits associated with increased bradykinin levels

Rationale

To compare the efficacy of telmisartan with the ACE inhibitor, ramipril, in preventing cardiovascular morbidity and mortality

To determine any additional benefit of combining telmisartan with an ACE inhibitor, compared with the ACE inhibitor alone

Objectives

Europe 23 countries

Australasia 2 countries

Asia 9 countries

North America 2 countries

South America 3 countries

Africa 1 country

A global trial

Argentina France Netherlands SpainAustralia Germany New Zealand SwedenAustria Greece Norway Switzerland Belgium Hong Kong Philippines TaiwanBrazil Hungary Poland ThailandCanada Ireland Portugal TurkeyChina Italy Russia UKCzech Republic Korea Singapore UkraineDenmark Malaysia Slovakia United Arab EmiratesFinland Mexico South Africa USA

Participating countries

1,360 5,14515,200

36,776

61,280

100,000

DETAIL IDNT CHARM LIFE VALUE ONTARGET

Clinical trial

Patient treatment years

ARB trial to datewill be the largest

55 years of age At high risk of cardiovascular disease No patients with congestive heart failure

Patient profile

Double-blind, double dummy, parallel-group study with three treatment arms:– telmisartan 80 mg once daily

– ramipril 10 mg once daily

– telmisartan 80 mg + ramipril 10 mg once daily

Study design

Micardis® 80 mg/day + ramipril 10 mg/day 7800 patients

Ramipril 10 mg/day 7800 patients

Micardis® 80 mg/day 7800 patients

5.5 years

Screening/enrolment Double-blind treatment

Study design

2001 2002 2003 2004 2005 2006 2007 2008

Randomization begins

Year

Timeline

Composite primary endpoint of: cardiovascular mortality stroke acute myocardial infarction hospitalization for congestive heart failure

Primary endpoint

Newly diagnosed congestive heart failure Revascularization procedures Newly diagnosed diabetes Dementia New-onset atrial fibrillation Microvascular complications of diabetes

Secondary endpoints

Telmisartan Randomized AssessmeNt Study in ACE-I

INtolerant Subjects with Cardiovascular Disease

Sponsored by Boehringer Ingelheim

Telmisartan Randomized AssessmeNt Study in ACE-I

INtolerant Subjects with Cardiovascular Disease

Sponsored by Boehringer Ingelheim

In HOPE, ramipril reduced the risk of cardiovascular events (cardiovascular mortality, myocardial infarction and stroke) by 22%

But, many patients cannot tolerate ACE inhibitor treatment due to side-effects, such as cough

TRANSCEND is the parallel study of ONTARGET to assess the protective effects of telmisartan in ACE inhibitor intolerant patients

Background

To evaluate the efficacy of telmisartan 80 mg monotherapy vs placebo in reducing cardiovascular morbidity and mortality in high-risk patients who are intolerant to ACE inhibitors

Objectives

55 years of age At high risk of cardiovascular disease No patients with congestive heart failure Intolerant to ACE inhibitors

Patient profile

Double-blind, parallel-group study Two treatment arms:

– telmisartan 80 mg once daily

– placebo

Study design

Placebo 2500 patients

Micardis® 80 mg/day 2500 patients

5.5 years

Screening/enrolment Double-blind treatment

Study design

Composite primary endpoint of: cardiovascular mortality stroke acute myocardial infarction hospitalization for congestive heart failure

Primary endpoint

Newly diagnosed congestive heart failure Revascularization procedures Newly diagnosed diabetes Dementia New-onset atrial fibrillation Microvascular complications of diabetes

Secondary endpoints