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Summary
of Tracleer™ 
(bosentan) efficacy data
Click here to access the
EU Summary of Product Characteristics and UK Prescribing Information
The
efficacy data presented from Studies 351 and BREATHE-1 demonstrate
Tracleer’s efficacy in the treatment of patients with pulmonary
arterial hypertension (PAH), both primary (PPH) and related
to scleroderma. The significant improvement seen in the primary
endpoint of the 6-minute walk test offers strong evidence
of the clinical impact of Tracleer therapy on this devastating
disease.
Tracleer
has a positive effect on important clinical parameters, such
as:
-
significant
increase in exercise capacity (6-minute walk test)
-
improvements
in WHO Functional Class
-
improvements
of haemodynamic factors
-
delay
of time to clinical worsening.
Efficacy
in PAH
Two pivotal clinical trials were conducted with Tracleer in
PAH, each designed to evaluate the efficacy and safety of
this oral ERA (Endothelin Receptor Antagonist) therapy. The
table below outlines the main features of each study.
Tracleer
clinical trials in PAH
Study
endpoints were chosen because of their clinical relevance.
The 6-minute walk test is a good measure of exercise capacity
and may compliment invasive standard prognostic markers, such
as RV haemodynamic variables. Baseline and follow-up haemodynamic
measures of pulmonary arterial pressure (PAP), stroke volume
index, right-atrial pressure and cardiac index are also clinically
meaningful parameters. The Borg Dyspnoea Index is employed
as a further useful clinical measure of breathlessness following
exercise testing.
The
WHO PAH Functional Assessment Classification of symptoms correlates
with life expectancy, with Class II and III patients having
an average survival of 3.5 years and Class IV patient survival
seen as 6 months.
Tracleer
Pivotal Studies (Study 351 & BREATHE-1)
Study
Design
The study designs differed slightly in the Tracleer dosage
regimen and the primary evaluation period.
Study
Endpoints:
Study
Demographics:
Primary
Endpoints
Tracleer therapy resulted in significant increases in exercise
capacity, as demonstrated through the 6-minute walk test primary
endpoints.
Study
351 showed, for Tracleer patients, a mean increase in the
distance walked from baseline to week 12 of 71m (p<0.05)
versus no change with placebo (mean decrease of 6m). The mean
change was 76m between groups (p=0.021). This improvement
for Tracleer patients continued through to week 20, where
the mean distance from baseline increased to 79m and the overall
walk distance compared to placebo was significantly better.
The
6-minute walk test results for BREATHE-1 reflected those seen
in Study 351. At week 16, the combined Tracleer treatment
groups showed a walk distance increase of 36m versus a decline
of 8m in the placebo patients, giving a mean difference between
the groups of 44m (p<0.001).
This
difference was greater (but not statistically significant)
in the 250mg patient group, however, both Tracleer treatment
doses demonstrated a significantly superior effect to placebo.
These
results deserve consideration in the context of the disease.
The randomised data collected in Study 351 and BREATHE-1 lend
a clinical relevance to these significant outcomes, offering
a new treatment option for the management of PAH.
Secondary endpoints
The secondary endpoints of the pivotal studies varied, but
provide a consistent view of the effects of Tracleer therapy
on a number of significant factors.
Haemodynamic measures
The functional improvement seen in the 6-minute walk test
was supported by parallel haemodynamic measures.
Borg
Dyspnoea Index
The changes seen in the Borg Dyspnoea Index, as a secondary
endpoint, supported the improvements seen in the 6-minute
walk test from both pivotal studies’ primary endpoint, meaning
that not only did patients cover a longer distance in the
6-minute walk test but were less dyspneic.
WHO
PAH Functional Assessment Classification
By week 12 (Study 351) the WHO Functional Class of Tracleer
patients was significantly improved compared to placebo (p=0.019).
Similarly, BREATHE-1 showed a mean treatment effect of improved
WHO Functional Class at week 16 of 12% in favour of Tracleer.
Clinical
worsening
In both pivotal studies, clinical worsening was defined by
a number of parameters.
Clinical
worsening assessments:
In
Study 351, no Tracleer patients had experienced clinical worsening
at week 12.
Kaplan-Meier
estimates of the time to clinical worsening in the BREATHE-1
study (ITT) population showed a significant event-free benefit
in patients on Tracleer therapy.
Tracleer
in PAH related to scleroderma
As PAH has a significant incidence and mortality in scleroderma,
patients diagnosed with PAH related to scleroderma were included
in both Study 351 and BREATHE-1 (for both studies, total n=52;
placebo group n=15; treatment group n=37).
Sub-analysis
of the scleroderma patients in BREATHE-1 has shown a similar
positive effect of Tracleer therapy to that of the overall
study population. Tracleer prevented the deterioration of
walking distance from baseline (+3m in n=33 Tracleer patients),
whilst for those patients on placebo, a decrease in walking
distance from baseline was observed (–40m in n=14 placebo
patients). A benefit was again seen in the time to clinical
worsening for Tracleer patients.
Long-term efficacy of Tracleer
Long-term efficacy and safety data are currently being collected
in the form of two open-label extension studies further to
the pivotal trials reviewed below. Study 353 is an open-label
extension study of patients who completed Study 351, whilst
Study 354 is an open-label extension study of patients who
completed BREATHE-1.
Data
collected thus far from Study 353 have supported the efficacy
data seen to date with Tracleer in PAH. Efficacy was maintained
in those patients who remained on Tracleer following therapy
in Study 351. For the ex-placebo patients from Study 351,
who were switched to Tracleer for the open-label extension
phase, an improvement in exercise capacity was seen within
4 weeks of commencement of therapy.
A
full report of these data is pending.
As
result of the study findings, Tracleer is indicated in Europe
for the treatment of pulmonary hypertension to improve exercise
capacity and symptoms in patients with grade III WHO Functional
Class.
References
-
Borg
GA. Psychophysical bases of perceived exertion. Med
Sci Sports Exerc (1982);14:377–381.
-
Gibbs
JSR et al. Recommendations on the management
of pulmonary hypertension in clinical practice. HEART
(Sept 2001);86(1):i1–i13.
-
Miyamoto
S. et al., Clinical correlates and prognostic
significance of six-minute walk test in patients with
primary pulmonary hypertension. Am. J. Respir. Crit.
Care Med., 161:487-492 (2000)
-
Sandoval
J. et al., Survival in primary pulmonary hypertension:
validation of a prognostic equation. Circulation,
89:1733-1744 (1994).
-
D’Alonzo
G.E. et al., Survival in patients with primary
pulmonary hypertension. Results from a national prospective
registry. Ann. Intern. Med., 115:343-349
(1991).
-
Rubin
L.J. Primary pulmonary hypertension, N. Engl. J. Med.,
336:111-117 (1997).
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