AMBITION: A Randomised, Multicenter Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a devastating, life threatening
disease. A number of treatments are available but no single drug has been
demonstrated to be consistently effective in treating all patients with PAH.
Combining medicines with different mechanisms of action is an evolving strategy
for the treatment of PAH. This approach is supported by data from several
exploratory studies in PAH demonstrating the synergistic benefits of combining
two or more drugs.
Ambrisentan (5 and 10 mg once daily) is an ETA-selective ERA that is approved
by the FDA and EMA for the treatment of PAH (iPAH and PAH-CTD) in patients with
WHO class II or III symptoms.
Tadalafil (40 mg once daily) is a PDE-5 inhibitor approved in numerous
countries for the treatment of PAH (iPAH and PAH -CTD) in patients with WHO
class II and III symptoms.
Because ambrisentan and tadalafil are both orally administered once a day, have
different mechanisms of action targeting different intracellular pathways, and
have not demonstrated any clinically relevant pharmacokinetic concerns when
coadministered, an ambrisentan/tadalafil combination therapy is a rational
treatment strategy for patients with PAH.
All of the larger clinical studies completed to date have evaluated combination
therapy as an add-on approach: the addition of a second PAH therapy to a
subject*s monotherapy regimen. It is unknown if PAH patients may have greater
improvements for sustained periods of time if combination PAH treatment is
initiated as first-line therapy, rather than delaying the addition of the
second therapy until the PAH status of the patient has reached a plateau or
subsequently deteriorated while receiving monotherapy. The primary objective of
this study is to compare the difference between two treatment strategies;
first-line combination therapy (ambrisentan and tadalafil) versus first-line
monotherapy (ambrisentan or tadalafil) in subjects with PAH. This will be
assessed by time to the first clinical failure event.

The primary objective of this study is to compare the two treatment strategies;
first-line combination therapy (ambrisentan and tadalafil) versus first-line
monotherapy (ambrisentan or tadalafil) in subjects with PAH. This will be
assessed by time to the first clinical failure event.
The secondary objectives of this study are to compare the change in other
clinical measures of PAH after initiating first-line combination therapy or
first-line monotherapy, in subjects with PAH.
The safety and tolerability of first-line combination therapy will be compared
to first-line monotherapy.
In addition, the effect of ambrisentan on exercise capacity at both peak and
trough plasma concentrations will be assessed in subjects with pulmonary
arterial hypertension (PAH).

Multicenter randomized double blinddouble dummy parallel group phase IV study.
Randomization (2:1:1):
1. First line combination therapy. Start with 5 mg ambrisentan and 20 mg
tadalafil daily, if well tolerated increase to resp. 10 mg daily after 8 weeks
and 40 mg after 4 weeks.
2. Ambrisentan monotherapy. Start with 5 mg ambrisentan fil daily, if well
tolerated increase to 10 mg daily after 8 weeks .
3. Tadalafil monotherapy. Start with 20 mg tadalafil daily, if well tolerated
increase to 40 mg daily after 4 weeks.
Additional randomization (1:1) for peak or trough measurements.
At least 24 weeks of treatment.
Stratification for aetiology of PAH.
Event-driven study. total study duration estimated at 3,5 years (82 events,
first clinical failure). Estimated median duration per patient 2 years plus 3
months.
Approx. 614 patients.
Independent data safety monitoring board.

Treatment with ambrisentan and/or tadalafil.

Risk: Adverse events of (combination of) study medication.
Burden: First 6 visits every 4-8 weeks and thereafter every 12 weeks. Duration
2-3 h. Final visit 4 weeks after end of treatment. Telephone call 4 weeks
therafter.
Blood draw during every visit (approx. 10-55 ml/visit). Optional farmacogenetic
test (10 ml of blood).
In addition: Physical examination 3x, ECG 3x, 6 min. walk test every visit,
lungfunction test 1x, oxymetry 1x, pregnancy test every visit , SF-36 en
Camphor questionnaires almost every visit.
Extra in comparison to regular care : more(especially 1st 6 visits) and longer
visits (extra number of visits depend on condition of individual patient), more
and more frequent blood tests (idem; per visit 0-40 ml extra), 6 min walk test
(every visit), 2 questionnaires (almost every visit).