A double blind, randomized, parallel, study to assess the effects of aliskiren/amlodipine and amlodipine monotherapy on ankle foot volume (AFV) in patients naïve to trial drugs with mild to moderate hypertension.

The renin-angiotensin system (RAS) plays a major role in the regulation of
arterial blood pressure and the pathogenesis of hypertension. Aliskiren is the
first in a new class of antihypertensives, direct renin inhibitor. Amlodipine
is a long-acting dihydropyridine calcium channel blocker and the most commonly
prescribed drug in this class. It has demonstrated clinical efficacy in a wide
range of the hypertensive patient population in reducing blood pressure. Ankle
edema is one of the most frequent side effects of antihypertensive therapy with
calcium channel blockers.

Primary objective:
To assess and compare the effects of aliskiren/amlodipine and amlodipine on
pedal edema after 4 weeks of treatment as measured by ankle foot volume (AFV)
(water displacement method) in patients with mild to moderate hypertension.

Secondary objective:
To assess the safety and tolerability of aliskiren/amlodipine and amlodipine in
patients with mild to moderate hypertension.

The study is planned as a multi-center, double blind, randomized, parallel
study with blinded 2-week placebo run-in phase in patients with mild to
moderate hypertension.

A total of 88 hypertensive male and female subjects will be enrolled and
randomized in equal numbers to 2 treatments. Each subject will participate in a
screening period (up to 14 days), a 2-week washout period, a 2-week blinded
run-in period, followed by one 4-week treatment period, and an end of study
evaluation.

During the washout period and during the single blinded placebo run-in period,
all patients will check blood pressure using a home blood pressure monitoring
device once daily in the morning. Patients must discontinue the washout period
or the run-in period if the blood pressure rises to unacceptable levels.

During each treatment period, the subject will receive one of the treatments at
a lower dose for 1 week on an out patient basis. The subject will then be force
up-titrated to the study dose which will continue for 3 more weeks.

Subjects will be instructed to return to the clinics at specified time for
safety and PK/PD assessments. Pharmacodynamic assessments (ankle foot volume)
will be assessed at the beginning, and after 4 weeks of treatment.

Similarly, safety assessments will be performed at screening, baseline, end of
week 1, end of week 4 and end of study. These will include physical
examinations, ECGs, vital signs, standard clinical laboratory evaluations
(hematology, blood chemistry, urinalysis), adverse event and serious adverse
event monitoring.

SPA100 arm: Aliskiren/amlopdipine 150/5 mg/day and placebo to amlodipine for
the first week and then up-titrated to aliskiren/amlodipine 300/10 mg/day
(2x150/5 mg) and placebo to amlodipine for the next 3 weeks.

Amlodipine arm: Amlodipine 5 mg/day and placebo to 150/5 mg
aliskiren/amlodipine for the first week and then up-titrated to amlodipine 10
mg/day and placebo to 300/10 mg (2x150/5 mg) Aliskiren/amlodipine for the next
3 weeks.

Burden:
Each subject will participate in a ascreening period (up to 14 days), a 1 to
3-week wash-out period, a 2-week blinded placebo run-in period, followed by one
4 week treatment period, and an end of study evaluation. At the screening
visit, if the subject meets all inclusion/exclusion criteria the subject will
be asked to discontinue or taper-off all current antihypertensive therapy
during the washout period and will then enter in a single-blind run-in phase
with placebo for 2 weeks. During each treatment period, the subject will
receive one of the treatments at a lower dose for 1 week on an out patient
basis. The subject will then be force up-titrated to the study dose which will
continue for 3 more weeks. Subjects will be instructed to return to the clinics
at specified time for safety and PK/PD assessments.
Safety assessments will include physical examinations, ECGs, vital signs,
standard clinical laboratory evaluations (hematology, blood chemistry,
urinalysis), adverse event and serious adverse event monitoring.

Potential risks:
Single dose and multiple dose administration of the fixed-dose combination in
healthy subjects and patients with hypertension was well tolerated and safe.
The most frequent AEs were peripheral edema, headaches, diarrhea, dizziness,
cough. Similar AEs can be expected for the current study.

Potential benefits:
This study is designed to evaluate whether the addition of aliskiren to
amlodipine can attenuate ankle edema formation in hypertensive patients treated
for 4 weeks. The combination of aliskiren/amlodipine (300/10 mg) has been
proven to be efficacious in decreasing blood pressure. Blood pressure reduction
may therefore be the main benefit for the subjects to participate in this
study. For subjects in the SPA group, there may be less side-effect in the form
of pedal edema.