A Phase-3 Randomized, Double-Blind, Efficacy and Safety Study Evaluating the Fixed Dose
Combinations of TAK-491 Plus Chlorthalidone (40/12.5 mg and 40/25 mg) in Subjects With
Grades 2 or 3 Essential Hypertension, Who Do Not Achieve Target Blood Pressure
Following Treatment With TAK-491 40 mg Monotherapy.

Nonclinical studies have indicated that TAK-491 reduces BP after single or
multiple daily dosing
without tachycardia and without rebound hypertension after the withdrawal of
treatment.
TAK-491 also demonstrated antiproteinuric effects in Wistar fatty rats with
overt nephropathy and
increased insulin sensitivity in spontaneously hypertensive rats. TAK-491 is
not expected to have
any untoward effects on the central nervous system or respiratory system. Its
effect on the
cardiovascular system in conscious dogs was limited to a reduction in systolic
BP (SBP), an
observation consistent with the pharmacodynamic profile of the compound.

TAK-491 has been evaluated in 17 phase 1 studies and 1 phase 2 study. The phase
3 program
consisted of 5 randomized, controlled, monotherapy studies of 6 weeks or 6
months duration;
2 randomized, controlled, 6-week studies in which TAK-491 was coadministered
with the
thiazide-type diuretic chlorthalidone or the calcium channel blocker (CCB)
amlodipine; and
2 open-label studies of up to 56 weeks duration. Results of the phase 3 program
demonstrated that,
relative to placebo, the TAK-491 20, 40, and 80 mg doses produce clinically and
statistically
significant reductions in SBP and diastolic blood pressure (DBP), as assessed
by both ambulatory
blood pressure monitoring (ABPM) and clinic blood pressure measurements. The
differences
between doses were greater for subgroups of subjects characterized by more
severe and/or
resistant hypertension, including black subjects, subjects with renal
impairment, and subjects with
grade 3 hypertension. In each study, most of the blood pressure-lowering effect
of TAK-491 was
observed within 2 weeks of treatment; a plateau of effect was generally reached
by week 4 and
reductions were maintained through week 6 in short-term studies and over the
long-term in two
6-month studies (and up to 1 year in open-label studies).
In two controlled studies, coadministration of TAK-491 with chlorthalidone
(491-009) and
amlodipine (491-010) provided additional blood pressure reduction compared with
chlorthalidone
or amlodipine monotherapy. In open-label studies, addition of diuretic therapy
to treatment with
TAK-491 led to additional blood pressure reductions in subjects who did not
reach blood pressure
targets after initiation of TAK-491.
In clinical studies, TAK-491 was well tolerated at doses up to 320 mg in
healthy subjects and up to
80 mg in hypertensive subjects (maximal dose evaluated in this population).

The objective of this phase-3 randomized study, with a double-blind treatment
period of 8 weeks
duration is to evaluate the efficacy and safety of the fixed dose combinations
of TAK-491 plus
chlorthalidone (40/12.5 mg and 40/25 mg) in subjects with grades 2 or 3
essential hypertension,
who do not reach target blood pressure after 4 weeks of single-blind
monotherapy treatment with
TAK-491 40 mg. It will therefore determine whether the TAK-491CLD FDC can
enable patients
with essential hypertension not adequately controlled on 40 mg TAK-491
monotherapy alone to
achieve target blood pressure. Patients with grades 2 or 3 hypertension [17]
not controlled on
TAK-491 40 mg monotherapy will be enrolled because these patients are likely to
benefit from the
addition of a second antihypertensive agent, in this case the diuretic
chlorthalidone, to achieve
target blood pressure. An FDC is also likely to improve patient compliance
compared with
co-administrating the two drugs separately.

This global phase-3 randomized study, with a double-blind treatment period of 8
weeks duration is designed to
evaluate the efficacy and safety of the fixed dose combinations (FDCs) of
TAK-491 plus chlorthalidone (40/12.5 mg
and 40/25 mg) in subjects with grades 2 or 3 essential hypertension who do not
achieve target blood pressure
following 4 weeks of single-blind monotherapy treatment with TAK-491 40 mg. The
subject must have grade 2-3
essential hypertension which is not adequately controlled, as defined by mean,
trough, sitting, clinic SBP:
* >=160 to <=180 mm Hg in subjects who have not received any antihypertensive
medication in the 14 days prior to
Visit 1
* >=150 to <=170 mm Hg in subjects taking 1 antihypertensive medication at Visit 1
* >=140 to <=160 mm Hg in subjects taking 2 antihypertensive medications at Visit
1
Approximately 390-405 patients (130-135/arm) will be randomized to one of the
three active treatment arms at
approximately 130 sites in Europe.
Subjects will be screened approximately 4 weeks before enrolment into a 4-week
single-blind TAK-491 40 mg
treatment period (Day -28 to Day -1). All subjects will participate in a
2-week, single-blind, placebo run-in period
(Days -42 to -29) immediately prior to the single-blind TAK-491 40 mg
monotherapy treatment period. Subjects
taking antihypertensive medications at Visit 1 are required to participate in
an additional 1-2-week washout period
(Days -56 or -49 to -42) of their previous antihypertensive agents. Subjects
taking 2 antihypertensive medications
should stop the longer acting drug on Day -56 and then stop the second drug on
Day -49. Subjects taking
1 antihypertensive medication should stop on Day -49 (unless this drug is
chlorthalidone or amlodipine which must be
stopped on Day -56). All subjects on previous antihypertensive medications
should have a minimum of 7 drug free
days prior to starting the placebo run-in. Subjects who have not received any
antihypertensive medication in the
14 days prior to Visit 1 can start the placebo run-in as soon as all relevant
inclusion and exclusion criteria, including
laboratory results, have been verified. Any subject taking other prohibited
medications must stop taking these by
Day -42.
Subjects who qualify for the single-blind TAK-491 40 mg monotherapy treatment
period [post-placebo run-in mean
24-hour systolic blood pressure (SBP) by ambulatory blood pressure monitoring
(ABPM) of 140-175 mm Hg
inclusive and a sitting clinic SBP measurement of 160-190 mm Hg inclusive] will
then receive 4 weeks treatment with
TAK-491 40 mg. Subjects who do not achieve target blood pressure following 4
weeks treatment with TAK-491
40 mg monotherapy (defined as trough, sitting, clinic SBP >= 140 mm Hg) will be
randomized on Day 1 in a 1:1:1 ratio
to receive double-blind treatment with either TAK-491 40 mg alone, TAK-491CLD
40/12.5 mg or TAK-491CLD
40/25 mg for 8 weeks. Subjects achieving target blood pressure following 4
weeks of single-blind TAK-491 40 mg
monotherapy treatment period will not be eligible for randomization and will be
withdrawn from the study.

Taking investigational product.

Subjects not controlled on TAK-491 40 mg monotherapy will be enrolled because
these subjects are likely to benefit from the addition of a second
antihypertensive agent, in this case the potent diuretic chlorthalidone, to
achieve target blood pressure. Initiation of combination treatment in these
uncontrolled patients is consistent with hypertension guidelines.

The exclusion criteria for the study ensure that subjects with significant
co-morbidity (e.g. severe cardiovascular disease or severe renal disease) who
may be at risk by participation in the study are excluded. In addition, serum
creatinine is being measured throughout the study and guidance for the
management, withdrawal and follow-up of subjects with creatinine elevations is
provided in Section 9.1.8.2 of the protocol. Patient safety is highlighted by
having graded blood pressure entry criteria related to the number of
antihypertensive medications being used by the subject, thereby reducing the
chance of significant rebound hypertension following withdrawal of any
medications during the washout period. If the patient is taking two
antihypertensive medications, the withdrawal will be staggered with the longer
acting medication being stopped first. Because of the long half-lives of
chlorthalidone and amlodipine, these medications will be required to be
washed-out during two
weeks prior to the start of the placebo run-in period. Subjects will also
perform home blood pressure monitoring throughout the study. Finally,
withdrawal criteria are clearly defined for subjects whose blood pressure
exceeds certain thresholds, outlined below.