Multi-center, Open-label, Extension Study to Evaluate the Long-term Efficacy and Safety of Oral Tolvaptan Tablet Regimens in Subjects with Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) is studying
an investigational drug called tolvaptan (the *Study Drug*). An
investigational drug is a drug that is being studied for approval by the United
States Food and Drug Administration (FDA) and EMA (European Medicines Agency).
Tolvaptan (Samsca®) is a drug approved for use in the United States (2009) in
patients with certain types of hyponatremia (hypervolemic and euvolemic
hyponatremia). Hyponatremia is low amount of sodium or salt in the blood.
Tolvaptan (Samsca®) is approved in the European Union (2009) for treatment for
a different type of hyponatremia (hyponatremia secondary to syndrome of
inappropriate antidiuretic hormone secretion (SIADH)).
The Study Drug has not been approved for use in the United States or in any
other country to treat Autosomal Dominant Polycystic Kidney Disease (ADPKD).
ADPKD is a disease that causes kidney cysts (like fluid-filled balloons),
worsening kidney function, and blood in the urine, kidney pain, high blood
pressure, kidney stones, kidney infections, and cysts in the brain or other
parts of the body. Tolvaptan is being studied as a possible treatment for
ADPKD. For those people with ADPKD, the kidneys respond abnormally to the
hormone vasopressin that may be involved in cyst development or growth in
humans. Tolvaptan interferes with vasopressin*s effects on the kidney, and
when taken chronically, appears to block cyst growth in animal models of
ADPKD. It is hoped that similar effects will be seen in humans. Tests will
tell how useful tolvaptan will be in treating ADPKD.

The objective of this extension study is to find out the potential long-term
benefits and safety of tolvaptan. During this study all participants will
receive tolvaptan.

PRIMARY OBJECTIVE is to demonstrate whether tolvaptan modifies ADPKD
progression as measured by changes from baseline (from trial 156-04-251) in
total kidney volume (TKV) and renal function.
Disease modification is evidenced by the maintenance of treatment group
differences (tolvaptan- versus placebo-treated subjects) observed at the end of
trial 156-04-251, as compared to the end of trial 156-08-271.

SECUNDARY OBJECTIVES are:
- To determine whether, for placebo-treated subjects from trial 156-04-251, the
annual rate of change (slope) in TKV and renal function changes during the
crossover from placebo to tolvaptan treatment.
- To explore exposure response relationship among all subjects enrolled in this
trial for changes in TKV, renal function and hypertension.

This is an international, multi-center, open-label, extension trial in adult
subjects with ADPKD treated with tolvaptan split-dose regimens for a minimum of
24 months.

During this study all participants will receive tolvaptan.

Tolvaptan (15 or 30 mg oral tablets) will be self-administered given in
split-doses separated by approximately 9 hours, first dose being given on
awaking, for a minimum of 24 months and up to 60 months. Regimens include
45/15, 60/30 and 90/30 mg of tolvaptan.
All subjects will be titrated to the last assigned dose group from their prior
trial.
Subjects will be able to increase, hold or step down in dose level during the
trial.

Tolvaptan (15 or 30 mg oral tablets) will be self-administered given in
split-doses separated by approximately 9 hours, first dose being given on
awaking, for a minimum of 24 months and up to 60 months.
Regimens include 45/15, 60/30 and 90/30 mg of tolvaptan.

All subjects will be titrated to the last assigned dose group from their prior
trial with the exception of subjects enrolling from protocol 156-04-250 where
titrations requirements may be waived.

Subjects will be able to increase, hold or step down in dose level during the
trial.

The subject receives a minimum of 24 months treatment + 7 day follow-up.

Subjects will be allowed to continue in the trial until the last subject
completes their Month 24 visit, up to 60 months.

For an overview of possible side effects of tolvaptan, see page 23-25 of the
protocol and page 8-10 of the patient information letter.
The most frequent side effects of tolvaptan are increased thirst, dry mouth and
headache.

Frequent complaints (seen in at least 3% of all participants) that have been
reported during studies of tolvaptan include increased thirst, increased heart
failure in individuals who already have heart failure, dry mouth, nausea,
increased urination (frequency and volume),dizziness, headache, constipation,
low blood pressure, soft stool, tiredness, trouble sleeping, chest pain,
increased level of potassium in the blood, decreased level of potassium in the
blood, low blood count, kidney or bladder infection, irregular heart beat
(atrial fibrillation), increased creatinine in the blood (a waste product taken
to the kidneys for filtering), vomiting, cough, rapid heart rate, worsening of
kidney function, infection in the lung, swelling in the arms or legs, pain in
the abdomen, back, arms, or legs, increased levels of uric acid in the blood,
and shortness of breath. These side effects may or may not be caused by
tolvaptan.

At the area where the blood is taken, there may be mild pain, bruising and
swelling. More rarely, the patient may faint and the area may become infected.

Can occur during the MRI scan in rare cases: local infection, irritation,
allergic reaction (at the area of the injection of the contrast fluid). Some
patients can feel uncomfortable in the MRI machine.