A Phase 2a, Single-Center Study Investigating the Short-Term Renal Hemodynamic Effects, Safety and Pharmacokinetics/ Pharmacodynamics of Oral Tolvaptan in Subjects with Autosomal Dominant Polycystic Kidney Disease at Various Stages of Renal Function

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 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 effective tolvaptan will be in treating ADPKD.

The purpose of the trial is to determine the effect of multiple doses of
tolvaptan on renal function in patients with autosomal dominant polycystic
kidney disease (ADPKD) at various stages of renal function. Additionally, the
short-term renal hemodynamic safety of tolvaptan will be assessed.

PRIMARY OBJECTIVE is to determine the effect of maximally tolerated doses of
tolvaptan at steady state on the measured glomerular filtration rate (GFR),
effective renal plasma flow (ERPF), and filtration fraction in subjects with
ADPKD, including those with severely impaired renal function.

SECUNDARY OBJECTIVES are:
- To assess the short-term renal hemodynamic safety of tolvaptan
- To determine the effect of tolvaptan on urine concentrations and excretion of
sodium, potassium, osmoles, creatinine, urea, uric acid, aldosterone and
albumin and the urine albumin/creatinine concentration ratios, urine volume,
plasma or serum concentrations of sodium, potassium, osmoles, creatinine, urea,
uric acid, albumin, cystatin C, active plasma renin, copeptin, and aldosterone,
the clearances of free water, sodium, potassium, osmoles, creatinine, urea, and
uric acid and the fractional clearances of free water, sodium, potassium, urea
and uric acid to creatinine clearance
- To determine the effect of tolvaptan on mean arterial blood pressure
- To characterize the plasma concentrations of tolvaptan and its metabolites
(DM-4103 and DM-4107)
- To determine short-term effects of tolvaptan on total kidney volume (TKV) as
measured by changes from baseline

This study is a single-center, sequential trial of the effect of multiple doses
of tolvaptan on renal function in subjects diagnosed with ADPKD.

This trial will include up to 36 male and female subjects aged 18 to 70 years,
inclusive, without previous exposure to tolvaptan.

Inclusion will be stratified for estimated glomerular filtration rate (eGFR)
using the 4 variable modification of diet in renal disease (MDRD) equation
(Levey AS, Bosch JP, Lewis JB, et al. Ann Intern Med, 1999; 130:461-470), with
3 strata:
1) > 60 mL/min*1.73 m2
2) 30-60 mL/min*1.73 m2
3) < 30 mL/min*1.73 m2.
Each stratum will contain a minimum of 6 subjects and up to 12 subjects.

The study medication is: 15 mg and 30 mg tolvaptan tablets for oral
administration.

During the treatment phase of 3 weeks, each subject will Initially receive a
daily split dose of 45/15 mg tolvaptan for 1 week, with the larger dose upon
awakening each day followed by the smaller dose approximately 8 hours later.
If the subject tolerates this dose, the daily split dose will be increased to
60/30 mg for a week, followed by a daily split dose of 90/30 mg the successive
week as tolerated.

Study participation for each subject will be up to 12 weeks: a 2- to 42-day
screening period, 3 week treatment period, and 3 week post-treatment period.
The expected duration of this trial from first subject screened to last subject
completed is 12 months.

During the 3-week treatment phase, each subject will receive a daily split dose
of 45/15 mg tolvaptan for 1 week, with the larger dose upon awakening each day
followed by the smaller dose approximately 8 hours later. If the subject
tolerates this dose, the daily split dose will be increased to 60/30 mg for a
week, followed by a daily split dose of 90/30 mg the successive week as
tolerated.

For an overview of possible side effects of tolvaptan, see page 20-21 of the
protocol and page 7-8 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.

Part of this study is the renal function investigation. This investigation is
being done in UMCG routinely to assess the renal function; we have ample
experience with these tests. For the renal function investigation the patient
will receive an infuse. Via this infuse the patient will be administered a low
dose of isotopes (0,4 ml/kg) as 'priming solution'. This solution consists of
0.04 MBq 125I-iothalamate and 0.03 MBq 131I-hippuran with 0.6 MBq
125I-iothalamate dissolved in NaCl 0,9%. Thereafter, a lower dose of isotopes
is administered via the infuse (0,015 MBq 125I-iothalamate and 0,02 MBq
131I-hippuran). In total, the patient will be at the infuse for 5,5 hours. A
'steady state' of the concentration of iothalamate en hippuran is reached after
1,5 hours. Thereafter, every hour blood is taken and every two hours urine is
captured to measure the amount of radiation. Risks of this investigation are
minimal (risk of hematomes at the place of the injection and flebitis). The
total dose of isotopes used during this investigation is so low that it amounts
to a lower dose of radiation than needed to make a photo of the thorax.
Therefore we can state that there is no increased radiation risk for the
patient.

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.