A Phase 3b, Multi-center, Open-label Trial to Evaluate the Long Term Safety of Immediate-release Tolvaptan (OPC-41061, 30 mg to 120 mg/day, Split dose) in Subjects with Autosomal Dominant Polycystic Kidney Disease

Tolvaptan (OPC-41061) is a selective arginine vasopressin (AVP) type 2 (V2)
receptor antagonist that is currently approved in the United States (US),
Europe, Australia, Canada, China, Hong Kong, Indonesia, Japan, Republic of
Korea, and Taiwan for various forms of hyponatremia, and in Japan for volume
overload in heart failure or liver cirrhosis.Tolvaptan is also being
investigated for the use in adults to treat autosomal dominant polycystic
kidney disease (ADPKD), an inherited condition which leads to progressive
destruction of normal kidney structure leading to end-stage renal disease
(ESRD). Though ADPKD is a rare genetic disease, it ranks as the 6th leading
cause of ESRD in the US (2.3% of the new ESRD cases).

There are currently no therapies which can slow the deterioration of kidney
function in ADPKD. Current management focuses on ameliorating symptoms of pain,
control of blood pressure, and treatment of infections with antibiotics. None
of these treatments target the underlying cause of the disease. Often, the only
definitive intervention for renal complications in ADPKD is kidney
transplantation, which typically occurs after years of hemodialysis.

In the US, the development program for tolvaptan for ADPKD was granted
Fast-track designation on 20 Jan 2006 and orphan drug
designation on 06 Apr 2012. Tolvaptan was designated as an orphan drug for
prevention of the progression of ADPKD in Japan on
11 Aug 2006. The European Medicines Agency (EMA) granted orphan designation for
the use of tolvaptan for the treatment of
ADPKD on 5 Aug 2013. If approved, tolvaptan would be the first available
therapy to slow kidney disease progression in adults
with ADPKD.

Tolvaptan was clinically effective in delaying decline of renal function, as
determined by changes in serum creatinine concentrations over 3 years, in an
international, multicenter, clinical trial in subjects with chronic kidney
disease (CKD) stage 1 to 3 due to ADPKD. This trial also demonstrated an acute
and persistent reduction on rate of kidney cystic growth.

The primary objective of this trial is to evaluate and describe the long-term
safety of tolvaptan.

This trial is a phase 3b, multi-center, open-label extension trial. Subjects
will be eligible for screening into this trial if they:
1. Participated in the double-blind Trial 156-13-210 (only upon successful
completion of their randomized 12-month period including post-treatment
follow-up, regardless of whether this was on-treatment or offtreatment), or
2. Participated in the open-label Trial 156-08-271. After consenting and
screening, eligible subjects will be assigned a new subject number and
administered tolvaptan at asplit-dose of 45/15 mg. Subjects will have the
opportunity for either up or down-titration to a maximum split tolvaptan dose
of 90/30 mg or a minimum split dose of 15/15 mg at the discretion of the
investigator according to individual tolerability.
Subjects entering the trial from Trial 156-08-271 may receive up to 33 months
of open-label tolvaptan therapy, and subjects entering the trial from Trial
156-13-210 may receive up to 15 to 21 months of open-label tolvaptan therapy.

For purposes of ensuring subject safety, all subjects will be monitored for
hepatic safety monthly until they have accumulated 18 months of tolvaptan
exposure. After that, and following the approval from the medical monitor,
hepatic monitoring will be required every 3 months. If subjects
approaching the 18-month threshold have had prior transaminase abnormalities (>
2 × upper limit of normal [ULN]), the investigator is responsible for
contacting the medical monitor to confirm the change in frequency from monthly
to every 3 months. Until their prior treatment
assignment is unblinded, all Trial 156-13-210 subjects who are eligible for
this trial are scheduled to have trial visits/ hepatic monitoring monthly for
the first 18 months of this trial. Once unblinding occurs, it can be determined
which subjects received tolvaptan in Trial 156-13-210. These subjects may have
their trial visits/hepatic transaminase monitoring change to every 3 months
sooner as their previous tolvaptan exposure in Trial 156-13-210 can count
towards the 18-month threshold. Enrollment in this trial will be closed when
the final eligible subject from Trial 156-13-210 enrolls in this trial.

The dose regimens to be used in this trial are 15/15 mg, 30/15 mg, 45/15 mg,
60/30 mg, and 90/30 mg. Tolvaptan tablets (15 mg or 30 mg) will be
self-administered orally as split-dose regimens, twice daily, once upon
awakening and another approximately 8 to 9 hours later. Doses will be recorded
as early dose/late dose (eg, 60/30 mg).

Clinical studies have shown that after the drug breaks down, by-products can
build up in the body. While these products do not appear to be active and
long-term studies in animals and in humans have been conducted, we do not know
whether there are other very long term effects in humans.

Frequent adverse effects (seen in at least 3% of all participants who received
tolvaptan regardless of their health before participating) that have been
reported during studies of tolvaptan and placebo include increased thirst,
increased severity of heart failure in individuals who already have heart
failure, dry mouth, nausea, increased urination (frequency and volume at day
and night), dizziness, constipation, low blood pressure, high blood pressure,
diarrhea, tiredness, trouble sleeping, increases or decreases in the level of
potassium in the blood, low blood count, kidney or bladder infection, increased
creatinine in the blood (a waste product taken to the kidneys for filtering),
vomiting, cough, decreased appetite, infection in the lung, swelling in the
arms or legs, headache, pain in the chest, kidneys, abdomen, back, arms, or
legs, fever, increased levels of uric acid in the blood, and shortness of
breath.

Less frequent but serious medical problems have been seen in some study
participants. These include heart failure, stroke, glaucoma, skin cancers or
even death. Because such serious medical problems are infrequent, and given the
seriousness of the participant's medical condition before the study it is not
known if such problems would have occurred whether the patient had participated
in the study or not.

During an investigational clinical study of tolvaptan for the treatment of
ADPKD, an increased risk of liver injury was found. Liver test abnormalities
and liver injury occurred more frequently in patients taking tolvaptan compared
to those taking placebo. These findings indicate that tolvaptan may cause
permanent liver injury. No ADPKD patient in a clinical trial has had signs of
permanent liver damage but it can occur and may require a liver transplant or
cause death. In other clinical trials of tolvaptan, (including the trials in
hyponatremia, heart failure, cirrhosis and hepatic edema patients), signs of
drug-induced liver damage have not been seen.