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
Phase: PHASE3
Conditions: Polycystic Kidney, Autosomal Dominant
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Protocol 156-13-211 
Confidential - Proprietary Information 
Protocol number: 156-13-211
Document title:   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  
Version number: 2.0
Date of the document: 06 March 2015
NCT number:   NCT02251275

1
2
128
Protocol and/or Protocol Amendments
Table of Contents
Table of Contents..................................................................................................
Study 156-13-211 Protocol Amendment 2; 06 March 2015.................................
Study 156-13-211 Protocol Amendment 3-UK; 06 March 2015..........................
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
1

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Protocol 156-13-211
Confidential - Otsuka Proprietary Information
2
06 March 2015
Protocol Synopsis 
Name of Sponsor:  Otsuka Pharmaceutical Development 
& Commercialization, Inc.
Name of Investigational Medicinal Product: Tolvaptan 
(OPC-41061)
Protocol # 156-13-211
IND# 72,975
EudraCT# 2014-001516-
19
Protocol Title:
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
Clinical Phase/Trial 
Type:
Phase 3b/Therapeutic use
Treatment Indication: Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Objective:
The primary objective of this trial is:

To evaluate and describe the long-term safety of tolvaptan.  
Trial Design:
This trial is a phase 3b, multi-center, open-label extension trial.
Subjects will be eligible for screening into this trial if they:

Completed and transferred from the double-blind 
Trial 156-13-210 (12-month period including 
post-treatment follow-up, regardless of whether this 
was on-treatment or off-treatment), or have completed 
all but the last follow-up visit, which will be combined 
with the first visit in this trial or

Completed Trial 156-08-271 or a prior tolvaptan 
ADPKD trial, or have completed all but the end of trial 
visit, which will be combined with the first visit in this 
trial or

Interrupted or discontinued treatment in a prior 
tolvaptan ADPKD trial (other than Trial 156-13-210).  
Subjects may be enrolled with medical monitor 
approval, and additional close monitoring may be 
required at the beginning of the trial
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 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
3

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
3
06 March 2015
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.
Subject Population:
This trial will include approximately 2,500 subjects over the 
age of 18 years with ADPKD diagnosed by Pei-Ravine criteria
(modified by magnetic resonance imaging [MRI]), and who
have completed or participated in a prior ADPKD 
interventional investigational medicinal product (IMP) trial.
Inclusion/Exclusion 
Criteria:
Main inclusion criteria:

Male and female subjects 18 years with a confirmed 
diagnosis of ADPKD (during participation in prior 
tolvaptan trials) who have 

Completed and transferred from the double-blind 
Trial 156-13-210 (12-month period including 
post-treatment follow-up, regardless of whether this 
was on-treatment or off-treatment), or 

Completed Trial 156-08-271 or a prior ADPKD 
tolvaptan trial, or

Interrupted or discontinued treatment in a prior 
tolvaptan ADPKD trial other than Trial 156-13-210.  
Subjects may be enrolled with the medical monitor 
approval, and additional close monitoring may be 
required at the beginning of the trial

Estimated glomerular filtration rate 
(eGFR) 20 mL/min/1.73m2 within 3 months of the 
baseline visit.  Subjects who have an eGFR 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
4

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
4
06 March 2015
≤20 mL/min/1.73m2 may be enrolled with medical 
monitor and sponsor approval and increased frequency of 
monitoring to ensure subjects’ safety.

Renal function will be assessed during screening by using 
historical laboratory values (within 3 months from the 
screening visit) for serum creatinine levels to calculate the 
eGFR.  The eGFR values will be estimated based on the 
Chronic Kidney Disease - Epidemiology (CKD-EPI) 
formula
Main exclusion criteria:

Need for chronic diuretic use

Hepatic impairment based on hepatic laboratory
assessments (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], bilirubin, total [BT]) other than 
that expected for ADPKD with cystic liver disease
Trial Site(s):
Approximately 220 enrolling sites including but not limited to 
the following regions: North America, South America, Eastern 
Europe, Western Europe, Russian Federation, and Australia.
Investigational 
Medicinal Product(s), 
Dose, Dosage 
regimen, Treatment 
period, Formulation, 
Mode of 
Administration:
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).  
Subjects will receive open-label tolvaptan for the duration of 
the trial. 
A subject’s starting dose in this trial will be dependent on the
trial in which they were previously enrolled:

156-13-210- initiated on tolvaptan at a split-dose of 
45/15 mg with upward titration every 3 to 4 days to 
60/30 mg or 90/30 mg per day according to tolerability

156-08-271- will retain the last dose level from 271 
and start at the same dose in this trial

Prior tolvaptan trials- initiated on tolvaptan at a 
split-dose of 45/15 mg with upward titration every 3 to 
4 days to 60/30 mg or 90/30 mg per day according to 
tolerability
Down titration to 30/15 mg or 15/15 mg will be allowed at the 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
5

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Protocol 156-13-211
Confidential - Otsuka Proprietary Information
10
06 March 2015
8.3
Accountability ...................................................................................................58
8.4
Returns and Destruction....................................................................................58
9
Records Management.........................................................................58
9.1
Source Documents.............................................................................................58
9.2
Data Collection..................................................................................................58
9.3
File Management at the Trial Site.....................................................................59
9.4
Records Retention at the Trial Site....................................................................59
10
Quality Control and Quality Assurance...........................................60
10.1
Monitoring.........................................................................................................60
10.2
Auditing.............................................................................................................60
11
Ethics and Responsibility...................................................................60
12
Confidentiality ....................................................................................60
13
Amendment Policy..............................................................................61
14
References............................................................................................62
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
11

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
11
06 March 2015
List of In-text Tables
Table 1.2-1
Vasopressin Blockade Across Differing Severities of 
ADPKD: Effect on Rate of Estimated Glomerular Filtration 
Decline in Chronic Kidney Disease Stages 1-3.............................18
Table 3.2-1
Trial Treatments.............................................................................25
Table 3.4.2-1
Inclusion Criteria ...........................................................................27
Table 3.4.3-1
Exclusion Criteria ..........................................................................28
Table 3.7-1
Schedule of Assessments...............................................................30
Table 3.7.2.2-1
Clinical Laboratory Assessments...................................................39
Table 4.1-1
Strong and Moderate CYP3A Inhibitors (partial list)....................47
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
12

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
12
06 March 2015
List of In-text Figures
Figure 3.1-1
Trial Design Schematic..................................................................23
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
13

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Protocol 156-13-211
Confidential - Otsuka Proprietary Information
15
06 March 2015
SD
Standard deviation
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
US or USA
United States or United States of America
WOCBP
Women of childbearing potential
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
16

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
16
06 March 2015
1
Introduction
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).  The 
disease affects the structure of the kidneys through proliferation and growth of numerous 
fluid-filled cysts.  The expanding cysts compress normal tissue and blood vessels 
resulting in ischemia, inflammation and fibrosis leading to progressive nephron loss.  The 
remaining nephrons are initially able to compensate through glomerular hyperfiltration up 
to a point when nephron loss is so great that compensation is no longer adequate and 
renal function begins to decline.  Clinical manifestations of kidney disease may be 
sporadic (hematuria, infections, pain) or chronic (hypertension, albuminuria, renal 
insufficiency) and indicate ongoing and cumulative damage to the kidney.
The number of diagnosed ADPKD cases was estimated at 116,228 in the US in 2009.  
The estimated prevalence of diagnosed ADPKD is similar in Europe and estimated to be 
< 5 per 10,000.1  Though a rare genetic disease, it ranks as the 6th leading cause of ESRD 
in the US (2.3% of the new ESRD cases).2  An estimated 45% to 70% of patients with 
ADPKD progress to ESRD by age 65.3  Over the past 30 years, the age of onset for 
ESRD among ADPKD patients has remained the same (median age of 54).  In contrast, 
effective therapy has delayed the onset of ESRD in patients with nephropathy due to 
hypertension, diabetes, and glomerulonephritis.
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 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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16.1.1 Protocol and Protocol Amendments
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Protocol 156-13-211
Confidential - Otsuka Proprietary Information
17
06 March 2015
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.4 5  Refer to the Tolvaptan Investigator’s Brochure 
(IB) for more information.4
1.1
Nonclinical Data
Rodent models of ADPKD and ex-vivo human ADPKD cell and tissue cultures have 
implicated AVP as a promoter of kidney cyst growth.6 7  AVP-induced cyclic adenosine 
monophosphate (cAMP) increases proliferation of ADPKD renal tubular epithelium and 
chloride-mediated, intra-cystic, fluid secretion.  This leads to cyst expansion which 
disrupts renal architecture leading to ischemia, kidney fibrosis, and irreversible damage 
to the kidney, ultimately impairing its function.  Tolvaptan inhibits cAMP production by 
blocking AVP binding to the renal AVP-V2 receptor.  For information on nonclinical 
toxicology and absorption, distribution and metabolism data on tolvaptan please refer to 
the most current version of the IB.4
1.2
Clinical Data
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.8  
These effects were consistent across each of these CKD stages, supporting tolvaptan’s 
potential utility in early to mid-stage disease (Table 1.2-1), and creating a compelling
argument for long-term effectiveness in those initiating therapy at an early stage and 
adhering to therapy as the disease progresses.  This trial also demonstrated an acute and 
persistent reduction on rate of kidney cystic growth.  The reductions in rate of kidney 
growth correlated with reductions in kidney pain and with preservation of renal function.  
Similar correlations were observed in a smaller, matched-control study 
(Study 156-09-283).9  Thus, the clinical data have confirmed the non-clinical effects seen 
in animals (see Section 1.1) and support approval of tolvaptan as the first agent to slow 
the progression of ADPKD.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
18

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CCI

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
19
06 March 2015
trials.  Overall, subjects were exposed to oral doses of tolvaptan ranging from 3.75 to 
480 mg.  The median exposure for all doses of oral formulations combined was 29 days, 
with a mean exposure of 228 days (346 days).
Pooled safety data from 80 trials indicate that the most commonly reported (> 3%) 
treatment-emergent adverse events (TEAEs) for tolvaptan-treated subjects were thirst 
(25.8%), dry mouth (10.8%) and pollakiuria (9.9%).
The most notable safety issue associated with chronic tolvaptan use, which was newly 
identified in Trial 156-04-251, was the potential for idiosyncratic hepatic toxicity. An 
imbalance in the proportion of subjects with elevated transaminases (tolvaptan > placebo) 
led to identification of 3 subjects (total, combined from Trials 156-04-251 and 
156-08-271) with laboratory and clinical evidence of potentially serious drug-induced 
liver injury (DILI).10 Based on the available data from the afore-mentioned trials, the 
sponsor proposes that appropriate subject monitoring and management be implemented to 
mitigate this potential risk in the ADPKD population.  
In this extension trial, subjects enrolling from the double-blind Trial 156-13-210 will 
have monthly visits and transaminase level assessments for the first 18 months while the 
treatment code from Trial 156-10-210 remains blinded, to ensure that all subjects have 
adequate safety monitoring during this period of susceptibility.  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.  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.  Subjects enrolling from the open-label 
Trial 156-08-271 will have transaminase assessments conducted every 3 months, since 
they will have already received tolvaptan for at least 18 months. The current IB lists all 
of the tolvaptan trials.  Subjects enrolling in this trial who were in a previous ADPKD 
tolvaptan trial other than Trials 156-13-210 and 156-08-271 will have monthly visits and 
alanine aminotransferase (ALT) level assessments for the first 18 months.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
20

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Protocol 156-13-211
Confidential - Otsuka Proprietary Information
23
06 March 2015
Figure 3.1-1
Trial Design Schematic
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated 
or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
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Protocol 156-13-211
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06 March 2015
3.2
Treatments
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.
Following consent, and once subjects have satisfied all of the inclusion criteria and none 
of the exclusion criteria, subjects will retain the subject number assigned from their 
previous trial.  Subjects will receive open-label tolvaptan for the duration of the trial. All 
subjects will be administered tolvaptan tablets in a daily split-dose, once upon awakening 
and another approximately 8 to 9 hours later (twice daily dosing).  The exact time of 
dosing may be adjusted based on wake/sleep habits (eg, standard 8 AM and 5 PM may be 
switched to 10 PM and 7 AM if working a night shift).  However, dosing times should be 
consistent for each individual’s daily dose to maximize receptor suppression.  Doses will 
be recorded as early dose/late dose (eg, 60/30 mg). 
A subject’s starting dose in this trial will be dependent on the trial in which they were 
previously enrolled:

156-13-210- initiated on tolvaptan at a split-dose of 45/15 mg with upward 
titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to 
tolerability

156-08-271- will retain the last dose level from 271 and start at the same dose in 
this trial

Prior tolvaptan trials- initiated on tolvaptan at a split-dose of 45/15 mg with 
upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to 
tolerability
Down titration to 30/15 mg and 15/15 mg is also permitted at the discretion of the 
investigator according to subject tolerability with medical monitor notification.  Further 
down titration to 30 or15 mg once daily may be allowed only for metabolic drug-drug 
interaction and requires medical monitor approval.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Protocol 156-13-211
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06 March 2015
Table 3.2-1
Trial Treatments
Trial Day
Time
Dose
Day 1 to last on-treatment visit
8:00 am
1 to 6 tolvaptan tablets (15 mg or 30 mg each)
4:00 to 5:00 pm
1 to 2 tolvaptan tablets (15 mg or 30 mg each)
Allowed doses are 45/15 mg, 60/30 mg, 
90/30 mg.  Down titration to 30/15 mg and 
15/15 mg will be allowed after discussion 
with the medical monitor.  Further down 
titration to 30 or 15 mg once daily may be 
allowed only for metabolic drug-drug 
interaction and requires medical monitor 
approval.
For subjects moving from the 156-13-210 trial and requiring tolvaptan titration, it will be 
conducted in the following way: subjects will be instructed to take tolvaptan starting at a 
split dose of 45/15 mg (as 3 tablets upon waking and 1 tablet approximately 8 to 9 hours 
later) and to titrate up every 3 to 4 days; first to 60/30 mg, then up to the maximum dose 
of 90/30 mg.  Titration will be accomplished by increasing the number of tablets/dose 
and/or switching from 15 mg tablets to 30 mg tablets.  Prior to each upward titration, the 
subject’s tolerability to the current dose will be assessed by asking, “Could you tolerate 
this dose of trial medication for the rest of your life?” Subjects will continue in the trial
with the regimen to which tolerability was established.
While taking tolvaptan, all subjects should be instructed to ingest fluids in anticipation of, 
or at the first sign of thirst in order to avoid excessive thirst or dehydration.  Additionally, 
subjects should ingest 1 to 2 cups of water before bedtime regardless of perceived thirst 
and replenish fluids overnight with each episode of nocturia.
3.2.1
Dosing with CYP3A4 Potent Inhibitors
Tolvaptan is a sensitive CYP3A4 substrate with 4-fold or higher increases in exposure 
following administration with potent CYP3A4 inhibitors.4  
For subjects requiring treatment with a potent CYP3A4 inhibitor and on a total daily 
tolvaptan dose of 90 or 120 mg, tolvaptan treatment should be reduced to 30 mg once 
daily.  The dose may be reduced to 15 mg once daily for tolerability.  For subjects on a 
total daily dose of 60 mg, tolvaptan treatment should be reduced to 15 mg once daily.  
For subjects on lower total daily doses, tolvaptan interruption should be considered if no 
alternative medications can be used. 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
26

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
26
06 March 2015
3.2.2
Dosing with CYP3A4 Moderate Inhibitors
For subjects who require dosing with a moderate inhibitor, initial tolvaptan reductions as 
shown below should be tried, with further dose reductions or interruption as necessary for 
tolerability.

90/30 mg to 45/15 mg

60/30 mg to 30/15 mg

45/15 mg to 15/15 mg

30/15 mg to 15 mg once daily

15/15 mg to 15 mg once daily
A partial list of strong and moderate CYP3A4 inhibitors can be found in Section 4.1.
3.3
Trial Population
This trial will include approximately 2,500 subjects over the age of 18 years with 
ADPKD diagnosed by Pei-Ravine criteria11 12 (modified by magnetic resonance imaging 
[MRI]) who completed or participated in a prior tolvaptan trial.  
3.4
Eligibility Criteria
3.4.1
Informed Consent
Each investigator has both ethical and legal responsibility to ensure that subjects being 
considered for inclusion in this trial are given a full explanation of the protocol and of 
their role and responsibilities in the proposed research.  This shall be documented on a 
written informed consent form (ICF) that shall be approved by the same institutional 
review board/independent ethics committee (IRB/IEC) responsible for approval of this 
protocol.  Each ICF will comply with the International Conference on Harmonisation 
(ICH) Good Clinical Practice (GCP) Guideline14 and local regulatory requirements, and 
must adhere to the ethical principles that have their origin in the Declaration of Helsinki.  
The investigator agrees to obtain sponsor approval of any written ICF used in the trial 
prior to submission to the IRB/IEC.
Investigators may discuss trial availability and the possibility for entry with a potential 
subject without first obtaining consent.  However, informed consent will be obtained 
from all subjects (or their guardian or legal representative) and documented prior to 
initiation of any procedures that are performed solely for the purpose of determining 
eligibility for this trial, including withdrawal from current medication(s).
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
27

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CCI

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
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06 March 2015
3.4.3
Exclusion Criteria
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3-1.
Table 3.4.3-1
Exclusion Criteria
1.
WOCBP who do not agree to practice 2 different methods of birth control or remain abstinent 
during the trial and for 30 days after the last dose of IMP. If employing birth control, 2 of the 
following precautions must be used: vasectomy of partner, tubal ligation, vaginal diaphragm, 
intrauterine device, birth control pill, birth control implant, birth control depot injection, condom, 
or sponge with spermicide.
2.
Women who are breast-feeding and/or who have a positive pregnancy test result prior to receiving
IMP.
3.
Need for chronic diuretic use.
4.
Hepatic impairment based on liver function abnormalities other than that expected for ADPKD 
with cystic liver disease during screening based on recent historical laboratory values (in the last 
3 months).  
5.
Subjects with contraindications to required trial assessments (contraindications to optional 
assessments, eg, MRI are not a limitation).
6.
Subjects who, in the opinion of the investigator or medical monitor, have a medical history or 
medical finding inconsistent with safety or trial compliance.  This includes prior evidence of 
significant hepatic injury deemed to be related to tolvaptan use.
WOCBP=women of childbearing potential; IMP=investigational medicinal product
Non-childbearing potential in women is defined as female subjects who are surgically 
sterile (ie, have undergone bilateral oophorectomy or hysterectomy) or female subjects 
who have been postmenopausal for at least 12 consecutive months.
Subjects may be rescreened, at the discretion of the medical monitor, if the exclusion 
characteristic has changed or resolved.  In the event that a subject is rescreened, a new 
ICF must be signed and a new screening number assigned and screening procedures 
repeated.
3.5
Trial Endpoints
3.5.1
Safety Endpoints
This trial will have no formal endpoints.  Safety variables will be summarized by 
descriptive statistics, (eg, proportion, mean, median, standard deviation [SD], minimum, 
and maximum values).  In general, summary statistics, including changes from baseline, 
will be provided for safety variables based on all available data.  Safety endpoints will be
as follows:

Adverse events

Vital signs
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
29

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CCI

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
31
06 March 2015
Screening 
(-30 to -1 days 
prior to Baseline)a
Baseline/ 
Day 0
Monthlyb
(± 7 days)
Every 
3 monthsb
(14 days)
Early 
Termination/End 
of Treatment
(+ 7 days)
Titration 
Contact 
(phone 
contact)
Follow-up
7 days post-
treatment
(+ 7 days)
Adverse events
Xn
-------------------------------------------------------------------------------------------------------------------
Concomitant medicationso 
-------------------------------------------------------------------------------------------------------------------
aThe last visit assessments from the previous trial can be combined with the screening and baseline visits for this trial, with all required assessments from each 
visit performed only once. 
bMonthly visits are for subjects < 18 months on tolvaptan, and every 3 month visits are for subjects > 18 months on tolvaptan. 
cIncludes prior trial identifiers (screening identification [ID], subject ID, site ID, prior tolvaptan ADPKD trial protocol number).
dVital signs at each visit include seated heart rate, calibrated blood pressure and post void body weight.  Height should be performed only at screening.
eCentral laboratory non-fasting serum laboratory tests will be performed.  All subjects must be monitored for hepatic safety monthly until they have known 
tolvaptan exposure data of at least 18 months.  After that, and following the approval of the medical monitor, hepatic monitoring will take place every 
3 months.  Trial 156-13-210 subjects who are eligible for this trial will have trial visits/hepatic monitoring monthly for the first 18 months of this trial then 
every 3 months thereafter, because their tolvaptan exposure will be unknown.  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 changed to every 3 months sooner as their 
previous tolvaptan exposure in Trial 156-13-210 can count towards the 18 month threshold. Subjects who enroll from other ADPKD tolvaptan trials will 
be monitored for hepatic safely monthly for their first 18 months they are in this trial.
fHepatitis testing at screening will be optional.  If hepatitis testing is performed, then both pre- and post-counseling activities relating to hepatitis testing are to 
be carried out based on local requirements and best practices.  Upon request, if clinically indicated and approved by the medical monitor, subjects may have 
the following evaluations in addition to the protocol-specified chemistry panel: serum calcium, phosphorous, parathyroid hormone, vitamin D, and 
bicarbonate levels.  
gA full liver function panel (AST, ALT, alkaline phosphatase, BT) will be done at screening.  All other liver function tests at subsequent visits are for ALT 
only, unless otherwise clinically indicated.  An ALT elevation > 2 × ULN should trigger prompt testing of hepatic function within 72 hours.  Any 
transaminase or bilirubin values which exceed 2 × ULN should prompt immediate retesting within 72 hours.  While values remain in an abnormal range, 
testing frequency should be increased to at least weekly for the first month, gradually returning to monthly, and every 3 months as indicated by the results.  
Local liver function panel analyses will also be performed more frequently, if necessary.  
hUrine osmolality is optional.
iA urine pregnancy test for pregnancy for women of childbearing potential (WOCBP) will be performed at screening, at every 3 months visits, at the End of 
Treatment (EoTx) visit, and at the follow-up visit.  On suspicion of pregnancy, an unscheduled urine or serum pregnancy testing will be performed.  
Positive urine pregnancy tests should be confirmed with a serum pregnancy test. 
jAt-home urine pregnancy test kits will be dispensed to WOCBP to be used if a menstrual period is missed between visits.  Kits will be dispensed as needed 
throughout the trial. 
kA full physical examination is required at screening.  At other visits, an optional “directed” physical examination may be performed to focus on PKD-related 
signs and symptoms. 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated 
or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
32

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CCI

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
33
06 March 2015
3.7.1
Schedule of Assessments
3.7.1.1
Screening (-30 days to 1 day prior to Baseline)
Screening for eligibility is required for all subjects. The screening and baseline visit may 
be combined with the last visit from either Trials 156-08-271 or 156-13-210 with all 
required assessments from each visit performed only once. Therefore, in some cases, if a 
subject enrolls in this trial from a prior tolvaptan trial, the end of trial or last follow-up 
visit for that trial and the screening and baseline visit for this one may occur 
simultaneously.  Required assessments for the screening visit are as follows:
1. Obtain subject consent.
2. Obtain subject’s new screening identification (ID) assigned by interactive 
response technology (IRT).
3. Determine subject eligibility through inclusion/exclusion criteria
4. Record demographic information and prior trial identifiers (screening ID, subject 
ID, site ID, prior tolvaptan ADPKD trial protocol number).
5. Record medical/ADPKD history using prior trial data.
6. Review dietary recommendations and compliance
7. Record vital signs (post-void weight and seated heart rate) and in-clinic calibrated 
blood pressure (BP) measurement.  Record height.
8. Collect blood for serum chemistry, liver function panel (ALT, AST, BT, bilirubin 
[direct], and alkaline phosphatase), serum sodium, serum creatinine, and 
hematology and coagulation. Hepatitis testing is optional. If hepatitis testing is 
performed, then both pre- and post-counseling activities relating to hepatitis 
testing are to be carried out based on local requirements and best practices.  
9. Collect urine for urinalysis, urine osmolality (optional), and urine specific gravity.
10. Perform urine pregnancy test on women of childbearing potential (WOCBP).  If 
positive, a follow-up serum test will be performed.
11. Conduct full physical examination.
12. Enter subject into interactive response technology (IRT) including prior trial 
identifier/information (protocol number, subject ID), confirmed dose regimen,
and scheduled date of next visit.
13. Assess AEs reported as ongoing or resolved from prior trial to determine entry as 
medical history or ongoing event for this trial.
14. Record ongoing concomitant medications. (This will happen only if the screening 
visit occurs simultaneously with the last visit from a previous tolvaptan trial).
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
34

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Protocol 156-13-211
Confidential - Otsuka Proprietary Information
40
06 March 2015
with commercially available, high-sensitivity kits supplied to the subject by the site 
(acquired by the sponsor).
3.7.2.3
Physical Examination and Vital Signs
A full physical examination will be performed and documented at the screening visit 
although this may be combined with the last visit from the previous trial. At other visits, 
an optional directed physical examination may be performed to focus on ADPKD-related 
signs and symptoms.  In some geographic regions, more frequent subject visits may be 
the norm; however vital signs and clinically significant physical findings will be recorded 
as an unscheduled visit in the electronic case report form (eCRF) as applicable. Any 
changes in medication or AEs will be recorded in the eCRF.
Height will be measured only at screening.  Body weight will be taken post-void.  It is 
preferable to use the same scale for each measurement.  Clinic scales should be calibrated 
at least yearly. The investigator or his/her appointed designee is primarily responsible to 
perform the physical examination.  If the appointed designee is to perform the physical 
examination, he/she must be permitted to do so by local regulations and his/her name 
must be included on any globally and locally required documents (eg, individual must be 
added for all sites on a US Food and Drug Administration (FDA) Form 1572, where local 
regulations allow, while local regulations determine their being named in the ICF).  
Whenever possible, the same individual should perform all physical examinations.  Any 
undesirable condition present at a post-treatment physical examination that was not 
present at the baseline examination should be documented as an AE and followed to a 
satisfactory conclusion.
Vital sign data, including seated blood pressure, heart rate, height, and weight will be 
taken at the visits identified in the Schedule of Assessments (Table 3.7-1).
3.7.2.4
Assessment of Liver Symptoms, Signs or Test Abnormalities
Testing for hepatic transaminase (ALT/AST), alkaline phosphatase, bilirubin direct, and 
BT will be performed during screening.  Subjects enrolling from the double-blind Trial 
156-13-210 will have monthly ALT assessments for the first 18 months while the 
treatment code from Trial 156-13-210 remains blinded to ensure that all subjects have 
adequate safety monitoring during this period of susceptibility.  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 changed to every 
3 months sooner as their previous tolvaptan exposure in Trial 156-13-210 can count 
towards the 18-month threshold.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
41

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
41
06 March 2015
Following the first 18 months, ALT assessments will be made every 3 months for 
Trial 156-13-210 subjects and for subjects from other tolvaptan ADPKD trials besides 
Trial 156-08-271.  
Subjects enrolling from the open-label Trial 156-08-271 who have tolvaptan exposure 
greater than 18 months will continue with ALT monitoring every 3 months.
Subjects enrolling from prior tolvaptan trials besides Trial 156-08-271 will have monthly 
ALT assessments for the first 18 months.  Upon reaching 18 months of exposure and 
after confirmation from the medical monitor, the frequency of ALT monitoring for these 
subjects will occur every 3 months.
ALT will also be assessed at the Early Termination/EoTx visit and at the 7-day Follow-
up visit.
Management of liver abnormalities is discussed in the paragraphs below.
3.7.2.4.1
Liver Test Abnormalities and Interruption/Discontinuation of 
Investigational Medicinal Product
An ALT elevation 2 × ULN or the appearance of any suspicious symptom or sign should 
trigger prompt testing of hepatic function (ie, within 72 hours).  Local laboratory testing 
is acceptable, ideally with a concurrent central laboratory sample for confirmation.  
Any transaminase or bilirubin values which exceed 2 × ULN should also prompt 
immediate retesting within 72 hours.  While values remain in an abnormal range, testing 
frequency should be increased to at least weekly for the first month, gradually returning 
to monthly, or every three months as indicated by the results.
Liver transaminase or bilirubin levels reaching or exceeding 2 × ULN that have an 
uncertain or rapidly increasing trajectory should prompt at least temporary IMP 
interruption. Tolvaptan should not be resumed until monitoring indicates abnormalities 
have resolved, are stable, or are not rapidly increasing, and then only with an increased 
frequency of monitoring.
Subjects would not typically be allowed to resume treatment with tolvaptan if they have:

transaminase levels rise above 8 × ULN,

transaminase levels are > 5 × ULN for more than 2 weeks, or

concurrent elevations of transaminase > 3 × ULN and BT > 2 × ULN.
Subjects with these levels of abnormality may be re-challenged with IMP if abnormalities 
were adjudicated as having a < 50% likelihood of being related to IMP (per DILI network 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
42

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3.8
Stopping Rules, Withdrawal Criteria, and Procedures
3.8.1
Entire Trial 
If the sponsor terminates or suspends the trial for safety or unanticipated other reasons, 
prompt notification will be given to investigators, IRBs/IECs, and regulatory authorities 
in accordance with regulatory requirements.
3.8.2
Individual Site
The investigator will notify the sponsor promptly if the trial is terminated by the 
investigator or the IRB/IEC at the site. If the investigator, IRB/IEC or sponsor decides to 
terminate or suspend the trial’s conduct at a particular center for safety, non-enrollment 
of subjects, non-compliance with the protocol, or unanticipated other reasons, the above 
and other parties, as required by the applicable regulatory requirements, will be promptly 
notified.
3.8.3
Individual Subject
If a subject discontinues the trial prematurely, the reason must be fully evaluated and 
recorded appropriately in source documents and the CRF.  If the subject is being 
withdrawn because of an AE, that AE should be indicated as the reason for withdrawal.  
All subjects have the right to withdraw at any time during treatment without prejudice.  
The investigator can discontinue a subject’s participation in the trial at any time if 
medically necessary.  It is preferred that subjects who permanently discontinue IMP will 
have the option to continue participation off IMP with regular scheduled visits or with a 
modified (ie, less frequent) schedule.  If subjects are unable or unwilling to complete the 
visits and procedures off IMP, the early termination/EoTx visit should be completed.  
The investigator may continue to contact those who discontinue IMP through to the final 
completion date of the trial or thereafter if needed to determine outcomes ie, vital status.  
In addition, subjects meeting the following criteria must be withdrawn from the trial:
a) Occurrence of any AE, intercurrent illness, or abnormality in a laboratory assessment 
which, in the opinion of the investigator, warrants the subject’s permanent withdrawal 
from the trial;
b) Subject noncompliance, defined as refusal or inability to adhere to the trial schedule or 
procedures (see Section 3.12);
c) At the request of the subject, investigator, sponsor, or regulatory authority;
d) Subject is lost to follow-up.
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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The investigator will notify the sponsor promptly when a subject is withdrawn.
3.9
Screen Failures
A screen failure subject is one from whom informed consent is obtained and is 
documented in writing (ie, subject signs an ICF), but who is not started on treatment.
3.10
Definition of Completed Subjects
For purposes of this trial, subjects who complete the EoTx visit will be defined as trial 
completers.
3.11
Definition of Subjects Lost to Follow-up
Subjects, or the subject’s parent/guardian who cannot be contacted on or before their final 
visit prior to the trial termination date, who do not have a known reason for 
discontinuation (eg, withdrew consent or AE) and for whom a current health status at the 
end of the trial cannot be determined will be classified as “lost to follow-up” as the 
reason for discontinuation.  Current health status can be determined from a variety of 
sources, either by obtaining acceptable documentation for death (ie, death certificate, 
medical records, public records, or statement by a family member or primary care 
physician) or acceptable documentation for life (ie, direct contact with the subject, 
medical records, successful telephone contact with the subject, statement by a family 
member or primary care physician, or public records).  It is expected that 3 documented 
attempts will be made to determine a subject’s current health status before assigning a 
“lost to follow-up” status.
3.12
Subject Compliance 
Subject compliance will be monitored by pill counts as IMP is returned.  Any subject 
who, without the instruction of the investigator, discontinues tolvaptan investigational 
product, discontinues tolvaptan for 30 consecutive days or misses > 30% of the doses 
intended for a period between visits (whichever is greater) will be deemed noncompliant. 
Depending on the circumstances leading to noncompliance, the subject may be 
withdrawn from the trial or discontinued from investigational product administration by
the investigator and/or sponsor.  It is preferred that subjects who discontinue tolvaptan, or 
are withdrawn by the investigator for reasons other than noncompliance or lost to follow-
up, will continue with regularly scheduled visits completing all procedures as provided in 
the protocol.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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3.13
Protocol Deviations
This trial is to be conducted as described in this protocol.  In the event of a significant 
deviation from the protocol due to an emergency, accident or mistake (eg, violation of 
informed consent process, IMP dispensing or subject dosing error, subject enrolled in 
violation of eligibility criteria or concomitant medication criteria), the investigator or 
designee must contact the sponsor at the earliest possible time.  This will allow an early 
joint decision regarding the subject’s continuation in the trial.  This decision will be 
documented by the investigator and the sponsor, and reviewed by the site monitor.
4
Restrictions
4.1
Prohibited or Restricted Medications
Medications or surgical therapies used for the purpose or potential for modifying the 
progression of PKD cyst growth or development will be prohibited.  These include, but 
are not restricted to, somatostatin agonists, rapamune (sirolimus), anti-sense ribonucleic 
acid therapies, vasopressin antagonists other than tolvaptan, (eg, OPC-31260 
(mozavaptan), Vaprisol (conivaptan), agonists (eg, desmopressin) and cyst 
decompression surgery.
Continuous or short-term use of other medications, while not prohibited, may be 
restricted by the investigator because of their potential for interference with tolvaptan 
metabolism (see Section 3.2.1 and Section 3.2.2). 
A partial list of strong and moderate CYP3A4 inhibitors can be found in Table 4.1-1
below:
Table 4.1-1
Strong and Moderate CYP3A Inhibitors (partial list)
amprenavir
atorvastin
aprepitant
chloramphenicol (if 
used orally)
cimetidine
clarithromycin
clotrimazole (if used 
orally)
danazol
delavirdine
diltiazem
erythromycin
fluconazole
fluvoxamine
indinavir
isoniazid
itraconzazole
josamycin
ketoconazole (if used 
orally)
nelfinavir
nefazadone
quinupristin/ dalfopristin
ritonavir
saquinavir
troleandomycin
verapamil
Seville orange products
grapefruit products
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Pharmacodynamic interactions are a consideration for the use of diuretics, which may be
only used intermittently, and not within 7 days of a urine assessment.  Diuretics are not 
generally recommended in ADPKD due to their tendency to increase AVP levels through 
relative dehydration or volume depletion; thus, chronic use of diuretics (eg, for 
hypertension) will be prohibited and is an exclusionary criterion for this trial. 
Some drugs are known to alter creatinine concentrations so, while not prohibited, subjects 
should alert their trial doctor, and any other health-care providers, to take this into 
consideration when considering changes in their prescribed or over-the-counter 
medications.  A list would include:  non-steroidal anti-inflammatory drugs like aspirin or 
ibuprofen, chemotherapy drugs, cephalosporin, the combination of elvitegravir, 
cobicistat, emtricitabine, and tenofovir (Stribild), dolutegravir, dronedarone, 
ranolazine, metformin, and trimethoprim.
4.2
Dietary Restrictions and Recommendations
Restriction of excess dietary sodium and cooked meat protein may prove beneficial to 
subjects with a history of, or predisposition for, hypertension or kidney disease in general 
and should be applied to all subjects diagnosed with advanced ADPKD, particularly if 
there is evidence for a propensity for rapid progression.  In the absence of alternate 
regional practices, dietary salt < 5g/day, dietary cooked meat protein < 1 g/kg/day and a
limit on caffeinated drinks/foods should also be given (no more than 2 coffee equivalents 
per day).  A history of alcohol and smoking intake will be collected at screening.  
Alcohol and tobacco consumption should be avoided or minimized as much as possible.
Additionally, fluid intake is generally encouraged in subjects with PKD.  Given the 
potential for dehydration with tolvaptan treatment, all subjects should be instructed to 
ingest fluids in anticipation of, or at the first sign of thirst in order to avoid excessive 
thirst or dehydration.  Upon consent, all subjects should receive the recommendation to 
ingest at least 2 to 3 liters of fluid (including in solid, semi-solid, and liquid foods) per 
day, unless otherwise directed by their trial doctor.  This recommendation should start 
during screening and continue through the end of the trial.  Additionally, subjects should 
ingest 1 to 2 cups of water before bedtime regardless of perceived thirst, and replenish
fluids overnight with each episode of nocturia.  Dehydration will be monitored by subject 
self-assessment of changes in body weight and reporting of symptoms.  Acute changes of 
> 3% of body weight (increase or decrease) over any 7-day period should be noted.  
Subjects should be instructed to report acute changes in body weight to the trial physician 
for further evaluation and recommendations.
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Subjects should be advised that the ingestion of pomelo, grapefruit, or Seville orange 
products would be expected to increase tolvaptan concentrations and these should be 
avoided.  In the event of an unintentional ingestion of such products, the investigator may 
ask the subject to temporarily interrupt the IMP. 
5
Reporting of Adverse Events
The following describes the methods and timing for assessing, recording, and analyzing 
safety parameters, as well as the procedures for eliciting reports of and recording and 
reporting AEs and intercurrent illnesses and the type and duration of the follow-up of 
subjects after AEs.
Medical follow up is expected for AEs which lead to discontinuation which are serious, 
or which are of special interest (eg, liver abnormalities, skin neoplasms, glaucoma).
ADPKD is a progressive disorder involving the kidney, liver and occasionally other 
organ systems.  A number of AEs may be associated with this disorder including urine 
concentration defects, hypertension, renal pain, renal infection, nephrolithiasis, 
hematuria, and ESRD.  As such, these events are considered “expected” in this trial 
population and will not qualify for the purposes of regulatory expedited reporting (eg, 
Suspected Unexpected Serious Adverse Reaction and investigational new drug [IND] 
safety reports).
5.1
Definitions
An AE is defined as any untoward medical occurrence associated with the use of an IMP
in humans, whether or not considered IMP related.
A suspected adverse reaction means any AE for which there is a reasonable possibility 
that the IMP caused the AE. For the purpose of IND safety reporting, “reasonable 
possibility” means there is evidence to suggest a causal relationship between the IMP and 
the AE. Suspected adverse reaction implies a lesser degree of certainty about causality.
A serious adverse event (SAE) includes any event that results in any of the following 
outcomes:
1. Death
2. Life-threatening, ie, the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred.  It does not include an 
event that, had it occurred in a more severe form, might have caused death.
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3. Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions.
4. Requires inpatient hospitalization or prolongs hospitalization
NOTE: A pre-scheduled hospitalization is not considered an SAE.
5. Congenital anomaly/birth defect
6. Other medically significant events that, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above, eg, allergic 
bronchospasm requiring intensive treatment in an emergency room or home, 
blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse.
Nonserious AEs are all AEs that do not meet the criteria for a "serious" AE.
Immediately Reportable Event (IRE):

Any SAE

Any AE (whether serious or nonserious) that necessitates discontinuation of IMP.

Any subject with a new liver test abnormality meeting the AE (whether serious or 
nonserious) or laboratory threshold criteria (whether considered an AE or not) for 
hepatic eCRF reporting.

Any subject reporting an AE of special interest (eg, skin neoplasms or glaucoma).

Pregnancies are also defined as IREs.  Although normal pregnancy is not an AE, 
it will mandate IMP discontinuation and must be reported on an IRE form to 
Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC).  
Pregnancy will only be documented on the AE eCRF if there is an abnormality or 
complication.

Additionally, in the EU region, events involving overdose, misuse and abuse as 
well as reported lack of efficacy must also be reported as IREs.
Clinical Laboratory Changes:  It is the investigator’s responsibility to review the results 
of all laboratory tests as they become available.  This review will be documented by the 
investigator’s dated signature on the laboratory report.  For each abnormal laboratory test 
result, the investigator needs to ascertain if this is an abnormal (ie, clinically significant) 
change from baseline for that individual subject. This determination, however, does not 
necessarily need to be made the first time an abnormal value is observed.  The 
investigator may repeat the laboratory test or request additional tests to verify the results 
of the original laboratory tests.  If this laboratory value is determined by the investigator 
to be an abnormal change from baseline for that subject, this is considered an AE.
Severity:  Adverse events will be graded on a 3-point scale and reported as indicated on 
the CRF.  The intensity of an adverse experience is defined as follows:
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1 = Mild:
Discomfort noticed, but no disruption to daily activity.
2 = Moderate:
Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe:
Inability to work or perform normal daily activity.
IMP Causality: Assessment of causal relationship of an AE to the use of the IMP:
Related: 
There is a reasonable probability or possibility of a temporal and 
causal relationship between the IMP and the AE.
Not Related: 
There is no temporal or causal relationship to the IMP 
administration.
5.2
Eliciting and Reporting Adverse Events
The investigator will periodically assess subjects for the occurrence of AEs.  In order to 
avoid bias in eliciting AEs, subjects should be asked the following non-leading question: 
“How have you felt since your last visit?”  All AEs (serious and nonserious) reported by 
the subject must be recorded on the source documents and eCRFs provided by the 
sponsor.
In addition, Quintiles (drug safety service) must be notified immediately by telephone or 
fax of any immediately reportable events according to the procedure outlined below in
Section 5.3.  Special attention should be paid to recording hospitalization and 
concomitant medications.
5.3
Immediately Reportable Events
The investigator must immediately report within 24 hours after either the investigator or 
site personnel become aware of any SAE, new liver laboratory abnormality requiring 
special liver eCRF completion, or confirmed pregnancy, by telephone or by fax to 
Quintiles (drug safety service) as outlined in Appendix 1.  An IRE form must be 
completed and sent by fax, email or overnight courier to the sponsor.  (Please note that 
the IRE form is NOT the AE eCRF).
Nonserious events that require discontinuation of IMP (including laboratory 
abnormalities) should be reported to the sponsor within 3 working days.  The IRE form 
must be completed and sent by fax, email, or overnight courier to the sponsor.
Subjects experiencing SAEs should be followed clinically until their health has returned 
to baseline status, or until all parameters have returned to normal, or have otherwise been 
explained.  It is expected that the investigator will provide or arrange appropriate 
supportive care for the subject.
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5.4
Pregnancy
Women of childbearing potential who are sexually active must use an effective method of 
birth control during the course of the trial and for 30 days after the last dose of IMP in a 
manner such that risk of failure is minimized.  Unless the subject is sterile (ie, women 
who have had an bilateral oophorectomy and/or hysterectomy or have been 
postmenopausal for at least 12 consecutive months or remains abstinent, 2 of the 
following precautions must be used: vasectomy, tubal ligation, intrauterine device, birth 
control pills, birth control depot injection, birth control implant, condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicide.  Any single method of birth control, 
including vasectomy and tubal ligation, may fail, leading to pregnancy.
Before enrolling WOCBP in this clinical trial, investigators must review guidelines about 
trial participation for WOCBP.  The topics should generally include:

General information

ICF

Pregnancy prevention information

Drug interactions with hormonal contraceptives.

Contraceptives in current use.

Guidelines for the follow-up of a reported pregnancy.
Prior to trial enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy.  The subject must sign an ICF stating that the above-mentioned risk factors 
and the consequences were discussed with her.
During the trial, all WOCBP should be instructed to contact the investigator immediately 
if they suspect they might be pregnant (eg, missed or late menstrual cycle).
If a subject or investigator suspects that the subject may be pregnant prior to IMP 
administration, the IMP administration must be withheld until the results of serum 
pregnancy tests are available.  If the pregnancy is confirmed, the subject must not receive 
the IMP and must not be enrolled in the trial.  If pregnancy is suspected while the subject 
is taking IMP, the IMP must be withheld immediately (if reasonable, taking into 
consideration any potential withdrawal risks) until the result of the pregnancy is known.  
If pregnancy is confirmed, the IMP will be interrupted or withheld in an appropriate 
manner (eg, dose tapering if necessary for subject safety) and the subject will continue to 
be monitored for the duration of the remainder of the trial or of their pregnancy.
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The investigator must immediately notify the sponsor of any pregnancy associated with 
IMP exposure, during the trial and for 30 days after the last dose of IMP and record the 
event on the IRE form and forward it to the sponsor.  The sponsor will forward 
Pregnancy Surveillance Form(s) for monitoring the outcome of the pregnancy.
Protocol required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies).  Other appropriate 
pregnancy follow-up procedures should be considered if indicated.  In addition, the 
investigator must report to the sponsor, on appropriate Pregnancy Surveillance form(s), 
follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome.  Infants will be followed for a minimum of 6 months.
5.5
Follow-up of Adverse Events
For this trial, AEs will be followed up for 7 days after the last dose of tolvaptan has been 
administered (follow-up period).
Subjects experiencing SAEs should be followed clinically until their health has returned 
to baseline status, or until all parameters have returned to normal, or have otherwise been 
explained.
5.5.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified on the last scheduled contact must be recorded on the 
AE eCRF with the current status noted.  All nonserious events that are ongoing at this 
time will be recorded as ongoing on the eCRF.
5.5.2
Follow-up of Post-Trial Serious Adverse Events
Serious AEs that are identified on the last scheduled contact must be recorded on the 
AE eCRF page and reported to the sponsor according to the reporting procedures outlined 
in Section 5.3.  This may include unresolved previously reported SAEs, or new SAEs.  
The investigator will follow SAEs until the events are resolved, or the subject is lost to 
follow-up.  Resolution means the subject has returned to the baseline state of health, or 
the investigator does not expect any further improvement or worsening of the subject’s 
condition.  The investigator will continue to report any significant follow-up information 
to OPDC up to the point the event has been resolved.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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8.3
Accountability
The investigator or designee must maintain an inventory record of IMP received, 
dispensed, administered, and returned.
8.4
Returns and Destruction
Upon completion or termination of the trial, all unused and/or partially used IMP must be 
returned to the sponsor or a designated agent.
All IMP returned to the sponsor must be accompanied by appropriate documentation and 
be identified by protocol number with trial site number on the outermost shipping 
container.  Returned supplies should be in the original containers (eg, subject kits).  The 
assigned trial monitor will facilitate the return of unused and/or partially used IMP.
9
Records Management
9.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation.  Source documents will include but are not limited to progress 
notes, electronic data, screening logs, and recorded data from automated instruments.  All 
source documents pertaining to this trial will be maintained by the investigators. 
Investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, 
and regulatory inspection(s) by providing direct access to source data/documents by
authorized persons as defined in the ICF.
9.2
Data Collection
During each subject’s visit to the clinic, a clinician participating in the trial will record 
progress notes to document all significant observations.  At a minimum, these notes will 
contain:

Documentation of the informed consent process, including any revised consents;

The date of the visit and the corresponding visit or Day in the trial schedule;

General subject status remarks, including any significant medical findings.  The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator's assessment of relationship to IMP must also be recorded;

Any changes in concomitant medications or dosages;

A general reference to the procedures completed; 

The signature (or initials) and date of each clinician (or designee) who made an entry 
in the progress notes.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above.  Any changes to information in the trial progress notes and other source 
documents will be initialed and dated on the day the change is made by a site staff 
member authorized to make the change.  Changes will be made by striking a single line 
through erroneous data (so as not to obliterate the original data), and clearly entering the 
correct data (eg, wrong data right data).  If the reason for the change is not apparent, a 
brief explanation for the change will be written in the source documentation by the 
clinician.
Information from the trial progress notes and other source documents will be entered by 
investigative site personnel directly onto eCRFs in the sponsor’s electronic data capture
system. Changes to the data will be captured by an automatic audit trail.
9.3
File Management at the Trial Site
The investigator will ensure that the trial site file is maintained in accordance with 
Section 8 of the ICH GCP Guideline and as required by applicable local regulations. The 
investigator/institution will take measures to prevent accidental or premature destruction 
of these documents.
9.4
Records Retention at the Trial Site
Regulatory requirements for the archival of records for this trial necessitate that 
participating investigators maintain detailed clinical data for the longest of the following 
three periods:

A period of at least 2 years following the date on which approval to market the IMP is 
obtained (or if IMP development is discontinued, the date regulatory authorities were 
notified of discontinuation); OR

A period of at least 3 years after the sponsor notifies the investigator that the final 
report has been filed with regulatory authorities.

Longer, region-specific storage requirements, if applicable.The investigator must not 
dispose of any records relevant to this trial without either (1) written permission from the 
sponsor or (2) provision of an opportunity for sponsor to collect such records.  The 
investigator will be responsible to maintain adequate and accurate electronic or hard copy 
source documents of all observations and data generated during this trial.  Such 
documentation is subject to inspection by the sponsor and relevant regulatory authorities.  
If the investigator withdraws from the trial (eg due to relocation or retirement), all trial-
related records should be transferred to a mutually agreed-upon designee within a 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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60
06 March 2015
sponsor-specified timeframe.  Notice of such transfer will be given to the sponsor in 
writing.
10
Quality Control and Quality Assurance 
10.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial carefully in a 
detailed and orderly manner in accordance with established research principles, the ICH 
GCP Guideline, and applicable regulatory requirements and local laws.  As part of a 
concerted effort to fulfill these obligations (maintain current personal knowledge of the 
progress of the trial), the sponsor's monitors will visit the site during the trial, as well as 
communicate frequently via telephone and written communications.
10.2
Auditing
The sponsor's Quality Management Unit (or representative) may conduct trial site audits.  
Audits will include but are not limited to IMP supply, presence of required documents, 
the informed consent process, and comparison of eCRFs with source documents.  The 
investigator agrees to participate with audits.
Regulatory authorities may inspect the investigator site during or after the trial.  The 
investigator will cooperate with such inspections and will contact the sponsor 
immediately if such an inspection occurs.
11
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, the ICH GCP Guideline, 
and applicable local laws and regulatory requirements. Each trial site will seek approval 
by an IRB or IEC according to regional requirements. The IRB/IEC will evaluate the 
ethical, scientific and medical appropriateness of the trial. Further, in preparing and 
handling CRFs, the investigator, sub-investigator and their staff will take measures to 
ensure adequate care in protecting subject privacy. To this end, a subject number and 
subject ID code will be used to identify each subject. 
Financial aspects, subject insurance and the publication policy for the trial will be 
documented in the agreement between the sponsor and the investigator.
12
Confidentiality
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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written permission.  Subject confidentiality requirements of the region(s) where the trial 
is conducted will be met.  However, authorized regulatory officials and sponsor personnel 
(or their representatives) will be allowed full access to inspect and copy the records.  All 
IMPs, subject bodily fluids, and/or other materials collected shall be used solely in 
accordance with this protocol, unless otherwise agreed to in writing by the sponsor.
Subjects will be identified only by initials and unique subject numbers in eCRFs.  Their 
full names may, however, be made known to a regulatory agency or other authorized 
officials if necessary.
13
Amendment Policy
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval by the IRB/IEC.  Any permanent change to the 
protocol, whether it be an overall change or a change for specific trial site(s), must be 
handled as a protocol amendment.  Any amendment will be written by the sponsor.  Each 
amendment will be submitted to the IRB/IEC.  Except for “administrative” or “non-
substantial” amendments, investigators will wait for IRB/IEC approval of the amended 
protocol before implementing the change(s).  Administrative amendments are defined as 
having no effect on the safety of subjects, conduct or management of the trial, trial 
design, or the quality or safety of IMP(s) used in the trial.  A protocol change intended to 
eliminate an apparent immediate hazard to subjects should be implemented immediately, 
followed by IRB/IEC notification within 5 working days.  The sponsor will submit 
protocol amendments to the applicable regulatory agencies.
When the IRB/IEC, investigators, and/or the sponsor conclude that the protocol 
amendment substantially alters the trial design and/or increases the potential risk to the 
subject, the currently approved written ICF will require similar modification.  In such 
cases, repeat informed consent will be obtained from subjects enrolled in the trial before 
expecting continued participation.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
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62
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14
References
1
European Medicines Agency, Public summary of opinion on orphan designation: 
Tolvaptan for the treatment of autosomal dominant polycystic kidney disease. 
Committee for Orphan Medicinal Products. 2013; EMA/COMP/444684/2013.
2
U S Renal Data System, USRDS 2012 Annual Data Report: Atlas of Chronic Kidney 
Disease and End-Stage Renal Disease in the United States, National Institutes of 
Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, 
MD, 2012
3
Lentine KL, Xiao H, Machnicki G, Gheorghian A, Schnitzler MA. Renal function 
and healthcare costs in patients with polycystic kidney disease. Clin J Am Soc 
Nephrol. 2010 Aug;5(8):1471-9.
4
OPC-41061 Investigator’s Brochure. Rockville (MD): Otsuka Pharmaceutical 
Development & Commercialization, Inc.; Edition 19 Otsuka Report, issued 11 July 
2013.
5
OPC-41061 Common Technical Document.  Rockville (MD): Otsuka Pharmaceutical 
Development & Commercialization, Inc.; Section 2.5: Clinical Overview; 2013.
6
Wang X, Gattone V 2nd, Harris PC, Torres VE. Effectiveness of vasopressin V2 
receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease 
development in the PCK rat. J Am Soc Nephrol. 2005 Apr;16(4):846-51. 
7
Reif GA, Yamaguchi T, Nivens E, Fujiki H, Pinto CS, Wallace DP. Tolvaptan 
inhibits ERK-dependent cell proliferation, Cl- secretion, and in vitro cyst growth of 
human ADPKD cells stimulated by vasopressin. Amer J Physiol Renal Physiol. 2011 
Nov;301(5):F1005-13.
8
Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, 
et al for the TEMPO 3:4 Trial Investigators.  Tolvaptan in patients with autosomal 
dominant polycystic kidney disease. N Engl J Med 2012;367:2407-18.
9
Higashihara E, Torres VE, Chapman AB, Grantham JJ, Bae K, Watnick TJ, et al. 
Tolvaptan in autosomal dominant polycystic kidney disease: three years' experience. 
Clin J Am Soc Nephrol. 2011 Oct;6(10):2499-507.
10 U.S. Food and Drug Administration. Guidance for Industry. Drug-induced liver 
injury: premarketing clinical evaluation [report on the internet]. 2009 Jul [cited 2012 
Oct 10];[about 23 p.].  Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceCompliance
RegulatoryInformation/Guidances/UCM174090.pdf.
11 Pei Y, Obaji J, Dupuis A, et al. Unified criteria for ultrasonographic diagnosis of 
ADPKD. J Am Soc Nephrol 2010 20: 205-212.
12 Ravine D, Gibson RN, Walker RG, et al. Evaluation of ultrasonographic diagnostic 
criteria for autosomal dominant polycystic kidney disease 1. Lancet 1994; 343:824-
827.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
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63

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Confidential - Otsuka Proprietary Information
63
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13 Levey AS, Stevens LA, et al. A new equation to estimate glomerular filtration rate.  
Ann Intern Med. 2009; 150:604-612.
14 International Conference on Harmonisation; Good Clinical Practice: Consolidated 
Guideline; Notice of Availability, 62 C.F.R. Sect. 90 (1997).
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
64

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Protocol 156-13-211
Confidential - Otsuka Proprietary Information
71
06 March 2015
Location
Old Text
Updated Text
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 off-treatment),or
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 a split-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.

Completed and 
transferred from the 
double-blind 
Trial 156-13-210 
(12-month period 
including post-treatment 
follow-up, regardless of 
whether this was on-
treatment or off-
treatment), or 

Completed 
Trial 156-08-271 or a 
prior tolvaptan ADPKD 
trial, or

Interrupted or 
discontinued treatment in 
a prior tolvaptan ADPKD 
trial (other than 
Trial 156-13-210).  
Subjects may be enrolled 
with the medical monitor 
approval, and additional 
close monitoring may be 
required at the beginning 
of the trial
For purposes of ensuring subject 
safety, all subjects will be 
monitored for hepatic safety 
monthly until 18 months of 
tolvaptan exposure has been 
collected..  After that, and 
following the approval from the 
medical monitor, hepatic 
monitoring will be required 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.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
72

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
72
06 March 2015
Location
Old Text
Updated Text
Enrollment in this trial will be 
closed when the final eligible 
subject from Trial 156-13-210 
enrolls in this trial.
Synopsis, Subject 
Population
This trial will include up to 2,450 
subjects over the age of 18 years with  
ADPKD diagnosed by Pei-Ravine 
criteria (modified by magnetic 
resonance imaging [MRI]).
Renal function will be assessed 
during screening by using historical 
laboratory values for serum creatinine 
levels to calculate the estimated 
glomerular filtration rate (eGFR).  
The eGFR values will be estimated 
based on the Chronic Kidney Disease 
- Epidemiology (CKD-EPI) formula.
This trial will include 
approximately 2,500 subjects over 
the age of 18 years with ADPKD 
diagnosed by Pei-Ravine criteria 
(modified by magnetic resonance 
imaging [MRI]), and who have 
completed or participated in a 
prior tolvaptan ADPKD 
interventional investigational 
medicinal product (IMP) trial.
Synopsis, 
Inclusion/Exclusion 
Criteria
Main inclusion criteria:
Male and female subjects 
18 years with ADPKD who have 
completed either Trial 156-13-210 or 
Trial 156-08-271
Diagnosis of ADPKD by modified 
Pei-Ravine criteria
eGFR 20 mL/min/1.73m2 within 
45 days of the baseline visit. Subjects 
who have an eGFR between 15 and 
19 mL/min/1.73m2 may be enrolled 
with medical monitor approval
Main exclusion criteria:

Need for chronic diuretic use

Hepatic impairment based on 
liver function assessments other 
than that expected for ADPKD 
with cystic liver disease
Main inclusion criteria:

Male and female subjects 
18 years with confirmed 
diagnosis of ADPKD (during 
participation in prior 
tolvaptan trials) who have 

Completed and 
transferred from the 
double-blind 
Trial 156-13-210 
(12-month period
including post-treatment 
follow-up, regardless of 
whether this was on-
treatment or off-
treatment), or 

Completed 
Trial 156-08-271 or a 
prior ADPKD tolvaptan 
trial, or

Interrupted or 
discontinued treatment in 
a prior tolvaptan ADPKD 
trial other than 
Trial 156-13-210.  
Subjects may be enrolled 
with the medical monitor 
approval, and additional 
close monitoring may be 
required at the beginning 
of the trial
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
73

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
73
06 March 2015
Location
Old Text
Updated Text

Estimated glomerular 
filtration rate
(eGFR) 20 mL/min/1.73m2 
within 45 days of the baseline 
visit.  Subjects who have an 
eGFR between 15 and 
19 mL/min/1.73m2 may be 
enrolled with medical monitor 
approval

Renal function will be assessed 
during screening by using 
historical laboratory values (in 
the last 30 days) for serum 
creatinine levels to calculate 
the eGFR.  the eGFR values 
will be estimated based on the 
Chronic Kidney Disease -
Epidemiology (CKD-EPI) 
formula
Main exclusion criteria:

Need for chronic diuretic use

Hepatic impairment based on 
hepatic laboratory assessments
(alanine aminotransferase 
[ALT], aspartate 
aminotransferase [AST], 
bilirubin, total [BT]) other than 
that expected for ADPKD with 
cystic liver disease
Synopsis, Trial Site(s)
Up to 220 sites which may include 
North America, South America, 
Russian Federation and Australia.  
Approximately 220 enrolling sites 
including but not limited to the 
following regions: North America, 
South America, Eastern Europe, 
Western Europe, Russian 
Federation, and Australia.  
Synopsis, 
Investigational 
Medicinal Product(s), 
Dose, Dosage regimen, 
Treatment period, 
Formulation, Mode of 
Administration
Tolvaptan tablets (15 mg or 30 mg) 
will be self-administered orally as 
split-dose regimens, once upon 
awakening and another approximately 
8 to 9 hours later. Doses will be 
expressed as early dose/late dose (eg, 
60/30 mg). Allowed doses are 
15/15 mg, 30/15 mg, 45/15 mg, 
60/30 mg and 90/30 mg.
All subjects will be started at a split-
dose of tolvaptan 45/15 mg and 
titrated according to tolerability. The 
dose range permitted will be a 
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).  
Subjects will receive open-label 
tolvaptan for the duration of the 
trial.  
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
74

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CCI

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
75
06 March 2015
Location
Old Text
Updated Text
Synopsis, Criteria for 
Evaluation
Safety:

AEs

Vital signs

Clinical laboratory 
assessments

Serum transaminase 
elevations for frequency (2x, 
3x, 5x and 10x upper limit 
normal [ULN]), time to 
onset, time to peak levels, 
time of offset (< 3x, 2x, or 
1x ULN), response to de-
challenge and re-challenge 
and frequency of progression 
to Hy’s laboratory criteria 
(alanine aminotransferase 
(ALT) or aspartate 
aminotransferase (AST) > 3x 
ULN and bilirubin, total 
(BT) > 2x ULN without 
alkaline phosphatase 
2x ULN)

Serum sodium excursions 
above 145, 150 or 
155 mmol/L or below 135, 
130 or 125 mmol/L

Interruptions of protocol 
specified therapies for 
hypernatremia or 
hyponatremia
Safety:

AEs

Vital signs

Clinical laboratory 
assessments

Serum transaminase 
elevations for frequency 
(2x, 3x, 5x and 10x ULN), 
time to onset, time to peak 
levels, time of offset (< 3x, 
2x, or 1x ULN), response to 
de-challenge and 
re-challenge and frequency 
of progression to Hy’s 
laboratory criteria (ALT or 
AST > 3x ULN and BT 
> 2x ULN without alkaline 
phosphatase 2x ULN)

Serum sodium excursions 
above 145, 150, or 
155 mmol/L or below 135, 
130, or 125 mmol/L
Synopsis, Statistical 
Methods
Sample size:  Sample size was not 
determined by a formal computation 
to achieve a target power.  No 
efficacy analyses are planned.  It is 
expected that approximately 2,450 
subjects may enroll from previous 
tolvaptan trials.
Sample size:  Sample size was not 
determined by a formal computation 
to achieve a target power.  No 
efficacy analyses are planned.  It is 
expected that approximately 2,500
subjects may enroll from previous 
tolvaptan trials.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
76

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Protocol 156-13-211
Confidential - Otsuka Proprietary Information
77
06 March 2015
Location
Old Text
Updated Text
.
Section 1.3, Known and 
Potential Risks and 
Benefits
In this extension trial, subjects 
enrolling from the double-blind 
Trial 156-13-210 will have monthly 
transaminase level assessments for 
the first 18 months while the 
treatment code from Trial 156-10-210 
remains blinded, to ensure that all 
subjects have adequate safety 
monitoring during this period of 
susceptibility. Monitoring will be 
quarterly for these subjects following 
the first 18 months of known 
exposure to tolvaptan. Subjects 
enrolling from the open-label Trial 
156-08-271 will have quarterly 
transaminase assessments conducted, 
since they will have already received 
tolvaptan for 2 years or more.
In this extension trial, subjects 
enrolling from the double-blind 
Trial 156-13-210 will have monthly 
visits and transaminase level 
assessments for the first 18 months 
while the treatment code from 
Trial 156-10-210 remains blinded, to 
ensure that all subjects have 
adequate safety monitoring during 
this period of susceptibility.  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 changed
to every 3 months sooner as their 
previous tolvaptan exposure in 
Trial 156-13-210 can count 
towards the 18-month threshold.  
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.  Subjects 
enrolling from the open-label Trial 
156-08-271 will have transaminase 
assessments conducted every 
3 months, since they will have 
already received tolvaptan for at 
least 18 months.    The current IB 
lists all of the tolvaptan trials.  
Subjects enrolling in this trial who 
were in a previous ADPKD trial 
other than Trials 156-13-210 and 
156-08-271 will have monthly 
visits and transaminase level 
assessments for the first 18 
months.
Section 2.1, Trial 
Rationale
...
Over the 3 years of placebo-
controlled treatment, ALT was 
elevated to a greater than three times 
the upper limit of normal (> 3 × 
ULN) in 4.4% of tolvaptan subjects 
compared with 1% of placebo 
subjects.  To date, 3 tolvaptan 
…
Over the 3 years of placebo-
controlled treatment, ALT was 
elevated to a greater than three times 
the upper limit of normal (> 3 × 
ULN) in 4.4% of tolvaptan subjects 
compared with 1% of placebo 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
78

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
78
06 March 2015
Location
Old Text
Updated Text
subjects’ transaminases and bilirubin 
levels reached Hy’s laboratory 
criteria (> 3 × and > 2 × ULN, 
respectively).  Upon discontinuation, 
all subjects’ liver tests showed 
reversibility of the elevation within 
approximately 4 months after 
tolvaptan was discontinued.  
Nevertheless, without adequate 
monitoring and management, it is 
estimated that a 1:3,000 risk for 
irreversible liver injury may exist
subjects.  To date, 3 tolvaptan 
subjects’ transaminases and bilirubin 
levels reached Hy’s laboratory 
criteria (> 3 × and > 2 × ULN, 
respectively).  Upon discontinuation, 
all subjects’ liver tests showed 
reversibility of the elevation within 
approximately 4 months after 
tolvaptan was discontinued.  
Nevertheless, without adequate 
monitoring and management, it is 
estimated that a 1:4,000 risk for 
irreversible liver injury may exist
Section 3.1, 
Type/Design of Trial
This trial is a phase 3b, multi-center, 
open-label trial.
Subjects will be eligible for screening 
into this trial if they:
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 off-treatment), or
Participated in the open-label 
Trial 156-08-271
Upon the successful completion of 
Trial 156-13-210 or Trial 156-08-
271, subjects will have an opportunity 
to enroll into Trial 156-13-211 
immediately following completion of 
the follow-up visit(s) of the previous 
trial. The last follow-up visit 
assessments can be utilized for 
screening into this trial. However, for 
subjects who require a longer period 
between completion of the preceding 
trial and entry into this trial, this may 
be allowed at the discretion of the 
medical monitor.
After consenting and screening, 
eligible subjects will be assigned a 
new subject number and administered 
tolvaptan at a split-dose of 45/15 mg. 
Subjects will have the opportunity for 
This trial is a phase 3b, multi-center, 
open-label trial.
Eligible subjects will have an 
opportunity to enroll into 
Trial 156-13-211 immediately 
following completion of the 
follow-up visit(s) of the previous 
trial.  The last visit assessments 
from the previous protocol can be 
combined with the screening visit 
for this trial, with all required 
assessments from each visit only 
performed once, as long as the 
time between the last follow-up 
visit assessments from the 
previous trial and the screening 
visit for this trial is within 30 days.  
Medical monitor approval is 
needed for enrollment of subjects 
whose completion of the preceding 
trial prior to entry in this trial 
exceeds 3 months, and these 
subjects will be required to 
undergo all screening and baseline 
assessments.
After consenting, subjects will be 
assigned a new screening number.  
Subjects who are found to be 
eligible will retain the same 
subject number they had been 
assigned in their previous trial..  
For purposes of ensuring subject 
safety, tolvaptan exposure of at 
least 18 months is required for all 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
79

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CCI

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
80
06 March 2015
Location
Old Text
Updated Text
Trial 156-13-210 subjects 
may opt to conclude their 
participation in this trial 
if tolvaptan becomes 
available before they 
complete 18 months of 
treatment in this trial 
Section 3.1.1, Figure 
3.1-1
See previous Figure at the end of 
Appendix 5.
See previous Figure at the end of 
Appendix 5
Section 3.2 Treatments 
Following consent, and once subjects 
have satisfied all of the inclusion 
criteria and none of the exclusion 
criteria, subjects will be assigned a 
new subject number and administered 
tolvaptan at a split-dose of 45/15 mg.  
Subjects will be titrated up to 
60/30 mg and 90/30 mg according to 
subject tolerability.  Down titration to 
30/15 mg and 15/15 mg is also 
permitted at the discretion of the 
medical monitor and individual 
subject tolerability.
All subjects will be administered 
tolvaptan tablets in a daily split-dose, 
once upon awakening and another 
approximately 8 to 9 hours later. The 
exact time of dosing may be adjusted 
based on wake/sleep habits (eg, 
standard 8 AM and 5 PM may be 
switched to 10 PM and 7 AM if 
working a night shift). However, 
dosing times should be consistent for 
each individual’s daily dose to 
maximize receptor suppression. 
Doses will be expressed as early 
dose/late dose (eg, 60/30 mg).
While taking tolvaptan, all subjects 
should be instructed to ingest fluids in 
anticipation of, or at the first sign of 
thirst in order to avoid excessive 
thirst or dehydration.  Additionally, 
subjects should ingest 1 to 2 cups of 
water before bedtime regardless of 
perceived thirst and replenish fluids 
overnight with each episode of 
nocturia.
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.
Following consent, and once 
subjects have satisfied all of the 
inclusion criteria and none of the 
exclusion criteria, subjects will 
retain their subject number 
assigned from their previous trial.  
Subjects will receive open-label 
tolvaptan for the duration of the 
trial. All subjects will be 
administered tolvaptan tablets in a 
daily split-dose, once upon 
awakening and another 
approximately 8 to 9 hours later 
(twice daily dosing).  The exact time 
of dosing may be adjusted based on 
wake/sleep habits (eg, standard 8 
AM and 5 PM may be switched to 
10 PM and 7 AM if working a night 
shift).  However, dosing times 
should be consistent for each 
individual’s daily dose to maximize 
receptor suppression.  Doses will be 
recorded as early dose/late dose (eg, 
60/30 mg). 
A subject’s starting dose in this 
trial will be dependent on the trial 
in which they were previously 
enrolled:

156-13-210- initiated on 
tolvaptan at a split-dose of 
45/15 mg with upward 
titration every 3 to 4 days to 
60/30 mg or 90/30 mg per day 
according to tolerability

156-08-271- will retain the last 
dose level from 271 and start 
at the same dose in this trial 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
81

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
81
06 March 2015
Location
Old Text
Updated Text

Prior tolvaptan trials-
initiated on tolvaptan at a
split-dose of 45/15 mg with 
upward titration every 3 to 
4 days to 60/30 mg or 90/30 
mg per day according to 
tolerability
Down titration to 30/15 mg and 
15/15 mg is also permitted at the 
discretion of the investigator 
according to subject tolerability 
with medical monitor notification.  
Further down titration to 30 or 
15 mg once daily may be allowed 
only for metabolic drug-drug 
interaction and requires medical 
monitor approval.
For subjects moving from the 
156-13-210 trial and requiring 
tolvaptan titration itwill be
conducted in the following way: 
Subjects will be instructed to take 
tolvaptan starting at a split dose of 
45/15 mg (as 3 tablets upon 
waking and 1 tablet approximately 
8 to 9 hours later) and to titrate up 
every 3 to 4 days; first to 60/30 mg, 
then up to the maximum dose of 
90/30 mg.  Titration will be 
accomplished by increasing the 
number of tablets/dose and/or 
switching from 15 mg tablets to 
30 mg tablets.  Prior to each 
upward titration, the subject’s 
tolerability to the current dose will 
be assessed by asking, “Could you 
tolerate this dose of trial 
medication for the rest of your 
life?” Subjects will continue in the 
trial with the regimen to which 
tolerability was established.
While taking tolvaptan, all subjects 
should be instructed to ingest fluids 
in anticipation of, or at the first sign 
of thirst in order to avoid excessive 
thirst or dehydration.  Additionally, 
subjects should ingest 1 to 2 cups of 
water before bedtime regardless of 
perceived thirst and replenish fluids 
overnight with each episode of 
nocturia.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
82

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Protocol 156-13-211
Confidential - Otsuka Proprietary Information
84
06 March 2015
Location
Old Text
Updated Text
identification [ID], subject 
ID, site ID)
4.
Record medical/ADPKD 
history using prior trial data
5.
Review dietary 
recommendations and 
compliance
6.
Record vital signs (post-void 
weight and seated heart rate) 
and in-clinic calibrated 
blood pressure (BP) 
measurement.  Record 
height
7.
Collect blood for serum 
chemistry, liver function 
panel (ALT, AST, bilirubin, 
total (BT), bilirubin (direct), 
and alkaline phosphatase), 
serum sodium, creatinine 
and hematology and 
coagulation.  Hepatitis 
testing is optional
8.
Collect urine for urinalysis, 
urine osmolality (optional), 
and urine specific gravity
9.
Perform urine pregnancy test 
on women of childbearing 
potential (WOCBP).  If 
positive, a follow-up serum 
test will be performed
10. Conduct full physical 
examination
11. Enter subject into interactive 
response technology (IRT) 
including prior trial 
identifier/information 
(protocol number, subject 
ID), confirmed dose regimen 
and scheduled date of next 
visit
12. Assess AEs reported as 
ongoing or resolved from 
inclusion/exclusion criteria.
3.
Record demographic 
information and prior trial 
identifiers (screening 
identification [ID], subject 
ID, site ID), prior 
tolvaptan ADPKD trial 
protocol number).
4.
Record medical/ADPKD 
history using prior trial 
data.
5.
Review dietary 
recommendations and
compliance.
6.
Record vital signs (post-
void weight and seated 
heart rate) and in-clinic 
calibrated blood pressure 
(BP) measurement.  Record 
height.
7.
Collect blood for serum 
chemistry, liver function 
panel (ALT, AST, bilirubin, 
total [BT], bilirubin 
[direct], and alkaline 
phosphatase), serum 
sodium, creatinine, and 
hematology and 
coagulation.  Hepatitis 
testing is optional.  If 
hepatitis testing is 
performed, then both pre-
and post-counseling 
activities relating to 
hepatitis testing are to be 
carried out based on local 
requirements and best 
practices.  
8.
Collect urine for urinalysis, 
urine osmolality (optional), 
and urine specific gravity.
9.
Perform urine pregnancy 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
85

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Protocol 156-13-211
Confidential - Otsuka Proprietary Information
95
06 March 2015
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Updated Text
optional for all subjects.  Urine 
pregnancy testing will be performed 
with commercially available, high-
sensitivity kits supplied to the 
subject by the site (acquired by the 
sponsor).
Table 3.7.2.2-, Clinical 
Laboratory 
Assessments
Please see original table at the end of 
Appendix 5,
Please see revised table at the end of 
Appendix 5,
Section 3.7.2.3, 
Physical Examination 
and Vital Signs (old 
text, Section 3.6.2.3)
A full physical examination will be 
performed and documented at the 
screening visit although this may be 
combined with the EoTx visit from 
the previous trial.  At other visits, an 
optional directed physical 
examination may be performed to 
focus on ADPKD- related signs and 
symptoms.  In some geographic 
regions, more frequent subject visits 
may be the norm; however vital signs 
and clinically significant physical 
findings will be recorded as an 
unscheduled visit in the electronic 
case report form (eCRF) as 
applicable.  Any changes in 
medication or AEs will be recorded in 
the eCRF.
Body weight will be taken post-void.  
It is preferable to use the same scale 
for each measurement.  Clinic scales 
should be calibrated at least yearly.  
The investigator or his/her appointed 
designee is primarily responsible to 
perform the physical examination.  ...
A full physical examination will be 
performed and documented at the 
screening visit although this may be 
combined with the last visit from the 
previous trial.  At other visits, an 
optional directed physical 
examination may be performed to 
focus on ADPKD- related signs and 
symptoms.  In some geographic 
regions, more frequent subject visits 
may be the norm; however vital 
signs and clinically significant 
physical findings will be recorded as 
an unscheduled visit in the electronic 
case report form (eCRF) as 
applicable.  Any changes in 
medication or AEs will be recorded 
in the eCRF.
Height will be measured only at 
screening.  Body weight will be 
taken post-void.  It is preferable to 
use the same scale for each 
measurement.  Clinic scales should 
be calibrated at least yearly.  The 
investigator or his/her appointed 
designee is primarily responsible to 
perform the physical examination.  
...
Section 3.7.2.4, 
Assessment of Liver 
Symptoms, Signs or 
Test Abnormalities (old 
text, Section 3.6.2.4)
Testing for hepatic transaminase 
(ALT/AST), alkaline phosphatase, 
bilirubin direct, and BT will be 
performed during screening.  Subjects 
enrolling from the double-blind Trial 
156-13-210 will have monthly ALT 
assessments for the first 18 months 
while the treatment code from Trial 
156-13-210 remains blinded to ensure 
that all subjects have adequate safety 
monitoring during this period of 
susceptibility.  Following the first 
18 months, ALT assessments will be 
made quarterly for these subjects.  
Subjects enrolling from the open-
Testing for hepatic transaminase 
(ALT/AST), alkaline phosphatase, 
bilirubin direct, and BT will be 
performed during screening.  
Subjects enrolling from the double-
blind Trial 156-13-210 will have 
monthly ALT assessments for the 
first 18 months while the treatment 
code from Trial 156-13-210 remains 
blinded to ensure that all subjects 
have adequate safety monitoring 
during this period of susceptibility.  
Once unblinding occurs, it can be 
determined which subjects 
received tolvaptan in Trial 156-13-
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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96

Protocol 156-13-211
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96
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Updated Text
label Trial 156-08-271 will have 
quarterly ALT assessments since they 
will have already received tolvaptan 
for 2 years or more.  Management of 
liver abnormalities is discussed in the 
paragraphs below.
210.  These subjects may have 
their trial visits/hepatic 
transaminase monitoring changed
to every 3 months sooner as their 
previous tolvaptan exposure in 
Trial 156-13-210 can count 
towards the 18-month threshold.
Following the first 18 months, ALT 
assessments will be made every 
3 months for Trial 156-13-210 
subjects and for subjects from 
other tolvaptan ADPKD trials 
besides Trial 156-08-271 .  Subjects 
enrolling from the open-label Trial 
156-08-271 who have tolvaptan 
exposure greater than 18 months 
will continue with ALT 
monitoring every 3 months.  
Subjects enrolling from prior 
tolvaptan trials besides 
Trial 156-08-271 will have 
monthly ALT assessments for the 
first 18 months.  Upon reaching 
18 months of exposure and after 
confirmation from the medical 
monitor, the frequency of ALT 
monitoring for these subjects will 
occur every 3 months.
ALT will also be assessed at the 
Early Termination/End of 
Treatment visit and at the 7-day
Follow-up visit.
Management of liver abnormalities 
is discussed in the paragraphs below.
Section 3.7.2.4.1, Liver 
Test Abnormalities and 
Interruption/
Discontinuation of 
Investigational 
Medicinal Product
(old text 
Section 3.6.2.4.1)
The appearance of any suspicious 
symptom or sign should trigger 
prompt testing of hepatic function (ie, 
within 72 hours).  Liver transaminase 
or bilirubin levels 2 × ULN should 
prompt immediate retesting within 
72 hours and tolvaptan should be 
temporarily interrupted.  Tolvaptan 
should not be resumed until 
monitoring indicates abnormalities 
have resolved, are stable or are not 
The appearance of any suspicious 
symptom or sign should trigger 
prompt testing of hepatic function 
(ie, within 72 hours).  Local 
laboratory testing is acceptable, 
ideally with a concurrent central 
laboratory sample for 
confirmation.
Any transaminase or bilirubin 
values which exceed 2 × ULN 
should also prompt immediate 
retesting within 72 hours.  While 
values remain in an abnormal 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
97

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Protocol 156-13-211
Confidential - Otsuka Proprietary Information
98
06 March 2015
Location
Old Text
Updated Text
Section 3.7.5, 
Treatment Interruption 
and Discontinuation
N/A
In this trial, it is expected that 
subjects may possibly have one or 
more planned or unplanned 
treatment interruptions.  If a 
subject’s IMP treatment must be 
interrupted for medical or surgical 
reasons, liver test abnormalities, use 
of a prohibited medication, or other 
reasons (eg, hospital admission for 
an invasive procedure, a major 
medical condition, surgery, dental 
work, or a temporary situation that 
prevents subject compliance with the 
IMP administration schedule), the 
investigator should be notified as 
soon as possible and the reason for 
treatment interruption must be 
documented in the source documents 
and CRF.  If permissible, the 
subject’s IMP may be resumed 
following approval by the medical 
monitor.
If IMP treatment is permanently 
discontinued, the reason for 
discontinuation must be recorded 
appropriately in the source document 
and in the CRF.
A subject who permanently 
discontinues IMP treatment may
have the option to end trial
participation (complete the early 
termination visit) or to continue 
participation off IMP and complete 
ongoing trial assessments as per 
protocol or with a modified (ie, less 
frequent) schedule as outlined in 
Section 3.8.3.
Section 3.8.1
3.7.1
Entire Trial or Treatment 
Arm(s)
3.8.1
Entire Trial
Section 3.8.3, 
Individual Subject
...  
All subjects have the right to 
withdraw at any time during 
treatment without prejudice.  The 
investigator can discontinue a 
subject’s participation in the trial at 
any time if medically necessary.  In 
addition, subjects meeting the 
following criteria must be withdrawn 
from the trial:
a) Occurrence of any AE, intercurrent 
...
All subjects have the right to 
withdraw at any time during 
treatment without prejudice.  The 
investigator can discontinue a 
subject’s participation in the trial at 
any time if medically necessary.  It 
is preferred that subjects who 
permanently discontinue IMP will 
have the option to continue 
participation off IMP with regular 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
99

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
99
06 March 2015
Location
Old Text
Updated Text
illness, or abnormality in a laboratory 
assessment which, in the opinion of 
the investigator, warrants the 
subject’s permanent withdrawal from 
the trial;
b) Treatment with a prohibited 
concomitant medication other than 
the use of appropriate medications for 
the treatment of AEs under direction 
of the investigator;
c) Subject noncompliance, defined as 
refusal or inability to adhere to the 
trial schedule or procedures (see 
Section 3.12);
d) At the request of the subject, 
investigator, sponsor, or regulatory 
authority;
e) Subject becomes pregnant; or 
f) Subject is lost to follow-up.
The investigator will notify the 
sponsor promptly when a subject is 
withdrawn.
scheduled visits or with a modified 
(ie, less frequent) schedule.  If 
subjects are unable or unwilling to 
complete the visits and procedures 
off IMP, the early 
termination/EoTx visit should be 
completed.  The investigator may
continue to contact those who 
discontinue IMP through to the 
final completion date of the trial 
or thereafter if needed to 
determine outcomes ie, vital 
status.  
In addition, subjects meeting the 
following criteria must be withdrawn 
from the trial:
a) Occurrence of any AE, 
intercurrent illness, or abnormality in 
a laboratory assessment which, in 
the opinion of the investigator, 
warrants the subject’s permanent 
withdrawal from the trial;
b) Subject noncompliance, defined 
as refusal or inability to adhere to the 
trial schedule or procedures (see 
Section 3.11);
c) At the request of the subject, 
investigator, sponsor, or regulatory 
authority;
d) Subject is lost to follow-up.
The investigator will notify the 
sponsor promptly when a subject is 
withdrawn.
Section 3.12, Subject 
Compliance
Subject compliance will be monitored 
by pill counts as IMP is returned.  
Any subject who, without the 
instruction of the investigator, 
discontinues tolvaptan investigational 
product without the instruction of the 
investigator, discontinues tolvaptan 
for 30 consecutive days or misses > 
30% of the doses intended for a 
period between visits (whichever is 
greater) will be deemed 
noncompliant.  ...
Subject compliance will be 
monitored by pill counts as IMP is 
returned.  Any subject who, without 
the instruction of the investigator, 
discontinues tolvaptan 
investigational product, discontinues 
tolvaptan for 30 consecutive days or 
misses > 30% of the doses intended 
for a period between visits 
(whichever is greater) will be 
deemed noncompliant.  ...
Section 3.13, Protocol
Deviations
This trial is to be conducted as 
described in this protocol.  In the 
event of a significant deviation from 
the protocol due to an emergency, 
This trial is to be conducted as 
described in this protocol.  In the 
event of a significant deviation from 
the protocol due to an emergency, 
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Updated Text
accident or mistake, the investigator 
or designee must contact the sponsor 
at the earliest possible time.  This will 
allow an early joint decision 
regarding the subject’s continuation 
in the trial.  This decision will be 
documented by the investigator and 
the sponsor, and reviewed by the 
monitor.
accident or mistake (eg, violation of 
informed consent process, IMP 
dispensing or subject dosing error, 
subject enrolled in violation of 
eligibility criteria or concomitant 
medication criteria), the 
investigator or designee must contact 
the sponsor at the earliest possible 
time.  This will allow an early joint 
decision regarding the subject’s 
continuation in the trial.  This 
decision will be documented by the 
investigator and the sponsor, and 
reviewed by the site monitor.
Section 4.1, Prohibited 
or Restricted 
Medications 
Medications or surgical therapies 
used for the purpose or potential for 
modifying the progression of PKD 
cyst growth or development will be 
prohibited.  These include, but are not 
restricted to, somatostatin agonists, 
rapamune (sirolimus), anti-sense 
ribonucleic acid therapies, tolvaptan, 
and other vasopressin antagonists, 
(eg, OPC-31260 (mozavaptan), 
Vaprisol (conivaptan), agonists (eg, 
desmopressin) and cyst 
decompression surgery.
Continuous or short-term use of other 
medications, while not prohibited, 
may be restricted by the investigator 
because of their potential for 
interference with tolvaptan 
metabolism (see Section 3.2.1 and 
Section 3.2.2). 
...
Some drugs are known to alter 
creatinine concentrations so, while 
not prohibited, subjects should alert 
their trial doctor, and any other 
health-care providers, to take this into 
consideration when considering
changes in their prescribed or over-
the-counter medications.  A list 
would include:  cimetidine, non-
steroidal anti-inflammatory drugs like 
aspirin or ibuprofen, chemotherapy 
drugs, cephalosporin, the 
combination of elvitegravir, 
cobicistat, emtricitabine, and 
tenofovir (StribildTM), dolutegravir, 
dronedarone, ranolazine, metformin, 
Medications or surgical therapies 
used for the purpose or potential for 
modifying the progression of PKD 
cyst growth or development will be 
prohibited.  These include, but are 
not restricted to, somatostatin 
agonists, rapamune (sirolimus), anti-
sense ribonucleic acid therapies, 
vasopressin antagonists other than 
tolvaptan, (eg, OPC-31260 
(mozavaptan), Vaprisol 
(conivaptan), agonists (eg, 
desmopressin) and cyst 
decompression surgery.
Continuous or short-term use of 
other medications, while not 
prohibited, may be restricted by the 
investigator because of their 
potential for interference with 
tolvaptan metabolism (see 
Section 3.2.1 and Section 3.2.2). 
A partial list of strong and 
moderate CYP3A4 inhibitors can 
be found in Table 4.1-1 below:
...
Some drugs are known to alter 
creatinine concentrations so, while 
not prohibited, subjects should alert 
their trial doctor, and any other 
health-care providers, to take this 
into consideration when considering 
changes in their prescribed or over-
the-counter medications.  A list 
would include:  non-steroidal anti-
inflammatory drugs like aspirin or 
ibuprofen, chemotherapy drugs, 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Old Text
Updated Text
and trimethoprim.
cephalosporin, the combination of 
elvitegravir, cobicistat, 
emtricitabine, and tenofovir 
(StribildTM), dolutegravir, 
dronedarone, ranolazine, metformin, 
and trimethoprim.
Table 4.1-1
N/A
Please see end of Appendix 5 for this 
new table.
Section 4.2, Dietary 
Restrictions and 
Recommendations
Restriction of excess dietary sodium 
and cooked meat protein may prove 
beneficial to subjects with a history 
of, or predisposition for, hypertension 
or kidney disease in general and 
should be applied to all subjects 
diagnosed with advanced ADPKD, 
particularly if there is evidence for a 
propensity for rapid progression.  In 
the absence of alternate regional 
practices, dietary salt < 5g/day, 
dietary cooked meat protein < 1 
g/kg/day and a limit on caffeinated 
drinks/foods should also be given (no 
more than 2 coffee equivalents per 
day).  
Restriction of excess dietary sodium 
and cooked meat protein may prove 
beneficial to subjects with a history 
of, or predisposition for, 
hypertension or kidney disease in 
general and should be applied to all 
subjects diagnosed with advanced 
ADPKD, particularly if there is 
evidence for a propensity for rapid 
progression.  In the absence of 
alternate regional practices, dietary 
salt < 5g/day, dietary cooked meat 
protein < 1 g/kg/day and a limit on 
caffeinated drinks/foods should also 
be given (no more than 2 coffee 
equivalents per day).  A history of 
alcohol and smoking intake will be 
collected at screening.  Alcohol 
and tobacco consumption should 
be avoided or minimized as much 
as possible.
Section 5, Reporting of 
Adverse Events
The following describes the methods 
and timing for assessing, recording, 
and analyzing safety parameters, as 
well as the procedures for eliciting 
reports of and recording and reporting 
AEs and intercurrent illnesses and the 
type and duration of the follow-up of 
subjects after AEs.
The following describes the methods 
and timing for assessing, recording, 
and analyzing safety parameters, as 
well as the procedures for eliciting 
reports of and recording and 
reporting AEs and intercurrent 
illnesses and the type and duration of 
the follow-up of subjects after AEs.
Medical follow up is expected for 
AEs which lead to discontinuation 
which are serious, or which are of 
special interest (eg, liver 
abnormalities, skin neoplasms, 
glaucoma).
Section 5.5, Follow-up 
of Adverse Events
For this trial, AEs will be followed up 
for 21 days after the last dose of 
tolvaptan has been administered 
(follow-up period).
Subjects experiencing SAEs should 
be followed clinically until their 
health has returned to baseline status, 
or until all parameters have returned 
For this trial, AEs will be followed 
up for 7 days after the last dose of 
tolvaptan has been administered 
(follow-up period).
Subjects experiencing SAEs should 
be followed clinically until their 
health has returned to baseline status, 
or until all parameters have returned 
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Revised Figure 3.1-1 - Trial Design Schematic:
Previous Table 3.2-1 - Trial Treatments:
Table 3.2-1
Trial Treatments
Trial Day
Time
Dose
Day 1 to last on-treatment visit
8:00 am
1 to 6 tolvaptan tablets (15 mg or 30 mg each)
4:00 to 5:00 pm
1 to 2 tolvaptan tablets (15 mg or 30 mg each)
Allowed doses are 45/15 mg, 60/30 mg, 
90/30 mg.  Down titration to 30/15 mg and 
15/15 mg will be allowed after discussion 
with the medical monitor.  
Revised Table 3.2-1 - Trial Treatments:
Table 3.2-1
Trial Treatments
Trial Day
Time
Dose
Day 1 to last on-treatment visit
8:00 am
1 to 6 tolvaptan tablets (15 mg or 30 mg each)
4:00 to 5:00 pm
1 to 2 tolvaptan tablets (15 mg or 30 mg each)
Allowed doses are 45/15 mg, 60/30 mg, 
90/30 mg.  Down titration to 30/15 mg and 
15/15 mg will be allowed after discussion 
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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with the medical monitor.  Further down 
titration to 30 or 15 mg once daily may be 
allowed only for metabolic drug-drug 
interaction and requires medical monitor 
approval.
Previous Table 3.4.2-1 – Inclusion Criteria:
Table 3.4.2-1 Inclusion Criteria
1.
Male and female subjects aged 18 years with ADPKD who have completed either trial 
156-13-210 or trial 156-08-271
2.
Diagnosis of ADPKD by modified Pei-Ravine criteria:

With family history: several cysts per kidney (3 if by sonography, 5 if by computed 
tomography or MRI).

Without family history: 10 cysts per kidney (by any radiologic method, above) and exclusion 
of other cystic kidney diseases.  Conditions to be excluded include: multiple simple renal 
cysts, renal tubular acidosis, cystic dysplasia of the kidney, multicystic kidney, multilocular 
cysts of the kidney, medullary cystic kidney and acquired cystic disease of the kidney.

Distribution and number of cysts consistent with the observed level of renal function deficit.
3.
Estimated glomerular filtration rate  20 mL/min/1.73 m2 (calculated using the CKD-EPI 
formula) within 45 days prior to the baseline visit.  Subjects who have an eGFR between 15 and 
19 mL/min/1.73 m2 may be permitted with documented medical monitor approval prior to 
enrollment.
Revised Table 3.4.2-1 – Inclusion Criteria:
Table 3.4.2-1 Inclusion Criteria
1.
Male and female subjects aged 18 years with confirmed diagnosis of ADPKD ( during 
participation in prior tolvaptan trials) who have

Completed and transferred from the double-blind Trial 156-13-210 (12-month 
period including post-treatment follow-up, regardless of whether this was on-
treatment or off-treatment), or 

Completed Trial 156-08-271 or a prior tolvaptan trial, or 

Interrupted or discontinued treatment in a tolvaptan trial other than 
Trial 156-13-210.  Subjects may be enrolled with the medical monitor approval, and 
additional close monitoring may be required at the beginning of the trial

Renal function will be assessed during screening using historical laboratory values 
(in the last 30 days) for serum creatinine levels to calculate the estimated 
glomerular filtration rate (eGFR).  The eGFR values will be estimated based on the 
Chronic Kidney Disease - Epidemiology (CKD-EPI) formula. (Levey AS et al. Ann 
Intern Med. 2009; 150:604–612)
2.
Estimated glomerular filtration rate  20 mL/min/1.73 m2 (calculated using the CKD-EPI 
formula) within 45 days prior to the baseline visit.  Subjects who have an eGFR between 15 and 
19 mL/min/1.73 m2 may be permitted with documented medical monitor approval prior to 
enrollment.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
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CCI

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Revised Table 3.7.2.2-1 - Clinical Laboratory Assessments:
Table 3.7.2.2-1
Clinical Laboratory Assessments
Hematology and Coagulation Panel:
Hemoglobin
Platelet count
Mean corpuscular hemoglobin concentration 
(MCHC)
Mean corpuscular volume (MCV)
Red blood cell (RBC) count
White blood cell (WBC) count with differential 
Prothrombin time (PT) as international normalized 
ratio (INR)
Activated partial thromboplastin time (aPTT)
Urinalysis Panel:
Appearance
Color 
Blood
Glucose
Microscopic analysis, WBC/RBC counts per high 
power field
pH
Protein 
Urine Chemistry
Osmolality (optional)
Specific gravity
Additional Tests:
Urine (or serum) pregnancy for WOCBP
Hepatitis (optional)
Serum Chemistry Panel:
Albumin
Blood urea nitrogen (BUN)
Serum calcium
Carbon dioxide
Serum chloride
Gamma-glutamyl transpeptidase
Cholesterol, total
Glucose
Lactate dehydrogenase (LDH)
Phosphorus
Potassium
Protein, total 
Uric acid
Liver Function Panel:
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Bilirubin, total (BT)
Bilirubin, direct
Creatinine
Sodium
WOCBP=women of childbearing potential.
New Table 4.1-1 Moderate and Strong CYP3A4 Inhibitors (partial list):
Table 4.1-1
Moderate and Strong CYP3A Inhibitors (partial list)
amprenavir
atorvastin
aprepitant
chloramphenicol (if 
used orally)
cimetidine
clarithromycin
clotrimazole (if used 
orally)
danazol
delavirdine
diltiazem
erythromycin
fluconazole
fluvoxamine
indinavir
isoniazid
itraconzazole
josamycin
ketoconazole (if used 
orally)
nelfinavir
nefazadone
quinupristin/ dalfopristin
ritonavir
saquinavir
troleandomycin
verapamil
Seville orange products
grapefruit products
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Administrative Change Number:
1
Issue Date:
05 September 2014
PURPOSE:
This administrative change will not affect the safety of subjects, the scope of the 
investigation, or the scientific quality of the trial.
The main purpose of this administrative change was to align safety endpoints between the 
synopsis and Section 3.5.1, and to clarify the timeline for when IRE forms must be 
completed and submitted to the sponsor.  In addition, a statement at the beginning of 
Section 3.5.1 explaining that the trial would have no formal endpoints had been 
inadvertently deleted in an earlier draft. 
BACKGROUND:
While reviewing the protocol before proceeding with the clinicaltrial.gov posting, a few 
inconsistencies were found.  It was decided that fixing the inconsistencies would provide 
better clarity. 
Sectional Revisions
Location
Old Text
Updated Text
Section 3.5.1 Safety 
Endpoints  
Safety endpoints will be as follows:

Adverse events

Vital signs

Clinical laboratory 
assessments

Serum transaminase 
elevations for frequency (2x, 
3x, 5x and 10x ULN), time 
to onset, time to peak levels, 
time of offset (< 3x, 2x, or 
1x ULN), response to de-
challenge and re-challenge 
and frequency of progression 
to Hy’s laboratory criteria 
(ALT or AST > 3x ULN and 
bilirubin, total (BT), 
> 2x ULN without alkaline 
phosphatase 2x ULN)

Serum sodium excursions 
above 145, 150, or 
155 mmol/L or below 135, 
This trial will have no formal 
endpoints.  Safety variables will be 
summarized by descriptive statistics, 
(eg, proportion, mean, median, 
standard deviation [SD], minimum, 
and maximum values).  In general, 
summary statistics, including 
changes from baseline, will be 
provided for safety variables based 
on all available data.  Safety 
endpoints will be as follows:

Adverse events

Vital signs

Clinical laboratory 
assessments

Serum transaminase 
elevations for frequency 
(2x, 3x, 5x and 10x ULN), 
time to onset, time to peak 
levels, time of offset (< 3x, 
2x, or 1x ULN), response to 
de-challenge and re-
challenge and frequency of 
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Updated Text
130, or 125 mmol/L

Interruptions of protocol-
specifed therapies for 
hypernatremia or 
hyponatremia
progression to Hy’s 
laboratory criteria (ALT or 
AST > 3x ULN and 
bilirubin, total (BT), 
> 2x ULN without alkaline 
phosphatase 2x ULN)

Serum sodium excursions 
above 145, 150, or 
155 mmol/L or below 135, 
130, or 125 mmol/L
Section 5.3,
Immediately Reportable 
Events
The investigator must immediately 
report within 24 hours after either the 
investigator or site personnel become 
aware of any SAE, an AE that 
necessitates IMP discontinuation, any 
new liver result meeting the AE 
laboratory threshold criteria, any AE 
of special interest or a confirmed 
pregnancy, by telephone or by fax to 
the sponsor as outlined in 
Appendix 1.  An IRE form must be 
completed and sent by fax, email or 
overnight courier to the sponsor.  
(Please note that the IRE form is 
NOT the AE eCRF).
The investigator must immediately 
report within 24 hours after either 
the investigator or site personnel 
become aware of any SAE, new liver 
laboratory abnormality requiring 
special liver eCRF completion, or 
confirmed pregnancy, by telephone 
or by fax to the sponsor as outlined 
in Appendix 1.  An IRE form must 
be completed and sent by fax, email,
or overnight courier to the sponsor.  
(Please note that the IRE form is 
NOT the AE eCRF).
Appendix 5, Title 
change 
Protocol Amendment
Protocol Amendments and 
Administrative Changes
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Amendment Number:
2
Issue Date:
06 Mar 2015
PURPOSE:
The purpose of this amendment was to increase the window from 30 days to up to 
3 months to allow use of historical laboratory values for screening, to add flexibility and 
allow combining of screening and baseline visits in the trial, and to provide clarification 
on trial discontinuation. The list of vendors was updated. Minor linguistic changes were 
made for clarity and typographical errors were corrected.  
BACKGROUND: 
Eligible subjects enrolling from Trials 156-08-271 or 156-13-210 can enroll before they 
complete the last visit in their respective trials, and the last visit as well as the screening 
and baseline visit in this trial can be combined into one visit with all required assessments 
from each visit performed only once, so long as the time between the last visit 
assessments from the previous trial and the screening visit for this trial is within 30 days.  
Other Revisions
Figure 3.1-1 - Trial Design Schematic
Table 3.4.2-1 - Inclusion Criteria 
Table 3.4.3-1 - Exclusion Criteria 
Table 3.7-1 - Schedule of Assessments footnotes
Sectional Revisions
Location
Old Text
Updated Text
Title page
Clinical Protocol
A Phase 3b, Multi-center, Open-label 
Trial to Evaluate the Long Term 
Safety of Titrated Immediate-release 
Tolvaptan (OPC 41061, 30 mg to 120 
mg/day, Split dose) in Subjects with 
Autosomal Dominant Polycystic 
Kidney Disease
Revised Clinical Protocol
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
Synopsis, Protocol Title 
A Phase 3b, Multi-center, Open-label 
Trial to Evaluate the Long Term 
Safety of Titrated Immediate-release 
A Phase 3b, Multi-center, Open-
label Trial to Evaluate the Long 
Term Safety of Immediate-release 
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Updated Text
Tolvaptan (OPC 41061, 30 mg to 120 
mg/day, Split dose) in Subjects with 
Autosomal Dominant Polycystic 
Kidney Disease
Tolvaptan (OPC 41061, 30 mg to 
120 mg/day, Split dose) in Subjects 
with Autosomal Dominant 
Polycystic Kidney Disease
Synopsis, Trial Design
   
Subjects will be eligible for screening 
into this trial if they:

Completed and transferred from 
the double-blind Trial 
156-13-210 (12-month period 
including post treatment follow-
up, regardless of whether this 
was on-treatment or off-
treatment), or 

Completed Trial 156-08-271 or a 
prior tolvaptan ADPKD trial, or 

Interrupted or discontinued 
treatment in a prior tolvaptan 
ADPKD trial (other than Trial 
156-13-210).  Subjects may be 
enrolled with medical monitor 
approval, and additional close 
monitoring may be required at 
the beginning of the trial
   
Subjects will be eligible for 
screening into this trial if they:

Completed and transferred from 
the double-blind Trial 
156-13-210 (12-month period 
including post treatment follow-
up, regardless of whether this 
was on-treatment or off-
treatment), or have completed 
all but the last follow-up visit, 
which will be combined with the 
first visit in this trial or

Completed Trial 156-08-271 or 
a prior tolvaptan ADPKD trial, 
or have completed all but the 
end of trial visit, which will be 
combined with the first visit in 
this trial or

Interrupted or discontinued 
treatment in a prior tolvaptan 
ADPKD trial (other than Trial 
156-13-210).  Subjects may be 
enrolled with medical monitor 
approval, and additional close 
monitoring may be required at 
the beginning of the trial
Synopsis, Inclusion and 
Exclusion Criteria

Estimated glomerular filtration 
rate (eGFR) 
20 mL/min/1.73m2 within 
45 days of the baseline visit.  
Subjects who have an eGFR 
between 15 and 
19 mL/min/1.73m2 may be 
enrolled with medical monitor 
approval

Renal function will be assessed 
during screening by using 
historical values (in the last 
30 days) for serum creatinine 
levels to calculate the eGFR.  
The eGFT values will be 
estimated based on the Chronic 
Kidney Disease – Epidemiology 
(CKD-EPI) formula.

Estimated glomerular filtration 
rate (eGFR) 
20 mL/min/1.73m2 within 
3 months of the baseline visit.  
Subjects who have an eGFR 
≤20 mL/min/1.73m2 may be 
enrolled with medical monitor 
and sponsor approval and 
increased frequency of 
monitoring to ensure subjects’ 
safety.

Renal function will be assessed 
during screening by using 
historical values (within 
3 months from the screening 
visit) for serum creatinine levels 
to calculate the eGFR.  The 
eGFR values will be estimated 
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based on the Chronic Kidney 
Disease – Epidemiology 
(CKD-EPI) formula.
Section 1.3, Known and 
Potential Risks and 
Benefits
...
...Subjects enrolling in this trial who 
were in a previous ADPKD tolvaptan 
trial other than Trials 156-13-210 and 
156-08-271 will have monthly visits 
and transaminase level assessments 
for the first 18 months.
...
...Subjects enrolling in this trial who 
were in a previous ADPKD 
tolvaptan trial other than Trials 
156-13-210 and 156-08-271 will 
have monthly visits and alanine 
aminotransferase (ALT) level 
assessments for the first 18 months.
Section 2.1, Trial 
Rationale 
Evidence from previous studies 
suggests that during the first 
18 months of long-term treatment in 
subjects with ADPKD, alanine 
aminotransferase (ALT) and/or 
aspartate aminotransferase (AST) 
elevations and evidence of 
idiosyncratic DILI occurs at a greater 
frequency in tolvaptan treated 
subjects.  ...
Evidence from previous studies 
suggests that during the first 
18 months of long-term treatment in 
subjects with ADPKD, ALT and/or 
aspartate aminotransferase (AST) 
elevations and evidence of 
idiosyncratic DILI occurs at a 
greater frequency in tolvaptan 
treated subjects.  ...
Section 3.1, 
Type/Design of Trial
...
Eligible subjects will have an 
opportunity to enroll into Trial 
156-13-211 immediately following 
completion of the follow-up visit(s) 
of the previous trial.  The last visit 
assessments from the previous 
protocol can be combined with the 
screening visit for this trial, with all 
required assessments from each visit 
only performed once, as long as the 
time between the last follow-up visit 
assessments from the previous trial 
and the screening visit for this trial is 
within 30 days.
...
These subjects may have their trial 
visits/hepatic transaminase 
monitoring changed to every 
3 months sooner as their previous 
tolvaptan exposure in 
Trial 156-13-210 can count towards 
the 18-month threshold.
...
Eligible subjects will have an 
opportunity to enroll into Trial 
156-13-211 following completion of 
the follow-up visit(s) of the previous 
trial.  Eligible subjects from 
Trials 156-08-271 and 156-13-210 
can have the last visit assessments 
from their previous respective 
protocols (end of trial visit for 
156-08-271 subjects and last 
follow-up visit for 
156-13-210 subjects) overlap the 
first visit in this trial.  These last visit 
assessments can be combined with 
the screening and baseline visits for 
this trial, with all required 
assessments from each visit 
performed only once, so long as the 
time between the last visit 
assessments from the previous trial 
and the screening visit for this trial is 
within 30 days.  If the first visit in 
this trial combines the last visit from 
a previous trial with both the 
screening and the baseline visits in 
this trial, the results from laboratory 
assessments performed at this 
combined visit will not be 
immediately available.  Should any 
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laboratory abnormalities be 
identified, the investigator will need 
to notify the subject and provide 
instructions regarding dosing or 
returning to the site for additional 
assessments.
...
These subjects may have their trial 
visits/hepatic transaminase 
monitoring changed to every 
3 months sooner as their previous 
tolvaptan exposure in 
Trial 156-13-210 can count towards 
the 18-month threshold.  Subjects 
from prior tolvaptan trials other than 
Trial 156-08-271 will have monthly 
trial visits/ALT level assessments for 
the first 18 months.  After that, the 
trial visits/ALT monitoring will be 
conducted every 3 months after the 
change in frequency is confirmed 
with the medical monitor.
Figure 3.1-1
Day 1
No clinic visit
First dose of the IMP
Day 1
No clinic visit
First dose of the IMP in Trial 211
Table 3.4.2-1, Inclusion 
Criteria
1. Male and female subjects aged 
18 years with confirmed diagnosis 
of ADPKD (during participation in 
prior tolvaptan trials) who have 

Completed and transferred from 
the double-blind 
Trial 156-13-210 (12-month 
period including post-treatment 
follow-up, regardless of whether 
this was on-treatment or off-
treatment), or

Completed Trial 156-08-271 or a 
prior tolvaptan trial, or

Interrupted or discontinued 
treatment in a tolvaptan trial 
other than Trial 156-13-210.  
Subjects may be enrolled with 
the medical monitor approval, 
and additional close monitoring 
may be required at the beginning 
of the trial

Renal function will be assessed 
during screening by using 
historical laboratory values (in 
the last 30 days) for serum 
Male and female subjects aged 
18 years with confirmed diagnosis 
of ADPKD (during participation in 
prior tolvaptan trials) who have 

Completed and transferred from 
the double-blind 
Trial 156-13-210 (12-month 
period including post-treatment 
follow-up, regardless of whether 
this was on-treatment or off-
treatment), or

Completed Trial 156-08-271 or 
a prior tolvaptan trial, or

Interrupted or discontinued 
treatment in a tolvaptan trial 
other than Trial 156-13-210.  
Subjects may be enrolled with 
the medical monitor approval, 
and additional close monitoring 
may be required at the 
beginning of the trial

Renal function will be assessed 
during screening by using 
historical laboratory values (in 
the last 3 months) for serum 
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creatinine levels to calculate the 
estimated glomerular filtration 
rate (eGFR).  The eGFR values 
will be estimated based on the 
Chronic Kidney Disease -
Epidemiology (CKD-EPI) 
formula. (Levey AS et al. Ann 
Intern Med. 2009; 150:604–612)
2. Estimated glomerular filtration rate 
20 mL/min/1.73 m2 (calculated 
using the CKD-EPI formula) within 
45 days prior to the baseline visit.  
Subjects who have an eGFR between 
15 and 19 mL/min/1.73 m2 may be 
permitted with documented medical 
monitor approval prior to enrollment
creatinine levels to calculate the 
estimated glomerular filtration 
rate (eGFR).  The eGFR values 
will be estimated based on the 
CKD-EPI formula. (Levey AS 
et al. Ann Intern Med. 2009; 
150:604–612)
2. Estimated glomerular filtration 
rate 20 mL/min/1.73 m2 
(calculated using the CKD-EPI 
formula) within 3 months prior to 
the baseline visit.  Subjects who 
have an eGFR ≤20 mL/min/1.73 m2
may be permitted to enter the trial 
with  medical monitor and sponsor 
approval and increased frequency of 
monitoring to ensure safety of 
subjects.
At end of table, abbreviations added:
eGFR=estimated glomerular 
filtration rate; CKD-EPI= Chronic 
Kidney Disease - Epidemiology
Table 3.4.3-1, 
Exclusion Criteria
1. Women of childbearing potential 
(WOCBP) who do not agree to 
practice 2 different methods of birth 
control or remain abstinent during the 
trial and for 30 days after the last 
dose of IMP.  If employing birth 
control, 2 of the following 
precautions must be used: vasectomy 
of partner, tubal ligation, vaginal 
diaphragm, intrauterine device, birth 
control.
…
4. Hepatic impairment based on liver 
function abnormalities other than that 
expected for ADPKD with cystic 
liver disease during screening.
1. WOCBP who do not agree to 
practice 2 different methods of birth 
control or remain abstinent during 
the trial and for 30 days after the last 
dose of IMP.  If employing birth 
control, 2 of the following 
precautions must be used: vasectomy 
of partner, tubal ligation, vaginal 
diaphragm, intrauterine device, birth 
control pill, birth control implant, 
birth control depot injection, 
condom, or sponge with spermicide.
…
4. Hepatic impairment based on liver 
function abnormalities other than 
that expected for ADPKD with 
cystic liver disease during screening
based on recent historical laboratory 
values (in the last 3 months).
Section 3.7, Trial 
Procedures, Table 3.7-1
Footnote a:
aThe last visit assessments from the 
previous protocol can be combined 
with the screening visit for this trial, 
with all required assessments from 
each visit performed only once.
...
Footnote g:
Footnote a:
aThe last visit assessments from the 
previous trial can be combined with 
the screening and baseline visits for 
this trial, with all required 
assessments from each visit 
performed only once.
...
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gA full liver function panel (AST, 
ALT, alkaline phosphatase, BT) will 
be done at screening.  All other liver 
function tests at subsequent visits are 
for ALT only, unless otherwise 
clinically indicated.  Any 
transaminase or bilirubin values 
which exceed 2 × ULN should 
prompt immediate retesting within 
72 hours.  While values remain in an 
abnormal range, testing frequency 
should be increased to at least weekly 
for the first month, gradually 
returning to monthly, and every 
3 months as indicated by the results.  
Local liver function panel analyses 
will also be performed more 
frequently, if necessary.
...
Footnote l:
lIf during the titration contact the 
determination is made to adjust the 
dose regimen, dose adjustments will 
be made using dispensed supply, and 
dose instructions will be provided by 
the investigator.  The subject’s 
current dose will be entered into the 
interactive response technology (IRT) 
at each visit.  Drug 
dispensation/reconciliation will be 
conducted on a monthly basis for 
subjects who have monthly trial visits 
and once every 3 months for subjects 
who have trial visits every 3 months.  
...
Footnote g:
gA full liver function panel (AST, 
ALT, alkaline phosphatase, BT) will 
be done at screening.  All other liver 
function tests at subsequent visits are
for ALT only, unless otherwise 
clinically indicated.  An ALT 
elevation > 2 × ULN should trigger
prompt testing of hepatic function 
within 72 hours. Any transaminase 
or bilirubin values which exceed 
2 × ULN should prompt immediate 
retesting within 72 hours.  While 
values remain in an abnormal range, 
testing frequency should be 
increased to at least weekly for the 
first month, gradually returning to 
monthly, and every 3 months as 
indicated by the results.  Local liver 
function panel analyses will also be 
performed more frequently, if 
necessary.
...
Footnote l:
lIf during the titration contact the 
determination is made to adjust the 
dose regimen, dose adjustments will 
be made using dispensed supply, and 
dose instructions will be provided by 
the investigator. The subject’s 
current dose will be entered into the 
interactive response technology 
(IRT) at each visit.  Drug 
dispensation/reconciliation will be 
conducted on a monthly basis for 
subjects who have monthly trial 
visits and once every 3 months for 
subjects who have trial visits every 
3 months.  If additional drug supply 
is required for titration purposes, the 
site will arrange a subject visit for 
dispensation.
...
Section 3.7.1.1, 
Screening (-30 days to 
1 day prior to Baseline)
Screening for eligibility is required 
for all subjects.  The screening visit 
may be combined with the last visit 
from the previous protocol with all 
required assessments from each visit 
only performed once.  In some cases, 
if a subject enrolls in this trial from a 
prior tolvaptan trial, the end of trial 
visit for that trial and the screening 
visit for this one may occur 
Screening for eligibility is required 
for all subjects.  The screening and 
baseline visit may be combined with 
the last visit from either the 
156-08-271 or 156-13-210 protocol 
with all required assessments from 
each visit performed only once.  
Therefore, in some cases, if a 
subject enrolls in this trial from a 
prior tolvaptan trial, the end of trial
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simultaneously.  Required 
assessments are as follows:
1.
Obtain subject consent.
2.
Determine subject eligibility 
through inclusion/exclusion criteria.  
3.
Record demographic 
information and prior trial identifiers 
(screening identification [ID], subject 
ID, site ID, prior tolvaptan ADPKD 
trial protocol number).
4.
Record medical/ADPKD 
history using prior trial data.
5.
Review dietary 
recommendations and compliance
….
or last follow-up visit for that trial 
and the screening and baseline visit 
for this one may occur 
simultaneously.  Required 
assessments for the screening visit 
are as follows:
1.
Obtain subject consent.
2.
Obtain subject’s new 
screening identification (ID)
assigned by interactive response 
technology (IRT).
3.
Determine subject 
eligibility through 
inclusion/exclusion criteria.  
4.
Record demographic 
information and prior trial identifiers 
(screening ID, subject ID, prior 
tolvaptan ADPKD trial protocol 
number).
5.
Record medical/ADPKD 
history using prior trial data.
6.
Review dietary 
recommendations and compliance
…
Section 3.7.2.4.1 Liver 
Test Abnormalities and 
Interruption/Discontinu
ation of Investigational 
Medical Product
The appearance of any suspicious 
symptom or sign should trigger 
prompt testing of hepatic function (ie, 
within 72 hours).  Local laboratory 
testing is acceptable, ideally with a 
concurrent central laboratory sample 
for confirmation.  
An ALT elevation > 2 × ULN or the
appearance of any suspicious 
symptom or sign should trigger 
prompt testing of hepatic function 
(ie, within 72 hours).  Local 
laboratory testing is acceptable, 
ideally with a concurrent central 
laboratory sample for confirmation.
Section 3.7.5, 
Treatment Interruption 
and Discontinuation
...
A subject who permanently 
discontinues IMP treatment may have 
the option to end trial participation 
(complete the early termination visit) 
or to continue participation off IMP 
and complete ongoing trial 
assessments as per protocol or with a 
modified (ie, less frequent) schedule 
as outlined in Section 3.8.3.
...
A subject who permanently 
discontinues IMP treatment ends
trial participation and the early 
termination visit should be 
completed.
Section 5.2, Eliciting 
and Reporting Adverse 
Events
… 
In addition, the sponsor must be 
notified immediately by telephone or 
fax of any immediately reportable 
events according to the procedure 
outlined below in Section 5.3.  …
… 
In addition, Quintiles (drug safety 
service) must be notified 
immediately by telephone or fax of 
any immediately reportable events 
according to the procedure outlined 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
123

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Protocol 156-13-211
Confidential - Otsuka Proprietary Information
124
06 March 2015
Previous Figure 3..-1 Trial Design Schematic
Revised Figure 3.1-1 Trial Design Schematic
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
125

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
125
06 March 2015
Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator's Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor's (or designee's) Clinical Research Agreement.
I will provide copies of the protocol to all physicians, nurses and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, [insert compound number], the 
concurrent medications, the efficacy and safety parameters and the conduct of the trial in general. 
I am aware that this protocol must be approved by the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC responsible for such matters in the clinical trial facility where 
[insert compound number] will be tested prior to commencement of this trial. I agree to adhere 
strictly to the attached protocol (unless amended in the manner set forth in Paragraph I of the 
sponsor's Clinical Research Agreement, at which time I agree to adhere strictly to the protocol as 
amended).
I understand that this IRB- or IEC-approved protocol will be submitted to the appropriate 
regulatory authority/ies by the sponsor. I agree that clinical data entered on case report forms by 
me and my staff will be utilized by the sponsor in various ways such as for submission to 
governmental regulatory authorities and/or in combination with clinical data gathered from other 
research sites, whenever applicable. I agree to allow sponsor monitors and auditors full access to 
all medical records at the research facility for subjects screened or enrolled in the trial.
I agree to await IRB/IEC approval before implementation of any protocol amendments to this 
protocol. If, however, there is an immediate hazard to subjects, I will implement the amendment 
immediately, and provide the information to the IRB/IEC within 5 working days. Administrative 
changes to the protocol will be transmitted to the IRB/IEC for informational purposes only.
I agree to provide all subjects with informed consent forms, as required by the applicable
regulations and by ICH guidelines. I agree to report to the sponsor any adverse experiences in 
accordance with the terms of the sponsor's Clinical Research Agreement and the relevant 
regional regulation(s) and guideline(s). I further agree to provide all required information 
regarding financial certification or disclosure to the sponsor for all investigators and sub-
investigators in accordance with the terms of the relevant regional regulation(s). I understand that 
participation in the protocol involves a commitment to publish the data from this trail in a 
cooperative publication prior to publication of efficacy and safety results on an individual basis.
________________________________________________
Principal or Coordinating Investigator Signature and Date
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
126

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Protocol 156-13-211
Confidential - Otsuka Proprietary Information
2
06 March 2015
Protocol Synopsis 
Name of Sponsor:  Otsuka Pharmaceutical Development 
& Commercialization, Inc.
Name of Investigational Medicinal Product: Tolvaptan 
(OPC-41061)
Protocol # 156-13-211
IND# 72,975
EudraCT# 2014-001516-
19
Protocol Title:
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
Clinical Phase/Trial 
Type:
Phase 3b/Therapeutic use
Treatment Indication: Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Objective:
The primary objective of this trial is:

To evaluate and describe the long-term safety of tolvaptan.  
Trial Design:
This trial is a phase 3b, multi-center, open-label extension trial.
Subjects will be eligible for screening into this trial if they:

Completed and transferred from the double-blind 
Trial 156-13-210 (12-month period including 
post-treatment follow-up, regardless of whether this 
was on-treatment or off-treatment), or have completed 
all but the last follow-up visit, which will be combined 
with the first visit in this trial or

Completed Trial 156-08-271 or a prior tolvaptan 
ADPKD trial, or have completed all but the end of trial 
visit, which will be combined with the first visit in this 
trial or

Interrupted or discontinued treatment in a prior 
tolvaptan ADPKD trial (other than Trial 156-13-210).  
Subjects may be enrolled with medical monitor 
approval, and additional close monitoring may be 
required at the beginning of the trial
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 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
129

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
3
06 March 2015
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.
Subject Population:
This trial will include approximately 2,500 subjects over the 
age of 18 years with ADPKD diagnosed by Pei-Ravine criteria
(modified by magnetic resonance imaging [MRI]), and who
have completed or participated in a prior ADPKD 
interventional investigational medicinal product (IMP) trial.
Inclusion/Exclusion 
Criteria:
Main inclusion criteria:

Male and female subjects 18 years with a confirmed 
diagnosis of ADPKD (during participation in prior 
tolvaptan trials) who have 

Completed and transferred from the double-blind 
Trial 156-13-210 (12-month period including 
post-treatment follow-up, regardless of whether this 
was on-treatment or off-treatment), or 

Completed Trial 156-08-271 or a prior ADPKD 
tolvaptan trial, or

Interrupted or discontinued treatment in a prior 
tolvaptan ADPKD trial other than Trial 156-13-210.  
Subjects may be enrolled with the medical monitor 
approval, and additional close monitoring may be 
required at the beginning of the trial

Estimated glomerular filtration rate 
(eGFR) 20 mL/min/1.73m2 within 3 months of the 
baseline visit.  Subjects who have an eGFR 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
130

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
4
06 March 2015
≤20 mL/min/1.73m2 may be enrolled with medical 
monitor and sponsor approval and increased frequency of 
monitoring to ensure subjects’ safety

Renal function will be assessed during screening by using 
historical laboratory values (within 3 months from the 
screening visit) for serum creatinine levels to calculate the 
eGFR.  The eGFR values will be estimated based on the 
Chronic Kidney Disease - Epidemiology (CKD-EPI) 
formula
Main exclusion criteria:

Need for chronic diuretic use

Hepatic impairment based on hepatic laboratory
assessments (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], bilirubin, total [BT]) other than 
that expected for ADPKD with cystic liver disease
Trial Site(s):
Approximately 220 enrolling sites including but not limited to 
the following regions: North America, South America, Eastern
Europe, Western Europe, Russian Federation, and Australia.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
131

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
5
06 March 2015
Investigational 
Medicinal Product(s), 
Dose, Dosage 
regimen, Treatment 
period, Formulation, 
Mode of 
Administration:
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).  
Subjects will receive open-label tolvaptan for the duration of 
the trial. 
A subject’s starting dose in this trial will be dependent on the
trial in which they were previously enrolled:

156-13-210- initiated on tolvaptan at a split-dose of 
45/15 mg with upward titration every 3 to 4 days to 
60/30 mg or 90/30 mg per day according to tolerability

156-08-271- will retain the last dose level from 271 
and start at the same dose in this trial

Prior tolvaptan trials- initiated on tolvaptan at a 
split-dose of 45/15 mg with upward titration every 3 to 
4 days to 60/30 mg or 90/30 mg per day according to 
tolerability
Down titration to 30/15 mg or 15/15 mg will be allowed at the 
discretion of the investigator according to individual 
tolerability and with medical monitor notification.  Further 
down titration to 30 or 15 mg once daily may be allowed only
for metabolic drug-drug interaction and requires medical 
monitor approval.
Trial Assessments:
Screening: Informed consent, medical history (including 
ADPKD updates, as required), determination of eligibility 
through inclusion/exclusion criteria, dietary review, vital signs, 
clinical laboratory assessments, physical examination, urine 
pregnancy test (women of child-bearing potential only
[WOCBP]), concomitant medications and laboratory tests to 
determine eligibility.
Safety:  Adverse events (AEs), vital signs, directed physical 
examination, dietary review, self-assessed drug tolerability, 
serum chemistry tests (including serum transaminases, alkaline 
phosphatase, bilirubin, and serum sodium) and concomitant 
medications.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
132

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Protocol 156-13-211
Confidential - Otsuka Proprietary Information
7
06 March 2015
Safety analyses:  Safety analysis will be conducted based on 
standard safety variables, including AEs, clinical laboratory 
data, physical examinations and vital signs.  Potentially 
clinically significant results in laboratory tests identified using 
prospectively defined criteria, including criteria on liver 
enzyme elevations, will be summarized.
Trial Duration:
Trial duration is planned to continue 

Until the last subject from Trial 156-13-210 completes 
18 months of tolvaptan treatment in this trial

All subjects will receive at least 18 months of tolvaptan 
treatment in the extension study.   Trial 156-13-210 
subjects or subjects enrolling from other trials may opt 
to conclude their participation in this trial if tolvaptan 
becomes available before they complete 18 months of 
treatment in this trial 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
134

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8.3
Accountability ...................................................................................................59
8.4
Returns and Destruction....................................................................................59
9
Records Management.........................................................................59
9.1
Source Documents.............................................................................................59
9.2
Data Collection..................................................................................................59
9.3
File Management at the Trial Site.....................................................................60
9.4
Records Retention at the Trial Site....................................................................60
10
Quality Control and Quality Assurance...........................................61
10.1
Monitoring.........................................................................................................61
10.2
Auditing.............................................................................................................61
11
Ethics and Responsibility...................................................................61
12
Confidentiality ....................................................................................61
13
Amendment Policy..............................................................................62
14
References............................................................................................63
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List of In-text Tables
Table 1.2-1
Vasopressin Blockade Across Differing Severities of 
ADPKD: Effect on Rate of Estimated Glomerular Filtration 
Decline in Chronic Kidney Disease Stages 1-3.............................19
Table 3.2-1
Trial Treatments.............................................................................26
Table 3.4.2-1
Inclusion Criteria ...........................................................................28
Table 3.4.3-1
Exclusion Criteria ..........................................................................29
Table 3.7-1
Schedule of Assessments...............................................................31
Table 3.7.2.2-1
Clinical Laboratory Assessments...................................................40
Table 4.1-1
Strong and Moderate CYP3A Inhibitors (partial list)....................48
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List of In-text Figures
Figure 3.1-1
Trial Design Schematic..................................................................24
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SAP
Statistical Analysis Plan
SD
Standard deviation
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
UK
United Kingdom
US or USA
United States or United States of America
WOCBP
Women of childbearing potential
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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1
Introduction
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).  The 
disease affects the structure of the kidneys through proliferation and growth of numerous 
fluid-filled cysts.  The expanding cysts compress normal tissue and blood vessels 
resulting in ischemia, inflammation and fibrosis leading to progressive nephron loss.  The 
remaining nephrons are initially able to compensate through glomerular hyperfiltration up 
to a point when nephron loss is so great that compensation is no longer adequate and 
renal function begins to decline.  Clinical manifestations of kidney disease may be 
sporadic (hematuria, infections, pain) or chronic (hypertension, albuminuria, renal 
insufficiency) and indicate ongoing and cumulative damage to the kidney.
The number of diagnosed ADPKD cases was estimated at 116,228 in the US in 2009.  
The estimated prevalence of diagnosed ADPKD is similar in Europe and estimated to be 
< 5 per 10,000.1  Though a rare genetic disease, it ranks as the 6th leading cause of ESRD 
in the US (2.3% of the new ESRD cases).2  An estimated 45% to 70% of patients with 
ADPKD progress to ESRD by age 65.3  Over the past 30 years, the age of onset for 
ESRD among ADPKD patients has remained the same (median age of 54).  In contrast, 
effective therapy has delayed the onset of ESRD in patients with nephropathy due to 
hypertension, diabetes, and glomerulonephritis.
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 
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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.4 5  Refer to the Tolvaptan Investigator’s Brochure 
(IB) for more information.4
1.1
Nonclinical Data
Rodent models of ADPKD and ex-vivo human ADPKD cell and tissue cultures have 
implicated AVP as a promoter of kidney cyst growth.6 7  AVP-induced cyclic adenosine 
monophosphate (cAMP) increases proliferation of ADPKD renal tubular epithelium and 
chloride-mediated, intra-cystic, fluid secretion.  This leads to cyst expansion which 
disrupts renal architecture leading to ischemia, kidney fibrosis, and irreversible damage 
to the kidney, ultimately impairing its function.  Tolvaptan inhibits cAMP production by 
blocking AVP binding to the renal AVP-V2 receptor.  For information on nonclinical 
toxicology and absorption, distribution and metabolism data on tolvaptan please refer to 
the most current version of the IB.4
1.2
Clinical Data
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.8  
These effects were consistent across each of these CKD stages, supporting tolvaptan’s 
potential utility in early to mid-stage disease (Table 1.2-1), and creating a compelling 
argument for long-term effectiveness in those initiating therapy at an early stage and 
adhering to therapy as the disease progresses.  This trial also demonstrated an acute and 
persistent reduction on rate of kidney cystic growth.  The reductions in rate of kidney 
growth correlated with reductions in kidney pain and with preservation of renal function.  
Similar correlations were observed in a smaller, matched-control study 
(Study 156-09-283).9  Thus, the clinical data have confirmed the non-clinical effects seen 
in animals (see Section 1.1) and support approval of tolvaptan as the first agent to slow 
the progression of ADPKD.
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trials.  Overall, subjects were exposed to oral doses of tolvaptan ranging from 3.75 to 
480 mg.  The median exposure for all doses of oral formulations combined was 29 days, 
with a mean exposure of 228 days (346 days).
Pooled safety data from 80 trials indicate that the most commonly reported (> 3%) 
treatment-emergent adverse events (TEAEs) for tolvaptan-treated subjects were thirst 
(25.8%), dry mouth (10.8%) and pollakiuria (9.9%).
The most notable safety issue associated with chronic tolvaptan use, which was newly 
identified in Trial 156-04-251, was the potential for idiosyncratic hepatic toxicity. An 
imbalance in the proportion of subjects with elevated transaminases (tolvaptan > placebo) 
led to identification of 3 subjects (total, combined from Trials 156-04-251 and 
156-08-271) with laboratory and clinical evidence of potentially serious drug-induced 
liver injury (DILI).10 Based on the available data from the afore-mentioned trials, the 
sponsor proposes that appropriate subject monitoring and management be implemented to 
mitigate this potential risk in the ADPKD population.  
In this extension trial, subjects enrolling from the double-blind Trial 156-13-210 will 
have monthly visits and transaminase level assessments for the first 18 months while the 
treatment code from Trial 156-10-210 remains blinded, to ensure that all subjects have 
adequate safety monitoring during this period of susceptibility.  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.  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.  Subjects enrolling from the open-label 
Trial 156-08-271 will have transaminase assessments conducted every 3 months, since 
they will have already received tolvaptan for at least 18 months. The current IB lists all 
of the tolvaptan trials.  Subjects enrolling in this trial who were in a previous ADPKD 
tolvaptan trial other than Trials 156-13-210 and 156-08-271 will have monthly visits and 
alanine aminotransferase (ALT) level assessments for the first 18 months.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
147

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CCI

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
23
06 March 2015
Medical monitor approval is needed for enrollment of subjects whose completion of the 
preceding trial prior to entry in this trial exceeds 3 months, and these subjects will be 
required to undergo all screening and baseline assessments.
After consenting, subjects will be assigned a new screening number.  Subjects who are 
found to be eligible will retain the same subject number they had been assigned in their 
previous trial.  For purposes of ensuring subject safety, tolvaptan exposure of at least 
18 months is required for all subjects.  While Trial 156-13-210 remains blinded, subjects 
enrolling from any prior trial besides Trial 156-08-271 are scheduled to have monthly 
hepatic monitoring for the first 18 months of this trial.  After that, following the approval 
of the medical monitor, hepatic monitoring will take place every 3 months.  Subjects 
enrolling from Trial 156-08-271 will have hepatic monitoring every 3 months.  All 
Trial 156-13-210 subjects who are eligible for this trial will initially be scheduled to have 
trial visits and hepatic monitoring monthly for the first 18 months, then every 3 months
thereafter, because their tolvaptan exposure cannot be determined since Trial 156-13-210 
is a double blind 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 changed to every 3 months sooner as their previous tolvaptan 
exposure in Trial 156-13-210 can count towards the 18-month threshold.  Subjects from 
prior tolvaptan trials other than Trial 156-08-271 will have monthly trial visits/ALT level 
assessments for the first 18 months.  After that, the trial visits/ALT monitoring will be 
conducted every 3 months after the change in frequency is confirmed with the medical 
monitor.
Enrollment in this trial will be closed when the last eligible subject from 
Trial 156-13-210 enrolls in this trial. 
The duration of this trial is planned to continue 

Until the last subject from Trial 156-13-210 completes 18 months of tolvaptan 
treatment in this trial

All subjects will receive at least 18 months of tolvaptan treatment in the extension 
study.  Trial 156-13-210 subjects or subjects enrolling from other trials may opt to 
conclude their participation in this trial if tolvaptan becomes available before they 
complete 18 months of treatment in this trial 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
150

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
24
06 March 2015
Figure 3.1-1
Trial Design Schematic
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated 
or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
151

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
25
06 March 2015
3.2
Treatments
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.
Following consent, and once subjects have satisfied all of the inclusion criteria and none 
of the exclusion criteria, subjects will retain the subject number assigned from their 
previous trial.  Subjects will receive open-label tolvaptan for the duration of the trial. All 
subjects will be administered tolvaptan tablets in a daily split-dose, once upon awakening 
and another approximately 8 to 9 hours later (twice daily dosing).  The exact time of 
dosing may be adjusted based on wake/sleep habits (eg, standard 8 AM and 5 PM may be 
switched to 10 PM and 7 AM if working a night shift).  However, dosing times should be 
consistent for each individual’s daily dose to maximize receptor suppression.  Doses will 
be recorded as early dose/late dose (eg, 60/30 mg). 
A subject’s starting dose in this trial will be dependent on the trial in which they were 
previously enrolled:

156-13-210- initiated on tolvaptan at a split-dose of 45/15 mg with upward 
titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to 
tolerability

156-08-271- will retain the last dose level from 271 and start at the same dose in 
this trial

Prior tolvaptan trials- initiated on tolvaptan at a split-dose of 45/15 mg with 
upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to 
tolerability
Down titration to 30/15 mg and 15/15 mg is also permitted at the discretion of the 
investigator according to subject tolerability with medical monitor notification.  Further 
down titration to 30 or15 mg once daily may be allowed only for metabolic drug-drug 
interaction and requires medical monitor approval.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
152

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
26
06 March 2015
Table 3.2-1
Trial Treatments
Trial Day
Time
Dose
Day 1 to last on-treatment visit
8:00 am
1 to 6 tolvaptan tablets (15 mg or 30 mg each)
4:00 to 5:00 pm
1 to 2 tolvaptan tablets (15 mg or 30 mg each)
Allowed doses are 45/15 mg, 60/30 mg, 
90/30 mg.  Down titration to 30/15 mg and 
15/15 mg will be allowed after discussion 
with the medical monitor.  Further down 
titration to 30 or 15 mg once daily may be 
allowed only for metabolic drug-drug 
interaction and requires medical monitor 
approval.
For subjects moving from the 156-13-210 trial and requiring tolvaptan titration, it will be 
conducted in the following way: subjects will be instructed to take tolvaptan starting at a 
split dose of 45/15 mg (as 3 tablets upon waking and 1 tablet approximately 8 to 9 hours 
later) and to titrate up every 3 to 4 days; first to 60/30 mg, then up to the maximum dose 
of 90/30 mg.  Titration will be accomplished by increasing the number of tablets/dose 
and/or switching from 15 mg tablets to 30 mg tablets.  Prior to each upward titration, the 
subject’s tolerability to the current dose will be assessed by asking, “Could you tolerate 
this dose of trial medication for the rest of your life?” Subjects will continue in the trial
with the regimen to which tolerability was established.
While taking tolvaptan, all subjects should be instructed to ingest fluids in anticipation of, 
or at the first sign of thirst in order to avoid excessive thirst or dehydration.  Additionally, 
subjects should ingest 1 to 2 cups of water before bedtime regardless of perceived thirst 
and replenish fluids overnight with each episode of nocturia.
3.2.1
Dosing with CYP3A4 Potent Inhibitors
Tolvaptan is a sensitive CYP3A4 substrate with 4-fold or higher increases in exposure 
following administration with potent CYP3A4 inhibitors.4  
For subjects requiring treatment with a potent CYP3A4 inhibitor and on a total daily 
tolvaptan dose of 90 or 120 mg, tolvaptan treatment should be reduced to 30 mg once 
daily.  The dose may be reduced to 15 mg once daily for tolerability.  For subjects on a 
total daily dose of 60 mg, tolvaptan treatment should be reduced to 15 mg once daily.  
For subjects on lower total daily doses, tolvaptan interruption should be considered if no 
alternative medications can be used. 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
153

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
27
06 March 2015
3.2.2
Dosing with CYP3A4 Moderate Inhibitors
For subjects who require dosing with a moderate inhibitor, initial tolvaptan reductions as 
shown below should be tried, with further dose reductions or interruption as necessary for 
tolerability.

90/30 mg to 45/15 mg

60/30 mg to 30/15 mg

45/15 mg to 15/15 mg

30/15 mg to 15 mg once daily

15/15 mg to 15 mg once daily
A partial list of strong and moderate CYP3A4 inhibitors can be found in Section 4.1.
3.3
Trial Population
This trial will include approximately 2,500 subjects over the age of 18 years with 
ADPKD diagnosed by Pei-Ravine criteria11 12 (modified by magnetic resonance imaging 
[MRI]) who completed or participated in a prior tolvaptan trial.  
3.4
Eligibility Criteria
3.4.1
Informed Consent
Each investigator has both ethical and legal responsibility to ensure that subjects being 
considered for inclusion in this trial are given a full explanation of the protocol and of 
their role and responsibilities in the proposed research.  This shall be documented on a 
written informed consent form (ICF) that shall be approved by the same institutional 
review board/independent ethics committee (IRB/IEC) responsible for approval of this 
protocol.  Each ICF will comply with the International Conference on Harmonisation 
(ICH) Good Clinical Practice (GCP) Guideline14 and local regulatory requirements, and 
must adhere to the ethical principles that have their origin in the Declaration of Helsinki.  
The investigator agrees to obtain sponsor approval of any written ICF used in the trial 
prior to submission to the IRB/IEC.
Investigators may discuss trial availability and the possibility for entry with a potential 
subject without first obtaining consent.  However, informed consent will be obtained 
from all subjects (or their guardian or legal representative) and documented prior to 
initiation of any procedures that are performed solely for the purpose of determining 
eligibility for this trial, including withdrawal from current medication(s).
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
154

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CCI

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
29
06 March 2015
Table 3.4.3-1
Exclusion Criteria
1.
WOCBP who do not agree to practice 2 different methods of birth control or remain abstinent 
during the trial and for 30 days after the last dose of IMP. If employing birth control, 2 of the 
following precautions must be used: vasectomy of partner, tubal ligation, vaginal diaphragm, 
intrauterine device, birth control pill, birth control implant, birth control depot injection, condom, 
or sponge with spermicide.
2.
Women who are breast-feeding and/or who have a positive pregnancy test result prior to receiving
IMP.
3.
Need for chronic diuretic use.
4.
Hepatic impairment based on liver function abnormalities other than that expected for ADPKD 
with cystic liver disease during screening based on recent historical laboratory values (in the last 
3 months).
5.
Subjects with contraindications to required trial assessments (contraindications to optional 
assessments, eg, MRI are not a limitation).
6.
Subjects who, in the opinion of the investigator or medical monitor, have a medical history or 
medical finding inconsistent with safety or trial compliance.  This includes prior evidence of 
significant hepatic injury deemed to be related to tolvaptan use.
WOCBP=women of childbearing potential; IMP=investigational medicinal product
Non-childbearing potential in women is defined as female subjects who are surgically 
sterile (ie, have undergone bilateral oophorectomy or hysterectomy) or female subjects 
who have been postmenopausal for at least 12 consecutive months.
Subjects may be rescreened, at the discretion of the medical monitor, if the exclusion 
characteristic has changed or resolved.  In the event that a subject is rescreened, a new 
ICF must be signed and a new screening number assigned and screening procedures 
repeated.
3.5
Trial Endpoints
3.5.1
Safety Endpoints
This trial will have no formal endpoints.  Safety variables will be summarized by 
descriptive statistics, (eg, proportion, mean, median, standard deviation [SD], minimum, 
and maximum values).  In general, summary statistics, including changes from baseline, 
will be provided for safety variables based on all available data.  Safety endpoints will be
as follows:

Adverse events

Vital signs

Clinical laboratory assessments

Serum transaminase elevations for frequency (2x, 3x, 5x and 10x ULN), time to 
onset, time to peak levels, time of offset (< 3x, 2x, or 1x ULN), response to 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
156

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Protocol 156-13-211
Confidential - Otsuka Proprietary Information
32
06 March 2015
Screening 
(-30 to -1 days 
prior to Baseline)a
Baseline/ 
Day 0
Monthlyb
(± 7 days)
Every 
3 monthsb
(14 days)
Early 
Termination/End 
of Treatment
(+ 7 days)
Titration 
Contact 
(phone 
contact)
Follow-up
7 days post-
treatment
(+ 7 days)
Adverse events
Xn
-------------------------------------------------------------------------------------------------------------------
Concomitant medicationso 
-------------------------------------------------------------------------------------------------------------------
aThe last visit assessments from the previous trial can be combined with the screening and baseline visits for this trial, with all required assessments from each 
visit performed only once. 
bMonthly visits are for subjects < 18 months on tolvaptan, and every 3 month visits are for subjects > 18 months on tolvaptan.
c Includes prior trial identifiers (screening identification [ID], subject ID, site ID, prior tolvaptan ADPKD trial protocol number).
dVital signs at each visit include seated heart rate, calibrated blood pressure and post void body weight.  Height should be performed only at screening.
e Central laboratory non-fasting serum laboratory tests will be performed.  All subjects must be monitored for hepatic safety monthly until they have known 
tolvaptan exposure data of at least 18 months.  After that, and following the approval of the medical monitor, hepatic monitoring will take place every 
3 months.  Trial 156-13-210 subjects who are eligible for this trial will have trial visits/hepatic monitoring monthly for the first 18 months of this trial then 
every 3 months thereafter, because their tolvaptan exposure will be unknown.  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 changed to every 3 months sooner as their previous tolvaptan 
exposure in Trial 156-13-210 can count towards the 18 month threshold. Subjects who enroll from other ADPKD tolvaptan trials will be monitored for 
hepatic safely monthly for their first 18 months they are in this trial.
f Hepatitis testing at screening will be optional.  If hepatitis testing is performed, then both pre- and post-counseling activities relating to hepatitis testing are to be 
carried out based on local requirements and best practices.  Upon request, if clinically indicated and approved by the medical monitor, subjects may have the 
following evaluations in addition to the protocol-specified chemistry panel: serum calcium, phosphorous, parathyroid hormone, vitamin D, and bicarbonate 
levels.  
gA full liver function panel (AST, ALT, alkaline phosphatase, BT) will be done at screening.  All other liver function tests at subsequent visits are for ALT only, 
unless otherwise clinically indicated.  An ALT elevation > 2 × ULN should trigger prompt testing of hepatic function within 72 hours.  Any transaminase values 
which exceed 2 × ULN should prompt immediate retesting within 72 hours.  While values remain in an abnormal range, testing frequency should be increased to 
at least weekly for the first month, gradually returning to monthly, and every 3 months as indicated by the results.  Local liver function panel analyses will also 
be performed more frequently, if necessary.  
hUrine osmolality is optional.
i A urine pregnancy test for pregnancy for women of childbearing potential (WOCBP) will be performed at screening, at every 3 months visits, at the End of 
Treatment (EoTx) visit, and at the follow-up visit.  On suspicion of pregnancy, an unscheduled urine or serum pregnancy testing will be performed.  Positive 
urine pregnancy tests should be confirmed with a serum pregnancy test. 
j At-home urine pregnancy test kits will be dispensed to WOCBP to be used if a menstrual period is missed between visits.  Kits will be dispensed as needed 
throughout the trial. 
kA full physical examination is required at screening.  At other visits, an optional “directed” physical examination may be performed to focus on PKD-related 
signs and symptoms. 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated 
or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
159

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CCI

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
34
06 March 2015
3.7.1
Schedule of Assessments
3.7.1.1
Screening (-30 days to 1 day prior to Baseline)
Screening for eligibility is required for all subjects. The screening and baseline visits
may be combined with the last visit from either Trials 156-08-271 or 156-13-210 with all 
required assessments from each visit performed only once. Therefore, in some cases, if a 
subject enrolls in this trial from a prior tolvaptan trial, the end of trial or last follow-up 
visit for that trial and the screening and baseline visit for this one may occur 
simultaneously.  Required assessments for the screening visit are as follows:
1. Obtain subject consent.
2. Obtain subject’s new screening identification (ID) assigned by interactive 
response technology (IRT)
3. Determine subject eligibility through inclusion/exclusion criteria.
4. Record demographic information and prior trial identifiers (screening ID, subject 
ID, site ID, prior tolvaptan ADPKD trial protocol number).
5. Record medical/ADPKD history using prior trial data.
6. Review dietary recommendations and compliance
7. Record vital signs (post-void weight and seated heart rate) and in-clinic calibrated 
blood pressure (BP) measurement.  Record height.
8. Collect blood for serum chemistry, liver function panel (ALT, AST, BT, bilirubin 
[direct], and alkaline phosphatase), serum sodium, serum creatinine, and 
hematology and coagulation. Hepatitis testing is optional. If hepatitis testing is 
performed, then both pre- and post-counseling activities relating to hepatitis 
testing are to be carried out based on local requirements and best practices.  
9. Collect urine for urinalysis, urine osmolality (optional), and urine specific gravity.
10. Perform urine pregnancy test on women of childbearing potential (WOCBP).  If 
positive, a follow-up serum test will be performed.
11. Conduct full physical examination.
12. Enter subject into IRT including prior trial identifier/information (protocol 
number, subject ID), confirmed dose regimen, and scheduled date of next visit.
13. Assess AEs reported as ongoing or resolved from prior trial to determine entry as 
medical history or ongoing event for this trial.
14. Record ongoing concomitant medications. (This will happen only if the screening 
visit occurs simultaneously with the last visit from a previous tolvaptan trial).
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
161

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Protocol 156-13-211
Confidential - Otsuka Proprietary Information
40
06 March 2015
panel, urine pregnancy test (WOCBP), urine osmolality (optional), and urine specific 
gravity.
7-day Follow-up visit (+ 7 days): ALT, serum creatinine, and urine pregnancy test
(WOCBP).
Table 3.7.2.2-1
Clinical Laboratory Assessments
Hematology and Coagulation Panel:
Hemoglobin
Platelet count
Mean corpuscular hemoglobin concentration
(MCHC)
Mean corpuscular volume (MCV)
Red blood cell (RBC) count
White blood cell (WBC) count with differential 
Prothrombin time (PT) as international normalized 
ratio (INR)
Activated partial thromboplastin time (aPTT)
Urinalysis Panel:
Appearance
Color 
Blood
Glucose
Microscopic analysis, WBC/RBC counts per high 
power field
pH
Protein 
Urine Chemistry
Osmolality (optional)
Specific gravity
Additional Tests:
Urine (or serum) pregnancy for WOCBP
Hepatitis (optional)
Serum Chemistry Panel:
Albumin
Blood urea nitrogen (BUN)
Serum calcium
Carbon dioxide
Serum chloride
Gamma-glutamyl transpeptidase
Cholesterol, total
Glucose
Lactate dehydrogenase (LDH)
Phosphorus
Potassium
Protein, total 
Uric acid
Liver Function Panel:
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Bilirubin, total (BT)
Bilirubin, direct
Creatinine
Sodium
If liver function panel, sodium and/or serum chemistry assessments are scheduled at the 
same visit, all values should be determined from the same blood sample.  Blood testing 
for hepatitis will be optional for all subjects.  Urine pregnancy testing will be performed 
with commercially available, high-sensitivity kits supplied to the subject by the site 
(acquired by the sponsor).
3.7.2.3
Physical Examination and Vital Signs
A full physical examination will be performed and documented at the screening visit 
although this may be combined with the last visit from the previous trial. At other visits, 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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16.1.1 Protocol and Protocol Amendments
167

Protocol 156-13-211
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41
06 March 2015
an optional directed physical examination may be performed to focus on ADPKD-related 
signs and symptoms.  In some geographic regions, more frequent subject visits may be 
the norm; however vital signs and clinically significant physical findings will be recorded 
as an unscheduled visit in the electronic case report form (eCRF) as applicable. Any 
changes in medication or AEs will be recorded in the eCRF.
Height will be measured only at screening.  Body weight will be taken post-void.  It is 
preferable to use the same scale for each measurement.  Clinic scales should be calibrated 
at least yearly. The investigator or his/her appointed designee is primarily responsible to 
perform the physical examination.  If the appointed designee is to perform the physical 
examination, he/she must be permitted to do so by local regulations and his/her name 
must be included on any globally and locally required documents (eg, individual must be 
added for all sites on a US Food and Drug Administration (FDA) Form 1572, where local 
regulations allow, while local regulations determine their being named in the ICF).  
Whenever possible, the same individual should perform all physical examinations.  Any 
undesirable condition present at a post-treatment physical examination that was not 
present at the baseline examination should be documented as an AE and followed to a 
satisfactory conclusion.
Vital sign data, including seated blood pressure, heart rate, height, and weight will be 
taken at the visits identified in the Schedule of Assessments (Table 3.7-1).
3.7.2.4
Assessment of Liver Symptoms, Signs or Test Abnormalities
Testing for hepatic transaminase (ALT/AST), alkaline phosphatase, bilirubin direct, and 
BT will be performed during screening.  Subjects enrolling from the double-blind Trial 
156-13-210 will have monthly ALT assessments for the first 18 months while the 
treatment code from Trial 156-13-210 remains blinded to ensure that all subjects have 
adequate safety monitoring during this period of susceptibility.  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 changed to every 
3 months sooner as their previous tolvaptan exposure in Trial 156-13-210 can count 
towards the 18-month threshold.
Following the first 18 months, ALT assessments will be made every 3 months for 
Trial 156-13-210 subjects and for subjects from other tolvaptan ADPKD trials besides 
Trial 156-08-271.  
Subjects enrolling from the open-label Trial 156-08-271 who have tolvaptan exposure 
greater than 18 months will continue with ALT monitoring every 3 months.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
168

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
42
06 March 2015
Subjects enrolling from prior tolvaptan trials besides Trial 156-08-271 will have monthly 
ALT assessments for the first 18 months.  Upon reaching 18 months of exposure and 
after confirmation from the medical monitor, the frequency of ALT monitoring for these 
subjects will occur every 3 months.
ALT will also be assessed at the Early Termination/EoTx visit and at the 7-day Follow-
up visit.
Management of liver abnormalities is discussed in the paragraphs below.
3.7.2.4.1
Liver Test Abnormalities and Interruption/Discontinuation of 
Investigational Medicinal Product
An ALT elevation 2 × ULN or the appearance of any suspicious symptom or sign should 
trigger prompt testing of hepatic function (ie, within 72 hours).  Local laboratory testing 
is acceptable, ideally with a concurrent central laboratory sample for confirmation.  
Any transaminase or bilirubin values which exceed 2 × ULN should also prompt 
immediate retesting within 72 hours.  While values remain in an abnormal range, testing 
frequency should be increased to at least weekly for the first month, gradually returning 
to monthly, or every three months as indicated by the results.
Liver transaminase levels reaching or exceeding 2 × ULN that have an uncertain or 
rapidly increasing trajectory should prompt at least temporary IMP interruption. 
Tolvaptan should not be resumed until monitoring indicates abnormalities have resolved, 
are stable, or are not rapidly increasing, and then only with an increased frequency of 
monitoring.
Subjects would not typically be allowed to resume treatment with tolvaptan if they have:

transaminase levels rise above 8 × ULN,

transaminase levels are > 5 × ULN for more than 2 weeks, or

concurrent elevations of transaminase > 3 × ULN and BT > 2 × ULN.
Subjects with these levels of abnormality may be re-challenged with IMP if abnormalities 
were adjudicated as having a < 50% likelihood of being related to IMP (per DILI network 
[DILIN] probability criteria)10 by an independent hepatic adjudication committee (HAC) 
and the investigator and medical monitor agree to an intensive monitoring plan to 
mitigate risk.  The subject must also be willing to comply with these monitoring 
measures, be informed of the potential risks, and consent to IMP re-challenge.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
169

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Protocol 156-13-211
Confidential - Otsuka Proprietary Information
45
06 March 2015
3.7.5
Treatment Interruption and Discontinuation
In this trial, it is expected that subjects may possibly have one or more planned or 
unplanned treatment interruptions.  If a subject’s IMP treatment must be interrupted for 
medical or surgical reasons, liver test abnormalities, use of a prohibited medication, or 
other reasons (eg, hospital admission for an invasive procedure, a major medical 
condition, surgery, dental work, or a temporary situation that prevents subject compliance 
with the IMP administration schedule), the investigator should be notified as soon as 
possible and the reason for treatment interruption must be documented in the source 
documents and case report form (CRF).  If permissible, the subject’s IMP may be 
resumed following approval by the medical monitor.
If IMP treatment is permanently discontinued, the reason for discontinuation must be 
recorded appropriately in the source document and in the CRF.
A subject who permanently discontinues IMP treatment  ends trial participation and the 
early termination visit should be completed.
3.7.6
End of Trial
The End of Trial date is defined as the last date of contact or the date of final contact 
attempt from the post-treatment Follow-up CRF page for the last subject completing or 
withdrawing from the trial.
3.7.7
Independent Data Monitoring Committee
For this trial, an Independent Data Monitoring Committee (IDMC), also known as a Data 
Safety and Monitoring Committee, will be established.  The role of the IDMC shall be
delineated in a separate IDMC Charter document, but in general this group will meet on a 
regular basis to ensure the safe and ethical treatment of trial subjects, ensure the scientific 
integrity of the trial, and to ensure the trial is conducted within the bounds of ethical 
medical practice. Adjudication results as determined by the HAC will be reported to the 
IDMC on a quarterly basis or more frequently as necessary. This IDMC may make 
recommendations to the sponsor and trial steering committee to amend or terminate the 
trial based on grounds of safety, futility, or greater than expected efficacy as defined by 
the accepted statistical practices and procedures detailed in their Charter.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
172

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
46
06 March 2015
3.8
Stopping Rules, Withdrawal Criteria, and Procedures
3.8.1
Entire Trial 
If the sponsor terminates or suspends the trial for safety or unanticipated other reasons, 
prompt notification will be given to investigators, IRBs/IECs, and regulatory authorities 
in accordance with regulatory requirements.
3.8.2
Individual Site
The investigator will notify the sponsor promptly if the trial is terminated by the 
investigator or the IRB/IEC at the site. If the investigator, IRB/IEC or sponsor decides to 
terminate or suspend the trial’s conduct at a particular center for safety, non-enrollment 
of subjects, non-compliance with the protocol, or unanticipated other reasons, the above 
and other parties, as required by the applicable regulatory requirements, will be promptly 
notified.
3.8.3
Individual Subject
If a subject discontinues the trial prematurely, the reason must be fully evaluated and 
recorded appropriately in source documents and the CRF.  If the subject is being 
withdrawn because of an AE, that AE should be indicated as the reason for withdrawal.  
All subjects have the right to withdraw at any time during treatment without prejudice.  
The investigator can discontinue a subject’s participation in the trial at any time if 
medically necessary.  It is preferred that subjects who permanently discontinue IMP will 
have the option to continue participation off IMP with regular scheduled visits or with a 
modified (ie, less frequent) schedule.  If subjects are unable or unwilling to complete the 
visits and procedures off IMP, the early termination/EoTx visit should be completed.  
The investigator may continue to contact those who discontinue IMP through to the final 
completion date of the trial or thereafter if needed to determine outcomes ie, vital status.  
In addition, subjects meeting the following criteria must be withdrawn from the trial:
a) Occurrence of any AE, intercurrent illness, or abnormality in a laboratory assessment 
which, in the opinion of the investigator, warrants the subject’s permanent withdrawal 
from the trial;
b) Subject noncompliance, defined as refusal or inability to adhere to the trial schedule or 
procedures (see Section 3.12);
c) At the request of the subject, investigator, sponsor, or regulatory authority;
d) Subject is lost to follow-up.
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The investigator will notify the sponsor promptly when a subject is withdrawn.
3.9
Screen Failures
A screen failure subject is one from whom informed consent is obtained and is 
documented in writing (ie, subject signs an ICF), but who is not started on treatment.
3.10
Definition of Completed Subjects
For purposes of this trial, subjects who complete the EoTx visit will be defined as trial 
completers.
3.11
Definition of Subjects Lost to Follow-up
Subjects, or the subject’s parent/guardian who cannot be contacted on or before their final 
visit prior to the trial termination date, who do not have a known reason for 
discontinuation (eg, withdrew consent or AE) and for whom a current health status at the 
end of the trial cannot be determined will be classified as “lost to follow-up” as the 
reason for discontinuation.  Current health status can be determined from a variety of 
sources, either by obtaining acceptable documentation for death (ie, death certificate, 
medical records, public records, or statement by a family member or primary care 
physician) or acceptable documentation for life (ie, direct contact with the subject, 
medical records, successful telephone contact with the subject, statement by a family 
member or primary care physician, or public records).  It is expected that 3 documented 
attempts will be made to determine a subject’s current health status before assigning a 
“lost to follow-up” status.
3.12
Subject Compliance 
Subject compliance will be monitored by pill counts as IMP is returned.  Any subject 
who, without the instruction of the investigator, discontinues tolvaptan investigational 
product, discontinues tolvaptan for 30 consecutive days or misses > 30% of the doses 
intended for a period between visits (whichever is greater) will be deemed noncompliant. 
Depending on the circumstances leading to noncompliance, the subject may be 
withdrawn from the trial or discontinued from investigational product administration by 
the investigator and/or sponsor.  It is preferred that subjects who discontinue tolvaptan, or 
are withdrawn by the investigator for reasons other than noncompliance or lost to follow-
up, will continue with regularly scheduled visits completing all procedures as provided in 
the protocol.
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3.13
Protocol Deviations
This trial is to be conducted as described in this protocol.  In the event of a significant 
deviation from the protocol due to an emergency, accident or mistake (eg, violation of 
informed consent process, IMP dispensing or subject dosing error, subject enrolled in 
violation of eligibility criteria or concomitant medication criteria), the investigator or 
designee must contact the sponsor at the earliest possible time.  This will allow an early 
joint decision regarding the subject’s continuation in the trial.  This decision will be 
documented by the investigator and the sponsor, and reviewed by the site monitor.
4
Restrictions
4.1
Prohibited or Restricted Medications
Medications or surgical therapies used for the purpose or potential for modifying the 
progression of PKD cyst growth or development will be prohibited.  These include, but 
are not restricted to, somatostatin agonists, rapamune (sirolimus), anti-sense ribonucleic 
acid therapies, vasopressin antagonists other than tolvaptan, (eg, OPC-31260 
(mozavaptan), Vaprisol (conivaptan), agonists (eg, desmopressin) and cyst 
decompression surgery.
Continuous or short-term use of other medications, while not prohibited, may be 
restricted by the investigator because of their potential for interference with tolvaptan 
metabolism (see Section 3.2.1 and Section 3.2.2). 
A partial list of strong and moderate CYP3A4 inhibitors can be found in Table 4.1-1
below:
Table 4.1-1
Strong and Moderate CYP3A Inhibitors (partial list)
amprenavir
atorvastin
aprepitant
chloramphenicol (if 
used orally)
cimetidine
clarithromycin
clotrimazole (if used 
orally)
danazol
delavirdine
diltiazem
erythromycin
fluconazole
fluvoxamine
indinavir
isoniazid
itraconzazole
josamycin
ketoconazole (if used 
orally)
nelfinavir
nefazadone
quinupristin/ dalfopristin
ritonavir
saquinavir
troleandomycin
verapamil
Seville orange products
grapefruit products
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Pharmacodynamic interactions are a consideration for the use of diuretics, which may be
only used intermittently, and not within 7 days of a urine assessment.  Diuretics are not 
generally recommended in ADPKD due to their tendency to increase AVP levels through 
relative dehydration or volume depletion; thus, chronic use of diuretics (eg, for 
hypertension) will be prohibited and is an exclusionary criterion for this trial. 
Some drugs are known to alter creatinine concentrations so, while not prohibited, subjects 
should alert their trial doctor, and any other health-care providers, to take this into 
consideration when considering changes in their prescribed or over-the-counter 
medications.  A list would include:  non-steroidal anti-inflammatory drugs like aspirin or 
ibuprofen, chemotherapy drugs, cephalosporin, the combination of elvitegravir, 
cobicistat, emtricitabine, and tenofovir (Stribild), dolutegravir, dronedarone, 
ranolazine, metformin, and trimethoprim.
4.2
Dietary Restrictions and Recommendations
Restriction of excess dietary sodium and cooked meat protein may prove beneficial to 
subjects with a history of, or predisposition for, hypertension or kidney disease in general 
and should be applied to all subjects diagnosed with advanced ADPKD, particularly if 
there is evidence for a propensity for rapid progression.  In the absence of alternate 
regional practices, dietary salt < 5g/day, dietary cooked meat protein < 1 g/kg/day and a
limit on caffeinated drinks/foods should also be given (no more than 2 coffee equivalents 
per day).  A history of alcohol and smoking intake will be collected at screening.  
Alcohol and tobacco consumption should be avoided or minimized as much as possible.
Additionally, fluid intake is generally encouraged in subjects with PKD.  Given the 
potential for dehydration with tolvaptan treatment, all subjects should be instructed to 
ingest fluids in anticipation of, or at the first sign of thirst in order to avoid excessive 
thirst or dehydration.  Upon consent, all subjects should receive the recommendation to 
ingest at least 2 to 3 liters of fluid (including in solid, semi-solid, and liquid foods) per 
day, unless otherwise directed by their trial doctor.  This recommendation should start 
during screening and continue through the end of the trial.  Additionally, subjects should 
ingest 1 to 2 cups of water before bedtime regardless of perceived thirst, and replenish 
fluids overnight with each episode of nocturia.  Dehydration will be monitored by subject 
self-assessment of changes in body weight and reporting of symptoms.  Acute changes of 
> 3% of body weight (increase or decrease) over any 7-day period should be noted.  
Subjects should be instructed to report acute changes in body weight to the trial physician 
for further evaluation and recommendations.
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Subjects should be advised that the ingestion of pomelo, grapefruit, or Seville orange 
products would be expected to increase tolvaptan concentrations and these should be 
avoided.  In the event of an unintentional ingestion of such products, the investigator may 
ask the subject to temporarily interrupt the IMP. 
5
Reporting of Adverse Events
The following describes the methods and timing for assessing, recording, and analyzing 
safety parameters, as well as the procedures for eliciting reports of and recording and 
reporting AEs and intercurrent illnesses and the type and duration of the follow-up of 
subjects after AEs.
Medical follow up is expected for AEs which lead to discontinuation which are serious, 
or which are of special interest (eg, liver abnormalities, skin neoplasms, glaucoma).
ADPKD is a progressive disorder involving the kidney, liver and occasionally other 
organ systems.  A number of AEs may be associated with this disorder including urine 
concentration defects, hypertension, renal pain, renal infection, nephrolithiasis, 
hematuria, and ESRD.  As such, these events are considered “expected” in this trial 
population and will not qualify for the purposes of regulatory expedited reporting (eg, 
Suspected Unexpected Serious Adverse Reaction and investigational new drug [IND] 
safety reports).
5.1
Definitions
An AE is defined as any untoward medical occurrence associated with the use of an IMP
in humans, whether or not considered IMP related.
A suspected adverse reaction means any AE for which there is a reasonable possibility 
that the IMP caused the AE. For the purpose of IND safety reporting, “reasonable 
possibility” means there is evidence to suggest a causal relationship between the IMP and 
the AE. Suspected adverse reaction implies a lesser degree of certainty about causality.
A serious adverse event (SAE) includes any event that results in any of the following 
outcomes:
1. Death
2. Life-threatening, ie, the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred.  It does not include an 
event that, had it occurred in a more severe form, might have caused death.
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3. Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions.
4. Requires inpatient hospitalization or prolongs hospitalization
NOTE: A pre-scheduled hospitalization is not considered an SAE.
5. Congenital anomaly/birth defect
6. Other medically significant events that, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above, eg, allergic 
bronchospasm requiring intensive treatment in an emergency room or home, 
blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse.
Nonserious AEs are all AEs that do not meet the criteria for a "serious" AE.
Immediately Reportable Event (IRE):

Any SAE

Any AE (whether serious or nonserious) that necessitates discontinuation of IMP.

Any subject with a new liver test abnormality meeting the AE (whether serious or 
nonserious) or laboratory threshold criteria (whether considered an AE or not) for 
hepatic eCRF reporting.

Any subject reporting an AE of special interest (eg, skin neoplasms or glaucoma).

Pregnancies are also defined as IREs.  Although normal pregnancy is not an AE, 
it will mandate IMP discontinuation and must be reported on an IRE form to 
Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC).  
Pregnancy will only be documented on the AE eCRF if there is an abnormality or 
complication.

Additionally, in the EU region, events involving overdose, misuse and abuse as 
well as reported lack of efficacy must also be reported as IREs.
Clinical Laboratory Changes:  It is the investigator’s responsibility to review the results 
of all laboratory tests as they become available.  This review will be documented by the 
investigator’s dated signature on the laboratory report.  For each abnormal laboratory test 
result, the investigator needs to ascertain if this is an abnormal (ie, clinically significant) 
change from baseline for that individual subject. This determination, however, does not 
necessarily need to be made the first time an abnormal value is observed.  The 
investigator may repeat the laboratory test or request additional tests to verify the results 
of the original laboratory tests.  If this laboratory value is determined by the investigator 
to be an abnormal change from baseline for that subject, this is considered an AE.
Severity:  Adverse events will be graded on a 3-point scale and reported as indicated on 
the CRF.  The intensity of an adverse experience is defined as follows:
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1 = Mild:
Discomfort noticed, but no disruption to daily activity.
2 = Moderate:
Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe:
Inability to work or perform normal daily activity.
IMP Causality: Assessment of causal relationship of an AE to the use of the IMP:
Related: 
There is a reasonable probability or possibility of a temporal and 
causal relationship between the IMP and the AE.
Not Related: 
There is no temporal or causal relationship to the IMP 
administration.
5.2
Eliciting and Reporting Adverse Events
The investigator will periodically assess subjects for the occurrence of AEs.  In order to 
avoid bias in eliciting AEs, subjects should be asked the following non-leading question: 
“How have you felt since your last visit?”  All AEs (serious and nonserious) reported by 
the subject must be recorded on the source documents and eCRFs provided by the 
sponsor.
In addition, Quintiles (drug safety service) must be notified immediately by telephone or 
fax of any immediately reportable events according to the procedure outlined below in
Section 5.3.  Special attention should be paid to recording hospitalization and 
concomitant medications.
5.3
Immediately Reportable Events
The investigator must immediately report within 24 hours after either the investigator or 
site personnel become aware of any SAE, new liver laboratory abnormality requiring 
special liver eCRF completion, or confirmed pregnancy, by telephone or by fax to 
Quintiles (drug safety service) as outlined in Appendix 1.  An IRE form must be 
completed and sent by fax, email or overnight courier to the sponsor.  (Please note that 
the IRE form is NOT the AE eCRF).
Nonserious events that require discontinuation of IMP (including laboratory 
abnormalities) should be reported to the sponsor within 3 working days.  The IRE form 
must be completed and sent by fax, email, or overnight courier to the sponsor.
Subjects experiencing SAEs should be followed clinically until their health has returned 
to baseline status, or until all parameters have returned to normal, or have otherwise been 
explained.  It is expected that the investigator will provide or arrange appropriate 
supportive care for the subject.
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5.4
Pregnancy
Women of childbearing potential who are sexually active must use an effective method of 
birth control during the course of the trial and for 30 days after the last dose of IMP in a 
manner such that risk of failure is minimized.  Unless the subject is sterile (ie, women 
who have had an bilateral oophorectomy and/or hysterectomy or have been 
postmenopausal for at least 12 consecutive months or remains abstinent, 2 of the 
following precautions must be used: vasectomy, tubal ligation, intrauterine device, birth 
control pills, birth control depot injection, birth control implant, condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicide.  Any single method of birth control, 
including vasectomy and tubal ligation, may fail, leading to pregnancy.  Abstinence is 
only acceptable when part of the preferred and usual lifestyle of the subject; should that 
lifestyle change, double barrier contraceptive methods should be employed.
Before enrolling WOCBP in this clinical trial, investigators must review guidelines about 
trial participation for WOCBP.  The topics should generally include:

General information

ICF

Pregnancy prevention information

Drug interactions with hormonal contraceptives.

Contraceptives in current use.

Guidelines for the follow-up of a reported pregnancy.
Prior to trial enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy.  The subject must sign an ICF stating that the above-mentioned risk factors 
and the consequences were discussed with her.
During the trial, all WOCBP should be instructed to contact the investigator immediately 
if they suspect they might be pregnant (eg, missed or late menstrual cycle).
If a subject or investigator suspects that the subject may be pregnant prior to IMP 
administration, the IMP administration must be withheld until the results of serum 
pregnancy tests are available.  If the pregnancy is confirmed, the subject must not receive 
the IMP and must not be enrolled in the trial.  If pregnancy is suspected while the subject 
is taking IMP, the IMP must be withheld immediately (if reasonable, taking into 
consideration any potential withdrawal risks) until the result of the pregnancy is known.  
If pregnancy is confirmed, the IMP will be interrupted or withheld in an appropriate 
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manner (eg, dose tapering if necessary for subject safety) and the subject will continue to 
be monitored for the duration of the remainder of the trial or of their pregnancy.
The investigator must immediately notify the sponsor of any pregnancy associated with 
IMP exposure, during the trial and for 30 days after the last dose of IMP and record the 
event on the IRE form and forward it to the sponsor.  The sponsor will forward 
Pregnancy Surveillance Form(s) for monitoring the outcome of the pregnancy.
Protocol required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies).  Other appropriate 
pregnancy follow-up procedures should be considered if indicated.  In addition, the 
investigator must report to the sponsor, on appropriate Pregnancy Surveillance form(s), 
follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome.  Infants will be followed for a minimum of 6 months.
5.5
Follow-up of Adverse Events
For this trial, AEs will be followed up for 7 days after the last dose of tolvaptan has been 
administered (follow-up period).
Subjects experiencing SAEs should be followed clinically until their health has returned 
to baseline status, or until all parameters have returned to normal, or have otherwise been 
explained.
5.5.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified on the last scheduled contact must be recorded on the 
AE eCRF with the current status noted.  All nonserious events that are ongoing at this 
time will be recorded as ongoing on the eCRF.
5.5.2
Follow-up of Post-Trial Serious Adverse Events
Serious AEs that are identified on the last scheduled contact must be recorded on the 
AE eCRF page and reported to the sponsor according to the reporting procedures outlined 
in Section 5.3.  This may include unresolved previously reported SAEs, or new SAEs.  
The investigator will follow SAEs until the events are resolved, or the subject is lost to 
follow-up.  Resolution means the subject has returned to the baseline state of health, or 
the investigator does not expect any further improvement or worsening of the subject’s 
condition.  The investigator will continue to report any significant follow-up information 
to OPDC up to the point the event has been resolved.
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59
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8.3
Accountability
The investigator or designee must maintain an inventory record of IMP received, 
dispensed, administered, and returned.
8.4
Returns and Destruction
Upon completion or termination of the trial, all unused and/or partially used IMP must be 
returned to the sponsor or a designated agent.
All IMP returned to the sponsor must be accompanied by appropriate documentation and 
be identified by protocol number with trial site number on the outermost shipping 
container.  Returned supplies should be in the original containers (eg, subject kits).  The 
assigned trial monitor will facilitate the return of unused and/or partially used IMP.
9
Records Management
9.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation.  Source documents will include but are not limited to progress 
notes, electronic data, screening logs, and recorded data from automated instruments.  All 
source documents pertaining to this trial will be maintained by the investigators. 
Investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, 
and regulatory inspection(s) by providing direct access to source data/documents by
authorized persons as defined in the ICF.
9.2
Data Collection
During each subject’s visit to the clinic, a clinician participating in the trial will record 
progress notes to document all significant observations.  At a minimum, these notes will 
contain:

Documentation of the informed consent process, including any revised consents;

The date of the visit and the corresponding visit or Day in the trial schedule;

General subject status remarks, including any significant medical findings.  The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator's assessment of relationship to IMP must also be recorded;

Any changes in concomitant medications or dosages;

A general reference to the procedures completed; 

The signature (or initials) and date of each clinician (or designee) who made an entry 
in the progress notes.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above.  Any changes to information in the trial progress notes and other source 
documents will be initialed and dated on the day the change is made by a site staff 
member authorized to make the change.  Changes will be made by striking a single line 
through erroneous data (so as not to obliterate the original data), and clearly entering the 
correct data (eg, wrong data right data).  If the reason for the change is not apparent, a 
brief explanation for the change will be written in the source documentation by the 
clinician.
Information from the trial progress notes and other source documents will be entered by 
investigative site personnel directly onto eCRFs in the sponsor’s electronic data capture
system. Changes to the data will be captured by an automatic audit trail.
9.3
File Management at the Trial Site
The investigator will ensure that the trial site file is maintained in accordance with 
Section 8 of the ICH GCP Guideline and as required by applicable local regulations. The 
investigator/institution will take measures to prevent accidental or premature destruction 
of these documents.
9.4
Records Retention at the Trial Site
Regulatory requirements for the archival of records for this trial necessitate that 
participating investigators maintain detailed clinical data for the longest of the following 
three periods:

A period of at least 2 years following the date on which approval to market the IMP is 
obtained (or if IMP development is discontinued, the date regulatory authorities were 
notified of discontinuation); OR

A period of at least 3 years after the sponsor notifies the investigator that the final 
report has been filed with regulatory authorities.

Longer, region-specific storage requirements, if applicable.The investigator must not 
dispose of any records relevant to this trial without either (1) written permission from the 
sponsor or (2) provision of an opportunity for sponsor to collect such records.  The 
investigator will be responsible to maintain adequate and accurate electronic or hard copy 
source documents of all observations and data generated during this trial.  Such 
documentation is subject to inspection by the sponsor and relevant regulatory authorities.  
If the investigator withdraws from the trial (eg due to relocation or retirement), all trial-
related records should be transferred to a mutually agreed-upon designee within a 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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61
06 March 2015
sponsor-specified timeframe.  Notice of such transfer will be given to the sponsor in 
writing.
10
Quality Control and Quality Assurance 
10.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial carefully in a 
detailed and orderly manner in accordance with established research principles, the ICH 
GCP Guideline, and applicable regulatory requirements and local laws.  As part of a 
concerted effort to fulfill these obligations (maintain current personal knowledge of the 
progress of the trial), the sponsor's monitors will visit the site during the trial, as well as 
communicate frequently via telephone and written communications.
10.2
Auditing
The sponsor's Quality Management Unit (or representative) may conduct trial site audits.  
Audits will include but are not limited to IMP supply, presence of required documents, 
the informed consent process, and comparison of eCRFs with source documents.  The 
investigator agrees to participate with audits.
Regulatory authorities may inspect the investigator site during or after the trial.  The 
investigator will cooperate with such inspections and will contact the sponsor 
immediately if such an inspection occurs.
11
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, the ICH GCP Guideline, 
and applicable local laws and regulatory requirements. Each trial site will seek approval 
by an IRB or IEC according to regional requirements. The IRB/IEC will evaluate the 
ethical, scientific and medical appropriateness of the trial. Further, in preparing and 
handling CRFs, the investigator, sub-investigator and their staff will take measures to 
ensure adequate care in protecting subject privacy. To this end, a subject number and 
subject ID code will be used to identify each subject. 
Financial aspects, subject insurance and the publication policy for the trial will be 
documented in the agreement between the sponsor and the investigator.
12
Confidentiality
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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written permission.  Subject confidentiality requirements of the region(s) where the trial 
is conducted will be met.  However, authorized regulatory officials and sponsor personnel 
(or their representatives) will be allowed full access to inspect and copy the records.  All 
IMPs, subject bodily fluids, and/or other materials collected shall be used solely in 
accordance with this protocol, unless otherwise agreed to in writing by the sponsor.
Subjects will be identified only by initials and unique subject numbers in eCRFs.  Their 
full names may, however, be made known to a regulatory agency or other authorized 
officials if necessary.
13
Amendment Policy
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval by the IRB/IEC.  Any permanent change to the 
protocol, whether it be an overall change or a change for specific trial site(s), must be 
handled as a protocol amendment.  Any amendment will be written by the sponsor.  Each 
amendment will be submitted to the IRB/IEC.  Except for “administrative” or “non-
substantial” amendments, investigators will wait for IRB/IEC approval of the amended 
protocol before implementing the change(s).  Administrative amendments are defined as 
having no effect on the safety of subjects, conduct or management of the trial, trial 
design, or the quality or safety of IMP(s) used in the trial.  A protocol change intended to 
eliminate an apparent immediate hazard to subjects should be implemented immediately, 
followed by IRB/IEC notification within 5 working days.  The sponsor will submit 
protocol amendments to the applicable regulatory agencies.
When the IRB/IEC, investigators, and/or the sponsor conclude that the protocol 
amendment substantially alters the trial design and/or increases the potential risk to the 
subject, the currently approved written ICF will require similar modification.  In such 
cases, repeat informed consent will be obtained from subjects enrolled in the trial before 
expecting continued participation.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
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63
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14
References
1
European Medicines Agency, Public summary of opinion on orphan designation: 
Tolvaptan for the treatment of autosomal dominant polycystic kidney disease. 
Committee for Orphan Medicinal Products. 2013; EMA/COMP/444684/2013.
2
U S Renal Data System, USRDS 2012 Annual Data Report: Atlas of Chronic Kidney 
Disease and End-Stage Renal Disease in the United States, National Institutes of 
Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, 
MD, 2012
3
Lentine KL, Xiao H, Machnicki G, Gheorghian A, Schnitzler MA. Renal function 
and healthcare costs in patients with polycystic kidney disease. Clin J Am Soc 
Nephrol. 2010 Aug;5(8):1471-9.
4
OPC-41061 Investigator’s Brochure. Rockville (MD): Otsuka Pharmaceutical 
Development & Commercialization, Inc.; Edition 19 Otsuka Report, issued 11 July 
2013.
5
OPC-41061 Common Technical Document.  Rockville (MD): Otsuka Pharmaceutical 
Development & Commercialization, Inc.; Section 2.5: Clinical Overview; 2013.
6
Wang X, Gattone V 2nd, Harris PC, Torres VE. Effectiveness of vasopressin V2 
receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease 
development in the PCK rat. J Am Soc Nephrol. 2005 Apr;16(4):846-51. 
7
Reif GA, Yamaguchi T, Nivens E, Fujiki H, Pinto CS, Wallace DP. Tolvaptan 
inhibits ERK-dependent cell proliferation, Cl- secretion, and in vitro cyst growth of 
human ADPKD cells stimulated by vasopressin. Amer J Physiol Renal Physiol. 2011 
Nov;301(5):F1005-13.
8
Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, 
et al for the TEMPO 3:4 Trial Investigators.  Tolvaptan in patients with autosomal 
dominant polycystic kidney disease. N Engl J Med 2012;367:2407-18.
9
Higashihara E, Torres VE, Chapman AB, Grantham JJ, Bae K, Watnick TJ, et al. 
Tolvaptan in autosomal dominant polycystic kidney disease: three years' experience. 
Clin J Am Soc Nephrol. 2011 Oct;6(10):2499-507.
10 U.S. Food and Drug Administration. Guidance for Industry. Drug-induced liver 
injury: premarketing clinical evaluation [report on the internet]. 2009 Jul [cited 2012 
Oct 10];[about 23 p.].  Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceCompliance
RegulatoryInformation/Guidances/UCM174090.pdf.
11 Pei Y, Obaji J, Dupuis A, et al. Unified criteria for ultrasonographic diagnosis of 
ADPKD. J Am Soc Nephrol 2010 20: 205-212.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
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190

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64
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12 Ravine D, Gibson RN, Walker RG, et al. Evaluation of ultrasonographic diagnostic 
criteria for autosomal dominant polycystic kidney disease 1. Lancet 1994; 343:824-
827.
13 Levey AS, Stevens LA, et al. A new equation to estimate glomerular filtration rate.  
Ann Intern Med. 2009; 150:604-612.
14 International Conference on Harmonisation; Good Clinical Practice: Consolidated 
Guideline; Notice of Availability, 62 C.F.R. Sect. 90 (1997).
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
191

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Protocol 156-13-211
Confidential - Otsuka Proprietary Information
72
06 March 2015
Sectional Revisions
Location
Old Text
Updated Text
Synopsis, Trial Design
Subjects will be eligible for screening 
into this trial if they:
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 off-treatment),or
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 a split-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.
Subjects will be eligible for 
screening into this trial if they:

Completed and 
transferred from the 
double-blind 
Trial 156-13-210 
(12-month period 
including post-treatment 
follow-up, regardless of 
whether this was on-
treatment or off-
treatment), or 

Completed 
Trial 156-08-271 or a 
prior tolvaptan ADPKD 
trial, or

Interrupted or 
discontinued treatment in 
a prior tolvaptan ADPKD 
trial (other than 
Trial 156-13-210).  
Subjects may be enrolled 
with the medical monitor 
approval, and additional 
close monitoring may be 
required at the beginning 
of the trial
For purposes of ensuring subject 
safety, all subjects will be 
monitored for hepatic safety 
monthly until 18 months of 
tolvaptan exposure has been 
collected..  After that, and 
following the approval from the 
medical monitor, hepatic 
monitoring will be required 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 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
199

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
73
06 March 2015
Location
Old Text
Updated Text
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.
Synopsis, Subject 
Population
This trial will include up to 2,450 
subjects over the age of 18 years with  
ADPKD diagnosed by Pei-Ravine 
criteria (modified by magnetic 
resonance imaging [MRI]).
Renal function will be assessed 
during screening by using historical 
laboratory values for serum creatinine 
levels to calculate the estimated 
glomerular filtration rate (eGFR).  
The eGFR values will be estimated 
based on the Chronic Kidney Disease 
- Epidemiology (CKD-EPI) formula.
This trial will include 
approximately 2,500 subjects over 
the age of 18 years with ADPKD 
diagnosed by Pei-Ravine criteria 
(modified by magnetic resonance 
imaging [MRI]), and who have 
completed or participated in a 
prior tolvaptan ADPKD 
interventional investigational 
medicinal product (IMP) trial.
Synopsis, 
Inclusion/Exclusion 
Criteria
Main inclusion criteria:
Male and female subjects 
18 years with ADPKD who have 
completed either Trial 156-13-210 or 
Trial 156-08-271
Diagnosis of ADPKD by modified 
Pei-Ravine criteria
eGFR 20 mL/min/1.73m2 within 
45 days of the baseline visit. Subjects 
who have an eGFR between 15 and 
19 mL/min/1.73m2 may be enrolled 
with medical monitor approval
Main exclusion criteria:

Need for chronic diuretic use

Hepatic impairment based on 
liver function assessments other 
than that expected for ADPKD 
with cystic liver disease
Main inclusion criteria:

Male and female subjects 
18 years with confirmed 
diagnosis of ADPKD (during 
participation in prior 
tolvaptan trials) who have 

Completed and 
transferred from the 
double-blind 
Trial 156-13-210 
(12-month period 
including post-treatment 
follow-up, regardless of 
whether this was on-
treatment or off-
treatment), or 

Completed 
Trial 156-08-271 or a 
prior ADPKD tolvaptan 
trial, or

Interrupted or 
discontinued treatment in 
a prior tolvaptan ADPKD 
trial other than 
Trial 156-13-210.  
Subjects may be enrolled 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
200

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
74
06 March 2015
Location
Old Text
Updated Text
with the medical monitor 
approval, and additional 
close monitoring may be 
required at the beginning 
of the trial

Estimated glomerular 
filtration rate
(eGFR) 20 mL/min/1.73m2 
within 45 days of the baseline 
visit.  Subjects who have an 
eGFR between 15 and 
19 mL/min/1.73m2 may be 
enrolled with medical monitor 
approval

Renal function will be assessed 
during screening by using 
historical laboratory values (in 
the last 30 days) for serum 
creatinine levels to calculate 
the eGFR.  the eGFR values 
will be estimated based on the 
Chronic Kidney Disease -
Epidemiology (CKD-EPI) 
formula
Main exclusion criteria:

Need for chronic diuretic use

Hepatic impairment based on 
hepatic laboratory assessments
(alanine aminotransferase 
[ALT], aspartate 
aminotransferase [AST], 
bilirubin, total [BT]) other than 
that expected for ADPKD with 
cystic liver disease
Synopsis, Trial Site(s)
Up to 220 sites which may include 
North America, South America, 
Russian Federation and Australia.  
Approximately 220 enrolling sites 
including but not limited to the 
following regions: North America, 
South America, Eastern Europe, 
Western Europe, Russian 
Federation, and Australia.  
Synopsis, 
Investigational 
Medicinal Product(s), 
Dose, Dosage regimen, 
Treatment period, 
Formulation, Mode of 
Administration
Tolvaptan tablets (15 mg or 30 mg) 
will be self-administered orally as 
split-dose regimens, once upon 
awakening and another approximately 
8 to 9 hours later. Doses will be 
expressed as early dose/late dose (eg, 
60/30 mg). Allowed doses are 
15/15 mg, 30/15 mg, 45/15 mg, 
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 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
201

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
75
06 March 2015
Location
Old Text
Updated Text
60/30 mg and 90/30 mg.
All subjects will be started at a split-
dose of tolvaptan 45/15 mg and 
titrated according to tolerability. The 
dose range permitted will be a 
maximum of 90/30 mg and a 
minimum of 15/15 mg.
approximately 8 to 9 hours later.  
Doses will be recorded as early 
dose/late dose (eg, 60/30 mg).  
Subjects will receive open-label 
tolvaptan for the duration of the 
trial.  
A subject’s starting dose in this 
trial will be dependent on the trial 
in which they were previously 
enrolled:

156-13-210- initiated on 
tolvaptan at a split-dose of 
45/15 mg with upward 
titration every 3 to 4 days to 
60/30 mg or 90/30 mg per day 
according to tolerability

156-08-271- will retain the last 
dose level from 271 and start 
at the same dose in this trial 

Prior tolvaptan trials-
initiated on tolvaptan at a 
split-dose of 45/15 mg with 
upward titration every 3 to 
4 days to 60/30 mg or 
90/30 mg per day according to 
tolerability
Down titration to 30/15 mg or 
15/15 mg daily will be allowed at 
the discretion of the investigator 
according to individual tolerability 
and with medical monitor 
notification.  Further down 
titration to 30 or 15 mg once daily 
may be allowed only for metabolic 
drug-drug interaction and 
requires medical monitor 
approval.
Synopsis, Trial 
Assessments
…
Screening: Informed consent, medical 
history (including ADPKD updates, 
as required), determination of 
eligibility through inclusion/exclusion 
criteria, dietary review, vital signs, 
clinical laboratory assessments, 
complete physical examination, urine 
pregnancy test (women of child-
bearing potential only [WOCBP]), 
concomitant medications and 
laboratory tests to determine 
eligibility.
...
…
Screening: Informed consent, 
medical history (including ADPKD 
updates, as required), determination 
of eligibility through 
inclusion/exclusion criteria, dietary 
review, vital signs, clinical 
laboratory assessments, physical 
examination, urine pregnancy test 
(women of child-bearing potential 
only [WOCBP]), concomitant 
medications and laboratory tests to 
determine eligibility.
...
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
202

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Protocol 156-13-211
Confidential - Otsuka Proprietary Information
79
06 March 2015
Location
Old Text
Updated Text
Section 2.1, Trial 
Rationale
...
Over the 3 years of placebo-
controlled treatment, ALT was 
elevated to a greater than three times 
the upper limit of normal (> 3 × 
ULN) in 4.4% of tolvaptan subjects 
compared with 1% of placebo 
subjects.  To date, 3 tolvaptan 
subjects’ transaminases and bilirubin 
levels reached Hy’s laboratory 
criteria (> 3 × and > 2 × ULN, 
respectively).  Upon discontinuation, 
all subjects’ liver tests showed 
reversibility of the elevation within 
approximately 4 months after 
tolvaptan was discontinued.  
Nevertheless, without adequate 
monitoring and management, it is 
estimated that a 1:3,000 risk for 
irreversible liver injury may exist
…
Over the 3 years of placebo-
controlled treatment, ALT was 
elevated to a greater than three times 
the upper limit of normal (> 3 × 
ULN) in 4.4% of tolvaptan subjects 
compared with 1% of placebo 
subjects.  To date, 3 tolvaptan 
subjects’ transaminases and bilirubin 
levels reached Hy’s laboratory 
criteria (> 3 × and > 2 × ULN, 
respectively).  Upon discontinuation, 
all subjects’ liver tests showed 
reversibility of the elevation within 
approximately 4 months after 
tolvaptan was discontinued.  
Nevertheless, without adequate 
monitoring and management, it is 
estimated that a 1:4,000 risk for 
irreversible liver injury may exist
Section 3.1, 
Type/Design of Trial
This trial is a phase 3b, multi-center, 
open-label trial.
Subjects will be eligible for screening 
into this trial if they:
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 off-treatment), or
Participated in the open-label 
Trial 156-08-271
Upon the successful completion of 
Trial 156-13-210 or Trial 156-08-
271, subjects will have an opportunity 
to enroll into Trial 156-13-211 
immediately following completion of 
the follow-up visit(s) of the previous 
trial. The last follow-up visit 
assessments can be utilized for 
screening into this trial. However, for 
subjects who require a longer period 
between completion of the preceding 
trial and entry into this trial, this may 
This trial is a phase 3b, multi-center, 
open-label trial.
Eligible subjects will have an 
opportunity to enroll into 
Trial 156-13-211 immediately 
following completion of the 
follow-up visit(s) of the previous 
trial.  The last visit assessments 
from the previous protocol can be 
combined with the screening visit 
for this trial, with all required 
assessments from each visit only 
performed once, as long as the 
time between the last follow-up 
visit assessments from the 
previous trial and the screening 
visit for this trial is within 30 days.  
Medical monitor approval is 
needed for enrollment of subjects 
whose completion of the preceding 
trial prior to entry in this trial 
exceeds 3 months, and these 
subjects will be required to 
undergo all screening and baseline 
assessments.
After consenting, subjects will be 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
206

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CCI

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
82
06 March 2015
Location
Old Text
Updated Text
thirst or dehydration.  Additionally, 
subjects should ingest 1 to 2 cups of 
water before bedtime regardless of 
perceived thirst and replenish fluids 
overnight with each episode of 
nocturia.
tolvaptan at a split-dose of 
45/15 mg with upward 
titration every 3 to 4 days to 
60/30 mg or 90/30 mg per day 
according to tolerability

156-08-271- will retain the last 
dose level from 271 and start 
at the same dose in this trial 

Prior tolvaptan trials-
initiated on tolvaptan at a 
split-dose of 45/15 mg with 
upward titration every 3 to 
4 days to 60/30 mg or 90/30 
mg per day according to 
tolerability
Down titration to 30/15 mg and 
15/15 mg is also permitted at the 
discretion of the investigator 
according to subject tolerability 
with medical monitor notification.  
Further down titration to 30 or 
15 mg once daily may be allowed 
only for metabolic drug-drug 
interaction and requires medical 
monitor approval.
For subjects moving from the 
156-13-210 trial and requiring 
tolvaptan titration it will be
conducted in the following way: 
Subjects will be instructed to take 
tolvaptan starting at a split dose of 
45/15 mg (as 3 tablets upon 
waking and 1 tablet approximately 
8 to 9 hours later) and to titrate up 
every 3 to 4 days; first to 60/30 mg, 
then up to the maximum dose of 
90/30 mg.  Titration will be 
accomplished by increasing the 
number of tablets/dose and/or 
switching from 15 mg tablets to 
30 mg tablets.  Prior to each 
upward titration, the subject’s 
tolerability to the current dose will 
be assessed by asking, “Could you 
tolerate this dose of trial 
medication for the rest of your 
life?” Subjects will continue in the 
trial with the regimen to which 
tolerability was established.
While taking tolvaptan, all subjects 
should be instructed to ingest fluids 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
209

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CCI

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
85
06 March 2015
Location
Old Text
Updated Text
2.
Determine subject eligibility 
through inclusion/exclusion 
criteria
3.
Record demographic 
information and prior trial 
identifiers (screening
identification [ID], subject 
ID, site ID)
4.
Record medical/ADPKD 
history using prior trial data
5.
Review dietary 
recommendations and 
compliance
6.
Record vital signs (post-void 
weight and seated heart rate) 
and in-clinic calibrated 
blood pressure (BP) 
measurement.  Record 
height
7.
Collect blood for serum 
chemistry, liver function 
panel (ALT, AST, bilirubin, 
total (BT), bilirubin (direct), 
and alkaline phosphatase), 
serum sodium, creatinine 
and hematology and 
coagulation.  Hepatitis 
testing is optional
8.
Collect urine for urinalysis, 
urine osmolality (optional), 
and urine specific gravity
9.
Perform urine pregnancy test 
on women of childbearing 
potential (WOCBP).  If 
positive, a follow-up serum 
test will be performed
10. Conduct full physical 
examination
11. Enter subject into interactive 
response technology (IRT) 
including prior trial 
identifier/information 
screening visit for this one may 
occur simultaneously. Required 
assessments are as follows:
1.
Obtain subject consent.
2.
Determine subject 
eligibility through 
inclusion/exclusion criteria.
3.
Record demographic 
information and prior trial 
identifiers (screening 
identification [ID], subject 
ID, site ID), prior 
tolvaptan ADPKD trial 
protocol number).
4.
Record medical/ADPKD 
history using prior trial 
data.
5.
Review dietary 
recommendations and
compliance.
6.
Record vital signs (post-
void weight and seated 
heart rate) and in-clinic 
calibrated blood pressure 
(BP) measurement.  Record 
height.
7.
Collect blood for serum 
chemistry, liver function 
panel (ALT, AST, bilirubin, 
total [BT], bilirubin 
[direct], and alkaline 
phosphatase), serum 
sodium, creatinine, and 
hematology and 
coagulation.  Hepatitis 
testing is optional.  If 
hepatitis testing is 
performed, then both pre-
and post-counseling 
activities relating to 
hepatitis testing are to be 
carried out based on local 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
212

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
86
06 March 2015
Location
Old Text
Updated Text
(protocol number, subject 
ID), confirmed dose regimen 
and scheduled date of next 
visit
12. Assess AEs reported as 
ongoing or resolved from 
prior trial to determine entry 
as medical history or 
ongoing event for this trial
requirements and best 
practices.  
8.
Collect urine for urinalysis, 
urine osmolality (optional), 
and urine specific gravity.
9.
Perform urine pregnancy 
test on women of 
childbearing potential 
(WOCBP).  If positive, a 
follow-up serum test will be 
performed.
10. Conduct full physical 
examination.
11. Enter subject into 
interactive response 
technology (IRT) including 
prior trial 
identifier/information 
(protocol number, subject 
ID), confirmed dose 
regimen, and scheduled 
date of next visit.
12. Assess AEs reported as 
ongoing or resolved from 
prior trial to determine 
entry as medical history or 
ongoing event for this trial.
13. Record ongoing 
concomitant medications. 
(This may be done if the 
screening visit occurs 
simultaneously with the 
last visit from a previous 
tolvaptan trial).
Section 3.7.1.2, 
Baseline (old text 
Section 3.6.1.2)
The baseline visit is the beginning of 
the treatment period in this trial.  At 
the baseline visit, subjects will be 
assigned a new subject number and 
the following assessments and 
procedures will be performed:
1.
Review inclusion/exclusion 
The baseline visit is the beginning of 
the treatment period in this trial.  At 
the baseline visit, subjects will 
retain the subject number assigned
in the previous tolvaptan trial, and 
the following assessments and 
procedures will be performed:
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
213

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Protocol 156-13-211
Confidential - Otsuka Proprietary Information
96
06 March 2015
Location
Old Text
Updated Text
If liver function panel, sodium 
and/or serum chemistry assessments 
are scheduled at the same visit, all 
values should be determined from 
the same blood sample.  Blood 
testing for hepatitis will be 
optional for all subjects.  Urine 
pregnancy testing will be performed 
with commercially available, high-
sensitivity kits supplied to the 
subject by the site (acquired by the 
sponsor).
Table 3.7.2.2-, Clinical 
Laboratory 
Assessments
Please see original table at the end of 
Appendix 5,
Please see revised table at the end of 
Appendix 5,
Section 3.7.2.3, 
Physical Examination 
and Vital Signs (old 
text, Section 3.6.2.3)
A full physical examination will be 
performed and documented at the 
screening visit although this may be 
combined with the EoTx visit from 
the previous trial.  At other visits, an 
optional directed physical 
examination may be performed to 
focus on ADPKD- related signs and 
symptoms.  In some geographic 
regions, more frequent subject visits 
may be the norm; however vital signs 
and clinically significant physical 
findings will be recorded as an 
unscheduled visit in the electronic 
case report form (eCRF) as 
applicable.  Any changes in 
medication or AEs will be recorded in 
the eCRF.
Body weight will be taken post-void.  
It is preferable to use the same scale 
for each measurement.  Clinic scales 
should be calibrated at least yearly.  
The investigator or his/her appointed 
designee is primarily responsible to 
perform the physical examination.  ...
A full physical examination will be 
performed and documented at the 
screening visit although this may be 
combined with the last visit from the 
previous trial.  At other visits, an 
optional directed physical 
examination may be performed to 
focus on ADPKD- related signs and 
symptoms.  In some geographic 
regions, more frequent subject visits 
may be the norm; however vital 
signs and clinically significant 
physical findings will be recorded as 
an unscheduled visit in the electronic 
case report form (eCRF) as 
applicable.  Any changes in 
medication or AEs will be recorded 
in the eCRF.
Height will be measured only at 
screening.  Body weight will be 
taken post-void.  It is preferable to 
use the same scale for each 
measurement.  Clinic scales should 
be calibrated at least yearly.  The 
investigator or his/her appointed 
designee is primarily responsible to 
perform the physical examination.  
...
Section 3.7.2.4, 
Assessment of Liver 
Symptoms, Signs or 
Test Abnormalities (old 
text, Section 3.6.2.4)
Testing for hepatic transaminase 
(ALT/AST), alkaline phosphatase, 
bilirubin direct, and BT will be 
performed during screening.  Subjects 
enrolling from the double-blind Trial 
156-13-210 will have monthly ALT 
assessments for the first 18 months 
while the treatment code from Trial 
156-13-210 remains blinded to ensure 
Testing for hepatic transaminase 
(ALT/AST), alkaline phosphatase, 
bilirubin direct, and BT will be 
performed during screening.  
Subjects enrolling from the double-
blind Trial 156-13-210 will have 
monthly ALT assessments for the 
first 18 months while the treatment 
code from Trial 156-13-210 remains 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
223

Protocol 156-13-211
Confidential - Otsuka Proprietary Information
97
06 March 2015
Location
Old Text
Updated Text
that all subjects have adequate safety 
monitoring during this period of 
susceptibility.  Following the first 
18 months, ALT assessments will be 
made quarterly for these subjects.  
Subjects enrolling from the open-
label Trial 156-08-271 will have 
quarterly ALT assessments since they 
will have already received tolvaptan 
for 2 years or more.  Management of 
liver abnormalities is discussed in the 
paragraphs below.
blinded to ensure that all subjects 
have adequate safety monitoring 
during this period of susceptibility.  
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 changed
to every 3 months sooner as their 
previous tolvaptan exposure in 
Trial 156-13-210 can count 
towards the 18-month threshold.
Following the first 18 months, ALT 
assessments will be made every 
3 months for Trial 156-13-210 
subjects and for subjects from 
other tolvaptan ADPKD trials 
besides Trial 156-08-271 .  Subjects 
enrolling from the open-label Trial 
156-08-271 who have tolvaptan 
exposure greater than 18 months 
will continue with ALT 
monitoring every 3 months.  
Subjects enrolling from prior 
tolvaptan trials besides 
Trial 156-08-271 will have 
monthly ALT assessments for the 
first 18 months.  Upon reaching 
18 months of exposure and after 
confirmation from the medical 
monitor, the frequency of ALT 
monitoring for these subjects will 
occur every 3 months.
ALT will also be assessed at the 
Early Termination/End of 
Treatment visit and at the 7-day
Follow-up visit.
Management of liver abnormalities 
is discussed in the paragraphs below.
Section 3.7.2.4.1, Liver 
Test Abnormalities and 
Interruption/
Discontinuation of 
Investigational 
Medicinal Product
(old text 
Section 3.6.2.4.1)
The appearance of any suspicious 
symptom or sign should trigger 
prompt testing of hepatic function (ie, 
within 72 hours).  Liver transaminase 
or bilirubin levels 2 × ULN should 
prompt immediate retesting within 
The appearance of any suspicious 
symptom or sign should trigger 
prompt testing of hepatic function 
(ie, within 72 hours).  Local 
laboratory testing is acceptable, 
ideally with a concurrent central 
laboratory sample for 
confirmation.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
224

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Section 3.8.3, 
Individual Subject
...  
All subjects have the right to 
withdraw at any time during 
treatment without prejudice.  The 
investigator can discontinue a 
subject’s participation in the trial at 
any time if medically necessary.  In 
addition, subjects meeting the 
following criteria must be withdrawn 
from the trial:
a) Occurrence of any AE, intercurrent 
illness, or abnormality in a laboratory 
assessment which, in the opinion of 
the investigator, warrants the 
subject’s permanent withdrawal from 
the trial;
b) Treatment with a prohibited 
concomitant medication other than 
the use of appropriate medications for 
the treatment of AEs under direction 
of the investigator;
c) Subject noncompliance, defined as 
refusal or inability to adhere to the 
trial schedule or procedures (see 
Section 3.12);
d) At the request of the subject, 
investigator, sponsor, or regulatory 
authority;
e) Subject becomes pregnant; or 
f) Subject is lost to follow-up.
The investigator will notify the 
sponsor promptly when a subject is 
withdrawn.
...
All subjects have the right to 
withdraw at any time during 
treatment without prejudice.  The 
investigator can discontinue a 
subject’s participation in the trial at 
any time if medically necessary.  It 
is preferred that subjects who 
permanently discontinue IMP will 
have the option to continue 
participation off IMP with regular 
scheduled visits or with a modified 
(ie, less frequent) schedule.  If 
subjects are unable or unwilling to 
complete the visits and procedures 
off IMP, the early 
termination/EoTx visit should be 
completed.  The investigator may
continue to contact those who 
discontinue IMP through to the 
final completion date of the trial 
or thereafter if needed to 
determine outcomes ie, vital 
status.  
In addition, subjects meeting the 
following criteria must be withdrawn 
from the trial:
a) Occurrence of any AE, 
intercurrent illness, or abnormality in 
a laboratory assessment which, in 
the opinion of the investigator, 
warrants the subject’s permanent 
withdrawal from the trial;
b) Subject noncompliance, defined 
as refusal or inability to adhere to the 
trial schedule or procedures (see 
Section 3.11);
c) At the request of the subject, 
investigator, sponsor, or regulatory 
authority;
d) Subject is lost to follow-up.
The investigator will notify the 
sponsor promptly when a subject is 
withdrawn.
Section 3.12, Subject 
Compliance
Subject compliance will be monitored 
by pill counts as IMP is returned.  
Any subject who, without the 
instruction of the investigator, 
discontinues tolvaptan investigational 
Subject compliance will be 
monitored by pill counts as IMP is 
returned.  Any subject who, without 
the instruction of the investigator, 
discontinues tolvaptan 
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product without the instruction of the 
investigator, discontinues tolvaptan 
for 30 consecutive days or misses > 
30% of the doses intended for a 
period between visits (whichever is 
greater) will be deemed 
noncompliant.  ...
investigational product, discontinues 
tolvaptan for 30 consecutive days or 
misses > 30% of the doses intended 
for a period between visits 
(whichever is greater) will be 
deemed noncompliant.  ...
Section 3.13, Protocol
Deviations
This trial is to be conducted as 
described in this protocol.  In the 
event of a significant deviation from 
the protocol due to an emergency, 
accident or mistake, the investigator 
or designee must contact the sponsor 
at the earliest possible time.  This will 
allow an early joint decision 
regarding the subject’s continuation 
in the trial.  This decision will be 
documented by the investigator and 
the sponsor, and reviewed by the 
monitor.
This trial is to be conducted as 
described in this protocol.  In the 
event of a significant deviation from 
the protocol due to an emergency, 
accident or mistake (eg, violation of 
informed consent process, IMP 
dispensing or subject dosing error, 
subject enrolled in violation of 
eligibility criteria or concomitant 
medication criteria), the 
investigator or designee must contact 
the sponsor at the earliest possible 
time.  This will allow an early joint 
decision regarding the subject’s 
continuation in the trial.  This 
decision will be documented by the 
investigator and the sponsor, and 
reviewed by the site monitor.
Section 4.1, Prohibited 
or Restricted 
Medications 
Medications or surgical therapies 
used for the purpose or potential for 
modifying the progression of PKD 
cyst growth or development will be 
prohibited.  These include, but are not 
restricted to, somatostatin agonists, 
rapamune (sirolimus), anti-sense 
ribonucleic acid therapies, tolvaptan, 
and other vasopressin antagonists, 
(eg, OPC-31260 (mozavaptan), 
Vaprisol (conivaptan), agonists (eg, 
desmopressin) and cyst 
decompression surgery.
Continuous or short-term use of other 
medications, while not prohibited, 
may be restricted by the investigator 
because of their potential for 
interference with tolvaptan 
metabolism (see Section 3.2.1 and 
Section 3.2.2). 
...
Some drugs are known to alter 
creatinine concentrations so, while 
not prohibited, subjects should alert 
their trial doctor, and any other 
health-care providers, to take this into 
Medications or surgical therapies 
used for the purpose or potential for 
modifying the progression of PKD 
cyst growth or development will be 
prohibited.  These include, but are 
not restricted to, somatostatin 
agonists, rapamune (sirolimus), anti-
sense ribonucleic acid therapies, 
vasopressin antagonists other than 
tolvaptan, (eg, OPC-31260 
(mozavaptan), Vaprisol 
(conivaptan), agonists (eg, 
desmopressin) and cyst 
decompression surgery.
Continuous or short-term use of 
other medications, while not 
prohibited, may be restricted by the 
investigator because of their 
potential for interference with 
tolvaptan metabolism (see 
Section 3.2.1 and Section 3.2.2). 
A partial list of strong and 
moderate CYP3A4 inhibitors can 
be found in Table 4.1-1 below:
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Updated Text
consideration when considering 
changes in their prescribed or over-
the-counter medications.  A list 
would include:  cimetidine, non-
steroidal anti-inflammatory drugs like 
aspirin or ibuprofen, chemotherapy 
drugs, cephalosporin, the 
combination of elvitegravir, 
cobicistat, emtricitabine, and 
tenofovir (StribildTM), dolutegravir, 
dronedarone, ranolazine, metformin, 
and trimethoprim.
...
Some drugs are known to alter 
creatinine concentrations so, while 
not prohibited, subjects should alert 
their trial doctor, and any other 
health-care providers, to take this 
into consideration when considering 
changes in their prescribed or over-
the-counter medications.  A list 
would include:  non-steroidal anti-
inflammatory drugs like aspirin or 
ibuprofen, chemotherapy drugs, 
cephalosporin, the combination of 
elvitegravir, cobicistat, 
emtricitabine, and tenofovir 
(StribildTM), dolutegravir, 
dronedarone, ranolazine, metformin, 
and trimethoprim.
Table 4.1-1
N/A
Please see end of Appendix 5 for this 
new table.
Section 4.2, Dietary 
Restrictions and 
Recommendations
Restriction of excess dietary sodium 
and cooked meat protein may prove 
beneficial to subjects with a history 
of, or predisposition for, hypertension 
or kidney disease in general and 
should be applied to all subjects 
diagnosed with advanced ADPKD, 
particularly if there is evidence for a 
propensity for rapid progression.  In 
the absence of alternate regional 
practices, dietary salt < 5g/day, 
dietary cooked meat protein < 1 
g/kg/day and a limit on caffeinated 
drinks/foods should also be given (no 
more than 2 coffee equivalents per 
day).  
Restriction of excess dietary sodium 
and cooked meat protein may prove 
beneficial to subjects with a history 
of, or predisposition for, 
hypertension or kidney disease in 
general and should be applied to all 
subjects diagnosed with advanced 
ADPKD, particularly if there is 
evidence for a propensity for rapid 
progression.  In the absence of 
alternate regional practices, dietary 
salt < 5g/day, dietary cooked meat 
protein < 1 g/kg/day and a limit on 
caffeinated drinks/foods should also 
be given (no more than 2 coffee 
equivalents per day).  A history of 
alcohol and smoking intake will be 
collected at screening.  Alcohol 
and tobacco consumption should 
be avoided or minimized as much 
as possible.
Section 5, Reporting of 
Adverse Events
The following describes the methods 
and timing for assessing, recording, 
and analyzing safety parameters, as 
well as the procedures for eliciting 
reports of and recording and reporting 
AEs and intercurrent illnesses and the 
type and duration of the follow-up of 
subjects after AEs.
The following describes the methods 
and timing for assessing, recording, 
and analyzing safety parameters, as 
well as the procedures for eliciting 
reports of and recording and 
reporting AEs and intercurrent 
illnesses and the type and duration of 
the follow-up of subjects after AEs.
Medical follow up is expected for 
AEs which lead to discontinuation 
which are serious, or which are of 
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Previous Figure 3.1-1 - Trial Design Schematic:
Revised Figure 3.1-1 - Trial Design Schematic:
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Previous Table 3.2-1 - Trial Treatments:
Table 3.2-1
Trial Treatments
Trial Day
Time
Dose
Day 1 to last on-treatment visit
8:00 am
1 to 6 tolvaptan tablets (15 mg or 30 mg each)
4:00 to 5:00 pm
1 to 2 tolvaptan tablets (15 mg or 30 mg each)
Allowed doses are 45/15 mg, 60/30 mg, 
90/30 mg.  Down titration to 30/15 mg and 
15/15 mg will be allowed after discussion 
with the medical monitor.  
Revised Table 3.2-1 - Trial Treatments:
Table 3.2-1
Trial Treatments
Trial Day
Time
Dose
Day 1 to last on-treatment visit
8:00 am
1 to 6 tolvaptan tablets (15 mg or 30 mg each)
4:00 to 5:00 pm
1 to 2 tolvaptan tablets (15 mg or 30 mg each)
Allowed doses are 45/15 mg, 60/30 mg, 
90/30 mg.  Down titration to 30/15 mg and 
15/15 mg will be allowed after discussion 
with the medical monitor.  Further down 
titration to 30 or 15 mg once daily may be 
allowed only for metabolic drug-drug 
interaction and requires medical monitor 
approval.
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Previous Table 3.4.2-1 – Inclusion Criteria:
Table 3.4.2-1 Inclusion Criteria
1.
Male and female subjects aged 18 years with ADPKD who have completed either trial 
156-13-210 or trial 156-08-271
2.
Diagnosis of ADPKD by modified Pei-Ravine criteria:

With family history: several cysts per kidney (3 if by sonography, 5 if by computed 
tomography or MRI).

Without family history: 10 cysts per kidney (by any radiologic method, above) and exclusion 
of other cystic kidney diseases.  Conditions to be excluded include: multiple simple renal 
cysts, renal tubular acidosis, cystic dysplasia of the kidney, multicystic kidney, multilocular 
cysts of the kidney, medullary cystic kidney and acquired cystic disease of the kidney.

Distribution and number of cysts consistent with the observed level of renal function deficit.
3.
Estimated glomerular filtration rate  20 mL/min/1.73 m2 (calculated using the CKD-EPI 
formula) within 45 days prior to the baseline visit.  Subjects who have an eGFR between 15 and 
19 mL/min/1.73 m2 may be permitted with documented medical monitor approval prior to 
enrollment.
Revised Table 3.4.2-1 – Inclusion Criteria:
Table 3.4.2-1 Inclusion Criteria
1.
Male and female subjects aged 18 years with confirmed diagnosis of ADPKD ( during 
participation in prior tolvaptan trials) who have

Completed and transferred from the double-blind Trial 156-13-210 (12-month 
period including post-treatment follow-up, regardless of whether this was on-
treatment or off-treatment), or 

Completed Trial 156-08-271 or a prior tolvaptan trial, or 

Interrupted or discontinued treatment in a tolvaptan trial other than 
Trial 156-13-210.  Subjects may be enrolled with the medical monitor approval, and 
additional close monitoring may be required at the beginning of the trial

Renal function will be assessed during screening using historical laboratory values 
(in the last 30 days) for serum creatinine levels to calculate the estimated 
glomerular filtration rate (eGFR).  The eGFR values will be estimated based on the 
Chronic Kidney Disease - Epidemiology (CKD-EPI) formula. (Levey AS et al. Ann 
Intern Med. 2009; 150:604–612)
2.
Estimated glomerular filtration rate  20 mL/min/1.73 m2 (calculated using the CKD-EPI 
formula) within 45 days prior to the baseline visit.  Subjects who have an eGFR between 15 and 
19 mL/min/1.73 m2 may be permitted with documented medical monitor approval prior to 
enrollment.
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Protocol 156-13-211
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06 March 2015
Revised Table 3.7.2.2-1 - Clinical Laboratory Assessments:
Table 3.7.2.2-1
Clinical Laboratory Assessments
Hematology and Coagulation Panel:
Hemoglobin
Platelet count
Mean corpuscular hemoglobin concentration 
(MCHC)
Mean corpuscular volume (MCV)
Red blood cell (RBC) count
White blood cell (WBC) count with differential 
Prothrombin time (PT) as international normalized 
ratio (INR)
Activated partial thromboplastin time (aPTT)
Urinalysis Panel:
Appearance
Color 
Blood
Glucose
Microscopic analysis, WBC/RBC counts per high 
power field
pH
Protein 
Urine Chemistry
Osmolality (optional)
Specific gravity
Additional Tests:
Urine (or serum) pregnancy for WOCBP
Hepatitis (optional)
Serum Chemistry Panel:
Albumin
Blood urea nitrogen (BUN)
Serum calcium
Carbon dioxide
Serum chloride
Gamma-glutamyl transpeptidase
Cholesterol, total
Glucose
Lactate dehydrogenase (LDH)
Phosphorus
Potassium
Protein, total 
Uric acid
Liver Function Panel:
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Bilirubin, total (BT)
Bilirubin, direct
Creatinine
Sodium
WOCBP=women of childbearing potential.
New Table 4.1-1 Moderate and Strong CYP3A4 Inhibitors (partial list):
Table 4.1-1
Moderate and Strong CYP3A Inhibitors (partial list)
amprenavir
atorvastin
aprepitant
chloramphenicol (if 
used orally)
cimetidine
clarithromycin
clotrimazole (if used 
orally)
danazol
delavirdine
diltiazem
erythromycin
fluconazole
fluvoxamine
indinavir
isoniazid
itraconzazole
josamycin
ketoconazole (if used 
orally)
nelfinavir
nefazadone
quinupristin/ dalfopristin
ritonavir
saquinavir
troleandomycin
verapamil
Seville orange products
grapefruit products
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Administrative Change Number:
1
Issue Date:
05 September 2014
PURPOSE:
This administrative change will not affect the safety of subjects, the scope of the 
investigation, or the scientific quality of the trial.
The main purpose of this administrative change was to align safety endpoints between the 
synopsis and Section 3.5.1, and to clarify the timeline for when IRE forms must be 
completed and submitted to the sponsor.  In addition, a statement at the beginning of 
Section 3.5.1 explaining that the trial would have no formal endpoints had been 
inadvertently deleted in an earlier draft. 
BACKGROUND:
While reviewing the protocol before proceeding with the clinicaltrial.gov posting, a few 
inconsistencies were found.  It was decided that fixing the inconsistencies would provide 
better clarity. 
Sectional Revisions
Location
Old Text
Updated Text
Section 3.5.1 Safety 
Endpoints  
Safety endpoints will be as follows:

Adverse events

Vital signs

Clinical laboratory 
assessments

Serum transaminase 
elevations for frequency (2x, 
3x, 5x and 10x ULN), time 
to onset, time to peak levels, 
time of offset (< 3x, 2x, or 
1x ULN), response to de-
challenge and re-challenge 
and frequency of progression 
to Hy’s laboratory criteria 
(ALT or AST > 3x ULN and 
bilirubin, total (BT), 
> 2x ULN without alkaline 
phosphatase 2x ULN)

Serum sodium excursions 
above 145, 150, or 
155 mmol/L or below 135, 
This trial will have no formal 
endpoints.  Safety variables will be 
summarized by descriptive statistics, 
(eg, proportion, mean, median, 
standard deviation [SD], minimum, 
and maximum values).  In general, 
summary statistics, including 
changes from baseline, will be 
provided for safety variables based 
on all available data.  Safety 
endpoints will be as follows:

Adverse events

Vital signs

Clinical laboratory 
assessments

Serum transaminase 
elevations for frequency 
(2x, 3x, 5x and 10x ULN), 
time to onset, time to peak 
levels, time of offset (< 3x, 
2x, or 1x ULN), response to 
de-challenge and re-
challenge and frequency of 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Location
Old Text
Updated Text
130, or 125 mmol/L

Interruptions of protocol-
specifed therapies for 
hypernatremia or 
hyponatremia
progression to Hy’s 
laboratory criteria (ALT or 
AST > 3x ULN and 
bilirubin, total (BT), 
> 2x ULN without alkaline 
phosphatase 2x ULN)

Serum sodium excursions 
above 145, 150, or 
155 mmol/L or below 135, 
130, or 125 mmol/L
Section 5.3,
Immediately Reportable 
Events
The investigator must immediately 
report within 24 hours after either the 
investigator or site personnel become 
aware of any SAE, an AE that 
necessitates IMP discontinuation, any 
new liver result meeting the AE 
laboratory threshold criteria, any AE 
of special interest or a confirmed 
pregnancy, by telephone or by fax to 
the sponsor as outlined in 
Appendix 1.  An IRE form must be 
completed and sent by fax, email or 
overnight courier to the sponsor.  
(Please note that the IRE form is 
NOT the AE eCRF).
The investigator must immediately 
report within 24 hours after either 
the investigator or site personnel 
become aware of any SAE, new liver 
laboratory abnormality requiring 
special liver eCRF completion, or 
confirmed pregnancy, by telephone 
or by fax to the sponsor as outlined 
in Appendix 1.  An IRE form must 
be completed and sent by fax, email,
or overnight courier to the sponsor.  
(Please note that the IRE form is 
NOT the AE eCRF).
Appendix 5, Title 
change 
Protocol Amendment
Protocol Amendments and 
Administrative Changes
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
244

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CCI

Protocol 156-13-211
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119
06 March 2015
Location
Old Text
Updated Text
72 hours.  While values remain in an 
abnormal range, testing frequency 
should be increased to at least weekly 
for the first month, gradually 
returning to monthly, and every 
3 months as indicated by the results.  
Local liver function panel analyses 
will also be performed more 
frequently, if necessary.
values remain in an abnormal range, 
testing frequency should be 
increased to at least weekly for the 
first month, gradually returning to 
monthly, and every 3 months as 
indicated by the results.  Local liver 
function panel analyses will also be 
performed more frequently, if 
necessary.
Section 5.4, Pregnancy
Women of childbearing potential who 
are sexually active must use an 
effective method of birth control 
during the course of the trial and for 
30 days after the last dose of IMP in a 
manner such that risk of failure is 
minimized.  Unless the subject is 
sterile (ie, women who have had an 
bilateral oophorectomy and/or 
hysterectomy or have been 
postmenopausal for at least 
12 consecutive months or remains 
abstinent, 2 of the following 
precautions must be used: vasectomy, 
tubal ligation, intrauterine device, 
birth control pills, birth control depot 
injection, birth control implant, 
condom or occlusive cap (diaphragm 
or cervical/vault caps) with 
spermicide.  Any single method of 
birth control, including vasectomy 
and tubal ligation, may fail, leading to 
pregnancy.
Women of childbearing potential 
who are sexually active must use an 
effective method of birth control 
during the course of the trial and for 
30 days after the last dose of IMP in 
a manner such that risk of failure is 
minimized.  Unless the subject is 
sterile (ie, women who have had an 
bilateral oophorectomy and/or 
hysterectomy or have been 
postmenopausal for at least 
12 consecutive months or remains 
abstinent, 2 of the following 
precautions must be used: 
vasectomy, tubal ligation, 
intrauterine device, birth control 
pills, birth control depot injection, 
birth control implant, condom or 
occlusive cap (diaphragm or 
cervical/vault caps) with spermicide.  
Any single method of birth control, 
including vasectomy and tubal 
ligation, may fail, leading to 
pregnancy.  Abstinence is only 
acceptable when part of the preferred 
and usual lifestyle of the subject;
should that lifestyle change double 
barrier contraceptive methods should 
be employed.
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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16.1.1 Protocol and Protocol Amendments
246

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120
06 March 2015
Amendment Number:
3
Issue Date:
06 Mar 2015
PURPOSE:
The purpose of this amendment was to increase the window from 30 days to up to 
3 months to allow use of historical laboratory values for screening, to add flexibility and 
allow combining of screening and baseline visits in the trial, and to provide clarification 
on trial discontinuation.  The list of vendors was updated. Minor linguistic changes were 
made for clarity and typographical errors were corrected.  
BACKGROUND: 
Eligible subjects enrolling from Trials 156-08-271 or 156-13-210 can enroll before they 
complete the last visit in their respective trials, and the last visit as well as the screening 
and baseline visit in this trial can be combined into one visit with all required assessments 
from each visit performed only once, so long as the time between the last visit 
assessments from the previous trial and the screening visit for this trial is within 30 days.  
Other Revisions
Figure 3.1-1 - Trial Design Schematic
Table 3.4.2-1 - Inclusion Criteria 
Table 3.4.3-1 - Exclusion Criteria 
Table 3.7-1 - Schedule of Assessments footnotes
Sectional Revisions
Location
Old Text
Updated Text
Title page
A Phase 3b, Multi-center, Open-label 
Trial to Evaluate the Long Term 
Safety of Titrated Immediate-release 
Tolvaptan (OPC 41061, 30 mg to 120 
mg/day, Split dose) in Subjects with 
Autosomal Dominant Polycystic 
Kidney Disease
…
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
…
Date of Amendment 3, UK
06 March 2015
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
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Protocol 156-13-211
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121
06 March 2015
Location
Old Text
Updated Text
Synopsis, Protocol Title 
A Phase 3b, Multi-center, Open-label 
Trial to Evaluate the Long Term 
Safety of Titrated Immediate-release 
Tolvaptan (OPC 41061, 30 mg to 120 
mg/day, Split dose) in Subjects with 
Autosomal Dominant Polycystic 
Kidney Disease
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
Synopsis, Trial Design
   
Subjects will be eligible for screening 
into this trial if they:

Completed and transferred from 
the double-blind Trial 
156-13-210 (12-month period 
including post treatment follow-
up, regardless of whether this 
was on-treatment or off-
treatment), or 

Completed Trial 156-08-271 or a 
prior tolvaptan ADPKD trial, or 

Interrupted or discontinued 
treatment in a prior tolvaptan 
ADPKD trial (other than Trial 
156-13-210).  Subjects may be 
enrolled with medical monitor 
approval, and additional close 
monitoring may be required at 
the beginning of the trial
   
Subjects will be eligible for 
screening into this trial if they:

Completed and transferred from 
the double-blind Trial 
156-13-210 (12-month period 
including post treatment follow-
up, regardless of whether this 
was on-treatment or off-
treatment), or have completed 
all but the last follow-up visit, 
which will be combined with the 
first visit in this trial or

Completed Trial 156-08-271 or 
a prior tolvaptan ADPKD trial, 
or have completed all but the 
end of trial visit, which will be 
combined with the first visit in 
this trial or

Interrupted or discontinued 
treatment in a prior tolvaptan 
ADPKD trial (other than Trial 
156-13-210).  Subjects may be 
enrolled with medical monitor 
approval, and additional close 
monitoring may be required at 
the beginning of the trial
Synopsis, Inclusion and 
Exclusion Criteria

Estimated glomerular filtration 
rate (eGFR) 
20 mL/min/1.73m2 within 
45 days of the baseline visit.  
Subjects who have an eGFR 
between 15 and 
19 mL/min/1.73m2 may be 
enrolled with medical monitor 
approval

Renal function will be assessed 
during screening by using 
historical values (in the last 
30 days) for serum creatinine 
levels to calculate the eGFR.  
The eGFT values will be 

Estimated glomerular filtration 
rate (eGFR) 
20 mL/min/1.73m2 within 
3 months of the baseline visit.  
Subjects who have an eGFR 
≤20 mL/min/1.73m2 may be 
enrolled with medical monitor 
and sponsor approval and 
increased frequency of 
monitoring to ensure subjects’ 
safety.

Renal function will be assessed 
during screening by using 
historical values (within 
3 months from the screening 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
248

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Protocol 156-13-211
Confidential - Otsuka Proprietary Information
123
06 March 2015
Location
Old Text
Updated Text
These subjects may have their trial 
visits/hepatic transaminase 
monitoring changed to every 
3 months sooner as their previous 
tolvaptan exposure in 
Trial 156-13-210 can count towards 
the 18-month threshold.
this trial, with all required 
assessments from each visit 
performed only once, so long as the 
time between the last visit 
assessments from the previous trial 
and the screening visit for this trial is 
within 30 days.  If the first visit in 
this trial combines the last visit from 
a previous trial with both the 
screening and the baseline visits in
this trial, the results from laboratory 
assessments performed at this 
combined visit will not be 
immediately available.  Should any 
laboratory abnormalities be 
identified, the investigator will need 
to notify the subject and provide 
instructions regarding dosing or 
returning to the site for additional 
assessments.
...
These subjects may have their trial 
visits/hepatic transaminase 
monitoring changed to every 
3 months sooner as their previous 
tolvaptan exposure in 
Trial 156-13-210 can count towards 
the 18-month threshold.  Subjects 
from prior tolvaptan trials other than 
Trial 156-08-271 will have monthly 
trial visits/ALT level assessments for 
the first 18 months.  After that, the 
trial visits/ALT monitoring will be 
conducted every 3 months after the 
change in frequency is confirmed 
with the medical monitor.
Figure 3.1-1
Day 1
No clinic visit
First dose of the IMP
Day 1
No clinic visit
First dose of the IMP in Trial 211
Table 3.4.2-1, Inclusion 
Criteria
1. Male and female subjects aged 
18 years with confirmed diagnosis 
of ADPKD (during participation in 
prior tolvaptan trials) who have 

Completed and transferred from 
the double-blind 
Trial 156-13-210 (12-month 
period including post-treatment 
follow-up, regardless of whether 
this was on-treatment or off-
treatment), or
Male and female subjects aged 
18 years with confirmed diagnosis 
of ADPKD (during participation in 
prior tolvaptan trials) who have 

Completed and transferred from 
the double-blind 
Trial 156-13-210 (12-month 
period including post-treatment 
follow-up, regardless of whether 
this was on-treatment or off-
treatment), or
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Old Text
Updated Text

Completed Trial 156-08-271 or a 
prior tolvaptan trial, or

Interrupted or discontinued 
treatment in a tolvaptan trial 
other than Trial 156-13-210.  
Subjects may be enrolled with 
the medical monitor approval, 
and additional close monitoring 
may be required at the beginning 
of the trial

Renal function will be assessed 
during screening by using 
historical laboratory values (in 
the last 30 days) for serum 
creatinine levels to calculate the 
estimated glomerular filtration 
rate (eGFR).  The eGFR values 
will be estimated based on the 
Chronic Kidney Disease -
Epidemiology (CKD-EPI) 
formula. (Levey AS et al. Ann 
Intern Med. 2009; 150:604–612)
2. Estimated glomerular filtration rate 
20 mL/min/1.73 m2 (calculated 
using the CKD-EPI formula) within 
45 days prior to the baseline visit.  
Subjects who have an eGFR between 
15 and 19 mL/min/1.73 m2 may be 
permitted with documented medical 
monitor approval prior to enrollment

Completed Trial 156-08-271 or 
a prior tolvaptan trial, or

Interrupted or discontinued 
treatment in a tolvaptan trial 
other than Trial 156-13-210.  
Subjects may be enrolled with
the medical monitor approval, 
and additional close monitoring 
may be required at the 
beginning of the trial

Renal function will be assessed 
during screening by using 
historical laboratory values (in 
the last 3 months) for serum 
creatinine levels to calculate the 
eGFR.  The eGFR values will be 
estimated based on the 
CKD-EPI formula. (Levey AS 
et al. Ann Intern Med. 2009; 
150:604–612)
2. Estimated glomerular filtration 
rate 20 mL/min/1.73 m2 
(calculated using the CKD-EPI 
formula) within 3 months prior to 
the baseline visit.  Subjects who 
have an eGFR ≤20 mL/min/1.73 m2
may be permitted to enter the trial 
with medical monitor and sponsor 
approval and increased frequency of 
monitoring to ensure safety of 
participants.
At end of table, abbreviations added:
eGFR=estimated glomerular 
filtration rate; CKD-EPI= Chronic 
Kidney Disease - Epidemiology
Table 3.4.3-1, 
Exclusion Criteria
1. Women of childbearing potential 
(WOCBP) who do not agree to 
practice 2 different methods of birth 
control or remain abstinent during the 
trial and for 30 days after the last 
dose of IMP.  If employing birth 
control, 2 of the following 
precautions must be used: vasectomy 
of partner, tubal ligation, vaginal 
diaphragm, intrauterine device, birth 
control.
…
4. Hepatic impairment based on liver 
function abnormalities other than that 
1. WOCBP who do not agree to 
practice 2 different methods of birth 
control or remain abstinent during 
the trial and for 30 days after the last 
dose of IMP.  If employing birth 
control, 2 of the following 
precautions must be used: vasectomy 
of partner, tubal ligation, vaginal 
diaphragm, intrauterine device, birth 
control pill, birth control implant, 
birth control depot injection, 
condom, or sponge with spermicide.
…
4. Hepatic impairment based on liver 
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125
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Location
Old Text
Updated Text
expected for ADPKD with cystic 
liver disease during screening.
function abnormalities other than 
that expected for ADPKD with 
cystic liver disease during screening
based on recent historical laboratory 
values (in the last 3 months).
Section 3.7, Trial 
Procedures, Table 3.7-1
Footnote a:
aThe last visit assessments from the 
previous protocol can be combined 
with the screening visit for this trial, 
with all required assessments from 
each visit performed only once.
...
Footnote g:
gA full liver function panel (AST, 
ALT, alkaline phosphatase, BT) will 
be done at screening.  All other liver 
function tests at subsequent visits are 
for ALT only, unless otherwise 
clinically indicated.  Any 
transaminase values which exceed 2 
× ULN should prompt immediate 
retesting within 72 hours.  While 
values remain in an abnormal range, 
testing frequency should be increased 
to at least weekly for the first month, 
gradually returning to monthly, and 
every 3 months as indicated by the 
results.  Local liver function panel 
analyses will also be performed more 
frequently, if necessary.
...
Footnote l:
lIf during the titration contact the 
determination is made to adjust the 
dose regimen, dose adjustments will 
be made using dispensed supply, and 
dose instructions will be provided by 
the investigator.  The subject’s 
current dose will be entered into the 
interactive response technology (IRT) 
at each visit.  Drug 
dispensation/reconciliation will be 
conducted on a monthly basis for 
subjects who have monthly trial visits 
and once every 3 months for subjects 
who have trial visits every 3 months.  
...
Footnote a:
aThe last visit assessments from the 
previous trial can be combined with 
the screening and baseline visits for 
this trial, with all required 
assessments from each visit 
performed only once.
...
Footnote g:
gA full liver function panel (AST, 
ALT, alkaline phosphatase, BT) will 
be done at screening.  All other liver 
function tests at subsequent visits are
for ALT only, unless otherwise 
clinically indicated.  An ALT 
elevation > 2 × ULN should trigger 
prompt testing of hepatic function 
within 72 hours.  Any transaminase 
values which exceed 2 × ULN 
should prompt immediate retesting 
within 72 hours.  While values 
remain in an abnormal range, testing 
frequency should be increased to at 
least weekly for the first month, 
gradually returning to monthly, and 
every 3 months as indicated by the 
results.  Local liver function panel 
analyses will also be performed 
more frequently, if necessary.
...
Footnote l:
lIf during the titration contact the 
determination is made to adjust the 
dose regimen, dose adjustments will 
be made using dispensed supply, and 
dose instructions will be provided by 
the investigator.  The subject’s 
current dose will be entered into the 
interactive response technology 
(IRT) at each visit.  Drug 
dispensation/reconciliation will be 
conducted on a monthly basis for 
subjects who have monthly trial 
visits and once every 3 months for 
subjects who have trial visits every 
3 months.  If additional drug supply 
is required for titration purposes, the 
site will arrange a subject visit for 
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Location
Old Text
Updated Text
dispensation.
...
Section 3.7.1.1, 
Screening (-30 days to 
1 day prior to Baseline)
Screening for eligibility is required 
for all subjects.  The screening visit 
may be combined with the last visit 
from the previous protocol with all 
required assessments from each visit 
only performed once.  In some cases, 
if a subject enrolls in this trial from a 
prior tolvaptan trial, the end of trial 
visit for that trial and the screening 
visit for this one may occur 
simultaneously.  Required 
assessments are as follows:
1.
Obtain subject consent.
2.
Determine subject eligibility 
through inclusion/exclusion criteria.  
3.
Record demographic 
information and prior trial identifiers 
(screening identification [ID], subject 
ID, site ID, prior tolvaptan ADPKD 
trial protocol number).
4.
Record medical/ADPKD 
history using prior trial data.
5.
Review dietary 
recommendations and compliance
…
Screening for eligibility is required 
for all subjects.  The screening and 
baseline visits may be combined 
with the last visit from either the 
156-08-271 or 156-13-210 protocol 
with all required assessments from 
each visit performed only once.  
Therefore, in some cases, if a 
subject enrolls in this trial from a 
prior tolvaptan trial, the end of trial
or last follow-up visit for that trial 
and the screening and baseline visit 
for this one may occur 
simultaneously.  Required 
assessments for the screening visit 
are as follows:
1.
Obtain subject consent.
2.
Obtain subject’s new 
screening identifcation (ID) 
assigned by interactive response 
technology (IRT).
3.
Determine subject 
eligibility through 
inclusion/exclusion criteria.  
4.
Record demographic 
information and prior trial identifiers 
(screening ID, subject ID, prior 
tolvaptan ADPKD trial protocol 
number).
5.
Record medical/ADPKD 
history using prior trial data.
6.
Review dietary 
recommendations and compliance
…
Section 3.7.2.4.1 Liver 
Test Abnormalities and 
Interruption/Discontinu
ation of Investigational 
Medical Product
The appearance of any suspicious 
symptom or sign should trigger 
prompt testing of hepatic function (ie, 
within 72 hours).  Local laboratory 
testing is acceptable, ideally with a 
concurrent central laboratory sample 
for confirmation.  
An ALT elevation > 2 × ULN or the
appearance of any suspicious 
symptom or sign should trigger 
prompt testing of hepatic function 
(ie, within 72 hours).  Local 
laboratory testing is acceptable, 
ideally with a concurrent central 
laboratory sample for confirmation.  
Section 3.7.5, 
Treatment Interruption 
and Discontinuation
...
A subject who permanently 
discontinues IMP treatment may have 
the option to end trial participation 
(complete the early termination visit) 
...
A subject who permanently 
discontinues IMP treatment ends
trial participation and the early 
termination visit should be 
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Protocol 156-13-211
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Previous Figure 3..-1 Trial Design Schematic
Revised Figure 3.1-1 Trial Design Schematic
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator's Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor's (or designee's) Clinical Research Agreement.
I will provide copies of the protocol to all physicians, nurses and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, [insert compound number], the 
concurrent medications, the efficacy and safety parameters and the conduct of the trial in general. 
I am aware that this protocol must be approved by the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC responsible for such matters in the clinical trial facility where 
[insert compound number] will be tested prior to commencement of this trial. I agree to adhere 
strictly to the attached protocol (unless amended in the manner set forth in Paragraph I of the 
sponsor's Clinical Research Agreement, at which time I agree to adhere strictly to the protocol as 
amended).
I understand that this IRB- or IEC-approved protocol will be submitted to the appropriate 
regulatory authority/ies by the sponsor. I agree that clinical data entered on case report forms by 
me and my staff will be utilized by the sponsor in various ways such as for submission to 
governmental regulatory authorities and/or in combination with clinical data gathered from other 
research sites, whenever applicable. I agree to allow sponsor monitors and auditors full access to 
all medical records at the research facility for subjects screened or enrolled in the trial.
I agree to await IRB/IEC approval before implementation of any protocol amendments to this 
protocol. If, however, there is an immediate hazard to subjects, I will implement the amendment 
immediately, and provide the information to the IRB/IEC within 5 working days. Administrative 
changes to the protocol will be transmitted to the IRB/IEC for informational purposes only.
I agree to provide all subjects with informed consent forms, as required by the applicable 
regulations and by ICH guidelines. I agree to report to the sponsor any adverse experiences in 
accordance with the terms of the sponsor's Clinical Research Agreement and the relevant 
regional regulation(s) and guideline(s). I further agree to provide all required information 
regarding financial certification or disclosure to the sponsor for all investigators and sub-
investigators in accordance with the terms of the relevant regional regulation(s). I understand that 
participation in the protocol involves a commitment to publish the data from this trail in a 
cooperative publication prior to publication of efficacy and safety results on an individual basis.
________________________________________________
Principal or Coordinating Investigator Signature and Date
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 156-13-211
16.1.1 Protocol and Protocol Amendments
256

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