Conditions: Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Keywords: Autosomal Dominant Polycystic Kidney Disease ADPKD Tolvaptan Renal cysts Chronic Kidney Disease Genetic Kidney Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 91
Healthy volunteers: no

Brief summary:
The primary objective of the study is to assess the long term safety of treatment with tolvaptan in children and adolescents with autosomal dominant polycystic kidney disease (ADPKD). The secondary objective is to assess the pharmacodynamics, pharmacokinetics, and efficacy of tolvaptan in the same participant population.

Detailed description:
Tolvaptan has been demonstrated to delay the decline of kidney function in adults with rapidly progressing ADPKD (chronic kidney disease \[CKD\] stages 1 to 3) as measured by estimated glomerular filtration rate (eGFR) and Total Kidney Volume (TKV).

This trial will be the first trial of tolvaptan in children and adolescents with ADPKD.

Participants in this study will be randomly assigned to one of two groups in Phase A; tolvaptan or placebo. Participants will have an equal chance of being assigned to either treatment group and will be stratified by age and gender into the following cohorts:

* Female participant ages 12 to 14 years, inclusive
* Female participant ages 15 to 17 years, inclusive
* Male participant ages 12 to 14 years, inclusive
* Male participant ages 15 to 17 years, inclusive

Phase (A) of this study will last 12 months. After that time, all participants who qualify will be assigned tolvaptan and will be treated with tolvaptan for 24 months (Phase B).

A qualified participant is defined as one who has completed Phase A on investigational medicinal product (IMP), is willing to continue in the trial, and who does not have any adverse events (AEs), which would require IMP discontinuation.

Participants in this study will be required to make monthly visits to the study clinic and will be closely monitored over the course of the study.

Arms:
arm 1: Participants received tolvaptan tablets, orally as a split dose (with the first dose taken upon awakening and the second dose taken approximately 8 hours later), and starting doses based on their weight as per the following specifications: ≥20 to 45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; \>75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to \<45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; \>75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter participants continued the same dose for 12 months. Doses may be titrated down dependent upon participant tolerability. arm 2: Participants received matching-placebo tablets, orally as a split-dose (with the first dose taken upon awakening and second dose taken approximately 8 hours later), and starting dose based on their weight as per the following specifications: ≥20 to \<45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; \>75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to \<45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; \>75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter participants continued the same dose for 12 months. Doses may be titrated down dependent upon participant tolerability. arm 3: Qualified participants (defined as those who were willing to continue in the trial and who did not have any adverse events \[AEs\] that would require investigational medicinal product \[IMP\] discontinuation) who received tolvaptan and completed Phase A were enrolled in Phase B and received tolvaptan tablets, orally as a split dose (with the first dose taken upon awakening and the second dose taken approximately 8 hours later), and starting dose based on their body weight as per following specifications: ≥20 to \<45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; \>75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to \<45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; \>75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter participants continued the same dose for 24 months. Doses may be titrated down dependent upon participant tolerability. arm 4: Qualified participants (defined as those who were willing to continue in the trial and who did not have any AEs that would require IMP discontinuation) who received matching-placebo and completed Phase A, were enrolled in Phase B and received tolvaptan tablets, orally as a split dose (with the first dose taken upon awakening and the second dose taken approximately 8 hours later), based on their current body weight as per following specifications: ≥20 to \<45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; \>75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to \<45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; \>75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter participants continued the same dose for 24 months. Doses may be titrated down dependent upon participant tolerability.

Interventions: intervention 1: Tolvaptan intervention 2: Tolvaptan Matching-placebo
Intervention descriptions: intervention 1: Tolvaptan spray-dried, immediate release tablets intervention 2: Tolvaptan matching-placebo tablets

Protocol document:
Prot_000.pdf: 
Table of Contents
Table of Contents.............................................................................................................
1
Study 156-12-298 Protocol Amendment 2; 29 Jul 2020..................................................
2
Study 156-12-298 Protocol Addendum; 29 Jul 2020.......................................................
115
Clinical Study Report 156-12-298
16.1.1 Protocol and Protocol Amendments
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Protocol 156-12-298
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Amendment 2, 29 Jul 2020
Protocol Synopsis 
Name of Sponsor:  Otsuka Pharmaceutical 
Development & Commercialization, Inc.
Name of Product:  JINARC®, Tolvaptan
(OPC-41061)
Protocol No.: 156-12-298
IND No.: 072975
EudraCT No.: 2016-000187-42
Protocol Title:
A Phase 3b, Two-part, Multicenter, One Year Randomized, 
Double-blind, Placebo-controlled Trial of the Safety, 
Pharmacokinetics, Tolerability, and Efficacy of Tolvaptan 
followed by a Two Year, Open-label Extension in Children and 
Adolescent Subjects with Autosomal Dominant Polycystic 
Kidney Disease (ADPKD)
Clinical Phase/Trial 
Type:
Phase 3b, therapeutic confirmatory
Treatment Indication: 
ADPKD
Objective(s): 
Primary: 
To assess the long term safety of treatment with 
tolvaptan in a pediatric and adolescent ADPKD 
population. 
Secondary: 
To assess the pharmacodynamics (PD),
pharmacokinetics (PK), and efficacy of tolvaptan
in children and adolescent subjects with ADPKD.
Trial Design:
Phase A is a randomized, double-blind, placebo-controlled phase 
to compare tolvaptan with placebo.  The duration of treatment is 
12 months. It is open to subjects between the ages of 4 and 17 
years, inclusive. Subjects between the ages of 12 and 17 years 
will be stratified by age and gender. When these stratified 
cohorts have been closed, enrollment for the trial will end.  
Qualified subjects who complete Phase A may continue in Phase 
B.  A qualified subject is defined as one who has completed 
Phase A on investigational medicinal product (IMP), is willing 
to continue in the trial, and who does not have any adverse 
events (AEs), which would require IMP discontinuation.
Phase B is an open-label phase during which qualified subjects 
will receive treatment with tolvaptan for 24 months. 
Clinical Study Report 156-12-298
16.1.1 Protocol and Protocol Amendments
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Subject Population:
In Phase A, the required population will consist of at least 
60 male and female subjects aged 12 to 17 years (inclusive),
with a diagnosis of ADPKD.
Randomization will be 1:1; tolvaptan to placebo.  Subjects ages 
12 to 17 will be stratified by age and gender in the following age 
cohorts: 

Female subjects ages 12 to 14 years, inclusive

Female subjects ages 15 to 17 years, inclusive

Male subjects ages 12 to 14 years, inclusive

Male subjects ages 15 to 17 years, inclusive
The trial is also open to children between the ages of 4 to 
11 years (inclusive) with ADPKD, who meet the study inclusion
criteria and who, in the opinion of the investigator, would 
benefit from treatment.  Including this latter group, the total trial 
population may, but is not required to, include approximately
100 subjects.  
Inclusion/Exclusion 
Criteria: 
Key Inclusion Criteria:

Male and female subjects aged 4 to 17 years (inclusive) with 
a diagnosis of ADPKD as defined by the presence of family 
history and/or genetic criteria AND who have at least 10 
renal cysts, each of which measure at least 0.5 cm, 
confirmed upon magnetic resonance imaging (MRI)
inspection; subjects under the age of 12 years must have at 
least 4 cysts that are at least 1 cm in size, confirmed by 
ultrasound.

Weight ≥20 kg.

Subjects with estimated glomerular filtration rate (eGFR)
≥60 mL/min/1.73m2 within 31 days prior to randomization 
(using the Schwartz formula, eGFR = 0.413 × height [cm] 
/serum creatinine mg/dL).

Independent in toileting.

Ability to swallow a tablet.
Key Exclusion Criteria:

Liver function tests including AST (aspartate 
aminotransferase), ALT (alanine aminotransferase)
> 1.5 × the upper limit of normal (ULN).

Nocturnal enuresis.

Need for chronic diuretic use.
Clinical Study Report 156-12-298
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
Subjects with advanced diabetes (eg, glycosylated 
hemoglobin > 7.5, and/or glycosuria by dipstick, significant 
proteinuria, retinopathy), evidence of additional significant 
renal disease(s) (ie, currently active glomerular nephritides), 
renal cancer, single kidney, or recent (within 6 months of 
screening) renal surgery or acute kidney injury.

Subjects having disorders in thirst recognition or inability to 
access fluids.  

Subjects with critical electrolyte imbalances, as determined 
by the investigator.

Subjects with, or at risk of, significant hypovolemia as 
determined by investigator.

Subjects with clinically significant anemia, as determined by 
investigator.

Subjects 12 years of age and older having contraindications 
to, or interference with MRI assessments (eg, ferro-magnetic 
prostheses, aneurysm clips, severe claustrophobia).

Subjects with a history of taking a vasopressin 
agonist/antagonist.

Subjects taking medications or having concomitant illnesses 
likely to confound endpoint assessments, including taking 
approved (ie, marketed) therapies for the purpose of 
affecting polycystic kidney disease (PKD) cysts such as 
tolvaptan, vasopressin antagonists, anti-sense ribonucleic 
acid (RNA) therapies, rapamycin, sirolimus, everolimus, or 
somatostatin analogs (ie, octreotide, sandostatin).

Subjects who have had cyst reduction surgery within 6 
weeks of the screening visit.
Trial Site(s):
The trial will be conducted at approximately 20 centers globally.
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Investigational 
Medicinal Product(s), 
Dose, Dosage 
regimen, Treatment 
period, Formulation, 
Mode of 
Administration:
Tolvaptan will be provided as 7.5, 15, and 30 mg spray-dried, 
immediate-release tablets with matching placebo.
Tolvaptan will be administered as a split-dose, with the first 
dose taken upon awakening and the second dose taken 
approximately 8 hours later.  
Subjects will be randomized to receive IMP defined as either 
active tolvaptan or matching placebo for 12 months.  Starting 
doses will be based on weight:

≥20 kg to < 45 kg, 15/7.5 mg tolvaptan (TLV) split-dose or 
matching placebo

≥45 kg to ≤ 75 kg, 30/15 mg TLV split-dose or matching 
placebo

> 75 kg, 45/15 mg TLV split-dose or matching placebo
After 1 week, subjects will be asked to up-titrate once from their 
starting dose.  

≥20 kg to < 45 kg, 30/15 mg TLV split-dose or matching 
placebo

≥45 kg to ≤ 75 kg, 45/15 mg TLV split-dose or matching 
placebo

> 75 kg, 60/30 mg TLV split-dose or matching placebo
Subjects may down-titrate at any time during the trial, however 
subjects will be asked to stay on the highest tolerable dose (by 
weight group) if possible.
It is recommended that each dose be administered with 240 mL 
of water, as part of the goal to maintain proper hydration status; 
the total 240 mL can be consumed over a 1-hour period 
following dosing.  
Trial Assessments:
Efficacy:

Total kidney volume assessed by MRI or ultrasound

Assessment of renal function (eGFR by Schwartz formula)
Pharmacokinetic: 

PK blood samples - sparse sampling and dense sampling in a 
subset of subjects
Pharmacodynamic:

Urine osmolality and specific gravity

24-hour fluid balance

Serum sodium, creatinine, and osmolality

Urine volume and urine sodium, creatinine, and osmolality
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
Fluid intake

Palatability and acceptability of tolvaptan formulation
Safety:  

AE reporting

Clinical laboratory tests (hematology, chemistry, urinalysis)

Vital signs

Physical examination including body weight and growth 
percentile

Tanner Staging

Vital status
Quality of Life (QoL): 

Generic Pediatric QoL questionnaire

Daytime and nighttime voids
Criteria for 
Evaluation:
Primary and secondary endpoints include the agreed upon 
endpoints in the Paediatric Investigational Plan (PIP).  In 
addition to the PD and PK objectives, the PIP requires the 
collection and descriptive analyses of safety and normal growth 
in this population.
Co-Primary Endpoints:  Change from baseline in spot urine 
osmolality (premorning dose) and specific gravity (premorning 
dose) after 1 week of daily dosing in Phase A.
Key Secondary Endpoint:  
The percent change from Phase A baseline in height-adjusted 
total kidney volume (htTKV) as measured by MRI at 12 months. 
Other Secondary Endpoints:

24-hour fluid balance prior to Week 1.

Change from baseline in renal function (eGFR by Schwartz 
formula) at each clinic visit (Week 1, Month 1, Month 6, 
Month 12) in Phase A.

Change from baseline in renal function (eGFR by Schwartz 
formula) at each clinic visit (Week 1, Month 1, Month 6, 
Month 12, Month 18, Month 24) in Phase B.

Percent change in htTKV as measured by MRI from Phase B 
baseline to Phase B Month 12.

Percent change in htTKV as measured by MRI from Phase B 
baseline to Phase B Month 24.

Pharmacodynamic (PD) endpoints of urine volume
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(including 24-hour fluid volume), fluid intake and fluid 
balance, sodium, creatinine, and free water clearance during 
dense PK sampling (after at least 1 month on IMP).

Proportions of each Tanner Stage by gender and age 
compared to normative populations at baseline, 6 months, 
and 12 months during the placebo-controlled phase 
(Phase A), and every 6 months during the open-label 
extension phase (Phase B).

Description of changes from baseline percentiles for height 
and weight by gender and age at baseline, 6 months, and 12 
months during the placebo-controlled phase (Phase A), and 
every 6 months during the open-label extension phase (Phase 
B).

Safety variables (changes from baseline in creatinine, vital 
signs, laboratory values including liver function tests [LFTs], 
rate of aquaretic AEs) in placebo and tolvaptan.
Statistical Methods:
Sample Size:
For the primary endpoint analysis, a sample size of at least 60 
subjects from 12 to 17 years of age inclusive is proposed for the 
Phase A of this trial. Since the data collected will be 
summarized using descriptive statistics and not aimed at testing 
a specific hypothesis, no formal power calculations are 
undertaken.
Key Datasets for Analysis:
The following datasets are defined for the efficacy and safety 
analysis in this trial:
Randomized:  Consists of all subjects who were randomized in 
this trial.
Full Analysis Set (FAS): Subjects who have been randomized 
to a treatment group, received at least 1 dose of the IMP, have 
both a Phase A baseline and at least 1 postbaseline efficacy 
evaluation.
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Safety:  Subjects that were administered at least 1 dose of IMP.
The FAS dataset, which is based on intent-to-treat principle, will 
be analyzed according to the treatment group to which each 
subject was randomized; the safety dataset will be analyzed 
according to the treatment received.
Efficacy Analysis:
Descriptive statistics will be presented on the co-primary 
endpoints, and key secondary endpoint by treatment groups.
Other secondary endpoints will also be summarized using 
descriptive statistics by treatment groups.
Safety Analyses:
Safety variables will be analyzed including AEs, changes from 
baseline in creatinine, vital signs, laboratory values including 
LFTs, and rate of aquaretic AEs in placebo and tolvaptan.  
Summarized statistics will be provided for the safety variables 
based on all available data in Phase B as well.  
Trial Duration:
Overall trial duration is expected to be approximately 4 years 
with a 1-year enrollment period.  Phase A will last 1 year for 
each subject, and Phase B will last 2 years for each subject.  
Maximum trial duration for each subject is 3 years and 30 days.  
Follow-up visits will be conducted at 7 (+2) days after the last 
dose of tolvaptan, and a final safety follow-up telephone contact 
will be conducted at 14 (+2) days after the last dose of tolvaptan 
for all subjects.
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Trial Conduct for COVID-19
All procedures and assessments in this protocol are to be followed to the fullest extent 
possible. The sponsor, in coordination with the site, investigator(s), and medical monitor, 
will continuously monitor and evaluate the benefits and risks to subject participation in 
the clinical trial as it related to COVID-19. If any protocol specified activities were not 
able to be performed, or cannot be performed due to COVID-19 considerations, refer to 
the COVID-19 Addendum for the appropriate measures to be followed. Appropriate 
measures may include replacing in-person visits with virtual visits (phone or video) as 
deemed necessary by the investigator to ensure subject safety and maintain protocol 
requirements.
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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
ADPKD
Autosomal dominant polycystic kidney disease
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC0-24h
Area under the concentration-time curve from time zero to 24 hours 
AVP
Arginine vasopressin
BT
Bilirubin, total
cAMP
Cyclic adenosine monophosphate
CKD
Chronic kidney disease
CKD-EPI
Chronic Kidney Disease-Epidemiology
Cmax
Maximum (peak) plasma concentration
Cmin
Minimum plasma concentration 
CRO
Clinical research organization
CSR
Clinical study report
CYP
Cytochrome P450
DILI
Drug-induced liver injury
DILIN
Drug Induced Liver Injury Network
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EoTx
End of Treatment
EudraCT
European Clinical Trial Data Base
FAS
Full Analysis Set
FDA
(United States) Food and Drug Administration
GCP
Good Clinical Practice
HAC
Hepatic adjudication committee
htTKV
Height-adjusted total kidney volume
IAF
Informed assent form
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
ID
Identification
IDMC
Independent data monitoring committee
IEC
Independent ethics committee
IMP
Investigational medicinal product
IND
Investigational new drug
INR
International normalized ratio
IRB
Institutional review board
IRE
Immediately reportable event
IXRS
Interactive response system
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LFT
Liver function test
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
OPDC
Otsuka Pharmaceutical Development & Commercialization
PD
Pharmacodynamic
PIP
Paediatric Investigational Plan
PK
Pharmacokinetic(s)
PKD
Polycystic kidney disease
PQC
Product Quality Complaint
QoL
Quality of Life
RBC
Red blood cell
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical Analysis Plan
TEAE
Treatment-emergent adverse event
TKV
Total kidney volume
tmax
TLV
Time to maximum (peak) plasma concentration
Tolvaptan
US or USA
United States or United States of America
ULN
Upper limit of normal
V2
Vasopressin Type 2
WBC
White blood cell
WOCBP
Women of childbearing potential
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When all subjects in Phase B either complete the Month 24 visit, or the last ongoing 
subject terminates early, the database will be locked, and a final CSR will be provided to 
the regulatory authorities.  
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measures at least 0.5 cm confirmed upon magnetic resonance imaging (MRI) inspection.  
In accordance with the PIP requirements, the trial will also allow subjects aged 4 to 
11 years who meet criteria for entry to be enrolled concurrently during the recruitment 
period for the target population.  It is expected that the trial may enroll approximately
100 subjects.
Subjects who are MRI-naive or under the age of 12 should have at least 4 cysts that are at 
least 1 cm in size confirmed by ultrasound prior to MRI inspection.
Treatment groups for the required population will be stratified by age and gender in the 
following age cohorts: 

Female subjects ages 12 to 14 years, inclusive

Female subjects ages 15 to 17 years, inclusive

Male subjects ages 12 to 14 years, inclusive

Male subjects ages 15 to 17 years, inclusive
When > 15 subjects are enrolled in an age cohort, new screening for that age cohort will 
be closed; subjects concurrently in screening for that age cohort may be enrolled if they 
meet inclusion/exclusion criteria.  When the last subject in the final age cohort for the 
required population has been achieved, enrollment in the trial will cease.  
The trial is also open to children between the ages of 4 to 11 years (inclusive) with 
ADPKD, who meet the above criteria and who, in the opinion of the investigator, would 
benefit from treatment.  Subjects, aged 4 to 11 years (inclusive), must have an ultrasound 
to assess renal cysts.  
Qualified subjects (as defined in Section 3.1) who complete Phase A on study medication 
are eligible to participate in Phase B.
3.3.2
Subject Numbering
All subjects will be given a unique 5 digit subject screening identification (ID) number
that starts with the letter “S” (SXXXXX).
3.4
Eligibility Criteria
3.4.1
Informed Consent/Informed Assent
Written informed consent will be freely obtained from all subjects’ guardian(s) or legally 
acceptable representative(s), as applicable for local laws.  Written informed assent will be 
freely obtained from all subjects.  Consent/assent will be documented on a written 
informed consent form (ICF) and informed assent form (IAF).  The ICF/IAF will be 
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Table 3.7-1
Schedule of Assessments Phase A
Screening 
(-30 to -1)
Baseline
(D 1)
Wk 1 
(-1/+3 D)
M1 (Wk 
4) (7 D)
M6
(±14 D)
Monthly
Safety 
Visits: 
M2, 3, 4, 
5, 7, 8, 9, 
10, 11 
(±4 D)a
Titration 
Contact 
(phone 
call or 
visit)
M12b 
(D365) 
(+14 D)/
End of 
Treatment 
(EoTx)c,d
Follow-Upc,d
7 D Post 
Last Dose 
(+2 D)
14 D Post 
Last Dose 
(+2 D)
Informed consent/assent
X
Inclusion/exclusion
X
X
Uroflowmetry 
Assessment
X
Demographics, 
medical/ADPKD historye
X
Tanner stagingf
X
X
X
MRI/ultrasoundg
X
X
Renal pelvic 
measurementh
X
X
X
Vital signsi
X
X
X
X
X
X
12-lead electrocardiogram
X
Body height and 
weight/growth 
percentilesj
X
Xj
Xj
Xj
X
X
Serum 
chemistry/hematology/
urinalysisk
X
X
X
Liver function 
tests/creatininek,l
X
X
X
X
X
X
X
X
Serum sodiumk
X
X
X
X
X
X
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mA urine or serum pregnancy test for pregnancy for females of childbearing potential (all females ≥12 years of age and females < 12 years of age who have 
started menstruating) will be performed.  On suspicion of pregnancy, an unscheduled urine or serum pregnancy testing will be performed.  Positive urine 
pregnancy tests must be confirmed with a serum pregnancy test. Investigator (or appropriate site staff) is advised to counsel participants on the risk of 
pregnancy while participating in a clinical trial as well as ensuring the child understands how pregnancies occur and can be avoided. This should be 
documented in source records.
nAs needed, a “directed” physical examination may be performed to focus on PKD-related signs and symptoms. 
oA subject who reaches Stage 5 (both in pubic hair and genitalia) does not need to continue with Tanner Staging.
pThe first dose of IMP will be administered to the subject in the clinic.  The last dose of Phase B will be taken the evening prior to the Month 24 visit.
qIf 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 recorded at each visit.  Drug reconciliation will be conducted at every 
visit.  If additional drug supply is required for titration purposes, the site will arrange a subject visit for dispensation.
 
 
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3.7.1
Schedule of Assessments
3.7.1.1
Randomized, Double-blind Phase A
3.7.1.1.1
Screening
The procedures listed below will be performed during the screening visit (Days −30 
to −1) to ensure that the subject qualifies for the trial.  
1) Trial procedures and information regarding the nature of the trial will be reviewed 
and written informed consent/assent will be obtained prior to any trial-related 
procedures.

Informed consent will be obtained from each subject’s parent/legal guardian 
or legally acceptable representative prior to any trial procedures being 
conducted.

Each subject who is able will indicate willingness to participate in the trial by 
signing or marking an assent form (as applicable) supplied for this purpose.

Informed consent/assent needs to be obtained each time a subject matriculates 
into the next age group.
2) Inclusion and exclusion criteria will be reviewed and documented.
3) Uroflowmetry assessment will be performed.
4) Demographic information will be collected.
5) Medical and ADPKD history will be recorded.  

Medical history should include the subject’s current list of medical problems.  

ADPKD medical history should include a diagnosis of ADPKD as defined by 
the presence of family history and/or genetic criteria AND who have at least 
10 renal cysts, each of which measures at least 0.5 cm, confirmed upon MRI 
inspection.  Younger subjects who are MRI-naive should have at least 4 cysts 
that are at least 1 cm in size, confirmed by ultrasound.

ADPKD genetic history to be collected if available, although it is not 
specifically required.  
6) Renal pelvis assessment will be performed by ultrasound.
7) Magnetic resonance imaging or ultrasound will be performed to confirm 
eligibility for the trial and to measure TKV.  The baseline imaging used must be 
the same imaging used throughout the trial (Phase A and Phase B).
8) Vital signs (seated blood pressure and heart rate) will be assessed.  Vital signs 
should be assessed prior to blood draws.  
9) A resting 12-lead electrocardiogram (ECG) will be performed after the subject 
has been supine and at rest ≥10 minutes.
10) Body height will be measured.
11) Body weight will be measured.  Body weight should be measured post-void.
12) Growth percentile will be calculated.
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
Subjects who take IMP through the Month 24 visit in Phase B and complete some 
or all of the trial visit assessments will be defined as On-treatment trial 
completers.  

Subjects who discontinue IMP prior to the Month 24 visit in Phase B and 
complete some or all of the trial visit assessments will be defined as Off-treatment 
trial completers.  

Subjects who are randomized, take IMP but do not complete the Phase A 
Month 12 visit or the Phase B Month 24 visit will be defined as Trial 
non-completers. 
3.11
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before their last trial visit during the treatment 
period, who do not have a known reason for discontinuation (eg, withdrew consent or 
AE), and for whom a survival status at the end of the trial cannot be determined will be 
classified as “lost to follow-up” as the reason for discontinuation.  Vital status can be 
determined from a variety of sources, either by obtaining acceptable documentation for 
death (ie, death certificate, medical records, public records, 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).
The site will make 3 documented attempts to contact the subject by telephone and in the 
event the site is unable to reach the subject by telephone, the site will attempt to contact 
the subject via certified mail or an alternative similar method, where appropriate, before 
assigning a “lost to follow-up” status.
3.12
Subject Compliance 
The date and time of the first dose of IMP administration will be recorded in source 
documentation and the eCRF.  The date and time of each dose administered in the clinic 
will also be recorded.  Information regarding any missed or inappropriately administered 
doses will also be documented in source documentation and the eCRF.
Accountability and compliance verification should be documented in the subject’s trial 
records.  Subjects must be counseled on the importance of taking the IMP as directed at 
all trial visits and work with their physicians around planned interruptions.  If poor 
compliance continues (eg, multiple missed doses resulting in < 80% overall compliance 
at any point in the trial), discontinuation from the trial should be considered.  This 
decision will be documented by the investigator in consultation with the medical monitor.
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3.13
Protocol Deviations
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, treatment assignment error, subject enrolled in violation of eligibility criteria or 
concomitant medication criteria), the investigator or designee will contact the sponsor at 
the earliest possible time by telephone.  The investigator and sponsor or designee will 
come as quickly as possible to a joint decision regarding the subject’s continuation in the 
trial.  This decision will be documented by the investigator and the sponsor or designee, 
and reviewed by the site monitor.
4
Restrictions
4.1
Prohibited 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 (RNA) therapies, tolvaptan, and other vasopressin antagonists eg, OPC-31260 
(mozavaptan), Vaprisol (conivaptan), or agonists (eg, desmopressin).    If a subject 
develops a medical need for cyst reduction therapy, during trial participation, this will be 
addressed with the appropriate physician.  The subject would then be discontinued from 
treatment at the time of surgical intervention.  The subject will remain in the trial and 
may restart treatment 6 weeks after surgical intervention at the discretion of the 
investigator.
Continuous or short-term use of other medications, while not prohibited, may be 
restricted by the investigator because of their potential for interference with metabolism 
or efficacy endpoints.  This includes the use of diuretics which may be used 
intermittently, but 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 due to potential endpoint interference and is an exclusionary criterion for 
this trial.  Subjects taking such agents must first sign an ICF and then agree to be 
switched to an alternate form of therapy in order to be eligible for the trial.  Subjects must 
be on a stable dose of their antihypertensive medications at randomization.
Some drugs are known to alter creatinine concentrations so, while not prohibited, subjects 
should alert their trial doctor, and any other healthcare providers, to take this into 
consideration when considering changes in their prescribed or over-the-counter 
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5
Reporting of Adverse Events
5.1
Definitions
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  AEs would not include information recorded as medical 
history at screening for pre-planned procedures for which the underlying condition was 
known and no worsening occurred.  An adverse reaction is any untoward and unintended 
response to an IMP related to any dose administered.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE.  For the purpose of Investigational New Drug (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.
An SAE includes any event that results in any of the following outcomes:

Death.

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.

Persistent or significant incapacity/disability or substantial disruption of the ability to 
conduct normal life functions.

Requires in-patient hospitalization or prolongs hospitalization.

Hospitalization itself should not be reported as an SAE; whenever possible the 
reason for the hospitalization should be reported.

Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other non-medical need) are not 
considered SAEs.

Congenital anomaly/birth defect.

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 Adverse Events are all AEs that do not meet the criteria for a “serious” AE.
Immediately Reportable Event (IRE):

Any SAE.
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5.2
Eliciting and Reporting Adverse Events
The investigator will periodically assess subjects for the occurrence of AEs.  To avoid 
bias in eliciting AEs, subjects should be asked the nonleading 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.  AE collection
(serious and nonserious) is to begin after a subject has signed the ICF.  
Use medical terminology in AE reporting.  Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms.  Exacerbation or disease progression should be reported as 
an AE only if there are unusual or severe clinical features that were not present, or 
experienced earlier, or not expected based on the course of the condition.
In addition, the sponsor must be notified immediately by telephone, fax, or e-mail of any 
IREs 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 (ie, within 24 hours) report after either the 
investigator or site personnel become aware of any IREs as defined in Section 5.1 by 
telephone, fax, or e-mail to the sponsor using the contact information on the cover page 
of this protocol.  An IRE form must be completed and sent by e-mail, fax, or overnight 
courier to the sponsor.  (Please note that the IRE form is NOT the AE eCRF page.)
Subjects experiencing IREs 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 and will provide prompt updates on the subject’s status to 
the sponsor.
5.4
Assessment of Liver Symptoms, Signs or Test Abnormalities
5.4.1
Potential Drug-Induced Liver Injury
For a subject who experiences an elevation in AST or ALT that is 3 times the upper 
limit of normal (ULN), BT and ALP should also be evaluated. If significant 
abnormalities in transaminases and/or bilirubin are confirmed, other testing to fully 
evaluate the likely proximate cause should be undertaken with the option of consulting 
with local hepatic experts for interpretation and guidance.  All results should be made 
available to the sponsor and the HAC.
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will be required during screening to confirm the stability of the abnormality prior to 
randomization to confirm eligibility. Management of such subjects should be closely
coordinated with the trial’s medical monitor. In these subjects, further changes in liver
test levels of > 2 × upper limit of their highest screening value at any point postscreening
should prompt re-testing within 48 to 72 hours. Should such an increase occur during 
treatment with IMP, the subject will be immediately discontinued from treatment.  IMP 
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. 
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5.4.3
Guidelines for Repeat Testing of Liver Transaminases
The following guideline for repeat testing may be used by investigators as a reference for 
any subject with an ALT or AST 2 ULN:

ALT, AST, ALP, and BT should be repeated within 48 to 72 hours (needed to 
confirm abnormalities and determine if they are increasing or decreasing).

Inquiries should be made about symptoms (fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, and/or rash) and signs like jaundice or yellowish 
discoloration of sclera.

Close observation is required if symptoms persist or repeat testing shows ALT or 
AST 3 ULN for subjects with normal baseline measures OR 2-fold increases 
above baseline values for subjects with elevated values before drug exposure.  If close 
monitoring is not possible, the drug should be interrupted until such monitoring is 
possible or the drug should be permanently discontinued.

All trial subjects with evidence of possible DILI should be followed until all 
abnormalities return to normal or to the baseline state.
Close observation may involve:

Repeating liver enzymes and serum bilirubin tests 2 or 3 times weekly.

Frequency of retesting can decrease to once a week or less if abnormalities stabilize 
or if the trial drug has been interrupted/discontinued and the subject is asymptomatic.

Obtaining a more detailed history of symptoms and prior or concurrent diseases.

Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
special diets, and change in diet.

Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis, nonalcoholic steatohepatitis; hypoxic/ischemic hepatopathy, and biliary 
tract disease.

Obtaining a history of exposure to environmental chemical agents.

Obtaining additional tests to evaluate liver function, as appropriate (eg, international 
normalized ratio [INR], direct bilirubin).

Considering gastroenterology or hepatology consultations.
5.4.4
Liver Test Abnormalities and Interruption/Discontinuation of 
Investigational Medicinal Product
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. IMP 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.
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
Drug interactions with hormonal contraceptives

Contraceptives in current use

Guidelines for the follow-up of a reported pregnancy
Before trial enrollment, females of childbearing potential must be advised of the 
importance of avoiding pregnancy during trial participation and the potential risk factors 
for an unintentional pregnancy.  The subject or the subject’s parent/legal guardian or 
legally acceptable representative must sign an ICF stating that the above-mentioned risk 
factors and the consequences were discussed with the subject and/or the parent/legal 
guardian or legally acceptable representative.
A urine and/or serum pregnancy test for human chorionic gonadotropin will be performed 
at screening on all females of childbearing potential.  If a urine test is performed and is 
positive, the investigator will follow-up with a confirmatory serum test.
During the trial, all females of childbearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (eg, missed or late 
menstrual cycle).
If a subject is suspected to be pregnant before she receives IMP, 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 test is known.  If pregnancy is confirmed, the IMP 
will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for subject safety) and the subject will be withdrawn from the trial.
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 from the date of 
birth.  
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5.6
Procedure for Breaking the Blind
Unblinding a subject’s treatment assignment in a double-blind, controlled trial should 
never be undertaken lightly as it can introduce bias in assessment of safety or efficacy. 
However, in circumstances where immediate knowledge of treatment assignment will 
meaningfully influence the current or future management of potentially serious AEs, 
breaking the blind may be appropriate.  
Unless the need for unblinding is urgent and obvious, the investigator is encouraged to 
contact the sponsor/Clinical Research Organization (CRO) medical advisor to discuss 
their rationale for unblinding.  However, to prevent delays to the investigator or medical 
personnel responding to a potentially emergent situation, unblinding of IMP will not be 
dependent upon the investigator receiving approval from the sponsor/CRO medical 
advisor (ie, the investigator will be able to obtain the code break information independent 
of the sponsor/CRO medical advisor).  The investigator must contact the sponsor/CRO 
medical advisor by telephone or e-mail with an explanation of the need for opening the 
treatment assignment code within 24 hours of opening the code.  If the blind is broken, 
the Clinical Safety and Pharmacovigilance department must be notified immediately (see 
the cover page of this protocol for contact information).  Documentation of breaking the 
blind should be recorded in the subject’s medical record with the date and time the blind 
was broken and the names of the personnel involved.  Once the blind is broken for a 
subject, that subject may not reinitiate treatment with the IMP.
5.7
Follow-up of Adverse Events 
For this trial, information on AEs will be collected from the signature of the informed 
consent until 14 days after the last dose of IMP has been administered or until 7 days in 
subjects who discontinued prior to randomization.  Follow-up of AEs is described below.
5.7.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eCRF page with the current status noted.  All nonserious events that are ongoing at 
the last scheduled contact will be recorded as ongoing on the CRF.  For any AE having 
been identified throughout the trial, during analysis, additional relevant medical history 
information may be requested to further ascertain causality (including, but not limited to, 
information such as risk-related behavior, family history and occupation).  
The investigator will follow all AEs until the events are resolved, stabilized, or the 
subject is lost to follow-up.  Resolution means that the subject has returned to the 
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6.2
Pharmacodynamic Methods-Dense Sampling
Urinary excretions will be determined as urine concentration × urine volume; missing 
values will not be imputed. If urine concentration or volume is missing for any interval, 
the 0 to 24 hour values will not be determined. Urine volumes of zero, and consequently 
nor reportable urine concentration, are not considered as missing data; values of 0 will be 
reported for volume and excretion.
Free water clearance will be determined as urine excretion rate − osmolar clearance. 
Osmolar, sodium, and creatinine clearances will be determined by standard methods with 
average serum concentration determined by averaging the concentrations at the beginning 
and end of the urine collection interval. If urine volume for a collection interval is 0, then 
the clearance value for that interval and the following interval will be determined by 
using the average value of the 3 serum concentrations, the urine volume of the second 
interval and the total time of the 2 collection intervals (eg, 2 to 4 hour collection has urine 
volume of 0 mL). Clearance for the 2 to 4 and 4 to 8 hour intervals will be determined 
using serum concentrations at 2, 4, and 8 hours, the urine volume from 4 to 8 hour 
interval and total collection time of 6 hours (8 minus 2). 
Values of urine osmolality will be summarized with descriptive statistics by total daily 
dose (all placebos grouped together) and collection interval. Sodium and creatinine urine 
concentrations will only be listed.
Values of excretions (osmoles, sodium, and creatinine) and clearances (free water, 
sodium, and creatinine) will be summarized with descriptive statistics by total daily dose 
(all placebos grouped together), collection interval, and 0 to 24 hours. 
Serum concentrations (osmolality, sodium, and creatinine) and change from predose will 
be summarized with descriptive statistics by total daily dose (all placebos grouped 
together), analyte, and time point.
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7.5
Primary and Secondary Endpoint Analyses
7.5.1
Primary Endpoint Analysis
The co-primary endpoints for the trial are the change from Phase A baseline in spot urine 
osmolality (premorning dose) and specific gravity (premorning dose) to Week 1.
Descriptive statistics will be presented on the co-primary endpoints, respectively:

Change from Phase A baseline in spot urine osmolality (premorning dose) to Week 1

Change from Phase A baseline in specific gravity (premorning dose) to Week 1
7.5.2
Key Secondary Endpoint Analysis
The key secondary endpoint is the percent change from Phase A baseline in htTKV as 
measured by MRI at 12 months.  Descriptive statistics will be presented on the key 
secondary endpoint.
7.5.3
Secondary Endpoint Analysis
Other secondary efficacy endpoints include:

24-hour fluid balance prior to Week 1.

Change from baseline in renal function (eGFR by Schwartz formula) at each clinic 
visit (Week 1, Month 1, Month 6, and Month 12) in Phase A.

Change from baseline in renal function (eGFR by Schwartz formula) at each clinic 
visit (Week 1, Month 1, Month 6, Month 12, Month 18, and Month 24) in Phase B.

Percent change in htTKV as measured by MRI from Phase B baseline to Phase B
Month 12.

Percent change in htTKV as measured by MRI from Phase B baseline to Phase B
Month 24.

Pharmacodynamic endpoints of urine volume (including 24-hour fluid volume), fluid 
intake and fluid balance, sodium, creatinine, and free water clearance during dense 
PK sampling (after at least 1 Month on IMP).

Proportions of each Tanner Stage by gender and age compared to normative 
populations at baseline, 6 months, and 12 months during the placebo-controlled phase 
(Phase A), and every 6 months during the open-label extension phase (Phase B).

Description of changes from baseline percentiles for height and weight by gender and 
age at baseline, 6 months, and 12 months during the placebo-controlled phase (Phase 
A), and every 6 months during the open-label extension phase (Phase B).

Safety variables (changes from baseline in creatinine, vital signs, laboratory values 
including LFTs, rate of aquaretic AEs) in placebo and tolvaptan.
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7.9.1
Adverse Events
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term.  The incidence of the following events will be 
summarized by treatment group:

Treatment-emergent AEs (TEAEs)

TEAEs by severity

TEAEs potentially causally related to the IMP

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the IMP
7.9.2
Clinical Laboratory Data
Summary statistics for changes from baseline in the clinical laboratory measurements
will be provided for the safety population.  Potentially clinically significant results in 
laboratory tests identified using prospectively defined criteria will also be summarized
for the safety population.
In addition, laboratory measurements that signal the potential for Hy’s Law will be 
reported. An incidence table and a listing will be provided for subjects who meet one or 
combinations of following criteria, without initial findings of cholestasis (ALP activity 
> 2 × ULN):

ALT or AST 3 × ULN 

Bilirubin 2 × ULN 
7.9.3
Physical Examination and Vital Signs Data
By-patient listings will be provided for physical examination.  Summary statistics for 
changes from baseline in vital signs and potentially clinically significant results in vital 
signs will be summarized for the safety population.
7.10
Other Analysis
The analyses for medical history, concomitant medications, and protocol deviations will 
be proposed with details in the SAP.
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8
Management of Investigational Medicinal Product
8.1
Packaging and Labeling
Trial medication will be provided to the investigator(s) by the sponsor (or designated 
agent).  Tolvaptan will be supplied as 7.5 mg (6 mm), 15 mg (8 mm), and 30 mg (8 mm)
spray-dried tablets and matching placebos.  Each package used in the dosing period will 
be labeled to clearly disclose the subject ID, compound ID, trial number, the sponsor’s 
name and address, instructions for use, route of administration, appropriate precautionary 
statements, and other information required by local regulatory authorities.
The current tolvaptan tablet formulation is limited to administration to those who can 
easily swallow a 6 or 8 mm tablet and who weigh ≥20 kg.
8.2
Storage
Tolvaptan and matching placebo tablets (IMP) should be stored according to the storage 
conditions indicated on the clinical label.  The clinical trial site staff or designated 
personnel will maintain a temperature log in the drug storage area recording the 
temperature at least once each working day.  The IMP will be stored in a securely locked 
cabinet or enclosure.  Access will be limited to investigators and their designees.  Neither 
investigators nor any designees may provide IMP to any subject not participating in this 
protocol.
8.3
Accountability
The investigator or designee must maintain an inventory record of tolvaptan (including 
investigational, active control, or placebo) received, dispensed, administered, destroyed,
and returned.
8.4
Returns and Destruction
Upon completion or termination of the trial, all unused and/or partially used IMP will be 
returned to the sponsor or a designated agent or destroyed at the clinical sites.  IMP may 
be destroyed by the clinical sites only if approved by the sponsor and IMP destruction 
meets all local regulations.
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.
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8.5
Reporting of Product Quality Complaints
A Product Quality Complaint (PQC) is any written, electronic, or verbal communication 
by a healthcare professional, consumer, subject, medical representative, Competent 
Authority, regulatory agency, partner, affiliate or other third party that alleges 
deficiencies or dissatisfaction related to identity, quality, labeling, packaging, reliability, 
safety, durability, tampering, counterfeiting, theft, effectiveness, or performance of a drug 
product or medical device after it is released for distribution.  Examples include, but are 
not limited to, communications involving:

Failure/malfunction of a product to meet any of its specifications

Incorrect or missing labeling

Packaging issues (eg, damaged, dirty, crushed, missing product)

Blister defects (eg, missing, empty blisters)

Bottle defects (eg, under/over-fill, no safety seal)

Vial defects

Product defect (eg, odor, chipped, broken, embossing illegible)

Loss or theft of product
8.5.1
Eliciting and Reporting Product Quality Complaints
The investigator or designee must record all PQCs identified through any means from the 
receipt of the IMP from the sponsor, or sponsor’s designee, through and including 
reconciliation and up to destruction, including subject dosing.  The investigator or 
designee must notify the sponsor (or sponsor’s designee) by e-mail or telephone within 
24 hours of becoming aware of the PQC according to the procedure outlined below.
Identification of a PQC by the subject should be reported to the site investigator, who 
should then follow one of the reporting mechanisms above.
8.5.2
Information Required for Reporting Purposes

Description of compliant

Reporter identification (eg, subject, investigator, site)

Reporter contact information (eg, address, phone number, e-mail address)

ID of material (product/compound name, coding)

Clinical protocol reference (number and/or trial name)

Dosage form/strength (if known)

Pictures (if available)

Availability for return
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8.5.3
Return Process
Indicate during the report of the PQC if the complaint sample is available for return.  If 
complaint sample is available for return, return it in the product retrieval package, which 
will be provided by the sponsor.
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation.
8.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
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 and made 
available for direct inspection by authorized persons.
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.  In all cases, subject confidentiality must be 
maintained in accordance with local regulatory requirements.
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;

Documentation of the investigator’s decision to enroll the subject into the trial, the 
review of all inclusion/exclusion criteria prior to IMP administration, and 
confirmation of the subject’s actual participation in the trial;

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; 
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during this trial including any data clarification forms received from the sponsor.  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 
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 in accordance 
with established research principles, the ICH E6 GCP: Consolidated Guidance, 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, e-mail, and written communications.  In addition, all investigators and 
clinical site personnel will undergo initial and ongoing training for this particular trial, 
and this training will be clearly documented.
10.2
Auditing
The sponsor's Quality Assurance 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 CRFs 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, FDA regulations, ICH GCP 
Guideline (E6), international ethical principles derived from the Declaration of Helsinki,
and Council for International Organizations of Medical Science guidelines, and 
applicable local laws and regulations.  Each trial site will seek approval/favorable opinion
by an IRB or IEC according to regional requirements, and the investigator will provide 
that documentation to the sponsor.  The IRB/IEC will evaluate the ethical, scientific and 
medical appropriateness of the trial.  Further, in preparing eCRFs, the investigator, 
sub-investigator and their staff will take measures to ensure adequate care in protecting 
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subject privacy.  To this end, a subject number and subject identification 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 
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) may be allowed full access to inspect and copy the records, 
consistent with local requirements.  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 unique subject numbers in eCRFs.  If further subject 
identification is required, subjects’ full names may be made known to a regulatory 
agency or other authorized officials if necessary, subject to local regulations.
13
Amendment Policy
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB/IEC.  Any 
permanent change to the protocol, whether 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, as required by local 
regulations.  Except for “administrative” or “non-substantial” amendments, investigators 
will wait for IRB/IEC approval/favorable opinion 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 after agreement by the 
sponsor and investigator, followed by IRB/IEC notification within local applicable 
timelines.  The sponsor will submit protocol amendments to the applicable regulatory 
agencies within local applicable timelines.
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 
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cases, after approval/favorable opinion of the new ICF by the IRB/IEC, repeat written 
informed consent will be obtained from subjects enrolled in the trial before expecting 
continued participation and before the amendment-specified changes in the trial are 
implemented.
14
Publication Authorship Requirements
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations).  According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met:
1. Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND
2. Drafting the work or revising it critically for important intellectual content; AND
3. Final approval of the version to be published; AND
4. Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors.
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial.  By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct.
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15
References
1
Sweeney W, Avner E.  Diagnosis and management of childhood polycystic kidney 
disease. Pediatr Nephrol 2011;26(5):675-92.
2
Cadnapaphornchai M, George D, McFann K, Wang W, Gitomer B, Strain J et al.  
Effect of pravastatin on total kidney volume, left ventricular mass index and 
microalbuminuria in pediatric autosomal dominant polycystic kidney disease. Clin J 
Am Soc Nephrol 2014;May 9:889-96.
3
Grantham J.  Rationale for early treatment of polycystic kidney disease. Pediatr 
Nephrol. 2015 Jul;30(7):1053-62.
4
Otsuka Pharmaceutical Development & Commercialization, Inc. Tolvaptan (OPC-
41061) Investigator's Brochure.  Version 21: 25 Aug 2015.
5
Wang X, Gattone II V, Harris P, Torres V.  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;16:846-851.
6
Reif G, Yamaguchi T, Nivens E, Fijike H, Pinto C, Wallace D.  Tolvaptan inhibits 
ERK-dependent cell proliferation, CI-secretion, and in vitro cyst growth of human 
ADPKD cells stimulated by vasopressin.  Amer J Physiol Renal Physiol.  
2011;301:F1005-13.
7
Torres V, Chapman A, Devuyst O, Gansevoort R, Grantham J et al.  Tolvaptan in 
patients with autosomal dominant polycystic kidney disease.  N Eng J Med.  
2012;Dec 20;367(25):2407-18.
8
Higashihara E, Torres V, Chapman A, Grantham J, Bae K, Watnick J et al.  
Tolvaptan in autosomal dominant polycystic kidney disease:  three years experience.  
Am Soc Nephrol. 2011;6:2499-2507.
9
Torres V, Bankir L, Grantham J.  A case for water in the treatment of polycystic 
kidney disease. Clin J Am Soc Nephrol. 2009;(4):1140-50.
10 OPC-41061 Common Technical Document. Rockville (MD): Otsuka Pharmaceutical 
Development and Commercialization, Inc. Section 2.5: Clinical Overview;2013.
11 Czerwiec F.  Evaluation of ADPKD progression during three years of open-label 
tolvalptan therapy in the 156-04-250 and 156-05-002 Trials:  Comparison to case-
matched subjects receiving standard of care in the Consortium for Radiological 
Imaging Studies of Polycystic Kidney Disease (CRISP I) and the Modification of 
Diet in Renal Disease (MDRD) studies.  Otsuka Clinical Study Report for Protocol 
156-09-283, issued 17 Oct 2011.
12 International Conference on Harmonisation (ICH). E6(R1): Good Clinical Practice: 
Consolidated Guideline [updated 1996 Jun 10].
13 Schwartz G, Munoz A, Schneider M, Mak R, Kaskel F, Warady B et al.  New 
equations to estimate GFR in children with CKD. J Am Soc Nephrol. 
2009;20(3):629-37.
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14 U.S. Food and Drug Administration. Guidance for Industry. Drug-induced liver 
injury: premarketing clinical evaluation [report on the Internet]. 2009 Jul [cited 15 
Feb 2014].
15 U.S. Food and Drug Administration.  [homepage on the Internet].  Silver Spring:  
[updated 05 Aug 2015; cited 12 Nov 2015].
16 US 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/GuidanceComplianceRegulatoryInformation/G
uidances/UCM174090.pdf.
17 O'Brian PC.  Procedures for comparing samples with multiple endpoints. Biometrics, 
1984;40:1079-87.
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Amendment 2, 29 Jul 2020
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 2
Tanner Staging
Classification of Sex Maturity Stages in Girls
Stage
Pubic Hair
Breasts
1
Preadolescent
Preadolescent
2
Sparse, lightly pigmented, straight, medial 
border of labia
Breast and papilla elevated as small mound; 
areolar diameter increased
3
Darker, beginning to curl, increased amount
Breast and areola enlarged, no contour 
separation
4
Coarse, curly, abundant but amount less than 
adult
Areola and papilla form secondary mound
5
Adult feminine triangle, spread to medial 
surface of thighs
Mature; nipple projects, areola part of the 
general breast contour
Classification of Sex Maturity Stages in Boys
Stage
Pubic Hair
Penis
Testes
1
Preadolescent
Preadolescent
Preadolescent
2
Scanty, long, slightly 
pigmented
Slight enlargement
Enlarged scrotum, pink 
texture altered
3
Darker, starts to curl, small 
amount
Longer
Larger
4
Resembles adult type but less 
in quantity; coarse, curly
Larger; glans and breadth 
increase in size
Larger, scrotum dark
5
Adult distribution, spread to 
medial surface of thighs
Adult size
Adult size
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Appendix 3
Dense PK and PD Sampling:  Assessment Schedule
Phase A Time Point
PK Plasma Sampling
PD Serum Samplingc
Predose (within 15 min prior to the morning 
dose)
X
X
1 hr postdose
X
2 hr postdose
X
X
4 hr postdose
X
X
8 hr postdosea,b
X
X
12 hr postdoseb
X
X
24 hr postdoseb
X
X
aWithin 15 minutes prior to the afternoon dose
bPost the morning dose
cSerum samples for determination of sodium, creatinine, and osmolality
Phase A Time Point
PD Urine Volume & 
Sampling
Fluid Intake
0-2 hr post morning dose
X
2-4 hr post morning dose
X
0-4 hr post morning dose
X
4-8 hr post morning dose
X
X
8-12 hr post morning dose
X
X
12-24 hr post morning dose
X
X
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Amendment 2, 29 Jul 2020
Amendment Number:
2
Approval Date:
29 Jul 2020
PURPOSE:
The purpose of this protocol amendment is to introduce a COVID-19 Addendum for any
protocol-specified activities that are not able to be performed or cannot be performed due
to COVID-19 considerations. Refer to the COVID-19 Addendum for the appropriate
measures to be followed. Minor editorial revisions were also made, for consistency with 
Otsuka style and for internal consistency.
BACKGROUND:
Protocol Amendment 2 revisions were made to introduce a COVID-19 addendum and to 
add a revised schedule of assessments for only Phase B as all assessments for Phase A 
have been completed at the time of this amendment.
MODIFICATIONS TO PROTOCOL:
General Revisions:

Updated the names and contact information of Sponsor representative on title 
page.

Added trial conduct information after the title page to introduce the COVID-19 
Addendum.

Added text in “other secondary endpoints” in Protocol Synopsis.

Updated text in Section 7.5.2 “Key Secondary Endpoint Analysis.”

Updated text in Section 7.5.3 “Secondary Endpoint Analysis.”

Deleted text in Section 7.7 “Exploratory Endpoint Analysis.”
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects. A complete redline version of this amendment 
showing all changes from the previous version will be produced and available upon final 
approval of this amendment.
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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 Trial 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, tolvaptan, 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 receive a 
favorable opinion by the Independent Ethics Committee (IEC) responsible for such matters in the 
clinical trial facility where tolvaptan 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 the sponsor's 
Clinical Trial 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 and designee 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 substantial 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 the required local applicable 
timelines. Administrative changes to the protocol will be transmitted to the IRB/IEC for 
informational purposes only, if required by local regulations.
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 Trial 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 trial in a cooperative publication 
before publication of efficacy and safety results on an individual basis may occur, and I consent to 
be acknowledged in any such cooperative publications that result.
____________________________
_____________________________
___________
Principal Investigator Print Name
Signature
Date
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This page is a manifestation of an electronically captured signature
SIGNATURE PAGE
Document Name: 156-12-298 Protocol Amendment 2
Document Number: 
Document Version: 8.0
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:min) -
UTC timezone
Clinical Pharmacology
Approval
29-Jul-2020
01:15:59
Clinical Approval
29-Jul-2020
12:02:03
Biostatistics Approval
28-Jul-2020
21:22:07
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Trial Conduct for COVID-19
All procedures and assessments in the protocol are to be followed to the fullest 
extent possible. The sponsor, in coordination with the site, investigator(s), and 
medical monitor, will continuously monitor and evaluate the benefits and risks to 
subject participation in the clinical trial as it relates to COVID-19. If any protocol-
specified activities were not able to be performed, or cannot be performed due to 
COVID-19 considerations, the appropriate measures to be followed will be provided 
in this document.
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Table of Contents
Trial Conduct for COVID-19 ...................................................................... 2
Table of Contents .......................................................................................... 3
List of In-text Tables..................................................................................... 4
List of In-text Figures ................................................................................... 5
List of Abbreviations and Definitions of Terms......................................... 6
1
Trial 156-12-298 COVID-19 Protocol Summary.............................. 7
1.1
Trial Design Schematic ...................................................................................... 7
1.2
Schedule of Assessments.................................................................................... 8
2
General Considerations..................................................................... 12
2.1
Reconsent ......................................................................................................... 12
2.2
Protocol Deviations.......................................................................................... 12
2.3
Guidance to Record Adverse Events and Discontinuations Due to 
COVID-19........................................................................................................ 12
2.4
Statistical Analyses........................................................................................... 13
2.5
Quality of Life Assessments............................................................................. 13
3
Trial Population ................................................................................. 13
3.1
Inclusion Criteria.............................................................................................. 13
3.2
Exclusion Criteria............................................................................................. 14
4
Trial Procedures................................................................................. 14
4.1
Safety Assessments .......................................................................................... 14
4.1.1
Vital Signs ..................................................................................................... 14
4.1.2
Pregnancy ...................................................................................................... 14
4.1.3
Laboratory Tests ............................................................................................ 16
4.1.4
Adverse Event/Concomitant Medication....................................................... 16
5
Investigational Medicinal Product ................................................... 16
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List of In-text Tables
Table 1.2-1
COVID-19 Impact Schedule of Assessments Phase B................... 9
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List of In-text Figures
Figure 1.1-1
COVID-19 Impact Trial Design Schematic (Phase B)................... 7
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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
ADPKD
Autosomal dominant polycystic kidney disease
AE
Adverse event
CRO
Clinical research organization
D
Day
eCRF
Electronic case report form
EoTx
End of Treatment
EudraCT
European Clinical Trial Data Base
FOCBP
Females of child bearing potential
IMP
Investigational medicinal product
IND
Investigational new drug
LFT
Liver function test
MRI
Magnetic resonance imaging
OPDC
Otsuka Pharmaceutical Development & Commercialization
PE
Physical Examination
QoL
Quality of Life
SAE
Serious adverse event
Wk
Week
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1
Trial 156-12-298 COVID-19 Protocol Summary
1.1
Trial Design Schematic
IMP = Investigational medicinal product
Figure 1.1-1
COVID-19 Impact Trial Design Schematic (Phase B)
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1.2
Schedule of Assessments
Sites were informed to complete the in-clinic visits via telephone/telemedicine. Details 
were provided on how to perform the following assessments: Directed PE, collection of 
vital signs/weight/temperature, 
, MRI/ultrasound, 
and collection of AEs and Concomitant Medications with the details listed in the 
footnotes in Table 1.2-1. The renal pelvis assessment via ultrasound and Tanner Staging 
would not be performed as these assessments require a subject to be in-clinic. It was 
offered to the sites to use a courier service to send IMP to the subjects if needed at the 
appropriate visits. In the event of any future resurgence of COVID-19, the sites will be 
notified to follow the assessments listed in this addendum. The sponsor will continue to 
monitor and evaluate the benefits and risks to subject participation in the clinical trial as 
it relates to COVID-19.
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2
General Considerations
2.1
Reconsent
If there is an immediate need to reconsent subjects during the period of COVID-19 
restrictions, a paper reconsent process will be followed and sites are encouraged to 
contact the contract research organization (CRO) and sponsor with questions.
2.2
Protocol Deviations
Protocol deviations that occur as a direct result of the COVID-19 pandemic must be 
recorded in electronic case report form (eCRF) separately from other protocol deviations 
as soon as they are identified and will be recorded as “Major” in eCRF for data capture 
purposes. Examples of the types of COVID-19 related deviations to be reported may 
include: missed visits, missed assessments, assessments performed remotely (completed 
outside of protocol procedure), missed investigational medicinal product (IMP) dose, 
IMP dispensed/returned via courier, IMP not returned to site/site unable to verify IMP 
compliance, out of window visits, and prohibited concomitant medications. A “direct 
result” is defined as being due to actual illness, or as a result of quarantine, social 
distancing, or site closures. All other deviations will follow the normal deviation process 
described in the protocol and should not be entered proactively by sites.
2.3
Guidance to Record Adverse Events and Discontinuations Due to 
COVID-19
If a subject tests positive with COVID-19, the subject must have a treatment interruption 
until the subject is no longer considered to have active virus and is free of any medical 
conditions associated with the infection. An adverse event (AE) of “Coronavirus 
Infection” OR “Coronavirus Positive Test Result” should be recorded on the AE page of 
the eCRF. A positive test result is not automatically a serious adverse event (SAE), unless 
an SAE criterion is met (eg, hospitalization). If the event meets the criteria for an SAE, 
the subject may restart treatment per Investigator clinical judgement and with Sponsor 
Medical Monitor approval. The subject must no longer be considered to have active virus 
infection and is free of any medical conditions associated with the infection. Baseline 
laboratory tests, including liver function, must be performed prior to reinitiating tolvaptan 
therapy.
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If, per the discretion of the investigator, a subject discontinues the trial due to COVID-19 
either because they test positive OR are presumed positive with COVID-19, then the 
primary reason for discontinuation should be reported as “Adverse Event” and indicate 
the AE number in the “Specify the reason for discontinuation” space that corresponds 
with the AE of “Coronavirus Infection” OR “Coronavirus Positive Test Result.” 
Remember to enter an AE on the AE page for the “Coronavirus Infection” OR 
“Coronavirus Positive Test Result.”
If a subject discontinues due to COVID-19 other than the subject testing positive OR
being presumed positive with COVID-19, then the primary reason for discontinuation
should be reported as “Other.” Be sure to specify the reason as “COVID-19” followed by 
the reason ensuring that the prefix of the description includes “COVID-19.”
2.4
Statistical Analyses
Any impact of COVID-19 on the planned statistical analyses for the trial will be 
described in the final statistical analysis plan.
 
 
 
 
 
 
 
3
Trial Population
3.1
Inclusion Criteria
There are no changes to the inclusion criteria due to COVID-19 for purposes of this
addendum.
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3.2
Exclusion Criteria
There are no changes to the exclusion criteria due to COVID-19 for purposes of this
addendum.
4
Trial Procedures
4.1
Safety Assessments
4.1.1
Vital Signs
Blood pressure, heart rate, weight, and temperature will all be measured as described in 
the protocol at the time points defined in this COVID-19 Addendum Schedule of 
Assessments (Table 1.2-1) with the following changes, if remote visits are necessary: 

Subjects will be asked to use any collection device, if available, until devices can be 
provided to subjects.

Where possible, site staff will remotely supervise the collection of measurements 
via video on the appropriate visits.

If remote supervision is not possible, subjects will be instructed to be as consistent 
as possible regarding the time of day the measurement is taken and how the 
measurement is taken. Subjects or their parent/guardian will notify site staff of the 
measurement results via telephone or other means, on the appropriate visits.

Site staff will instruct the subjects or their parent/guardian to follow the procedures in 
the trial guidance for blood pressure and heart rate collection.

Site staff will be instructed to record the measurement in the subject’s eCRF, and if 
there are believed to be any errors, inconsistencies, or safety concerns with the home 
measurement, the medical monitor should be notified.
4.1.2
Pregnancy
Pregnancy tests will be performed as described in the protocol at the time points defined 
in this COVID-19 Addendum Schedule of Assessments (Table 1.2-1) with the following 
changes: 

For planned visits that require a pregnancy test for females of child bearing potential, 
the site will take dipstick(s) from the central lab kit/bulk supply and include it with 
the IMP delivery package.
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
For the initial remote visit, two dipsticks will be sent to the subject to allow for a 
repeat in case the test is positive. 

For subsequent visits, the site will decide whether to send 2 dipsticks at each 
subject shipment, or whether to help the subject manage the dipsticks at 
sequential visits (eg, test is negative, one dipstick left at subject home, the subject 
will be instructed to retain the spare dipstick for next testing, thus sending only 
one; or just sending 2 dipsticks to subject every time just to be on the safe side).

Site will inform the subject (or caregiver, as applicable) of instructions (verbally or in 
writing within the shipment, if EC approval is received).

Applicable subjects will perform a pregnancy test prior to dosing with IMP, ensuring 
a date and time-stamped picture or video of the result is taken, followed by 
notification to the site staff of the results via telephone, or other means, on the 
appropriate visits. Subjects will also provide the site staff with the date- and time-
stamped picture/video.

If negative, site to inform the subject to proceed with dosing.

If positive, the site must instruct the subject to immediately stop taking IP, and the 
site will refer to the Pregnancy section of the protocol for appropriate immediately 
reportable event reporting.

Further instruction must be agreed upon in consultation with the sponsor but an 
option may include the site informing the subject to continue to withhold IMP and to 
perform a repeat urine pregnancy test in 2 days (> 48 hours from first test). Subjects 
would again be asked to take a date and time-stamped picture or video of the result, 
followed by notification to the site staff of the results via telephone, or other means. 
Subjects would also provide the site staff with the date- and time-stamped 
picture/video.

If the second result is positive, the subject will be discontinued from the trial, and 
be instructed to contact their healthcare professional and the trial site (if possible) 
for further instructions.

If the second result is negative, the site will contact the CRO and sponsor for 
guidance and next steps.
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4.1.3
Laboratory Tests
The liver function test (LFT), serum chemistry, hematology, serum sodium, creatinine 
and urinalysis should be completed at a local laboratory or via a home health nurse. The 
local lab should have the proper protections in place for the subject to limit the exposure 
to COVID-19 and following the current local restrictions, guidance, and regulatory 
authority directions. The monthly safety labs must be completed in order for the subject 
to remain on IMP. If the subject is unable to have the labs drawn, the subject must have a 
treatment interruption until the labs can be completed. All labs should be assessed at the 
same time as the LFTs; however, if the results for serum chemistry, hematology, serum 
sodium, creatinine and urinalysis are not available, the subject can continue in the study. 
All attempts to obtain the required lab results should be made. How the labs were 
obtained (ie, via local lab, home health nurse) should be documented in the subject’s 
source.
4.1.4
Adverse Event/Concomitant Medication
The site should contact the subject by telephone at each visit to periodically assess for the 
occurrence of AEs.  To avoid bias in eliciting AEs, subjects should be asked the 
nonleading 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.
5
Investigational Medicinal Product
Clinical sites are permitted to ship IMP directly to subjects per agreed study processes 
due to COVID-19 restrictions.
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This page is a manifestation of an electronically captured signature
SIGNATURE PAGE
Document Name: 156-12-298 Protocol Addendum
Document Number: 
Document Version: 3.0
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:min) -
UTC timezone
Clinical Approval
29-Jul-2020
12:00:36
Biostatistics Approval
28-Jul-2020
21:22:37
Clinical Pharmacology
Approval
29-Jul-2020
01:16:28
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SAP_001.pdf: 
Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational New Drug 
Tolvaptan (OPC-41061)
Protocol No. 156-12-298
IND No. 072975
EudraCT No. 2016-000187-42
A Phase 3b, Two-part, Multicenter, One Year Randomized, Double-blind, 
Placebo-controlled Trial of the Safety, Pharmacokinetics, Tolerability, and Efficacy of 
Tolvaptan followed by a Two Year Open-label Extension in Children and Adolescent 
Subjects with Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Statistical Analysis Plan
Version 1.0: 05 Feb 2020
Version 2.0: 30 Nov 2021
Protocol Version 1.0:  17 Feb 2016
Administrative Change 1: 19 Feb 2016
Amendment 1: 08 Aug 2016
 Amendment 2: 29 Jul 2020
Confidential
May not be used, divulged, published, or otherwise disclosed without the prior written 
consent of Otsuka Pharmaceutical Development & Commercialization, Inc.
Clinical Study Report 156-12-298
16.1.9 Documentation of Statistical Methods
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Statistical Analysis Plan 
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Table of Contents
Table of Contents ..........................................................................................2
1
Introduction..........................................................................................4
2
Trial Objectives ....................................................................................4
3
Trial Design...........................................................................................4
3.1
Type/Design of Trial ...........................................................................................4
3.2
Trial Treatments ..................................................................................................8
3.2.1
Treatment in Phase A........................................................................................8
3.2.1.1
Dosing for Dense PK and PD Sampling .......................................................9
3.2.2
Treatment in Phase B........................................................................................9
3.3
Trial Population...................................................................................................9
4
Sample Size .........................................................................................10
5
Statistical Analysis Datasets..............................................................10
5.1
Analysis Datasets ..............................................................................................10
5.2
Handling of Missing Data .................................................................................11
6
Trial Conduct......................................................................................11
6.1
Subject Disposition ...........................................................................................11
6.2
Treatment Compliance ......................................................................................12
6.3
Prior and Concomitant Medications..................................................................12
6.4
Protocol Deviations...........................................................................................12
7
Demographic and Baseline Characteristics .....................................12
8
Primary and Secondary/ Exploratory Endpoints Analyses ...........12
8.1
Primary Endpoint Analysis ...............................................................................12
8.2
Key Secondary Endpoint Analysis....................................................................13
8.3
Other Secondary Endpoints Analyses...............................................................13
8.4
Subgroup Analyses............................................................................................14
8.5.1
Technical Computational Details for the Analysis of the Exploratory 
Endpoints........................................................................................................15
9
Safety Analyses...................................................................................16
9.1
Extent of Exposure............................................................................................16
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Statistical Analysis Plan 
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9.2
Adverse Events..................................................................................................17
9.3
Clinical Laboratory Data...................................................................................17
9.4
Vital Sign Data..................................................................................................18
9.5
Physical Examination Data ...............................................................................18
9.6
Electrocardiogram Data.....................................................................................18
10
Pharmacodynamic Analyses..............................................................18
11
Interim Analysis .................................................................................19
12
Monitoring of Safety Data .................................................................19
12.1
Independent Data Monitoring Committee.........................................................19
12.2
Hepatic Adjudication Committee......................................................................19
13
References ...........................................................................................20
14
Appendices..........................................................................................21
Appendix 1:...Criteria of Potentially Clinically Significant Laboratory Test Abnormalities
21
Appendix 2: ............Criteria of Potentially Clinically Significant Vital Sign Abnormalities
23
Appendix 3:..............................................................................................Document History
24
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Statistical Analysis Plan 
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1
Introduction
This statistical analysis plan (SAP) documents the statistical methodology and data 
analysis algorithms and conventions to be applied for statistical analysis and reporting of 
efficacy, safety, and pharmacodynamic data of Trial 156-12-298. All amendments to the 
protocol are taken into consideration in developing this SAP.
2
Trial Objectives
The primary objective is to evaluate the long term safety effects of treatment with 
tolvaptan in a pediatric and adolescent Autosomal Dominant Polycystic Kidney Disease 
(ADPKD) population.
The secondary objective is to assess the pharmacodynamics (PD), pharmacokinetics 
(PK), and efficacy of tolvaptan in children and adolescent subjects with ADPKD.
3
Trial Design
3.1
Type/Design of Trial
The trial will comprise 2 phases as described below:
Phase A is a randomized, double-blind, placebo-controlled phase to compare tolvaptan 
with placebo.  The duration of treatment is 12 months.  It is open to subjects between the 
ages of 4 and 17 years, inclusive.  Subjects between the ages of 12 and 17 years will be 
stratified by age and gender.  When these stratified cohorts have been closed, enrollment 
for the trial will end (Figure 3.1-1).  Additionally, subjects aged 4 to 11 years may be 
eligible for participation following discussion with the medical monitor.
Qualified subjects who complete Phase A may continue into Phase B.  A qualified 
subject is defined as one who is willing to continue in the trial and who does not have any 
AEs that would require investigational medicinal product (IMP) discontinuation.
Phase B is an open-label phase during which subjects who have completed Phase A of 
the trial will receive treatment with tolvaptan for 24 months (Figure 3.1-2).
When all subjects in Phase A have either completed the Month 12 visit or early 
terminated from the trial, a snapshot of the data will be taken.  At that time, the snapshot 
will be unblinded, and results analyzed and reported in an interim clinical study report 
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Statistical Analysis Plan 
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(CSR) to provide early information on safety.  The protocol may be amended to further 
ensure continuing safety and tolerability measures are in place.  
When all subjects in Phase B either complete the Month 24 visit, or the last ongoing 
subject terminates early, the database will be locked, and a final CSR will be provided to 
the regulatory authorities.
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3.2
Trial Treatments
Tolvaptan will be provided as 7.5, 15, and 30 mg spray-dried, immediate-release tablets 
with matching placebo.  Tolvaptan will be administered as a split-dose, with the first dose 
taken upon awakening and the second dose taken approximately 8 hours later.  
3.2.1
Treatment in Phase A 
Subjects will be randomized to receive IMP defined as either active tolvaptan or 
matching placebo for 12 months.  Starting doses will be based on weight as denoted 
below in Table 3.2.1-1.  
After 1 week, subjects who have tolerated their initial dose will up-titrate once from their 
starting dose (Table 3.2.1-2).  Subjects may down-titrate at any time during the trial, 
however subjects will be asked to stay on the highest tolerable dose (by weight group) if 
possible (Table 3.2.1-3). 
It is recommended that each dose be administered with 240 mL of water, as part of the 
goal to maintain proper hydration status; the total 240 mL can be consumed over a 1-hour 
period following dosing.  Water intake will be recorded for all in-clinic dosing.  
Table 3.2.1-1
Starting Tolvaptan Dose
Body Weight
Time
Split-dosea
≥ 20 kg to < 45 kg
Upon awakening / 8 hours later
15/7.5 mg TLV or matching 
placebo
≥ 45 kg to ≤ 75 kg
Upon awakening / 8 hours later
30/15 mg TLV or matching 
placebo
> 75 kg
Upon awakening / 8 hours later
45/15 mg TLV or matching 
placebo
TLV = tolvaptan.
a Split-dosing will be twice daily dosing with the larger dose taken upon awakening and the smaller dose taken 
approximately 8 hours later. 
Doses may be titrated down dependent upon subject tolerability.  
Table 3.2.1-2
Up-titration Steps
Current Dose
Up-titrated Dose
Body Weight
15/7.5 mg TLV or matching placebo
30/15 mg
≥ 20 kg to < 45 kg
30/15 mg TLV or matching placebo
45/15 mg
≥ 45 kg to ≤ 75 kg
45/15 mg TLV or matching placebo
60/30 mg
> 75 kg
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Table 3.2.1-3
Down-titration Steps
Current Dose
Down-titrated Dose
7.5 mg once daily upon awakening 
Subject to be withdrawn from IMP
7.5/7.5 mg
7.5 mg once daily upon awakening
15/7.5 mg
7.5/7.5 mg
22.5/15 mg
15/7.5 mg
30/15 mg
22.5/15 mg
45/15 mg
30/15 mg
60/30 mg
45/15 mg
Subjects should attempt to complete 7 days of dosing between down-titration steps to 
provide the best opportunity for a subject to be given their maximally tolerated dose.
3.2.1.1
Dosing for Dense PK and PD Sampling
A subset of 20 subjects, half on tolvaptan and half on placebo, in the 12 to 17 year old 
age group will have dense PK sampling after at least 1 month on IMP.  The blind will be 
maintained by utilizing the Interactive response system (IXRS) to determine how many 
subjects on tolvaptan or placebo have been assessed and closing a group when 
10 subjects have completed.  The doses that the subjects will be given will be from their 
currently prescribed IMP.  The morning dose will be administered at approximately 
8:00 AM in the fasting state (no food within 8 hours prior to dosing or within 2 hours 
postdosing), the afternoon dose 8 hours later, and with dinner served at least 2 hours 
postdose.  Each dose will be administered with 240 mL still, room temperature water; the 
total 240 mL can be consumed over a 1-hour period following dosing.
3.2.2
Treatment in Phase B 
Subjects who have completed Phase A on treatment and continue in Phase B will receive 
open-label tolvaptan for up to 24 months.  In order to preserve the blind in Phase A, 
subjects will be started at a dose based on their current body weight (see Table 3.2.1-1) 
and after 1 week, they will be asked to up-titrate once from their starting dose.  Subjects 
who wish to lower their dose secondary to tolerance will have their doses adjusted as 
necessary.
3.3
Trial Population
The target trial population will be at least 60 male and female subjects aged 12 to 
17 years (inclusive), with a diagnosis of ADPKD as defined by the presence of family 
history and/or genetic criteria AND who have at least 10 renal cysts, each of which 
measures at least 0.5 cm confirmed upon magnetic resonance imaging (MRI) inspection.  
In accordance with the PIP requirements, the trial will also allow subjects aged 4 to 
11 years who meet criteria for entry to be enrolled concurrently during the recruitment 
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period for the target population.  It is expected that the trial may enroll approximately 
100 subjects.
Subjects who are MRI-naive or under the age of 12 should have at least 4 cysts that are at 
least 1 cm in size confirmed by ultrasound prior to MRI inspection. 
Treatment groups for the required population will be stratified by age and gender in the 
following age cohorts: 

Female subjects ages 12 to 14 years, inclusive

Female subjects ages 15 to 17 years, inclusive

Male subjects ages 12 to 14 years, inclusive

Male subjects ages 15 to 17 years, inclusive
When > 15 subjects are enrolled in an age cohort, new screening for that age cohort will 
be closed; subjects concurrently in screening for that age cohort may be enrolled if they 
meet inclusion/exclusion criteria.  When the last subject in the final age cohort for the 
required population has been achieved, enrollment in the trial will cease.  
The trial is also open to children between the ages of 4 to 11 years (inclusive) with 
ADPKD, who meet the above criteria and who, in the opinion of the investigator, would 
benefit from treatment.  Subjects, aged 4 to 11 years (inclusive), must have an ultrasound 
to assess renal cysts.  
Qualified subjects who complete Phase A are eligible to participate in Phase B.
4
Sample Size 
A sample size of at least 60 subjects from 12 to 17 years of age inclusive is proposed for 
the Phase A of this trial.  It is expected that the trial may enroll approximately 100 
subjects in total. Since the data collected will be summarized using descriptive statistics 
and not aimed at testing a specific hypothesis, no formal power calculations are 
undertaken.
5
Statistical Analysis Datasets
5.1
Analysis Datasets
The following analysis sets are defined for the efficacy and safety analysis in this trial.
Randomized: It consists of all subjects who were randomized in the trial.
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Full Analysis Set (FAS) for Phase A consists of all subjects who have been randomized 
to a treatment group, received at least 1 dose of the IMP, have both a Phase A baseline 
and at least 1 post-baseline efficacy evaluation.  They will be analyzed according to the 
treatment group to which they were randomized. FAS for Phase B consists of all subjects 
wo enrolled to Phase B, received at least 1 dose of the IMP, have both a baseline and at 
least 1 post-baseline efficacy evaluation in Phase B. The FAS, which is based on intent-
to-treat principle, will be the primary analysis set for efficacy analyses on the 
primary/key secondary endpoints and other secondary endpoints.
Safety Analysis Set (SAS): It consists of all subjects who were administered at least 1 
dose of IMP. The safety dataset will be used for safety analyses. The safety datasets for 
each phase are defined as:
I.
Phase A Safety Set: All subjects who randomized and receive at least one 
dose of IMP in Phase A.
II.
Phase B Safety Set: All subjects who are enrolled into Phase B and receive at 
least one dose of IMP in Phase B.  
5.2
Handling of Missing Data
All safety/efficacy data will be summarized for observed (non-missing) values only.  
Missing data will be mitigated by encouraging subjects who withdrew from treatment to 
return for their remaining visits for collection of assessments as noted in the Schedule of 
Assessments, Table 3.7-1 for Phase A and Table 3.7-2 for Phase B, in protocol.
6
 Trial Conduct
In general, analyses methods stated in Section 6 to Section 9 will apply to Phase A and 
Phase B unless otherwise specified. In the final CSR, Phase A and Phase B will be 
reported separately unless otherwise specified.
6.1
Subject Disposition 
The number of subjects who have been randomized, the number of subjects who are 
treated, and the number of subjects who discontinue from the trial, together with the 
reasons for discontinuation taken from the case report form (CRF) status page will be 
provided.
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6.2
Treatment Compliance
Treatment compliance will be calculated by dividing the total dosage taken by the total 
dosage the subjects are scheduled to take during the treatment phase based on the Study 
Medication panel of CRF.  
6.3
Prior and Concomitant Medications
Use of concomitant medications prior to the start of trial medication will be summarized 
by number and percentage of users by treatment group.  
Concomitant medications used post-baseline will be summarized in two categories of 
time interval:  during the trial medication period and after the trial medication period.  In 
each case, the use of concomitant medications will be summarized by number and 
percentage of users by treatment group.
6.4
Protocol Deviations
Major protocol deviations data will be summarized by type of deviations (eg, deviations 
in entry criteria, dosing, randomization, concomitant medication, procedural, etc) by 
center and treatment group.  In addition, a subject listing will be provided describing the 
deviations for each subject.
7
Demographic and Baseline Characteristics
Demographic characteristics and medical history at screening will be summarized by 
descriptive statistics, eg, proportion, mean, median, SD, minimum and maximum values.   
Baseline characteristics will be summarized for Treatment Phase A and Treatment Phase 
B, respectively.
For the Randomized Sample, baseline disease evaluation will be summarized by 
treatment group and overall with the mean, median, range and standard deviation 
presented.
8
Primary and Secondary/ Exploratory Endpoints Analyses  
8.1
Primary Endpoint Analysis
The co-primary endpoints for the trial are the change from Phase A baseline in spot urine 
osmolality (premorning dose) and specific gravity (premorning dose) to Week 1. 
Two variables will be derived for the co-primary outcomes:

Change from Phase A baseline in spot urine osmolality (premorning dose) to Week 1

Change from Phase A baseline in specific gravity (premorning dose) to Week 1
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Descriptive statistics will be presented on the co-primary endpoints by treatment group, 
respectively.
Baseline measurements of co-primary efficacy variables are defined as their last 
measurements prior to the first dose of trial medication in Phase A.
8.2
Key Secondary Endpoint Analysis
The key secondary endpoint is the percent change from Phase A baseline in height-
adjusted total kidney volume (htTKV) as measured at 12 months.  
Descriptive statistics will be presented on the key secondary endpoint by treatment group.
Baseline measurements of key secondary efficacy variable is defined as its last 
measurement prior to the first dose of trial medication in Phase A.
8.3
Other Secondary Endpoints Analyses
Other secondary efficacy endpoints include:

24-hour fluid balance prior to Week 1.

Change from baseline in renal function (eGFR by Schwartz formula) at each clinic 
visit (Week 1, Month 1, Month 6, and Month 12 in Phase A).

Change from baseline in renal function (eGFR by Schwartz formula) at each clinic 
visit (Week 1, Month 1, Month 6, Month 12, Month18, and Month 24 in Phase B).

Percent change in htTKV as measured by MRI from Phase B baseline to Phase B 
Month 12.

Percent change in htTKV as measured by MRI from Phase B baseline to Phase B 
Month 24.

Pharmacodynamic (PD) endpoints of urine volume (including 24-hour fluid volume), 
fluid intake and fluid balance, sodium, creatinine, and free water clearance during 
dense PK sampling (after at least 1 Month on IMP).

Proportions of each Tanner Stage by gender and age compared to normative 
populations at baseline, 6 months, and 12 months during the placebo-controlled phase 
(Phase A), and every 6 months during the open-label extension phase (Phase B).

Changes from baseline percentiles for height and weight by gender and age at 
baseline, 6 months, and 12 months during the placebo-controlled phase (Phase A), 
and every 6 months during the open-label extension phase (Phase B).

Safety variables (changes from baseline in creatinine, vital signs, laboratory values 
including liver function tests [LFTs], rate of aquaretic AEs) in placebo and tolvaptan.
For all of the secondary endpoints in Phase A, descriptive statistics by visit will be 
presented by treatment group. For the secondary endpoints in Phase B, descriptive 
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9
Safety Analyses
In general, Phase A baseline measurements of safety variables are defined as their last 
measurements prior to the randomization for the safety population. Phase B baseline 
measurements of safety variables are defined as the last measurements prior to the first 
dose of IMP in Phase B.  Safety analysis will be conducted based on the safety 
population, defined in Section 5.1. Standard safety variables to be analyzed include AEs, 
change from baseline in creatinine, vital signs, laboratory values including liver function 
tests (LFTs), and rate of aquaretic AEs.  In general, descriptive statistics will be provided 
for Phase A safety variables and Phase B safety variables as well. 
Subgroup analysis of key safety endpoints by age cutoff (<12 years vs. ≥ 12 years) will 
be summarized.
9.1
Extent of Exposure
A subject’s duration of exposure is defined as the trial medication end date - trial 
medication start date + 1 in each phase.  Duration of exposure will be summarized by 
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treatment group in Phase A and by previous Phase A treatment group (Tolvaptan and 
placebo) and pooled in Phase B.  
9.2
Adverse Events 
All adverse events (AE) will be coded by MedDRA System Organ Class (SOC) and 
Preferred Term (PT).  A treatment-emergent AE (TEAE) is defined as an AE which starts 
after start of trial medication), or an AE continues from baseline of the specific phase and 
becomes serious, worsening, trial drug-related or results in death, discontinuation, 
interruption or reduction of trial medication during this phase.  The incidences of the 
following treatment-emergent adverse events (TEAEs) will be summarized by treatment 
groups:

TEAEs by severity

Potentially drug-related TEAEs

TEAEs with an outcome of death

Serious TEAEs

Discontinuations due to TEAEs
Incidences of AEs above will be tabulated by treatment for Phase A safety dataset and 
Phase B safety dataset, respectively.
9.3
Clinical Laboratory Data
Summary statistics for changes from baseline in the clinical laboratory measurements 
will be provided for the safety population. Potentially clinically significant results in 
laboratory tests identified using prospectively defined criteria will also be summarized.
According to the Food and Drug Administration (FDA) Guidance2, laboratory 
measurements that signal the potential for drug-induced liver injury (DILI) will be 
reported.  An incidence table and a listing will be provided for subjects who meet one or 
combinations of the following criteria: 
1) ALT (alanine transaminase) or AST (aspartate transaminase) ≥ 3x upper limit of 
normal (ULN) (or baseline value for subjects with abnormal baseline)
2) Increase in bilirubin ≥ 2x ULN (or baseline value for subjects with abnormal 
baseline)
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9.4
Vital Sign Data
Summary statistics for changes from baseline in vital signs and potentially clinically 
significant results in vital signs will be summarized for the safety population. For a 
subject with repeat measures in either vital signs or lab tests at a visit, the last repeat will 
be used in the by visit summary.  However, for outlier analysis (such as clinically 
significant abnormalities), data from all visits, no matter they are from the original visits, 
repeats, or unscheduled visits, will be included.
9.5
Physical Examination Data
By-patient listings will be provided for physical examination.
9.6
Electrocardiogram Data
Electrocardiogram (ECG) data will not be summarized since ECG data will be collected 
at the screening visit only.
10
Pharmacodynamic Analyses
Urinary excretions will be determined as urine concentration × urine volume; missing 
values will not be imputed.  If urine concentration or volume is missing for any interval, 
the 0 to 24 hour values will not be determined.  Urine volumes of zero, and consequently 
non reportable urine concentration, are not considered as missing data; values of 0 will be 
reported for volume and excretion.
Free water clearance will be determined as urine excretion rate − osmolar clearance. 
Osmolar, sodium, and creatinine clearances will be determined by standard methods with 
average serum concentration determined by averaging the concentrations at the beginning 
and end of the urine collection interval.  If urine volume for a collection interval is 0, then 
the clearance value for that interval and the following interval will be determined by 
using the average value of the 3 serum concentrations, the urine volume of the second 
interval and the total time of the 2 collection intervals (eg, 2 to 4 hour collection has urine 
volume of 0 mL).  Clearance for the 2 to 4 and 4 to 8 hour intervals will be determined 
using serum concentrations at 2, 4, and 8 hours, the urine volume from 4 to 8 hour 
interval and total collection time of 6 hours (8 minus 2). 
Values of urine osmolality will be summarized with descriptive statistics by total daily 
dose (all placebos grouped together) and collection interval.  Sodium and creatinine urine 
concentrations will only be listed.
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Values of excretions (osmoles, sodium, and creatinine) and clearances (free water, 
sodium, and creatinine) will be summarized with descriptive statistics by total daily dose 
(all placebos grouped together), collection interval, and 0 to 24 hours. 
Serum concentrations (osmolality, sodium, and creatinine) and change from predose will 
be summarized with descriptive statistics by total daily dose (all placebos grouped 
together), analyte, and time point.
11
Interim Analysis
No interim analysis is planned before all randomized subjects either complete the 
Month 12 visit or early terminate in Phase A, the double-blind, placebo-controlled 
portion of this protocol.  A snapshot of the database will be taken after all subjects in 
Phase A have completed or early terminated, these data will be unblinded, and an interim 
CSR will be written to provide early information on safety.
12
Monitoring of Safety Data
12.1
Independent Data Monitoring Committee
An independent data monitoring committee (IDMC) will be established for this trial.  
This committee 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.  It 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 to be detailed in their charter.  The specific duties of 
the IDMC will be detailed in a separate IDMC charter document.
12.2
Hepatic Adjudication Committee
A hepatic adjudication committee (HAC) has been convened for the purpose of oversight 
of hepatic events.  The HAC will independently determine probable cause(s) of any 
hepatic event occurring during the trial and will communicate with the IDMC that 
oversees the trial.  
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13 References
1
Schwartz G, Munoz A, Schneider M, Mak R, Kaskel F, Warady B et al. New 
equations to estimate GFR in children with CKD. J Am Soc Nephrol. 
2009;20(3):629-37.
2
Guidance for Industry, Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 
US Department of Health and Human Services, Food and Drug Administration, and 
Center for Drug Evaluation and Research (CDER), July 2009.
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14
Appendices
Appendix 1: Criteria of Potentially Clinically Significant Laboratory Test 
Abnormalities 
Laboratory Test Abnormalities due to Test Value Increase
Test Result Grade
Test
Abnormality
0
1
2
3
4
APTT (sec)
Increase
ULN
>ULN - 
1.5xULN
>1.5xULN - 
2xULN
>2xULN
ALT (SGPT) 
(IU/L)
Increase
ULN
>ULN - 
3xULN
>3xULN - 
5xULN
>5xULN - 
20xULN
>20xULN
AST (SGOT) 
(IU/L)
Increase
ULN
>ULN - 
3xULN
>3xULN - 
5xULN
>5xULN - 
20xULN
>20xULN
Bilirubin, Total 
(mg/dL)
Increase
ULN
>ULN - 
2xULN
>2xULN - 
3xULN
>3xULN - 
10xULN
>10xULN
Creatinine 
(mg/dL)
Increase 
B*
>B – 1.5xB
>1.5 x B – 3 
x B
> 3 x B – 6 
x B
> 6 x B
Eosinophils, 
Absolute 
(Thous/μL)
Increase
≤0.65
>0.65-1.5
>1.5-5
>5
Glucose (mg/dL)
Increase
≤115
>115-160
>160-250
>250-500
>500
Hemoglobin 
(g/dL)
Increase
ULN
>ULN-20
>20-21
>21-22.5
>22.5
Potassium 
(mEq/L)
Increase
ULN
>ULN-5.5
>5.5-6
>6-7
>7
INR
Increase
ULN
>ULN - 
1.5xULN
>1.5xULN - 
2xULN
>2xULN 
Sodium (mg/dL)
Increase
<145
146 - 150
151 - 155
156 - 160
>160
Triglycerides 
(mg/dL)
Increase
ULN
>ULN - 
2.5xULN
>2.5xULN - 
5xULN
>5xULN - 
6xULN
>6xULN
Urea Nitrogen 
(mg/dL)
Increase
≤22
>22-26
>26-31
>31
White Blood 
Count 
(Thous/μL)
Increase
≤10.79
9
>10.799-15
>15-20
>20-25
>25
*B= Baseline
Laboratory Test Abnormalities due to Test Value Decrease
Test Result Grade
Test
Abnormality
-4
-3
-2
-1
0
Glucose 
(mg/dL)
Decrease
<30
30-<40
40-<55
55-<65
≥65
Hemoglobin 
(g/dL)
Decrease
<6.5
6.5-<8
8-<10
10-<LLN
LLN
Lymphocytes, 
Absolute 
(Thous/μL)
Decrease
<0.2
0.2-<0.5
0.5-<0.8
0.8-<LLN
LLN
Neutrophils, 
Absolute 
(Thous/μL)
Decrease
<0.5
0.5-<1
1-<1.5
1.5-<LLN
LLN
Platelet Count 
Decrease
<25
25-<50
50-<75
75-<LLN
LLN
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Test Result Grade
Test
Abnormality
-4
-3
-2
-1
0
(Thous/μL)
Potassium 
(mEq/L)
Decrease
<2.5
2.5-<3
3-<LLN
LLN
Sodium 
(mg/dL)
Decrease
<120
120-124
125-129
130-135
≥136
White Blood 
Count 
(Thous/μL)
Decrease
<1
1-<1.5
1.5-<2.5
2.5-<3.501
≥3.501
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Appendix 2: Criteria of Potentially Clinically Significant Vital Sign 
Abnormalities
Criteria (meet either one will count)
Test 
Parameters
Unit
Age
Limit
Change from baseline
Heart Rate
bpm
4 - 14 Years       <= 50
>= 140        
Decrease >= 15
 Increase >= 15            
15 Years and 
older    
<=50
>= 120        
Decrease >= 15
Increase >= 15            
4 – 12 Years
<=70
>= 130        
Decrease >= 20
Increase>=20
SBP, Sitting
mmHg
13 – 17 Years     <= 120 
>= 144        
Decrease >= 20
Increase>=20
4 – 12 Years
<= 50 
>= 86          
Decrease >= 15
Increase>=15
DBP, Sitting
mmHg
13 – 17 Years     <= 80  
>= 92          
Decrease >= 15
Increase>=15
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Appendix 3: Document History 
Dates/Author
Description of Updates
Version
Document Updates
05 Feb 2020
NA
1.0
Original Version
(Approved prior to 
Phase A’s database 
lock on 21 Feb 
2020)
Clinical Study Report 156-12-298
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30 Nov 2021
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.0
Updated Version
(Prior to final 
database lock)
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This page is a manifestation of an electronically captured signature
SIGNATURE PAGE
Document Name: 15612298 SAP_30NOV2021_Final
Document Number: 
Document Version: 2.0
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:min) -
UTC timezone
Clinical Approval
01-Dec-2021
19:46:43
Biostatistics Approval
30-Nov-2021
22:28:55
Clinical Study Report 156-12-298
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