Clinical trial NCT04182958
Conditions: Healthy Adult Male
Sponsor: Otsuka Pharmaceutical Co., Ltd.
Start date: 2019-11-25; Completion date: 2019-12-19
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
* To determine the mass balance of totalradioactivity following a single IV infusionof (14C)-OPC-61815.
* To determine routes and rates of elimination of total radioactivity following a single IV infusion of (14C)-OPC-61815
* To assess the PK of total radioactivity in plasma and whole blood following a single IV infusion of (14C)-OPC-61815
* To assess the PK of OPC-61815 free form and OPC-41061 in plasma following a single IV infusion of (14C)-OPC-61815

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: (14C)-OPC-61815
Intervention descriptions: intervention 1: On the morning of Day 1, all subjects will receive a single IV infusion of (14C) OPC-61815

Protocol documents:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A Phase I, Open-Label Trial to Assess the Mass Balance and Pharmacokinetics of a 
Single Intravenous Administration of (14C)-OPC-61815 to Healthy Male Japanese 
Subjects 
 
 
 
 
NCT Number: NCT04182958 
PRT NO.: 263-102-00006 
Version Date: 14 November 2019 (Amendment 1) 


 
 
 
 
CLINICAL STUDY PROTOCO
L
 
 
 
 
A Phase I, Open
-
Label Trial to Assess the Mass Balance and Pharmacokinetics of a
 
Single Intravenous Administration of (
14
C)
-
OPC
-
61815 to Healthy Male 
Japanese
 
S
u
bjects
 
 
 
 
 
NCT Number: 
NCT04182958
 
P
RT NO.


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Table of Contents 
Table of Contents ........................................................................................... 2 
List of In-text Tables ..................................................................................... 7 
List of In-text Figures .................................................................................... 8 
1 
Protocol Summary ................................................................................ 9 
1.1 
Synopsis...............................................................................................................9 
1.2 
Schema ..............................................................................................................14 
1.3 
Schedule of Assessments...................................................................................15 
2 
Introduction ........................................................................................ 19 
2.1 
Trial Rationale ...................................................................................................19 
2.2 
Background .......................................................................................................19 
2.3 
Summary of Nonclinical Pharmacokinetics ......................................................19 
2.4 
Summary of Clinical Experience ......................................................................21 
2.4.1 
Safety ..............................................................................................................21 
2.4.2 
Pharmacokinetics ............................................................................................23 
2.5 
Known and Potential Risks and Benefits ..........................................................23 
3 
Objectives and Endpoints .................................................................. 24 
4 
Trial Design ......................................................................................... 25 
4.1 
Type/Design of Trial .........................................................................................25 
4.2 
Scientific Rationale for Trial Design .................................................................26 
4.3 
Dosing Rationale ...............................................................................................27 
4.4 
End of Trial Definition ......................................................................................27 
4.5 
Definition of Completed Subjects .....................................................................27 
5 
Trial Population .................................................................................. 28 
5.1 
Subject Selection and Numbering .....................................................................28 
5.2 
Eligibility Criteria ..............................................................................................28 
5.2.1 
Inclusion Criteria ............................................................................................28 
5.2.2 
Exclusion Criteria ...........................................................................................29 
5.3 
Lifestyle Considerations/Trial Restrictions .......................................................30 
5.3.1 
Meals and Dietary Restrictions .......................................................................30 
5.3.2 
Caffeine, Alcohol, and Tobacco .....................................................................31 


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5.3.3 
Activity ...........................................................................................................31 
5.4 
Screen Failures ..................................................................................................31 
6 
Trial Treatments ................................................................................. 32 
6.1 
Trial Treatments Administered .........................................................................32 
6.1.1 
Medical Devices .............................................................................................32 
6.2 
Management of Investigational Medicinal Product ..........................................32 
6.2.1 
Packaging and Labeling ..................................................................................32 
6.2.2 
Storage ............................................................................................................33 
6.2.3 
Accountability .................................................................................................33 
6.2.4 
Returns and Destruction .................................................................................33 
6.2.5 
Reporting of Product Quality Complaints ......................................................33 
6.2.5.1 
Eliciting and Reporting Product Quality Complaints .................................34 
6.2.5.2 
Information Required for Reporting Purposes ............................................34 
6.2.5.3 
Return Process .............................................................................................34 
6.2.5.4 
Assessment/Evaluation ...............................................................................34 
6.2.6 
Investigational Medicinal Product Reserve Sample Requirements ................34 
6.3 
Measures to Minimize/Avoid Bias ....................................................................34 
6.4 
Subject Compliance ...........................................................................................35 
6.5 
Concomitant Medications or Therapies ............................................................35 
6.5.1 
Prohibited Medications ...................................................................................35 
6.5.2 
Rescue Medication ..........................................................................................36 
6.6 
Intervention After the End of the Trial ..............................................................36 
7 
Stopping Rules, Withdrawal Criteria, and Procedures .................. 36 
7.1 
Entire Trial or Treatment ...................................................................................36 
7.2 
Individual Site ...................................................................................................36 
7.3 
Treatment Interruption ......................................................................................37 
7.4 
Individual Subject Discontinuation ...................................................................37 
7.4.1 
Treatment Discontinuation .............................................................................37 
7.4.2 
Documenting Reasons for Treatment Discontinuation ...................................37 
7.4.3 
Withdrawal of Consent or Assent ...................................................................38 
7.4.4 
Procedures to Encourage Continued Trial Participation ................................39 
7.5 
Definition of Subjects Lost to Follow-up ..........................................................39 


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8 
Trial Procedures ................................................................................. 40 
8.1 
Efficacy Assessments ........................................................................................40 
8.2 
Pharmacokinetic Assessments ...........................................................................40 
8.2.1 
Pharmacokinetic Blood/Plasma Samples .......................................................40 
8.2.2 
Pharmacokinetic Urine and Feces Samples ....................................................41 
8.2.3 
Analytical Methodology .................................................................................42 
8.3 
Pharmacodynamic Assessments ........................................................................42 
8.4 
Pharmacogenomic Assessments ........................................................................42 
8.5 
Biomarker Assessments ....................................................................................42 
8.6 
Future Biospecimen Research Samples ............................................................42 
8.7 
Safety Assessments ...........................................................................................42 
8.7.1 
Clinical Laboratory Assessments ...................................................................42 
8.7.2 
Physical Examination .....................................................................................43 
8.7.3 
Vital Signs ......................................................................................................43 
8.7.4 
Electrocardiogram ...........................................................................................43 
8.7.5 
Suicidality Monitoring ....................................................................................43 
8.7.6 
Other Safety Variables ....................................................................................44 
8.8 
Adverse Events ..................................................................................................44 
8.8.1 
Definitions ......................................................................................................44 
8.8.2 
Eliciting and Reporting Adverse Events .........................................................46 
8.8.3 
Immediately Reportable Events ......................................................................46 
8.8.4 
Medical Device Incidents (Including Malfunctions) ......................................47 
8.8.5 
Adverse Events of Special Interest .................................................................47 
8.8.6 
Potential Serious Hepatotoxicity ....................................................................47 
8.8.7 
Procedure for Breaking the Blind ...................................................................47 
8.8.8 
Follow-up of Adverse Events .........................................................................47 
8.8.8.1 
Follow-up of Nonserious Adverse Events ..................................................47 
8.8.8.2 
Follow-up of Immediately Reportable Events ............................................47 
8.8.8.3 
Follow-up and Reporting of Immediately Reportable Events 
Occurring After Last Scheduled Contact ....................................................48 
8.9 
Treatment of Overdose ......................................................................................48 
8.10 
Subject Assessment Recording .........................................................................48 
8.11 
Other Assessments ............................................................................................48 


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9 
Statistical Considerations .................................................................. 49 
9.1 
Sample Size .......................................................................................................49 
9.2 
Datasets for Analysis .........................................................................................49 
9.3 
Handling of Missing Data for Primary and Secondary Endpoint Analysis ......49 
9.4 
Statistical Analyses............................................................................................49 
9.4.1 
Efficacy Analyses ...........................................................................................49 
9.4.2 
Safety Analysis ...............................................................................................49 
9.4.2.1 
Adverse Events ...........................................................................................49 
9.4.2.2 
Clinical Laboratory Data .............................................................................50 
9.4.2.3 
Physical Examination and Vital Signs Data ...............................................50 
9.4.2.4 
Electrocardiogram Data ..............................................................................50 
9.4.2.5 
Other Safety Data ........................................................................................50 
9.4.3 
Other Analyses ................................................................................................50 
9.4.3.1 
Analysis of Demographic and Baseline Characteristics .............................50 
9.4.3.2 
Pharmacokinetic Analysis ...........................................................................50 
9.4.3.3 
Pharmacodynamics Analysis ......................................................................51 
9.4.3.4 
Pharmacokinetic/Pharmacodynamics Analysis ..........................................51 
9.4.3.5 
Pharmacogenomics Analysis ......................................................................51 
9.4.3.6 
Exploratory Endpoint Analysis ...................................................................51 
9.5 
Interim Analysis and Adaptive Design .............................................................51 
9.5.1 
Data Monitoring Committee ...........................................................................51 
10 
Supporting Documentation and Operational Considerations ....... 52 
10.1 
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations .............52 
10.1.1 
Ethics and Responsibility ...............................................................................52 
10.1.2 
Informed Consent ...........................................................................................52 
10.1.3 
Confidentiality ................................................................................................53 
10.1.4 
Quality Control and Quality Assurance ..........................................................53 
10.1.4.1 
Monitoring ..................................................................................................53 
10.1.4.2 
Auditing ......................................................................................................53 
10.1.5 
Protocol Deviations ........................................................................................54 
10.1.6 
Records Management .....................................................................................54 
10.1.6.1 
Source Documents ......................................................................................54 


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10.1.6.2 
Data Collection ...........................................................................................55 
10.1.6.3 
File Management at the Trial Site ...............................................................55 
10.1.6.4 
Records Retention at the Trial Site .............................................................56 
10.1.6.5 
Publication Authorship Requirements ........................................................56 
10.2 
Appendix 2: Clinical Laboratory Evaluations ...................................................58 
10.3 
Appendix 3: Total Blood Volume .....................................................................59 
10.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information ........................................................................................................60 
10.5 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments.......................................................................................................62 
10.6 
Appendix 6: Abbreviations ...............................................................................63 
10.7 
Appendix 7: Protocol Amendments ..................................................................64 
10.7.1 
Protocol Amendment(s)/Administrative Change(s) .......................................65 
10.7.1.1 
Protocol Amendment 1 ...............................................................................65 
11 
References ............................................................................................ 66 
 


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List of In-text Tables 
Table 1.1-1 
Trial Objectives and Endpoints ....................................................... 9 
Table 1.3-1 
Schedule of Assessments .............................................................. 15 
Table 1.3-2 
Time Windows for Assessments ................................................... 18 
Table 2.4.2-1 
Pharmacokinetic Data for OPC-61815 Free Form ........................ 23 
Table 3-1 
Trial Objectives and Endpoints ..................................................... 24 
Table 10.2-1 
Clinical Laboratory Evaluations ................................................... 58 
Table 10.3-1 
Total Blood Volume ..................................................................... 59 
 
 


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List of In-text Figures 
Figure 1.2-1 
Trial Design Schematic ................................................................. 14 


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Protocol Summary 
1.1 
Synopsis 
Name of Sponsor: Otsuka Pharmaceutical Co., Ltd 
Name of Investigational Medicinal Product: (14C)-OPC-61815 
Protocol No.: 263-102-00006 
EudraCT No.: 2019-001968-29 
Protocol Title: A Phase I, Open-Label Trial to Assess the Mass Balance and 
Pharmacokinetics of a Single Intravenous Administration of (14C)-OPC-61815 to Healthy 
Male Japanese Subjects 
Protocol Lay Person Short Title: A Phase I, Open-Label Trial to Assess the 
Absorption, Metabolism, and Excretion of (14C)-OPC-61815 in Healthy Male Japanese 
Subjects 
Clinical Phase/Trial Type: Phase I 
Treatment/Indication: Cardiac edema 
Objectives and Endpoints: 
Table 1.1-1 
Trial Objectives and Endpoints 
Objectives 
Endpoints 
Primary:   
To determine the mass balance of total radioactivity 
following a single intravenous (IV) infusion of 
(14C)-OPC-61815. 
 
To determine routes and rates of elimination of total 
radioactivity following a single IV infusion of 
(14C)-OPC-61815. 
 
To assess the pharmacokinetic (PK) of total 
radioactivity in plasma and whole blood following a 
single IV infusion of (14C)-OPC-61815. 
 
To assess the PK of OPC-61815 free form and 
OPC-41061 in plasma following a single IV infusion 
of (14C)-OPC-61815. 
 
 
The PK parameter endpoints for OPC-61815 
free form and OPC-41061 in plasma, and total 
radioactivity in whole blood and plasma, and the 
PK parameter endpoints for total radioactivity in 
urine and feces are detailed in Section 9.4.3.2. 
 
To identify and characterize metabolites in plasma, 
urine, and feces following a single IV infusion of 
(14C)-OPC-61815. 
Metabolic profile of (14C)-OPC-61815 and 
identification of radiolabeled metabolites 
present at >10% of the total drug-related 
exposure (AUC) plasma. 
Secondary:  
To assess the safety and tolerability of a single IV 
infusion of (14C)-OPC-61815. 
 
Adverse events, clinical laboratory evaluations, 
physical examination findings, vital signs (blood 


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pressure, pulse rate), body weight, and 12-lead 
electrocardiogram parameters. 
 
Trial Design: 
Single-site, open-label, nonrandomized, single intravenous (IV) dose trial in healthy male 
Japanese subjects. 
Potential subjects will be screened to assess their eligibility to enter the trial within 
28 days prior to the dose administration. Subjects will be enrolled and admitted into the 
trial site on Day -1. On Day 1, all subjects will receive a single IV infusion of 16 mg 
containing approximately 75.1 μCi (2.78 MBq) of (14C)-OPC-61815 infused over 60 
minutes (55 to 65 minutes, inclusive) in the fasted state. 
Subjects will be confined to the trial site until at least Day 9. Subjects will be discharged 
from the trial site on Day 9 if the following discharge criteria are met: 
• ≥ 90% mass balance recovery, and/or  
• < 1% of the total radioactive dose is recovered in combined excreta (urine and 
feces) in 2 consecutive 24-hour periods.  
If these criteria are not met by Day 9, subjects will remain at the trial site until any one of 
the discharge criterion are met up to a maximum of Day 10 to continue 24-hour blood, 
urine, and feces collections for total radioactivity, unless otherwise agreed upon by the 
sponsor and investigator.  
If criteria are not met by Day 10, subjects may be asked to collect 24-hour excreta 
samples on up to 2 further occasions on a nonresidential basis to allow extrapolation of 
urinary and fecal excretion. If needed, the 2 additional 24-hour nonresidential collections 
will start on Days 10 and 11 (to be brought to the trial site at the end of the collection 
interval on Days 11 and 12, respectively). If on the second occasion the subject has still 
not met the desired criterion, then the subject will be discharged from the trial, per 
investigator and sponsor decision. 
Trial Population: 
It is planned for at least 8 healthy male Japanese subjects to be dosed to ensure that 
6 subjects complete the IV infusion. Up to a maximum of 10 subjects will be dosed in 
total. 
Key Inclusion/Exclusion Criteria: 
Key inclusion criteria include but are not limited to the following: Male subjects between 
35 and 55 years of age, inclusive; hold a valid Japanese passport and be first-generation 


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Japanese, defined as the subject, the subject’s biological parent, and all of the subject’s 
biological grandparents being of exclusive Japanese descent, have been born in Japan, 
and not lived outside of Japan for more than 5 years; with a body mass index between 
18.5 and 28.0 kg/m2, inclusive, and a total body weight between 50 and 100 kg, inclusive; 
in good health, determined by no clinically significant findings from medical history, 
physical examination, 12-lead electrocardiogram (ECG), vital sign measurements, and 
clinical laboratory evaluations (congenital nonhemolytic hyperbilirubinemia [eg, 
suspicion of Gilbert’s syndrome based on total and direct bilirubin] is not acceptable) at 
Screening and Check-in as assessed by the investigator (or designee); and have a history 
of a minimum of 1 bowel movement per day.  
Key exclusion criteria include but are not limited to the following: History of stomach or 
intestinal surgery or resection that would potentially alter absorption and/or excretion 
(including cholecystectomy; uncomplicated appendectomy and hernia repair will be 
allowed); poor peripheral venous access; participation in a clinical trial involving 
administration of an investigational drug (new chemical entity and/or OPC-61815) in the 
past 90 days prior to dosing or 5 half-lives of the investigational drug; subjects with 
exposure to significant diagnostic or therapeutic radiation (eg, serial X-ray, computed 
tomography scan, barium meal) or current employment in a job requiring radiation 
exposure monitoring within 12 months prior to Check-in; subjects who have participated 
in any clinical trial involving a radiolabeled investigational drug within 12 months prior 
to Check-in. 
Trial Site(s): 1 site in the UK 
Investigational Medicinal Product(s), Dose, Dosage Regimen, Treatment Duration, 
Formulation, Mode of Administration: 
(14C)-OPC-61815:  Subjects will receive a single IV infusion of 16 mg (14C)-OPC-61815, 
containing approximately 75.1 μCi (2.78 MBq), over a period of 60 minutes (55 to 
65 minutes, inclusive) on Day 1 of the trial. 
Trial Assessments: 
Assessments for PK: Blood sampling for OPC-61815 free form and OPC-41061 plasma 
concentrations, whole blood and plasma total radioactivity, and metabolite profiling and 
identification (plasma). Urine sampling for total radioactivity and metabolite profiling 
and identification. Feces sampling for measurement of total radioactivity and where 
possible, metabolite profiling and identification. 


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Assessments for Safety: Adverse events, clinical laboratory evaluations, physical 
examination findings, vital signs (supine blood pressure and pulse rate), body weight, and 
12-lead ECG. 
Screening/Other: demographics, medical history, prior/concomitant medications, urine 
drug screen, alcohol breath test, serology, oral body temperature, and height. 
Data Monitoring Committee: No 
Statistical Methods: 
Pharmacokinetic parameters will be summarized using descriptive methodology. The 
following PK parameter endpoints for OPC-61815 free form and OPC-41061 in plasma 
and total radioactivity in whole blood and plasma will be calculated using standard 
noncompartmental methods: area under the concentration-time curve (AUC) from time 
zero to infinity (AUC∞), AUC calculated to the last observable concentration at time t 
(AUCt), maximum peak concentration of the drug (Cmax), time to maximum peak 
concentration (tmax), time of last measurable (positive) concentration (tlast), and 
terminal-phase elimination half-life (t1/2,z). The total body clearance (CL) will also be 
determined for OPC-61815 free form. The AUC ratios of whole blood total radioactivity 
relative to plasma total radioactivity (ratios of Blood/Plasma for both AUC∞ and AUCt) 
will be calculated. 
The following PK parameter endpoints for total radioactivity in urine will be calculated: 
amount excreted in urine (Ae,u), cumulative Ae,u, percentage excreted in urine (%fe,u), 
and cumulative %fe,u. The following PK parameter endpoints for total radioactivity in 
feces will be calculated: amount excreted in feces (Ae,f), cumulative Ae,f, percentage 
excreted in feces (%fe,f), and cumulative %fe,f. Overall amount and percent of total 
radioactivity in excreta (combined urine and feces) will be calculated. 
No formal statistical analysis will be performed. 
Trial Duration: 
Each subject in this trial is expected to participate in the following periods of the trial 
(approximate durations listed): 
•
Screening period (27 days; Day -28 to Day -2)
•
Check-in (Day -1)
•
Treatment period:
− Dose administration on Day 1
− Minimum treatment period duration: 9 days (Day 1 to Day 9)


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− Maximum treatment period duration: 12 days (Day 1 to Day 12) 
− Including an outpatient follow-up for 48 hours, if applicable (at 
investigator’s discretion; Day 10 to Day 12) 
Final Discharge from trial will be day of discharge from residential treatment period or 
the day of last outpatient visit if required to attend them based on the discharge criteria. 
The total duration of trial participation for each subject (from Screening through Final 
Discharge from trial) is anticipated to be a maximum of approximately 40 days. 
 


 
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1.2 
Schema 
 
a Subjects can be discharged on Day 9 if the following discharge criteria are met: ≥ 90% mass balance recovery and/or < 1% of the total radioactive dose is recovered in combined 
excreta (urine and feces) in 2 consecutive 24-hour periods. If the discharge criteria are not met, subjects will be asked to remain resident within at the trial site and additional 
24-hour collection (blood, urine, and feces) for total radioactivity will continue until these criteria are met, up to a maximum of Day 10. 
b Up to 2 additional 24-hour nonresidential collections (urine and feces) for total radioactivity may occur if discharge criteria have not been met by Day 10. Subjects will collect 
excreta samples at home for the 24-hour period prior to the clinic visit and deliver them to the trial site at the end of the collection interval, within 24 hours 
Figure 1.2-1 
Trial Design Schematic 


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1.3 
Schedule of Assessments 
Table 1.3-1 
Schedule of Assessments  
Period 
Screening 
Day -28 to 
Day -2 
Check-in 
Day -1 
Days 1 to 8 
Dischargea  
Days 9 to 10  
Outpatient 
Visitsb  
Days 11 to 12 
ENTRANCE/HISTORY  
Informed consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
Medical history 
X 
Xc 
 
 
 
Urine drug screen 
X 
X 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
Serology 
X 
 
 
 
 
Height and body weight 
Xd 
Xe 
24 and 48 hours after the start of infusione 
 
 
INVESTIGATIONAL MEDICINAL PRODUCT ADMININSTRATION 
(14C)-OPC-61815 
 
 
Day 1 (0 hours) 
 
 
PHARMACOKINETICS 
Blood sampling for 
OPC-61815 free form 
and OPC-41061 
concentration (plasma) 
 
 
Predose and 1 hour (end of infusion), and 1.5, 2, 3, 4, 6, 12, 24, 
and 48 hours after the start of infusion 
 
 
Blood sampling for total 
radioactivity (whole 
blood and plasma) 
 
 
Predose and 1 hour (end of infusion), and 1.5, 2, 3, 4, 6, 12, 24, 
48, 72, 96, 120, 144, and 168 hours after the start of infusion 
Xa 
 


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Table 1.3-1 
Schedule of Assessments  
Blood sampling for 
metabolite profiling and 
identification (plasma) 
 
 
Predose and 1 hour (end of infusion), and 1.5, 2, 3, 4, 6, 12, 24, 
48, 72, 96, 120, 144, and 168 hours after the start of infusion 
 
 
Urine collection for total 
radioactivity and 
metabolite profiling and 
identification  
 
 
Predose (from Check-in to 0 hours) and 0 to 24, 24 to 48, 48 to 72, 
72 to 96, 96 to 120, 120 to 144, and 144 to 168 hours after the 
start of infusion 
Xa 
Xb 
Feces collection for total 
radioactivity and 
metabolite profiling and 
identification 
 
 
Predose (from Check-in to 0 hours) and 0 to 24, 24 to 48, 48 to 72, 
72 to 96, 96 to 120, 120 to 144, and 144 to 168 hours after the 
start of infusion 
Xa 
Xb 
SAFETY 
Adverse event recording 
X 
X 
Ongoing 
X 
X 
Prior/concomitant 
medication monitoring 
X 
X 
Ongoing  
X 
X 
Clinical laboratory 
evaluations 
X 
X 
1.5i, 24, and 48 hours after start of infusion 
Xg 
 
Physical examination 
X 
Xf 
1.5, 24, and 48 hours after start of infusionf 
Xf, h 
 
Supine blood pressure 
and pulse rate 
X 
X 
1.5, 24, and 48 hours after the start of infusion 
Xh 
 
Oral body temperature 
X 
 
 
 
 
12-lead 
electrocardiogram 
X 
X 
24 and 48 hours after the start of infusion 
Xg 
 
a Subjects can be discharged on Day 9 if the following discharge criteria are met: ≥ 90% mass balance recovery and/or < 1% of the total radioactive dose is recovered in combined 
excreta (urine and feces) in 2 consecutive 24-hour periods. If the discharge criteria are not met, subjects will be asked to remain resident within at the trial site and additional 
24-hour collection (blood, urine, and feces) for total radioactivity will continue until these criteria are met, up to a maximum of Day 10. 
b Up to 2 additional 24-hour nonresidential collections (urine and feces) for total radioactivity may occur if discharge criteria have not been met by Day 10. Subjects will collect 
excreta samples at home for the 24-hour period prior to the clinic visit and deliver them to the trial site at the end of the collection interval, within 24 hours.  
c Interim medical history.  


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d Height measured at Screening only.  
e Weight only.  
f Symptom-directed physical examination. 
g Day 9. 
h Only on day of Discharge. 
i At this time point only blood samples will be taken for clinical laboratory evaluation. 
 
 


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Table 1.3-2 
Time Windows for Assessments 
Item 
Day 
Time point 
relative to 
start of 
infusion (h) 
Window 
Blood sampling for 
Pharmacokinetics 
1 
predose 
Within 2 hours of IMP administration 
1 
Within 2 minutes after end of IMP 
administration 
1.5 
Specified time point ±2 minutes 
2 
Specified time point ±3 minutes 
3 
Specified time point ±5 minutes 
4 
Specified time point ±10 minutes 
6, 12 
Specified time point ±15 minutes 
2 
24 
Specified time point ±30 minutes 
3 
48 
Specified time point ±30 minutes 
Clinical laboratory 
evaluations 
1 
1.5 
Specified time point ±10 minutes 
2 
24 
Specified time point ±120 minutes 
3 
48 
Specified time point ±120 minutes 
Physical examination 
1 
1.5 
Specified time point ±10 minutes 
2 
24 
Specified time point ±60 minutes 
3 
48 
Specified time point ±60 minutes 
Blood pressure and pulse 
rate 
1 
1.5 
Specified time point ±10 minutes  
2 
24 
Specified time point ±60 minutes 
3 
48 
Specified time point ±60 minutes 
Body weight 
2 
24 
Specified time point ±60 minutes 
3 
48 
Specified time point ±60 minutes 
12-lead electrocardiogram 
2 
24 
Specified time point ±60 minutes 
3 
48 
Specified time point ±60 minutes 
Abbreviations: h = hour; IMP = investigational medicinal product.


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2 
Introduction 
OPC-61815 is a compound based on the arginine vasopressin V2-receptor antagonist 
tolvaptan (OPC-41061 used henceforth). OPC-41061 was developed as an oral aquaretic 
agent for the treatment of fluid volume overload conditions and has been approved for the 
indication of hyponatremia in the US and European countries. OPC-61815 is being 
developed as an injection formulation, which is expected to provide new clinical benefit 
in the treatment of hyponatremia and various edematous diseases in patients who have 
difficulty in swallowing or poor absorption of oral medications. 
Please refer to the OPC-61815 Investigator’s Brochure (IB)1 for more detailed 
information. 
2.1 
Trial Rationale 
The purpose of this trial is to determine the absorption, metabolism, and excretion of 
(14C)-OPC-61815 and to characterize and determine the metabolites present in plasma, 
urine, and, where possible, feces in healthy male Japanese subjects following a single 
intravenous (IV) dose. Knowledge of the absorption, metabolism, and excretion of parent 
drug and identification/characterization of its metabolites is useful for evaluating the 
Metabolites in Safety Testing requirements elucidated in the International Conference on 
Harmonisation M32 and the likelihood of effects of renal or hepatic impairment on the 
disposition of OPC-61815 and the likelihood for drug-drug interactions with OPC-61815.  
2.2 
Background 
OPC-61815 is a compound for which the low water solubility of OPC-41061 has been 
improved by phosphorylation of the hydroxide of the benzazepine ring. In the body, 
OPC-61815 is thought to be metabolized to OPC-41061 via hydrolysis of the phosphate 
ester by alkaline phosphatase and acid phosphatase.   
2.3 
Summary of Nonclinical Pharmacokinetics 
The pharmacokinetics (PK) of OPC-61815 following single IV dosing were investigated 
in nonfasting rats and dogs. In both species, the plasma concentrations of OPC-61815 
(disodium salt [free form]) and its active metabolite OPC-41061 increased 
dose-dependently. The extrapolated plasma concentration at time zero (C0) and the area 
under the concentration-time curve (AUC) from time zero to infinity (AUC∞) of 
OPC-61815 (free form) in male rats were both 1.6 times higher than those in female rats. 
A sex difference in the plasma concentration-time course of OPC-41061 was observed, 
with the maximum peak concentration of the drug (Cmax) and AUC∞ in female rats being 
respectively 2.4 and 5.8 times higher than those in male rats, indicating a higher plasma 


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concentration in females. In dogs, the C0 and AUC∞ of OPC-61815 (free form) in males 
were both 0.6 times those in females, while no clear sex difference was observed for 
OPC-41061. In both species, OPC-41061 was detected in plasma at 5 minutes postdose, 
indicating rapid hydrolysis from OPC-61815 to OPC-41061. 
Following a single IV dose of (14C)-OPC-61815 at 12.75 mg/kg to male rats, 
radioactivity was distributed into the liver, small intestine, kidney, and adrenal gland at 
higher levels than the plasma Cmax. Although, the plasma concentration of radioactivity 
was lower in female rats than in male rats, no sex differences were observed in the tissue 
concentrations of radioactivity. At 168 hours postdose, the concentrations of radioactivity 
were below the lower limit of quantification in almost all tissues. As a result of 
quantitative autoradiography in pregnant rats, radioactivity concentrations in all fetal 
tissues were comparable to or lower than the blood concentration in the dams, indicating 
low transfer of OPC-61815 to fetuses. 
The distribution of radioactivity to blood cells was 1.24% to 14.69% in male rats, 1.40% 
to 26.04% in female rats, and 0.49% to 18.03% in male dogs, indicating low distribution 
to blood cells in both species. 
Following a single IV dose of OPC-61815 to male rats and dogs, in rats, the AUC∞ of the 
metabolites DM-4103 and DM-4107 were respectively 1.5 to 4.0 times and 0.17 to 0.62 
times that of OPC-41061, and in dogs, the plasma concentrations of DM-4103 and DM-
4107 were both lower than that of OPC-41061.  
When (14C)-OPC-61815 was incubated with human liver, kidney, lung, and small 
intestine 9000 g supernatant fractions (S9), OPC-61815 underwent hydrolysis to 
OPC-41061. OPC-61815 also underwent hydrolysis to OPC-41061 when incubated with 
human-derived acid phosphatase and alkaline phosphatase. In an investigation of the in 
vitro metabolism of OPC-61815 by human liver S9 fraction and human hepatocytes, all 
metabolites detected were the same as those of OPC-41061, and no metabolite with a 
phosphate group was detected in the metabolic reaction of (14C)-OPC-61815 with human 
liver S9 fraction. 
Following a single IV dose of (14C)-OPC-61815 at 12.75 mg/kg to male and female rats, 
the urinary and fecal excretion of radioactivity up to 168 hours postdose was 4.59% and 
91.08%, respectively, in male rats, and 4.74% and 93.26%, respectively, in female rats, 
showing that the radioactivity administered was excreted mainly in feces. The biliary 
excretion of radioactivity was 92.2% in male rats and 91.5% in female rats. In male rats, 
61.0% of the radioactivity administered was resorbed via enterohepatic circulation. No 
obvious sex difference was noted in urinary, fecal, or biliary excretion in rats. Following 


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a single IV dose of (14C)-OPC-61815 at 3.825 mg/kg to male dogs, the urinary and fecal 
excretion of radioactivity up to 168 hours postdose was 5.32% and 89.50%, respectively.  
2.4 
Summary of Clinical Experience 
2.4.1 
Safety 
In a Phase I single IV dose trial in healthy male adults (protocol No.: 263-08-001), 
OPC-61815 at 0.3, 1, 3, 7.5, 15, or 30 mg or placebo was administered intravenously over 
5 minutes to 54 subjects. Twenty-four adverse events (AEs) occurred in 13 of 36 subjects 
(36.1%) in the OPC-61815 group, and 12 AEs occurred in 5 of 18 subjects (27.8%) in the 
placebo group. The AEs that occurred in at least 2 subjects in the OPC-61815 group were 
2 occurrences each of ventricular extrasystoles, abdominal pain, and blood cholesterol 
increased. Of these all but 1 case of abdominal pain, were considered to be potentially 
drug-related treatment-emergent AEs (TEAEs). All AEs in this trial were mild in severity 
and resolved with or without treatment. The above results demonstrated that a single IV 
dose of OPC-61815 at 0.3 to 30 mg is well-tolerated in healthy male adults. 
In a Phase I multiple IV dose trial in healthy male adults (protocol No.: 263-09-001), 
OPC-61815 at 1.25, 5, or 20 mg or placebo was administered intravenously over 
1 minute to 36 subjects. After receiving a single dose, subjects were given a 1-day dose 
intermission and then received multiple once-daily IV doses for 7 days. In total, 168 AEs 
occurred in 24 of 27 subjects (88.9%) in the OPC-61815 group and 5 AEs occurred in 4 
of 9 subjects (44.4%) in the placebo group. The AEs reported in at least 3 subjects in the 
OPC-61815 group were as follows: 39 occurrences of feeling abnormal in 9 subjects, 
31 occurrences of pruritus in 5 subjects, 5 occurrences of blood uric acid increased in 
5 subjects, 4 occurrences of diarrhoea in 4 subjects, 24 occurrences of pruritus 
generalized in 3 subjects, 8 occurrences of erythema in 3 subjects, and 4 occurrences of 
bradycardia in 3 subjects. Of these events, 38 occurrences of feeling abnormal in 
8 subjects, 5 occurrences of blood uric acid increased in 5 subjects, 30 occurrences of 
pruritus in 4 subjects, 24 occurrences of pruritus generalized in 3 subjects, 8 occurrences 
of erythema in 3 subjects, 16 occurrences of hypoesthesia in 2 subjects, 2 occurrences of 
diarrhea in 2 subjects, 9 occurrences of nausea in 2 subjects, and 7 occurrences of 
pruritus genital in 1 subject were judged to be potentially drug-related TEAEs. No deaths 
or other serious potentially drug-related TEAEs were observed. All AEs reported in the 
OPC-61815 group were mild or moderate in severity and resolved without treatment. The 
results demonstrated that OPC-61815 is well-tolerated in healthy male adults when 
administered intravenously once daily for 7 days at up to 20 mg. However, based on the 
fact that potentially drug-related TEAEs that did not occur after oral administration of 
OPC-41061, such as feeling abnormal, pruritus, and erythema, occurred with a high 


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incidence during or immediately after repeated administration of OPC-61815; 
OPC-61815 solution was suspected to be involved in the occurrence of such potentially 
drug-related TEAEs. 
In order to explore causes of the potentially drug-related TEAEs and explore the injection 
duration able to reduce the occurrence of these potentially drug-related TEAEs, a Phase I 
IV infusion rate trial (protocol No.: 263-10-005) was conducted. A single dose of 
OPC-61815 at 7.5 or 15 mg or placebo was administered intravenously over 2 hours, 
5 minutes, or 1 minute to healthy male adult subjects. Adverse events occurred in 6 of 12 
subjects in the OPC-61815 group and 5 of 6 subjects in the placebo group after 
administration over 2 hours; 10 of 12 subjects in the OPC-61815 group and 3 of 6 
subjects in the placebo group after administration over 5 minutes; and 10 of 12 subjects 
in the OPC-61815 group and 4 of 6 subjects in the placebo group after administration 
over 1 minute. All the AEs reported were mild or moderate in severity. Adverse events 
(feeling abnormal, feeling hot, erythema, hyperhidrosis, pruritus, rash, urticaria, nausea, 
epigastric discomfort, and dyspnea) similar to feeling abnormal, pruritus, or erythema, 
which occurred with a high incidence in the multiple IV dose trial of OPC-61815 
(protocol No.: 263-09-001) were extracted as AEs of special interest (AESI). Adverse 
events of special interest were reported in 1 of 12 subjects in the OPC-61815 group and 3 
of 6 subjects in the placebo group after administration over 2 hours (pruritus, rash, 
urticaria, and feeling abnormal). A relationship to the trial drug was ruled out for AEs 
that occurred in 1 subject (rash) in the OPC-61815 group and 2 subjects in the placebo 
group (feeling abnormal and urticaria), out of the above AEs. After administration over 
5 minutes, AESIs were reported in 9 of 12 subjects in the OPC-61815 group and 2 of 
6 subjects in the placebo group (dyspnea, erythema, hyperhidrosis, pruritus, feeling 
abnormal, and feeling hot). All these AEs were assessed as related to the trial drug. After 
administration over 1 minute, AESIs were reported in 10 of 11 subjects in the 
OPC-61815 group and 4 of 6 subjects in the placebo group (nausea, epigastric 
discomfort, erythema, hyperhidrosis, pruritus, feeling abnormal, and feeling hot). All 
these AEs, except for 1 event (erythema) in the OPC-61815 group, were assessed as 
related to the trial drug. All potentially drug-related TEAEs occurred during or 
immediately after IV dosing, and most of them resolved without treatment within 
10 minutes of the start of trial drug administration. There were no clinically significant 
changes from baseline in plasma histamine concentration. As shown above, causes of 
AESIs remained unknown. 


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2.4.2 
Pharmacokinetics 
Pharmacokinetic data for OPC-61815 free form following single and multiple IV doses 
is presented in the table below. The PK data for OPC-61815 free form following 1- and  
5-minute infusions is available in the IB1, along with PK data for OPC-41061 and major 
metabolites for all studies. 
Table 2.4.2-1 
Pharmacokinetic Data for OPC-61815 Free Form 
Dose (mg) 
AUC∞ 
(ng.h/mL) 
AUCt 
(ng.h/mL) 
Cmax 
(ng/mL) 
tmax 
(h)a 
t1/2 
(h) 
Single IV dose – Mean (SD) 
0.3 mg 
- 
7.803 (8.170) 53.02 (29.28) 
0.020 (0-0.25) 
- 
1 mg 
175.0 (-) 
85.90 (21.91) 182.2 (21.72) 
0.000 (0-0.25) 
0.7170 (0-0) 
3 mg 
427.2 (61.14) 
374.3 (52.91) 559.5 (85.52) 
0.000 (0-0.02) 
0.6335 (0.1065) 
7.5 mg 
1242 (182.2) 
1144 (171.1) 
1832 (294.2) 
0 (0-0) 
1.172 (0.2819) 
15 mg 
3008 (416.6) 
2868 (362.3) 
3348 (637.7) 
0.000 (0-0.25) 
1.730 (0.3279) 
30 mg 
4882 (817.9) 
4727 (839.9) 
7670 (755.3) 
0 (0-0) 
1.683 (0.4837) 
Multiple IV dose – Day 1: Mean (SD) 
1.25 mg 
211.8 (32.11) 
167.3 (32.55) 371.8 (78.15) 
3.0 (3-3) 
0.5308 (0.1074) 
5 mg 
886.7 (140.8) 
784.0 (150.2) 
1165 (394.4) 
3.0 (3-15) 
1.193 (0.3741) 
20 mg 
3379 (492.8) 
3178 (400.1) 
4351 (1496) 
3.0 (3-15) 
2.510 (1.927) 
Multiple IV dose – Day 9: Mean (SD) 
1.25 mg 
169.0 (33.05)b 
- 
320.0 (89.42) 
3.0 (3-15) 
0.5748 (0.1549) 
5 mg 
924.8 (136.9)b 
- 
1375 (368.4) 
3.0 (3-3) 
1.329 (0.4530) 
20 mg 
3416 (344.7)b 
- 
4137 (955.7) 
3.0 (3-15) 
2.419 (1.145) 
Abbreviations: AUC∞ = area under the concentration-time curve from time zero to infinity; AUCt = area 
under the concentration-time curve calculated to the last observable concentration at time t; AUC24h = area 
under the concentration-time curve from time zero until 24 hours postdose; Cmax = maximum peak 
concentration; IV = intravenous; tmax = time to maximum peak concentration; t1/2 = elimination half-life. 
a median (min-max) 
b AUC24h 
2.5 
Known and Potential Risks and Benefits 
Healthy subjects in the current trial will not receive any health benefit (beyond that of an 
assessment of their medical status) from participating in the trial. The risks of 
participation are primarily those associated with adverse reactions to the trial treatment 


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and the IV doses, although there may also be some discomfort from collection of blood 
samples and other trial procedures.  
No deaths or other serious adverse events (SAEs) were reported in the Phase I trials of 
OPC-61815 in healthy adult male subjects (263-08-001, 263-09-001, and 263-10-005). 
Feeling abnormal, feeling hot, erythema, hyperhidrosis, pruritus, rash, urticaria, nausea, 
epigastric discomfort, and dyspnea were frequently reported following IV dosing of 
OPC-61815 in Trials 263-09-001 and 263-10-005, and were considered AESIs. In Trial 
263-10-005, 1- and 5-minute administrations were associated with frequent occurrences 
of AESIs in OPC-61815-treated subjects, whereas following a 2-hour administration, 
only 1 subject experienced an AESI, and this was considered unrelated to trial drug. 
These findings suggest that a longer duration of OPC-61815 administration would reduce 
the risk of developing these events.  
All potentially trial drug-related AEs reported in completed Phase I trials occurred during 
or immediately after trial drug administration. Most events spontaneously resolved within 
10 minutes after start of trial drug administration, subjects should be closely monitored 
for skin symptoms following start of trial drug administration. 
More information about the known and expected benefits, risks, and reasonably 
anticipated AEs associated with OPC-61815 may be found in the IB.1  
The trial site will receive updated versions of the IB, when available, and the trial site 
should refer to the most current version as needed. 
3 
Objectives and Endpoints 
Table 3-1 
Trial Objectives and Endpoints 
Objectives 
Endpoints 
Primary:   
To determine the mass balance of total 
radioactivity following a single IV infusion 
of (14C)-OPC-61815. 
 
To determine routes and rates of elimination 
of total radioactivity following a single IV 
infusion of (14C)-OPC-61815. 
 
To assess the PK of total radioactivity in 
plasma and whole blood following a single 
IV infusion of (14C)-OPC-61815. 
 
 
The PK parameter endpoints for 
OPC-61815 free form and OPC-41061 
in plasma, and total radioactivity in 
whole blood and plasma, and the PK 
parameter endpoints for total 
radioactivity in urine and feces are 
detailed in Section 9.4.3.2. 
 
 
 
 
 
 
 


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To assess the PK of OPC-61815 free form 
and OPC-41061 in plasma following a 
single IV infusion of (14C)-OPC-61815. 
 
 
To identify and characterize metabolites in 
plasma, urine, and feces following a single 
IV infusion of (14C)-OPC-61815. 
Metabolic profile of (14C)-OPC-61815 
and identification of radiolabeled 
metabolites present at >10% of the total 
drug-related exposure (AUC) plasma. 
Secondary:  
To assess the safety and tolerability of a 
single IV infusion of (14C)-OPC-61815. 
 
Adverse events, clinical laboratory 
evaluations, physical examination 
findings, vital signs (blood pressure, 
pulse rate), body weight, and 12-lead 
electrocardiogram parameters. 
Section 9.4 describes the statistical analysis of the endpoints. 
4 
Trial Design 
4.1 
Type/Design of Trial 
This will be a Phase I, single-site, open-label, nonrandomized, single IV dose trial in 
healthy male Japanese subjects. 
Potential subjects will be screened to assess their eligibility to enter the trial within 
28 days prior to the dose administration. Subjects will be enrolled and admitted into the 
trial site on Day -1. On Day 1, all subjects will receive a single IV infusion of 16 mg 
(14C)-OPC-61815, containing approximately 75.1 μCi (2.78 MBq), over 60 minutes (55 
to 65 minutes, inclusive) in the fasted state. 
It is planned for at least 8 subjects to be dosed to ensure that 6 subjects complete the IV 
infusion. Up to a maximum of 10 subjects will be dosed in total. 
An overview of the trial design is shown in Figure 1.2-1. 
Subjects will be confined to the trial site until at least Day 9. Subjects will be discharged 
from the trial site on Day 9 if the following discharge criteria are met: 
• ≥ 90% mass balance recovery, and/or  
• < 1% of the total radioactive dose is recovered in combined excreta (urine and 
feces) in 2 consecutive 24-hour periods.  
If these criteria are not met by Day 9, subjects will remain at the trial site until any one of 
the discharge criterion are met up to a maximum of Day 10 to continue 24-hour blood, 


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urine, and feces collections for total radioactivity, unless otherwise agreed upon by the 
sponsor and investigator.  
If criteria are not met by Day 10, subjects may be asked to collect 24-hour excreta 
samples on up to 2 further occasions on a nonresidential basis to allow extrapolation of 
urinary and fecal excretion. If needed, the 2 additional 24-hour nonresidential collections 
will start on Days 10 and 11 (to be brought to the trial site at the end of the collection 
interval on Days 11 and 12, respectively). If on the second occasion the subject has still 
not met the desired criterion, then the subject will be discharged from the trial, per 
investigator and sponsor decision. 
Final Discharge from trial will be day of discharge from residential treatment period or 
the day of last outpatient visit if required to attend them based on the discharge criteria. 
The total duration of trial participation for each subject (from Screening through Final 
Discharge from trial) is anticipated to be a maximum of approximately 40 days. 
The start of the trial is defined as the date the first enrolled subject signs an informed 
consent form (ICF). The point of enrollment occurs at the time of subject number 
allocation. The end of trial is defined as the last date of contact or the date of final contact 
attempt for the last subject completing or withdrawing from the trial.  
A Schedule of Assessments is presented in Table 1.3-1 (Section 1.3). 
4.2 
Scientific Rationale for Trial Design 
This trial will be open-label because the primary endpoints of the trial are considered 
objective. Conducting the trial in healthy subjects mitigates the potential confounding 
effects of the disease state and concomitant medications. 
Subjects over 35 years of age will be used to minimize the risk to fertility in healthy 
subjects. Japanese subjects are to be recruited with a view to possibly submitting a 
marketing application for OPC-61815 in Japan in the future. 
Female subjects will be excluded to align with regulatory guidance. The “as low as (is) 
reasonably achievable” (ALARA) principle prescribed by the International Commission 
in Radiological Protection (ICRP)3 recommends that radiation exposure to subjects 
should be kept ALARA; therefore, if no specific reason exists to include females (ie, no 
available data suggest metabolism of the trial drug is different in females versus males), 
then the radiation exposure to female subjects should ideally be kept at zero by not 
including females in this radioactivity trial and only enrolling and dosing male subjects. 
The duration of the IV infusion was selected to minimize the risk of frequently observed 
TEAEs including feeling abnormal, pruritus, and erythema during the trial; and it is 


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planned for at least 8 subjects to be dosed to ensure that 6 subjects complete the IV 
infusion, with up to a maximum of 10 subjects being dosed in total. 
4.3 
Dosing Rationale 
A single dose level of 16 mg, containing approximately 75.1 μCi (2.78 MBq) of 
(14C)-OPC-61815, will be administered to each subject. This equates to a radioactivity 
exposure of approximately 1 mSv. The radioactive dose is an acceptable dose to give to 
healthy subjects and is considered adequate to define the disposition of (14C)-OPC-61815.  
The committed effective radiation doses to be administered have been calculated by 
Public Health England’s (PHE) Centre for Radiation, Chemical, and Environmental 
Hazards, based on the results of a preclinical mass balance trial and a quantitative whole 
body autoradiography trial.4 The effective radiation dose is defined as being within dose 
limits for members of the public (Category II trial, World Health Organization)5 with a 
minor associated risk (risk Category IIa, ICRP).3  
In order to provide the optimal conditions for the objectives of the trial to be met, the 
radioactive dose considered for administration will be reviewed following calculation by 
PHE, together with any bioanalytical data from the preclinical species to ensure 
radioactivity concentrations in urine, feces, and plasma are detectable for sufficient 
periods postdose. 
Intravenous administration was chosen since this is the intended clinical route of 
administration. Based on the nonclinical data and the known PK of OPC-61815, the 
sample collection timing and duration of this trial are considered adequate to achieve the 
trial objectives. 
A 16-mg dose of (14C)-OPC-61815 is within the anticipated clinical dose range and is 
considered to be high enough to fully characterize the single IV dose PK of the parent 
compound.  
4.4 
End of Trial Definition 
The end of trial date is defined as the last date of contact or the date of final contact 
attempt for the last subject completing or withdrawing from the trial. 
4.5 
Definition of Completed Subjects 
The treatment period is defined as the time period during which subjects are evaluated for 
primary and/or secondary objectives of the trial irrespective of whether or not the subject 
was administered the complete dose of the IMP. For purposes of this trial, subjects who 
complete Final Discharge from the trial will be defined as trial completers. 


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5 
Trial Population 
It is planned for at least 8 healthy male Japanese subjects to be dosed to ensure that 
6 subjects complete the IV infusion. Up to a maximum of 10 subjects will be dosed in 
total.  
5.1 
Subject Selection and Numbering 
All subjects will be given a unique subject identifier (ID; site number [3 digits] + subject 
number ['S' + 5 digits] upon providing consent). Site number will be designated by the 
sponsor. The subject number will be given sequentially from S00001. 
Demographic information (collection date, year of birth, age, sex, race, ethnicity, 
country) and medical history will be recorded in eCRF at Screening visit. 
5.2 
Eligibility Criteria 
Exceptions for eligibility criteria will not be permitted during the trial, neither by the 
investigator nor by the medical monitor. 
5.2.1 
Inclusion Criteria 
Subjects are required to meet all of the following criteria at the Screening visits, unless 
otherwise stated: 
1) Male subjects between 35 and 55 years of age, inclusive. 
2) Hold a valid Japanese passport and be first-generation Japanese, defined as the 
subject, the subject’s biological parent, and all of the subject’s biological 
grandparents being of exclusive Japanese descent, have been born in Japan, and 
not lived outside of Japan for more than 5 years. 
3) Body mass index between 18.5 to 28.0 kg/m2 (inclusive); and a total body weight 
between 50 and 100 kg, inclusive. 
4) In good health, determined by no clinically significant findings from medical 
history, physical examination, 12-lead ECG, vital sign measurements, and clinical 
laboratory evaluations (congenital nonhemolytic hyperbilirubinemia [eg, 
suspicion of Gilbert’s syndrome based on total and direct bilirubin] is not 
acceptable) at Screening and Check-in as assessed by the investigator (or 
designee). 
5) Subjects will agree to use contraception as detailed in Section 10.4. 
6) Able to comprehend and willing to sign an ICF and to abide by the trial 
restrictions. 
7) History of a minimum of 1 bowel movement per day. 


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5.2.2 
Exclusion Criteria 
Subjects will be excluded if they meet any of the following exclusion criteria at the 
Screening visit, unless otherwise stated: 
1) Significant history or clinical manifestation of any metabolic, allergic, 
dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, 
gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as 
determined by the investigator (or designee). 
2) History of significant hypersensitivity, intolerance, or allergy to any drug 
compound, food, or other substance, unless approved by the investigator (or 
designee). 
3) History of stomach or intestinal surgery or resection that would potentially alter 
absorption and/or excretion (including cholecystectomy; uncomplicated 
appendectomy and hernia repair will be allowed). 
4) Abnormal laboratory values at Screening or Check-in, as confirmed by repeat, 
including the following: 
a) Alanine aminotransferase (ALT) level above 1.5 x upper limit of normal 
(ULN) 
b) Aspartate aminotransferase (AST) level above 1.5 x ULN 
c) Total bilirubin level above 1.5 x ULN 
5) History of alcoholism or drug/chemical abuse within 2 years prior to Check-in. 
6) Alcohol consumption of >14 units per week for males. One unit of alcohol equals 
½ pint (285 mL) of beer or lager, 1 glass (125 mL) of wine, or 1/6 gill (25 mL) of 
spirits. 
7) Positive alcohol breath test result or positive urine drug screen (confirmed by 
repeat) at Screening or Check-in. 
8) Positive hepatitis panel and/or positive human immunodeficiency virus test. 
9) Participation in a clinical trial involving administration of an investigational drug 
(new chemical entity and/or OPC-61815) in the past 90 days prior to dosing or 
5 half-lives of the investigational drug. 
10) Use or intend to use any medications/products known to alter drug absorption, 
metabolism, or elimination processes, including St. John’s wort, within 30 days 
prior to Check-in, unless deemed acceptable by the investigator (or designee). 
11) Use or intend to use any prescription medications/products within 30 days prior to 
Check-in, unless deemed acceptable by the investigator (or designee). 
12) Use or intend to use slow-release medications/products considered to still be 
active within 30 days prior to Check-in, unless deemed acceptable by the 
investigator (or designee). 


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13) Use or intend to use any nonprescription medications/products including vitamins, 
minerals, and phytotherapeutic/herbal/plant-derived preparations within 14 days 
prior to Check-in, unless deemed acceptable by the investigator (or designee). 
14) Use of tobacco- or nicotine-containing products within 3 months prior to 
Check-in, or positive cotinine at Screening or Check-in. 
15) Receipt of blood products within 2 months prior to Check-in. 
16) Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior 
to Screening, or platelets from 6 weeks prior to Screening; or plans to donate 
blood within 2 months of trial completion. 
17) Poor peripheral venous access. 
18) Subjects with exposure to significant diagnostic or therapeutic radiation (eg, serial 
X-ray, computed tomography scan, barium meal) or current employment in a job 
requiring radiation exposure monitoring within 12 months prior to Check-in. 
19) Subjects who have participated in any clinical trial involving a radiolabeled 
investigational drug within 12 months prior to Check-in. 
20) Subjects who, in the opinion of the investigator (or designee), should not 
participate in this trial. 
Contraceptive guidance and collection of pregnancy information can be found in 
Section 10.4. 
Subjects must agree to restrictions to medications and lifestyle described in Section 6.5.1 
and Section 5.3, respectively. 
5.3 
Lifestyle Considerations/Trial Restrictions 
The following lifestyle considerations apply for the trial: 
• Subjects should refrain from donation of blood from 3 months prior to Screening, 
plasma from 2 weeks prior Screening, or platelets from 6 weeks prior to 
Screening; or plans to donate blood within 2 months of Final Discharge from trial. 
• Subjects should not have received blood products within 2 months prior to 
Check-in. 
• Subjects should follow contraception guidance as detailed in Section 10.4. 
5.3.1 
Meals and Dietary Restrictions 
While confined at the trial site, subjects will receive a standardized, high-fiber diet at 
scheduled times that do not conflict with other trial-related activities. Prune juice may be 
administered on an as-needed basis to aid in normal bowel function and will not be 
considered a concomitant medication. Subjects will be fasted overnight (at least 8 hours) 
before collection of blood samples for clinical laboratory evaluations.  


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Foods and beverages containing poppy seeds, grapefruit, star fruit, or Seville oranges will 
not be allowed from 7 days prior to Check-in until Final Discharge from trial.   
5.3.2 
Caffeine, Alcohol, and Tobacco 
Caffeine-containing foods and beverages will not be allowed from 36 hours before 
Check-in until Final Discharge from trial. 
Consumption of alcohol will not be permitted from 36 hours prior to Check-in until Final 
Discharge from trial. 
Use of tobacco- or nicotine-containing products will not be permitted from 3 months 
prior to Check-in until Final Discharge from trial. 
Information regarding the subject’s alcohol, caffeine, and smoking habits will be 
documented in the subject’s eCRF. The collection dates and results of the alcohol breath 
test and cotinine test for smoking will be documented in the subject’s eCRF. 
5.3.3 
Activity 
Subjects are required to refrain from strenuous exercise from 7 days before Check-in 
until Final Discharge from trial and will otherwise maintain their normal level of physical 
activity during this time (ie, will not begin a new exercise program nor participate in any 
unusually strenuous physical exertion). 
5.4 
Screen Failures 
Subjects who sign an ICF but who are not started on treatment are permitted to be 
re-screened. In the event that the subject is re-screened for trial participation, and the 
re-screening is not completed within the original Screening window, a new ICF must be 
signed. 
A screen failure is a subject from whom informed consent is obtained and is documented 
in writing (ie, subject signs an ICF), but who does not receive trial treatment. 
If the subject meets the definition of a screen failure in this trial, the following 
information will be recorded in the eCRF: 
• Date of informed consent 
• Visit date (Screening visit) 
• Demographics (collection date, year of birth, age, sex, race, ethnicity, country) 
• Result of eligibility assessment 
• Screen failure date 
• Reason for screen failure 


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6 
Trial Treatments 
6.1 
Trial Treatments Administered 
Subjects will receive a single IV infusion of 16 mg (14C)-OPC-61815, containing 
approximately 75.1 μCi (2.78 MBq), over a period of 60 minutes (55 to 65 minutes, 
inclusive) on Day 1 of the trial.  
Subjects may be asked to be supine for the IV infusion. The subject’s start and end time 
of infusion will be documented in the source data and eCRF. If the infusion is 
interrupted, the time (start and end of interruption) for each interruption, reason for 
interruption, if the administration was temporarily suspended and resumed, and if the full 
dose was administered will be documented in the subject’s source documents and eCRF. 
Subjects will be dosed in numerical order.  
For information regarding the criteria required to be met for subject discharge, see 
Section 4.1. 
6.1.1 
Medical Devices 
Not applicable. 
6.2 
Management of Investigational Medicinal Product 
For full details on IMP management, please refer to the Pharmacy Manual.  
6.2.1 
Packaging and Labeling 
Active pharmaceutical ingredient (API; nonradiolabeled powder) will be supplied by the 
sponsor. Arcinova will synthesize the radiolabeled API (powder) and dilute this to the 
correct specific radioactivity with the nonradiolabeled API. Covance will manufacture 
and label the IMP, such that each unit dose contains a total of 16 mg OPC-61815 
containing approximately 75.1 μCi (2.78 MBq) of (14C).  
Each vial of IMP used will be labeled to clearly disclose the subject number, compound 
ID, batch/lot numbers, the storage conditions, for clinical trial use only, protocol number, 
sponsor/trial site name and address, instructions for use, route of administration, and 
appropriate precautionary statements, and any other information required by local 
regulatory authorities.  
Arcinova will provide a Certificate of Analysis for the radiolabeled API and Covance 
will provide a Certificate of Analysis for the IMP. A Certificate of Release authorized by 
a Qualified Person in the European Union will also be issued, by a Covance Qualified 
Person, for the IMP prior to administration to subjects. 


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6.2.2 
Storage 
The IMP will be stored according to the instructions on the label at the trial site in a 
location that is locked with restricted access. 
The trial site staff will maintain a temperature log in the IMP storage area to record the 
temperature. 
6.2.3 
Accountability 
The investigator or designee must maintain an inventory record of IMP received, 
dispensed, administered, and returned. Neither the investigator nor any designees may 
provide IMP to any subject not participating in this protocol. This drug accountability 
record will be available for inspection at any time. At the completion of the trial, the 
original drug accountability record will be available for review by the sponsor upon 
request.  
The Pharmacy Manual will detail the procedure for determining residual radioactivity in 
the equipment used for IV infusions. Any unused assembled unit doses will be retained 
until completion of the trial.  
6.2.4 
Returns and Destruction 
Upon completion or termination of the trial, all used IMP containers, unused IMP, and 
partially used IMP will be disposed of after confirmation with the sponsor. 
6.2.5 
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) 
• Bottle defects (eg, under/over-fill, no safety seal) 
• Vial defects 
• Loss or theft of product 


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6.2.5.1 
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. 
For any PQC, please contact the Covance Pharmacy Manager (+44 [0]113 301 3519). If 
Covance receive a PQC by telephone, then information will be provided to sponsor by 
e-mail (PQC_263-102-00006@otsuka.jp). 
6.2.5.2 
Information Required for Reporting Purposes 
• Description of complaint 
• Reporter identification (eg, subject, investigator, site, etc.) 
• Reporter contact information (eg, address, telephone 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 
6.2.5.3 
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 a packaging specified 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. 
6.2.5.4 
Assessment/Evaluation 
Assessment and evaluation of PQCs will be handled by the sponsor or its designee. 
6.2.6 
Investigational Medicinal Product Reserve Sample Requirements 
Not applicable. 
6.3 
Measures to Minimize/Avoid Bias 
This is an open-label trial. 


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6.4 
Subject Compliance 
The following measures will be employed to ensure treatment compliance: 
• All doses will be administered under the supervision of suitably qualified trial site 
staff. 
• A predose and postdose inventory of IMP will be performed. 
6.5 
Concomitant Medications or Therapies 
The investigator will record all medications and therapies taken by the subject from 
6 weeks prior to signing of informed consent through the end of the treatment period 
(defined as the time period during which subjects are evaluated for primary and/or 
secondary objectives) on the eCRF. The investigator will also record all medications and 
therapies taken by the subject for treatment of an AE or which caused an AE until the end 
of the trial (defined as the last date of contact or date of final contact attempt) on the 
eCRF. 
For concomitant medications, the following will be recorded in the eCRF: medication, 
indication, dose, frequency, route, start date, and end date. For concomitant therapy, the 
following will be recorded in the eCRF: therapy, indication, start date, and end date. 
6.5.1 
Prohibited Medications 
As described in the exclusion criteria (Section 5.2.2), subjects are prohibited from use of 
any prescription and/or nonprescription medications/products (including vitamins, 
minerals, and phytotherapeutic/herbal/plant-derived preparations; medications/products 
known to alter drug absorption; metabolism, or elimination processes, slow-release 
medications/products considered active within 30 days prior to Check-in) for varying 
times prior to Check-in.  
None of the medications specified below, excluding the planned IMP, are allowed to be 
taken for the following periods throughout the trial, unless the investigator (or designee) 
and/or sponsor have given their prior consent: 
• The use of any medications/products know to alter drug absorption, metabolism, 
or elimination processes, including St. John’s wort, is prohibited within 30 days 
prior to Check-in until Final Discharge from trial. 
• The use of any prescription medications/products is prohibited within 30 days 
prior to Check-in until Final Discharge from trial. 
• The use of any slow-release medications/products considered to still be active is 
prohibited within 30 days prior to Check-in until Final Discharge from trial. 


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• The use of nonprescription medications/products, including vitamins, minerals, 
and phytotherapeutic/herbal/plant-derived preparations, is prohibited within 
14 days prior to Check-in until Final Discharge from trial. 
Restrictions/prohibitions on the intake of products, food, beverages, containing 
grapefruit, Seville orange, or star fruit due to OPC-41061 and its metabolites being 
metabolized mainly by CYP3A4 are detailed in Section 5.3.1.  
The administration of any other concomitant medications during the trial is prohibited 
without prior approval of the investigator (or designee), unless its use is deemed 
necessary for treatment of an AE. Any medication taken by a subject during the course of 
the trial and the reason for its use will be documented in the source data and eCRF. 
6.5.2 
Rescue Medication 
Not applicable. 
6.6 
Intervention After the End of the Trial 
Not applicable. 
7 
Stopping Rules, Withdrawal Criteria, and Procedures 
7.1 
Entire Trial or Treatment 
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to the investigators, Ethics Committee (EC), and regulatory authorities in 
accordance with regulatory requirements. 
The trial may be discontinued at the discretion of the investigator (or designee), sponsor, 
or medical monitor if any of the following criteria are met: 
• Adverse events unknown to date (ie, not previously reported in any similar 
investigational drug trial with respect to their nature, severity, and/or duration) 
• Increased frequency, severity, and/or duration of known, anticipated, or 
previously reported AEs (this may also apply to AEs defined at Check-in as 
baseline signs and symptoms) 
• Medical or ethical reasons affecting the continued performance of the trial 
• Difficulties in the recruitment of subjects 
• Cancelation of drug development. 
7.2 
Individual Site 
Trial site participation may be discontinued by the sponsor, the investigator, or the EC, if 
judged to be necessary for medical, safety, regulatory, ethical, or other reasons consistent 


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with applicable laws, regulations, and Good Clinical Practice (GCP). The investigator 
will notify the sponsor promptly if the trial is terminated by the investigator or the EC at 
the site. 
7.3 
Treatment Interruption 
During the IV infusion all subjects should be monitored closely. Symptoms and signs that 
may occur as part of an infusion reaction include, but are not limited to: fever, chills, 
nausea, headache, bronchospasm, hypotension, angioedema, throat irritation, rash, 
pruritus, myalgia, and dizziness. In the event that a significant infusion reaction occurs, if 
the investigator determines necessary, supportive care should be employed in accordance 
with the symptoms/signs. 
If the infusion is interrupted: the start and end time for each interruption, reason for 
interruption, if the administration was temporarily suspended and resumed, and if the full 
dose was administered, will be documented in the subject’s source documents and eCRF. 
7.4 
Individual Subject Discontinuation 
7.4.1 
Treatment Discontinuation 
After treatment assignment, a subject may stop treatment permanently for a variety of 
reasons. Treatment discontinuations may be initiated by a subject who is not satisfied 
with treatment or may become medically necessary due to AE, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator.  
If a subject is withdrawn from trial, the sponsor will be notified and the date and 
reason(s) for the withdrawal will be documented in the subject’s eCRF. If a subject is 
withdrawn, efforts will be made to perform all discharge assessments, if possible 
(Table 1.3-1). Other procedures may be performed at the investigator’s (or designee’s) 
and/or sponsor’s discretion. If the subject is in-house, these procedures should be 
performed before the subject is discharged from the clinic. The investigator (or designee) 
may also request that the subject return for an additional Follow-up visit. All withdrawn 
subjects will be followed until resolution of all their AEs or until the unresolved AEs are 
judged by the investigator (or designee) to have stabilized. 
Subjects who do not complete the IV infusion of (14C)-OPC-61815 may be replaced, with 
up to a maximum of 10 subjects being dosed in total.  
7.4.2 
Documenting Reasons for Treatment Discontinuation 
A subject may discontinue the trial or be withdrawn from the trial for the reasons listed 
below: 


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•  Adverse event 
− Subject decides to discontinue because of annoyance or discomfort due to a 
nonserious AE, which is not otherwise determined to be an undue hazard 
− Continuing infusion of the IMP places the subject at undue risk as determined 
by the investigator (eg, a safety concern that is possibly, probably, or likely 
related to IMP) 
− Serious adverse event  
− Other potentially IMP-related safety concerns or AEs 
• Death 
• Lost to follow-up 
• Physician decision 
• Protocol deviation 
• Site terminated by sponsor 
• Trial terminated by sponsor 
• Withdrawal by subject 
• Other 
If the subject discontinues the trial due to an AE, the investigator, or other trial personnel, 
will make every effort to follow the event until it has resolved or stabilized. Follow-up 
procedures in Section 7.4.1 must be followed. 
7.4.3 
Withdrawal of Consent or Assent 
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Subjects cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation. The investigator can also 
discontinue a subject’s participation in the trial at any time if medically necessary. Unless 
the subject provides their written withdrawal of consent or there is other written 
documentation by the investigator confirming the subject’s verbal intent to completely 
withdraw from the trial, subjects should be followed for all protocol-specified evaluations 
and assessments, if possible. 
Complete withdrawal of consent requires a subject’s refusal of ALL of the following 
methods of follow-up: 
• Participation in all follow-up procedures specified in the protocol (whether 
in-clinic, by telephone, or by an in-home visit). 
• Participation in a subset of protocol-specified follow-up procedures (by a 
frequency schedule and method, as agreed by subject and staff). 


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• Contact of the subject by trial personnel, even if only by telephone, to assess 
current medical condition, and obtain necessary medical or laboratory reports 
relevant to the trial’s objectives. 
• Contact of alternative person(s) who have been designated in source records as 
being available to discuss the subject’s medical condition, even if only by 
telephone, mail, or e-mail (eg, family, spouse, partner, legal representative, friend, 
neighbor, or physician). 
• Access to medical information from alternative sources (eg, hospital/clinic 
medical records, referring doctor’s notes, public records, dialysis, transplantation, 
vital registries, or social media sources). 
Withdrawal of consent is a critical trial event and, therefore, should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial. 
A subject may initially express their desire to discontinue IMP administration, which is 
not equivalent to a complete withdrawal of consent for further participation (see 
Section 7.4.1). A subject may, however, indicate that further trial participation is creating 
a burden on their work, school, or social schedule. Therefore, the investigator should 
follow the instructions outlined in Section 7.4.2 to determine if the subject can continue 
participation in the trial if modifications to his/her treatment and/or Schedule of 
Assessments can be accommodated. Only subjects who withdraw their permission for all 
of the above methods of follow-up are considered to have completely withdrawn their 
consent to participate in the trial. 
7.4.4 
Procedures to Encourage Continued Trial Participation 
Not applicable. 
7.5 
Definition of Subjects Lost to Follow-up 
Subjects who cannot be contacted on or before Final Discharge from trial, 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”. Survival 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). 


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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. 
If the subject was classified as “lost to follow-up,” “Were you able to contact the 
subject?,” “Date of contact/Date of final contact attempt,” and “Contact method” will be 
recorded in the subject’s eCRF. 
8 
Trial Procedures 
The assessments to be conducted during the trial are summarized in 
Section 1.3_Schedule_of_Assessments. 
Every effort will be made to schedule and perform the procedures as closely as possible 
to the nominal time, giving considerations to appropriate posture conditions, practical 
restrictions, and the other procedures to be performed at the same time point.  
The highest priority procedures will be performed closest to the nominal time. The order 
of priority for scheduling procedures around a time point is (in descending order of 
priority):  
• dosing  
• blood samples  
• urine and feces collections for PK assessments  
• any other procedures (ECGs will be scheduled before vital signs measurements).  
Where activities at a given time point coincide, consideration must be given to ensure 
that the following order of activities is maintained: ECGs, vital signs, blood draws. 
8.1 
Efficacy Assessments 
Not applicable. 
8.2 
Pharmacokinetic Assessments 
8.2.1 
Pharmacokinetic Blood/Plasma Samples 
Blood samples will be collected by venipuncture or cannulation at the times indicated in 
the Schedule of Assessments (Table 1.3-1) for determination of OPC-61815 free form 
and OPC-41061 concentrations, total radioactivity, and metabolite profiling and 
identification. Blood samples will be collected from the contralateral arm to the arm/hand 
used for dose administration. 


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Blood samples will be collected in vacutainers containing K2EDTA and processed into 
plasma. Approximately 1 × 2 mL blood sample will be collected for total radioactivity in 
whole blood and approximately 1 × 5 mL blood sample will be collected for total 
radioactivity in plasma. Approximately 1 × 3 mL blood sample will be collected for 
OPC-61815 free form and OPC-41061 concentrations in plasma. Approximately 1 × 
10 mL blood sample will be collected for metabolite profiling and identification in 
plasma.  
Procedures for collection, processing, and shipping of blood samples will be detailed in a 
separate document. If any unknown metabolites are detected and further investigation is 
necessary, a part of the plasma samples will be shipped on dry ice to the sponsor (Otsuka 
Pharmaceutical Co., Ltd., Tokushima Research Institute) and used for the structure 
elucidation of unknown metabolites, which will be conducted separately. The 
investigation of these unknown metabolites will be reported separately, and the report 
will not be appended to the clinical study report. 
The dates and times of blood collections will be documented in the subject’s eCRF. 
8.2.2 
Pharmacokinetic Urine and Feces Samples 
Urine will be collected over the time intervals indicated in the Schedule of Assessments 
(Table 1.3-1) for determination of total radioactivity and metabolite profiling and 
identification.  
Feces will be collected over the time intervals indicated in the Schedule of Assessments 
(Table 1.3-1) for determination of total radioactivity, and, where possible, metabolite 
profiling and identification. If possible, a single baseline fecal sample will be collected 
from after Check-in on Day -1 until just prior to dose administration on Day 1.  
Procedures for collection, processing, and shipping of urine and fecal collections will be 
detailed in a separate document. If any unknown metabolites are detected and further 
investigation is necessary, a part of the urine samples and/or extracted feces samples will 
be shipped on dry ice to the sponsor (Otsuka Pharmaceutical Co., Ltd., Tokushima 
Research Institute) and used for the structure elucidation of unknown metabolites, which 
will be conducted separately. The investigation of these unknown metabolites will be 
reported separately, and the report will not be appended to the clinical study report. 
The start and end dates and times of each urine collection time point interval and the total 
volume of urine collected in each time point interval will be documented in the subject’s 
eCRF. The start and end dates and times of each fecal collection time point interval and 
the total weight of the collected fecal samples for each time point interval will be 
documented in the subject’s eCRF. 


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8.2.3 
Analytical Methodology 
Plasma concentrations of OPC-61815 free form and OPC-41061 will be determined using 
a validated analytical procedure. Whole blood, plasma, urine, and feces total radioactivity 
will be determined with liquid scintillation counting. Profiling and identification of 
metabolites in plasma, urine, and, where possible, feces will be conducted using standard 
laboratory procedures. 
8.3 
Pharmacodynamic Assessments 
Not applicable. 
8.4 
Pharmacogenomic Assessments 
Not applicable. 
8.5 
Biomarker Assessments 
Not applicable. 
8.6 
Future Biospecimen Research Samples 
Not applicable. 
8.7 
Safety Assessments 
Details pertaining to the definitions, collection, reporting, and follow-up of AEs are 
described in Section 8.8. 
8.7.1 
Clinical Laboratory Assessments 
Clinical laboratory samples will be collected at the time points described in the Schedule 
of Assessments (Table 1.3-1) to perform the clinical laboratory evaluations described in 
Section 10.2.  
For assessment of hematology and serum chemistry, 7.5 mL of blood will be required at 
each time point (Table 1.3-1), and for assessment of serology (Screening only; 
Table 1.3-1), 3.5 mL of blood will be required. 
Subjects will be asked to provide urine samples for drugs of abuse screen and cotinine test, 
and will undergo an alcohol breath test at the times indicated in the Schedule of Assessments 
(Table 1.3-1). An investigator (or designee) will perform a clinical assessment of all clinical 
laboratory data. 
The dates and times of collections for clinical laboratory evaluations will be documented 
in the subject’s eCRF. The results of the drugs of abuse screen, cotinine test, and alcohol 
breath test at Screening and/or Check-in will be documented in the subject’s eCRF. 


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8.7.2 
Physical Examination 
A full physical examination or symptom-directed physical examination will be performed 
at the time points as specified in the Schedule of Assessments (Table 1.3-1). 
The dates, times, and results of the physical examinations will be documented in the 
subject’s eCRF. 
8.7.3 
Vital Signs 
Supine blood pressure, supine pulse rate, and oral body temperature will be assessed at 
the times indicated in the Schedule of Assessments (Table 1.3-1). Vital signs may also be 
performed at other times if judged to be clinically appropriate or if the ongoing review of 
the data suggests a more detailed assessment of vital signs is required. 
All measurements will be performed singly, and repeated once if outside the relevant 
clinical reference range. 
Subjects must be supine for at least 5 minutes before blood pressure and pulse rate 
measurements. 
The dates, times, and results of the vital sign measurements (supine blood pressure, 
supine pulse rate, and oral body temperature) will be documented in the subject’s eCRF. 
8.7.4 
Electrocardiogram 
Resting 12-lead ECGs will be recorded after the subject has been supine and at rest for at 
least 5 minutes at the times indicated in the Schedule of Assessments (Table 1.3-1).  
Single 12-lead ECGs will be performed singly, and repeated once if the Investigator 
deems a repeat is indicated. 
Additional 12-lead ECGs may be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of 
ECGs is required. The investigator (or designee) will perform a clinical assessment of 
each 12-lead ECG. 
The dates, times, and results of the 12-lead ECG (PR interval, QRS, QT-interval, and QT 
interval corrected for heart rate using Fridericia’s formula) will be documented in the 
subject’s eCRF. 
8.7.5 
Suicidality Monitoring 
Not applicable. 


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8.7.6 
Other Safety Variables 
Weight will be assessed at the times indicated in the Schedule of Assessments 
(Table 1.3-1). The date, time, and weight will be documented in the subject’s eCRF at 
each scheduled time point. 
8.8 
Adverse Events 
8.8.1 
Definitions 
An AE is defined as any untoward medical occurrence in a clinical trial subject 
administered an IMP and which does not necessarily have a causal relationship with this 
treatment. Adverse events 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.  
Treatment-emergent AEs are defined as AEs with an onset date on or after the start of 
open-label treatment. In more detail, TEAEs are all AEs which started after start of 
open-label IMP treatment; or if the event was continuous from pre-IMP treatment and 
was worsening, serious, IMP-related, or resulted in death, discontinuation, interruption, 
or reduction of IMP. 
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 inpatient 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 nonmedical need) are not 
considered SAEs. 
− Prescheduled hospitalization to address a condition that has existed prior to 
the signing of the ICF should not be considered an SAE. 


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• 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 AEs are all AEs that do not meet the criteria for a "serious" AE.  
Adverse Events of Special Interest: A noteworthy event for the particular product/IMP or 
class of products that a sponsor may wish to monitor carefully. All AESIs are to be 
reported as immediately reportable events (IREs). 
Immediately Reportable Event: 
• Any SAE. 
• Any AE related to occupational exposure. 
• Potential serious hepatotoxicity (see Section 8.8.6). 
• Pregnancy in a female partner of a male subject are also defined as IREs. 
Although this will only occur in a female partner of a male subject, it must be 
reported on an IRE form and the Pregnancy Surveillance Form(s) to the sponsor. 
Pregnancy will only be documented on the AE eCRF if there is an abnormality or 
complication. This includes pregnancy of the partner of the subject. 
Clinical Laboratory Test Value Changes: It is the investigator’s responsibility to review 
the results of laboratory tests for each individual subject as they become available. This 
review will be documented by the investigator’s dated signature on the laboratory report. 
The investigator may repeat the laboratory test or request additional tests to verify the 
results of the original laboratory tests. If this laboratory value is considered medically 
relevant (ie, clinically significant) by the investigator (subject is symptomatic, requiring 
corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation, and/or fulfills a seriousness criterion, this is considered an AE.  
Severity: Adverse events will be graded on a 3-point scale and reported as indicated on 
the eCRF. The severity of an adverse experience is defined as follows: 
1 = Mild:  
Discomfort noticed, but no disruption to daily activity. 
2 = Moderate: 
Discomfort sufficient to reduce or affect normal daily activity. 
3 = Severe: 
Inability to work or perform normal daily activity. 


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IMP Causality: Assessment of causal relationship of an AE to the use of the IMP is 
defined as follows: 
Related:  
There is a reasonable possibility of a temporal and causal 
relationship between the IMP and the AE. 
Not Related:  
There is no temporal or causal relationship between the IMP and 
the AE. 
8.8.2 
Eliciting and Reporting Adverse Events 
The investigator will regularly 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?.” Subjects will also be encouraged to spontaneously report AEs 
occurring at any other time during the trial to the investigator (or designee). 
All AEs (serious and nonserious) reported by the subject must be recorded on the source 
documents and eCRF provided by the sponsor. Adverse event collection will begin after a 
subject signs the ICF to Final Discharge from the trial. 
Medical terminology should be used for 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. 
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 8.8.3. Special attention should 
be paid to recording hospitalization and concomitant medications. 
Adverse event, start date, end date (if possible, start date and time, end date and time), 
seriousness, severity, relationship to trial treatment (IMP Causality), action taken with 
trial treatment and outcome will be recorded on the source documents and in the eCRF. 
8.8.3 
Immediately Reportable Events 
The investigator must immediately report (within 24 hours), using an IRE form, after 
he/she or site personnel become aware of any IRE (SAE, AE related to occupational 
exposure, potential serious hepatotoxicity, or confirmed pregnancy), by e-mail to the 
sponsor (Otsuka Global Intake: Global_Intake@otsuka-us.com). The sponsor is 
responsible for coordinating the reporting of SAEs/IREs in accordance with the European 
Directive 2001/20/EC.  
Patient confidentiality must be protected and contact information such as name, address, 
telephone number, or any other protected health information as determined by applicable 
local regulation should be redacted when forwarding Safety Information and supporting 
documentation. 


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8.8.4 
Medical Device Incidents (Including Malfunctions) 
Not applicable. 
8.8.5 
Adverse Events of Special Interest 
Not applicable. 
8.8.6 
Potential Serious Hepatotoxicity 
For a subject who experiences an elevation in AST or ALT that is ≥3 x ULN, a total 
bilirubin level should also be evaluated. If the total bilirubin is ≥2 x ULN, complete an 
IRE form with all values listed and also report as an AE on the eCRF. 
8.8.7 
Procedure for Breaking the Blind 
This trial will not use blinding procedures. 
8.8.8 
Follow-up of Adverse Events 
8.8.8.1 
Follow-up of Nonserious Adverse Events 
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eCRF with the current status (ongoing or resolved/recovered) noted. All nonserious 
events (that are not IREs) that are ongoing at the last scheduled contact will be recorded 
as ongoing on the eCRF. For any AE having been identified throughout the trial, during 
analysis, additional relevant medical history information may be requested by the sponsor 
to further ascertain causality (including, but not limited to, information such as 
risk-related behavior, family history, and occupation). 
8.8.8.2 
Follow-up of Immediately Reportable Events 
This trial requires that subjects be actively monitored for IREs up to 30 days after the 
IMP is administered. 
Immediately reportable events that are identified or ongoing at the last scheduled 
contact must be recorded as such on the AE eCRF page and the IRE form. If updated 
information (eg, resolved status) on IRE status becomes available after a subject’s last 
scheduled contact (up to last in-clinic visit for the entire trial), this must be reported to the 
sponsor and recorded on the AE eCRF page and the IRE form, according to the 
appropriate reporting procedures described in Section 8.8.3. 


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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. The 
investigator will follow IREs until the events are: 
•
resolved,
•
stabilized,
•
the subject is lost to follow-up, or
•
has died.
Resolution means that the subject has returned to the baseline state of health and 
stabilized means that the investigator does not expect any further improvement or 
worsening of the subject’s condition. The investigator will continue to report any 
significant follow-up information to the sponsor up to the point the event has resolved or 
stabilized, or the subject is lost to follow-up, or has died. 
Refer to Section 10.4 for additional information regarding the follow-up period for 
pregnant partners of male subjects. 
8.8.8.3 
Follow-up and Reporting of Immediately Reportable Events 
Occurring After Last Scheduled Contact 
Any new IREs reported to the investigator which occur after the last scheduled contact 
and are determined by the investigator to be reasonably associated with the use of the 
IMP, should be reported to the sponsor according to the procedures outlined in 
Section 8.8.3. This may include IREs that are captured on follow-up telephone contact or 
at any other time point after the defined trial period and continue to report any significant 
follow-up information to the sponsor until the events are resolved or stabilized, or the 
subject is lost to follow-up or has died. 
8.9 
Treatment of Overdose 
There is no specific antidote for OPC-61815 and its primary active metabolite, 
OPC-41061. The signs and symptoms of an acute overdose can be anticipated to be those 
of excessive pharmacologic effect: a rise in serum sodium concentration, polyuria, thirst, 
and dehydration/hypovolemia, and these would be managed as medically appropriate 
(refer to the IB Section 6.3 for overdose treatment).1 
8.10 
Subject Assessment Recording 
Not applicable. 
8.11 
Other Assessments 
Not applicable. 


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9 
Statistical Considerations 
9.1 
Sample Size 
No formal statistical assessment of sample size has been conducted. The sample size 
chosen for this trial is common in human radiolabeled studies and is considered sufficient 
to achieve the objectives of the trial. It is planned for at least 8 healthy male Japanese 
subjects to be dosed to ensure that 6 subjects complete the IV infusion. Up to a maximum 
of 10 subjects will be dosed in total. 
9.2 
Datasets for Analysis 
The safety population will include all subjects that received (14C)-OPC-61815.  
The PK population will include all subjects that received (14C)-OPC-61815 (full dose 
within the time frame of 55 to 65 minutes, inclusive) and have evaluable PK data.  
9.3 
Handling of Missing Data for Primary and Secondary Endpoint 
Analysis 
Please refer to the Statistical Analysis Plan for these details. 
9.4 
Statistical Analyses 
9.4.1 
Efficacy Analyses 
Not applicable. 
9.4.2 
Safety Analysis 
9.4.2.1 
Adverse Events 
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities (latest version at time of data reporting) preferred term. The incidence of the 
following events will be summarized: 
• TEAEs 
• TEAEs by severity 
• TEAEs potentially causally related to the IMP 
• TEAEs with an outcome of death 
• Serious TEAEs 
• TEAEs leading to withdrawal of IMP/withdrawal from study  


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9.4.2.2 
Clinical Laboratory Data 
Data will be summarized and listed by subject. No formal statistical analysis will be 
performed.  
9.4.2.3 
Physical Examination and Vital Signs Data 
Vital sign data will be summarized and listed by subject. Physical examination data will 
be listed by subject. No formal statistical analysis will be performed.  
9.4.2.4 
Electrocardiogram Data 
Data will be summarized and listed by subject. No formal statistical analysis will be 
performed.  
9.4.2.5 
Other Safety Data 
Weight data will be summarized and listed by subject. No formal statistical analysis will 
be performed. 
9.4.3 
Other Analyses 
9.4.3.1 
Analysis of Demographic and Baseline Characteristics 
Data will be summarized and listed by subject. No formal statistical analysis will be 
performed.  
9.4.3.2 
Pharmacokinetic Analysis 
For the primary objectives, the following PK parameter endpoints for OPC-61815 free 
form and OPC-41061 in plasma, and total radioactivity in whole blood and plasma will 
be calculated using standard noncompartmental methods: AUC from time zero to infinity 
(AUC∞), AUC calculated to the last observable concentration at time t (AUCt), Cmax, time 
to maximum peak concentration (tmax), time of last measurable (positive) concentration 
(tlast), and terminal-phase elimination half-life (t1/2,z). The total body clearance (CL) will 
also be determined for OPC-61815 free form. In addition, AUC ratios of whole blood 
total radioactivity relative to plasma total radioactivity (ratios of Blood/Plasma Ratio for 
both AUC∞ and AUCt) will be calculated. The following PK parameter endpoints for 
total radioactivity in urine will be calculated: amount excreted in urine (Ae,u), cumulative 
Ae,u, percentage excreted in urine (%fe,u), and cumulative %fe,u; and the following PK 
parameter endpoints for total radioactivity in feces will be calculated: amount excreted in 
feces (Ae,f), cumulative Ae,f, percentage excreted in feces (%fe,f), and cumulative %fe,f. 
Overall amount and percent of total radioactivity in excreta (combined urine and feces) 
will be calculated. 
Additional noncompartmental PK parameters may be determined where appropriate. 


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Pharmacokinetic parameters will be summarized using descriptive methodology. No 
formal statistical analysis will be performed. 
For the primary objective to identify and characterize metabolites in plasma, urine, and 
feces, the endpoint is the metabolic profile of (14C)-OPC-61815 and identification of 
radiolabeled metabolites present at >10% of the total drug-related exposure (AUC) 
plasma. 
9.4.3.3 
Pharmacodynamics Analysis 
No pharmacodynamics analysis is planned. 
9.4.3.4 
Pharmacokinetic/Pharmacodynamics Analysis 
Not applicable. 
9.4.3.5 
Pharmacogenomics Analysis 
No pharmacogenomics analysis is planned. 
9.4.3.6 
Exploratory Endpoint Analysis 
Not applicable. 
9.5 
Interim Analysis and Adaptive Design 
No interim analysis or adaptive design is applicable. 
9.5.1 
Data Monitoring Committee 
Not applicable. 
 


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10 
Supporting Documentation and Operational Considerations 
10.1 
Appendix 1: Regulatory, Ethical, and Trial Oversight 
Considerations 
10.1.1 
Ethics and Responsibility 
This trial must be conducted in compliance with the protocol, International Council for 
Harmonisation (ICH) GCP: Consolidated 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. The trial site will 
seek approval/favorable opinion by an EC according to regional requirements, and the 
investigator will provide that documentation to the sponsor. The EC will evaluate the 
ethical, scientific, and medical appropriateness of the trial. Further, in preparing and 
handling eCRF and safety information, including IREs, the investigator, subinvestigator, 
and their staff will take measures to ensure adequate care in protecting subject privacy. 
To this end, a subject ID 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. 
10.1.2 
Informed Consent 
Informed consent will be freely obtained from all subjects (or their guardian or legally 
acceptable representative, as applicable for local laws). The ICF will be approved by the 
same EC that approves this protocol.  
Each ICF will comply with the ICH GCP: Consolidated Guideline E66 and local 
regulatory requirements. The investigator will ensure that the sponsor reviews and 
authorizes any written site-specific ICF used in the trial before submission to the EC.  
Investigators may discuss trial availability and the possibility for entry with a potential 
subject without first obtaining consent. However, informed consent must be obtained and 
documented before initiation of any procedures that are performed solely for the purpose 
of determining eligibility for this trial, including withdrawal from current medication(s).  
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care. 
Prospective trial subjects will be provided with the ICF by trial site staff. Once 
appropriate essential information has been provided and fully explained in layman’s 
language to the subject by the investigator (or a qualified designee), and it has been 
documented that the subject has had the opportunity to ask questions, the EC-approved 


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written ICF will be signed and dated by both the subject and the person obtaining consent 
(investigator or designee), as well as by any other parties required by the EC. The subject 
will receive a copy of the signed ICF; the original shall be kept on file by the investigator. 
Subjects may be asked to sign additional ICFs if the protocol is amended and the changes 
to the protocol results in additional information that needs to be provided to the subjects, 
so that they can make a knowledgeable and voluntary decision on continued trial 
participation. Female partners of male subjects who become pregnant during the course 
of the trial may be asked to sign additional ICFs in order to collect additional information 
regarding the nonsubject partner and fetus. 
10.1.3 
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 ID in eCRF. 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. 
10.1.4 
Quality Control and Quality Assurance 
10.1.4.1 
Monitoring 
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the ICH GCP: Consolidated Guideline (E6), 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 trial 
site personnel will undergo initial and ongoing training for this particular trial, and this 
training will be clearly documented. 
10.1.4.2 
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, 


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the informed consent process, and a review of the eCRF with source documents, as 
applicable. 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. 
10.1.5 
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, subject enrolled in violation of eligibility criteria, or concomitant medication 
criteria), the investigator or designee will contact the sponsor or designee at the earliest 
possible time by telephone or via e-mail. 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. 
Any major protocol deviation will be recorded in the eCRF along with the start date and 
details of the deviation. 
10.1.6 
Records Management 
10.1.6.1 
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, medical 
records, 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/institution will permit trial-related monitoring, audits, EC 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. 


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10.1.6.2 
Data Collection 
During each subject’s visit to the site, an investigator or their designee participating in the 
trial will record information 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;  
• The signature (or initials) and date of the investigator (or designee) who made an 
entry in the medical record. 
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above. 
Information from medical records and other source documents will be entered by 
investigative site personnel onto eCRFs in the sponsor’s electronic data capture (EDC) 
system that is 21 CRF Part 11 compliant. Changes to the data will be captured by an 
automatic audit trail in the EDC system. 
Electronic data not entered on eCRF, such as data received from central laboratories and 
central ECG readers, will be reconciled using key data fields by the sponsor or the 
Contract Research Organization with the eCRF data to ensure consistency. 
10.1.6.3 
File Management at the Trial Site 
The investigator will ensure that the trial site file is maintained in accordance with 
Section 8 of the ICH GCP: Consolidated Guideline (E6) and as required by applicable 
local regulations. The investigator/institution will take measures to prevent accidental or 
premature destruction of these documents. 


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10.1.6.4 
Records Retention at the Trial Site 
Regulatory requirements for the archival of records for this trial necessitate that 
participating investigators maintain detailed clinical data for the longest of the following 
3 periods: 
• A period of at least 2 years after the date on which approval to market the drug is 
obtained (or if IMP development is discontinued, the date regulatory authorities 
were notified of discontinuation); OR 
• A period of at least 3 years after the sponsor notifies the investigator that the final 
report has been filed with regulatory authorities. 
• Longer, region-specific storage requirements, if applicable.  
The investigator must not dispose of any records relevant to this trial without either 
(1) written permission from the sponsor or (2) provision of an opportunity for sponsor to 
collect such records. The investigator will be responsible to maintain adequate and 
accurate electronic or hard copy source documents of all observations and data generated 
during this trial 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 time frame. Notice of such transfer will be given to the sponsor in 
writing. 
10.1.6.5 
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. 


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Investigators or other trial subjects 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 subjects consent to such acknowledgment in any 
publications resulting from its conduct. 


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10.2 
Appendix 2: Clinical Laboratory Evaluations 
The tests detailed in Table 10.2-1 will be performed. 
 Table 10.2-1 
Clinical Laboratory Evaluations 
Hematology: 
Hematocrit 
Hemoglobin (HGB) 
Ery. Mean Corpuscular HGB 
Ery. Mean Corpuscular HGB Concentration 
Ery. Mean Corpuscular Volume 
Platelet count 
Erythrocyte count 
Leukocytes count with differential  
 
Urinalysis: 
Occult Blood 
Glucose 
ketones 
Microscopic analysis, White Blood Cell/Red 
Blood Cell counts per high powered field 
pH 
Protein 
Specific Gravity 
Serum Chemistry: 
Alkaline Phosphatase  
Alanine Aminotransferase 
Aspartate Aminotransferase 
Uric acid 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Direct bilirubin 
Gamma Glutamyl Transferase 
Glucose 
Lactic Dehydrogenase 
Inorganic phosphate 
Potassium 
Total bilirubin 
Total protein  
Sodium 
Triglycerides 
 
Serology (only analyzed at Screening) 
Hepatitis B surface antigen 
Hepatitis C antibody 
Human immunodeficiency virus (HIV): 
HIV-1 and HIV-2 antibodies and p24 antigen 
Drug screen (only analyzed at Screening and 
Check-in) 
Including but not limited to: 
Amphetamines/methamphetamines 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Cotinine  
Ecstasy 
Methadone 
Phencyclidine 
Opiates 
Oxycodone 
Tetrahydrocannabinol/cannabinoids 
Tricyclic antidepressants 
Alcohol breath test 
 


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10.3 
Appendix 3: Total Blood Volume 
The following blood volumes are the maximum that will be withdrawn for each subject. 
Table 10.3-1 
Total Blood Volume 
Up to Day 9 (inclusive)a 
Volume per blood 
sample (mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Clinical laboratory 
evaluations 
7.5 
6 
45 
Serology 
3.5 
1 
3.5 
Plasma for 
OPC-61815 free 
form and 
OPC-41061 
concentrations 
3 
10 
30 
Whole blood for 
total radioactivity 
2 
16 
32 
Plasma for total 
radioactivity 
5 
16 
80 
Plasma for 
metabolite profiling 
and identification 
10 
15 
150 
Total 
340.5 
a Subjects could be discharged on Day 9 if the discharge criteria are met or may be resident within the 
Clinical Research Unit for an additional 24-hour collection (blood) for total radioactivity up to Day 10. 
If extra blood samples are required, the maximum blood volume to be withdrawn per 
subject will not exceed 500 mL. 


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10.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Male subjects with partners of non-childbearing potential (defined as permanently sterile 
[due to hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy as reported 
by medical history and/or medical records; surgical sterilization to have occurred a 
minimum of 6 weeks, or at the investigator’s discretion, prior to Screening] or 
postmenopausal [defined as females at least 45 years of age with amenorrhea for 
12 months without an alternative medical reason]) must use a male barrier method of 
contraception (ie, male condom with spermicide) from Check-in until 90 days after Final 
Discharge.  
Male subjects (even with history of vasectomy) with partners of childbearing potential 
must use a male barrier method of contraception (ie, male condom with spermicide) in 
addition to a second method of acceptable contraception from Check-in until 90 days 
after Final Discharge. Acceptable second methods of contraception for female partners 
include: 
• hormonal injection (as prescribed) 
• combined oral contraceptive pill or progestin/progestogen-only pill (as 
prescribed) 
• combined hormonal patch (as prescribed) 
• combined hormonal vaginal ring (as prescribed) 
• surgical method (bilateral tubal ligation or Essure® [hysteroscopic bilateral tubal 
occlusion]) 
• hormonal implant (as prescribed) 
• hormonal or non-hormonal intrauterine device (as prescribed) 
• over-the-counter sponge with spermicide 
• diaphragm in conjunction with spermicide (as prescribed) 
• cervical cap in conjunction with spermicide (as prescribed) 
An acceptable second method of contraception for male subjects is vasectomy that has 
been performed at least 90 days prior to the Screening visit, with verbal confirmation of 
surgical success. 
Sexual intercourse with female partners who are pregnant or breastfeeding should be 
avoided unless condoms are used from the time of Check-in until 90 days after Final 
Discharge. Male subjects are required to refrain from donation of sperm from Check-in 
until 90 days after Final Discharge.  


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Subjects who practice true abstinence, because of the subject’s lifestyle choice (ie, the 
subject should not become abstinent just for the purpose of trial participation), are exempt 
from contraceptive requirements. Periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal are not acceptable methods of 
contraception. If a subject who is abstinent at the time of signing the ICF becomes 
sexually active they must agree to use contraception as described previously. 
For subjects who are exclusively in same-sex relationships, contraceptive requirements do 
not apply. If a subject who is in a same-sex relationship at the time of signing the ICF 
becomes engaged in a heterosexual relationship, they must agree to use contraception as 
described previously. 
Before enrolling males in this clinical trial, investigators must review the below 
information about trial participation as part of the ICF process. The topics should 
generally include: 
• General information 
• Informed consent form 
• Pregnancy prevention information 
• Contraceptives in current use 
• Follow-up of a reported pregnancy 
Before trial enrollment, males must be advised of the importance of avoiding pregnancy 
during trial participation and the potential risk factors for an unintentional pregnancy. 
Subjects must sign the ICF confirming that the above-mentioned risk factors and the 
consequences were discussed. 
Male subjects must be instructed to contact the investigator immediately, during the trial, 
if their partner suspects that they might be pregnant (eg, missed or late menstrual cycle). 
The investigator must immediately notify the sponsor (within 24 hours) of any pregnancy 
associated with IMP exposure during the trial and for at least 30 days after dose of IMP, 
and record the event on the IRE form and forward it to the sponsor. The sponsor will 
forward the Pregnancy Surveillance Form(s) to the investigator for monitoring the 
outcome of the pregnancy. 
The investigator must report to the sponsor, on the 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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10.5 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments 
Liver function tests should be promptly performed in subjects taking (14C)-OPC-61815 
who report symptoms that may indicate liver injury, including fatigue, anorexia, nausea, 
right upper abdominal discomfort, vomiting, fever, rash, pruritus, jaundice, or dark urine. 
If liver injury is suspected, appropriate treatment should be instituted, and investigations 
should be performed to determine the probable cause. 


Protocol 263-102-00006 
63 
Confidential - Proprietary Information 
 
Amendment 1 Approval: 14 November 2019 
10.6 
Appendix 6: Abbreviations 
Abbreviation 
Definition 
AE 
Adverse event 
Ae,f 
Amount excreted in feces 
AESI 
Adverse event of special interest 
Ae,u 
Amount excreted in urine 
ALARA 
as low as (is) reasonably achievable 
ALT 
Alanine aminotransferase 
API 
Active pharmaceutical ingredient 
AST  
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC∞ 
Area under the concentration-time curve from time zero to infinity 
AUCt 
Area under the concentration-time curve calculated to the last 
observable concentration at time t 
CL 
Total body clearance  
Cmax 
Maximum peak concentration of the drug 
CRU 
Clinical Research Unit 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
%fe,f 
Percentage excreted in feces 
%fe,u 
Percentage excreted in urine 
GCP 
Good Clinical Practice 
HGB 
Hemoglobin  
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICRP 
International Commission in Radiological Protection 
IMP 
Investigational medicinal product 
IRE 
Immediately reportable event 
IV 
Intravenous 
PHE 
Public Health England 
PK 
Pharmacokinetic 
PQC 
Product quality complaint 
SAE 
Serious adverse event 
t1/2 
Elimination half-life 
t1/2,z 
Terminal-phase elimination half-life 
TEAE 
Treatment-emergent adverse event 
tmax 
Time to reach maximum peak concentration 
ULN 
Upper limit of normal 
 


Protocol 263-102-00006 
64 
Confidential - Proprietary Information 
 
Amendment 1 Approval: 14 November 2019 
10.7 
Appendix 7: Protocol Amendments 
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the EC. Any permanent 
change to the protocol, whether an overall change or a change for specific trial site, must 
be handled as a protocol amendment. Any amendment will be written by the sponsor. 
Each amendment will be submitted to the EC, as required by local regulations. Except for 
“administrative” or “nonsubstantial” amendments, investigators will wait for EC 
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 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 EC notification within local applicable timelines. The sponsor 
will submit protocol amendments to the applicable regulatory agencies within local 
applicable timelines. 
When the EC, investigators, and/or the sponsor conclude that the protocol amendment 
substantially alters the trial design and/or increases the potential risk to the subject, the 
currently approved written ICF will require similar modification. In such cases, after 
approval/favorable opinion of the new ICF by the EC, 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. 


Protocol 263-102-00006 
65 
Confidential - Proprietary Information 
 
Amendment 1 Approval: 14 November 2019 
10.7.1 
Protocol Amendment(s)/Administrative Change(s) 
10.7.1.1 
Protocol Amendment 1 
Amendment 1 Approval Date: 
14 November 2019  
 
PURPOSE: 
 
• To increase the time window for clinical laboratory evaluations from ±60 minutes to 
±120 minutes for the 24- and 48-hour postdose safety samples. 
• To clarify that subjects may be dosed either in the morning or in the afternoon. 
 
BACKGROUND: 
The changes are needed for logistical reasons at the site. 
MODIFICATIONS TO PROTOCOL: 
General Revisions: 
• The trial design section was amended to remove the specification that subjects will be 
dosed, and associated additional excreta samples will be collected, in the morning. 
• The time windows for clinical laboratory evaluations at the 24- and 48-hour 
timepoints relative to the start in infusion were updated to ±120 minutes. 
ADDITIONAL RISK TO THE SUBJECT: 
There are no additional risks to the subjects. 


Protocol 263-102-00006 
66 
Confidential - Proprietary Information 
 
Amendment 1 Approval: 14 November 2019 
11 
References 
1.  Otsuka Pharmaceutical Co., Ltd. OPC-61815 - Investigator’s Brochure (Version 8). 
2019.  
2.  International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite 
Guideline: Guidance on Nonclinical Safety Studies for the Conduct of Human 
Clinical Trials and Marketing Authorization for Pharmaceuticals M3(R2) Questions 
and Answers (R2) [Internet]. International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use; 2012. 
Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E
1/Step4/E1_Guideline.pdf 
3.  ICRP. Radiological Protection in Biomedical Research. ICRP Publ 62 Ann ICRP. 
1992;22(3).  
4.  Public Health England, London, UK. Assessment of the Radiation Dose to Male 
Volunteers from the Intravenous Dosing of 14C-OPC-61815. 2019.  
5.  World Health Organization. Use of ionising radiation and radionuclides on human 
beings for medical research, training, and nonmedical purposes. 1977.  
6.  International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH). Integrated Addendum to ICH E6(R1): 
Guideline for Good Clinical Practice E6(R2) [Internet]. International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use 
(ICH); 2016. Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E
6/E6_R2__Step_4.pdf 
 
 
 
 


Protocol 263-102-00006 
Agreement 
1, the undersigned pnnc1pal mvestlgator, have read and understand the p10tocol (111cluding the 
Investigator's Brochure) and agree that 1t contams all the ethical, legal and scientific mfonnation 
necessary to conduct this tnal m accordance with the prmc1ples of Good Climcal Prachces and as 
described herein and m the sponsor's (or des1gnee's) Chmcal Tnal Agreement. 
I will provide copies of the protocol to all physicians, nurses, and other profess10nal personnel to 
whom I delegate tnal respons1bihties I will discuss the protocol with them to ensure that they are 
sufficiently mformed regarding the mve::.hgat10nal new drug, (l4C)-OPC-6l815, the concurrent 
medications, the efficacy and safety parameters and the conduct of the tnal 111 general I am aware that 
this protocol must be approved by the Inst1tut1onal Review Board or 1ece1ve a favorable opm10n by 
the Independent Ethics Committee responsible for such matters m the chmcal tnal facility where 
(14C)-OPC-61815 will be te::.ted pnor to commencement of this tnal I agree to adhere stnctly to the 
attached protocol (unles::. amended m the manner set forth m the sponsor's Clm1cal Trial Agreement, at 
which hme I agree to adhere stnctly to the p1otocol as amended) 
I understand that this EC-approved protocol will be submitted to the appropnate regulatory 
authonty/ies by the sponsor J agree that cbmcal data entered on eCRF by me and my staff will be 
utilized by the sponsor m various ways, such as for subrmss1on to governmental regulato1y authonties 
and/or m combmatton with clinical data gathered fiom other research sites, whenever applicable I 
agree to allow sponsor and des1gnee monitors and auditois full access to all medical records at the 
research fac1l1ty for sub1ects screened 01 enrolled m the tual. 
I agree to await EC app1oval before implementat1011 of any substantial amendments to tlus ptotocol If, 
howeve1, there 1s an munediate hazard to subjects, I w11l 11nplernent the amendment 1mmed1ately, and 
provide the mfo1mation to the EC wnhm the ieqmred local applicable t1melmes Administrat1\'e 
changes to the p1otocol will be tranf>m1tted to the EC for informat10nal pt1rposes only, if required by 
local regulations 
I agree to provide all subjects with mformed consent forms, as ieqmred by the applicable regulat10ns 
and by ICH gu1delmes J agree to report to the sponsor any adyerse expenences in accordance with the 
tenns of the sponsor's Cltmcal Tnal Agreement and the relevant iegional regulation(s) and 
gmdelme(s) I further agree to provide all required mformatton regardmg financial cert1ficatio11 or 
d1sclosure to the sponsor for all mvestigators and submvestigators m accordance with the tenns of the 
relevant reg10nal regulat10n(s). I understand tl1at partic1pat1on m the protocol mvolves a commitment 
to publish the data from this trial ma cooperative pubhcat1on before publication of efficacy and safety 
results on an md1VIdual basis may occm, and I consent to be acknowledged m any such cooperative 
publications tliat re&ult. 
Pnnc1pal Investigator Pnnt Name 
S1gnarure 
Date 
Sponsor Representative Prmt Name 
Date 
67 
Confidential - Prop11etary lnformat10n 
Amendment 1 Approval· 14 November 2019 
PPD
PPD

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
A Phase I, Open-Label Trial to Assess the Mass Balance and 
Pharmacokinetics of a Single Intravenous Administration of 
(14C)-OPC-61815 to Healthy Male Japanese Subjects 
 
 
 
 
 
NCT Number: NCT04182958 
PRT NO.: 263-102-00006 
Version Date: 11 December 2019 (Version 1.0) 


TITLE PAGE
Statistical Analysis Plan
A Phase I, Open-Label Trial to Assess the Mass Balance and 
Pharmacokinetics of a Single Intravenous Administration of 
(14C)-OPC-61815 to Healthy Male Japanese Subjects
SAP Version: 1
SAP Status: Final
SAP Date: 11 December 2019
Investigational Product: (14C)-OPC-61815
Protocol Reference: 263-102-00006
Covance Study: 8401548
Sponsor:
Otsuka Pharmaceutical Co., Ltd
2-9 Kanda-Tsukasamachi                            
Chiyoda-ku                                                   
Tokyo 101-8535                                             
Japan
Study Site:
Covance Clinical Research Unit Ltd.
Springfield House, Hyde Street
Leeds, LS2 9LH
UK
Principal Investigator:
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor.
PPD


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CONFIDENTIAL
Covance Study: 8401548
Protocol Reference: 263-102-00006
Version 1, Final, 11 December 2019
Page 2 of 18
TABLE OF CONTENTS
TITLE PAGE.............................................................................................................................1
TABLE OF CONTENTS...........................................................................................................2
LIST OF ABBREVIATIONS....................................................................................................4
1. INTRODUCTION .................................................................................................................6
2. STUDY OBJECTIVES..........................................................................................................6
2.1. Primary Objectives..........................................................................................................6
2.2. Secondary Objective .......................................................................................................7
3. STUDY ENDPOINTS...........................................................................................................7
3.1. Primary Endpoints...........................................................................................................7
3.1. Secondary Endpoints.......................................................................................................8
4. STUDY DESIGN...................................................................................................................8
5. SAMPLE SIZE JUSTIFICATION ........................................................................................9
6. STUDY TREATMENTS.......................................................................................................9
7. DEFINITIONS OF POPULATIONS ....................................................................................9
7.1. All Subjects Population.................................................................................................10
7.2. Safety Population ..........................................................................................................10
7.3. Pharmacokinetic Population .........................................................................................10
8. STATISTICAL METHODOLOGY....................................................................................10
8.1. General..........................................................................................................................10
8.1.1. Calculation of the Summary Statistics ...................................................................10
8.1.2. Repeat and Unscheduled Readings ........................................................................11
8.2. Subject Disposition and Population Assignment..........................................................11
8.3. Screening Demographics ..............................................................................................11
8.4. Prior and Concomitant Medication...............................................................................11
8.5. Pharmacokinetic Assessments ......................................................................................12
8.5.1. Pharmacokinetic Analysis ......................................................................................12
8.5.3. Pharmacokinetic Statistical Methodology..............................................................14
8.6. Safety and Tolerability Assessments ............................................................................15
8.6.1. Adverse Events.......................................................................................................15
8.6.2. Clinical Laboratory Parameters..............................................................................16
8.6.3. Vital Signs Parameters ...........................................................................................17
8.6.4. Body Weight...........................................................................................................17


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8.6.5. 12-lead Electrocardiogram Parameters ..................................................................17
8.6.6. Other Assessments .................................................................................................17
8.6.7. Safety and Tolerability Statistical Methodology....................................................17
9. INTERIM ANALYSES.......................................................................................................17
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........17
11. REFERENCES ..................................................................................................................17
12. APPENDICES ...................................................................................................................18


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Covance Study: 8401548
Protocol Reference: 263-102-00006
Version 1, Final, 11 December 2019
Page 4 of 18
LIST OF ABBREVIATIONS
Abbreviations pertain to the statistical analysis plan (SAP) only (not the tables, figures, and 
listings [TFLs]).
ADaM
analysis data model
AE
adverse event
AUC
area under the concentration-time curve
AUC
area under the concentration-time curve from time 0 to infinity
AUCt
area under the concentration-time curve calculated to the last observable 
concentration at time t
BLQ
below the limit of quantification
CDISC
Clinical Data Interchange Standards Consortium
CL
total body clearance
Cmax
maximum peak concentration 
CSR
clinical study report
CV%
coefficient of variation
ECG
electrocardiogram
ICF
informed consent form
ICH
International Council for/Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use
IV
intravenous
LLOQ
lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
NC
not calculated
NR
no result
NS
no sample
PK
pharmacokinetic(s)
PT
preferred term
R2-adj 
adjusted coefficient for determination of exponential fit
SAP
statistical analysis plan
SD
standard deviation
t1/2,z
terminal–phase elimination half-life
TEAE
treatment-emergent adverse event
TFL
table, figure, and listing
tlast
time of last measurable (positive) concentration
tmax
time to maximum peak concentration
WHODrug
World Health Organization Drug Dictionary 
λz
apparent terminal elimination rate constant
λz Lower 
start of exponential fit
λz N 
number of data points included in the log-linear regression


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Covance Study: 8401548
Protocol Reference: 263-102-00006
Version 1, Final, 11 December 2019
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λz Span Ratio 
time period over which λz was determined as a ratio of t1/2,z
λz Upper 
end of exponential fit
%AUCextrap
percentage of AUC that is due to extrapolation from the last measurable 
concentration to infinity


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Covance Study: 8401548
Protocol Reference: 263-102-00006
Version 1, Final, 11 December 2019
Page 6 of 18
1. INTRODUCTION
This SAP has been developed after review of the clinical study protocol (Final Version 1.0
dated 17 June 2019 and Amendment 1.0 dated 14 November 2019) and electronic case report 
form.
This SAP describes the planned analysis of the pharmacokinetic (PK), safety and tolerability
data from this study. A detailed description of the planned TFLs to be presented in the 
clinical study report (CSR) is provided in the accompanying TFL shells document.
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with Otsuka Pharmaceutical Co., Ltd. A limited amount of 
information about this study (eg, objectives, study design) is given to help the reader’s 
interpretation. This SAP must be finalized prior to the lock of the clinical database for this 
study. When the SAP and TFL shells are approved, they will serve as the template for this 
study’s CSR.
This SAP supersedes any statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed 
and will be identified accordingly in the CSR. Any substantial deviations from this SAP will 
be agreed with Otsuka Pharmaceutical Co., Ltd and identified in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 guideline Statistical Principles for Clinical Trials
and ICH E3 guideline Structure and Content of Clinical Study Reports.1,2
The document history is presented in Appendix 1.
2. STUDY OBJECTIVES
2.1. Primary Objectives
●
To determine the mass balance of total radioactivity following a single intravenous 
(IV) infusion of (14C)-OPC-61815.
●
To determine routes and rates of elimination of total radioactivity following a single 
IV infusion of (14C)-OPC-61815.
●
To assess the PK of total radioactivity in plasma and whole blood following a single 
IV infusion of (14C)-OPC-61815.
●
To assess the PK of OPC-61815 free form and OPC-41061 in plasma following a 
single IV infusion of (14C)-OPC-61815.
●
To identify and characterize metabolites in plasma, urine, and feces following a single 
IV infusion of (14C)-OPC-61815.


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Protocol Reference: 263-102-00006
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2.2. Secondary Objective
●
To assess the safety and tolerability of a single IV infusion of (14C)-OPC-61815.
3. STUDY ENDPOINTS
3.1. Primary Endpoints
The PK parameter endpoints for OPC-61815 free form and OPC-41061 in plasma, and total 
radioactivity in whole blood and plasma are:

Area under the concentration-time curve (AUC) from time 0 to infinity (AUC∞)

AUC calculated to the last observable concentration at time t (AUCt)

maximum peak concentration (Cmax),

time to maximum peak concentration (tmax)

time of last measurable (positive) concentration (tlast)

terminal-phase elimination half-life (t1/2,z)
The total body clearance (CL) will also be determined for OPC-61815 free form. In addition, 
AUC ratios of whole blood total radioactivity relative to plasma total radioactivity (ratios of 
Blood/Plasma Ratio for both AUC∞and AUCt) will be calculated.
The following PK parameter endpoints for total radioactivity in urine (calculated and reported 
separately in the radioanalysis report “Analysis of Total Radioactivity in Blood, Plasma and 
Excreta” [Covance study: 8405603] by Covance Laboratories) are:

amount excreted in urine per sampling interval (Ae,u)

cumulative Ae,u, 

percentage of drug dose excreted in urine per sampling interval (%fe,u)

cumulative %fe,u
The following PK parameter endpoints for total radioactivity in feces (calculated and reported 
separately in the radioanalysis report by Covance Laboratories) are:

amount excreted in feces per sampling interval (Ae,f)

cumulative Ae,f

percentage of drug dose excreted in feces per sampling interval (%fe,f)

cumulative %fe,f


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Covance Study: 8401548
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Overall amount and percent of total radioactivity in excreta (combined urine and feces per 
sampling interval and cumulative; calculated and reported separately in the radioanalysis 
report by Covance Laboratories).
For the primary objective to identify and characterize metabolites in plasma, urine, and feces, 
the endpoint is the metabolic profile of (14C)-OPC-61815 and identification of radiolabeled 
metabolites present at >10% of the total drug-related exposure (AUC) plasma (calculated and 
reported separately in the metabolite profiling report [Covance study: 8405604] by Covance 
Laboratories).
3.1. Secondary Endpoints
The secondary endpoints are adverse events (AEs), clinical laboratory evaluations, physical 
examination findings, vital signs (blood pressure, pulse rate), body weight, and 12-lead
electrocardiogram (ECG) parameters.
4. STUDY DESIGN
This will be a Phase I, single-site, open-label, nonrandomized, single IV dose trial in healthy 
male Japanese subjects.
Potential subjects will be screened to assess their eligibility to enter the trial within 28 days 
prior to the dose administration. Subjects will be enrolled and admitted into the trial site on 
Day -1. On Day 1, all subjects will receive a single IV infusion of 16 mg (14C)-OPC-61815, 
containing approximately 75.1 μCi (2.78 MBq), over 60 minutes (55 to 65 minutes, 
inclusive) in the fasted state.
It is planned for at least 8 subjects to be dosed to ensure that 6 subjects complete the IV 
infusion. Up to a maximum of 10 subjects will be dosed in total.
Subjects will be confined to the trial site until at least Day 9. Subjects will be discharged from 
the trial site on Day 9 if the following discharge criteria are met:

≥ 90% mass balance recovery, and/or

< 1% of the total radioactive dose is recovered in combined excreta (urine and feces) in 2 
consecutive 24-hour periods.
If these criteria are not met by Day 9, subjects will remain at the trial site until any one of the 
discharge criterion are met up to a maximum of Day 10 to continue 24-hour blood, urine, and 
feces collections for total radioactivity, unless otherwise agreed upon by the sponsor and 
investigator.
If criteria are not met by Day 10, subjects may be asked to collect 24-hour excreta samples on 
up to 2 further occasions on a nonresidential basis to allow extrapolation of urinary and fecal 
excretion. If needed, the 2 additional 24-hour nonresidential collections will start on Days 10 
and 11 (to be brought to the trial site at the end of the collection interval on Days 11 and 12, 
respectively). If on the second occasion the subject has still not met the desired criterion, then 
the subject will be discharged from the trial, per investigator and sponsor decision.


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Final Discharge from trial will be day of discharge from residential treatment period or the 
day of last outpatient visit if required to attend them based on the discharge criteria. The total 
duration of trial participation for each subject (from Screening through Final Discharge from 
trial) is anticipated to be a maximum of approximately 40 days. 
The start of the trial is defined as the date the first enrolled subject signs an informed consent 
form (ICF). The point of enrollment occurs at the time of subject number allocation. The end 
of trial is defined as the last date of contact or the date of final contact attempt for the last 
subject completing or withdrawing from the trial.
A schematic of the study design is presented in Figure 1.
Figure 1:
Study Design
5. SAMPLE SIZE JUSTIFICATION
No formal statistical assessment of sample size has been conducted. The sample size chosen 
for this trial is common in human radiolabeled studies and is considered sufficient to achieve 
the objectives of the trial. It is planned for at least 8 healthy male Japanese subjects to be 
dosed to ensure that 6 subjects complete the IV infusion. Up to a maximum of 10 subjects 
will be dosed in total.
6. STUDY TREATMENTS
The study treatment is (14C)-OPC-61815.
7. DEFINITIONS OF POPULATIONS
Any protocol deviations will be considered prior to database lock for their importance and 
taken into consideration when assigning subjects to populations.


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7.1. All Subjects Population
The all subjects population will include all subjects who signed the ICF and had any study 
assessment recorded in the database per the protocol.
7.2. Safety Population
The safety population will include all subjects that received (14C)-OPC-61815.
7.3. Pharmacokinetic Population
The PK population will include all subjects that received (14C)-OPC-61815 (full dose within 
the time frame of 55 to 65 minutes, inclusive) and have evaluable PK data.
8. STATISTICAL METHODOLOGY
8.1. General
Listings will be provided for all data captured in the database, with the exception of medical 
history. Listings will include all subjects assigned to the all subjects population and include 
data up to the point of study completion or discontinuation. Any subject who discontinued the 
study will be identified accordingly in the listings. Summaries will include the subjects 
assigned to the relevant population based on data type.
Data analysis will be performed using the SAS® statistical software package Version 9.4 (or 
higher if upversioned during the study).
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1 (or higher if upversioned during the 
study) and CDISC ADaM Implementation Guide Version 1.1 (or higher if upversioned
during the study). Pinnacle 21 Community Validator Version 2.2.0 (or higher if upversioned
during the study) will be utilized to ensure compliance with CDISC standards.
Where reference is made to ‘all calculations’, this includes, but is not limited to, summary 
statistics.
8.1.1. Calculation of the Summary Statistics
For continuous data the following rules will be applied:
●
Missing values will not be imputed, unless specifically stated otherwise.
●
Unrounded data will be used in the calculation of summary statistics.
●
If number of subjects with valid observations (n) <3, summary statistics will not be 
calculated, with the exception of n, minimum, and maximum.
●
As Early Termination data is not associated with any scheduled timepoint, it will be 
excluded from all calculations of summary statistics.


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For categorical data the following rules will be applied:
●
If the categories of a parameter are ordered (eg, AE severity), all categories between 
the possible minimum and maximum categories will be included, even if n = 0 for a 
given category. If the categories are not ordered (eg, race), only those categories for 
which there is at least 1 subject represented will be included.
●
Missing values will not be imputed, with the exception of AEs where the ‘worst-case’
approach will be taken (see Section 8.6.1), or unless specifically stated otherwise. A 
‘missing’ category will be included for any parameter for which information is 
missing. This will ensure that the population size totals are consistent across different 
parameters.
8.1.2. Repeat and Unscheduled Readings
For vital signs and ECG data only, any predose value recorded in addition to the original 
value or a postdose value recorded within 15 minutes of the original value will be defined as 
a repeat value; any postdose value recorded more than 15 minutes after the original value will 
be defined as an unscheduled value. For all other data types (eg, laboratory parameters), any 
value recorded in addition to the original value will be defined as an unscheduled value.
The original value will be replaced by the last associated repeat value in all calculations.
As unscheduled values are not associated with any scheduled timepoint, they will be 
excluded from all calculations.
8.2. Subject Disposition and Population Assignment
Subject disposition and population assignment will be listed.
A summary table will be provided, based on the all subjects population.
8.3. Screening Demographics
The screening demographics including age, sex, race, ethnicity, country, height, body weight,
and body mass index will be listed.
A summary table will be provided, based on the safety population.
8.4. Prior and Concomitant Medication
Prior medication will be defined as medication that ends prior to the start of the infusion. 
Concomitant medication will be defined as medication that starts after the start of the infusion
or starts but does not end prior to the start of the infusion.
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODrug) Global, Format B2, Version September 2018 (or later if upversioned
during the study). Prior and concomitant medications will be listed.


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8.5. Pharmacokinetic Assessments
8.5.1. Pharmacokinetic Analysis
The following PK parameters will be determined where possible from the plasma 
concentrations of OPC-61815 free form and OPC-41061, and total radioactivity in whole 
blood and plasma using non compartmental methods performed using Phoenix WinNonlin 
(Certara USA Inc, Version 8.1 or higher):
Parameter
Definition
AUCt
area under the concentration-time curve calculated to the last 
observable concentration at time t
AUC
area under the concentration-time curve from time 0 to infinity
%AUCextrap
percentage of AUC that is due to extrapolation from the last 
measurable concentration to infinity
Cmax
maximum peak concentration
tmax
time to maximum peak concentration
tlast
time of last measurable (positive)  concentration
t1/2,z
terminal–phase elimination half-life
CL
total body clearance (OPC-61815 free form only)
AUC∞  Blood 
/Plasma Ratio
AUC∞of total radioactivity in whole blood relative to AUC∞of total 
radioactivity in plasma
AUCt 
Blood/Plasma 
Ratio
AUCt of total radioactivity in whole blood relative to AUCt of total 
radioactivity in plasma
The parameters related to the regression analysis for the terminal elimination phase shown 
below will be presented in the listings only and not summarized:
Regression 
Parameter
Definition
λz Lower 
start of exponential fit
λz Upper 
end of exponential fit
λz N 
number of data points included in the log-linear regression
R2-adj 
adjusted coefficient for determination of exponential fit
λz
apparent terminal elimination rate constant
λz Span Ratio 
time period over which λz was determined as a ratio of t1/2,z
Additional PK parameters may be determined where appropriate.
The PK analysis will be carried out using actual postdose times recorded in the raw data. If 
actual times are missing, nominal times will be used. 
Concentrations will be used as supplied by the analytical laboratory for PK analysis. The 
units of concentration and resulting PK parameters, with amount or concentration in the unit, 
will be presented as they are received from the analytical laboratory. 
Cmax, tmax, and tlast will be obtained directly from the concentration-time profiles.  


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When Cmax occurs at more than 1 timepoint, tmax will be assigned to the first occurrence of
Cmax.
The urine and fecal PK parameters for total radioactivity in urine and feces will be calculated 
where possible and reported separately in the radioanalysis report by Covance Laboratories.
Identification of radiolabeled metabolites present at >10% of the total drug-related exposure 
(AUC) will be reported separately in the metabolite profiling report by Covance Laboratories.
8.5.1.1. Criteria for Handling Concentrations Below the Limit of Quantification
Predose concentration values that are below the level of quantification (BLQ) will be set to 0
and postdose concentration values that are BLQ will be set to missing for the purposes of PK 
analysis, with defined exceptions as follows;
●
If there are late positive concentration values following 2 BLQ concentration values 
in the apparent terminal phase, these values will be evaluated. If these values are 
considered to be anomalous, they will be set to missing.
●
If an entire plasma/blood concentration-time profile is BLQ, the profile will be 
excluded from the PK analysis.
●
If a predose plasma/blood concentration is missing, this value will be set to 0 by 
default.
8.5.1.2. Criteria for the Regression Analysis of the Terminal Elimination Phase 
●
At least 3 data points will be included in the regression analysis and preferably should 
not include Cmax.
●
When assessing terminal elimination phases, the adjusted coefficient of determination 
for exponential fit (R2-adj) will be used as a measure of the goodness of fit of the data 
points to the determined line. 
●
The λz will not be assigned if the R2-adj value of the regression line is <0.8. In cases 
where the λz is not assigned all regression based parameters (including R2-adj) will 
not be calculated.
●
Time period used for the estimation of t1/2,z will be calculated over a time period of at 
least 2 half-lives (λz Span Ratio >2), where possible. Where λz Span Ratio <2 the 
robustness of t1/2,z will be discussed in the CSR.
8.5.1.3. Calculation of Area Under the Concentration-time Curve
●
The minimum requirement for the calculation of AUC will be the inclusion of at least 
3 consecutive concentrations above the lower limit of quantification (LLOQ), with at 
least 1 of these concentrations following Cmax.
●
AUCs will be calculated using the Linear Trapezoidal Linear/Log Interpolation
method. 


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8.5.1.4. Anomalous Values
●
If a value is considered to be anomalous due to being inconsistent with the expected 
PK profile, it may be appropriate to exclude this point from the PK analysis. 
However, the exclusion of data must have strong justification and will be documented 
in the raw data and the CSR.
8.5.2. Presentation of Pharmacokinetic Data
8.5.2.1. Presentation Pharmacokinetic Concentration Data
●
The following rules will be applied if there are values that are BLQ or if there are 
missing values (eg, no result [NR] or No Sample [NS]) in a concentration data series 
to be summarized:
o
For the calculation of summary statistics, predose BLQ values will be set to 
zero and postdose BLQ values will be set to missing.
o
If an embedded BLQ value is considered anomalous within the 
concentration-time profile, this value will be excluded from the summary 
statistics.
o
Where there is NR or NS, these will be set to missing.
o
If there are less than 3 non-missing values in the data series, only the min, max 
and n will be presented. The other summary statistics will be denoted as not 
calculated (NC). 
Where there is a PK blood sampling time deviation from the nominal sampling time
occurring outside the PK sampling time windows specified in the protocol, the concentration 
will be excluded from the summary statistics and summary concentration-time figures and 
flagged in the concentration listings.
8.5.2.2. Presentation Pharmacokinetic Parameters
Individual PK parameters will be presented to 3 significant figures with the exception of tmax, 
tlast, λz Lower and λz Upper which will be presented to 2 decimal places.
For the calculation of summary statistics of PK parameters, all NR and NC values in a data 
series will be set to missing.
The AUC values will be set to NC if they have been calculated using fewer than 3 
concentrations, and/or 3 concentrations if the last is Cmax.
8.5.3. Pharmacokinetic Statistical Methodology
All PK concentrations and parameters will be listed.
Summary tables, mean (+ SD) figures, overlaying individual figures, and individual figures
by time postdose will be provided for plasma PK concentrations. All figures will be produced 


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on both linear and semi-logarithmic scales. The +SD bars will be only displayed on the linear 
scale.
Summary tables will be provided for all PK parameters, with the exception of 
regression-related PK parameters. 
No inferential statistical analyses are planned.
8.6. Safety and Tolerability Assessments
8.6.1. Adverse Events
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA)
Version 22.1 (or higher if upversioned during the study).
A treatment-emergent adverse event (TEAE) will be defined as an AE that starts during or 
after the start of the infusion, or starts prior to the start of the infusion and increases in 
severity after the start of the infusion.
A treatment-related TEAE will be defined as a TEAE with a relationship of related to the 
study treatment, as determined by the investigator.
All AEs will be listed. In addition to the data recorded in the database, the listings will 
include derived onset time and duration. Onset time will be calculated from the time of the 
start of the infusion for TEAEs only.
The frequency of subjects with TEAEs and the number of TEAEs will be summarized for the 
following categories:
●
TEAEs (overall, serious, leading to discontinuation of study treatment, and leading to 
death)
●
TEAEs by severity
●
Treatment-related TEAEs (overall, serious, leading to discontinuation of study 
treatment, and leading to death) 
●
Treatment-related TEAEs by severity
The frequency of subjects will be summarized separately for TEAEs and treatment-related 
TEAEs by the following:
●
System organ class, and preferred term (PT)
●
PT


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For the AE data the following rules will apply:
●
For the derivation of TEAE status: If the start date/time of an AE is incomplete or 
missing, a AE will be assumed to be a TEAE, unless the incomplete start date/time or 
the end date/time indicates a AE started prior to the start of the infusion.
●
For the derivation of treatment-related TEAE status: If the study treatment
relationship for a TEAE is missing, a TEAE will be assumed to be a treatment-related 
TEAE.
●
For the derivation of onset time: If the start date/time of an AE is missing, onset time 
will not be calculated. If the start date/time of an AE is incomplete, where possible, 
the minimum possible onset time will be calculated and presented in ‘≥DD:HH:MM’ 
format (eg, if the date/time of the start of the infusion is 01MAY2019/08:00 and 
recorded start date/time of an AE is 03MAY2019, then the minimum possible onset 
time will be calculated by assuming the AE started at the first hour and minute of 
03MAY2019 [03MAY2019/00:00], thus will be presented as onset time ≥01:16:00 in
the listing).
●
For the derivation of duration: If the end date/time of an AE is missing, duration will 
not be calculated. If the start or end date/time of an AE is incomplete, where possible, 
the maximum possible duration will be calculated and presented in ‘≤DD:HH:MM’ 
format (eg, if the start of an AE date/time is 01MAY2019/08:00 and its recorded end 
date/time is 03MAY2019, then the maximum possible duration will be calculated by 
assuming the AE ended at the last hour and minute of 03MAY2019 
[03MAY2019/23:59], thus will be presented as duration ≤02:15:59 in the listing).
●
For the calculation of summary statistics: If the severity of a TEAE is missing, a 
TEAE will be counted under the maximum severity possible.
●
For the calculation of summary statistics: If a subject experienced multiple TEAEs 
with the same PT for the same treatment, this will be counted as 1 TEAE for that 
treatment under the maximum severity recorded.
8.6.2. Clinical Laboratory Parameters
All clinical laboratory parameters will be listed; any value outside the clinical reference range 
will be flagged. Separate listings will be provided for any parameter for which there is any 
individual subject value outside the respective clinical reference range.
Summary tables and boxplots by timepoint will be provided for serum chemistry and 
hematology parameters.
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags, calculation of summary statistics, and presentation in the figures,
<x and ≤x values will be set to 0, whereas >x and ≥x values will be set to x.


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8.6.3. Vital Signs Parameters
All vital signs parameters will be listed; any value outside the clinical reference range will be 
flagged.
Summary tables and boxplots by timepoint will be provided for all vital signs parameters.
8.6.4. Body Weight
The body weight will be listed.
A summary table by timepoint will be provided.
8.6.5. 12-lead Electrocardiogram Parameters
All 12-lead ECG parameters will be listed; any value outside the clinical reference range will 
be flagged.
Summary tables and boxplots by timepoint will be provided for all 12-lead ECG parameters
8.6.6. Other Assessments
All other safety and tolerability assessments not detailed in the above sections will be listed 
only.
Medical history will be listed.
8.6.7. Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
9. INTERIM ANALYSES
No interim analysis or adaptive design is applicable.
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES
There were no significant changes from the protocol-specified analyses.
11. REFERENCES
1. ICH. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9). 
5 February 1998.
2. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports 
(E3). 30 November 1995.


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12. APPENDICES
Appendix 1:
Document History
Version, Status
Date of Change
Summary/Reason for Changes
Version 1, Final
NA
NA; the first version
NA = not applicable