Clinical trial NCT04992442
Conditions: Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2020-07-09; Completion date: 2020-08-18
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine absolute bioavailability (ABA) of TAK-935 (F) following a single microdose intravenous (IV) administration of 50 microgram (μg) (approximately 1 microcurie \[μCi\]) \[14C\]TAK-935 and a single oral administration of 3×100 mg milligram (mg) TAK-935 tablets in Treatment Period 1, and to assess the mass balance, characterize the pharmacokinetics (PK) of TAK-935 and metabolite \[M-I (N-oxide)\] in plasma and urine, and total radioactivity concentration equivalents in plasma and whole blood following a single oral administration of 300 mg (approximately 100 μCi) \[14C\]TAK-935 in Treatment Period 2.

Detailed description:
The drug being tested in this study is called TAK-935 (also known as soticlestat/OV935). The study determines ABA in Treatment Period 1, and the absorption, metabolism, excretion, and mass balance of TAK-935 after single oral administration in Treatment Period 2 in healthy adult male participants, by collecting plasma, urine, and feces samples for drug concentration analysis, and plasma, whole blood, urine, and fecal samples for total radioactivity analysis and metabolic profiling.

The study will enroll approximately 6 healthy adult male participants. The study is designed to consist of 2 periods: Treatment Period 1 (ABA Study Period) and Treatment Period 2 (Absorption, Distribution, Metabolism, and Elimination \[ADME\] Study Period). In Treatment Period 1, all participants will receive a single unlabelled oral dose of TAK-935 as 3×100 mg tablets and a microdose IV infusion of 50 μg (approximately 1 μCi) \[14C\]TAK-935, followed by a Washout Period of 7 days before the dose in Treatment Period 2. In Treatment Period 2, all participants will receive a single dose of 300 mg (approximately 100 μCi) \[14C\]TAK-935 as an oral solution.

This single center trial will be conducted in the United States. The overall time to participate in this study is approximately 65 days including Screening Period. Participants will be contacted approximately 30 days after the last dose of study drug for a follow-up assessment. This compound was transferred to Takeda and acquired on 29 March 2021. This registration is retrospective due to the transfer of ownership.

Arms: arm 1: TAK-935 3×100 mg, tablets, orally, once on Day 1, followed by \[14C\]TAK-935 50 micrograms (μg) \[approximately 1 μCi\], IV infusion, once on Day 1 of Treatment Period 1, followed by a Washout Period of 7 days, further followed by \[14C\]TAK-935 300 mg (approximately 100 μCi) solution, orally, once on Day 1 of Treatment Period 2.
Interventions: intervention 1: TAK-935 Oral Tablet intervention 2: [14C]TAK-935 IV Infusion intervention 3: [14C]TAK-935 Oral Solution
Intervention descriptions: intervention 1: TAK-935 tablet intervention 2: \[14C\]TAK-935 IV infusion intervention 3: \[14C\]TAK-935 oral solution

Protocol documents:
Prot_000.pdf: 



Title: A Phase 1 Study to Assess Absolute Bioavailability of TAK-935 (OV935) and to 
Characterize Mass Balance, Pharmacokinetics, Metabolism, and Excretion of [14C]TAK-935 
(OV935) in Healthy Adult Male Participants 
NCT Number: NCT04992442
Protocol Approve Date: 04 June 2020
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


Protocol TAK-935-20-001 (OV935) 
04 June 2020 
Page 1 of 78 
PROTOCOL TAK-935-20-001 (OV935) 
A Phase 1 Study to Assess Absolute Bioavailability of TAK-935 (OV935) and to Characterize 
Mass Balance, Pharmacokinetics, Metabolism, and Excretion of [14C]TAK-935 (OV935) in 
Healthy Adult Male Participants 
Sponsor: 
Sponsor Contact: 
Medical Monitor: 
IND Number: 
121,234
Date of Final Protocol: 
04 June 2020
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
cterize
erize
V935)
935) in
alal Proto
Pro
Commercial Use Only and Subject 
Property of Ta


Protocol TAK-935-20-001 (OV935) 
04 June 2020 
Page 2 of 78 
SPONSOR SIGNATURE PAGE 
PROTOCOL TITLE: A Phase 1 Study to Assess Absolute Bioavailability of TAK-935 (OV935) and 
to Characterize Mass Balance, Pharmacokinetics, Metabolism, and Excretion of [14C]TAK-935 
(OV935) in Healthy Adult Male Participants
PROTOCOL NUMBER: TAK-935-20-001 (OV935) 
Date 
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
AK-935
935 (
retion o
etion o
No
Commercial Use Only 


 
Protocol TAK-935-20-001 (OV935)  
 
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Page 3 of 78 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure (IB) (IB, Ed.5) for TAK-935-20-001 (OV935). 
I have read the TAK-935-20-001 (OV935) study protocol and agree to conduct the study in 
accordance with this protocol, all applicable government regulations, the principles of the 
International Council for Harmonisation (ICH) E6 Guidelines for Good Clinical Practice (GCP), 
and the principles of the World Medical Association Declaration of Helsinki. I also agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol.  
I will permit study related monitoring, audits, institutional review board (IRB)/independent 
ethics committee (IEC ) review and regulatory inspection, providing direct access to source 
data/documents. 
 
Signature of Investigator
Date 
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
1 (OV93
(OV9
study in
study
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Protocol TAK-935-20-001 (OV935)  
 
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PROCEDURES IN CASE OF EMERGENCY 
Emergency Contact Information 
Study Role 
Name 
Address and Telephone Number 
Clinical Project Leader 
Clinical Project Leader 
Medical Monitor 
Drug Safety Physician 
24-Hour Emergency 
Contact 
Clinical Operations Leader 
Key Study Participants 
Study Role 
Name 
Address and Telephone Number 
Clinical Project Leader 
Clinical Project Leader 
Medical Monitor 
Drug Safety Physician 
Statistician 
Certified Clinical 
Laboratory 
Total Radioactivity 
Determination 
PPD
PPD
Property of Takeda: For Non-Co
Co
sician
sician
No
Fo
ed
ed Clin
Clin
boratory
orato
ed
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perty of Takeda: For Non-Commercial Use Only
nly
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able Terms of Use
one Num
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Commercia


 
Protocol TAK-935-20-001 (OV935)  
 
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1. 
SYNOPSIS 
 
Name of Sponsor/Company: 
Ovid Therapeutics Inc. 
Name of Investigational Product: TAK-935 (soticlestat [OV935])  
Name of Active Ingredient: Soticlestat TAK-935 (OV935) 
Title of Study: A Phase 1 Study to Assess Absolute Bioavailability of TAK-935 (OV935) and to 
Characterize Mass Balance, Pharmacokinetics, Metabolism, and Excretion of [14C]TAK-935 
(OV935) in Healthy Adult Male Participants  
Study Center(s): Single site in the USA 
Length of Study: Approximately 65 days from the start 
of Screening Period until Follow-up 
Estimated date first participant enrolled:  07/2020 
Estimated date last participant completed: 10/2020 
Phase of Development:  
Phase 1 
Planned Duration of Treatment: Approximately 65 days including the Screening Period. 
Screening period: 28 days 
Treatment Period 1: at least 6 days (up to 8 days) 
Washout period: at least 7 days (from last dosing in Period 1 to dosing in Period 2)  
Treatment Period 2: at least 6 days (up to 11 days) 
Follow-up period: 30 days (from dosing in Period 2) 
Objectives and Endpoints: 
Study Primary Objectives: 
Period 1 (Absolute Bioavailability [ABA]) 
 To determine ABA of TAK-935 following a single microdose intravenous (IV) 
administration of 50 µg (approximately [~] 1 microcurie [µCi]) [14C]TAK-935 and a single 
oral administration of 300 mg TAK-935. 
Period 2 (absorption, distribution, metabolism, and elimination [ADME]) 
 To assess the mass balance (ie, cumulative excretion of total radioactivity in urine and 
feces) following a single oral administration of 300 mg (~100 µCi) [14C]TAK-935. 
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 To characterize the pharmacokinetics (PK) of TAK-935 and its metabolite (M-I) in plasma 
and urine, and total radioactivity concentration equivalents in plasma and whole blood 
following a single oral administration of 300 mg (~100 µCi) [14C]TAK-935. 
Study Secondary Objectives: 
Period 1 (ABA): 
 To determine the PK of [14C]TAK-935 following a single IV administration of 50 µg 
(~1 µCi) [14C]TAK935 and the PK of TAK-935 and M-I following a single oral 
administration of 300 mg TAK-935. 
 To determine fecal and urinary excretion of the parent [14C]TAK-935 following a single IV 
administration of 50 µg (1 µCi) [14C]TAK-935. 
Period 2 (ADME): 
 To assess the metabolic profile of TAK-935 in plasma, urine, and feces following a single 
oral administration of 300 mg (~100 µCi) [14C]TAK-935. 
Periods 1 (ABA) and 2 (ADME): 
 To assess the safety of TAK-935 during the ABA and ADME study periods. 
Study Primary Endpoints 
Period 1 (ABA): 
 Absolute bioavailability (F) as percent F (%F) for TAK-935. 
Period 2 (ADME): 
 Percent of total radioactivity excreted in urine (Cum%Dose[u]) and feces 
(Cum%Dose[f]) relative to the administered radioactive dose (Combined 
Cum%Dose). 
 Amount of total radioactive excreted in urine (Ae[u]) and feces (Ae[f]) and the 
percent of administered radioactive dose excreted in urine and feces within a given 
collection interval urine (%Dose[u]) and feces (%Dose[f]). 
 PK parameters Cmax, tmax, t1/2z, AUC∞, AUCt, and AUClast for TAK-935 in plasma. 
 PK parameters Cmax, tmax, t1/2z, AUC∞, AUCt, and AUClast for total radioactivity 
concentration equivalents in plasma and whole blood. 
 PK parameters for renal clearance (CLR) for TAK-935 in urine. 
 PK parameters for amount excreted in each collection interval (Aet1-t2) for TAK-935 in 
urine. 
 The change over time in percentage of [14C] radioactivity in whole blood relative to 
plasma (ie, whole blood:plasma partitioning ratio). 
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Study Secondary Endpoints  
Period 1 (ABA): 
 PK parameters Ceoi (IV infusion), Cmax (oral), tmax (oral), AUC∞, AUCt, AUClast, and t1/2z 
for TAK-935, and [14C]TAK-935 in plasma. 
 Total radioactivity excreted and percentage of dose excreted in the feces (Ae[f] and 
%Dose[f]) and urine (Ae[u] and %Dose[u]) as total radioactivity following IV dosing. 
Period 2 (ADME): 
 Metabolic profile of TAK-935 in plasma, urine, and feces following a single oral 
administration of 300 mg (~100 µCi) [14C]TAK-935. 
Periods 1 (ABA) and 2 (ADME): 
 
Tabulated treatment-emergent adverse events (TEAEs) and summary statistics for 
clinically relevant 12-lead electrocardiograms (ECGs), vital signs, and clinical 
laboratory test results. 
Study Design and Methodology:  
This is an open-label, 2-period, fixed-sequence, single-dose study in 6 healthy adult male 
participants. 
On Day 1 of Period 1 (ABA Study Period), participants will receive a single unlabeled oral 
300 mg dose of TAK-935 in tablet form (three 100 mg tablets). At 0.17 hours (10 minutes) 
post oral dosing (ie, 15 minutes prior to the median tmax for the oral unlabeled dose 
[~ 0.42 hours or 25 minutes]), participants will receive a 15-minute IV infusion of a 
microdose of 50 µg (approximately equivalent to ~1 µCi) [14C]TAK-935. Serial blood sampling 
will be performed up to 48 hours (Day 3) to determine the PK of TAK-935 and M-I 
metabolite (and others, if applicable) in plasma for the oral dose and [14C]-total radioactivity 
and PK of [14C]TAK-935 in the plasma for the IV dose. Urine and fecal output will also be 
collected up to 120 hours post dose to determine [14C]-total radioactivity. Collection of 
urine and fecal samples will continue until one of the release criteria (participants remain in 
the clinical research unit [CRU]) is met (ie, 80% or greater of the total dose of radioactivity 
administered is recovered in urine and fecal samples or the excretion of radioactivity in the 
urine and feces combined has declined to ≤1% of the total administered radioactivity for at 
least 2 consecutive intervals where both a urine and fecal sample are collected) or up to 
Day 8, but no less than Day 6, for [14C]-total radioactivity excretion in urine and feces. 
Participants who meet release criteria before Day 8 will remain confined in the CRU until 
Day -1 of Period 2 and throughout Period 2 (until Period 2 discharge criteria are met). 
There will be a washout period of at least 7 days between the last dose in Period 1 and the 
dose in Period 2. 
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On Day 1 of Period 2 (ADME Study Period), participants will receive a single oral dose of 
300 mg (~100 μCi) [14C]TAK-935 in solution. Serial blood sampling will be performed and 
urine and feces will be collected to determine the PK of TAK-935 and M-I metabolite (and 
others, if applicable) in plasma and urine, and total radioactivity in plasma, whole blood, 
urine, and feces, and to characterize the metabolite profiles of TAK--935 in plasma, urine, 
and feces. Complete urinary and fecal output will be collected during the confinement 
period until discharge criteria are met (anticipated to be 10 days post dose or less). 
In Period 2, participants will be confined to the CRU for at least 5 days post dose (ie, 
120 hours) and until 90% or greater of the total dose of radioactivity administered is 
recovered in urine and fecal samples. If less than 90% of the total dose of radioactivity 
administered is recovered in urine and fecal samples the participant will continue to stay at 
the CRU until a discharge criterion is met (ie, 90% or greater of the total dose of 
radioactivity administered is recovered in urine and fecal samples or the excretion of 
radioactivity in the urine and feces combined has declined to ≤1% of the total administered 
radioactivity per 24 hour interval for at least 2 consecutive intervals where both a urine and 
fecal sample are collected) or up to Day 11 (ie, 240 hours).  
Since up to an approximate 24-hour time lag is anticipated for radioactivity counting of 
samples, actual participant release from the CRU may occur 1 day after discharge criteria 
are met. 
In both periods, any participant who experiences emesis within 1 hour post oral dosing will 
be excluded in the PK data analysis and may be replaced with a new participant. For a 
participant who drops out in Period 2, the replacement participant will be required to 
complete Period 2 only. If a participant experiences emesis after dosing in Period 2, vomitus 
will be collected throughout the study and assayed for total radioactivity. 
The clinic will contact all participants (including participants who terminate the study early) 
30 ± 2 days after the last study drug administration to determine if any adverse events (AEs) 
have occurred since the last study visit. 
Main Criteria for Inclusion: 
In order to be eligible for study participation, participants must: 
1. Healthy adult male, ≥19 and ≤55 years of age at the time of the first dose of study drug. 
2. Weighs at least 50 kg and body mass index (BMI) ≥18.0 and ˂32.0 kg/m2 at screening. 
3. Continuous nonsmoker who has not used nicotine -containing products (including 
vaping) for at least 3 months prior to the first dosing and throughout the study, based 
on participant self -reporting. 
4. Medically healthy with no clinically significant medical history, physical examination, 
laboratory profiles, vital signs or ECGs, as deemed by the Investigator or designee. 
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Main Criteria for Exclusion: 
The participant must be excluded from participating in the study if the participant:  
1. Is mentally or legally incapacitated or has significant emotional problems at the time of 
the Screening visit or expected during the conduct of the study. 
2. History or presence of clinically significant medical or psychiatric condition or disease in 
the opinion of the Investigator or designee. 
3. History or presence of cataracts or other clinically significant vision disturbances. 
4. Abnormal clinical laboratory test results at the Screening visit that suggest a clinically 
significant underlying disease that would compromise the well-being of the participant 
(if the participant has alanine aminotransferase [ALT] and/or aspartate 
aminotransferase [AST] >2.5 × the upper limit of normal [ULN], the Medical Monitor 
should be consulted)  
5. Abnormal and clinically significant ECG abnormality at Screening visit: 
a. QT interval with Fridericia’s correction method (QTcF) >450 ms confirmed 
with one repeat testing. 
6. History or presence of gastritis, gastrointestinal tract, gastric bypass surgery, or hepatic 
disorder or other clinical condition which, in the opinion of the Investigator or designee, 
may affect the absorption, distribution, metabolism, or elimination of study drug. 
7. History of any illness that, in the opinion of the Investigator or designee, might confound 
the results of the study or poses an additional risk to the participant by their 
participation in the study. 
8. History or presence of alcohol or drug abuse within the past 2 years prior to Screening 
visit. 
9. History or presence of hypersensitivity or idiosyncratic reaction to the study drug or 
related compounds. 
10. Has a risk of suicide according to the Investigator’s clinical judgment (eg, per 
Columbia -Suicide Severity Rating Scale [C-SSRS]), or has made a suicide attempt in the 
previous year prior to Screening visit. 
11. Has infrequent bowel movements (less than approximately once per day) within 30 days 
prior to first dosing. 
12. Recent history of abnormal bowel movements, such as diarrhea, loose stools, or 
constipation, within 2 weeks prior to first dosing. 
13. Has received radiolabeled substances or has been exposed to radiation sources within 
12 months of first dosing or is likely to receive radiation exposure or radioisotopes 
within 12 months of first dosing such that participation in this study would increase their 
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total exposure beyond the recommended levels considered safe (ie, weighted annual 
limit recommended by the International Commission of Radiological Protection [ICRP] of 
3000 mrem). 
14. Unable to refrain from or anticipates the use of: 
 Any drug, including prescription and nonprescription medications, herbal remedies, 
or vitamin supplements within 14 days prior to the first dosing and throughout the 
study, including the follow-up period. Thyroid hormone replacement medication 
may be permitted if the participant has been on the same stable dose for the 
immediate 3 months prior to first study drug administration. After the first dose of 
study drug, ibuprofen (up to 1.2 g per 24 hours) may be administered at the 
discretion of the Investigator or designee. Milk of Magnesia (ie, magnesium 
hydroxide) (≤60 mL per day) may be administered to ensure defecation, at 
discretion of the Investigator or designee. 
 Any drugs known to be significant inducers of Cytochrome P450 (CYP) 3A4, 
CYP2C19, or uridine diphosphate glucuronosyltransferase (UGT), including St. John’s 
Wort, within 28 days prior to the first dosing and throughout the study, including 
the follow-up period. Appropriate sources (eg, Flockhart Table™) will be consulted 
to confirm lack of PK/pharmacodynamic interaction with study drug. 
 Alcohol, as defined in Table 3 . 
Investigational Product, Dosage, and Mode of Administration:  
TAK-935 in Period 1 will be provided as 100 mg tablets; 
[14C]TAK-935 in Period 1 will be provided as an IV solution  
[14C]TAK-935 in Period 2 will be provided as an oral solution  
Treatments in each period are described as follows:  
Period 1:  
300 mg TAK-935 (3 x 100mg tablets) administered orally at Hour 0 on Day 1 
followed by 50 µg (~1 μCi) [14C]TAK-935 IV solution administered at Hour 0.17 
(10 minutes post oral dosing) for 15 minutes. 
Period 2:  
300 mg (~100 μCi) [14C]TAK-935  administered as an oral solution at Hour 0 on 
Day 1 of Period 2. 
Reference Therapy, Dosage, and Mode of Administration:  
Not Applicable 
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Statistical methods:  
PK Analysis: 
Descriptive statistics will be provided for the total radioactivity (whole blood, plasma, urine, 
feces, and if applicable, emesis), plasma and urine TAK-935 concentrations and PK 
parameters, and [14C]TAK935 plasma, urine, and feces radioactivity concentration 
equivalent, using appropriate summary statistics to be fully specified in the statistical 
analysis plan (SAP). 
ABA of TAK-935 will be estimated using a ninety percent (90%) confidence interval (CI) 
constructed for the difference in least squares mean (LSM) on the log scale for dose 
normalized AUC∞ between a single oral dose and the IV microdose. Exponentiating the log-
scale 90% CI will provide a 90% CI for the dose-normalized AUC∞ geometric mean ratio 
(TAK-935 administered as oral dose / [14C]TAK-935 administered as IV microdose). AUClast 
will be analyzed in a similar fashion if AUC∞ cannot be calculated. 
Mass balance will be calculated as a sum of the percent of the total radioactivity recovered 
in urine and feces plus any radioactivity dose due to emesis (if any occurred) relative to the 
administered radioactivity dose. 
Safety: 
Safety will be monitored through AEs, 12-lead ECGs, vital sign measurements, C-SSRS, 
clinical laboratory tests, and physical examinations. AEs will be tabulated and summary 
statistics for the 12-lead ECGs, vital signs, and clinical laboratory tests may be computed and 
provided, as deemed clinically appropriate. 
Sample Size Justification:  The sample size of 6 healthy adult male participants was selected 
without statistical considerations and is deemed adequate to meet the study objectives. In 
addition, this sample size is limited based on clinical considerations for this type of study 
and in order to limit exposure to radioactivity. 
Interim Analysis: Not Applicable 
 
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Protocol TAK-935-20-001 (OV935) 
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2.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES
TABLE OF CONTENTS 
PROTOCOL TAK-935-20-001 (OV935) ........................................................................................1 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
1. 
SYNOPSIS ...................................................................................................................5 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............12 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................17 
4. 
INTRODUCTION ......................................................................................................21 
4.1. 
Background .................................................................................................................21 
4.1.1. 
Nonclinical Metabolism ..............................................................................................21 
4.1.2. 
Clinical Pharmacokinetics ..........................................................................................22 
4.1.3. 
Clinical Safety ............................................................................................................23 
4.2. 
Rationale for the Proposed Study ...............................................................................24 
4.3. 
Benefit/Risk Profile ....................................................................................................24 
5. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................26 
5.1. 
Hypothesis ..................................................................................................................26 
5.2. 
Study Objectives and Endpoints .................................................................................26 
6. 
INVESTIGATIONAL PLAN .....................................................................................29 
6.1. 
Summary of Study Design ..........................................................................................29 
6.1.1 
Confinement ...............................................................................................................32 
6.2. 
Discussion of Design and Control ..............................................................................33 
7. 
STUDY POPULATION .............................................................................................34 
7.1. 
Inclusion Criteria ........................................................................................................34 
7.2. 
Exclusion Criteria .......................................................................................................35 
7.3. 
Excluded Medications, Supplements, Dietary Products .............................................37 
7.4. 
Diet, Fluid, Activity ....................................................................................................39 
7.4.1. 
Diet and Fluid .............................................................................................................39 
7.4.2. 
Activity .......................................................................................................................39 
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7.5. 
Discontinuations .........................................................................................................39 
7.5.1. 
Discontinuation of Participants ...................................................................................39 
7.5.2. 
Criteria for Discontinuation or Withdrawal of a Participant ......................................40 
7.5.3. 
Discontinuation of Study Sites/Site Terminated by Sponsor .....................................41 
7.5.4. 
Discontinuation of the Study/Study Terminated by Sponsor .....................................41 
8. 
TREATMENT ............................................................................................................42 
8.1. 
Materials and Supplies ................................................................................................42 
8.1.1. 
Clinical Study Drug TAK-935 Tablet ........................................................................42 
8.1.2. 
[14C]TAK-935 IV Sterile Solution ..............................................................................42 
8.1.3. 
[14C]TAK-935 Oral Solution ......................................................................................42 
8.1.4. 
Clinical Study Drug Labeling .....................................................................................42 
8.2. 
Clinical Study Drug Inventory and Storage ................................................................42 
8.3. 
Treatments Administered ............................................................................................42 
8.4. 
Method of Assignment to Treatment ..........................................................................43 
8.5. 
Rationale for Selection of Doses in the Study ............................................................44 
8.6. 
Blinding ......................................................................................................................44 
8.7. 
Treatment Compliance ................................................................................................44 
9. 
STUDY ASSESSMENTS ..........................................................................................46 
9.1. 
Safety Assessments .....................................................................................................46 
9.1.1. 
Physical Examination .................................................................................................46 
9.1.2. 
Neurological Examination Procedure .........................................................................46 
9.1.3. 
Height and Weight ......................................................................................................47 
9.1.4. 
BMI .............................................................................................................................47 
9.1.5. 
Vital Signs ..................................................................................................................47 
9.1.6. 
Serum Chemistry, Hematology, and Urinalysis .........................................................47 
9.1.7. 
12-Lead ECG ..............................................................................................................48 
9.1.8. 
Columbia-Suicide Severity Rating Scale (CSSRS) ....................................................49 
9.2. 
Safety Evaluations ......................................................................................................49 
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9.2.1. 
Adverse Events ...........................................................................................................49 
9.2.1.1. 
Severity Assessment ...................................................................................................50 
9.2.1.2. 
Causality Assessment .................................................................................................50 
9.2.1.3. 
Serious Adverse Events ..............................................................................................51 
9.2.1.4. 
Suspected Unexpected Serious Adverse Reactions ....................................................52 
9.2.1.5. 
Reporting Adverse Events ..........................................................................................52 
9.2.1.6. 
Sponsor Reporting Requirements ...............................................................................53 
9.2.1.7. 
Investigator Reporting Requirements .........................................................................53 
9.2.2. 
Exposure During Pregnancy and/or Lactation ............................................................53 
9.2.3. 
Safety Monitoring .......................................................................................................54 
9.2.3.1. 
Reporting of Abnormal Liver Function Tests ............................................................54 
9.2.3.2. 
Reporting of QTcF interval increase ..........................................................................54 
9.3. 
Sample Collection and Testing ...................................................................................55 
9.3.1. 
Blood Sampling and Processing .................................................................................55 
9.3.2. 
PK Measurements .......................................................................................................56 
9.3.2.1. 
Whole Blood and Plasma for PK Measurements .......................................................56 
9.3.3. 
Urine for PK Measurements .......................................................................................57 
9.3.4. 
Feces for PK Measurements .......................................................................................58 
9.3.5. 
Additional PK Measurements .....................................................................................58 
9.3.6. 
Biomarker Measurements ...........................................................................................58 
9.4. 
Data Collection and Storage .......................................................................................58 
10. 
STATISTICAL METHODS AND PLANNED ANALYSES ...................................60 
10.1. 
General Considerations ...............................................................................................60 
10.2. 
Determination of Sample Size ....................................................................................60 
10.3. 
Analysis Sets ...............................................................................................................60 
10.3.1. 
Pharmacokinetic Set ...................................................................................................60 
10.3.2. 
Safety Set ....................................................................................................................60 
10.4. 
Demographics and Other Baseline Characteristics .....................................................60 
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10.5. 
Participant Disposition ................................................................................................60 
10.6. 
Pharmacokinetic Analysis ..........................................................................................61 
10.6.1. 
Analysis of Mass Balance ...........................................................................................61 
10.6.2. 
Whole Blood to Plasma Partitioning Ratio .................................................................61 
10.6.3. 
Metabolite Profiling ....................................................................................................61 
10.7. 
PD Analysis ................................................................................................................61 
10.8. 
Safety Analysis ...........................................................................................................61 
10.8.1. 
Adverse Events ...........................................................................................................62 
10.8.2. 
Clinical Laboratory Evaluation ...................................................................................62 
10.8.3. 
Vital Signs ..................................................................................................................62 
10.8.4. 
Other Safety Parameters .............................................................................................62 
10.9. 
Interim Analysis and Criteria for Early Termination .................................................62 
10.10. 
Other Statistical Issues ................................................................................................62 
10.10.1. 
Missing or Invalid Data ..............................................................................................63 
10.10.2. 
Interim Analyses .........................................................................................................63 
11. 
INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS ..................................................................................................64 
11.1. 
Informed Consent .......................................................................................................64 
11.1.1. 
Informed Consent Procedure ......................................................................................64 
11.2. 
Administrative Procedures ..........................................................................................65 
11.3. 
Ethical Review ............................................................................................................65 
11.4. 
Regulatory Considerations ..........................................................................................66 
11.5. 
Confidentiality ............................................................................................................66 
11.5.1. 
Investigator Information .............................................................................................66 
11.5.2. 
Protocol Signatures .....................................................................................................66 
11.5.3. 
Final Report Signature ................................................................................................67 
11.6. 
Publication Policy .......................................................................................................67 
12. 
LIST OF REFERENCES ............................................................................................68 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ....................................................................69 
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APPENDIX 2. CLINICAL LABORATORY TESTS (STUDY TAK-935-20-001 
[OV935]): ...................................................................................................................72 
APPENDIX 3. SAMPLE COLLECTION SCHEDULE ............................................................74 
APPENDIX 4. SAMPLING SUMMARY (STUDY TAK-935-20-001 [OV935]): ...................78 
 
List of Tables 
Table 1:  
Objectives and Endpoints ...........................................................................................26 
Table 2: 
Planned Dose Levels of TAK-935 and [14C]TAK-935 .............................................30 
Table 3:  
Excluded Medications, Supplements, and Dietary Products ......................................38 
Table 4:  
Primary Specimen Collections ...................................................................................55 
Table 5:  
Blood Collection Schedule (Period 1-ABA Study Period) .........................................74 
Table 6:  
Urine and Fecal Sampling Schedule (Period 1 – ABA Study Period) .......................75 
Table 7:  
Blood Collection Schedule (Period 2 - ADME Study Period) ...................................76 
Table 8:  
Urine and Fecal Sampling Schedule (Period 2 - ADME Study Period) .....................77 
Table 9:  
Protocol TAK-935-20-001 (OV935):Blood Sampling Summary ..............................78 
 
List of Figures 
Figure 1: 
Illustration of Study Design for Clinical Protocol TAK-935-20-001 (OV935) .........31 
 
  
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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation  
Definition 
24HC 
24S-hydroxycholesterol 
~ 
Approximately  
% 
Percent 
%Dose(f) 
Percent of administered radioactive dose excreted in feces within a given 
collection interval 
%Dose(u) 
Percent of administered radioactive dose excreted in urine within a given 
collection interval  
%F 
Percent absolute oral bioavailability 
[14C] 
Carbon-14; radiocarbon 
ABA 
Absolute bioavailability 
ADME  
Absorption, distribution, metabolism, and elimination 
AE 
Adverse event 
Aet1-t2 
Amount of drug excreted in the urine from time 1 to time 2 
Ae(f) 
Amount of total radioactivity excreted in feces within a given collection interval 
Ae(u) 
Amount of total radioactivity excreted in urine within a given collection interval 
AGP 
α-1-acid glycoprotein 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC  
Area under the concentration-time curve  
AUCextrap% 
Area under the curve from the last quantifiable concentration to infinity 
calculate dosing the observed value of the last quantifiable concentration, 
expressed as a percentage of AUC∞ 
AUClast 
Area under the concentration-time curve from time 0 to time of the last 
quantifiable concentration 
AUCt 
Area under the concentration-time curve from time 0 to time t 
AUC∞ 
Area under the concentration-time curve from time 0 to infinity 
BCRP 
Breast cancer resistance protein 
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Abbreviation  
Definition 
BMI 
Body mass index 
Bpm 
Beats per minute 
C-SSRS 
Columbia-suicide severity rating scale 
Ceoi 
Concentration at end of infusion 
CH24H 
Cholesterol 24S hydroxylase 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CLR 
Renal clearance 
cm 
Centimeter 
Cmax 
Maximum observed concentration 
CRF 
Case report form 
CRU 
Clinical research unit 
COVID-19 
Novel coronavirus 2019 
Cum%dose 
Combined cumulative percent of administered radioactive dose recovered in 
feces and urine 
Cum%dose(f) 
Cumulative percent of administered radioactive dose recovered in feces 
Cum%dose(u) 
Cumulative percent of administered radioactive dose recovered in urine 
CYP 
Cytochrome P450 
ECG 
Electrocardiogram 
F 
Bioavailability 
FDA 
Food and Drug Administration 
G 
Gram 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus  
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Abbreviation  
Definition 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
50% inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICRP 
International Commission on Radiological Protection 
ID 
Identification number 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
kg 
Kilogram 
λz 
Terminal disposition phase rate constant 
LFT 
Liver Function Test 
LSM 
Least-squares mean 
μCi 
Microcurie 
μg 
Microgram 
μmol 
Micromolar 
m2 
Meters squared 
MBq 
Megabecquerel 
MedDRA® 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
min 
Minute 
mL 
Milliliter 
mmHg 
Millimeter of mercury 
mrem 
Millirem 
msec 
Millisecond 
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Abbreviation  
Definition 
mSv 
Millisievert 
oz 
Ounce 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic(s) 
QD 
Once daily 
QTcF 
QT interval with Fridericia’s correction method 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SUSARs 
Suspected unexpected serious adverse reactions 
t1/2z 
Terminal disposition phase half-life 
TEAE 
Treatment-emergent adverse event 
tmax 
Time of first occurrence of Cmax 
UGT 
Uridine diphosphate glucuronosyltransferase 
ULN 
Upper limit of normal 
US 
United States 
USA 
United States of America 
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4.
INTRODUCTION 
4.1.
Background 
TAK-935 is a potent and selective cholesterol 24S hydroxylase (CH24H) inhibitor currently in 
development for adjunct treatment of developmental and epileptic encephalopathies (DEEs). 
In the brain, cholesterol is metabolized by CH24H, which is specifically and constitutively 
expressed in neurons, to 24S-hydroxycholesterol (24HC). This cholesterol metabolite, 24HC, 
leaves the brain via lipoproteins and is excreted in bile. Aberrant cholesterol metabolism is 
implicated in epilepsy disorders and syndromes. 
TAK-935 is a first-in-class therapeutic candidate that has the potential to control seizures in 
treatment-resistant participants with epilepsy by reducing over-activated glutamate signaling. 
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4.1.2.
Clinical Pharmacokinetics 
The PK, safety, and tolerability of TAK-935 have been evaluated in 4 Phase 1 clinical studies in 
healthy participants and 1 Phase 1b/2a study in participants with DEE. 
TAK-935 was rapidly absorbed following both single-dose (15 to 1350 mg) and multiple-dose 
(100 to 600 mg) oral administration as a solution or tablet formulation under fasted conditions 
in healthy participants. TAK-935 plasma concentration reached maximal levels within median 
0.25 to 0.52 hours following single doses. Following multiple doses (10 or 14 days) of TAK-935 
100 mg once daily (QD), 300 mg QD, 300 mg twice daily (BID), 400 mg QD and 600 mg QD 
(without up-titration) as solution under fasted condition, TAK-935 had rapid absorption with 
median tmax of 0.33 to 0.5 hours. Mean TAK-935 t½z was similar between Day 1 and Day 14, 
ranging from 3.49 to 4.83 hours. Over the 4-fold dose range of 100 to 400 mg QD after 
multiple-dose administration, mean TAK-935 Cmax and AUCʏ on Day 14 increased by 6.08 and 
6.12 folds, respectively. Doses of 100 or 400 mg QD for 14 days did not show apparent 
exposure accumulation on Day 14 when compared with Day 1, while 300 mg QD for 14 days 
showed about 1.74- and 1.42-fold increase of Cmax and AUCʏ on Day 14, respectively. 
Approximately 0.08% to 0.25% of the administered TAK-935 dose was excreted in urine across 
all dose groups following a single- and multiple-oral doses. M-I metabolite showed median tmax 
values ranged from 0.5 to 1.0 hours and mean t½z values ranged from 2.32 to 3.88 hours. The 
exposure of M-I was comparable between Day 1 and Day 14 following 100, 300, and 400 mg QD 
of TAK-935 for 14 days, with MR decreased with increasing dose, ranging from 0.44 to 0.26 on 
Day 14.
The effect of food on the PK of TAK-935 was investigated. Food decreased TAK-935 Cmax by 60%, 
but had little impact on the total TAK-935 exposure of the tablet formulation as AUClast and 
AUCьdecreased by only 11%. After single oral dose of TAK-935 15 to 1350 mg or multiple oral 
dose of TAK-935 100 to 600 mg, a generally dose-dependent decrease in plasma 24HC 
concentrations was observed, with more profound decreases at higher doses. In the 
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multiple-dose study, plasma 24HC inhibition appeared to approach steady state on Day 7, with 
time-matched percent change in 24HC AUEC24 ranging from 46.82% to 62.66% on Day 14 across 
the doses of 100 to 400 mg QD. 
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4.2.
Rationale for the Proposed Study 
The PK, metabolic pathways, and routes of elimination of TAK-935 have been evaluated in vitro 
and in vivo in preclinical species, being summarized in the IB (IB Ed 5). Further, PK of non-
radiolabeled TAK-935 have been evaluated in humans in multiple studies (summarized in the 
IB Ed 5). 
The primary purposes of the present study are to characterize the ABA (Period 1) and the 
absorption, metabolism, excretion, and mass balance of TAK-935 after single oral 
administration (Period 2) in healthy adult male participants by collecting plasma, urine, and 
feces samples for drug concentration analysis (via radioisotopic quantitation), and plasma, 
whole blood, urine, and fecal samples for total radioactivity analysis and metabolic profiling, as 
appropriate. The study will provide data required to evaluate the mass balance and the 
metabolic profile of TAK-935 in humans. Based on preclinical radioisotopic analysis, most of the 
radioactivity from a [14C]TAK-935 dose was eliminated within 72 hours post dose in rats and 
120 hours post dose in dogs; thus, more than 90% of the radioactivity in humans should be 
eliminated within 120 hours post dose. 
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5. 
STUDY OBJECTIVES AND ENDPOINTS 
5.1. 
Hypothesis 
Not Applicable. 
5.2. 
Study Objectives and Endpoints 
Study objectives and associated endpoints are presented in Table 1. The frequency and timing 
of study measurements is provided in the Schedule of Assessments (Appendix 1). Information 
regarding sample collection and safety data collection are presented in Section 9. 
Table 1:  
Objectives and Endpoints 
 
Objective 
Endpoint 
Primary 
Period 1 (ABA) 
 To determine ABA of TAK-935 
following a single microdose IV 
administration of 50 µg (~1 µCi) 
[14C]TAK-935 and a single oral 
administration of 300 mg TAK-935. 
Period 1 (ABA): 
 Absolute bioavailability (F) as 
percent F (%F) for TAK-935. 
Period 2 (ADME) 
 To assess the mass balance 
(ie, cumulative excretion of total 
radioactivity in urine and feces) following 
a single oral administration of 300 mg 
(~100 µCi) [14C]TAK-935. 
 To characterize the PK of TAK-935 and 
M-I in plasma and urine, and total 
radioactivity concentration equivalents in 
plasma and whole blood following a 
single oral administration of 
300 mg (~100 µCi) [14C]TAK-935. 
Period 2 (ADME): 
 Percent of total radioactivity 
excreted in urine (Cum%Dose[u]) and 
feces (Cum%Dose[f]) relative to the 
administered radioactive dose 
(Combined Cum%Dose). 
 Amount of total radioactive 
excreted in urine (Ae[u]) and feces 
(Ae[f]) and the percent of 
administered radioactive dose 
excreted in urine and feces within a 
given collection interval (urine 
%Dose[u]) and feces (%Dose[f]). 
 PK parameters Cmax, tmax, t1/2z, 
AUC∞, AUCt, and AUClast for TAK-935 in 
plasma. 
 PK parameters Cmax, tmax, t1/2z, 
AUC∞, AUCt, and AUClast for total 
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radioactivity concentration 
equivalents in plasma and whole 
blood. 
 PK parameters for renal clearance 
(CLR) for TAK-935 in urine. 
 PK parameters for amount 
excreted in each collection interval 
(Aet1-t2) for TAK-935 in urine. 
 The change over time in 
percentage of [14C]radioactivity in 
whole blood relative to plasma 
(ie, whole blood:plasma partitioning 
ratio). 
 The change over time in 
percentage of [14C]radioactivity in 
whole blood relative to plasma 
(ie, whole blood:plasma partitioning 
ratio). 
Secondary 
Periods 1 (ABA) 
 To determine the PK of [14C]TAK-935 
following a single IV administration of 
50 µg (~1 µCi) [14C]TAK-935 and the PK of 
TAK-935 following a single oral 
administration of 300 mg TAK-935. 
 To determine fecal and urinary 
excretion of the parent [14C]TAK-935 
following a single IV administration of 
50 µg (~1 µCi) [14C]TAK-935. 
Periods 1 (ABA) 
 PK parameters Ceoi (IV infusion), 
Cmax (oral), tmax (oral), AUC∞, AUCt, 
AUClast, and t1/2z for TAK-935, and 
[14C]TAK-935 in plasma. 
 Total radioactivity excreted and 
percentage of dose excreted in the 
feces (Ae[f] and %Dose[f]) and urine 
(Ae[u] and %Dose[u]) as total 
radioactivity following IV 
administration. 
Period 2 (ADME) 
 To assess the metabolic profile of 
TAK-935 in plasma, urine, and feces 
following a single oral administration of 
300 mg (~100 µCi) [14C]TAK-935. 
Period 2 (ADME) 
 Metabolic profile of TAK-935 in 
plasma, urine, and feces following a 
single oral administration of 300 mg 
(~100 µCi) [14C]TAK-935. 
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Periods 1 (ABA) and 2 (ADME) 
 To assess the safety of TAK-935 
during the ABA and ADME study periods. 
Periods 1 (ABA) and 2 (ADME) 
 Tabulated TEAEs and summary 
statistics for clinically relevant 
12-lead ECGs, vital signs, and clinical 
laboratory tests results.  
 
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6. 
INVESTIGATIONAL PLAN 
6.1. 
Summary of Study Design 
This is an open-label, 2-period, fixed-sequence, single-dose study in 6 healthy adult male 
participants. 
On Day 1 of Period 1 (ABA Study Period), participants will receive a single unlabeled oral 300 mg 
dose of TAK-935 in tablet form (three 100 mg tablets). At 0.17 hours (10 minutes) post oral 
dosing (ie, 15 minutes prior to the median tmax for the oral unlabeled dose [~ 0.42 hours or 
25 minutes]), participants will receive a 15-minute IV infusion of a microdose of 50 µg 
(equivalent to ~1 µCi) [14C]TAK-935. Serial blood sampling will be performed up to 48 hours 
(Day 3) to determine the PK of TAK-935 and M-I metabolite (and others, if applicable) in plasma 
for the oral dose and [14C]-total radioactivity and PK of [14C]TAK-935 in the plasma for the IV 
dose. Urine and fecal output will also be collected up to 120 hours post dose to determine [14C]-
total radioactivity. Collection of urine and fecal samples will continue until one of the release 
criteria (participants remain in CRU) is met (ie, 80% or greater of the total dose of radioactivity 
administered is recovered in urine and fecal samples or the excretion of radioactivity in the 
urine and feces combined has declined to ≤1% of the total administered radioactivity for at 
least 2 consecutive intervals where both a urine and fecal sample are collected) or up to Day 8, 
but no less than Day 6, for [14C]-total radioactivity excretion in urine and feces. Participants who 
meet release criteria before Day 8, but no less than Day 6, will remain confined in the CRU until 
Day -1 of Period 2 and throughout Period 2 (until Period 2 discharge criteria are met). 
There will be a washout period of at least 7 days between the last dose in Period 1 and the dose 
in Period 2. 
On Day 1 of Period 2 (ADME Study Period), participants will receive a single oral dose of 300 mg 
(~100 μCi) [14C]TAK-935 in solution. Serial blood sampling will be performed and urine and feces 
will be collected to determine the PK of TAK-935 and M-I metabolite in plasma and urine, and 
total radioactivity in plasma, whole blood, urine, and feces, and to characterize the metabolite 
profiles of TAK-935 in plasma, urine, and feces. Complete urinary and fecal output will be 
collected during the confinement period until discharge criteria are met (anticipated to be 
10 days post dose or less). 
In Period 2, participants will be confined in the CRU for at least 5 days post dose (ie, 120 hours) 
and until 90% or greater of the total dose of radioactivity administered is recovered in urine 
and fecal samples. If less than 90% of the total dose of radioactivity administered is recovered 
in urine and fecal samples, participants will be confined in the clinic until a discharge criterion is 
met (ie, 90% or greater of the total dose of radioactivity administered is recovered in urine and 
fecal samples or the excretion of radioactivity in the urine and feces combined has declined to 
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≤1% of the total administered radioactivity per 24 hour interval for at least 2 consecutive 
intervals where both a urine and fecal sample are collected) or up to Day 11 (ie, 240 hours). 
Since up to an approximate 24-hour time lag is anticipated for radioactivity counting of 
samples, actual participant release from the CRU may occur 1 day after discharge criteria are 
met. 
In both periods, any participant who experiences emesis within 1 hour post oral dosing will be 
excluded in the PK data analysis and may be replaced with a new participant. For a participant 
who drops out in Period 2, the replacement participant will be required to complete Period 2 
only. If a participant experiences emesis after dosing in Period 2, vomitus will be collected 
throughout the study and assayed for total radioactivity. 
The clinic will contact all participants (including participants who terminate the study early) 
30 ± 2 days after the last study drug administration to determine if any AEs have occurred since 
the last study visit. 
The planned dose levels of TAK-935 to be evaluated are outlined in Table 2 
Table 2: 
Planned Dose Levels of TAK-935 and [14C]TAK-935 
 
Dose 
Route of Administration 
Period 1  
TAK-935 
300 mg 
Oral tablet 
[14C]TAK-935 
50 µg (~1 µCi) 
IV infusion 
Period 2  
[14C]TAK-935 
300 mg (~100 µCi) 
Oral Solution 
 
 
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)LJXUH illustrates the study design. 
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6.1.1. 
Confinement 
In Period 1, participants will be confined in the CRU from Day -1 of Period 1 and throughout 
Period 2. Participants may be asked to come to CRU earlier in Period 1 to undergo additional 
COVID-19 precaution procedures. All participants, including participants who meet one of the 
release criteria (ie, 80% or greater of the total dose of radioactivity administered is recovered in 
urine and fecal samples or the excretion of radioactivity in the urine and feces combined has 
declined to ≤1% of the total administered radioactivity for at least 2 consecutive intervals 
where both a urine and fecal sample are collected) before Day 8 of Period 1, but no less than 
Day 6, will remain confined in the CRU until they meet discharge criteria in Period 2. 
In Period 2, participants will be confined for at least 5 days post dose (ie, 120 hours of Period 2) 
and until ≥90% of the total dose of radioactivity administered has been recovered in the urine 
and feces samples. 
If less than 90% of the total dose of radioactivity administered is recovered in urine and fecal 
samples, the participant will continue to stay at the CRU until a discharge criterion is met. 
Participants will be eligible for discharge if they meet either one of the following discharge 
criteria or up to Day 11 (ie, 240 hours) of Period 2: 
 ≥90% of the total dose of radioactivity administered has been recovered in the urine and 
feces; or  
 There is ≤1% of the total administered radioactivity in each of two consecutive 24 hour 
intervals where both a urine and fecal sample is provided. 
All urine and fecal collections will be analyzed for radioactivity levels to determine if the 
discharge criteria are met.  
It is expected that the majority (≥90%) of the administered radioactivity will be recovered 
within 10 days post dose or less. 
Release of participants who do not meet a discharge criterion by 240 hours (Period 2) will be 
reviewed on a case-by-case basis. 
Since up to an approximate 24-hour time lag is anticipated for radioactivity counting of 
samples, actual participant release from the CRU may occur 1 day after discharge criteria are 
met. 
At all times, a participant may be required to remain at the CRU for longer at the discretion of 
the Investigator or designee. 
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6.2. 
Discussion of Design and Control 
In Period 1 of the study, the ABA of TAK-935 will be estimated using a labeled IV microdose 
infusion administered 0.17 hours (10 minutes) after an unlabeled oral dose in order to 
characterize the disposition properties of TAK-935. In Period 1, characterization of ABA will be 
achieved by collecting plasma samples for drug concentration analysis, and plasma, urine, and 
fecal samples for total radioactivity analysis following unlabeled oral dose and labelled IV 
microdose of TAK-935. In order to determine ABA accurately and reliably, a healthy adult 
population is chosen. 
Characterization of the disposition of a drug following IV administration facilitates the 
understanding of fundamental aspects of TAK-935’s PK that cannot be determined from oral 
dosing alone, including bioavailability, intrinsic clearance, and volume of distribution. The 
results of this study will contribute to a robust understanding of the PK characteristics of 
TAK-935. 
In Period 2 of the study, characterization of the ADME and mass balance of TAK-935 after oral 
administration of a single 300 mg (~100 μCi) [14C]TAK-935 will be achieved by collecting plasma 
samples for drug concentration analysis, and plasma, urine, and fecal samples for total 
radioactivity analysis and metabolic profiling. The study will provide data required to evaluate 
the mass balance and the metabolic profile of TAK-935 in humans. 
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7. 
STUDY POPULATION 
Individuals who do not meet the criteria for participation in this study (screen failure) may not 
be re-screened. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, are not permitted. 
7.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if they meet all the following criteria 
and none of the exclusion criteria: 
1. Healthy adult male, ≥19 and ≤55 years of age at the time of first dose of study drug. 
2. Weighs at least 50 kg and BMI ≥18.0 and ˂32.0 kg/m2 at Screening visit. 
3. Continuous nonsmoker who has not used nicotine-containing products (including vaping) 
for at least 3 months prior to the first dosing and throughout the study, based on 
participant self-reporting  
4. Medically healthy with no clinically significant medical history, physical examination, 
laboratory profiles, vital signs or ECGs, as deemed by the Investigator or designee. 
5. Participants who are sexually active with a female partner of childbearing potential must 
use a highly effective or effective method of contraception as indicated below or true sexual 
abstinence, only if this is in line with the preferred and usual lifestyle of the participant. 
True abstinence is defined for male participants as refraining from heterosexual intercourse 
during the entire period of the study, from 1 month prior to the first dose until 90 days after 
the last dosing.  
Sexually active male participants (post-pubertal unless permanently sterilized by bilateral 
orchidectomy) must agree to use male contraception (condom) during the study and for 
minimum of 90 days/3 sperm cycles following the last dose of study drug. Male participants 
must also not donate sperm during the screening and treatment periods and for at least 90 
days after the last dose of TAK-935. 
Female partners of male participants who are of childbearing potential must use a highly 
effective or effective method of birth control during the study and for (minimum of 
3 months/3 menstrual cycles following the last dose of study drug. 
Highly effective contraceptive methods are as follows: 
a. Combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation: 
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 Oral 
 Intravaginal 
 Transdermal 
b. Progestogen-only hormonal contraception associated with inhibition of 
ovulation: 
 Oral 
 Injectable 
 Implantable 
c. Intrauterine device 
d. Intrauterine hormone-releasing system 
e. Bilateral tubal occlusion 
Acceptable effective contraceptive methods are as follows: 
a. Progestogen-only oral hormonal contraception, where inhibition of ovulation is 
not the primary mode of action 
b. Male or female condom with or without spermicide 
c. Cap, diaphragm, or sponge with spermicide 
6. Understands the study procedures and agrees to participate by providing written informed 
consent, and be willing and able to comply with all study procedures and restrictions. 
7.2. Exclusion Criteria 
Participants will be excluded from study enrollment if they meet any of the following criteria: 
1. Is mentally or legally incapacitated or has significant emotional problems at the time of the 
Screening visit or expected during the conduct of the study. 
2. History or presence of clinically significant medical or psychiatric condition or disease in the 
opinion of the Investigator or designee. 
3. History or presence of cataracts or other clinically significant vision disturbances. 
4. Abnormal clinical laboratory test results at the Screening visit that suggest a clinically 
significant underlying disease that would compromise the well-being of the patient (if the 
patient has ALT and/or AST >2.5 × the ULN, the Medical Monitor should be consulted). 
5. Abnormal and clinically significant ECG abnormality at Screening visit: 
a. QTcF >450 ms confirmed with one repeat testing. 
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6. History or presence of gastritis, gastrointestinal tract, gastric bypass surgery, or hepatic 
disorder or other clinical condition which, in the opinion of the Investigator or designee, 
may affect the absorption, distribution, metabolism, or elimination of study drug. 
7. History of any illness that, in the opinion of the Investigator or designee, might confound 
the results of the study or poses an additional risk to the participant by their participation in 
the study. 
8. History or presence of alcohol or drug abuse within the past 2 years prior to Screening visit. 
9. History or presence of hypersensitivity or idiosyncratic reaction to the study drug(s) or 
related compounds. 
10. Has a risk of suicide according to the Investigator’s clinical judgment (eg, per C-SSRS), or has 
made a suicide attempt in the previous year prior to Screening visit. 
11. Positive urine drug or alcohol results at screening or first check-in. 
12. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface 
antigen (HBsAg), hepatitis C virus (HCV) or COVID-19. 
13. Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening. 
14. Seated heart rate is lower than 40 bpm or higher than 99 bpm at Screening visit. 
15. Estimated creatinine clearance <80 mL/min at Screening visit. 
16. Has tattoo(s) or scarring at or near the site of IV infusion or any other condition which may 
interfere with infusion site examination, in the opinion of the Investigator. 
17. Has infrequent bowel movements (less than approximately once per day) within 30 days 
prior to first dosing. 
18. Recent history of abnormal bowel movements, such as diarrhea, loose stools, or 
constipation, within 2 weeks prior to first dosing. 
19. Has received radiolabeled substances or has been exposed to radiation sources within 
12 months of first dosing or is likely to receive radiation exposure or radioisotopes within 
12 months of first dosing such that participation in this study would increase their total 
exposure beyond the recommended levels considered safe (ie, weighted annual limit 
recommended by the ICRP of 3000 mrem). 
20. Unable to refrain from or anticipates the use of: 
 Any drug, including prescription and nonprescription medications, herbal remedies, or 
vitamin supplements within 14 days prior to the first dosing and throughout the study, 
including the follow-up period. Thyroid hormone replacement medication may be 
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permitted if the participant has been on the same stable dose for the immediate 
3 months prior to first study drug administration. After the first dose of study drug, 
ibuprofen (up to 1.2 g per 24 hours) may be administered at the discretion of the 
Investigator or designee. Milk of Magnesia (ie, magnesium hydroxide) (≤60 mL per day) 
may be administered to ensure defecation, at discretion of the Investigator or designee. 
 Any drugs known to be significant inducers of CYP3A4, CYP2C19 or UGT, including St. 
John’s Wort, within 28 days prior to the first dosing and throughout the study, including 
the follow-up period. Appropriate sources (eg, Flockhart Table™) will be consulted to 
confirm lack of PK/pharmacodynamic interaction with study drug(s). 
 Alcohol, as defined in Table 3. 
21. Has been on a diet incompatible with the on-study diet, in the opinion of the Investigator or 
designee, within the 30 days prior to the first dosing and throughout the study. 
22. Donation of blood or significant blood loss within 56 days prior to the first dosing. 
23. Plasma donation within 7 days prior to the first dosing. 
24. Participation in another clinical study within 30 days prior to the first dosing. The 30day 
window will be derived from the date of the last blood collection or dosing, whichever is 
later, in the previous study to Day 1 of Period 1 of the current study. 
7.3. Excluded Medications, Supplements, Dietary Products  
Concomitant medications will be prohibited as listed in the exclusion criteria in Section 7.2. 
After the first dose of study drug, ibuprofen (up to 1.2 g per 24 hours) may be administered at 
the discretion of the Investigator or designee. Thyroid hormone replacement medication may 
be permitted if the subject has been on the same stable dose for the immediate 3 months prior 
to first study drug administration. 
Prune juice or milk of Magnesia (ie, magnesium hydroxide) (≤60 mL per day) may be 
administered ensure defecation, at discretion of the Investigator or designee. 
If deviations occur, the Investigator or designee in consultation with the Sponsor if needed will 
decide on a case by case basis whether the subject may continue participation in the study. 
All medications taken by subjects during the course of the study will be recorded. 
Use of excluded agents (prescription or nonprescription) or dietary products is outlined in 
Table 3. 
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Table 3:  
Excluded Medications, Supplements, and Dietary Products 
Category 
Between Screening and Randomization (Days -
28 to pre dose [Day 1]) 
Post-Randomization (Day 1) to 
Follow-Up  
Alcohol 
Prohibited from 48 hours prior to first dosing 
Prohibited from 48 hours prior 
to first dosing until the end of PK 
sample (blood, urine and feces) 
collection in Period 2. 
Xanthine and/or caffeine 
Prohibited from 24 hours prior to first dosing (a) 
Prohibited from 24 hours prior 
to first dosing until the end of PK 
sample (blood, urine and feces) 
collection in Period 2 (a). 
Medications 
See Sections 7.2 and 7.3 
See Sections 7.2 and 7.3 
Nicotine 
Prohibited from 3 months prior to first dosing  
Prohibited from 3 months prior 
to first dosing until the end of PK 
sample (blood, urine and feces) 
collection in Period 2. 
Food substance 
 
 
Grapefruit/Seville 
orange 
Prohibited from 14 days prior to first dosing 
Prohibited from 14 days prior to 
first dosing until end of PK 
collection in Period 2 
(a) Small amounts of caffeine derived from normal foodstuffs eg, 250 mL/8 oz/1 cup decaffeinated coffee or 
other decaffeinated beverage, per day, with the exception of espresso; 45 g/1.5 oz chocolate bar, per day, 
would not be considered a deviation to this restriction.  
Participants will be excluded from study enrollment if they meet any of the following criteria: 
[1] Investigator site personnel directly affiliated with this study and/or their 
immediate family. Note: immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted. 
[2] Ovid employees, Takeda employees, or employees 
 
[3] Currently enrolled in a clinical study involving an investigational product or 
nonapproved use of a drug or device (other than the investigational product used 
in this study), or concurrently enrolled in any other type of medical research 
judged not to be scientifically or medically compatible with this study. 
[4] Have participated, within the last 30 days in a clinical study involving an 
investigational product [other than the investigational product used in this study]. 
If the previous investigational product has a long half-life, three months or five 
half-lives (whichever is longer) should have passed. 
[5] Have previously completed or withdrawn from this study or any other study 
investigating TAK-935. 
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[6] Are unwilling or unable to comply with the use of a data collection device to 
directly record data from the participant. 
7.4. 
Diet, Fluid, Activity  
7.4.1. 
Diet and Fluid 
Water (except water provided with each oral dosing) will be restricted 1 hour prior to and 
1 hour after each oral study drug administration, but will be allowed ad libitum at all other 
times. Other fluids may be given as part of meals and snacks but will be restricted at all other 
times throughout the confinement period. 
Participants will fast overnight for at least 10 hours prior to each oral study drug administration 
and will continue to fast for at least 4 hours post oral dosing. 
When confined, standard meals and snacks will be provided at appropriate times, except when 
they are required to fast. When confined in the CRU, participants will be required to fast from 
all food and drink except water between meals and snacks. Prune juice may be provided at any 
time, at the discretion of the study Investigator or designee. 
7.4.2. 
Activity 
Participants will remain ambulatory or seated upright for the first 4 hours post oral dosing, 
except when they are supine or semi-reclined for study procedures (eg, IV dosing on Day 1 of 
Period 1). 
Participants will be instructed to refrain from strenuous physical activity which could cause 
muscle aches or injury, including contact sports at any time from screening until completion of 
the study. 
Participants will be prohibited from smoking and vaping throughout the study. 
7.5. 
Discontinuations 
7.5.1. 
Discontinuation of Participants 
The criteria for enrollment must be followed explicitly. If the investigative site identifies a 
participant who did not meet enrollment criteria and who was inadvertently enrolled, the 
Sponsor must be notified. If the Sponsor identifies a participant who did not meet enrollment 
criteria and who was inadvertently enrolled, the investigator site will be notified. A discussion 
must occur between the Sponsor and the Investigator to determine whether the participant 
may continue in the study, with or without investigational product. Inadvertently enrolled 
participants may be maintained in the study and on investigational product when the Sponsor 
agrees with the Investigator that it is medically appropriate for that participant. The participant 
may not continue in the study with or without investigational product if the Sponsor does not 
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agree with the Investigator’s determination it is medically appropriate for the participant to 
continue. The Investigator must obtain documented approval from the Sponsor to allow the 
inadvertently enrolled participant to continue in the study with or without investigational 
product. 
7.5.2. 
Criteria for Discontinuation or Withdrawal of a Participant 
Participants are free to withdraw from the study at any time for any reason. 
In addition, participants may be withdrawn from the study by the Investigator or designee for 
the following reasons: 
 AEs. 
 Positive urine drug or alcohol results. 
 Difficulties in blood collection. 
In Period 1 or 2, any participant who experiences emesis within 1 hour following the oral dose 
may be discontinued, excluded from the final data analysis, and may be replaced with a new 
participant. In Period 2, if a participant experiences emesis after oral dosing, vomitus will be 
collected throughout the study and assayed for total radioactivity. 
A participant may be withdrawn by the Investigator (or designee) or the Sponsor if enrollment 
into the study is inappropriate, the study plan is violated, or for administrative and/or other 
safety reasons. 
 Enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study 
 Investigator Decision [Physician Decision] 
− The investigator decides that the participant should be discontinued from the 
study 
 Participant Decision [Withdrawal by Participant] 
− The participant requests to be withdrawn from the study 
 Sponsor Decision 
− The Sponsor or its designee discontinues the study or discontinues the 
participant’s participation in the study for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and GCP 
− The Sponsor or its designee stops the clinical study at a particular site 
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 Adverse Event  
− If the investigator decides that the participant should be withdrawn because of a 
serious AE or a clinically significant laboratory value, the investigational product 
is to be discontinued and appropriate measures are to be taken. The Sponsor or 
its designee is to be alerted immediately. Refer to Safety Evaluations Section 9.2. 
Liver Function Test (LFT) Abnormalities: 
Study drug should be discontinued immediately with appropriate clinical follow-up (including 
repeat laboratory tests, until a participant’s laboratory profile has returned to normal/baseline 
status, see Section 9.1.6), if the following circumstances occur at any time during study drug 
treatment: 
– alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 × upper 
limit of normal (ULN), or 
– ALT or AST >5 × ULN and persists for more than 2 weeks, or 
– ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or 
– ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
QTcF interval > 500 ms: 
Study drug should be discontinued immediately with appropriate clinical follow-up if a QTcF 
interval >500 ms is detected by ECG and confirmed with a repeat ECG. Appropriate clinical 
follow-up includes a repeat ECG. Participants who discontinue the study early will have end of 
study procedures performed as shown in the Schedule of Assessments (Appendix 1). 
7.5.3. 
Discontinuation of Study Sites/Site Terminated by Sponsor 
Study site participation may be discontinued if the Sponsor or its designee, the investigator, or 
the IRB/IEC of the study site judges it necessary for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and GCP. 
7.5.4. 
Discontinuation of the Study/Study Terminated by Sponsor 
The study will be discontinued if the Sponsor or its designee judges it necessary for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and GCP. 
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8. 
TREATMENT 
8.1. 
Materials and Supplies 
8.1.1. 
Clinical Study Drug TAK-935 Tablet 
A single unlabeled 300 mg dose of TAK-935 (3 x 100 mg tablets) will be administered in Period 1 
of the study. 
8.1.2. 
[14C]TAK-935 IV Sterile Solution 
An IV dose of 50 μg [14C]TAK-935 (~1 µCi) will be administered as a 15-minute infusion at 
0.17 hours (10 minutes) after the TAK-935 oral dose (see Section 6.1) in Period 1 of the study. 
The drug product is prepared in the CRU pharmacy as an IV solution. The solution will be 
prepared and labeled by licensed pharmacy staff according to the procedures outlined in the 
pharmacy manual. 
8.1.3. 
[14C]TAK-935 Oral Solution 
A single oral dose of 300 mg (~100 μCi) [14C]TAK-935 will be administered as an oral solution in 
Period 2. 
8.1.4. 
Clinical Study Drug Labeling 
TAK-935 tablet, [14C]TAK-935 IV solution, and [14C]TAK-935 oral solution will be affixed with 
clinical labels in accordance with local regulatory requirements. 
8.2. 
Clinical Study Drug Inventory and Storage 
The Sponsor will supply sufficient quantities of TAK-935 products to allow completion of this 
study.  
 will provide sufficient quantities of preparation and/or dilution solutions to allow 
completion of the study. The same lot number will be used throughout the study. 
The lot numbers and expiration dates (where available) of the study drugs supplied will be 
recorded in the final report. 
Records will be made of the receipt, preparation, dispensing, and final disposition of the study 
drugs supplied. All TAK-935 products will be prepared and labeled by licensed pharmacy staff 
according to the procedures outlined in the pharmacy manual. 
8.3. 
Treatments Administered 
TAK-935 in Period 1 will be provided as 100 mg tablets; 
[14C]TAK-935 in Period 1 will be provided as an IV solution  
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[14C]TAK-935 in Period 2 will be provided as an oral solution  
Period 1: On Day 1, participant will receive a single unlabelled oral dose of TAK-935 300 mg 
tablets followed by a 15 minute IV infusion of a microdose of 50 µg (1 µCi) [14C]TAK-935 at 
0.17 hours (10 minutes) post oral dose. 
Period 2: On Day 1, participant will receive a single oral dose of 300 mg (~100 μCi) [14C]TAK-935 
in solution. 
Treatments in each period are described as follows:  
Period 1:   
300 mg TAK-935 (3 x 100mg tablets) administered orally at Hour 0 on 
Day 1 followed by 50 µg (~1 μCi) [14C]TAK-935 IV solution administered 
at Hour 0.17 (10 minutes post oral dosing) for 15 minutes. 
Period 2:   
300 mg (~100 μCi) [14C]TAK-935  administered as an oral solution at 
Hour 0 on Day 1 of Period 2. 
The oral doses of TAK-935 and [14C]TAK-935 will be administered following an overnight fast 
with approximately 240 mL of water, then will be instructed to fast for an additional 4 hours. All 
participants may then consume water ad libitum with the exception of 1 hour before and 
1 hour after oral administration. The exact clock time of oral dosing will be recorded. 
The IV dose will be administered over approximately 15 minutes. The start and end time of the 
IV infusion will be recorded. 
Participants should be instructed not to crush split or chew TAK-935 tablets in Period 1 
The pharmacy at the CRU will provide the IV dose for the 15-minute infusion, the oral tablets 
dose in individual unit dose containers, and the oral dose solution for each participant. 
8.4. 
Method of Assignment to Treatment 
Each participant will be assigned a unique identification number upon screening. Participants 
who complete the study screening assessments and meet all the eligibility criteria will be 
assigned a unique identification number at the time of the first dosing, different from the 
screening number, and will receive the corresponding product. 
Participants will receive each treatment on one occasion. 
Discontinued participants may be replaced at the discretion of the Sponsor. 
If replacement participant participants are used, the replacement participant number will be 
100 more than the original (e.g., Participant No. 101 will replace Participant No. 1). 
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8.6.
Blinding 
This is an open-label study. 
8.7.
Treatment Compliance 
A qualified designee will be responsible for monitoring the administration of the timed oral 
doses. A mouth check will be performed by the qualified designee to ensure that the 
participants have swallowed the study drug. Once a participant has finished the dosing water, 
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the qualified designee will use a flashlight and a tongue depressor to check the participant’s 
mouth. Participants’ hands will also be verified to ensure that the study drug was ingested. 
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9.
STUDY ASSESSMENTS  
The Schedule of Study Procedures (Appendix 1) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the Investigator or designee and/or the 
Sponsor for reasons related to participant safety. 
For this study, the collections for blood, urine, and feces for total radioactivity, plasma and 
urine concentrations, and metabolite profiling for TAK-935 are the critical parameters and need 
to be collected as close to the exact time point as possible. All other procedures should be 
completed as close to the prescribed/scheduled time as possible but can be performed prior or 
after the prescribed/scheduled time. 
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures. 
9.1.
Safety Assessments 
9.1.1.
Physical Examination
A full physical examination will be performed as outlined in the Schedule of Study Procedures 
(Appendix 1). Each examination will include the following assessments: general appearance; 
skin; head, ear, eye, nose, and throat; neck; lymph node; chest; heart; abdominal cavity; limb; 
central nervous system; and musculoskeletal. 
If clinically significant changes from Screening/Baseline are noted, the changes will be 
documented as AEs in the AE CRF. Screening/Baseline events will be documented in the 
Medical History CRF. Clinical significance is defined as any variation in physical findings that has 
medical relevance and may result in an alteration in medical care. The Investigator will continue 
to monitor the participant until the parameter returns to Baseline or until the Investigator 
determines that follow-up is no longer medically necessary. 
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9.1.3.
Height and Weight 
Body height (cm) and weight (kg) will be reported as outlined in the Schedule of Study 
Procedures (Appendix 1).Weight and height are to be measured while the participant is 
wearing indoor clothing and with shoes off. 
9.1.4.
BMI 
BMI will be calculated based on the height and weight measured at Screening visit. 
9.1.5.
Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure, and heart rate 
(beats per minute), will be measured as outlined in the Schedule of Study Procedures 
(Appendix 1). Additional vital signs may be taken at any other times, if deemed necessary. 
Vital signs should be measured at the same time of day if possible. When vital signs are 
scheduled at the same time as blood draws, the blood draw will take priority and vital signs will 
be obtained within 15 minutes before or after the scheduled blood draw, if possible. 
All vital signs data collected will be recorded on the source documents and in the CRF. Blood 
pressure and heart rate measurements will be performed with participants in a seated position, 
except when they are supine or semi-reclined because of study procedures and/or AEs 
(eg, nausea, dizziness) or if deemed necessary by the Investigator or designee. 
Blood pressure and heart rate will be measured within 24 hours prior to Day 1 dosing of each 
period for the pre dose time point. When scheduled post dose, vital signs will be performed 
within approximately 15 minutes of the scheduled time point. 
If clinically significant vital sign changes as compared to Screening/Baseline are noted, the 
changes will be documented as AEs in the AE CRF. Screening/Baseline events will be 
documented in the Medical History CRF. Clinical significance is defined as any variation in vital 
signs that has medical relevance and may result in an alteration in medical care. The 
Investigator will continue to monitor the participant until the parameter returns to Baseline or 
until the Investigator determines that follow-up is no longer medically necessary
9.1.6.
Serum Chemistry, Hematology, and Urinalysis 
Serum chemistry, hematology, and urinalysis will be performed at the times specified in 
Appendix 1. Specific laboratory assessments are provided in Appendix 2.  
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Laboratory assessments for safety will be tested at a central laboratory facility. Laboratory 
reports will be made available to the Investigators in a timely manner for clinical management 
of participants. 
It is anticipated that some laboratory values may be outside of the normal value range due to 
the underlying disease. As in routine practice, the Investigators should use their medical 
judgment when assessing clinical significance. Clinical significance is defined as any variation in 
laboratory measurements which has medical relevance and which results in a change in medical 
care. If clinically significant laboratory changes from Baseline are noted, the changes will be 
documented as AEs in the AE CRF. The Investigator will also assess the relationship to study 
treatment for all clinically significant out of range values. The Investigator will continue to 
monitor the participant with additional laboratory assessments until (1) values have reached 
normal range and/or Baseline, or (2) in the judgment of the Investigator, out of range values 
are not related to the administration of study drug or other protocol-specific procedures. 
 If participants experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, 
serum alkaline phosphatase, ALT, AST, total bilirubin, gamma-glutamyl transferase (GGT), and 
INR) should be performed within a maximum of 7 days and preferably within 48-72 hours after 
the abnormality was noted. (Refer to Section 7.5.2 and Section 9.2.3 for the appropriate 
guidance on reporting abnormal liver function tests.) 
If ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions the investigator must 
contact the Medical Monitor for consideration of additional testing, close monitoring, possible 
discontinuation of study drug, discussion of the relevant participant details and possible 
alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 9.2.1.5). 
9.1.7. 
12-Lead ECG 
Single 12-lead ECGs will be performed as outlined in the Schedule of Study Procedures 
(Appendix 1). Additional ECGs may be taken at any other times, if deemed necessary by the 
Investigator or designee. 
ECGs will be performed with participants in a supine position. All ECG tracings will be reviewed 
by the Investigator or designee. ECGs will be measured within 24 hours prior to Day 1 dosing of 
each period for the pre dose time point. When scheduled post dose, ECGs will be performed 
within approximately 20 minutes of the scheduled time point. 
Study drug should be discontinued immediately with appropriate clinical follow-up if a QTcF 
interval >500 ms is detected by ECG and confirmed with a repeat ECG. Appropriate clinical 
follow-up includes a repeat ECG (Refer to Section 7.5.2 and Section 9.2.3.1 for the appropriate 
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guidance on QTcF measurement). The abnormality should be recorded as an AE (please refer to 
Section 9.2.1.5). 
9.2.
Safety Evaluations 
Investigators are responsible for monitoring the safety of participants who have entered this 
study and for alerting Ovid or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the participant. 
The investigator is responsible for the appropriate medical care of participants during the study. 
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious, considered related to the study treatment or the study, or that caused the 
participant to discontinue before completing the study. The participant should be followed until 
the event is resolved or explained. Frequency of follow-up evaluation is left to the discretion of 
the Investigator. 
9.2.1.
Adverse Events 
An AE is any untoward medical occurrence in a participant or clinical study participant 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable or unintended sign (for example, 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether considered related to this medicinal product. 
The definition of an AE also covers medication errors and uses outside what is foreseen in the 
protocol only if an AE results from the error, including intentional misuse, abuse, and overdose 
of the product. 
Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital), and anticipated day-to-day fluctuations of pre-existing disease(s) or 
condition(s) present or detected at the start of the study that do not worsen are not AEs. 
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Ovid has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent. Study site personnel will record the occurrence and 
nature of each participant’s pre-existing conditions, including clinically significant signs and 
symptoms of the disease under treatment in the study. 
After the informed consent form (ICF) is signed, site personnel will record any change in the 
condition(s) and the occurrence and nature of any AEs. If a participant experiences an AE after 
signing informed consent, but prior to receiving investigational product, the event will be 
reported, but will be classified as a pre-treatment AE unless the investigator feels the event 
may have been caused by a protocol procedure. 
In addition, all AEs occurring after the participant receives the first dose of investigational 
product must be reported to Ovid or its designee via the eCRF. 
9.2.1.1. 
Severity Assessment 
Investigators will be instructed to rate the severity of AEs using the following criteria: 
Mild  
Events require minimal or no treatment and do not interfere with the participant’s 
daily activities. 
Moderate  Events result in a low level of inconvenience or concerns with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
Severe  
Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually incapacitating. 
Change in severity of an AE should be documented based on specific guidelines in the CRF 
Completion Guidelines. 
Severity and seriousness must be differentiated: severity describes the intensity of an AE, while 
the term seriousness refers to an AE that has met the criteria for an SAE. 
9.2.1.2. 
Causality Assessment 
Investigators will be instructed to report to Ovid or its designee their assessment of the 
potential relatedness of each AE to protocol procedure and/or study drug via the CRF. 
An Investigator causality assessment (Not Related, Unlikely Related, Possibly Related or 
Related) must be provided for all AEs (both serious and non-serious). This assessment must be 
recorded in the CRF and any additional forms as appropriate. 
Relationship of AEs to the defined study treatment, will be determined by the Investigator 
according to the following criteria. Please note that not all criteria must be present to be 
indicative of a particular relationship 
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Not Related 
Exposure to the defined study treatment did not occur, or 
the occurrence of the AE is not reasonably related in time. 
 
Unlikely Related 
The AE occurred in a reasonable time after the defined 
study treatment and is doubtfully related to the 
investigational agent/procedure 
 
Possibly Related 
The defined study treatment and the AE were reasonably 
related in time, and the AE could be explained equally well 
by causes other than exposure to the defined study 
treatment 
 
Related 
The defined study treatment and the AE were reasonably 
related in time, and the AE was more likely explained by 
exposure to the defined study treatment than by other 
causes, or the defined study treatment was the most likely 
cause of the AE 
 
If a participant’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Ovid or its designee via CRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment. 
9.2.1.3. 
Serious Adverse Events 
Serious adverse event collection begins after the participant has signed informed consent. If a 
participant experiences an SAE after signing informed consent, but prior to receiving 
investigational product, the event will be reported, but will be classified as a pre-treatment SAE 
unless the investigator feels the event may have been caused by a protocol procedure. 
Planned surgeries and/or hospitalizations should not be reported as SAEs unless the underlying 
medical condition has worsened during the course of the study. 
An SAE is any AE from this study that results in one or more of the following outcomes: 
 Results in death  
 Requires or prolongs hospitalization 
 Is life threatening (that is, immediate risk of dying) 
 Persistent or significant disability/incapacity 
 Congenital anomaly or birth defect 
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x Other medically important serious event 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
Serious adverse events occurring up to and including the participant’s last study visit will be 
collected, regardless of the investigator’s opinion of causation. 
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the study may be 
found in the IB (IB Ed 5). 
9.2.1.4.
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure. 
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidance or national regulatory requirements in participating countries 
require the reporting of SUSARs. Ovid has procedures that will be followed for the recording 
and expedited reporting of SUSARs that are consistent with global regulations and the 
associated detailed guidance. 
9.2.1.5.
Reporting Adverse Events 
All non-serious AEs must be recorded in the CRF upon awareness.  
Any AE that meets SAE criteria (Section 9.2.1.3) must immediately (i.e., within 24 hours) be sent 
to the Sponsor upon learning of any SAE that occurs (whether or not attributable to the study 
drug). It is the Investigator’s responsibility to ensure that SAE reporting procedures are followed 
appropriately. All SAE reports and any revisions to an SAE report must be sent to the following 
email. All supporting source information concerning the SAE (e.g., hospital records) should also 
be provided by email.  
Email:   
If there is a question concerning an SAE, the site needs guidance regarding reporting of an SAE, 
the site is returning a call from the Sponsor’s safety specialist, or the site urgently needs to 
report an SAE or make the Sponsor aware of an SAE, the safety hotline should be used. 
SAE Hotline:
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If an SAE is reported via the hotline, the site should first submit the SAE paper form and then 
enter the SAE in the eCRF. Any AE that meets SAE criteria must be entered into the EDC system 
immediately (ie, within 1 business day) after site personnel first learns about the event in 
addition to emailing the SAE Report form. 
All SAEs must be reported starting from the time that informed consent for study participation 
is provided. If the Investigator becomes aware of an SAE within 30 days after the participant’s 
last dose of study drug or within 30 days after the last study visit, the SAE must be reported. 
Serious AEs must be followed until the event resolves, the event or sequelae stabilize, or it is 
unlikely that additional information can be obtained after demonstration of due diligence with 
follow-up efforts (i.e., the participant or health care practitioner is unable to provide additional 
information, or the participant is lost to follow up). Serious AEs that occur more than 30 days 
after the last dose of study drug need not be reported unless the Investigator considers them 
related to study drug. 
9.2.1.6. 
Sponsor Reporting Requirements 
The Sponsor or its legal representative is responsible for notifying the relevant regulatory 
authorities of SAEs meeting the reporting criteria. This protocol will use the current IB as the 
Reference Safety Document. The expectedness and reporting criteria of an SAE will be 
determined by the Sponsor from the Reference Safety Information which is the IB (IB Ed 5). 
9.2.1.7. 
Investigator Reporting Requirements 
The Investigator must fulfill all local regulatory obligations required for the study Investigators. 
It is the PI’s responsibility to notify the IRB or IEC of all SAEs that occur at his or her site. 
Investigators will also be notified of all SUSAR events that occur during the clinical study. Each 
site is responsible for notifying its IRB/IEC of these additional SAEs. 
9.2.2. 
Exposure During Pregnancy and/or Lactation 
Exposure during pregnancy (also referred to as exposure in-utero) can be the result of either 
maternal exposure or transmission of drug product via semen following paternal exposure. 
If a participant’s partner becomes pregnant while treated or exposed to study drug, the 
investigator must submit a pregnancy form to Ovid via the same method as SAE reporting. 
Pharmacovigilance will supply the Investigator with a copy of a “Pregnancy Reporting and 
Outcome Form/Breast Feeding.” When the outcome of the pregnancy becomes known, the 
form should be completed and returned to Ovid or Ovid Pharmacovigilance delegate. If 
additional follow-up is required, the Investigator will be requested to provide the information. 
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Pregnancy is not regarded as an AE unless there is a suspicion that study drug may have 
interfered with the effectiveness of a contraceptive medication. However, complications of 
pregnancy and abnormal outcomes of pregnancy are AEs and may meet criteria for an SAE 
(such as ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death, or 
congenital anomaly). Elective abortions without complications should not be reported as AEs. 
9.2.3. 
Safety Monitoring 
The Ovid medical monitor and/or Pharmacovigilance physician will monitor safety data 
throughout the course of the study. 
Ovid will review SAEs within time frames mandated by company procedures. The Ovid medical 
monitor will, as appropriate, consult with the functionally independent Pharmacovigilance 
therapeutic area physician.  
9.2.3.1. 
Reporting of Abnormal Liver Function Tests 
If a participant is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases CRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed. 
If a participant is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and 
reported as per Section 9.2.1.5. The investigator must contact the Medical Monitor for 
discussion of the relevant participant details and possible alternative etiologies, such as acute 
viral hepatitis A or B or other acute liver disease or medical history/concurrent medical 
conditions. Follow-up laboratory tests as described in Section 9.1.6 must also be performed. 
In addition, a CRF must be completed and transmitted with the SAE Report form (as per 
Section 9.2.1.5). 
9.2.3.2. 
Reporting of QTcF interval increase 
If a participant is noted to have QTcF interval > 500 ms on 2 consecutive occasions, the study 
drug should be discontinued immediately and abnormality should be recorded as an AE.  
The investigator must contact the Medical Monitor for discussion of the relevant participant 
details and possible alternative etiologies, such as medical history/concurrent medical 
conditions. Follow-up ECG measurements as described in Section 9.1.7 must also be performed. 
In addition, a CRF must be completed and transmitted with the SAE Report form (as per 
Section 9.2.1.5). 
 
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9.3.
Sample Collection and Testing 
9.3.1.
Blood Sampling and Processing 
Primary specimen collection parameters are provided in Table 4.  
Instructions for whole blood, plasma, urine, fecal samples processing and handling will be 
provided separately. 
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results. Tests are run and confirmed promptly whenever scientifically 
appropriate. When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the test runs, or to retain the samples until the end of the study to confirm that the 
results are valid. Certain samples may be retained for a longer period, if necessary, to comply 
with applicable laws, regulations, or laboratory certification standards. 
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9.3.2. 
PK Measurements  
9.3.2.1. 
Whole Blood and Plasma for PK Measurements 
The following PK parameters for whole blood and plasma radioactivity concentration 
equivalents (plasma in both Periods 1 and 2, whole blood in Period 2 only) and for plasma 
TAK-935 concentrations (Periods 1 and 2) will be calculated, unless otherwise specified: 
AUClast: 
Area under the concentration-time curve from time 0 to time of the last 
quantifiable concentration. 
AUCt: 
Area under the concentration-time curve from time 0 to time of the last 
common time point “t” at which total radioactivity and TAK-935 are 
quantifiable for all participants.  
AUC∞: 
Area under the concentration-time curve from time 0 to infinity, 
calculated using the observed value of the last quantifiable 
concentration. 
AUCextrap%: 
Area under the curve from the last quantifiable concentration to infinity 
calculated using the observed value of the last quantifiable 
concentration, expressed as a percentage of AUC∞. 
Cmax: 
Maximum observed concentration. 
λz: 
Terminal disposition phase rate constant. 
tmax: 
Time of first occurrence of Cmax. 
t1/2z: 
Terminal disposition phase half-life. 
The following PK parameters for plasma concentrations of [14C]TAK-935 following IV infusion 
(Period 1) will be calculated, unless otherwise specified: 
AUClast: 
Area under the concentration-time curve from time 0 to time of the last 
quantifiable concentration. 
AUCt: 
Area under the concentration-time curve from time 0 to time of the last 
common time point “t” at which plasma total radioactivity and plasma 
TAK-935 are quantifiable for all participants. 
AUC∞: 
Area under the concentration-time curve from time 0 to infinity, 
calculated using the observed value of the last quantifiable 
concentration. 
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AUCextrap%: 
Area under the curve from the last quantifiable concentration to infinity 
calculated using the observed value of the last quantifiable 
concentration, expressed as a percentage of AUC∞. 
Ceoi: 
Concentration at the end of infusion. 
λz: 
Terminal disposition phase rate constant. 
t1/2z: 
Terminal disposition phase half-life. 
No value for λz, AUC∞, AUCextrap%, or t1/2z will be reported for cases that do not exhibit a 
terminal log-linear phase in the concentration versus time profile. 
No PK parameters will be calculated for participants with detectable concentrations or 
radioactivity concentration equivalents at 2 or fewer consecutive time points. 
Individual and mean plasma concentration- or radioactivity concentration equivalent-time 
curves (both linear and log-linear) will be included in the final report. 
The ABA parameters for TAK-935 (Period 1) will be calculated as follows: 
F: 
Absolute bioavailability, calculated for plasma TAK-935. 
%F: 
Percent absolute bioavailability, calculated for plasma TAK-935 as 
[Dose (IV) x AUC∞ (oral)] / [Dose (oral) x AUC∞ (IV)] x 100. 
9.3.3. 
Urine for PK Measurements 
The following PK parameters for urine [14C]TAK-935 concentrations (Period 1; IV dose), and for 
urine TAK-935 concentrations and urine total radioactivity (both Periods 1 and 2) will be 
calculated, unless otherwise specified: 
Aet1-t2: 
Amount of drug excreted in urine from time 1 to time 2. 
Ae(u): 
Cumulative amount excreted in urine. 
%Dose(u): 
Percent of administered radioactive dose excreted in urine within a 
given collection interval. 
Cum%Dose(u): 
Cumulative percent of administered dose excreted in urine. 
CLR: 
Renal clearance. 
Total radioactivity excreted in urine will be presented in mass equivalent units. 
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9.3.4. 
Feces for PK Measurements 
The following PK parameters for fecal [14C]TAK-935 concentrations (Period 1; IV dose), and for 
fecal total radioactivity (both Periods 1 and 2) will be calculated, unless otherwise specified: 
Ae(f): 
Cumulative amount of total radioactivity excreted in feces. 
%Dose(f): 
Percent of administered radioactive dose excreted in feces within a 
given collection interval. 
Cum%Dose(f): 
Cumulative percent of administered dose excreted in feces. 
Total radioactivity excreted in feces will be presented in mass equivalent units. 
9.3.5. 
Additional PK Measurements 
The following PK parameters for combined urine and fecal total radioactivity (Period 1, IV dose 
and Period 2) will be calculated, unless otherwise specified: 
Combined 
Cum%Dose: 
Cumulative combined percent of administered dose excreted in urine 
and feces. 
9.3.6. 
Biomarker Measurements  
Not applicable 
9.4. 
Data Collection and Storage 
All clinical raw data will be recorded promptly, accurately, and legibly, either directly into the 
data capture system as e-source data, or indelibly on paper (eg, ECG readings). A detailed list of 
the type (electronic or paper) and location for all source data will be included in the Trial 
Master File. When recorded electronically, case report forms will be electronically generated. 
All raw data will be preserved to maintain data integrity. The investigator or designee will 
assume the responsibility of ensuring the completeness, accuracy, and timeliness of the clinical 
data. 
The electronic data capture system is fully validated and Code of Federal Regulations Title 21 
Part 11 compliant. The electronic data capture system will maintain a complete audit trail of all 
data changes. At each scheduled monitoring visit, the Investigator or designee will cooperate 
with the Sponsor’s representative(s) for the periodic review of study documents to ensure the 
accuracy and completeness of the data capture system. 
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Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data. This information will be provided to the respective study sites by 
means of electronic or manual queries. 
The Investigator or designee will prepare and maintain adequate and accurate study 
documents (medical records, ECGs, AE and concomitant medication reporting, raw data 
collection forms) designed to record all observations and other pertinent data for each 
participant receiving study drug. 
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10. 
STATISTICAL METHODS AND PLANNED ANALYSES 
10.1. 
General Considerations 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a SAP. The SAP will be prepared and finalized before database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives. Additional statistical analyses other than those 
described in this section may be performed if deemed appropriate. 
10.2. 
Determination of Sample Size 
The sample size of 6 male healthy participants was selected without statistical considerations 
and is deemed adequate to meet the study objectives. In addition, this sample size is limited 
based on clinical considerations for this type of study and in order to limit exposure to 
radioactivity. 
10.3. 
Analysis Sets 
10.3.1. 
Pharmacokinetic Set 
All participants who comply sufficiently with the protocol and display an evaluable PK profile 
(eg, exposure to treatment, availability of measurements and absence of major protocol 
violations) will be included in the statistical analyses. 
10.3.2. 
Safety Set 
All participants who received at least one dose of the study drug will be included in the safety 
evaluations. 
10.4. 
Demographics and Other Baseline Characteristics 
Continuous demographic data (ie, age, weight, height, and BMI) will be listed and summarized 
using appropriate summary statistics. Categorical demographic data (ie, sex, race, and ethnicity) 
will also be listed and tabulated. 
10.5. 
Participant Disposition 
All participants who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported. If known, a reason for their discontinuation will be 
given. 
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10.6. 
Pharmacokinetic Analysis 
Descriptive statistics will be provided for the total radioactivity (whole blood, plasma, urine, 
feces, and if applicable, emesis), TAK-935 concentrations and PK parameters (plasma and 
urine), and [14C]TAK-935 plasma, urine, feces radioactivity concentrations equivalent, using 
appropriate summary statistics to be fully specified in the SAP.  
PK parameters for whole blood and plasma concentrations (as appropriate) and total 
radioactivity will be calculated as described in Section 9.3.2.1 and for urine and feces, as 
described in Sections 9.3.3 and 9.3.4, respectively. 
ABA of TAK-935 (Period 1) will be estimated using a 90% CI constructed for the difference in LS 
mean on the log scale for dose normalized AUC∞ between a single oral dose and the IV 
microdose. Exponentiating the log-scale 90% CI will provide a 90% CI for the dose normalized 
AUC∞ geometric mean ratio (TAK-935 administered as oral dose / [14C]TAK-935 administered as 
IV microdose). AUClast will be analyzed in a similar fashion if AUC∞ cannot be calculated. 
10.6.1. 
Analysis of Mass Balance 
In Period 2, mass balance will be calculated as a sum of the percent of the total radioactivity 
recovered in urine and feces plus any radioactivity dose lost due to emesis (if any occurred) 
relative to the administered radioactivity dose. 
10.6.2. 
Whole Blood to Plasma Partitioning Ratio 
In Period 2, ratios of the concentration of [14C] radioactivity and TAK-935 in whole blood 
relative to plasma will be estimated (eg, whole blood:plasma partitioning ratio). The ratio of 
AUC∞ total radioactivity in blood and plasma will also be calculated. 
10.6.3. 
Metabolite Profiling 
In Period 2, TAK-935 metabolite profiling will be performed in plasma, urine, and feces 
containing sufficient amounts of radioactivity. The percent of dose represented by each of the 
metabolites, if any, will be calculated using the radioactivity concentration equivalent data 
combined with the metabolite profiling data. The percentage of each identified metabolite, if 
any, to total radioactivity in the plasma will be estimated based on plasma metabolite profiling 
data. 
10.7. 
PD Analysis  
Not applicable. 
10.8. 
Safety Analysis 
All safety data will be listed in the listings. 
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Dosing dates and times will be listed by participant. 
Quantitative safety data as well as the difference to baseline, when appropriate, will be 
summarized using the appropriate descriptive statistics. 
10.8.1. 
Adverse Events 
AEs will be coded using the most current version of Medical Dictionary for Regulatory Activities 
(MedDRA® version 21 or higher) available 
 and summarized by treatment for the 
number of participants reporting the TEAE and the number of TEAEs reported. A by participant 
AE data listing including verbatim term, coded term, treatment, severity, and relationship to 
treatment will be provided. AE listing will be provided. 
10.8.2. 
Clinical Laboratory Evaluation 
Clinical laboratory results will be summarized by treatment and point of time of collection and a 
shift table describing out of normal range shifts will be provided. 
10.8.3. 
Vital Signs 
Vital signs assessments will be summarized by treatment and point of time of collection. 
10.8.4. 
Other Safety Parameters 
Physical examination findings will be presented in the data listings. 
ECGs will be summarized by treatment and point of time of collection. 
Medical history, and concurrent conditions will be coded using the MedDRA® and concomitant 
medications will be coded using the World Health Organization drug and will be listed by 
participant. 
C-SSRS findings will be presented in the data listings. 
10.9. 
Interim Analysis and Criteria for Early Termination 
Not applicable 
10.10. 
Other Statistical Issues 
Significance Levels: 
There is no hypothesis test for this study, only summary statistics will be provided. No 
significance level is specified. 
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10.10.1. 
Missing or Invalid Data 
Techniques for handling missing data will be specified in detail in the SAP. 
10.10.2. 
Interim Analyses  
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary, the appropriate Sponsor personnel will be consulted to determine whether it is 
necessary to amend the protocol. 
Details of all statistical analyses are contained in the study SAP. 
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11. 
INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY CONSIDERATIONS 
11.1. 
Informed Consent 
The investigator is responsible for ensuring that the participant understands the potential risks 
and benefits of participating in the study, including answering any questions the participant 
may have throughout the study and sharing in a timely manner any new information that may 
be relevant to the participant’s willingness to continue his participation in the study. 
The ICF will be used to explain the potential risks and benefits of study participation to the 
participant in simple terms before the participant is entered into the study, and to document 
that the participant is satisfied with his understanding of the risks and benefits of participating 
in the study and desires to participate in the study. 
The investigator is responsible for ensuring that informed consent is given by each participant. 
This includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of investigational 
product. 
11.1.1. 
Informed Consent Procedure 
Informed consent must be obtained before the participant enters into the study, and before 
any protocol-directed procedures are performed. 
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the participants in non-technical terms. Participants or their legally authorized 
representative will be required to read, sign and date an ICF summarizing the discussion prior 
to screening, and will be assured that they may withdraw from the study at any time without 
jeopardizing their medical care. 
Participants and/or their legally authorized representative will be given a copy of their signed 
ICF. 
A unique participant identification (ID) number (participant number) will be assigned to each 
participant and will be used throughout the study. 
The Investigator is responsible throughout the study for ensuring that the participant 
understands the potential risks and benefits of participating in the study, including answering 
any questions the participant may have throughout the study and sharing in a timely manner 
any new information that may be relevant to the participant’s willingness to continue his 
participation in the study. 
The ICF will be used to explain the potential risks and benefits of study participation to the 
participant in simple terms before the participant is entered into the study, and to document 
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that the participant is satisfied with his or her understanding of the risks and benefits of 
participating in the study and desires to participate in the study. 
The Investigator is responsible for ensuring that informed consent is given by each participant. 
This includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of study drug. 
11.2. 
Administrative Procedures  
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain participant confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the participant, except as necessary for monitoring and auditing by the sponsor, 
its designee, US FDA, Health Authorities, Ethics Committees, and/or IRBs.  
The Investigator and all employees and coworkers involved with this study may not disclose or 
use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the Sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
11.3. 
Ethical Review 
The Sponsor or its representatives must approve all ICFs before they are used at investigative 
sites(s). All ICFs must be compliant with the ICH guideline on GCP. 
Documentation of IRB/IEC approval of the protocol and the ICF must be provided to the 
Sponsor before the study may begin at the investigative site(s). The IRB/IEC(s) will review the 
protocol as required. 
The study site’s IRB/IEC(s) should also be provided with the following: 
 The current IB and updates during the study (IB Ed 5) 
 ICF 
 Relevant curricula vitae 
Only a Sponsor and IRB/IEC approved protocol and ICF may be used by the investigative site. 
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11.4.
Regulatory Considerations 
This study will be conducted in accordance with: 
 Consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
 The ICH GCP Guideline [E6] 
 Applicable FDA regulations
 Applicable laws and regulations 
The investigator or designee will promptly submit the protocol to applicable IRB/IEC(s). 
An identification code assigned by the investigator to each participant will be used in lieu of the 
participant’s name to protect the participant’s identity when reporting AEs and/or other study-
related data. 
11.5.
Confidentiality  
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain participant confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the participant, except as necessary for monitoring and auditing by the sponsor, 
its designee, US Food and Drug Administration, Health Authorities, Ethics Committees, and/or 
IRBs. The Investigator and all employees and coworkers involved with this study may not 
disclose or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the Sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
11.5.1.
Investigator Information 
11.5.2.
Protocol Signatures 
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of 
the study.  
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Sponsor representative. 
11.5.3.
Final Report Signature 
The investigator will sign the final clinical study report for this study, indicating agreement with 
the analyses, results, and conclusions of the report. 
The Sponsor’s responsible medical officer and statistician will approve the final clinical study 
report for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study. 
11.6.
Publication Policy 
The full terms regarding publication of the results of this study are outlined in the Clinical Study 
Agreement, Statement of Agreement, or the Master Clinical Study Agreement. Publication is 
permitted only after multi-center results are available and all disclosure requirements for 
clinical study registries have been met. Any data to be submitted for publication, including 
abstract submissions or presentations, are required to be submitted 
 for review at least 
30 days prior to submission. 
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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12. 
LIST OF REFERENCES 
21CFR361.1 FDA CFR Code of Federal Regulations Title 21, Volume 5, 01 Apr 2019 
ICRP Draft 2005 Recommendations on Radiological Protection: People Against Radiation 
Exposure In The Aftermath Of A Radiological Attack April 2004 (A Report from a Task Group of 
the ICRP) 
OV/TAK-935 Global Investigator Brochure Ed 5 22 Jan 2019. 
 
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CCI
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CCI
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se
CCI


 
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APPENDIX 2. 
CLINICAL LABORATORY TESTS (STUDY TAK-935-20-001 [OV935]): 
Protocol TAK-935-20-001 (OV935): Clinical Laboratory Tests 
Hematology: 
Clinical Chemistry: 
Erythrocytes  
Sodium 
Hemoglobin 
Potassium 
Hematocrit 
Total bilirubin 
Red blood cell indices 
Direct bilirubin 
Mean corpuscular volume reticulocytes 
Indirect bilirubin 
Ret. mean corpuscular hemoglobin 
Alkaline phosphatase 
Ret. corpuscular hemoglobin content 
Alanine aminotransferase (ALT) 
Reticulocyte distribution width 
Aspartate aminotransferase (AST) 
White blood cell count and differential 
Gamma-glutamyl transferase (GGT) 
Blood urea nitrogen (BUN) 
Neutrophils, segmented 
Creatinine 
Lymphocytes 
Urea 
Monocytes 
Calcium 
Eosinophils 
Phosphate 
Basophils 
Glucose, fasting 
Platelets 
Albumin 
Mean platelet volume 
Coagulation: 
Prothrombin time/INR 
Activated partial thromboplastin time 
Protein 
Alpha1-acidic glycoprotein (AGP) 
(screening only) 
 
Urinalysis: 
Carbon dioxide 
pH 
Magnesium 
Protein 
Chloride 
Glucose 
 
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Ketones 
 
Bilirubin 
 
Erythrocytes 
 
Leukocyte esterase 
 
Nitrite 
Urobilinogen 
Calcium 
 
Calcium/Creatinine 
 
Microscopy 
 
Other Laboratory Tests 
COVID-19 
HIV 
HBsAg 
HCV  
Urine alcohol screen 
Urine drug screen 
 
 
 
 
 
 
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CCI
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CCI
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CCI
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CCI
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CCI
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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1 Study to Assess Absolute Bioavailability of TAK-935 (OV935) and to 
Characterize Mass Balance, Pharmacokinetics, Metabolism, and Excretion of [14C]TAK-935 
(OV935) in Healthy Adult Male Participants 
NCT Number: NCT04992442
SAP Approve Date: 16 September 2020 
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


STATISTICAL ANALYSIS PLAN 
A Phase 1 Study to Assess Absolute Bioavailability of TAK-935 (OV935) and to 
Characterize Mass Balance, Pharmacokinetics, Metabolism, and Excretion of [14C]TAK-935 
(OV935) in Healthy Adult Male Participants 
Protocol No: TAK-935-20-001 (OV935) 
Final Protocol Date: 04 June 2020 
Protocol Clarification Letter Date: 19 June 2020 
Compound Name: Soticlestat (TAK 935, OV935) 
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S T A TI S TI C A L A N A L Y SI S P L A'.\ 
P A G E 
C o m p o u n d 1\ a m e : S o ticlestat ( T A K 9 3 5. 
Pr ot oc ol : T A K -9 3 5 -2 0 -0 0l ( 0 V 9 3 5 > 
St u d y Titl e : A P h as e I St u d y t o Assess A bs ol ut e Bi o a v a ila bilit y off A K- 9 3 5 ( 0 V 9 3 5) a n d t o 
C ha racteri ze M a ss Bala nce. P h a n n a c o ki n di c-.; , v kt a b o!;s m a n d 
(lf j q C J T A K- 9 3 5 
( O V 9 3 5) i n Healt h y A d ult Male P arti ci p a nts 
Iss ue Date: 1 6 S e p t e m b er 2 0 2 0 
Si g n at ur e
St at isti c al A nal ys is P l an, 1 6 S e pt e m b er 2 0 2 1i 
P.! g e 2 of 
I 
P P D
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


 
Statistical A nal ysis Pla n, 1 6 Se pte m ber 2 0 2 0 
Pa ge 3 of 1 3 1 
S T A TI S TI C A L A N A L Y SI S P L A N SI G N A T U R E P A G E 
C o m p o u n d Na me: S oticlestat ( T A K 9 3 5, O V 9 3 5) 
Pr ot oc ol: T A K- 9 3 5- 2 0- 0 0 1 ( O V 9 3 5) 
St u d y Title: A P hase 1 St u d y t o Assess A bs ol ute  Bi oa vaila bilit y of T A K- 9 3 5 ( O V 9 3 5) a n d t o 
C haracterize Mass Bala nce, P har mac o ki ne tics, Meta b olis m, a n d E xcreti o n of [1 4C] T A K- 9 3 5 
( O V 9 3 5) i n Healt h y A d ult Male Partici pa nts 
Iss ue Date: 1 6 Se pte m ber 2 0 2 0 
 
Si g nat ure
_ _ _ _ 
 
Si g nat ure
_ _ _ _ 
 
P P D
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


 
Statistical Analysis Plan, 16 September 2020 
Page 4 of 131 
TABLE OF CONTENTS 
ABBREVIATIONS ...................................................................................................................6 
1. 
INTRODUCTION ..............................................................................................................9 
2. 
OBJECTIVES AND ENDPOINTS ....................................................................................9 
2.1 
Objectives ..................................................................................................................9 
2.2 
Endpoints ................................................................................................................10 
3. 
STUDY DESIGN .............................................................................................................11 
4. 
ANALYSIS POPULATIONS ..........................................................................................14 
4.1 
Analysis Populations ...............................................................................................14 
4.2 
Preliminary Data and Interim Analysis ...................................................................14 
5. 
TREATMENT DESCRIPTIONS .....................................................................................14 
6. 
PHARMACOKINETIC ANALYSIS ...............................................................................15 
6.1 
Measurements and Collection Schedule .................................................................15 
6.2 
Bioanalytical Methods ............................................................................................19 
6.2.1 TAK-935 and M-I .......................................................................................19 
6.2.2 [14C]TAK-935 .............................................................................................19 
6.2.3 Total Radioactivity ......................................................................................19 
6.3 
Investigational Product and PK Analyte Information .............................................19 
6.3.1 TAK-935 and M-I .......................................................................................20 
6.3.2 Total Radioactivity ......................................................................................20 
6.4 
TAK-935 and Metabolite Concentrations ...............................................................20 
6.5 
NonCompartmental Pharmacokinetic Analysis and Parameter Calculation ...........21 
6.5.1 Whole Blood and Plasma Pharmacokinetic Parameters .............................21 
6.5.2 Urine and Feces Pharmacokinetic Parameters ............................................25 
6.6 
Data Summarization and Presentation ....................................................................27 
6.7 
Statistical Analysis of PK Parameters .....................................................................28 
7. 
SAFETY ...........................................................................................................................28 
7.1 
Subject Discontinuation ..........................................................................................29 
7.2 
Demographics .........................................................................................................29 
7.3 
Adverse Events........................................................................................................29 
7.4 
Clinical Laboratory Tests (Serum Chemistry, Hematology, Coagulation, 
Urinalysis) ...............................................................................................................30 
7.5 
Vital Signs ...............................................................................................................31 
7.6 
Electrocardiogram ...................................................................................................31 
7.7 
Concomitant Medications .......................................................................................31 
7.8 
Physical Examination ..............................................................................................31 
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7.9 
Neurological Examination ......................................................................................32 
7.10 Columbia Suicide Severity Rating Scale (C-SSRS) ...............................................32 
8. 
SUMMARY OF CHANGES FROM PROTOCOL-PLANNED ANALYSIS ................32 
9. 
SUMMARY TABLES AND FIGURES ..........................................................................32 
9.1 
In-text Summary Tables and Figures ......................................................................32 
9.2 
Section 14 Summary Tables and Figures ................................................................35 
9.3 
Section 16 Data Listings .........................................................................................45 
10. TABLE AND FIGURE SHELLS .....................................................................................50 
10.1 In-text Summary Table Shells .................................................................................51 
10.2 Figure Shells ...........................................................................................................61 
10.3 Section 14 Summary Table Shells ..........................................................................72 
11. LISTING SHELLS ...........................................................................................................93 
 
 
 
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Statistical Analysis Plan, 16 September 2020 
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ABBREVIATIONS 
%Dose 
Percentage of the dose eliminated/recovered in a given 
collection interval 
%Dose[f] 
Percentage of the dose excreted in feces in a given 
interval 
%Dose[u] 
Percentage of the dose excreted in urine in a given 
interval 
%F 
Percent absolute bioavailability 
λz; Kel 
Terminal disposition phase rate constant 
ABA; F 
Absolute bioavailability 
ADME 
Absorption, distribution, metabolism, and excretion 
Ae 
Amount eliminated/recovered in a given collection 
interval 
AE(s) 
Adverse event(s) 
Ae[f], Aet1-t2 
Amount eliminated/recovered in feces in a given 
interval 
Ae[u]; Aet1-t2 
Amount eliminated/recovered in urine in a given 
interval 
AMS 
Accelerator mass spectrometry 
ANOVA 
Analysis of variance 
AUC∞; AUC0-∞; AUC0-inf 
Area under the concentration-time curve from time 0 
to infinity, calculated using the observed value of the 
last quantifiable concentration. 
AUC0-t Ratio 
Ratio between plasma TAK-935, M-I, or 
[14C]TAK-935 AUC0-t and plasma total radioactivity 
AUC0-t. 
AUCCLR 
Area under the concentration time curve from time 0 
to time of the last common time point at which an 
analyte is quantifiable in the urine and plasma of a 
given subject 
AUCextrap% 
Area under the curve from the last quantifiable 
concentration to infinity calculated using the observed 
value of the last quantifiable concentration, expressed 
as a percentage of AUC0-∞. 
AUClast; AUC0-last 
Area under the concentration-time curve from time 0 
to time of the last quantifiable concentration 
AUCt; AUC0-t 
Area under the concentration time curve from time 0 
to time of the last common time point “t” for all 
participants at which an analyte (i.e., TAK-935, M-I, 
or [14C]TAK-935) and total radioactivity are 
quantifiable in plasma. 
BLQ 
Below the limit of quantitation 
Ceoi 
Concentration at the end of the infusion 
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Statistical Analysis Plan, 16 September 2020 
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CIs 
Confidence intervals 
CLR 
Renal clearance 
Cmax 
Maximum observed concentration 
Combined Cum%Dose 
Cumulative percentage of the dose 
eliminated/recovered in urine and feces combined 
COVID-19 
Novel coronavirus 2019 
CRF 
Case report form 
CRU 
Clinical research unit 
CS 
Clinically significant 
CSR 
Clinical study report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
Cum%Dose 
Cumulative percentage of the dose 
eliminated/recovered in successive collection intervals 
Cum%Dose[f] 
Cumulative percentage of the dose 
eliminated/recovered in feces 
Cum%Dose[u] 
Cumulative percentage of the dose 
eliminated/recovered in urine 
CumAe 
Cumulative amount eliminated/recovered in 
successive collection intervals 
CV% 
Arithmetic percent coefficient of variation 
DNAUC0-∞300; DNAUC0-inf300 AUC0-∞ normalized to a 300 mg dose 
DNAUC0-last300 
AUC0-last normalized to a 300 mg dose 
ECG(s) 
Electrocardiogram(s) 
Geom CV% 
Geometric percent coefficient of variation 
Geom Mean 
Geometric mean 
GMRs 
Geometric least-squares mean ratios 
HPLC-MS/MS 
High performance liquid chromatography-tandem 
mass spectrometry 
HR 
Heart rate 
ICH 
International Council for Harmonisation 
IV 
Intravenous 
LLOQ 
Lower limit of quantitation 
LS 
Least-squares 
Mean 
Arithmetic mean 
MedDRA® 
Medical Dictionary for Regulatory Activities 
MPRAUC0-∞ 
Metabolite-to-parent ratio of AUC0-∞ 
MW 
Molecular weight 
n 
Number of observations 
NCS 
Not clinically significant 
Pharmacokinetic(s) 
PK 
PI 
Principal Investigator 
PT 
Preferred Term 
QTc 
Corrected QT interval 
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Statistical Analysis Plan, 16 September 2020 
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QTcF 
QT interval corrected using Fridericia’s formula 
R2 
Coefficient of determination 
SAEs 
Serious adverse events 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SEM 
Standard error of the mean 
SOC 
System Organ Class 
t1/2z 
Terminal disposition phase half-life 
TEAEs 
Treatment-emergent adverse events 
TFLs 
Tables, figures, and listings 
tmax 
Time of first occurrence of Cmax 
ULOQ 
Upper limit of quantitation 
WHO 
World Health Organization 
 
 
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Statistical Analysis Plan, 16 September 2020 
Page 9 of 131 
1. INTRODUCTION 
The following statistical analysis plan (SAP) provides the framework for the 
summarization of the data from this study. The SAP may change due to unforeseen 
circumstances. Any changes made from the planned analysis within protocol after 
locking the database will be documented in the clinical study report (CSR). The 
section referred to as Table Shells within this SAP describes the traceability of the 
tables, figures, and listings (TFLs) back to the data. Note that the header for this page 
will be the one used for the main body of the CSR.  
Any additional exploratory analyses not addressed within this SAP and/or driven by 
the data, or requested by the SPONSOR, will be considered out of scope and must be 
described in the CSR.  
2. OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
Primary 
Period 1 (ABA) 
• 
To determine absolute bioavailability (ABA) of TAK-935 following a single 
microdose intravenous (IV) administration of 50 µg (~1 µCi) [14C]TAK-935 and a 
single oral administration of 300 mg TAK-935. 
Period 2 (ADME) 
• 
To assess the mass balance (i.e., cumulative excretion of total radioactivity in 
urine and feces) following a single oral administration of 300 mg (~100 µCi) 
[14C]TAK-935. 
• 
To characterize the pharmacokinetics (PK) of TAK-935 and M-I in plasma and 
urine, and total radioactivity concentration equivalents in plasma and whole blood 
following a single oral administration of 300 mg (~100 µCi) [14C]TAK-935. 
Secondary 
Period 1 (ABA) 
• 
To determine the PK of [14C]TAK-935 following a single IV administration of 
50 µg (~1 µCi) [14C]TAK-935 and the PK of TAK-935 following a single oral 
administration of 300 mg TAK-935. 
• 
To determine fecal and urinary excretion of the parent [14C]TAK 935 following a 
single IV administration of 50 µg (~1 µCi) [14C]TAK-935. 
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Statistical Analysis Plan, 16 September 2020 
Page 10 of 131 
Period 2 (ADME) 
• 
To assess the metabolic profile of TAK-935 in plasma, urine, and feces following 
a single oral administration of 300 mg (~100 µCi) [14C]TAK-935. 
Periods 1 (ABA) and 2 (ADME) 
• 
To assess the safety of TAK-935 during the ABA and ADME study periods. 
Note: this SAP does not address the secondary objective of assessing the metabolic 
profile of TAK-935 in plasma, urine, and feces.  This objective will be assessed by 
Takeda. 
2.2 
Endpoints 
Primary 
Period 1 (ABA) 
• 
Absolute bioavailability (F) as percent F (%F) for TAK-935. 
Period 2 (ADME) 
• 
Percent of total radioactivity excreted in urine (Cum%Dose[u]) and feces 
(Cum%Dose[f]) relative to the administered radioactive dose (Combined 
Cum%Dose). 
• 
Amount of total radioactivity excreted in urine (Ae[u]) and feces (Ae[f]) and the 
percent of administered radioactive dose excreted in urine and feces within a 
given collection interval (urine %Dose[u]) and feces (%Dose[f]). 
• 
PK parameters Cmax, tmax, t1/2z, AUC∞, AUCt, and AUClast for TAK-935 in plasma. 
• 
PK parameters Cmax, tmax, t1/2z, AUC∞, AUCt, and AUClast for total radioactivity 
concentration equivalents in plasma and whole blood. 
• 
PK parameters for renal clearance (CLR) for TAK-935 in urine. 
• 
PK parameters for amount excreted in each collection interval (Aet1-t2) for 
TAK-935 in urine. 
• 
The change over time in percentage of [14C]-radioactivity in whole blood relative 
to plasma (i.e., whole blood:plasma partitioning ratio). 
 
 
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Statistical Analysis Plan, 16 September 2020 
Page 11 of 131 
Secondary 
Period 1 (ABA) 
• 
PK parameters including concentration at the end of the infusion (Ceoi) (IV 
infusion), Cmax (oral), tmax (oral), AUC∞, AUCt, AUClast, and t1/2z for TAK 935, 
and [14C]TAK-935 in plasma. 
• 
Total radioactivity excreted and percentage of dose excreted in the feces (amount 
eliminated/recovered in feces [Ae(f)] and %Dose(f)) and amount 
eliminated/recovered in urine [Ae(u)] and %Dose(u)) as total radioactivity 
following IV administration. 
Period 2 (ADME) 
• 
Metabolic profile of TAK-935 in plasma, urine, and feces following a single oral 
administration of 300 mg (~100 µCi) [14C]TAK-935. 
Periods 1 (ABA) and 2 (ADME) 
• 
Tabulated treatment-emergent adverse events (TEAEs) and summary statistics for 
clinically relevant 12-lead electrocardiograms (ECGs), vital signs, and clinical 
laboratory tests results. 
Note: this SAP does not address the secondary endpoint of the metabolic profile of 
TAK-935 in plasma, urine, and feces. This endpoint will be determined by Takeda. 
3. STUDY DESIGN 
This was an open-label, 2-period, fixed-sequence, single-dose study in 6 healthy adult 
male participants. 
On Day 1 of Period 1 (ABA Study Period), participants received a single oral 300 mg 
dose of unlabeled TAK-935 in tablet form (3 x 100 mg tablets). At 0.17 hours 
(10 minutes) post oral dosing (i.e., 15 minutes prior to the median tmax for the oral 
unlabeled dose [~ 0.42 hours or 25 minutes]), participants received a 15-minute IV 
infusion of a microdose of 50 µg (~1 µCi) [14C]TAK-935. Serial blood sampling was 
performed up to 48 hours (Day 3) to determine the PK of TAK-935 and its M-I 
metabolite (and others, if applicable) in plasma for the oral dose and total 
radioactivity and PK of [14C]TAK-935 in the plasma for the IV dose. Urine and fecal 
output were also collected up to 120 hours postdose to determine total radioactivity 
recovery. Collection of urine and fecal samples continued until one of the release 
criteria was met (i.e., 80% or greater of the total dose of radioactivity administered is 
recovered in urine and fecal samples or the excretion of radioactivity in the urine and 
feces combined had declined to ≤ 1% of the total administered radioactivity for at 
least 2 consecutive intervals where both a urine and fecal sample were collected) or 
up to Day 8, but no less than Day 6, for total radioactivity excretion in urine and 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


 
Statistical Analysis Plan, 16 September 2020 
Page 12 of 131 
feces. Participants who met release criteria before Day 8, but no less than Day 6, were 
to remain confined in the clinical research unit (CRU) until Day -1 of Period 2 and 
throughout Period 2 (until a Period 2 discharge criterion was met). 
There was a washout period of at least 7 days between the last dose in Period 1 and 
the dose in Period 2. 
On Day 1 of Period 2 (ADME Study Period), participants received a single oral dose 
of 300 mg (~100 μCi) [14C]TAK-935 in solution. Serial blood sampling was 
performed and urine and feces were collected to determine the PK of TAK-935 and 
M-I in plasma and urine; and total radioactivity in plasma, whole blood, urine, and 
feces; and to characterize the metabolite profiles of TAK-935 in plasma, urine, and 
feces. Complete urinary and fecal output were collected during the confinement 
period until a discharge criterion was met. 
In Period 2, participants were confined in the CRU for at least 5 days postdose (i.e., 
120 hours) and until 90% or greater of the total dose of radioactivity administered 
was recovered in urine and fecal samples. If less than 90% of the total dose of 
radioactivity administered was recovered in urine and fecal samples, participants 
were to be confined in the clinic until a discharge criterion was met (i.e., 90% or 
greater of the total dose of radioactivity administered is recovered in urine and fecal 
samples or the excretion of radioactivity in the urine and feces combined had declined 
to ≤ 1% of the total administered radioactivity per 24 hour interval for at least 2 
consecutive intervals where both a urine and fecal sample were collected) or up to 
Day 11 (i.e., 240 hours). Release of participants who do not meet a discharge criterion 
by 240 hours (Period 2) was to be reviewed on a case-by-case basis. At all times, a 
participant may have been required to remain at the CRU for longer at the discretion 
of the Investigator or designee. 
Since up to an approximate 24-hour time lag was anticipated for radioactivity 
counting of samples, actual participant release from the CRU may have occurred 1 
day after a discharge criterion was met. 
In both periods, any participant who experienced emesis within 1-hour post oral 
dosing was to be excluded in the PK data analysis and may have been replaced with a 
new participant. If a participant discontinued in Period 2, the replacement participant 
was to complete Period 2 only. If a participant experienced emesis after dosing in 
Period 2, vomitus was to be collected throughout the study and assayed for total 
radioactivity. 
The clinic was to contact all participants (including participants who terminated the 
study early) 30 ± 2 days after the last study drug administration to determine if any 
adverse events (AEs) had occurred since the last study visit. 
 
 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


 
Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 1 3  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


 
Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
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4.  A N A L Y SI S P O P U L A TI O N S  
4. 1  
A n al ysis P o p ul ati o ns 
P h ar m a c o ki netic Set  
All partici pa nts w h o c o m plie d s ufficie ntl y wit h t he pr ot oc ol a n d dis pla ye d a n 
e val ua ble P K pr ofile (e . g., e x p os ure t o treat me nt, a vaila bilit y of meas ure m e nts a n d 
a bse nce of maj or pr ot o c ol vi olati o ns) will be i ncl u de d i n t he statistical a nal ys es.  
S af et y P o p ul ati o n 
All partici pa nts w h o recei ve d at least o ne d ose of t he st u d y dr u g will be i ncl u de d i n 
t he safet y e v al uati o ns. 
4. 2  
Preli mi n ar y  D at a a n d I nteri m A n al ysis 
5.  T R E A T M E N T D E S C RI P TI O N S  
T h e treat me nts a d mi nistere d will be descri be d i n t he P K ta bles a n d fi g ures as f oll o ws: 
Tre at me nt  
Descri pti o n  
3 0 0 m g  T A K  9 3 5  P O:  
a si n gle oral d ose of 3 0 0 m g T A K -9 3 5  i n P eri o d 1 
5 0  µ g  (~ 1  μ Ci)  [1 4C] T A K -9 3 5  I V: 
a si n gle i ntra ve n o us i nf usi o n of 5 0  µ g  (~ 1  μ Ci)  
[1 4C] T A K -9 3 5  a d mi nistere d o ver  1 5  mi n ute s fr o m 1 0 t o 
2 5 mi n utes after t he oral d ose of T A K -9 3 5  i n P eri o d 1 
3 0 0  m g  (~ 1 0 0  μ Ci)  [ 1 4 C]T A K -9 3 5  P O:  a si n gle oral d ose of 3 0 0 m g ( ~ 1 0 0  μ Ci) [ 1 4C] T A K -9 3 5  i n 
P eri o d 2  
F or safet y ta bles a n d listi n gs, d ue t o s paci n g li mitati o n, treat me nts will be c o de d 
usi n g A a n d B wit h t he f oll o w f o ot n otes: 
Treat me nt  A:  3 0 0 m g T A K -9 3 5 ( 3 x 1 0 0 m g ta blets) a d mi nistere d orall y at H o ur 0 o n Da y 1 
f oll o we d b y 5 0 μ g ( ~ 1 μ Ci) [1 4C] T A K -9 3 5 I V s ol uti o n a d mi nistere d at H o ur 0. 1 7 
( 1 0 mi n utes  p ost oral d osi n g) f or 1 5 mi n utes   
Treat me nt B:  3 0 0 m g ( ~ 1 0 0 μ Ci) [ 1 4C] T A K -9 3 5 a d mi nistere d as a n oral s ol uti o n at H o ur 0 o n Da y 1  
 
 
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


 
Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 1 5  of 1 3 1  
6.  P H A R M A C O KI N E TI C A N A L Y SI S  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


 
Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 1 6  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 1 7  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 1 8  of 1 3 1  
All c o nce ntrati o n dat a will be i ncl u de d i n t he calc ulati o n of t he i n di vi d ual P K 
para meters , t he i n di vi d ual c o nce ntrati o n vers us ti me pl ots ( base d o n act u al sa m ple 
ti mes), a n d t he mea n c o n ce ntrati o n vers us ti me, i n di vi d ual a n d mea n w h ole 
bl o o d: plas ma partiti o ni n g r ati o vers us ti me, a n d i n di vi d ual a n d mea n c u m ulati ve 
perce nt a ge of t h e d ose r ec o vere d v ers us ti me pl ots ( base d o n n o mi nal sa m ple ti mes) . 
H o we ver, if t here ar e a n y si g nifica nt d e viati o ns  fr o m n o mi nal sa m ple ti mes, s o me 
c o nce ntr ati o n data ma y b e e x cl u de d fr o m mea n c o nce ntrati o n -ti me pl ots a n d/ or 
a d diti o nal c o nce ntr ati o n-ti me pl ots of t he mea n data ma y b e pr o vi de d. Al l d e viati o ns 
a n d e x cl u de d data will be pr o vi de d a n d disc usse d i n t he C S R. 
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 1 9  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


 
Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 2 0  of 1 3 1  
6. 3. 1  T A K - 9 3 5 a n d M-I 
Plas ma  will be a nal yze d f or T A K - 9 3 5 a n d M-I c o nce ntrati o ns  f oll o wi n g a si n gle oral 
d ose of 3 0 0 m g T A K - 9 3 5 i n Peri o d 1. Plas ma, uri ne, a n d feces will be a nal yz e d f or 
[1 4C] T A K - 9 3 5 c o nce ntrati o ns f oll o wi n g a si n gle micr o d ose of 5 0 µ g  (~ 1  μ Ci) 
[1 4C] T A K - 9 3 5 a d mi nistere d via a 1 5 - mi n ute I V i nf usi o n fr o m 1 0 t o 2 5 mi n utes after 
t he oral d ose of T A K - 9 3 5 i n Peri o d 1. Uri ne will be a nal yz e d f or T A K - 9 3 5 a n d M-I 
c o nce ntr ati o ns f oll o wi n g a si n gle oral d ose of 3 0 0 m g ( ~ 1 0 0 μ Ci) [ 1 4C] T A K - 9 3 5 i n 
Peri o d 2. 
 
. 
6. 3. 2  T ot al R a di o acti vit y 
Plas ma, uri ne, a n d feces will be a nal yze d f or t otal ra di oacti vit y f oll o wi n g a si n gle 
micr o d ose of 5 0 µ g ( ~ 1  μ Ci) [ 1 4C] T A K - 9 3 5 a d mi nistere d via a 1 5 - mi n ute I V i nf usi o n 
fr o m 1 0 t o 2 5 mi n utes after t he oral d ose of T A K- 9 3 5 i n Peri o d 1. W h ole bl o o d, 
plas ma, uri ne, a n d f eces will be a nal yze d f or t otal ra di oacti vit y f oll o wi n g a si n gle oral 
d ose of 3 0 0 m g ( ~ 1 0 0 μ Ci) [ 1 4C] T A K - 9 3 5 i n Peri o d 2. C o nce ntrati o ns of total 
ra di oacti vit y i n all matrices will be meas ure d i n d p m/ m L or d p m/ g  of sa m pl e , a n d 
t hese will be c o n verte d t o T A K- 9 3 5 e q ui val e nt c o nce ntrati o ns ( n g e q T A K- 9 3 5/ m L 
or n g e q T A K- 9 3 5/ g) b y di vi di n g t hese d p m/ m L or d p m/ g c o n ce ntrati o ns b y t he 
s pecific acti vit y of t he a d mi nistere d ra di oacti ve d ose (e. g., d p m/ n g). 
6. 4  
T A K - 9 3 5 a n d Met a b olite C o nce ntr ati o ns  
C o nce ntrati o n data d eter mi ne d at t he c ollecti o n ti mes a n d per t he bi o a nal ytic al 
met h o ds descri be d i n Secti o n 6. 1 a n d Secti o n 6. 2, res pect i vel y, will be use d f or t he 
calc ulati o n of plas ma a n d uri ne T A K -9 3 5 a n d  M-I; plas ma, uri ne, a n d feces 
[1 4C] T A K - 9 3 5; a n d w h ole bl o o d, plas ma , uri ne, a n d feces t otal ra di oacti vit y P K 
para meters . 
I n or der t o pl ot M-I c o nce ntrati o ns al o n g wit h T A K- 9 3 5 c o nce ntrati o ns a n d t otal 
ra di oacti vit y T A K- 9 3 5 c o nce ntrati o n e q ui val e nts i n t he sa me fi g ures, plas ma M-I 
c o nce ntr ati o ns will als o be prese nt e d i n T A K- 9 3 5 e q ui vale nts (i.e., n g T A K- 9 3 5/ m L) 
usi n g t he f oll o wi n g f or m ula: 
M-I c o nce ntrati o n ( n g T A K- 9 3 5/ m L) = M-I c o nce ntrati o n ( n g/ m L) x M W
T A K -9 3 5 / M WM-I  
I n a d diti o n, t he arit h metic mea n plas ma c o nce ntrati o ns of ot her meta b olites (i.e., n ot 
i ncl u di n g M-I) c o m bi ne d i n T A K- 9 3 5 e q ui vale nts i n Peri o d 2 will be esti mate d a n d 
pl otte d al o n g wit h plas m a T A K - 9 3 5 a n d M-I (i n T A K - 9 3 5 e q ui val e nt) 
c o nce ntr ati o ns, a n d w h ol e bl o o d a n d plas ma t otal ra di oacti vit y c o nce ntrati o n 
e q ui vale nts i n t he sa me i n-te xt fi g ures. T he arit h metic mea n plas ma c o n ce ntrati o ns of 
ot her meta b olites c o m bi ne d will be deter mi ne d usi n g t he f oll o wi n g f or m ul a: 
Mea n
( Ot h er M eta b olit es ) = Mea n ( Tot al R a di oacti vit y) – [Mea n
(T A K -9 3 5 ) + Mea n ( M-I)] 
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


 
Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 2 1  of 1 3 1  
6. 5  
N o n C o m p art me nt al P h ar m ac o ki netic A n al ysis a n d P ar a meter C alc ul ati o n 
6. 5. 1  W h ole Bl o o d a n d Pl as m a P h ar m ac o ki netic P a r a meters  
T he a p pr o pri ate n o nc o m part me ntal P K para meters will be calc ulate d fr o m t he w h ole 
bl o o d a n d plas ma t otal ra di oacti vit y c o n ce ntrati o n e q ui vale nt ( plas ma i n b ot h 
Peri o ds 1 a n d 2, w h ole bl o o d i n Peri o d 2 o nl y) a n d plas ma T A K - 9 3 5 a n d M-I 
c o nce ntr ati o n ( Peri o ds 1 a n d 2) vers us ti me dat a usi n g P h oe ni x ®  Wi n N o nli n®  
Versi o n  8. 1 or hi g her. Act ual sa m ple ti mes will be use d i n t he calc ulati o ns of t he P K 
para meters. T he calc ulati o n of t he act ual ti mes f or plas ma T A K - 9 3 5 a n d M-I P K 
sa m ples i n Peri o d 1 will be  i n res pect t o t he ti me of t he si n gle oral d ose of 3 0 0 m g 
T A K - 9 3 5 i n Peri o d 1. T h e calc ul ati o n of t he act u al ti mes f or plas ma [1 4C] T A K - 9 3 5 
a n d t otal ra di oacti vit y P K sa m ples i n Peri o d 1 will be i n res pect t o t he ti me of t he 
start of t he 1 5-mi n ute I V i nf usi o n of 5 0 µ g  (~ 1  μ Ci ) [1 4C] T A K - 9 3 5 i n Peri o d 1. T he 
calc ulati o n of t he act ual ti mes f or plas ma T A K - 9 3 5 a n d M-I P K sa m ples, a n d w h ole 
bl o o d a n d plas ma t otal ra di oacti vit y P K sa m ples i n Peri o d 2 will be i n res pect t o t he 
ti me of t he si n gle or al d ose of 3 0 0 m g ( ~ 1 0 0 μ Ci) [ 1 4C] T A K- 9 3 5 i n Peri o d 2. All P K 
para meters i ncl u de d i n t h e pr ot oc ol are liste d  i n Ta ble  6. 5 bel o w, a n d are d efi ne d as 
a p pr o priate f or st u d y desi g n. 
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 2 2  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 2 3  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 2 4  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 2 5  of 1 3 1  
T he f oll o wi n g n o n c o m part me ntal P K para met ers will be calc ulate d f or uri ne , feces, 
a n d uri ne a n d feces c o m bi ne d [1 4C] T A K - 9 3 5 c o nce ntrati o ns ( Peri o d 1), uri ne 
T A K - 9 3 5 a n d M-I c o n ce ntrati o ns ( Peri o d 2), a n d uri ne, feces, a n d uri ne a n d feces 
c o m bi ne d t otal ra di oacti vit y c o nce ntrati o n e q ui val e nts ( Peri o ds 1 a n d 2) , as 
a p pr o priate, usi n g S A S ®  Versi o n 9. 4 or hi g her. All P K para meters i ncl u d e d i n t he 
pr ot oc ol are liste d i n Ta ble  6. 7 bel o w a n d are defi ne d as a p pr o priate f or st u d y desi g n. 
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 2 6  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


 
Statistical Analysis Plan, 16 September 2020 
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6.6 
Data Summarization and Presentation 
All statistics will be generated using SAS® Version 9.4 or higher. 
Concentrations data will be listed and summarized by analyte, treatment, and time 
point for all subjects in the PK Population. Concentration data will be presented with 
the same level of precision as received from the bioanalytical laboratory. Descriptive 
statistics, including the number of observations (n), arithmetic mean (Mean), standard 
deviation (SD), arithmetic percent coefficient of variation (CV%), standard error of 
the mean (SEM), minimum, median, and maximum will be calculated for all nominal 
concentration time points. Excluded subjects will be included in the concentration 
listings, but will be excluded from the descriptive statistics and noted as such in the 
tables. All BLQ values will be presented as “BLQ” in the concentration listings and 
footnoted accordingly. Whole blood:plasma total radioactivity partitioning ratios will 
be listed and summarized by time point for all subjects in the PK Population using the 
same descriptive statistics as above, and also including Geom Mean and geometric 
percent coefficient of variation (Geom CV%). 
Urine sample weight (including additive(s), if any) and fecal homogenate weight will 
be listed and summarized by collection interval for all subjects in the PK Population. 
Urine sample and fecal homogenate weight data will be presented with the same level 
of precision as received from the clinic. These data will be summarized using the 
same descriptive statistics as for the concentration data. Excluded subjects will be 
included in the listings, but will be excluded from the descriptive statistics and noted 
as such in the tables. 
PK parameters will be listed and summarized by analyte and treatment for all subjects 
in the PK Population. Pharmacokinetic parameters will be reported to 3 significant 
figures for individual parameters, with the exception of tmax, which will be presented 
with 3 decimal places. Descriptive statistics (n, arithmetic mean, SD, CV%, SEM, 
minimum, median, maximum, Geom Mean, and Geom CV%) will be calculated for 
all PK parameters. Excluded subjects will be listed in the PK parameter tables, but 
will be excluded from the descriptive statistics and noted as such in the tables. 
The level of precision for each descriptive statistic will be presented as follows: 
minimum/maximum with same precision as individual values, mean/median/Geom 
Mean with one more level of precision than minimum/maximum, SD/SEM with one 
more level of precision than mean/median/Geom Mean, n will be presented as an 
integer, and CV%/Geom CV% will be presented to the nearest tenth. 
Mean and individual whole blood and plasma concentration-time profiles will be 
presented on linear and semi-log scales. Linear mean plots will be presented with and 
without SD. Mean and individual whole blood:plasma partitioning ratio-time profiles 
will be presented on linear scale with and without SD. Mean and individual urine, 
feces, and urine and feces combined cumulative excretion (recovery)-time profiles 
will be presented on linear scale with and without SD.  
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


 
Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 2 8  of 1 3 1  
A rit h metic mea n plas ma T A K - 9 3 5-e q ui vale nt c o n ce ntrati o ns of ot her meta b olites 
c o m bi ne d i n Peri o d 2 will be pl otte d al o n g wit h T A K - 9 3 5 a n d M-I (as T A K- 9 3 5 
e q ui vale nt) c o n ce ntrat i o ns, a n d w h ole bl o o d a n d plas ma t otal ra di oacti vit y 
c o nce ntr ati o n e q ui vale nts i n t he sa me i n-te xt fi g ures o n li near a n d se mi -l o g scales 
wit h o ut S D bars.  
Arit h metic mea n C u m % D ose f or ot her meta b olites c o m bi ne d i n uri ne i n Peri o d  2 will 
be prese nt e d i n t he te xt of t he C S R b ut n ot i n a n y ta bles or fi g ures. 
7.  S A F E T Y  
All case r e p ort f or m ( C R F) data will be liste d b y s u bject a n d c hr o n ol o gicall y b y 
assess me nt ti me p oi nts. T his will i ncl u de rec hec ks, u nsc he d ule d assess me nts, a n d 
earl y ter mi nati o n.  
A p plica ble c o nti n u o us varia bles will be s u m marize d usi n g n, arit h metic mea n, S D, 
mi ni m u m, me dia n, a n d ma xi m u m.  
T he le vel of pr ecisi o n will be prese nte d as f oll o ws: mi ni m u m/ ma xi m u m i n t he sa me 
precisi o n as i n t he data b ase, mea n/ me dia n i n o ne m ore precisi o n le vel t ha n 
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


 
Statistical Analysis Plan, 16 September 2020 
Page 29 of 131 
minimum/maximum, SD in one more precision level than mean/median, and n and % 
will be presented as an integer. 
Where individual data points are missing because of dropouts or other reasons, the 
data will be summarized based on reduced denominators. 
7.1 
Subject Discontinuation 
Subjects will be summarized by the number of subjects dosed, completed, and 
discontinued the study with discontinuation reasons. 
7.2 
Demographics 
Descriptive statistics will be calculated for continuous variables (age, weight, height, 
and body mass index). Age will be derived from date of birth to date of first dosing. 
Frequency counts will also be provided for categorical variables (race, ethnicity, and 
sex). 
7.3 
Adverse Events 
All adverse events (AEs) occurring during this clinical trial will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA®), Version 23.0.  
All AEs captured in the database will be listed in by-subject data listings including 
verbatim term, coded term, treatment, severity, relationship to study drug, and action; 
however, only treatment-emergent AEs (TEAEs) will be summarized.  
A TEAE is defined as an AE that is starting or worsening at the time of or after study 
drug administration. Each TEAE will be attributed to a treatment based on the onset 
date and time of the AE.  
If an AE increases in severity, that AE will be given a resolution date and time and a 
new record will be initiated with the new severity. If the severity of an AE remains 
the same or decreases, the AE will be kept open through to resolution.  
If the onset time of an AE is missing and the onset date is the same as or occurs after 
the treatment dosing date, then the AE will be considered treatment emergent. If the 
onset date of an AE is missing, then the AE will be considered treatment emergent. 
TEAEs will be tabulated by System Organ Class (SOC) and Preferred Term (PT). 
Summary tables will include the number of subjects reporting the AE and as a percent 
of the number of subjects dosed by treatment and overall. The number of AEs will be 
tabulated in a similar manner. A table summarizing the number of TEAEs by severity 
and relationship to study drug will also be included.  
Serious adverse events (SAEs) and AEs leading to discontinuation, if present, will 
also be listed. Applicable narratives will be included in the CSR.  
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Statistical Analysis Plan, 16 September 2020 
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7.4 
Clinical Laboratory Tests (Serum Chemistry, Hematology, Coagulation, 
Urinalysis) 
Clinical laboratory tests for serum chemistry, hematology, coagulation, and urinalysis 
will be performed at Screening, Day -1 and Day 3 of each period, and Discharge or 
Early Termination. 
All clinical laboratory data will be listed by subject and presented using conventional 
units to align with the CRF. 
Out-of-normal range flags will be recorded as follows: high (H) and low (L) for 
numerical results and did-not-match (*) for categorical results. If a value fails the 
reference range, it will automatically be compared to a computer clinically significant 
(CS) range. If the value falls within the computer CS range, it will be noted as “N” 
for not clinically significant (NCS). If the value fails (i.e., falls outside of the CS 
range) the computer CS range, it will be flagged with a “Y” which prompts the 
Principal Investigator (PI) to determine how the out-of-range value should be 
followed using 4 Investigator flags: "N", not clinically significant, "R", requesting a 
recheck, "^", checking at the next scheduled visit, or "Y", clinically significant. To 
distinguish the PI flag from the computer CS range flags, the PI flags of “N” and “Y” 
will be presented as “-” and “+”, respectively, in the data listing. Additionally, the PI 
will provide a fourth flag when the third flag indicates “R” or “^”. This fourth flag is 
intended to capture final CS (+)/NCS (-) when the third flag does not document 
significance. 
Out-of-range values and corresponding recheck results will be listed. Results that are 
indicated as CS by the PI will be listed by subject in a table. This table will also list 
the results at all other time points for the laboratory test and subject with at least one 
value deemed as CS by the PI. 
For all numeric laboratory values, descriptive statistics will be presented for each 
laboratory test by assessment time point (and by treatment for baseline and Day 3 
time points). Change from baseline will be summarized in a similar manner. Baseline 
is defined as the result closest and prior to dose which may include unscheduled or 
recheck results. This will typically be the result collected on Day -1 of each period. 
Postdose unscheduled events or rechecks will not be included in summaries. 
Similarly, early termination results will not be included in summaries. 
For each laboratory test, a shift table will be developed to compare the frequency of 
the results at baseline (above normal, normal, or below normal) with the respective 
Day 3 postdose results. For urinalysis tests, the categories are normal and outside 
normal.  
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Statistical Analysis Plan, 16 September 2020 
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7.5 
Vital Signs 
Blood pressure (systolic and diastolic), heart rate, respiratory rate, and temperature 
will be measured at Screening, Day -1 (within 24 hours prior to oral dosing) and Day 
1 Hour 0.5 of each period, Day 1 Hour 2 of Period 2, and Discharge or Early 
Termination (respiratory rate and temperature will not be measured at Discharge or 
Early Termination). 
Descriptive statistics will be presented for each vital sign parameter by assessment 
time point (and by treatment for baseline and Day 1 Hour 0.5 and Hour 2 [Period 2 
only] time points). Change from baseline will be summarized in a similar manner. 
Baseline is defined as the result closest and prior to dose which may include 
unscheduled or recheck results. This will typically be the result obtained on Day -1 of 
each period. Postdose unscheduled events or rechecks will not be included in 
summaries. Similarly, early termination results will not be included in summaries. 
7.6 
Electrocardiogram 
12-lead ECGs [heart rate (HR), PR, QRS, QT, and corrected QT (QTc) interval using 
Fridericia’s correction (QTcF)] will be performed at Screening, Day -1 (within 24 
hours prior to oral dosing) of each period, Day 1 Hour 0.5 of Period 2, and Discharge 
or Early Termination. 
Descriptive statistics will be presented for each ECG parameter by assessment time 
point (and by treatment for baseline and Day 1 Hour 0.5 [Period 2 only] time points). 
Change from baseline will be summarized in a similar manner. Baseline is defined as 
the result closest and prior to dose which may include unscheduled or recheck results. 
This will typically be the result obtained on Day -1 of each period. Postdose 
unscheduled events or rechecks will not be included in summaries. Similarly, early 
termination results will not be included in summaries.  
All ECG data will be listed by subject and QTcF values that are > 450 msec and 
increase from baseline > 30 msec will be flagged. 
7.7 
Concomitant Medications 
All concomitant medications recorded during the study will be coded with the World 
Health Organization (WHO) Dictionary Version 01-Mar-2020 b3 and listed. 
7.8 
Physical Examination 
Physical examinations will be performed at Screening Day -1 of each period, and 
Discharge or Early Termination. Symptom-driven physical examinations may be 
performed any time, at the Investigator’s discretion. Abnormal findings will be 
reported as medical history or adverse events. All data found in the CRF will be 
listed.  
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Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 3 2  of 1 3 1  
7. 9  
Ne ur ol o gic al E x a mi n ati o n 
Ne ur ol o gical e x a mi nati o ns will b e perf or me d at Scree ni n g D a y - 1 of eac h peri o d, a n d 
Disc har ge or Earl y T er mi nati o n. Res ults of ne ur ol o gical e x a mi nati o ns will be liste d 
b y s u bject.  
7. 1 0  
C ol u m bi a S uici de Se verit y R ati n g Sc ale ( C -S S R S)  
Assess me nts of C - S S R S q uesti o n naires will be perf or me d usi ng Baseli ne/ S cree ni n g 
Versi o n at scr ee ni n g a n d Si nce Last Visit Versi o n at Da y - 1 of eac h peri o d, Da y 3 of 
Peri o d 1, a n d Disc har ge or Earl y Ter mi nati o n. T he C- S S R S res ults will be liste d b y 
s u bject. 
8.  S U M M A R Y O F C H A N G E S F R O M P R O T O C O L -P L A N N E D A N A L Y SI S  
T he a nal yses d escri be d i n t his S A P are ali g ne d wit h t h ose a nal ys es descri be d i n t he 
pr ot oc ol. 
9.  S U M M A R Y T A B L E S A N D FI G U R E S  
S u m mar y ta bles a n d fi g ures are n u m bere d f oll o wi n g t he I nt er nati o nal C o u ncil f or 
Har m o nisati o n ( I C H) str uct ure b ut ma y be re n u m bere d as a p pr o pri ate d uri n g t he 
c o m pilati o n of t he ta bles a n d fi g ures f or t he C S R . Note t hat all s u m mar y ta bles a n d 
fi g ur es will be ge nerate d usi n g S A S®  Versi o n  9. 4 or hi g her.  
 
 
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


 
Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 3 3  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 3 4  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 3 5  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 3 6  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 3 7  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 3 8  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 3 9  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 4 0  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 4 1  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 4 2  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 4 3  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 4 4  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 4 5  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 4 6 of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 4 7  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 4 8  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e


Sta tistical A nal ysis Pla n, 1 6 Se pte m ber  2 0 2 0  
P a ge 4 9  of 1 3 1  
C CI
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e