A Dose-Blind Extension Study With Double-blind, Placebo-Controlled, Randomized Withdrawal Period to Evaluate the Safety and Explore the Pharmacokinetics and Pharmacodynamics of TAK-994 in Adults With Narcolepsy With Cataplexy (Narcolepsy Type 1)
Phase: PHASE2
Conditions: Narcolepsy Type 1 (NT 1)
Sponsor: Takeda

TAKEDA PHARMACEUTICALS
PROTOCOL
A Dose-Blind Extension Study With Double-blind, Placebo-Controlled, Randomized 
Withdrawal Period to Evaluate the Safety and Explore the Pharmacokinetics and 
Pharmacodynamics of TAK-994 in Adults With Narcolepsy With Cataplexy 
(Narcolepsy Type 1) 
TAK-994 Extension and Randomized Withdrawal Study in Adult Subjects With Narcolepsy 
Type 1
Sponsor:
Takeda Development Center Americas, Inc.
95 Hayden Avenue
Lexington MA 02421
USA 
Study Number:
TAK-994-1504
IND Number:
142658
EudraCT Number:
2021-000251-39
Compound:
TAK-994
Date:
03 February 2021
Version/Amendment 
Number:
Initial version
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.
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1.0
ADMINISTRATIVE INFORMATION 
1.1
Contacts 
A separate contact information list will be provided to each site.
Takeda Development Center Americas, Inc. sponsored investigators per individual country 
requirements will be provided with emergency medical contact information cards to be carried by 
each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
Contact
Serious adverse event and pregnancy reporting
Pharmacovigilance:
US and Canada: PVSafetyAmericas@tpna.com
Rest of World: eupc@tgrd.com
Fax: +1 224 554 1052
Responsible Medical Officer 
(carries overall responsibility for the conduct of the 
study)
Name: 
 MD
Telephone/office: 
Mobile :
E-mail:
24-hour urgent medical contact
US TMA:
Toll-Free:
Mobile: 
EU TMA: 
Mobile:
JAPAN TMA:
Toll-Free:
Mobile:
IQVIA 24 hr Medical Emergency Contact Center 
US numbers: +1 973-659-6677 or
+1 512 652 0191
Eu number: +33186990019
EU: European Union; TMA: Takeda Medical Affairs; US: United States.
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1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this study protocol and also in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation (ICH) E6 Good Clinical Practice (GCP): 
Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
Electronic signatures are provided on the last page of this document.
 MD, PhD
Global Clinical 
, 
Neuroscience Therapeutic Area Unit
Date
 PhD
Biostatistics
Date
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the investigator’s brochure, package 
insert, and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

ICH, E6 GCP: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, and 
regulations.

Regulatory requirements for reporting serious adverse events (SAEs) defined in Section 10.2
of this protocol.

Terms outlined in the study site agreement.

Responsibilities of the investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................17
3.1
Study-Related Responsibilities.................................................................................17
3.2
Coordinating Investigator.........................................................................................17
3.3
List of Abbreviations ...............................................................................................18
3.4
Corporate Identification...........................................................................................19
4.0
INTRODUCTION.........................................................................................................20
4.1
Background .............................................................................................................20
4.1.1
Disease Background ........................................................................................20
4.1.2
Summary of Nonclinical Data..........................................................................21
4.1.3
Clinical Study Experience................................................................................22
4.2
Rationale for the Proposed Study.............................................................................24
4.3
Benefit-Risk Profile .................................................................................................25
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................26
5.1
Objectives................................................................................................................26
5.1.1
Primary Objective............................................................................................26
5.1.2
Secondary Objective........................................................................................26
5.1.3
Exploratory Objective(s)..................................................................................27
5.2
Endpoints.................................................................................................................27
5.2.1
Primary Endpoints ...........................................................................................27
5.2.2
Secondary Endpoints .......................................................................................28
5.2.3
Exploratory Endpoints .....................................................................................28
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................28
6.1
Study Design ...........................................................................................................28
6.2
Justification for Study Design, Dose, and Endpoints ................................................31
6.2.1
Study Design Rationale....................................................................................31
6.2.2
Dose Rationale ................................................................................................32
6.2.3
Endpoint Rationale ..........................................................................................32
6.2.3.1
Safety Endpoints......................................................................................32
6.2.3.2
6.2.3.3
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6.3
Premature Termination or Suspension of Study or Study Site...................................33
6.3.1
Criteria for Premature Termination or Suspension of the Study........................33
6.3.2
Criteria for Premature Termination or Suspension of Study Sites.....................34
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites..............................................................................34
6.4
Study Beginning and End/Completion .....................................................................35
6.4.1
Definition of Beginning of the Study ...............................................................35
6.4.2
Definition of End of the Study.........................................................................35
6.4.3
Definition of Study Completion.......................................................................35
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............35
7.1
Inclusion Criteria .....................................................................................................35
7.2
Exclusion Criteria ....................................................................................................36
7.3
Excluded Medications..............................................................................................37
7.4
Diet, Fluid, Activity Control ....................................................................................39
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................40
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................42
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................42
8.1
Study Drug and Materials ........................................................................................42
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling ..................................42
8.1.1.1
Study Drug ..............................................................................................42
8.1.1.2
Study Drug Labeling................................................................................42
8.1.1.3
Ancillary Materials..................................................................................43
8.1.1.4
Sponsor-Supplied Drug............................................................................43
8.1.2
Storage ............................................................................................................43
8.1.3
Dose and Regimen...........................................................................................43
8.1.4
Overdose .........................................................................................................44
8.2
Study Drug Assignment and Dispensing Procedures ................................................44
8.3
Randomization Code Creation and Storage..............................................................45
8.4
Study Drug Blind Maintenance................................................................................45
8.5
Unblinding Procedure..............................................................................................45
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................45
9.0
STUDY PLAN ..............................................................................................................46
9.1
Study Procedures.....................................................................................................46
9.1.1
Critical Procedures Based on Study Objectives: Timing of Procedures ............46
9.1.2
Alternative Approaches to Study Procedures and Data Collection Due to 
COVID-19 or Other Unavoidable Circumstances.............................................46
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9.1.3
Contraception and Pregnancy Avoidance Procedure ........................................48
9.1.3.1
Male Subjects and Their Female Partners ................................................48
9.1.3.2
Female Subjects and Their Male Partners ................................................48
9.1.3.3
Definitions and Procedures for Contraception and Pregnancy Avoidance
................................................................................................................48
9.1.3.4
General Guidance With Respect to the Avoidance of Pregnancy..............50
9.1.4
Pregnancy........................................................................................................51
9.2
Administrative Procedures.......................................................................................51
9.2.1
Informed Consent Procedure............................................................................51
9.2.2
Demographics, Medical History, and Medication History Procedure................51
9.2.3
Documentation of Concomitant Medications ...................................................52
9.2.4
Documentation of Concurrent Medical Conditions...........................................52
9.3
Clinical Procedures and Assessments.......................................................................52
9.3.1
AE Monitoring ................................................................................................52
9.3.2
Vital Sign Procedure........................................................................................52
9.3.3
Weight, Height, and Body Mass Index.............................................................53
9.3.4
ECG Procedure................................................................................................53
9.3.5
Physical Examination Procedure......................................................................54
9.3.6
9.3.7
C-SSRS ...........................................................................................................54
9.3.8
Clinical Laboratory Procedures and Assessments.............................................54
9.4
9.4.1
9.4.1.1
9.4.1.2
9.4.2
9.4.2.1
9.4.2.2
9.4.2.3
9.4.2.4
9.4.2.5
9.4.2.6
9.4.2.7
9.4.2.8
9.4.2.9
9.5
Documentation of Screen Failure.............................................................................60
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9.6
Documentation of Study Entrance............................................................................61
9.7
Biomarker Measurements ........................................................................................61
9.7.1
9.7.2
9.8
Monitoring Subject Treatment Compliance..............................................................61
9.9
Schedule of Observations and Procedures................................................................61
9.10
Post Study Care .......................................................................................................62
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................62
10.1
Definitions...............................................................................................................62
10.1.1
PTEs................................................................................................................62
10.1.2
AEs .................................................................................................................62
10.1.3
Additional Points to Consider for PTEs and AEs .............................................62
10.1.4
SAEs ...............................................................................................................64
10.1.5
AEs of Special Interest.....................................................................................65
10.1.6
Intensity of PTEs and AEs ...............................................................................65
10.1.7
Causality of AEs..............................................................................................65
10.1.8
Relationship to Study Procedures.....................................................................66
10.1.9
Start Date.........................................................................................................66
10.1.10 Stop Date.........................................................................................................66
10.1.11 Frequency........................................................................................................66
10.1.12 Action Concerning Study Drug........................................................................66
10.1.13 Outcome..........................................................................................................66
10.2
Procedures...............................................................................................................67
10.2.1
Collection and Reporting of AEs .....................................................................67
10.2.1.1
PTE and AE Collection Period.................................................................67
10.2.1.2
PTE and AE Reporting ............................................................................67
10.2.2
Collection and Reporting of SAEs ...................................................................68
10.2.3
Reporting of Abnormal LFTs...........................................................................69
10.3
Follow-up of SAEs ..................................................................................................69
10.3.1
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...69
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................70
12.0
DATA HANDLING AND RECORDKEEPING............................................................70
12.1
eCRFs......................................................................................................................70
12.2
Record Retention .....................................................................................................71
13.0
STATISTICAL METHODS..........................................................................................72
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13.1
Statistical and Analytical Plans ................................................................................72
13.1.1
Baseline Definition..........................................................................................72
13.1.2
Analysis Sets ...................................................................................................72
13.1.2.1
Active Drug Extension Period..................................................................72
13.1.2.2
Randomized Withdrawal Period ..............................................................73
13.1.3
Analysis of Demographics and Other Baseline Characteristics.........................73
13.1.3.1
Active Drug Extension Period..................................................................73
13.1.3.2
Randomized Withdrawal Period ..............................................................73
13.1.4
13.1.4.1
13.1.4.2
13.1.5
13.1.6
13.1.7
Safety Analysis................................................................................................75
13.1.7.1
AEs .........................................................................................................75
13.1.7.2
Clinical Laboratory Evaluation ................................................................75
13.1.7.3
Vital Signs and ECGs ..............................................................................75
13.1.7.4
Other Safety Parameters ..........................................................................76
13.2
Interim Analysis ......................................................................................................76
13.3
Determination of Sample Size..................................................................................76
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................76
14.1
Study-Site Monitoring Visits ...................................................................................76
14.2
Protocol Deviations..................................................................................................77
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................77
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................77
15.1
IRB and/or IEC Approval ........................................................................................78
15.2
Subject Information, Informed Consent, and Subject Authorization .........................78
15.3
Subject Confidentiality ............................................................................................79
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................80
15.4.1
Publication and Disclosure...............................................................................80
15.4.2
Clinical Trial Registration................................................................................80
15.4.3
Clinical Trial Results Disclosure......................................................................81
15.5
Insurance and Compensation for Injury....................................................................81
16.0
REFERENCES..............................................................................................................82
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LIST OF IN-TEXT TABLES
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................38
Table 9.a
Clinical Laboratory Tests...................................................................................55
Table 10.a
Takeda Medically Significant AE List................................................................65
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................30
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................84
Appendix B
Responsibilities of the Investigator.....................................................................89
Appendix C
Elements of the Subject Informed Consent.........................................................91
Appendix D
Investigator Consent to Use of Personal Information..........................................94
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Criteria for Inclusion:
Subject eligibility is determined according to the following criteria before entry into the study: 
1.
Subject with a diagnosis of NT1 who has completed TAK-994-1501 Part B before enrollment (which will occur 
immediately following the final TAK-994-1501 assessments), and for whom the investigator has no clinical 
objection they be enrolled. 
2.
Subject is capable of understanding and complying with protocol requirements.
3.
Male subject who is not sterilized and sexually active with a female partner of childbearing potential, must use 
barrier contraception from signing of informed consent until 5 half-lives of TAK-994 plus 90 days after the last 
dose of study drug. In addition, they must be advised not to donate sperm during this period.
4.
Female subject of childbearing potential who is sexually active with a male partner who is not sterilized, must 
agree to use highly effective methods of contraception from signing of informed consent until 5 half-lives of 
TAK-994 plus 30 days after the last dose of study drug. In addition, they must be advised not to donate ova during 
this period.
5.
Subject must agree to participate by providing written informed consent.
Criteria for Exclusion:
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1.
Subject has a clinically significant moderate or severe ongoing adverse event (AE) related to the study drug from 
the prior study. 
2.
Subject has used/uses disallowed concomitant medication. 
3.
Subject, in the opinion of the investigator, is unlikely to comply with the clinical study protocol or is unsuitable 
for any reason.
4.
The subject is an employee of the sponsor or study site or an immediate family member (eg, spouse, parent, child, 
sibling) of an employee of the sponsor or study site who is directly involved in the conduct of the study. 
5.
The subject has a known hypersensitivity to any component of the formulation of TAK-994 or related 
compounds. 
6.
The subject has a positive pregnancy test or is a lactating/breastfeeding woman. 
7.
The subject had major surgery or donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks before 
Baseline I (excluding samples taken as part of TAK-994-1501).
8.
The subject’s renal creatinine clearance is ≤50 mL/min. 
9.
Has liver function tests (alanine aminotransferase, aspartate aminotransferase) higher than 1.5 times the upper 
limit of normal at any visit in TAK-994-1501.
10. The subject has a risk of suicide according to endorsement of Item 4 or 5 on the Columbia Suicide Severity Rating 
Scale (C-SSRS) at any visit during TAK-994-1501 and/or has made a suicide attempt during TAK-994-1501. 
11. The subject has past or current epilepsy or seizure, except for a single febrile seizure in childhood. 
12. The subject has a clinically significant history of head injury or head trauma per the judgment of the investigator. 
13. The subject has a history of cerebral ischemia, transient ischemic attack, intracranial aneurysm, or arteriovenous 
malformation.
14. The subject has known coronary artery disease, a history of myocardial infarction, angina, cardiac rhythm 
abnormality, or heart failure.
15. The subject has an electrocardiogram (ECG) with a QT interval with Fridericia correction method >450 ms (men) 
or >470 ms (women) at Baseline I.
16. The subject has a resting heart rate outside of the range of 40 to 100 beats per minute, confirmed on repeat testing 
within a maximum of 30 minutes at Baseline I.
17. The subject has medical condition other than narcolepsy, such as medically significant unstable cardiovascular, 
pulmonary, hepatic, renal, or gastrointestinal disease, that would preclude enrollment in the view of the 
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investigator.
18. The subject has current or recent (within 6 months) gastrointestinal disease that is expected to influence the 
absorption of drugs (ie, a history of malabsorption, esophageal reflux, peptic ulcer disease, erosive esophagitis, 
frequent [more than once per week] occurrence of heartburn, or any surgical intervention).
19. The subject is an excessive (>600 mg/day) caffeine user 1 week before Baseline I. 
20. The subject used any product with stimulating or sedating properties, anticataplexy medications, selective 
serotonin reuptake inhibitor, tricyclic antidepressants, or sodium oxybate at any time post baseline during 
TAK-994-1501.
21. The subject has any other medical condition, such as anxiety, depression, heart disease, or significant hepatic, 
pulmonary, or renal disease, that requires the subject to take excluded medications or at the time of Baseline I the 
subject is being treated with nasal/oro-nasal positive airway pressure for any reason. 
22. The subject is unwilling to abstain from driving and operating dangerous or hazardous machinery during study 
participation. 
23. The subject has a positive urine screen for drugs of abuse (findings confirmed) and/or positive alcohol test during 
any visit in TAK-994-1501. 
24. The subject has a history of drug or alcohol abuse within the 12 months before Baseline I (Diagnostic and 
Statistical Manual of Mental Disorders, Edition 5 criteria). 
25. The subject has a nicotine dependence that is likely to have an effect on sleep (eg, a subject who routinely 
awakens at night to smoke) and/or an unwillingness to discontinue all smoking and nicotine use during the 
confinement portions of the study.
26. The subject has a usual bedtime later than 2400 (12:00 AM, midnight) or an occupation requiring nighttime shift 
work or variable shift work within the past 6 months or travel with significant jet lag within 14 days before 
Baseline I.
Criteria for Evaluation and Analyses:
Primary Endpoints:

Subjects with at least 1 treatment-emergent adverse event (TEAE) during the active drug extension period of the 
study.

Subjects with at least 1 markedly abnormal value (MAV) for postdose laboratory values during the active drug 
extension period of the study.

Subjects with at least 1 MAV for postdose vital signs during the active drug extension period of the study.

Subjects with at least 1 MAV for postdose ECG parameters during the active drug extension period of the study.
Secondary Endpoints:

Subjects with at least 1 TEAE during the randomized withdrawal period of the study.

Subjects with at least 1 MAV for postdose laboratory values during the randomized withdrawal period of the 
study.

Subjects with at least 1 MAV for postdose vital signs during the randomized withdrawal period of the study.

Subjects with at least 1 MAV for postdose ECG parameters during the randomized withdrawal period of the 
study.
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
study-related responsibilities template. The vendors identified in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Coordinating Investigator 
Takeda will select a signatory coordinating investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study drug, their expertise in the therapeutic area and the conduct of clinical research 
as well as study participation. The signatory coordinating investigator will be required to review 
and sign the clinical study report and by doing so agrees that it accurately describes the results of 
the study.
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3.3
List of Abbreviations
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
bpm
beats per minute
BMI
body mass index
BP
blood pressure
CFR
Code of Federal Regulations
CNS
central nervous system
COVID-19
coronavirus disease 2019
CSF
cerebrospinal fluid
C-SSRS
Columbia Suicide Severity Rating Scale
DNS
disturbed nighttime sleep
DTA
diphtheria toxin A
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EDS
excessive daytime sleepiness
ePRO
electronic patient-reported outcome
FDA
Food and Drug Administration
FIH
first-in-human
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GLDH
glutamate dehydrogenase
GLP
Good Laboratory Practice
hCG
human chorionic gonadotropin
HR
heart rate
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
IRT
interactive response technology
KO
knockout
LFT
liver function test
MAV
markedly abnormal value
MedDRA
Medical Dictionary for Regulatory Activities
MSLT
multiple sleep latency test
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NOAEL
no-observed-adverse-effect level
NT1
narcolepsy type 1
NT2
narcolepsy type 2
OAB
overactive bladder
OAB-qLF
Overactive Bladder Questionnaire – Long Form
OX
orexin
OX1R
orexin type 1 receptor
OX2R
orexin type 2 receptor
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PPBC
Patient Perception of Bladder Control
PROMIS
Patient-Reported Outcomes Measurement Information System
PSG
polysomnography
PTE
pretreatment event
QTc
corrected QT
QTcF
QT interval with Fridericia correction method
REM
rapid eye movement
SAE
serious adverse event
SAP
statistical analysis plan
SUSAR
Suspected Unexpected Serious Adverse Reaction
TEAE
treatment-emergent adverse event
TG
transgenic
TK
toxicokinetic
ULN
upper limit of normal
VAS
visual analog scale
WT
wild-type
3.4
Corporate Identification 
TDCA
Takeda Development Center Americas, Inc.
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4.0
INTRODUCTION
4.1
Background
4.1.1
Disease Background
The orexinergic system is a major wake-promoting system of the brain. It is comprised of 2 types 
of wake promoting orexin (OX) neurons, localized in a specific region of the lateral and posterior 
hypothalamus and have excitatory projections to wide areas of the central nervous system (CNS) 
including the basal forebrain and brainstem nuclei involved in maintaining wakefulness (ie, 
cholinergic neurons of the reticular activating system, histaminergic tuberomammillary nucleus, 
noradrenergic locus coeruleus, dopaminergic ventral lateral area, and the serotonergic dorsal raphe 
nucleus). The OX system acts to coordinate and synchronize the wake-promoting centers of the 
brain and when absent (ie, in patients with narcolepsy type 1 [NT1], sleep/wake instability results). 
The orexinergic system is also involved in several other functions, such as feeding, reward, and 
sympathetic activity.
Two orexinergic neuropeptides, OX-A and OX-B, have been identified to date. These 
neuropeptides exert effects via 2 types of G protein–coupled OX receptors: orexin type 1 receptor 
(OX1R) and orexin type 2 receptor (OX2R). OX-A has a high affinity to OX1R and OX2R, and 
OX-B has a high affinity to OX2R. The 2 types of OX receptors have a distinct distribution in the 
arousal network: the locus coeruleus contains only OX1Rs, the tuberomammillary nucleus
contains only OX2Rs, and both receptor types occur in the dorsal raphe nucleus and ventral 
tegmental area. The 2 types of OX receptors also make distinct contributions to the regulation of 
arousal. OX2Rs in the tuberomammillary nucleus are essential for the maintenance of 
wakefulness, whereas both receptor types are required for the inhibition of rapid eye movement 
(REM) sleep [1].
The pathological loss of orexinergic neurons is associated with the development of NT1 [2]. 
Narcolepsy is a rare, acquired, chronic neurologic disorder that alters sleep-state stability. The 
cardinal symptom of narcolepsy is excessive daytime sleepiness (EDS), described as a sudden 
overpowering need to sleep during the day normal periods of alertness. Intrusion of REM sleep 
phenomena into wakefulness also can also occur. These REM-like phenomena may include 
cataplexy (sudden loss of muscle tone triggered by strong emotions), hypnagogic/hypnopompic 
hallucinations (hallucinatory phenomenon that can include mental, auditory, tactile, or uncinate 
events typically occurring during the transitions into and out of sleep), and sleep paralysis (similar 
to cataplexy, ie, acute onset of muscle atonia accompanied by a somatic feeling of general 
paralysis, usually occurring during the transition from wakefulness into sleep). Disturbed 
nighttime sleep (DNS) is a common narcolepsy related symptom, with difficulty maintaining 
continuous nocturnal sleep manifested by frequent awakenings with prompt return back into sleep. 
Together, these 5 clinical features (EDS, cataplexy, hypnagogic/hypnopompic hallucinations, 
sleep paralysis, and DNS) comprise the narcolepsy symptom pentad. It has been estimated that 
only 20% to 30% of patients have all components of the pentad at any one time. Narcolepsy type 2 
(NT2) or narcolepsy without cataplexy accounts for 20% to 40% of all cases of narcolepsy but it is 
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important to know that cataplexy onset can occur many years after the onset of EDS (cases of 10-
to 20-year delay have been described).
Narcolepsy has been classified by the International Classification of Sleep Disorders – Third 
Edition diagnostic criteria as either NT1 or NT2, on the basis of the presence or absence of 
cataplexy and on levels associated with demonstrably absent or low levels of OX1 in the 
cerebrospinal fluid (CSF) (if measured). NT1 is characterized by EDS and the presence of 
cataplexy. CSF levels of OX are absent or less than one-third of normal (typically <110 pg/mL). In 
contrast, patients with NT2 do not have cataplexy, and CSF levels of OX1 range from >110 pg/mL 
to normal levels. Both in NT1 and NT2, patients have exhibited sleep-onset REM periods on 
polysomnography (PSG)/multiple sleep latency test (MSLT) testing and have average sleep onset 
latencies of the MSLT of <8 minutes averaged over 5 naps. Approximately 70% of those with 
narcolepsy are classified as having NT1.
The pathophysiology of NT1 has a presumed, though unproven, autoimmune basis in individuals 
with a specific genetic predisposition, the most common of which is the HLA DQB1*06:02 (major 
histocompatibility complex, class II, DQ beta 1) [3,4]. The proposed etiology involves T-cell–
mediated destruction of OX-producing neurons in the hypothalamus [4-6]. Loss of OX-producing 
neurons is reflected by low CSF OX levels [7]. The pathophysiology of NT2 is not well 
understood.
On the basis of the aforementioned data demonstrating that partial or complete OX deficiency 
plays an important role in the development of EDS, OX replacement therapy is expected to 
improve EDS through a pathophysiology-directed mechanism of action. A novel drug that acts to 
help address the deficiency of OX may address the spectrum of narcolepsy symptoms and may 
have greater efficacy than currently approved drugs for EDS and cataplexy.
TAK-994 is a first-in-class, orally available, highly selective OX2R agonist being developed by 
Takeda for the treatment of narcolepsy with or without cataplexy (NT1 or NT2).
4.1.2
Summary of Nonclinical Data
TAK-994 was studied in wild-type (WT) mice and cynomolgus monkeys as well as in 
2 narcolepsy models (OX/ataxin-3 transgenic [TG] mice and OX-tTA;TetO diphtheria toxin A 
[DTA] mice), and OX2R knockout (KO) mice. TAK-994 significantly and dose-dependently 
enhanced wakefulness, both in WT mice during the sleep phase and in OX/ataxin-3 TG mice 
during both the active and sleep phase. TAK-994 was active at a 3-fold lower dose in OX/ataxin-3 
TG mice compared with WT mice; effective doses of TAK-994 in OX/ataxin-3 TG mice and WT 
mice were 3 and 10 mg/kg, respectively. TAK-994 also dose-dependently and significantly 
increased wakefulness in OX-tTA;TetO DTA mice during the active phase. TAK-994 also 
suppressed cataplexy-like episodes both in OX/ataxin-3 TG mice and OX-tTA;TetO DTA mice 
during the active phase. In contrast, TAK-994 did not show an arousal effect in OX2R KO mice, 
consistent with selectivity for OX2R. Nonhuman primates such as cynomolgus monkeys are 
diurnal animals whose sleep/wake structure is monophasic and resembles that of humans. 
TAK-994 also significantly enhanced wakefulness in cynomolgus monkeys during the sleep 
phase. 
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In in vivo cardiovascular studies, blood pressure (BP) increases were observed at ≥20 mg/kg 
(10 mg/kg, twice daily) in conscious telemeterized monkeys. The increased BP was attributed to 
the pharmacological action of TAK-994 at OX2R in the CNS, since it has been reported that 
intracerebroventricular administrations of OX increased arterial BP in rats mainly via OX2R [8]. 
The prolongation of PR interval and shortening of QT/corrected QT (QTc) intervals observed at 
≥100 mg/kg and 1000 mg/kg, respectively, were deemed to be of no toxicological importance 
because of the low magnitude of these changes. The no-observed-effect level on the 
cardiovascular system in monkeys could not be determined on the basis of the BP and heart rate 
(HR) increases seen at the lowest dose tested, 20 mg/kg. However, after 1-week repeated oral 
administration of TAK-994 in conscious telemeterized monkeys at 100 mg/kg, the increased BP 
and HR observed on the first day of dosing was attenuated on the second day of dosing and had 
disappeared by the final day of dosing. Since no arrhythmias were observed, and the values of the 
shortened QTc intervals at nighttime did not deviate largely from those during the daytime, the 
prolonged PR intervals at ≥100 mg/kg/d and shortened QT and QTc intervals at 1000 mg/kg/d 
were considered to be nonadverse.
In toxicity studies up to 39 weeks (9 months) duration in monkeys and up to 26 weeks (6 months)
in rats, safety margins were achieved compared with the doses planned for clinical studies. 

A Good Laboratory Practice (GLP)-compliant 26-week oral gavage toxicity and toxicokinetic 
(TK) study was conducted in Sprague-Dawley rats at dose levels of 0, 50, 150, and 
1000 mg/kg/d with an 8-week recovery period. Adverse fluorosis was observed at 
1000 mg/kg/d with evidence of increased fluoride levels in the plasma. Based on these results, 
the no-observed-adverse-effect level (NOAEL) was set at 150 mg/kg/d. 

A GLP-compliant 39-week oral gavage toxicity and TK study was conducted in cynomolgus 
monkeys at dose levels of 0, 60, 200, and 1000 mg/kg/day (0, 30, 100, and 500 mg/kg twice 
daily with a 6-hour interval between doses). No adverse findings were noted at any dose level. 
Based on these results, the NOAEL of TAK-994 was set at 
1000 (500 twice daily) mg/kg/d for both sexes. 
Additional details on the nonclinical data for TAK-994 are available in the TAK-994-1501 parent 
protocol and the investigator’s brochure.
4.1.3
Clinical Study Experience
At the time of protocol writing, 1 clinical study of TAK-994 has been completed (TAK-994-1001) 
and 2 clinical studies are ongoing (TAK-994-1501 and TAK-994-1503). 
TAK-994-1001 was a first-in-human (FIH), phase 1, double-blind, safety, tolerability, 
pharmacokinetic (PK), and pharmacodynamic (PD) study of single and 14-day multiple rising oral 
doses of TAK-994 in healthy non-Japanese and Japanese adult subjects, as well as healthy elderly 
subjects. The study also assessed the effect of food on the PK of a single dose of the tablet 
formulation of TAK-994. The study included assessment of TAK-994 CSF concentrations to 
evaluate the CNS penetration relative to systemic exposure in support of dose selection as well as 
exploratory PD/efficacy.
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Following single- and multiple-dose oral administration of TAK-994 to healthy subjects under 
fasted conditions, TAK-994 was readily absorbed into the systemic circulation. After single-dose 
administration, peak exposure increased near dose proportionally, while total exposure increased 
slightly greater than dose proportionally. At steady-state, peak and total exposure of TAK-994 
appeared to increase dose proportionally when comparing the twice daily dose regimens where 
TAK-994 was administered at the same amount for 14 consecutive days.
After single-dose administration, TAK-994 displayed a multiexponential disposition phase with 
an estimated mean terminal elimination half-life ranging from 3.053 to 12.472 hours across doses. 
There were no apparent dose-related trends in TAK-994 clearance across the groups assessed. 
TAK-994 exposure did not appear to accumulate after once or twice daily dosing in any of the dose 
groups and study parts (≤9%) with the exception of the 120 mg AM/60 mg PM dose group where 
a slight drug accumulation was observed when comparing Day 14 to Day 1. Overall, urinary 
excretion of TAK-994 was minimal and not impacted by dose level. 
Further, ingesting a high-fat, high-calorie meal immediately before administering a low dose 
(30 mg) of TAK-994, increased the peak (~50%) and total exposure (~25%) of TAK-994. 
Ingesting a standardized, non–high-fat meal immediately before administering a higher dose 
(180 mg) of TAK-994, increased peak exposure (42%) but had no effect on total exposure.
There were no deaths or SAEs in any treatment group of any part throughout the study. All 
reported treatment-emergent adverse events (TEAEs) were mild or moderate in severity, except 1 
severe TEAE syncope, that was assessed as not related to study drug by the investigator. Two 
subjects discontinued due to TEAEs. One subject treated with placebo discontinued from Part B 
due to presyncope, which was assessed as moderate in intensity and related to study drug by the 
investigator. One subject who received TAK-994 200 mg twice daily discontinued from Part E 
due to alanine aminotransferase (ALT) increased, which was assessed as mild and related to the 
study drug by the investigator. 
Considering all parts together, 1 or more renal and urinary TEAEs were reported (incontinence, 
pollakiuria, micturition urgency, dysuria) in 24 subjects, including 1 in the placebo group. No 
related medical history was reported in these subjects; however, no subjects discontinued due to 
these TEAEs. These were mild or moderate in intensity and all events resolved within a few days. 
There events were reported in subjects with no specific relation with dose levels, sex, race, or age. 
These events were assessed related to the study treatment. No actions were taken in response to the 
event. Higher frequency of renal and urinary TEAEs were noted in the TAK-994 treated group 
compared with the placebo.
A total of 8 subjects reported increased alertness (hypervigilance) ranging for a few hours to a few 
days. All events were assessed related to the study drug, resolved, and had no specific relation with 
dose levels, sex, race, or age. Two subjects reported mild euphoria that were resolved. These 
events were assessed related to the study treatment and occurred in subjects receiving TAK-994. 
No actions were taken in response to the event. Twenty-four subjects (2 subjects in placebo group 
and 22 in the TAK-994 group) also reported insomnia within the first 2 to 3 days of first dose. 
These were mild or moderate in intensity and all events resolved. The events were reported in 
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subjects with no specific relation with dose levels, sex, race, or age. These events were assessed 
related to the study treatment. No actions were taken in response to the event.
Three subjects exposed to TAK-994 had ALT elevations. All events were mild, related, and 
resolved without treatment. Three subjects exposed to TAK-994 had glutamate dehydrogenase 
(GLDH) elevations (reference range <6.4 U/L). In addition, 1 subject treated with placebo had 
elevated GLDH. 
Transient increases in BP and PR were observed across all parts receiving multiple dosing on the 
basis of markedly abnormal values (MAVs); however, no notable trend was observed. One subject 
receiving 200 mg TAK-994 in Part B had a TEAE of BP increased. The event was assessed as
moderate in intensity and drug-related by the investigator. No other clinically significant changes 
in BP from baseline were reported for any subject during the study and no subjects discontinued 
from the study due to an elevation in BP.
No clinically significant electrocardiogram (ECG) abnormalities were reported during the study.
TAK-994 was considered to be safe and well tolerated up to 450 mg single dose and 200 mg twice 
daily 14-day repeat dose both in healthy adults and elderly subjects. The maximum repeated dose 
tested in healthy subjects was 200 mg twice daily and it was well tolerated. 
Additional details on the clinical data for TAK-994 are available in the investigator’s brochure.
4.2
Rationale for the Proposed Study
Nonclinical pharmacology studies showed that wake-promoting effects of TAK-994 were 
observed following chronic dosing for up to 14 days. Clinical information from FIH study 
TAK-994-1001 in healthy subjects showed that TAK-994 is safe when administered at a dose of 
up to 450 mg single dose and up to 200 mg twice daily repeat dose both in healthy adult and 
elderly subjects. 
Narcolepsy is a long-term illness and maintenance therapy is recommended to prevent relapse. 
This study is being conducted to evaluate the safety of subjects on continued treatment with 
TAK-994 as well as during a withdrawal period. The primary objective of the current study is, 
therefore, to evaluate the safety and tolerability of TAK-994 in the active drug extension period of 
the study over a period of up to 8 weeks (for subjects who received active treatment in 
TAK-994-1501). The secondary objective is to evaluate the safety and tolerability of TAK-994 vs 
placebo in the randomized withdrawal period of the study over a period of up to 4 weeks. The 
primary endpoint will be assessed upon completion of the active drug extension period of the 
study; the secondary endpoint will be assessed upon completion of the randomized withdrawal 
part of the study. 
Additional rationale relating to the study design, TAK-994 dose administered, and study endpoints 
is provided in Section 6.2.
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4.3
Benefit-Risk Profile
This 8-week extension study followed by a 4-week randomized withdrawal period will include 
safety/tolerability, 
 evaluations in subjects with NT1 after multiple-dose oral 
administration of TAK-994.
Patients with NT1 are deficient in OX and hence are the first individuals who would most benefit
from treatment with an OX2R agonist. If TAK-994 is efficacious for EDS and catalepsy, subjects 
receiving the drug may benefit during the period of study drug administration. Subjects will also
receive medical examinations and information about their overall health. Results of this study are 
critical in planning future clinical studies with TAK-994, and it is possible that the information 
obtained in the study will be beneficial to patients with narcolepsy in the future.
Safety data informing the risk profile for TAK-994 are limited to the mode of action, data from 
nonclinical toxicology studies, and safety and tolerability data from TAK-994-1001: 

Based on nonclinical safety pharmacology data, the primary potential risk is increased BP. A 
safety pharmacology study of TAK-994 in monkeys found mild to moderate degrees of 
transient elevated BP at all doses tested on initial dosing, although effects on BP and HR were 
no longer observed at 7 days of dosing. The cardiovascular effects noted in nonclinical models 
with OX2R agonists are considered potentially on-mechanism on the basis of published 
literature [9]. In TAK-994-1001, BP elevation (>5 mm Hg above placebo) was observed on 
Day 1; however, the elevations were not sustained beyond Day 4. In addition, preliminary 
results from TAK-994-1501 confirmed that there appears to be no clear dose-response 
relationship for BP elevation. However, to mitigate a potential BP risk, BP will be measured 
frequently in this study; stopping rules for individual subjects (as well as the treatment of 
increased BP) and the overall study have been established and are noted in Section 7.5 and 
Section 6.3, respectively.

Other effects in nonclinical studies included vomiting at high doses and minor changes in ECG 
parameters. ECG findings in the study were considered nonadverse. The ECG data in healthy 
subjects in TAK-994-1001 and preliminary results from TAK-994-1501 showed no clinically 
significant findings. To mitigate any possible risk, ECG parameters will be monitored in this 
study.

Additionally, it is possible that a long half-life may result in insomnia, which has been seen in 
healthy subjects in TAK-994-1001. Though insomnia is thought less likely to occur in patients 
with NT1 due to their marked OX deficiency, stopping rules have been created for severe 
and/or persistent insomnia (Section 7.5).

The TEAEs that have occurred in TAK-994-1001 have primarily been graded as mild. TEAEs 
generally increased in number with increasing dose or exposure. The tolerability of 200 mg 
twice daily in the multiple rising dose cohort was acceptable, although TEAEs of urinary 
frequency and urgency have been reported, and this will be monitored in the current study. In 
addition, subjects will be asked to complete the Overactive Bladder Questionnaire - Long 
Form (OAB-qLF) and Patient Perception of Bladder Control (PPBC) Questionnaire at several 
time points throughout the study.
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
The TAK-994–related hepatocellular injury observed in the non-Tg rasH2 mice is thought to 
be of limited relevance to human safety risk assessment. In TAK-994-1001, a pooled aggregate 
analysis of liver function tests (LFTs) and GLDH that included observed and change from 
baseline by visit date was conducted and did not show clinically meaningful difference 
between TAK-994 and placebo arms. In addition, there were no clinically significant changes 
of fluoride laboratory test results. LFTs will be monitored throughout the study; however, no 
specific monitoring of GLDH is planned. Weekly measurements are felt to be sufficient to 
adequately monitor for evidence of injury. See Section 7.5 and Section 6.3 for individual and 
cohort stopping rules related to LFT changes. 
This study has been designed to mitigate potential safety risks on the basis of clinical and 
nonclinical findings. The principal mitigation strategy for these risks includes appropriate 
selection of the study population; intermittent use of the inpatient clinical research unit setting, 
which permits close monitoring and rapid institution of appropriate care as needed; appropriate 
specified monitoring procedures; periodic laboratory tests, ECGs, and vital signs assessments; and 
use of experienced staff trained in study procedures. 
Overall, there is manageable risk associated with the noninvasive procedures planned for this 
study. Potential risks relating to study procedures include the following:

Study procedure-specific risks, including issues relating to blood collection for safety 
 
assessments (eg, venipuncture may cause bruising).

Acute hypersensitivity/anaphylactic reactions to new chemical entities, which is always a 
possible risk in any clinical study. Appropriate procedures will be used to manage such 
possible risks.
Review of available data supports a favorable benefit-risk ratio for this study of TAK-994. To date, 
the observed nonclinical and clinical safety data for TAK-994, including mild and manageable 
adverse events (AEs), are acceptable considering its potential clinical benefit.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective is to evaluate the safety and tolerability of TAK-994 in the active drug 
extension period of the study over a period of up to 8 weeks.
5.1.2
Secondary Objective
The secondary objective is to evaluate the safety and tolerability of TAK-994 versus placebo in the 
randomized withdrawal period of the study over a period of up to 4 weeks.
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During confinement, study drug will be administered TAK-994/placebo orally in the morning (at 
approximately 0800) and in the afternoon (approximately 1300) per the Schedule of Study 
Procedures (Appendix A) and Section 8.1.3. Study assessments will be obtained per the Schedule 
of Study Procedures (Appendix A) in accordance with the priority specified in Section 9.1.1. 
Subjects will remain as inpatient from check-in at Days 55 and 83 and will be discharged after 
completion of all planned assessments on Days 57 and 84, respectively.
While at home, subjects will take TAK-994/placebo orally twice daily at approximately the same 
times each day, with the first dose given in the morning and the second dose approximately 5 hours 
later and will continue to complete the daily ePRO diary. 
Subjects will return to the clinic for safety, 
 assessments on in-clinic visit days. 
Subjects will return home on the discharge day after each in-clinic period. 
A follow-up will be planned approximately 2 weeks after the final study drug intake. 
Sites should see subjects at the study site to conduct the in-clinic study procedures. In unavoidable 
circumstances (eg, a widespread disease outbreak or natural disaster) that impact the study site’s 
ability to conduct study procedures according to the Schedule of Study Procedures (Appendix A), 
contingency measures may be implemented. Restrictions of human activities or institution 
activities placed by hospitals, local, state, and national governments may prevent conduct of study 
procedures according to the Schedule of Study Procedures (Appendix A). Alternative approaches 
to study procedures and data collection for the current study are described in Section 9.1.2.
6.2
Justification for Study Design, Dose, and Endpoints
6.2.1
Study Design Rationale
Several key considerations were taken into account when designing the study, because the 
information generated will inform the design and dose selection for the further development of 
TAK-994 as a potential treatment for NT1. These considerations are described below.
Due to the character of the disorder, long-term studies are necessary to demonstrate that the 
short-term effect is maintained over time. As recommended in the Food and Drug Administration 
(FDA) Guidance for Industry [10], a randomized withdrawal study is the most appropriate design 
to use to evaluate the maintenance of treatment effect.
The current dose-blinded study will evaluate safety and efficacy over a period of up to 12 weeks, 
bringing the total exposure in combination with TAK-994-1501 Part B up to 20 weeks. With that 
this study can further characterize the safety of TAK-994. Further, a 4-week randomized 
withdrawal period was chosen to assess 
 of continued treatment with TAK-994 versus 
switching to placebo to investigate the potential for relapse in subjects treated with TAK-994 for 
up to 16 weeks. The 4-week period was estimated to be sufficient to capture any withdrawal effect, 
if present, taking into account the potential that after a longer exposure the 
 
.
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
Data from drug(s) of the same class or methodology(ies) used in this study become available 
and result in the study being stopped for a nonsafety-related reason.

The study is stopped because of nonscientific and nonsafety reasons, such as slow enrollment.

Unanticipated concerns of safety to the study subjects arise from this clinical study or 
additional nonclinical or clinical studies with TAK-994 or drug(s) of the same class.

Study-specific stopping criteria are met by any of the following criteria:
–
BP increase: If 4 or more subjects in the same arm meet the individual subject stopping 
criteria for BP increases defined in Section 7.5, then further dosing will be stopped. 
–
Insomnia: If 4 or more subjects in the same arm meet the individual subject stopping 
criteria for severe insomnia defined in Section 7.5, then further dosing will be stopped. 
–
LFT: If 3 or more subjects in the same arm meet the individual subject stopping criteria for 
abnormalities, as defined in Section 7.5, then further dosing will be stopped. 
–
SAE: If 3 or more subjects in the same arm meet the individual subject stopping criteria or 
3 or more experience an SAE that is drug-related in investigator’s and sponsor’s opinions, 
then further dosing will be stopped.

The study will be paused for further evaluation if any of the following criteria are met:
–
≥10% or 3 subjects in the same arm, whichever is higher, experience a similar SAE.
–
≥10% or 3 subjects in the same arm, whichever is higher, experience a similar severe AE, 
with the exception of insomnia.
–
≥10% or 3 subjects in the same arm, whichever is higher, discontinue study for safety 
reasons.
–
≥1 death in the same arm determined by the investigator to be related to study drug.

The sponsor terminates or suspends the study, or any study cohort, at any time for any other 
clinical or administrative reasons.
6.3.2
Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, if the site (including the 
investigator) is unable to ensure adequate performance of the study, or as otherwise permitted by 
the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites
If the sponsor, an institutional review board (IRB)/independent ethics committee (IEC), or 
regulatory authority elects to terminate or suspend the study or the participation of a study site, a 
study-specific procedure for early termination or suspension will be provided by the sponsor; the 
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procedure will be followed by applicable study sites during the course of termination or study 
suspension. If the site closure is due to coronavirus disease 2019 (COVID-19), this should be 
captured on the electronic case report form (eCRF), end of treatment disposition page.
6.4
Study Beginning and End/Completion
6.4.1
Definition of Beginning of the Study
The study begins when the first subject signs the study informed consent form.
6.4.2
Definition of End of the Study
The study ends when the last subject completes the last planned or follow-up visit/interaction 
associated with a planned visit (this can be a phone contact), withdraws from the study, or is lost to 
follow-up (ie, the investigator is unable to contact the subject).
6.4.3
Definition of Study Completion
For an individual subject, study completion is defined as when the subject is examined after 
receiving all planned intervention/treatment to collect final data for all primary, secondary, and 
exploratory endpoints.
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed before randomization or first dose or 
other.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria before entry into the study: 
1. Subject with a diagnosis of NT1 who has completed TAK-994-1501 Part B before enrollment 
(which will occur immediately following the final TAK-994-1501 assessments), and for whom 
the investigator has no clinical objection they be enrolled. 
2. Subject is capable of understanding and complying with protocol requirements.
3. Male subject who is not sterilized and sexually active with a female partner of childbearing 
potential, must use barrier contraception from signing of informed consent until 5 half-lives of 
TAK-994 plus 90 days after the last dose of study drug. In addition, they must be advised not to 
donate sperm during this period. Definitions and procedures for adequate contraception, 
pregnancy avoidance, and reporting responsibilities are defined in Sections 9.1.3 and 9.1.4.
4. Female subject of childbearing potential who is sexually active with a male partner who is not 
sterilized, must agree to use highly effective methods of contraception from signing of 
informed consent until 5 half-lives of TAK-994 plus 30 days after the last dose of study drug. 
In addition, they must be advised not to donate ova during this period. Definitions and 
procedures for adequate contraception, pregnancy avoidance, and reporting responsibilities are 
defined in Sections 9.1.3 and 9.1.4.
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5. Subject must agree to participate by providing written informed consent.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. Subject has a clinically significant moderate or severe ongoing AE related to the study drug 
from the prior study. 
2. Subject has used/uses disallowed concomitant medication. 
3. Subject, in the opinion of the investigator, is unlikely to comply with the clinical study 
protocol or is unsuitable for any reason.
4. The subject is an employee of the sponsor or study site or an immediate family member 
(eg, spouse, parent, child, sibling) of an employee of the sponsor or study site who is directly 
involved in the conduct of the study. 
5. The subject has a known hypersensitivity to any component of the formulation of TAK-994 or 
related compounds.
6. The subject has a positive pregnancy test or is a lactating/breastfeeding woman.
7. The subject had major surgery or donated or lost 1 unit of blood (approximately 500 mL) 
within 4 weeks before Baseline I (excluding samples taken as part of TAK-994-1501).
8. The subject’s renal creatinine clearance is ≤50 mL/min.
9. Has LFTs (ALT, aspartate aminotransferase [AST]) higher than 1.5 times the upper limit of 
normal (ULN) at any visit in TAK-994-1501.
10. The subject has a risk of suicide according to endorsement of Item 4 or 5 on the C-SSRS at any 
visit during TAK-994-1501 and/or has made a suicide attempt during TAK-994-1501. 
11. The subject has past or current epilepsy or seizure, except for a single febrile seizure in 
childhood.
12. The subject has a clinically significant history of head injury or head trauma per the judgment 
of the investigator.
13. The subject has a history of cerebral ischemia, transient ischemic attack, intracranial 
aneurysm, or arteriovenous malformation.
14. The subject has known coronary artery disease, a history of myocardial infarction, angina, 
cardiac rhythm abnormality, or heart failure.
15. The subject has an ECG with a QT interval with Fridericia correction method (QTcF) >450 ms 
(men) or >470 ms (women) at Baseline I.
16. The subject has a resting HR outside of the range of 40 to 100 beats per minute (bpm), 
confirmed on repeat testing within a maximum of 30 minutes at Baseline I.
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17. The subject has a medical condition other than narcolepsy, such as medically significant 
unstable cardiovascular, pulmonary, hepatic, renal, or gastrointestinal disease, that would 
preclude enrollment in the view of the investigator.
18. The subject has current or recent (within 6 months) gastrointestinal disease that is expected to 
influence the absorption of drugs (ie, a history of malabsorption, esophageal reflux, peptic 
ulcer disease, erosive esophagitis, frequent [more than once per week] occurrence of 
heartburn, or any surgical intervention).
19. The subject is an excessive (>600 mg/d) caffeine user 1 week before Baseline I.
20. The subject used any product with stimulating or sedating properties, anticataplexy 
medications, selective serotonin reuptake inhibitor, tricyclic antidepressants, or sodium 
oxybate at any time post baseline during TAK-994-1501.
21. The subject has any other medical condition, such as anxiety, depression, heart disease, or 
significant hepatic, pulmonary, or renal disease, that requires the subject to take excluded 
medications (see Section 7.3) or at the time of Baseline I the subject is being treated with 
nasal/oro-nasal positive airway pressure for any reason.
22. The subject is unwilling to abstain from driving and operating dangerous or hazardous 
machinery during study participation.
23. The subject has a positive urine screen for drugs of abuse (findings confirmed) and/or positive 
alcohol test during any visit in TAK-994-1501. 
24. The subject has a history of drug or alcohol abuse within the 12 months before Baseline I 
(Diagnostic and Statistical Manual of Mental Disorders, Edition 5 criteria).
25. The subject has a nicotine dependence that is likely to have an effect on sleep (eg, a subject 
who routinely awakens at night to smoke) and/or an unwillingness to discontinue all smoking 
and nicotine use during the confinement portions of the study.
26. The subject has a usual bedtime later than 2400 (12:00 AM, midnight) or an occupation 
requiring nighttime shift work or variable shift work within the past 6 months or travel with 
significant jet lag within 14 days before Baseline I.
7.3
Excluded Medications 
Excluded medications and dietary products are shown in Table 7.a.
Excluded medications are the same as those excluded in TAK-994-1501; however, washout 
periods for these medications do not apply for this study as subjects should have already completed 
washout before the first dose of study drug in TAK-994-1501.
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Table 7.a
Excluded Medications, Supplements, and Dietary Products
Prohibited Drug or Drug Category
Drugs Restricted From Baseline I a Until 1 Week After Final
Study Drug Intake (Unless Otherwise Specified)
Any investigational drug other than TAK-994
<60 days before Baseline I or 5 half-lives, whichever is longer
Psychostimulants
Methylphenidate hydrochloride, modafinil, armodafinil, 
methamphetamine hydrochloride, solriamfetol, atomoxetine, and 
pitolisant are not allowed
Sodium or multisalt oxybate 
Not allowed 
Antipsychotic drugs
Not allowed 
Antianxiety/sleeping drugs
(tranquilizers/sleeping medications including
benzodiazepines, nonbenzodiazepine drugs, and
melatoninergic agonists)
Not allowed 
Antidepressants
Not allowed
Mood stabilizers (such as lithium or valproic acid 
or other antipsychotic drugs)
Not allowed
Anticonvulsants
Not allowed
Sleeping pills
Including Chinese medicine (Yokukansan,
Yokukansankachinpihange) used for insomnia
Not allowed
Anti–Parkinson disease drugs (completely
excluded)
Not allowed 
Adrenocorticosteroids (excluded except for
inhaled and topical)
Systemic administration permissible during the study for 
purposes of treating an AE only
Interferon, interleukin-formulation (excluded)
Not allowed
Muscle-relaxant drug (eg, baclofen)
Not allowed 
Antihistamines
Only centrally acting antihistamines are prohibited.
Loratadine is also prohibited.
The use of antihistamines and steroids are allowed for the 
management of severe allergic reactions.
Antitussives with CNS action
Not allowed 
Antiemetics with CNS action
Not allowed 
Narcotic analgesics and nonnarcotic analgesics, 
varencicline (CHANTIX)
Use of over-the-counter pain medications (acetaminophen;
excluding occasional use of ibuprofen, naproxen, and aspirin) is
prohibited unless otherwise approved by the principal
investigator after consultation with the sponsor or designee (ie,
medical monitor)
St. John’s wort, health foods containing
melatonin
Not allowed 
Known moderate and strong CYP3A inhibitors or
inducers are available in reference b
Not allowed 
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Table 7.a
Excluded Medications, Supplements, and Dietary Products
Prohibited Drug or Drug Category
Drugs Restricted From Baseline I a Until 1 Week After Final
Study Drug Intake (Unless Otherwise Specified)
Known P-gp inhibitors (azithromycin, captopril, 
carvedilol, felodipine, quercetin, quinidine, 
ranolazine, ticagrelor)
Not allowed
Known CYP3A substrates with narrow
therapeutic range including but not limited to
ergot alkaloids, fentanyl, pimozide, astemizole,
terfenadine, systemic corticosteroids (dose
equivalent to ≥10 mg prednisone per day),
nisoldipine, lovastatin, simvastatin, midazolam,
triazolam, buspirone, almorexant, lemborexant,
suvorexant, lurasidone, naloxegol, tilidine,
sildenafil, vardenafil, cilostazol, and eletriptan
Not allowed
Known sensitive OATP1B1 substrates including
but not limited to pravastatin, rosuvastatin, 
pitavastatin, atorvastatin, elagolix, repaglinide, 
valsartan
Not allowed
Sensitive P-gp substrates with narrow therapeutic
range: digoxin, dabigatran etexilate, fexofenadine
Not allowed
Sensitive BCRP substrates: sulfasalazine 
Not allowed
Chinese herbal medicine
Topical use is allowed; 
Systemic use is not allowed
AE: adverse event; BCRP: breast cancer resistance protein; CNS: central nervous system; CYP: cytochrome P450; OATP: organic 
anion transporter type; P-gp: P-glycoprotein.
If medications are required to treat an AE, certain medications, including supplements, may be allowed after discussion and 
agreement between the sponsor and principal investigator, unless the investigator or designee considers immediate administration 
necessary.
a Baseline I of the current study (TAK-994-1504) is the completion date (final discharge date) of the preceding study 
(TAK-994-1501).
b fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and
-inducers, Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inductors, Accessed 27 January 2021.
Subjects may take any medication that is not prohibited in Table 7.a. The investigator or 
subinvestigator will consult with the sponsor medical monitor or designee before allowing any 
concomitant medication during the study. Subjects will also be instructed not to take any 
medications, including over-the-counter drugs, without prior consultation with the investigator or 
subinvestigator.
The use of any investigational drug other than TAK-994 is not permitted throughout any study 
participation period.
7.4
Diet, Fluid, Activity Control 

Consumption of all fruit juices and fruit other than grapefruit fruit and grapefruit juice is 
allowed on all days of the study.
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–
ALT >3 × ULN twice consecutively at least 24 to 48 hours apart.

Suicidality: Study drug should be discontinued immediately for subjects at imminent 
risk of suicide per the C-SSRS (endorsement on items 4 or 5) or per the investigator’s 
clinical judgment.

BP increase: Study drug should be discontinued immediately if the median of 3 
in-clinic BP measurements (at least 10 minutes apart) meets any of the following 
criteria:
–
Systolic BP ≥160 mm Hg and/or diastolic BP ≥100 mm Hg.
–
Neurologic or cardiac findings associated with increases in BP.
In the event of BP values meeting the criteria above, the subject will be treated for 
elevated BP according to the best judgment of the investigator and in accordance with 
good medical practice, and, if needed, further emergency medical evaluation sought. If 
the study drug is discontinued in any subject due to a BP increase, the subject will not 
be rechallenged with TAK-994.
Any subject found to have significantly elevated BP as an outpatient should be treated 
per standard to care to obtain BP lowering. The sponsor or designee (ie, medical 
monitor) should be notified and consulted.

Pulse rate increase: Increased from baseline earlier in the day and sustained pulse rate 
>100 bpm measured during the in-clinic visit will result in stopping treatment.

Insomnia: Study drug should be discontinued for subjects with sustained severe or 
serious insomnia as determined by the principal investigator after consultation with the 
sponsor or designee (ie, medical monitor).
2. Significant protocol deviation: The discovery postrandomization that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued participation 
poses an unacceptable risk to the subject’s health.
3. Lost to follow-up: The subject did not return to the clinic and 3 attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documents. A certified letter can be sent as a last attempt.
4. Voluntary withdrawal: The subject wishes to withdraw from the study. The reason for 
withdrawal, if provided, should be recorded in the eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE should not be recorded in the “voluntary withdrawal” category). If a subject chooses to 
withdraw from study participation due to personal concerns related to the COVID-19 
pandemic (other than a COVID-19–related AE), this should be specified as the reason for 
subject withdrawal in the eCRF.
5. Pregnancy, as described in Section 9.1.4.
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6. Study termination: The sponsor, IRB, IEC, or regulatory agency terminates the study. Criteria 
for premature cohort and/or study termination are provided in Section 6.3.
7. Lack of efficacy.
8. Other: The reason for discontinuation should be entered into the eCRF including unavoidable 
circumstances such as the COVID-19 pandemic.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
early termination visit. The investigator should consult with the sponsor or designee (ie, medical 
monitor) before subject discontinuation whenever possible.
Discontinued or withdrawn subjects will not be replaced.
8.0
CLINICAL STUDY MATERIAL MANAGEMENT
This section contains information regarding all medications and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of study material.
8.1
Study Drug and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
8.1.1.1
Study Drug
Details regarding the dosage form description and strengths of the active drug and matching 
placebo can be found in the pharmacy manual. Study drug will be packaged to support enrollment 
as required. 
Tablet strengths for this study are 10, 30, and 90 mg.
On occasion in unavoidable circumstances such as the COVID-19 pandemic, additional drug 
supply may be provided to subjects (either at an in-person visit or delivered to subject’s residence) 
to cover extended periods between on-site visits. Any additional re-supply must be reviewed and 
approved in advance by the sponsor or designee.
8.1.1.2
Study Drug Labeling
Study drug containers will be affixed with a clinical label in accordance with local regulatory 
requirements.
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8.1.1.3
Ancillary Materials 
All ancillary supplies will be provided by either the study site or the sponsor or designee, based 
upon availability. The list of ancillary supplies and source information can be found in the 
pharmacy manual or in the referenced compounding manual when applicable. If provided by the 
sponsor, unused ancillary supplies will be accounted for and disposed of as directed by the sponsor 
or designee.
8.1.1.4
Sponsor-Supplied Drug
Sponsor-supplied drugs referenced in other sections of the protocol include the following: 
TAK-994 and matching placebo.
8.1.2
Storage
Study drug at the sites must be stored in a secure, limited-access location under the storage 
conditions specified on the label and remain in the original container until dispensed. The 
temperature excursion information can be found in the pharmacy manual. Receipt and dispensing 
of study drug at the study site must be recorded by authorized personnel.
8.1.3
Dose and Regimen
Each subject in this study will be instructed to take study drug twice daily: the first dose will be 
taken in the morning upon awakening and the second dose will be taken approximately 5 hours 
later. Both doses should be taken without food. A minimum of 4 hours apart is required between 
the morning and afternoon doses. The second dose should be taken no later than 1400 based on the 
elimination half-life of TAK-994.
During the confinement periods (as indicated in Section 6.0), the first dose of 
TAK-994/matched placebo will be administered in the morning by mouth (at approximately 0800) 
with 240 mL of water after an overnight fast of at least 8 hours; subjects will then be allowed to 
have a morning meal approximately one-half to one hour after study drug administration. The 
second dose of TAK-994/matched placebo will be administered orally approximately 5 hours later 
at the site. Subjects may consume water ad libitum. Standardized meals (approximately 30% fat 
content relative to total calories) will be administered at approximately 4 (lunch) and 10 (dinner) 
hours after the morning dose.
Note: The first dose of TAK-994 in TAK-994-1504 will need to be held until after the Day 57 
assessments in TAK-994-1501.
While at home, subjects will be instructed to take TAK-994/matched placebo upon arising in the 
morning as close to 0800 as possible (±1 hour) and have breakfast approximately one-half to one 
hour after study drug intake whenever possible. Subjects will be instructed to take the second dose 
approximately 5 hours after the morning dose and no later than 1400 in the afternoon. The second 
dose should be taken without food on an empty stomach (approximately 1 hour before eating or 2 
hours after eating) whenever possible. Subjects are encouraged to take study drug at 
approximately the same time each day in the morning (first dose) and afternoon (second dose). 
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Breakfast and lunch should be standard meals each containing approximately 30% fat (relative 
total calories). Subjects will be provided written instructions by the site on how to take study drug 
(dosing and mealtimes) at home. Subjects should avoid meals with high-fat content (typically 
>50% calorie content).
Tablets should be taken with a large glass of water (approximately 240 mL total). Subjects should 
swallow the study drug whole and not chew it or manipulate it in any way before swallowing. 
Subjects should be instructed to take not more than the prescribed dose at any time. If a subject 
fails to take the TAK-994/matched placebo dose within the time frame specified, they should be 
instructed to take it at least 30 minutes before the next scheduled meal. Under no circumstance 
should a subject repeat a dose or double-up doses. If the second dose is missed, that dose should be 
skipped and should not be taken again until the next morning. Both doses should never be taken at 
one time.
Subjects will be instructed to record their dose of TAK-994/matched placebo each day, or any 
skipped or mistimed doses, in their electronic dosing diary. Additional steps may be taken to 
ensure subjects understand the dosing instructions and that they follow the correct TAK-994 
dosing regimen, such as additional site communication with the subject throughout the treatment 
course, that is, on-site visits, phone or video calls, or other methods to demonstrate compliance and 
understanding of dose instructions may be employed. 
Subjects will adhere to the medication and dietary restrictions described in Sections 7.3 and 7.4.
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of study drug, to or by a 
study subject, at a dose above that which is assigned to that individual subject according to the 
study protocol.
All cases of overdose (with or without associated AEs) will be documented on an overdose page of 
the eCRF, in order to capture this important safety information consistently in the database. Cases 
of overdose without manifested signs or symptoms are not considered AEs. AEs associated with 
an overdose will be documented on AE eCRF(s) according to Section 10.0.
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2.
In the event of drug overdose, the subject should be treated symptomatically.
8.2
Study Drug Assignment and Dispensing Procedures
All consented subjects will be given a unique subject number (site number plus a unique sequential 
number) that will be used to identify the subject for all procedures that occur during the study. 
Each subject will be assigned only 1 subject number. Subject numbers must not be reused for 
different subjects.
On the first day of the active drug extension period and the first day of the double-blind 
randomized withdrawal period, subjects will be assigned a randomization number at the clinical 
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site. The randomization number encodes the subject treatment assignment according to the 
randomization schedule generated before the study. 
Subject and randomization numbers will be recorded on the eCRF. Each subject will be dispensed 
blinded study drug assigned by the IRT system throughout the study.
8.3
Randomization Code Creation and Storage
Before the start of the active drug extension period and before the start of the randomized 
withdrawal period, randomization personnel of the sponsor or designee will generate the 
randomization schedule for the IRT system. The randomization will be stratified by regions: North 
America, Europe, Japan, and South Korea. Details are in the IRT system specifications. The 
pharmacy manual includes instructions for emergency unblinding.
8.4
Study Drug Blind Maintenance 
The investigator and subjects will be blinded to treatment assignment. Emergency randomization 
code access will be made available through the IRT system in accordance with the standard 
operating procedures of the clinical site. 
The study drug blind will be maintained through a randomization schedule held by the IRT system.
8.5
Unblinding Procedure 
The study drug blind shall not be broken by the investigator unless information concerning the 
study drug is necessary for the medical treatment of the subject. If possible, the sponsor or 
designee (ie, medical monitor) should be contacted before the blind is broken. Unblinding will be 
performed per the standard operating procedures of the study site.
The sponsor must be notified as soon as possible if the study drug blind is broken. The date, time, 
and reason the blind is broken must be recorded in the source documents and the same information 
(except the time) must be recorded on the eCRF.
If any site personnel are unblinded, study drug must be stopped immediately and the subject must 
be withdrawn from the study. 
8.6
Accountability and Destruction of Sponsor-Supplied Drugs
The investigator is responsible for keeping accurate records of the study drug received from the 
sponsor or designee, the amount dispensed to and returned by the subjects, and the amount 
remaining at the end of the study. For all study sites, the local country sponsor personnel or 
designee will provide appropriate documentation that must be completed for study drug 
accountability, return, and destruction.
When subjects come back to the site visit, they need to bring back the study drug. The site will 
check and confirm the compliance. 
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–
Other than discharge visits, alternative methods for conducting subject visits (eg, video 
conferencing, telephone visits, or in-home study visits conducted by study site personnel or 
designated medical personnel, contingent upon local regulations) may be used per approval 
by the sponsor or designee: 

Under these circumstances, collection of certain study assessments may be omitted 
and visit windows may be extended. 

When approval is given for a subject to miss an in-person study visit, a study site 
physician will speak directly with the subject by telephone or other medium (eg, a 
computer-based video communication) during each visit window to assess subject 
safety and overall clinical status. 

The study site physician or other qualified site personnel should conduct the 
following assessments within specified-visit window time frames: AE assessments, 
documentation of concomitant medication, administration of C-SSRS (at applicable 
visits), and an assessment of clinical symptoms.

For this study, home nurses or other qualified clinical personnel may be deployed at 
the request of the site, when appropriate. Advance approval from the sponsor or 
designee should be obtained.

Other study assessments may be collected using an alternative method as feasible and 
may involve audio or video recording where allowed by local regulation. This will be 
documented in the study records.

Subjects may choose to get a COVID-19 vaccine at any time during this study.

In some instances, sites may need to split visits or sites may only be able to perform a 
few procedures on site and some procedures may need to be performed remotely. 
Sites should inform sponsor or designee when this occurs.

Sites may seek approval to extend a visit window in order to conduct an on-site visit. 
Assessments that cannot be completed during the protocol-specified window or 
within the visit window granted by the sponsor or designee will be considered 
missing data and such departures will be recorded in the study records. 

There will be no interval longer than 2 weeks between successive visits at which 
clinical laboratory tests are performed and vital signs are measured. Should the 
period of 2 weeks be met for a particular subject, the site should reach out to the 
sponsor or designee to discuss withdrawal of the subject.
–
Study site personnel may dispense additional study drug to subjects at a visit to allow for 
potentially longer intervals between visits than originally planned per protocol, or study 
drug may be supplied to subjects via delivery by site personnel or by courier.
–
Early termination visits should be performed in person. When it is not possible for the 
subject to come to the study site and the protocol-specified visit window cannot be 
extended further, the preferred alternative for the early termination visit is for qualified 
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study site personnel or designated clinical personnel to go to the subject’s residence and
conduct the protocol-specified procedures in that location. Assessments collected at a 
subject’s residence should comply with applicable local regulations. If neither option is 
available with sponsor or designee approval, sites may conduct early termination 
procedures remotely as is feasible.
All subject discontinuations and alternative approaches to study procedures (ie, procedures not 
conducted per the Schedule of Study Procedures) due to the COVID-19 pandemic must be 
documented in the study records. Data collected using alternative methods may be handled 
differently in the final data analyses. This will be documented in the statistical analysis plan (SAP).
For this study, subjects may receive the COVID-19 vaccination. Sites should document the 
vaccination dosing on concomitant medication page.
9.1.3
Contraception and Pregnancy Avoidance Procedure
9.1.3.1
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the study, and for 5 half-lives PLUS 
90 days after last dose of study drug, nonsterilized** male subjects who are sexually active with a 
female partner of childbearing potential* must use barrier contraception (eg, condom with or 
without spermicidal cream or jelly). In addition, they must be advised not to donate sperm during 
this period. Women of childbearing potential who are partners of male subjects are also advised to 
use additional contraception as shown in the list containing highly effective/effective 
contraception detailed in Section 9.1.3.3.
9.1.3.2
Female Subjects and Their Male Partners
From signing of informed consent, throughout the duration of the study, and for 5 half-lives PLUS 
30 days after last dose of study drug, female subjects of childbearing potential* who are sexually 
active with a nonsterilized male partner** must use 2 highly effective methods of contraception 
(from the list detailed in Section 9.1.3.3). 
In addition, they must not donate ova during this period.
9.1.3.3
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* A woman is considered a woman of childbearing potential, that is, fertile, following menarche 
and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses 
for 12 months without an alternative medical cause. A high follicle-stimulating hormone (FSH) 
level in the postmenopausal range (FSH >40 IU/L) may be used to confirm a postmenopausal state 
in younger women (eg, those aged <45 years) or women who are not using hormonal contraception 
or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient.
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** Sterilized males should be at least 1 year post–bilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). In this study, the only acceptable methods of contraception are: 

Nonhormonal Methods: 
–
Intrauterine device.
–
Bilateral tubal occlusion.
–
Vasectomized partner (provided that partner is the sole sexual partner of the study 
participant and that the vasectomized partner has received medical assessment of the 
surgical success).

Hormonal Methods: Hormonal contraception may be susceptible to interaction with the 
investigative compound or concomitant medications, which may reduce the efficacy of the 
contraception method. Therefore, study subjects using hormonal contraception must also 
use an additional barrier method (male condom, female condom, or diaphragm) throughout 
the duration of the study, and for 5 half-lives PLUS 30 days after last dose of study drug.
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation. Contraception must be initiated at least 3 months before the 
first dose of study drug. The options below are included in the category of combined 
hormonal contraception:

Oral.

Intravaginal (eg, ring).

Transdermal.
–
Progestogen-only hormonal contraception associated with inhibition of ovulation. 
Important: Progestogen-only hormonal contraception must be initiated at least
3 months before the first dose of study drug. If female subjects have been taking 
progestogen-only hormonal contraception for less than 3 months before the first dose 
of study drug, female subjects must also (or partners of male subjects are advised to) 
employ a barrier method (male condom, female condom, or diaphragm) until she has 
been on contraceptive for 3 months. The options below are included in the category of 
progestogen-only hormonal contraception:

Oral.

Injectable.

Implantable.
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2. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.

Declared sexual abstinence is NOT an acceptable method of contraception (unless 
approved by the investigator).
3. Subjects will be provided with information on highly effective/effective methods of 
contraception as part of the subject informed consent process and will be asked to sign a 
consent form stating that they understand the requirements for avoidance of pregnancy, 
donation of ova, and sperm donation during the course of the study.
4. During the course of the study, regular human chorionic gonadotropin (hCG) pregnancy tests 
will be performed only for women of childbearing potential and all subjects (male and female) 
will receive continued guidance with respect to the avoidance of pregnancy and ova/sperm 
donation as part of the study procedures. 
5. In addition to a negative serum hCG pregnancy test at the start of the study, female subjects of 
childbearing potential must also have confirmed menses in the month before first dosing (no 
delayed menses). Subjects must also have a negative urine pregnancy test within 24 hours 
before receiving the first dose of investigational drug as close as possible and before the first 
dose of investigational drug, preferably on the same day.
9.1.3.4
General Guidance With Respect to the Avoidance of Pregnancy
Such guidance should include a reminder of the following:

Contraceptive requirements of the study.

Reasons for use of barrier methods (ie, condom) in male subjects with pregnant partners.

Assessment of subject compliance through questions such as:
–
Have you used the contraception consistently and correctly since the last visit?
–
Have you forgotten to use contraception since the last visit? 
–
Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”).
–
Is there a chance you could be pregnant?
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9.1.4
Pregnancy
If any subject is found to be pregnant during the study, she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued. In addition, any pregnancies in the 
partner of a male subject during the study or for 5 half-lives PLUS 90 days after the last dose, 
should also be recorded following authorization from the subject’s partner. 
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
Subjects randomized to placebo need not be followed.
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the female 
subject/female partner of the subject was participating in a clinical study at the time she became 
pregnant and provide details of the study drug the subject received (blinded or unblinded, as 
applicable).
All pregnancies, including female partners of male subjects, in subjects on active study drug will
be followed up to final outcome, using the pregnancy form. Pregnancies will remain blinded to the 
study team. The outcome, including any premature termination, must be reported to the sponsor. 
An evaluation after the birth of the child will also be conducted.
9.2
Administrative Procedures
9.2.1
Informed Consent Procedure
Informed consent must be obtained before the subject enters into the study, and before any 
protocol-directed procedures are performed. The requirements of the informed consent (and 
e-consent, if applicable, as per local regulations) are described in Appendix C. Additional 
information on the informed consent procedure is provided in Section 15.2.
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is obtained; this subject number will be used throughout the study.
9.2.2
Demographics, Medical History, and Medication History Procedure
Demographic information obtained during TAK-994-1501 will be used for this extension study 
and will include date of birth, sex, race (reported by the subject), Hispanic ethnicity information, 
height, weight, caffeine consumption, alcohol consumption, and smoking status. (Note that only 
Baseline I height and weight will be obtained from TAK-994-1501; additional measurements are 
planned in the current study.). Information on the primary disease was also collected in 
TAK-994-1501 and will be included in this extension study’s database. 
Medical history information obtained during TAK-994-1501 will be used for this extension study 
and will include any significant conditions or diseases, including those reported as AEs during 
TAK-994-1501, relevant to the disease under study that resolved at or before signing of informed 
consent. Ongoing conditions, including AEs that started during TAK-994-1501 and were ongoing 
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at start of this study, are considered concurrent medical conditions in this extension study (see 
Section 9.2.4).
Medication history information obtained during TAK-994-1501 will be used for this extension 
study and will include any medication, including that administered during TAK-994-1501, 
relevant to eligibility criteria and efficacy/safety evaluation stopped at or before signing of 
informed consent. The nonproprietary name, route of administration, dates of initial and final 
administrations, and reasons for use must also be recorded.
9.2.3
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study drug. These may be prescribed 
by a physician or obtained by the subject over the counter. Concomitant medication is not provided 
by the sponsor. At each study visit, subjects will be asked whether they have taken any medication 
other than the study drug (used from signing of informed consent through the end of the study), 
and all medication including vitamin supplements, over-the-counter medications, and oral herbal 
preparations, must be recorded in the eCRF.
The nonproprietary name, route of administration, dates of initial and final administrations, and 
reasons for use must also be recorded.
9.2.4
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent of this extension study. This includes clinically significant 
laboratory, ECG, or physical examination abnormalities noted at baseline examination, according 
the judgment of the investigator and thus also include AEs that started during TAK-994-1501 that
were ongoing at that study’s final visit. The condition (ie, diagnosis) should be described.
9.3
Clinical Procedures and Assessments
9.3.1
AE Monitoring
A complete description of PTE and AE collection procedures is provided in Section 10.0.
9.3.2
Vital Sign Procedure
Vital signs, including body temperature, respiratory rate, BP (systolic and diastolic, resting more 
than 5 minutes), and pulse (bpm), will be obtained at the times indicated in the Schedule of Study 
Procedures (Appendix A). 
Body temperature will be measured with an oral (temperature taken at floor of the mouth), 
tympanic, or infra-axillary thermometer. The same method (eg, oral, tympanic, or infra-axillary) 
must be used for all subsequent measurements for each individual subject.
When assessed in the clinic, BP will be checked (single measurement) with the subject lying in a 
bed resting for a minimum of 5 minutes with the head of the bed at 30 degrees. In the event of 
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conflicts between scheduled BP assessment and 
, BP assessments should be 
taken first.
9.3.3
Weight, Height, and Body Mass Index
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The body mass index (BMI) is calculated using metric units with the formula provided below. 
Height is recorded in centimeters without decimal places. Weight is collected in kilograms (kg) 
with 1 decimal place. BMI should be derived as:
Metric:
BMI = weight (kg) / height (m)2
Note that although height is reported in centimeters, the formula uses meters for height; meters can 
be determined from centimeters by dividing by 100. Thus, for example, if height = 176 cm 
(1.76 meters) and weight = 79.2 kg, then BMI = 79.2/1.762 = 25.56818 kg/m2
The values should be reported to 1 decimal place by rounding. Thus, in the above example BMI 
would be reported as 25.6 kg/m2. 
9.3.4
ECG Procedure 
ECG monitoring will be performed at the times indicated in the Schedule of Study Procedures 
(Appendix A).
Special care must be taken for proper lead placement by qualified personnel. Skin should be clean 
and dry before lead placement. Subjects may need to be shaved to ensure proper lead placement. 
Subjects should be resting in a semirecumbent position for at least 5 minutes before each ECG 
measurement and will remain in that position until the ECG is completed. The principal 
investigator should arrange to have a study cardiologist available as needed to review ECG 
tracings with abnormalities.
If a subject demonstrates an increase in QTcF interval ≥40 milliseconds compared with a baseline 
measurement, the ECG will be repeated within 5 minutes. The average value of the QTcF interval 
from the 2 ECGs will represent the value at that time point. If the average QTcF interval increase 
from baseline for any postdose time point is ≥40 milliseconds, the subject will continue to be 
monitored by repeat 12-lead ECGs every 60 minutes for at least 4 hours or until the QTcF interval 
is within 40 milliseconds of the baseline value. If prolongation of the QTcF interval 
≥40 milliseconds persists, a consultation with a study cardiologist may be appropriate and the 
sponsor should be notified.
If the QTcF interval is ≥500 milliseconds, the sponsor should be notified and the ECGs should be 
reviewed by a cardiologist. The subject should be considered for transfer to a location where closer 
monitoring is available.
If the subject has unstable hemodynamics, or has any clinically significant dysrhythmias noted by 
telemetry, the subject should be immediately transferred to an acute care setting for definitive 
therapy.
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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis a
RBCs
WBCs with absolute differential
Hemoglobin
Hematocrit
Platelets
PT/INR b
ALT
Albumin
Alkaline phosphatase
AST
Total bilirubin c
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
GGT
Potassium
Sodium
Calcium
Carbon dioxide
Triglycerides
Lipid panel (HDL, LDL, total 
cholesterol)
Chloride
Glucose
Blood
Glucose
Urine specific gravity
Nitrite
Protein
Other:
Serum
Serum/Plasma 
Urine
Female subjects of childbearing 
potential only: β-hCG (for 
pregnancy)
Aldosterone, renin
Female subjects of childbearing potential 
only: hCG (for pregnancy)
For all subjects: drug screening 
(amphetamines, barbiturates, 
benzodiazepines, buprenorphine/metabolite, 
cannabinoids, cocaine/metabolites, MDMA, 
methadone/metabolite, opiates, 
oxycodone/oxymorphone, phencyclidine)
Confirmatory urine drug screen tests d
Alcohol test: with a breathalyzer 
initially and, if positive, a serum 
ethanol level will be obtained
ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGT: γ-glutamyl transferase; HDL: high-density lipoprotein; 
hCG: human chorionic gonadotropin; INR: international normalized ratio; LDL: low-density lipoprotein; MDMA: 
3,4-methylenedioxy-methamphetamine; PT: prothrombin time; RBC: red blood cell; WBC: white blood cell.
a Urine microscopy will be performed if urinalysis is abnormal. Microscopy consists of RBC count/high-power field, 
WBC/high-power field, and casts.
b If ALT or AST >3 times the ULN
c If value above the upper limit of normal, total bilirubin will be fractionated.
d Applicable throughout the study in regions where available.
The central laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who is responsible for 
reviewing and filing these results.
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9.10
Post Study Care
Study drug will not be available upon completion of the subject’s participation in the study. The 
subject should be returned to the care of a physician and standard therapies as required.
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1
PTEs
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but before administration of any study drug; it 
does not necessarily have to have a causal relationship with study participation.
10.1.2
AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory value), symptom, or disease temporally associated with the use of a drug whether or not 
it is considered related to the drug.
10.1.3
Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered PTEs or 
AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study drug or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/AE.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a PTE(s) or as an AE(s).
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Laboratory values and ECG findings:

Changes in laboratory values or ECG findings are only considered to be PTEs or AEs if they 
are judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory or ECG re-test and/or continued monitoring of an abnormal value or finding are not 
considered an intervention. In addition, repeated or additional noninvasive testing for 
verification, evaluation or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, x-rays) should NOT be recorded as PTEs unless related 
to study procedures. However, if the subject experiences a worsening or complication of such a 
concurrent medical condition, the worsening or complication should be recorded appropriately 
as a PTE (worsening or complication occurs before start of study drug) or an AE (worsening or 
complication occurs after start of study drug). Investigators should ensure that the event term 
recorded captures the change in the condition (eg, “worsening of…”).

If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, epilepsy) any 
occurrence of an episode should only be captured as a PTE/AE if the condition becomes more 
frequent, serious or severe in nature. Investigators should ensure that the AE term recorded 
captures the change in the condition from baseline (eg “worsening of…”).

If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be recorded as a PTE/AE if occurring to a 
greater extent to that which would be expected. Investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after the start of study drug, 
the worsening or complication should be recorded as an AE. Investigators should ensure that 
the AE term recorded captures the change in the PTE (eg, “worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study 
drug, the worsening or complication should be recorded as a new AE. Investigators should 
ensure that the AE term recorded captures the change in the condition (eg, “worsening of…”).
Changes in intensity of AEs/serious PTEs:

If the subject experiences changes in intensity of an AE/serious PTE, the event should be 
captured once with the maximum intensity recorded.
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Preplanned procedures (surgeries or interventions):

Preplanned procedures (surgeries or therapies) that were scheduled before signing of informed 
consent are not considered PTEs or AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of 
the condition should be recorded as a PTE or an AE. Complications resulting from any planned 
surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing illness 
and lack of therapeutic efficacy.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of 
the eCRF.
10.1.4
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.
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
Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Hepatic necrosis
Torsade de pointes/ventricular fibrillation/ventricular 
tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizure
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis 
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson syndrome Confirmed or suspected transmission of infectious agent by a 
medicinal product
COVID-19 related disease
Neuroleptic malignant syndrome/malignant hyperthermia
COVID-19 pneumonia
Spontaneous abortion/stillbirth and fetal death
AE: adverse event; SAE: serious adverse event.
Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered as “Important Medical 
Events” satisfying SAE reporting requirements. 
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5
AEs of Special Interest
No AEs of special interest have been defined for this study.
10.1.6
Intensity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.7
Causality of AEs
The relationship of each AE to study drug(s) will be assessed using the following categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant medications and concurrent treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant medications and concurrent treatments.
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10.1.8
Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and AEs.
The relationship should be assessed as related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as not related. 
10.1.9
Start Date
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or investigator.
10.1.10
Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but with 
sequelae, or the subject died.
10.1.11
Frequency 
Episodic AEs/PTE (eg, vomiting) or those that occur repeatedly over a period of consecutive days 
are intermittent. All other events are continuous.
10.1.12
Action Concerning Study Drug 

Drug withdrawn: a study drug is stopped due to the particular AE.

Dose not changed: the particular AE did not require stopping a study drug.

Unknown: only to be used if it has not been possible to determine what action has been taken.

Not applicable: a study drug was stopped for a reason other than the particular AE, for 
example, the study has been terminated, the subject died, dosing with study drug was already 
stopped before the onset of the AE.

Dose interrupted: the dose was interrupted due to the particular AE.
10.1.13
Outcome

Recovered/resolved: subject returned to first assessment status with respect to the AE/PTE.

Recovering/resolving: the intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving”.

Not recovered/not resolved: there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/PTE state remaining “Not 
recovered/not resolved”.
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
Resolved with sequelae: the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis.

Fatal: the AEs/PTEs that are considered as the cause of death. 

Unknown: the course of the AE/PTE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1
Collection and Reporting of AEs
10.2.1.1
PTE and AE Collection Period
Collection of AEs (ie, AEs, SAEs, special interest AEs, and abnormal LFTs) will commence at the 
time the subject takes his/her first dose of TAK-994. Routine collection of AEs will continue until 
approximately 30 days or 5.5 half-lives, whichever is longer, after the last dose of study drug. For 
subjects who discontinue before the administration of study drug, AEs will be followed until the 
subject discontinues study participation.
Because this study is designed to have subjects complete assessments for TAK-994-1501 and then 
shortly thereafter begin assessments for the current study, the PTE collection window for this 
protocol is brief. After signing of the ICF, it commences after the first assessment and ends upon 
intake of the first dose of TAK-994.
10.2.1.2
PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in
laboratory values have returned to baseline or there is a satisfactory explanation for the change. 
Nonserious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study drug or 
not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All PTEs and AEs will be documented in the PTE/AE page of the eCRF, 
whether or not the investigator concludes that the event is related to the drug treatment. The 
following information will be documented for each event:
1. Event term.
2. Start and stop date and time.
3. Frequency.
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4. Intensity.
5. Investigator’s opinion of the causal relationship between the event and administration of study 
drug(s) (related or not related) (not completed for PTEs).
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.
7. Action concerning study drug (not applicable for PTEs).
8. Outcome of event.
9. Seriousness.
In addition, additional information regarding following AEs may be collected on eCRF:
10. Increased urinary urgency and frequency (daily urinary frequency), urinary incontinence.
ePRO will not be used as a primary means to collect AEs. However, should the investigator 
become aware of a potential AE through the information collected with this instrument, proper 
follow-up with the patient for medical evaluation should be undertaken. Through this follow-up if 
it is determined that an AE not previously reported has been identified, normal reporting 
requirements should be applied.
10.2.2
Collection and Reporting of SAEs
When an SAE occurs through the AE collection period, it should be reported according to the 
procedure outlined below:
SAEs should be reported via SAE eCRF in Rave electronic data capture (EDC), which is the 
preferred method of reporting. A Takeda SAE form must be completed, in English, and signed by 
the investigator immediately or within 24 hours of first onset or notification of the event. The 
information should be completed as fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study drug(s).

Causality assessment.
If access to Rave EDC is not feasible within 24 hours of receiving the event, the paper SAE form 
should be submitted via fax. The SAE form should be completed within 24 hours of first onset or 
notification of the event, signed by the investigator, and transmitted via fax or email to the 
attention of the contact listed in Section 1.1. In case of fax, site personnel need to confirm 
successful transmission of all pages and include an email address on the fax cover sheet so that an 
acknowledgment of receipt can be returned via email within 1 business day.
Email submission of SAE forms (to the appropriate email address listed below) with a PDF 
attachment should only be used in the case where fax is not possible and access to Rave EDC is not 
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feasible within 24 hours of receiving the event. In case of email, site personnel need to confirm 
successful transmission by awaiting an acknowledgment of the receipt via e mail within 1 business 
day.

United States and Canada: PVSafetyAmericas@tpna.com.

Rest of World: eupv@tgrd.com.
If SAEs are reported via fax or by email, Rave EDC must be updated as soon as possible with the 
appropriate information.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of SAEs that begin before the first administration of investigational product will follow 
the same procedure for SAEs occurring on treatment.
10.2.3
Reporting of Abnormal LFTs 
If a subject is noted to have ALT or AST elevated >3 × ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE, and the subject should be withdrawn from the study. In 
addition, an LFT Increases eCRF 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 subject 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 10.2.2. The investigator must contact the sponsor or designee for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease. Follow-up laboratory tests as described in Section 9.3.8 must also be 
performed. 
10.3
Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date, the 
investigator should update SAE eCRF in Rave EDC or complete a follow-up SAE form or provide 
other written documentation and fax it immediately within 24 hours of receipt. Copies of any 
relevant data from the hospital notes (eg, ECGs, laboratory tests, discharge summary, postmortem 
results) should be sent to the addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.3.1
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency, and IRBs or IECs, as applicable, in accordance with national regulations in the 
countries where the study is conducted. Relative to the first awareness of the event by/or further 
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provision to the sponsor or sponsor’s designee, SUSARs will be submitted to the regulatory 
authorities as expedited report within 7 days for fatal and life-threatening events and 15 days for 
other serious events, unless otherwise required by national regulations. The sponsor will also 
prepare an expedited report for other safety issues where these might materially alter the current 
benefit-risk assessment of a study drug/sponsor supplied drug or that would be sufficient to 
consider changes in the study drug/sponsor supplied drug administration or in the overall conduct 
of the trial. The study site also will forward a copy of all expedited reports to his or her IRB or IEC 
in accordance with local regulations.
11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.
12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent medical conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization Drug Dictionary.
12.1
eCRFs
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Corrections are recorded in an audit trail that captures the old information, new information, 
identification of the person making the correction, date the correction was made, and reason for 
change. Reasons for significant corrections should additionally be included.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the eCRFs should be made by the investigator with use of change and modification records of 
the eCRFs. The principal investigator must review the data change for completeness and accuracy 
and must sign and date.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
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and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, ICH 
E6 Section 4.9.5 requires the investigator to retain essential documents specified in ICH E6 
(Section 8) until at least 2 years after the last approval of a marketing application for a specified 
drug indication being investigated or, if an application is not approved, until at least 2 years after 
the investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 
Section 4.9.5 states that the study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the study site agreement between the 
investigator and sponsor.
Refer to the study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
The investigator and the head of the study site agree to keep the records stipulated in Section 12.1
and those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, temporary media such as thermal 
sensitive paper, source worksheets, all original signed and dated informed consent forms, subject 
authorization forms regarding the use of personal health information (if separate from the 
informed consent forms), and detailed records of drug disposition to enable evaluations or audits 
from regulatory authorities, the sponsor or its designees. Any source documentation printed on 
degradable thermal sensitive paper should be photocopied by the site and filed with the original in 
the subject’s chart to ensure long-term legibility. Furthermore, ICH E6 Section 4.9.5 requires the 
investigator and the head of the study site to retain essential documents specified in ICH E6 
(Section 8) until at least 2 years after the last approval of a marketing application for a specified 
drug indication being investigated or, if an application is not approved, until at least 2 years after 
the investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 
Section 4.9.5 states that the study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the study site agreement between the 
investigator and/or the head of the study site and sponsor.
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13.1.7
Safety Analysis
13.1.7.1
AEs
13.1.7.1.1
Active Drug Extension Period
TEAEs will be summarized using the active drug extension safety set. No statistical testing or 
inferential statistics will be generated.
All AEs will be coded using MedDRA. Data will be summarized by treatment and overall using 
Preferred Term and primary System Organ Class.
13.1.7.1.2
Randomized Withdrawal Period
TEAEs will be summarized using the randomized withdrawal safety set. No statistical testing or 
inferential statistics will be generated.
All AEs will be coded using MedDRA. Data will be summarized by treatment and overall using 
Preferred Term and primary System Organ Class.
13.1.7.2
Clinical Laboratory Evaluation
13.1.7.2.1
Active Drug Extension Period
Safety clinical laboratory evaluation data will be summarized by treatment group and overall 
(number of subjects, mean, SD, median, minimum, and maximum) for baseline, postdose, and 
change from baseline. Observed values and change from Baseline I in these parameters will be 
summarized by treatment and overall.
Subjects meeting markedly abnormal criteria for safety clinical laboratory assessments will be 
listed and summarized by treatment group and overall. The MAV criteria will be defined in the 
SAP.
13.1.7.2.2
Randomized Withdrawal Period
Safety clinical laboratory evaluation data will be summarized by treatment group and overall 
(number of subjects, mean, SD, median, minimum, and maximum) for baseline, postdose, and 
change from baseline. Observed values and change from Baseline II in these parameters will be 
summarized by treatment and overall. 
Subjects meeting markedly abnormal criteria for safety clinical laboratory assessments will be 
listed and summarized by treatment group and overall. The MAV criteria will be defined in the 
SAP.
13.1.7.3
Vital Signs and ECGs
The relationships between TAK-994 exposure and selected safety measures (such as change from 
baseline in systolic BP, diastolic BP, and HR) will be explored graphically, as data permit. Details 
will be described in the SAP.
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13.1.7.3.1
Active Drug Extension Period
All vital signs and ECG assessments will be summarized for Baseline I, postdose, and change from 
baseline by treatment and time, if deemed appropriate.
Subjects meeting markedly abnormal criteria for vital signs and ECG assessments will be listed 
and summarized by treatment group and overall. The MAV criteria will be defined in the SAP.
13.1.7.3.2
Randomized Withdrawal Period
Where appropriate, BP and pulse measurements will be summarized by treatment group and 
overall (number of subjects, mean, SD, median, minimum, and maximum) for baseline, postdose,
and change from baseline by treatment and time point. Linear mixed-effect models for the repeated 
measures will be performed to evaluate the drug effect on BP and pulse using data from inpatient 
monitoring. In these analyses, change from time-matched baseline will be the response and 
baseline, treatment, time point, and the treatment by time point interaction will be the fixed effects.
All other vital signs and ECG assessments will be summarized for Baseline II, postdose, and 
change from baseline by treatment and time, if deemed appropriate.
Subjects meeting markedly abnormal criteria for vital signs and ECG assessments will be listed 
and summarized by treatment group and overall. The MAV criteria will be defined in the SAP.
13.1.7.4
Other Safety Parameters
Physical examination findings and C-SSRS data will be presented in the data listings.
13.2
Interim Analysis
No interim analysis is planned.
13.3
Determination of Sample Size
There is no sample size justification for this study. All subjects in Part B of TAK-994-1501 willing
and eligible to participate and meeting the selection criteria will be enrolled in the active drug 
extension period of the study. Subjects who complete the active drug extension period and willing 
to continue to the randomized withdrawal period will be randomized.
14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and the study site guarantee access to source documents by the sponsor or its 
designee (contract research organization) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or sponsor’s 
designee (as long as blinding is not jeopardized), including but not limited to the investigator’s 
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binder, study drug, subject medical records, informed consent documentation, and review of 
eCRFs and associated source documents. It is important that the investigator and other study 
personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances (such as the 
COVID-19 pandemic) arise that will require deviation from protocol-specified procedures, the 
investigator should consult with the sponsor or designee (and IRB or IEC, as required) to 
determine the appropriate course of action. There will be no exemptions (a prospectively approved 
deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. 
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator guarantee access for quality assurance auditors to all study 
documents as described in Section 14.1.
15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
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15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB 
or IEC for the protocol’s review and approval. This protocol, the investigator’s brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity/signing a contract for the clinical study). The IRB or IEC approval must refer to 
the study by exact protocol title, number, and version date; identify versions of other documents 
(eg, informed consent form) reviewed; and state the approval date. The sponsor will ship 
drug/notify site once the sponsor has confirmed the adequacy of site regulatory documentation 
and, when applicable, the sponsor has received permission from competent authority to begin the 
study. 
Study sites must adhere to all requirements stipulated by their respective IRB or IEC. This may 
include notification to the IRB or IEC regarding protocol amendments, updates to the informed 
consent form, recruitment materials intended for viewing by subjects, local safety reporting 
requirements, reports and updates regarding the ongoing review of the study at intervals specified 
by the respective IRB or IEC, and submission of the investigator’s final status report to IRB or 
IEC. All IRB and IEC approvals and relevant documentation for these items must be provided to 
the sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
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participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor before use. 
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. 
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and before the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and before subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical trial database or documentation via a subject identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
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To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit the monitor or the sponsor’s designee, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the study site agreement, any public disclosure 
(including publicly accessible websites) related to the protocol or study results, other than study 
recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the study site agreement. In the event of any discrepancy between the protocol and 
the study site agreement, the study site agreement will prevail.
15.4.2
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
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inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to the sponsor providing this information to callers must provide the 
sponsor with a written notice requesting that their information not be listed on the registry site. 
15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov and/or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the sponsor 
or sponsor’s designee.
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
study-related duties and functions, the investigator/institution should ensure that this 
individual or party is qualified to perform those study-related duties and functions and should 
implement procedures to ensure the integrity of the study-related duties and functions 
performed and any data generated.
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, before the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs (and ePROs), hospital records, laboratory results, etc, and maintain these data for a 
minimum of 2 years following notification by the sponsor that all investigations have been 
discontinued or that the regulatory authority has approved the marketing application. The 
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investigator should contact and receive written approval from the sponsor before disposing of 
any such documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix C
Elements of the Subject Informed Consent 
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject may discontinue 
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participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject will be informed in a timely manner if information becomes 
available that may be relevant to the subject’s willingness to continue participation in the 
study.
22. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
23. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) That personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) It is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) That personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study drug(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) That subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) That the subject’s identity will remain confidential in the event that study results are 
published.
24. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from signing the informed consent and throughout the duration of the study, and for 5 
half-lives PLUS 30 days after last dose. Regular pregnancy tests will be performed throughout 
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the study for all female subjects of childbearing potential. If a subject is found to be pregnant 
during study, study drug will be discontinued and the investigator will offer the subject the 
choice to receive unblinded treatment information.
25. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study, and for 5 half-lives 
PLUS 90 days after last dose. If the partner or wife of the subject is found to be pregnant during 
the study, the investigator will offer the subject the choice to receive unblinded treatment 
information.
26. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.
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Appendix D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study drug.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
For non-commercial use only

For non-commercial use only