A Randomized, Double-blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of TAK-861 for the Treatment of Narcolepsy With Cataplexy (Narcolepsy Type 1)
Phase: PHASE2
Conditions: Narcolepsy Type 1
Sponsor: Takeda

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TAKEDA PHARMACEUTICALS
PROTOCOL
A Randomized, Double-blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and 
Tolerability of TAK-861 for the Treatment of Narcolepsy With Cataplexy (Narcolepsy Type 1)
A Study to Evaluate the Efficacy, Safety, and Tolerability of TAK-861 for the Treatment of 
Narcolepsy With Cataplexy 
Sponsor:
Takeda Development Center Americas, Inc.
95 Hayden Avenue
Lexington, MA 02421 USA
Study Number:
TAK-861-2001
Study Phase:
2
IND Number:
154232
EudraCT/CTIS 
Number:
2022-001654-38
ClinicalTrials.gov:
Posting planned prior 
to study start
WHO Universal Trial 
Number:
U1111-1277-4261
Investigational 
Product:
TAK-861
Date:
17 Aug 2022
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. 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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INVESTIGATOR AGREEMENT 
I confirm that I have read and understand this protocol, the investigator’s brochure (IB), 
prescribing information, 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, life, dignity, integrity, confidentiality of personal information, safety, privacy, and well-
being of study participants in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

ICH GCP.

All applicable laws and regulations, including, without limitation, data privacy laws and
regulations.

Regulatory requirements for reporting serious adverse events (SAEs) as defined in this
protocol.

Terms outlined in the clinical study site agreement.

Responsibilities of the investigator as described in this protocol.
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a potential participant to obtain their informed consent to 
participate.
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study.
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study, I will communicate my intention 
immediately in writing to the sponsor.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Name and Location of Facility (City, State/Province)
Location of Facility (Country)
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ADMINISTRATIVE INFORMATION 
CONTACTS
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in relevant guidelines provided to the site.
Takeda Development Center Americas, Inc.–sponsored investigators will be provided with 
emergency medical contact information cards to be provided to each study participant and 
carried by each participant per individual country requirements.
ADDITIONAL INFORMATION 
A separate contact information list will be provided to each site.
Contact Type/Role
Contact
Serious adverse event and pregnancy reporting
Pharmacovigilance
Takeda Development Center Americas, Inc.
Fax: +1 224-554-1052
Email: PVSafetyAmericas@tpna.com
24-hour urgent medical contact
North America: +1 888 483 7729 
Europe, Middle East and Africa/Asia Pacific: +44 122 337 
4240
PRODUCT QUALITY COMPLAINTS
A product quality complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, strength, purity, 
effectiveness, or performance of a product, device, or combination product after it is released for 
distribution. 
Report product complaints using the form called “Clinical Trial Material Complaint Form.” 
Send it to the following email address: 
ctmcomplaint@takeda.com
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TABLE OF CONTENTS
APPROVALS.............................................................................................................................2
ADMINISTRATIVE INFORMATION.......................................................................................4
ADDITIONAL INFORMATION................................................................................................4
PRODUCT QUALITY COMPLAINTS......................................................................................4
TABLE OF CONTENTS............................................................................................................5
1.
PROTOCOL SUMMARY.............................................................................................12
1.1
Synopsis ..................................................................................................................12
1.2
Schema....................................................................................................................21
1.3
Schedule of Activities..............................................................................................22
2.
INTRODUCTION.........................................................................................................29
2.1
Study Rationale .......................................................................................................29
2.2
Background .............................................................................................................29
2.2.1.
Summary of Nonclinical Data..........................................................................30
2.2.2.
Summary of Effects in Humans .......................................................................30
2.3
Benefit-Risk Assessment .........................................................................................33
2.3.1.
Potential Benefits.............................................................................................33
2.3.2.
Potential Risks.................................................................................................33
3.
OBJECTIVES, ENDPOINTS........................................................................................34
3.1
Objectives and Endpoints.........................................................................................34
3.2
Estimands ................................................................................................................36
4.
STUDY DESIGN..........................................................................................................36
4.1
Overall Design.........................................................................................................36
4.2
Scientific Rationale for Study Design ......................................................................37
4.2.1.
Rationale for Study Population ........................................................................37
4.2.2.
Rationale for Study Design..............................................................................37
4.2.3.
Rationale for Endpoints ...................................................................................38
4.2.3.1.
Safety Endpoints......................................................................................38
4.2.3.2.
Efficacy Endpoints ..................................................................................38
4.2.4.
Participant Input into Design............................................................................39
4.3
Justification for Dose...............................................................................................39
4.4
End of Study/Study Completion Definition..............................................................39
5.
STUDY POPULATION................................................................................................39
5.1
Inclusion Criteria .....................................................................................................39
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5.2
Exclusion Criteria ....................................................................................................41
5.3
Lifestyle Considerations ..........................................................................................45
5.3.1.
Meals and Dietary Restrictions ........................................................................45
5.3.2.
Activity ...........................................................................................................46
5.3.3.
Contraception for Participants of Childbearing Potential or Capable of 
Producing Viable Sperm..................................................................................46
5.4
Screening.................................................................................................................46
5.4.1.
Screen Failures ................................................................................................46
5.5
Criteria for Temporarily Delaying Randomization ...................................................47
5.6
Enrollment...............................................................................................................47
6.
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY..............................47
6.1
Study Interventions Administered............................................................................47
6.2
Preparation, Handling, Storage, and Accountability .................................................48
6.2.1.
Accountability Throughout the Study...............................................................48
6.2.2.
Receiving Product at the Site ...........................................................................49
6.2.3.
Labeling ..........................................................................................................49
6.2.4.
Dispensing/Administration ..............................................................................49
6.2.4.1.
Dispensing...............................................................................................49
6.2.4.2.
Administration.........................................................................................49
6.3
Measures to Minimize Bias: Randomization and Blinding .......................................51
6.3.1.
Randomization.................................................................................................51
6.3.2.
Blinding the Treatment Assignment.................................................................51
6.3.3.
Unblinding.......................................................................................................51
6.4
Study Drug Compliance...........................................................................................51
6.5
Dose Modification ...................................................................................................51
6.6
Continued Access to Study Intervention after the End of the Study..........................51
6.7
Treatment of Overdose ............................................................................................51
6.8
Concomitant Therapy...............................................................................................52
6.8.1.
Excluded Treatments .......................................................................................52
6.8.2.
Permitted Concomitant Medications ................................................................54
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ......................................................................54
7.1
Discontinuation of Study Intervention......................................................................54
7.2
Participant Discontinuation/Withdrawal from the Study...........................................56
7.3
Lost to Follow-up ....................................................................................................56
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8.
STUDY ASSESSMENTS AND PROCEDURES ..........................................................56
8.1
Demographics, Medical History, Medication History and Administrative 
Procedures...............................................................................................................57
8.1.1.
Demographics..................................................................................................57
8.1.2.
Medical History...............................................................................................57
8.1.3.
Prior and Concomitant Treatments/Medications...............................................58
8.1.4.
Diagnostic Criteria/Disease Classification........................................................58
8.1.4.1.
Diagnostic Criteria for NT1.....................................................................58
8.1.4.2.
HLA Genotyping.....................................................................................59
8.1.5.
Administrative Procedures (Contingency Measures for Unavoidable 
Circumstances) ................................................................................................59
8.2
Efficacy Assessments...............................................................................................61
8.2.1.
Primary Efficacy Measurement........................................................................61
8.2.2.
Other ...............................................................................................................61
8.2.2.1.
.......................................................................................................61
8.2.2.2.
............................................................................61
8.2.2.3.
Clinical Outcome Assessments ................................................................62
8.3
Safety Assessments..................................................................................................65
8.3.1.
Physical Examinations.....................................................................................65
8.3.2.
Vital Signs.......................................................................................................65
8.3.2.1.
Weight, Height, and BMI.........................................................................66
8.3.3.
ECG ................................................................................................................66
8.3.4.
Clinical Safety Laboratory Tests......................................................................67
8.3.5.
Pregnancy Testing ...........................................................................................68
8.3.6.
Suicidal Ideation and Behavior Risk Monitoring..............................................68
8.3.7.
Other ...............................................................................................................68
8.3.7.1.
....................................................................68
8.3.7.2.
.....................................................................................................68
8.3.8.
AEs, SAEs, and Other Safety Reporting ..........................................................68
8.3.8.1.
Time Period and Frequency for Collecting AE and SAE Information.......69
8.3.8.2.
Method of Detecting AEs and SAEs ........................................................69
8.3.8.3.
Follow-up of AEs and SAEs....................................................................69
8.3.8.4.
Regulatory Reporting Requirements for SAEs.........................................69
8.3.8.5.
Pregnancy in a Participant or Participant’s Partner During the Study .......70
8.3.8.6.
AEs of Special Interest ............................................................................70
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8.4
...........................................................................................................................70
8.4.1.
.................................................................71
8.5
Genetics...................................................................................................................71
8.5.1.
..........................................................................71
8.5.2.
HLA Genotyping .............................................................................................72
8.6
......................................................................................72
8.7
Immunogenicity Assessments ..................................................................................72
9.
STATISTICAL CONSIDERATIONS ...........................................................................72
9.1
Statistical Hypotheses..............................................................................................72
9.1.1.
Primary Endpoint.............................................................................................72
9.1.2.
Secondary Endpoints .......................................................................................72
9.2
Analysis Sets ...........................................................................................................73
9.2.1.
Safety Set ........................................................................................................73
9.2.2.
.............................................................................................................73
9.2.3.
Full Analysis Set..............................................................................................73
9.3
Efficacy Analyses....................................................................................................73
9.3.1.
Primary Efficacy Endpoint...............................................................................73
9.3.2.
Secondary Efficacy Endpoints .........................................................................73
9.3.3.
...................................................................................73
9.4
Safety Analyses .......................................................................................................74
9.5
Other Analyses ........................................................................................................74
9.5.1.
....................................................................................................74
9.5.2.
..............................................................................................74
9.6
..................................................................................74
9.7
..................................................................................75
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS....76
10.1
Regulatory, Ethical, and Study Oversight Considerations.........................................76
10.1.1.
Regulatory and Ethical Considerations.............................................................76
10.1.2.
Financial Disclosure ........................................................................................76
10.1.3.
Informed Consent Process ...............................................................................76
10.1.4.
Data Protection................................................................................................77
10.1.4.1. Notice Regarding the Use and Transfer of the Investigator’s Personal 
Information..............................................................................................78
10.1.5.
Committees Structure ......................................................................................80
10.1.5.1. IRB and/or IEC Approval........................................................................80
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10.1.5.2. Other Committees....................................................................................81
10.1.6.
Dissemination of Clinical Study Data ..............................................................81
10.1.6.1. Study Results Disclosure .........................................................................81
10.1.7.
Data Quality Assurance ...................................................................................81
10.1.7.1. Protocol Deviations .................................................................................82
10.1.7.2. Study-Site Monitoring Visits ...................................................................82
10.1.7.3. Audits......................................................................................................83
10.1.8.
Source Documents...........................................................................................83
10.1.8.1. eCRFs......................................................................................................83
10.1.8.2. Documentation and Retention of Records................................................84
10.1.8.3. Data Handling .........................................................................................85
10.1.8.4. Record Retention.....................................................................................85
10.1.9.
Study and Site Start and Closure......................................................................86
10.1.9.1. First Act of Recruitment ..........................................................................86
10.1.9.2. Study/Site Termination............................................................................86
10.1.9.3. Optional Study Participant Interviews......................................................88
10.1.10. Publication Policy............................................................................................88
10.1.11. Responsibilities of the Sponsor and the Investigator.........................................89
10.1.11.1. Sponsor Responsibilities..........................................................................89
10.1.11.2. Investigator Responsibilities ....................................................................90
10.2
Clinical Laboratory Tests.........................................................................................91
10.2.1.
Clinical Laboratory Assessments and Other Safety Assessments......................92
10.2.2.
..................................................93
10.3
AEs and SAEs: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting ..........................................................................................................93
10.3.1.
Definition of AE..............................................................................................93
10.3.2.
Definition of SAE............................................................................................95
10.3.3.
Additional Considerations in Identifying and Defining AEs.............................96
10.3.3.1. Defining Discrete AEs.............................................................................96
10.3.3.2. AEs of Special Interest ............................................................................97
10.3.4.
Recording and Follow-Up of AE and/or SAE ..................................................98
10.3.4.1. Frequency................................................................................................98
10.3.4.2. Intensity...................................................................................................98
10.3.4.3. Causality/Relatedness..............................................................................99
10.3.4.4. Action Taken.........................................................................................100
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10.3.4.5. Outcome................................................................................................100
10.3.4.6. Follow-Up .............................................................................................101
10.3.5.
Expedited Reporting of SAEs and Selected AEs ............................................102
10.3.5.1.
...........................102
10.3.5.2. Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities.............................................................................................102
10.4
Contraceptive and Barrier Guidance.......................................................................103
10.4.1.
Definitions.....................................................................................................103
10.4.2.
Contraception Guidance.................................................................................103
10.4.3.
Pregnancy......................................................................................................106
10.5
...107
10.6
Country-specific Requirements..............................................................................108
10.7
Abbreviations and Definitions................................................................................109
10.7.1.
Abbreviations ................................................................................................109
10.8
Protocol Amendment History.................................................................................111
11.
REFERENCES............................................................................................................112
LIST OF TABLES
Table 1.a
........................................................................................22
Table 1.b
........................27
Table 6.a
Study Intervention(s) Administered: Drug..........................................................48
Table 6.b 
...........................................52
Table 8.a
.............................................................................57
Table 10.a
Protocol-Required Laboratory Tests...................................................................92
Table 10.b
Acceptable Contraception Methods and Lactation Guidance for this Study ......105
Table 10.c
Unacceptable Contraception Methods ..............................................................106
Table 10.d
.......................................................................................108
LIST OF FIGURES
Figure 1.a
....................................................................................................21
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1.
Protocol Summary
1.1
Synopsis
Name of Sponsor(s):
Takeda Development Center Americas, Inc.
95 Hayden Avenue
Lexington MA 02421
USA
Compound:
TAK-861
Study Number: 
TAK-861-2001
Phase:
2
IND No.: 
154232
EudraCT No.: 
2022-001654-38
Title of Protocol: 
A Randomized, Double-blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of TAK-
861 for the Treatment of Narcolepsy With Cataplexy (Narcolepsy Type 1)
Short Title:
A Study to Evaluate the Efficacy, Safety, and Tolerability of TAK-861 in the Treatment for Narcolepsy With 
Cataplexy 
Number of participants:
A total of approximately 100 participants (20 per arm)
Investigator(s): Multicenter global study
Site(s) and Region(s): Up to approximately 70 sites across North America, Europe, and Asia Pacific
Study Period (planned): Q1 2023 to Q2 2024
Objectives and Endpoints
Objectives
Endpoints
Primary

To assess the effect of TAK-861 on excessive
daytime sleepiness (EDS) as measured by sleep
latency from the Maintenance of Wakefulness
Test (MWT).

Change from baseline to Week 8 in mean sleep
latency from the MWT
Secondary

To assess the effect of TAK-861 on EDS as
measured by the Epworth Sleepiness Scale
(ESS) total score.

Change from baseline to Week 8 in ESS total
score

To assess the effect of TAK-861 on cataplexy
as assessed by the weekly cataplexy rate
(WCR).

WCR at Week 8

To evaluate the safety and tolerability of TAK-
861.

Occurrence of at least 1 treatment-emergent
adverse event (TEAE).
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
Additional/Exploratory
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Table 1.b
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Table 1.b
 
 
 
 
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Table 6.a describes the interventions administered in all arms of this study.
Details regarding the dosage form description and strengths, or composition for the 
extemporaneous preparation, of the active drug and placebo, can be found in the IB. Study drug 
will be packaged to support the enrollment of participants as required.
Table 6.a
Study Intervention(s) Administered: Drug
Intervention Label
TAK-861
Placebo 
Intervention Name
TAK-861
Placebo 
Former Name(s) or 
Alias(es)
NA
NA
Intervention 
Description
Information provided in the IB
Information provided in the IB
Excipients
Information provided in the IB
Information provided in the IB
Type
Drug
Placebo 
Dose Formulation
Tablet
Tablet
Unit Dose 
Strength(s)
Information provided in the IB
Information provided in the IB
Dosage Level(s)
See Section 4.3
See Section 4.3
Route of 
Administration
Oral
Oral
Use
Experimental
Placebo
Classification
Investigational medicinal product
NA
Authorization Status
Not authorized in any region
NA
Sourcing
Provided centrally by the sponsor or 
designee
Provided centrally by the sponsor or 
designee
Packaging and 
Labeling
Information provided in pharmacy manual
Information provided in pharmacy manual
IB: investigator’s brochure; NA: not applicable.
6.2
Preparation, Handling, Storage, and Accountability 
For preparation, handling, and storage of the sponsor-supplied study product, refer to the 
pharmacy manual.
6.2.1.
Accountability Throughout the Study
The investigator or designee must ensure that the sponsor-supplied study product is used in 
accordance with the protocol and is only dispensed to/used for participants enrolled in the study. 
To document appropriate use of sponsor-supplied study product (Section 6.1), the investigator or 
designee must maintain 100% accountability for all sponsor-supplied study interventions that the 
site receives and dispenses during their entire participation in the study. 
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6.3
Measures to Minimize Bias: Randomization and Blinding 
6.3.1.
Randomization 
Randomization personnel of the sponsor or designee will generate the randomization schedule 
for the IRT system. 
. Details are in the IRT system 
specifications. 
6.3.2.
Blinding the Treatment Assignment 
This is a double-blind study; the investigator and participants are blinded to treatment 
assignment. Blinded study drug supply will be provided, and the standard operating procedures 
of the study site for maintaining the double-blind will be followed. 
6.3.3.
Unblinding 
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 participant. If possible, the sponsor or 
designee (eg, medical monitor) should be contacted before the blind is broken. Unblinding will 
be performed per the standard operating procedures of the study site.
6.4
Study Drug Compliance
When participants are dosed at the site, they will receive study intervention under medical 
supervision. The date and time of each dose administered in the clinic will be recorded in the 
source documents and dosing e-diary. The study participant identification will follow the 
standard operating procedure of the site and the pharmacy manual.
When participants take the study drug at home, they should record the time of the dose in their 
dosing e-diary (a component of the e-diary).
Participants must be instructed how and where to return unused study intervention and 
empty/used study intervention packaging for drug accountability. 
6.5
Dose Modification
6.6
Continued Access to Study Intervention after the End of the Study 
After the completion of the current study, participants will have the option to participate in an 
LTE study under a separate protocol (assuming the protocol is open for enrollment).
6.7
Treatment of Overdose 
In this study, an overdose is defined as a known deliberate or accidental administration of the 
study intervention, either to or by a study participant, at a dose above that assigned to that 
individual participant.
In the event of a drug overdose, the participant should be treated symptomatically.
All cases of overdose or medication error must be documented on the eCRF. Because these 
events are not, in and of themselves, AEs, they should be reported regardless of whether any 
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manifested signs or symptoms are considered AEs. If there are signs and symptoms meeting the 
criteria for reporting as AEs or SAEs, they should also be reported, as described in Section 10.3.
6.8
Concomitant Therapy 
6.8.1.
Excluded Treatments
Restricted medications and supplements are shown in Table 6.b. Restricted medications may be 
discontinued earlier than, but not later than, the required start of the restriction period. For 
example, the PI may decide to have participant restrict medications for a longer period before 
baseline to ensure the participant’s narcolepsy symptoms have returned to baseline. 
Administration of any drugs used for the treatment of narcolepsy with cataplexy (NT1) must be 
discontinued. The investigator will determine the schedule for tapering of antidepressants and 
stimulants. Hormonal contraceptives are not excluded.
Participants may receive the COVID-19 vaccination; however, vaccinations 
 
before checkin at any visit will not be allowed. Sites should document the vaccination dosing on 
the concomitant medication page.
Meals and dietary restrictions are discussed in Section 5.3.1.
Table 6.b
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Table 6.b
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Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (for example, 
withdrawal due to an AE should not be recorded in the “voluntary withdrawal” category). 
Similarly, lack of efficacy should not be recorded in the “voluntary withdrawal” category.

Study terminated by sponsor. 
The sponsor, institutional review board (IRB), or independent ethics committee (IEC), or 
regulatory agency terminates the study.

Other (specify).
Note: The specific reasons should be recorded in the “specify” field of the eCRF, including 
unavoidable circumstances such as the COVID-19 pandemic
7.2
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the physician or at the institution, or may be withdrawn at any time 
at the discretion of the investigator or sponsor (eg, in the interest of participant safety). The 
investigator is encouraged to discuss withdrawal of a participant with the medical monitor when 
possible. 
The investigator may discontinue a participant’s study participation at any time during the study 
when the participant meets the study termination criteria described in Section 7.1.
At the time of discontinuing from the study, if possible, an early termination visit should be 
conducted, as shown in the SOA (see Table 1.a). The primary criterion for termination must be 
recorded by the investigator. See SOA for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.
Participants who discontinue or withdraw may be replaced.
7.3
Lost to Follow-up
The participant may be lost to follow-up as defined in Section 7.1.
8.
Study Assessments and Procedures 
Written or electronic informed consent must be obtained (signed and dated) before study 
assessments and procedures can be performed, as described in Section 10.1.3.
The following sections describe the study procedures and data to be collected at planned time 
points per the SOA (see Table 1.a). Protocol waivers or exemptions are not allowed. 
Repeat or unscheduled samples may be taken for safety reasons or due to technical issues with 
the samples. Whenever possible, the same person should perform each assessment.
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8.1.4.2.
HLA Genotyping 
HLA DQB1*06:02 typing will be obtained from participants during screening unless previous 
HLA results are reviewed and accepted by the PI and included in the source study 
documentation. Almost all patients with NT1 who experience cataplectic attacks have this HLA 
genotype (heterozygous or homozygous expression), which has been found to correlate with low 
OX concentrations in the CSF. Therefore, this genotype is viewed as a surrogate biomarker in 
the right clinical setting. 
8.1.5.
Administrative Procedures (Contingency Measures for Unavoidable 
Circumstances)
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 SOA (see Table 1.a), 
contingency measures may be implemented. In acknowledgement of study site, hospital, local, 
state, and national restrictions established in response to circumstances like COVID-19, the 
following measures are being taken for the current study:

For participants active in the study, all attempts should be made to perform the assessments 
with the participant present at the site using the visit windows. Exceptions may be granted for 
alternative approaches to study procedures and data collection through approval by the 
sponsor or designee. Such instances must be documented in the study records and may 
include the following:
–
Sites impacted by the COVID-19 pandemic or similar unavoidable circumstances, must 
contact the sponsor or designee to discuss individual participant and site circumstances to 
obtain approval for use of alternative approaches to study procedures and data collection 
due to COVID-19 or other unavoidable circumstances.
–
Sites may seek approval from the sponsor or designee to continue participants in the 
study despite departures from the SOA (see Table 1.a). The PI is expected to evaluate the 
impact to the safety of the study participants and site personnel for participants to 
continue. In evaluating such requests, the sponsor or designee will give the highest 
priority to the safety and welfare of the participants. Participants must be willing and able 
to continue taking study drug and remain compliant with the protocol. 
–
Alternative methods for conducting participant 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 participant to miss an in-person study visit, a study site 
physician will speak directly with the participant by telephone or other medium (eg, a 
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computer-based video communication) during each visit window to assess participant 
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.

Vaccinations 
 before check-in at any visit will not be allowed. 
Participants may choose to get a COVID-19 vaccine at any other 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 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 approximately 2 weeks between successive 
visits at which clinical laboratory tests are performed and vital signs are measured. 
Should the period of 4 weeks be met for a particular participant, the site should 
contact the sponsor or designee to discuss withdrawal of the participant. Local 
laboratories may be used if necessary.
–
Study site personnel may dispense additional study drug to participants at a visit to allow 
for potentially longer intervals between visits than originally planned per protocol, or 
study drug may be supplied to participants via delivery by site personnel or by courier.
–
Early termination visits should be performed in person. When it is not possible for the 
participant 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 
study site personnel or designated clinical personnel to go to the participant’s residence 
and conduct the protocol-specified procedures in that location. Assessments collected at a 
participant’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.
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The investigator and any qualified designees are responsible for collecting, detecting, 
documenting, and recording events that meet the definition of an AE or SAE. They remain 
responsible for follow-up of these events (see Section 10.3.4). 
8.3.8.1.
Time Period and Frequency for Collecting AE and SAE Information
All AEs will be collected from the signing of the ICF until final follow-up visit or rollover into 
the LTE at the time points specified in the SOA (see Table 1.a). 
All SAEs will be recorded and reported to the sponsor or designee immediately. Under no 
circumstance should this exceed 24 hours. The investigator will also submit any updated SAE 
data within 24 hours of it being available.
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must promptly 
notify the sponsor via the reporting method described in Section 10.3.4.6.
8.3.8.2.
Method of Detecting AEs and SAEs
At each study visit specified in the SOA, participants will be questioned in a general way to 
ascertain if AEs have occurred since the previous visit. Open-ended and nonleading verbal 
questioning of the participant is the preferred method to inquire about AE occurrences without 
introducing bias. Participants may report AEs occurring at any time during the study.
8.3.8.3.
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All participants experiencing AEs, whether considered associated 
with the use of the study drug or not, will be documented in the AE page of the eCRF. 
All AEs must be monitored until the end of the study or until the event resolves, stabilizes, is 
otherwise explained, or the participant is lost to follow-up as defined in Section 7.3. 
SAEs must be monitored until resolution, stabilization, the event is otherwise explained, or the 
participant is lost to follow-up. 
Information to be documented for each event is defined in Section 10.3.4.
Further information on follow-up procedures is provided in Section 10.3. 
8.3.8.4.
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a study 
intervention under clinical investigation are met. The sponsor has a legal responsibility to notify 
both the local regulatory authority and other regulatory agencies about the safety of a study 
intervention under clinical investigation. The sponsor will comply with country-specific 
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10.
Supporting Documentation and Operational Considerations 
10.1
Regulatory, Ethical, and Study Oversight Considerations 
10.1.1.
Regulatory and Ethical Considerations 
This study will be conducted with the highest respect for the individual participants according to 
the ethical principles that have their origin in the Declaration of Helsinki, and the ICH 
Harmonised Tripartite Guideline for GCP. 
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, current ICH GCP Guidelines, as well as all applicable national
and local laws and regulations.
10.1.2.
Financial Disclosure 
Takeda is funding this study and will make payments to the study site for the conduct of the 
study (and, if applicable, investigators and/or other study staff), as specified in the Clinical Study 
Site Agreement(s).
Regulatory authorities including the Food and Drug Administration require Takeda to submit 
disclosures of investigators’ and subinvestigators’ financial interests and arrangements. For this 
reason, Takeda will provide the investigators and sub-investigators with a form for the disclosure 
of their financial arrangements during the course of the study and for 1 year after the completion 
of the study. 
The financial disclosure form must be signed by each investigator and sub-investigator before 
the study starts at their study site. Any potential conflicts of interest that are not covered by this 
form should be disclosed separately to Takeda before the start of the study at their site.
Specific financial arrangements requiring disclosure would include any arrangement whereby the 
outcome of the study could be influenced by the value of the compensation for conducting the 
study, or other payments the investigator received from the sponsor. Examples include: any 
significant payments from the sponsor or subsidiaries such as a grant to fund ongoing research, 
compensation in the form of equipment, retainer for ongoing consultation, or honoraria; any 
proprietary interest in study intervention; and any significant equity interest in the sponsor or 
subsidiaries as defined in 21 Code of Federal Regulations 54 2(b) (1998). 
The investigator and sub-investigator should declare all institutional affiliations on the curricula 
vitae that they provided to sponsor before the start of the study.
10.1.3.
Informed Consent Process 
It is the responsibility of the investigator to obtain written and/or electronic informed consent 
from all participants before any study-related procedures including screening assessments. All 
eConsent documentation must be in accordance with applicable regulations and GCP:
The participants must receive an explanation of what the study involves, including but not 
limited to: the objectives, potential benefits and risk, inconveniences, and the participant’s rights 
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and responsibilities. eConsent provides the same information as written consent forms, but in an 
electronic format that may include multimedia components. eConsent does not replace the 
important discussion between the study participant and site staff or investigator. Regardless of 
the consent format – written or eConsent – the investigational site is responsible for the 
consenting process.
After the participant has received and read (or been read) the participant information, they will 
be requested to sign and date the informed eConsent form or a certified translation if applicable. 
Persons consenting via eConsent, where available, will electronically sign consent forms. (Paper 
consent forms will be used instead, if required by local regulations.)
A copy of the informed eConsent documentation (ie, a complete set of participant information 
sheets and fully executed signature pages) must be provided to the participant, as applicable. 
This document may require translation into the local language. Signed eConsent forms must 
remain in each participant’s study file at the site (either in their original, signed paper form or as 
a certified copy if applicable for electronic signature) and must be available for verification at 
any time.
The PI provides the sponsor with a copy of the eConsent form that was reviewed by the IRB/EC 
and received their favorable opinion/approval. A copy of the IRB/EC’s written favorable 
opinion/approval of these documents must be provided to the sponsor before the start of the 
study unless it is agreed to and documented (abiding by regulatory guidelines and national 
provisions) before study start that another party is responsible for this action. Additionally, if the 
IRB/IEC requires modification of the sample participant information and eConsent document 
provided by the sponsor, the documentation supporting this requirement must be provided to the 
sponsor.
10.1.4.
Data Protection
The confidentiality of records that may be able to identify participants will be protected in 
accordance with applicable laws, regulations, and guidelines.
After participants have consented to take part in the study, the sponsor and/or its representatives 
reviews their source documents and data collected during the study. These records and data may, 
in addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market TAK-861; national or local regulatory authorities; and the IRB(s)/IEC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of participants’ identities. Participants are assigned a 
unique identifying number; however, their initials and date of birth may also be collected, if 
permitted under local laws governing privacy. 
The results of studies containing participants’ unique identifying number, relevant source 
documents, and possibly initials and dates of birth, where allowed per local law, may be 
transferred to, and used in, other countries that may not afford the same level of protection that 
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applies within the countries where this study is conducted. The purpose of any such transfer 
would include: to support regulatory submissions, to conduct new data analyses to publish or 
present the study results, or to answer questions asked by regulatory or health authorities. 

The sponsor will assign each participant a unique identifier. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.

The investigator must inform the participant that their personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant who will be required to give consent for their data to 
be used as described in the ICF. 

The investigator must inform the participant that their source documents may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
All United States-based sites and laboratories or entities providing support for this study, must, 
where applicable, comply with the Health Insurance Portability and Accountability Act of 1996. 
A site that is not a covered entity as defined by Health Insurance Portability and Accountability 
Act must provide documentation of this fact to the sponsor or designee.
10.1.4.1.
Notice Regarding the Use and Transfer of the Investigator’s Personal 
Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and telephone number, and other personally identifiable information such as education 
and professional details, payment-related details (if applicable), identity information (eg, medical 
registration number) and information relating to his or her interactions and activities with or 
involving Takeda. In addition, investigator’s personal information may be transferred to other 
parties located in countries throughout the world including the following:

Takeda, its affiliates, and their licensing partners.

Business partners assisting Takeda, its affiliates, and their 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.
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–
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.
In addition, where required by law or industry codes of practice, Takeda and/or its affiliates may 
have to report or publicly disclose any payments or transfers of value made in connection with 
the study by or on behalf of Takeda and/or its affiliates or their service providers to the 
investigator or their institution.
The legal basis on which Takeda and its affiliates will process the investigator’s personal 
information for the above purposes are to comply with a legal obligation; or to perform any 
contract in place with the investigator (if applicable); or to meet the legitimate research, 
scientific and business interests of Takeda and its affiliates, including ensuring the proper 
performance of this study to the applicable standards, appropriate reporting of study results and 
archiving of study-related records and information, and further development and registration of 
the study drug or other compounds. The investigator may not be able to opt-out of this 
processing, or the investigator’s choice to opt-out may impact his or her ability to continue to 
participate in this study and/or future studies involving Takeda and/or its affiliates. 
Takeda and its affiliates will maintain physical, administrative and technical safeguards to 
protect the investigator’s personal information from loss, misuse, unauthorized access, 
disclosure, alteration or destruction. The 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.
However, where investigator’s personal information is transferred to Takeda affiliates, licensing 
partners, business partners or service providers in such countries, Takeda will ensure that all 
adequate safeguards are in place and that all applicable laws and regulations are complied with in 
connection with such transfers.
The investigator’s personal information will only be stored as long as necessary for the purposes 
for which it was collected participant to local laws and regulations and legitimate scientific, 
research and business needs.
Individuals located in the European Economic Area and in certain other countries have certain 
data participant rights which may be participant to limitations and/or restrictions. These rights 
include the right to: (i) request access to and rectification or erasure of their personal data; (ii) 
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obtain restriction of processing or to object to processing of their personal data; (iii) the right to 
data portability; and (iv) obtain additional information regarding the safeguards Takeda has in 
place for cross-border transfers of their personal data. If the investigator wishes to exercise one 
of these rights, the investigator may use the contact information below. 
Individuals located in the European Economic Area and in certain other countries may also have 
the right to lodge a complaint about the processing of their personal data with their local data 
protection authority.
The investigator can contact Takeda to exercise his or her rights, make inquiries or submit 
complaints concerning Takeda’s processing of his or her personal information. Takeda will take 
appropriate steps to address requests, inquiries and complaints. Takeda will respond to such 
requests within thirty (30) business days.
Contact Details:
Mailing Address: Attn: Data Protection Officer, Legal Department, Takeda Pharmaceuticals 
International AG, Thurgauerstrasse 130, CH-8152 Glattpark-Opfikon (Zurich), Switzerland.
Email Address: dataprivacy@takeda.com
The investigator acknowledges and authorizes the use of his or her personal information by 
Takeda and other parties for the purposes described above.
10.1.5.
Committees Structure 
10.1.5.1.
IRB and/or IEC Approval
IRBs/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 IRBs/IECs. If any member of the IRBs/IECs
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 Federalwide 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 IRBs/ 
IECs for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and, if 
applicable, participant recruitment materials and/or advertisements and other documents required 
by all applicable laws and regulations, must be submitted to a central or local IRBs/IECs for
approval. 
The IRB’s/IEC’s written approval of the protocol and participant ICF 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).
The IRBs/IECs approval must refer to the study by exact protocol title, number, and version 
date; identify versions of other documents (eg, ICF) reviewed; and state the approval date. If 
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Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan/contracts.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, participants’ 
source documents, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor or designee is responsible for the data management of this study, including quality 
checking of the data.
The sponsor assumes accountability for actions delegated to other individuals (eg, contract 
research organizations [CROs]).
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 2 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor.
10.1.7.1.
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study participants. Should other unexpected circumstances 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.
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the participant, or confound interpretation of primary study 
assessment.
10.1.7.2.
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 head guarantee access to source documents by the sponsor or 
its designee (CRO and/or auditor) and by the IRB/IEC or any other health authority governing 
the study, per local/regional regulation.
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authorities. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. eCRFs must be completed in English. 
The investigator has full responsibility for the accuracy and authenticity of all data entered on the 
eCRFs. Details are provided in Section 10.1.11.2.
A study monitor from the sponsor or its designee will visit each site in accordance with the 
monitoring plan and review the eCRF data against the source data for completeness and 
accuracy. Auditors, IRB/IEC members, or regulatory inspectors may also check the eCRF entries 
against the source documents.
Discrepancies between source data and data entered on the eCRF will be addressed by qualified 
site personnel. When a data discrepancy warrants correction, the correction will be made by 
authorized site personnel. 
After the lock of the 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. 
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. Reasons for significant corrections should also be included. The PI 
must review the data change for completeness and accuracy, and must sign, or sign and seal, and 
date. In 
 the eCRF Data Clarification Form will be provided by the sponsor or designee.
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. 
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. 
All data will have separate source documentation; no data will be recorded directly onto the 
eCRF.
10.1.8.2.
Documentation and Retention of Records
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. Source documents provide evidence for the existence of the 
participant and substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. A definition of what constitutes source data and its origin can be found in 
Section 10.1.8.4.
Data entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The investigator may need to request 
previous source documents or transfer records, depending on the study. Also, current source 
documents must be available.
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Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. A risk-based monitoring 
approach will be used.
10.1.8.3.
Data Handling
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, medical history, and concurrent medical conditions will be coded using the MedDRA. 
Drugs will be coded using the World Health Organization Drug Dictionary/Japanese Drug 
Dictionary.
Data are to be entered into a clinical database as specified in the data management plan or 
similar. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
10.1.8.4.
Record Retention
The following procedure applies to countries other than 
.
The investigator agrees to keep the records stipulated in Section 10.1.8.1 and those documents 
that include (but are not limited to) the study-specific documents, the identification log of all 
participating participants, source documents, temporary media such as thermal sensitive paper, 
source worksheets, all original signed and dated informed eConsent forms (including consent to 
use digital tools and applications, if applicable), participant authorization forms regarding the use 
of personal health information (if separate from the informed eConsent forms), query 
responses/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 participant’s chart to ensure long-term 
legibility. Furthermore, ICH E6(R2) Section 5.5.11 requires the investigator to retain essential 
documents specified in ICH E6(R2) (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(R2) Section 5.5.11 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.
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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 following procedure applies to sites in 
 only:
The investigator and the head of the study site agree to keep the records stipulated in 
Section 10.1.8.1 and those documents that include (but are not limited to) the study-specific 
documents, the identification log of all participating participants, source documents, temporary 
media such as thermal sensitive paper, source worksheets, all original signed and dated informed 
eConsent forms, participant authorization forms regarding the use of personal health information 
(if separate from the informed eConsent forms), telemedicine records, and query responses/ 
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 participant’s chart to ensure long-term legibility. The 
investigator and the head of the institution are required to retain essential relevant documents 
until the day specified as 1) or 2) below, whichever comes later. However, if the sponsor 
requests a longer time period for retention, the head of the institution should discuss how long 
and how to retain those documents with the sponsor.
1. The day on which marketing approval of the study drug is obtained (or the day 3 years after 
the date of notification in the case that the investigation is discontinued).
2. The day 3 years after the date of early termination or completion of the study. 
In addition, the investigator and the head of the institution should retain the essential relevant 
documents until the receipt of a sponsor-issued notification to state the retention is no longer 
required. 
When proceeding to the local postmarketing study, the investigator and the head of the 
institution are required to retain essential relevant documents until the end of re-examination or 
re-evaluation, whichever comes later. However, if the sponsor requests a longer time period for 
retention, the head of the institution should discuss how long and how to retain those documents 
with the sponsor. 
10.1.9.
Study and Site Start and Closure
10.1.9.1.
First Act of Recruitment 
The first act of recruitment is the first site open.
For clinical trial disclosure purposes, the study start date is the date when the first participant 
signed the ICF.
10.1.9.2.
Study/Site Termination 
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
The sponsor reserves the right to close the study site at its sole discretion. Study sites will be 
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closed on study completion. A study site is considered closed when all required documents and 
study supplies have been collected and a study-site closure visit has been performed.
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies, CRO(s), and IRBs/IECs are notified as appropriate and as specified in applicable 
regulatory requirements. Additionally, the discontinuation of a registered clinical study which 
has been posted to a designated public website will be updated accordingly. Further, the 
investigator shall promptly inform the participants and should assure appropriate participant 
therapy and/or follow-up. If the study is terminated, the sponsor will make an end of study 
declaration to the relevant competent authority as required by Article 10( e) of Directive 
2001/20/EC and the European Union (EU) Clinical Trial Regulation. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

For study termination or suspension:
–
Discontinuation of further study intervention development.
–
New information or other evaluation regarding the safety or efficacy of the study drug 
that indicates a change in the known benefit-risk profile for TAK-861 such that the 
benefit-risk is no longer acceptable for participants participating in the study.
–
The DMC recommends that the study should be suspended or terminated. 
–
A finding (eg, PK, PD) from another nonclinical or clinical study using the study drug 
leads to the study being stopped for reasons unrelated to safety.
–
Data from drug(s) of the same class or methodology (or methodologies) used in this study 
become available and result in the study being stopped for reasons unrelated to safety.
–
Significant violation of GCP that compromises the ability to achieve the primary study 
objectives or compromises participant safety.
–
The sponsor terminates or suspends the study at any time for any other clinical or 
administrative reasons, eg, slow enrollment.

For site termination or suspension:
–
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines.
–
Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants 
by the investigator.
–
Total number of participants enrolled earlier than expected.
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10.1.11.
Responsibilities of the Sponsor and the Investigator
10.1.11.1. Sponsor Responsibilities
The sponsor is responsible for designing and performing the study in accordance with ICH GCP 
Guideline E6, EU Directive 2001/20/EC, other applicable regulatory requirements and 
guidelines, and rules considering the rights, safety, and well-being of human participants.
The sponsor will perform all study-related activities with the exception of those identified in the 
clinical supplier list in the study manual. The identified vendors will perform these activities 
either in full or in partnership with the sponsor.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or designee) is responsible for the preparation, submission, and confirmation 
of receipt of any regulatory authority approvals required before release of study intervention for 
shipment to the site.
Takeda is funding the study and is responsible for collecting financial disclosure information 
from investigators and sub-investigators, for submission to regulatory authorities 
(Section 10.1.2).
The sponsor/ designee will supply the following:

Documentation required for the study conduct, including but not limited to the study 
protocol, IB, study operations manual, other study conduct/ management documents and 
sample informed consent.

Access to the IEC/IRB-approved version via an eConsent platform (Section 10.1.3).

eCRFs, data management, and site monitoring (Section 10.1.7), including reconciliation with 
source documents (Section 10.1.8).
The sponsor is responsible for protecting the confidentiality of participants’ data 
(Section 10.1.4).
The sponsor will fulfill its role in forming and managing any special committees as described in 
Section 10.1.5.
The sponsor is responsible for the reporting of data to regulators and the public disclosure of data 
as described in (Section 10.1.6). The sponsor is also responsible for maintaining a publication 
policy (Section 10.1.10) that balances the protection of participants’ data (Section 10.1.4), public 
disclosure requirements (Section 10.1.6), and industry publication standards.
The sponsor and/or designee selects sites and performs study site start and closure activities 
(Section 10.1.9).
The sponsor will supply insurance for each participant in the study in accordance with the 
regulations applicable to the site where the participant 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 participants. Refer to the study site agreement regarding the sponsor’s 
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policy on participant compensation and treatment for injury. If the investigator has questions 
regarding this policy, he or she should contact the sponsor or sponsor’s designee.
10.1.11.2. Investigator Responsibilities 
The investigator must perform the study in accordance with ICH GCP Guideline E6, EU 
Directive 2001/20/EC, other applicable regulatory requirements and guidelines, and rules 
considering the rights, safety, and well-being of human participants.
The investigator and any sub-investigators must adhere to this protocol, with major 
responsibilities summarized below.
It is the investigator’s responsibility to ensure that adequate time, resources, and appropriately 
trained personnel are available before committing to participate in this study. 
Each of the investigators will maintain a list of appropriately qualified persons to whom they 
have delegated significant study-related tasks. Investigators will provide their own curricula vitae 
and those of their sub-investigators to the study sponsor (or designee) before starting the study, 
and will, on request of the sponsor, provide additional documentation of any licenses and 
certifications necessary to demonstrate these qualifications. 
The investigator and sub-investigators are required to disclose any potential conflicts of interest 
during or within 1 year after the end of the study (Section 10.1.2).
The investigator will either conduct the activities in the protocol personally or provide guidance 
and supervision to the staff who assist. The investigator will provide necessary information about 
the protocol and the responsibilities of individual personnel. The investigator will ensure that 
study-related procedures, including study specific (nonroutine/nonstandard panel) screening 
assessments are NOT performed on potential participants, before the receipt of written approval 
from relevant governing bodies/authorities.
The investigator will communicate with the local IRB/IEC to ensure that it has performed initial 
review, continuing review, and approval of the protocol. The investigator will promptly report all 
changes in research activity and all anticipated risks to participants to the IRB/IEC. The 
investigator will report on the progress of the study to the IRB/IEC at least once per year and will 
issue a final report within 3 months of study completion.
The investigator will obtain valid informed consent from each participant in the study 
(Section 10.1.3). The investigator is responsible for screening participants and for enrolling only 
those participants who have met protocol eligibility criteria. If a potential research participant has 
a primary care physician, the investigator should, with the participant’s consent, inform them of 
the participant’s participation in the study. 
The investigator must protect the participant’s privacy rights as described in Section 10.1.4 and 
explain to the participant how their data will be used. The publication policy also encompasses 
some elements designed to protect individual participants’ data (Section 10.1.10).
The investigator will prepare and maintain adequate case histories of all participants entered into 
the study, including hospital records and laboratory results (Section 10.1.8). The investigator will 
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be responsible for reviewing data, reports, and interlaboratory/reader standardization methods (if 
applicable). The investigator or the investigator’s designee (ie, authorized site personnel, as 
stated in the site delegation log) must enter data from the source documents (Section 10.1.8) into 
the eCRF with guidance from the study CRF Completion Guidelines or similar. The investigator 
will prepare correct and complete eCRFs for all participants and/or will check and confirm the 
contents of eCRFs entered by the subinvestigator or transcribed from the source data. The 
investigator will electronically sign the eCRFs as a means of attesting to the integrity of the data 
and will submit them to the sponsor. Furthermore, the investigator must retain full responsibility 
for the accuracy and authenticity of all data entered on the eCRFs. The investigator will maintain 
current records of the receipt, administration, and disposition of sponsor-supplied drugs 
(Section 10.1.7).
The investigator will 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 investigator should contact and receive written approval 
from the sponsor before disposing of any such documents (Section 10.1.8).
The investigator will facilitate monitoring and auditing activities and will allow the regulatory 
authorities to inspect and copy GCP-specified essential documents.
The investigator has overall responsibility for dispensing study drug will return all unused 
sponsor-supplied study intervention, containers, and other study materials to the sponsor on 
completing or leaving the study. If the investigator suspends or terminates the study at their site, 
the investigator will promptly inform the sponsor and the IRBs/IECs and provide them with a 
detailed written explanation (Section 10.1.9). 
Upon study completion, the investigator will provide the sponsor, IRB/IEC, and regulatory 
agency with final reports and summaries as required by (inter)national regulations
10.1.11.2.1.
PI/Coordinating Investigator
The PI/coordinating investigator will be required to review and sign the final clinical study report 
and by doing so agrees that it accurately describes the results of the study, in compliance with 
Directive 2001/83/EC as amended by Directive 2003/63/EC and ICH Guidance E3 (1995).
10.2
Clinical Laboratory Tests 
Table 10.a lists the tests that will be performed for each laboratory specimen. These tests will be 
performed by the central laboratory.
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations.
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be sufficient to consider changes in the study drug/sponsor supplied drug administration or in 
the overall conduct of the study. 
The study site will forward a copy of all expedited reports to its IRB or IEC in accordance with 
local regulations.
10.4
Contraceptive and Barrier Guidance 
10.4.1.
Definitions 
For the purposes of this study, reproductive status is defined as follows: 

Non-pregnant: Negative urine and/or serum β-hCG pregnancy test result

Person who is not of childbearing potential:
–
Premenarchal and 1 of the following: 

Tanner stage 1.

Younger than 9 years of age.
–
Surgically sterile for at least 6 weeks at screening (defined as having undergone one of 
the following procedures: hysterectomy, bilateral tubal ligation, bilateral oophorectomy 
or bilateral salpingectomy).
–
Postmenopausal at screening (defined as no menses for 12 months without an alternative 
medical cause). A high 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.

Person who is of childbearing potential: after menarche and until becoming post-
menopausal unless permanently sterile by the definition above.

Male who is not fertile: pre-puberty OR post-puberty but permanently sterile by bilateral 
orchidectomy. 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.

Male who is fertile: post puberty, unless permanently sterile by the definition above.
10.4.2.
Contraception Guidance
In this study, the use of highly effective contraception is generally required unless otherwise 
noted. In addition, contraceptive use should be consistent with local regulations regarding the use 
of contraceptive methods for participants in clinical studies.
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The failure rates of contraceptives that are used consistently and correctly may differ in typical 
use. Therefore, when study participation requires any of these methods of contraception to be 
used, participants must commit to using them:

Consistently throughout the required period.

Correctly, as described below and in any labeling associated with the method.
Contraception requirements depend in part on the reproductive status of the participant and the 
participant’s partner. 
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Table 10.b
Acceptable Contraception Methods and Lactation Guidance for this Study
Highly Effective Contraceptives: Failure rate of <1% per year - when used consistently and correctly
User Dependent

Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulationa,b
–
Oral 
–
Intravaginal 
–
Transdermal 

Progestogen only hormonal contraception associated with inhibition of ovulationa,b
–
Oral 
–
Injectable

Sexual abstinence c 
Low User Dependency

Implantable progestogen only hormonal contraception associated with inhibition of ovulationa,b

Intrauterine device 

Intrauterine hormone-releasing system 

Bilateral tubal occlusion

Vasectomy; vasectomized partner d,e
Measures Intended to Prevent Fetal and Neonatal Exposure via Sperm or Breastmilk

Participants with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal 
intercourse or use a male condom during each episode of penile penetration throughout the duration of the study 
and for 
days after the last dose of study drug. 
a Hormonal contraceptives must be stabilized 
.
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. Therefore, participants using hormonal contraception to fulfill the requirement for highly 
effective contraception must also use a barrier method of contraception (eg, condom use) during the treatment period 
and for 
 after the last dose of study treatment (i.e., a total of 
).
c Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.
d A vasectomy is a highly effective contraceptive method only if the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used.
e For participants of childbearing ability, having a vasectomized partner is a highly effective contraception method 
provided that the partner is the participant’s sole partner and that the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used.
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Table 10.c
Unacceptable Contraception Methods
Methods that are unacceptable in any study requiring contraception

Periodic abstinence (calendar, symptothermal, post-ovulation methods) 

Withdrawal (coitus interruptus) 

Spermicides only

Lactational amenorrhea method 

Use of both female condom and male condom together at the same time
Contraceptives that are effective but have a failure rate of >1% per year when used consistently and correctly 
are insufficient in a study requiring highly effective contraception (ie, <1% failure rate)

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action

Male or female condom with or without spermicide

Cap, diaphragm or sponge with spermicide
In addition, male participants must be advised not to donate sperm from signing of the ICF to  
days after the last dose of study drug.
10.4.3.
Pregnancy
If any participant is found to be pregnant during the study, the participant should be withdrawn 
and any sponsor-supplied intervention(s) should be immediately discontinued.
If a participant’s partner becomes pregnant during the study or within 
days 
after the last dose, the participant’s partner should be asked for consent to record and follow the 
pregnancy. 
If the pregnancy occurs during or after administration of blinded intervention(s), the investigator 
must inform the participant of their right to receive treatment information. If the participant 
chooses to receive unblinded treatment information, the individual blind should be broken by the 
investigator.
If the pregnant participant or the participant’s pregnant partner agrees, the investigator should 
notify their primary care physician that the participant/participant’s partner was participating in a 
clinical study when they became pregnant and provide details about the intervention the 
participant received (blinded or unblinded, as applicable). 
If the pregnancy occurs during administration of active study intervention (eg, from Day 1) until 
the last follow-up, the pregnancy should be reported immediately, using a pregnancy notification 
form, to the contact listed in the contact information list.
Pregnancies for which regulatory reporting is not required include:

Pregnancies that occurred during the pretreatment phase.

Pregnancies in participants (or their partners) who were unblinded and found to be 
randomized to placebo.
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IB
investigator’s brochure
ICF
informed consent form (including electronic consent where applicable)
ICH
International Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
ICSD-3
International Classification of Sleep Disorders, 3rd Edition
IEC
independent ethics committee
IRB
institutional review board
IRT
Interactive Response Technology
LTE
long-term extension
MDE
major depressive episode
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed model for repeated measures
MSLT
multiple sleep latency test
MWT
Maintenance of Wakefulness Test
NT1
narcolepsy type 1
NT2
narcolepsy type 2
OX
orexin
OX1R
orexin type-1 receptor
OX2R
orexin type-2 receptor
PD
pharmacodynamic(s)
PI
principal investigator
PK
pharmacokinetic(s)
PSG
polysomnography
QD
once daily
QTcF
QT interval with Fridericia correction method
REM
rapid eye movement
RSI
reference safety information
SAE
serious adverse event
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SOA
schedule of activities
SOREMP
sleep onset REM period
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
WCR
weekly cataplexy rate
10.8
Protocol Amendment History 
Date
Document
Global/Country/Site Specific
17 Aug 2022
Original Protocol
Global 
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Appendix 2:
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Appendix 3: ICSD-3 Criteria for NT1
The criteria for NT1 (narcolepsy with cataplexy) are as follows: Criteria a) and b) must be met.
a) The participant has daily periods of irrepressible need to sleep or daytime lapses into sleep 
occurring for at least 3 months.
b) The presence of 1 and 2 or 3 of the following:
1. Cataplexy (as defined under essential features).
2. A mean sleep latency of ≤8 minutes and 2 or more SOREMPs on a MSLT performed 
according to standard techniques. A SOREMP (defined as the appearance of REM sleep 
within 15 minutes of sleep onset) on the preceding nocturnal polysomnogram may 
replace 1 of the SOREMPs on the MSLT.
3. The cerebrospinal fluid hypocretin-1 concentration, measured by immunoreactivity, is 
either ≤110 pg/mL or less than one-third of the mean values obtained in normal 
participants with the same standardized assay.
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