A Randomized, Double-blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of TAK-861 for the Treatment of Narcolepsy Without Cataplexy (Narcolepsy Type 2)
Phase: PHASE2
Conditions: Narcolepsy Type 2
Sponsor: Takeda

For non-commercial use only

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 Without Cataplexy 
(Narcolepsy Type 2) 
A Study to Evaluate the Efficacy, Safety, and Tolerability of TAK-861 for the Treatment of 
Narcolepsy Without Cataplexy  
Sponsor: 
Takeda Development Center Americas, Inc. 
95 Hayden Avenue 
Lexington, MA 02421 USA 
Study Number: 
TAK-861-2002 
Study Phase: 
2 
IND Number: 
154232 
EudraCT/CTIS 
Number: 
2022-002966-34 
ClinicalTrials.gov: 
Posting planned 
before study start 
Investigational 
Product: 
TAK-861 
Date: 
13 September 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. 
For non-commercial use only

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CONFIDENTIAL 
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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CONFIDENTIAL 
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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CONFIDENTIAL 
TABLE OF CONTENTS 
CONFIDENTIAL PROPERTY OF TAKEDA ...............................................................................1 
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 .........................................................................................................................20 
1.3 
Schedule of Activities ..................................................................................................21 
2.
INTRODUCTION .............................................................................................................32 
2.1 
Study Rationale ............................................................................................................32 
2.2 
Background ..................................................................................................................32 
2.2.1. 
Summary of Nonclinical Data .............................................................................33 
2.2.2. 
Summary of Effects in Humans ..........................................................................33 
2.3 
Benefit-Risk Assessment .............................................................................................35 
2.3.1. 
Potential Benefits .................................................................................................35 
2.3.2. 
Potential Risks .....................................................................................................36 
3.
OBJECTIVES, ENDPOINTS ............................................................................................38 
3.1 
Objectives and Endpoints ............................................................................................38 
3.2 
Estimands .....................................................................................................................39 
4.
STUDY DESIGN...............................................................................................................40 
4.1 
Overall Design .............................................................................................................40 
4.2 
Scientific Rationale for Study Design..........................................................................41 
4.2.1. 
Rationale for Study Population ...........................................................................41 
4.2.2. 
Rationale for Study Design .................................................................................41 
4.2.3. 
Rationale for Endpoints .......................................................................................41 
4.2.3.1. 
Safety Endpoints .........................................................................................41 
4.2.3.2. 
Efficacy Endpoints ......................................................................................42 
4.2.4. 
Participant Input into Design ...............................................................................42 
4.3 
Justification for Dose ...................................................................................................42 
4.4 
End of Study/Study Completion Definition .................................................................43 
5.
STUDY POPULATION ....................................................................................................43 
5.1 
Inclusion Criteria .........................................................................................................43 
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5.2 
Exclusion Criteria ........................................................................................................44 
5.3 
Lifestyle Considerations ..............................................................................................48 
5.3.1. 
Meals and Dietary Restrictions ...........................................................................48 
5.3.2. 
Activity ................................................................................................................49 
5.3.3. 
Contraception for Participants of Childbearing Potential or Capable of 
Producing Viable Sperm ......................................................................................49 
5.4 
Screening......................................................................................................................49 
5.4.1. 
Screen Failures ....................................................................................................49 
5.5 
Criteria for Temporarily Delaying Randomization......................................................50 
5.6 
Enrollment....................................................................................................................50 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ...............................51 
6.1 
Study Interventions Administered ...............................................................................51 
6.2 
Preparation, Handling, Storage, and Accountability ...................................................52 
6.2.1. 
Accountability Throughout the Study .................................................................52 
6.2.2. 
Receiving Product at the Site ..............................................................................53 
6.2.3. 
Labeling ...............................................................................................................53 
6.2.4. 
Dispensing/Administration ..................................................................................53 
6.2.4.1. 
Dispensing ...................................................................................................53 
6.2.4.2. 
Administration.............................................................................................53 
6.3 
Measures to Minimize Bias: Randomization and Blinding .........................................55 
6.3.1. 
Randomization .....................................................................................................55 
6.3.2. 
Blinding the Treatment Assignment ....................................................................55 
6.3.3. 
Unblinding ...........................................................................................................55 
6.4 
Study Drug Compliance ...............................................................................................55 
6.5 
Dose Modification .......................................................................................................55 
6.6 
Continued Access to Study Intervention after the End of the Study ...........................55 
6.7 
Treatment of Overdose ................................................................................................56 
6.8 
Concomitant Therapy...................................................................................................56 
6.8.1. 
Excluded Treatments ...........................................................................................56 
6.8.2. 
Permitted Concomitant Medications ...................................................................58 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL..........................................................................59 
7.1 
Discontinuation of Study Intervention .........................................................................59 
7.2 
Participant Discontinuation/Withdrawal from the Study .............................................60 
7.3 
Lost to Follow-up .........................................................................................................61 
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8. 
STUDY ASSESSMENTS AND PROCEDURES .............................................................61 
8.1 
Demographics, Medical History, Medication History and Administrative 
Procedures ....................................................................................................................62 
8.1.1. 
Demographics ......................................................................................................62 
8.1.2. 
Medical History ...................................................................................................62 
8.1.3. 
Prior and Concomitant Treatments/Medications .................................................63 
8.1.4. 
Diagnostic Criteria/Disease Classification ..........................................................63 
8.1.4.1. 
Diagnostic Criteria for NT2 ........................................................................63 
8.1.5. 
Administrative Procedures (Contingency Measures for Unavoidable 
Circumstances) ....................................................................................................64 
8.2 
Efficacy Assessments...................................................................................................65 
8.2.1. 
Primary Efficacy Measurement ...........................................................................65 
8.2.2. 
Other ....................................................................................................................66 
8.2.2.1. 
 ...........................................................................................................66 
8.2.2.2. 
................................................................................66 
8.2.2.3. 
Clinical Outcome Assessments ...................................................................67 
8.3 
Safety Assessments ......................................................................................................70 
8.3.1. 
Physical Examinations .........................................................................................70 
8.3.2. 
Vital Signs ...........................................................................................................70 
8.3.2.1. 
Weight, Height, and BMI ............................................................................71 
8.3.3. 
ECG .....................................................................................................................71 
8.3.4. 
Clinical Safety Laboratory Tests .........................................................................72 
8.3.5. 
Pregnancy Testing ...............................................................................................73 
8.3.6. 
Suicidal Ideation and Behavior Risk Monitoring ................................................73 
8.3.7. 
Other ....................................................................................................................73 
8.3.7.1. 
 .......................................................................73 
8.3.7.2. 
 .........................................................................................................73 
8.3.8. 
AEs, SAEs, and Other Safety Reporting .............................................................74 
8.3.8.1. 
Time Period and Frequency for Collecting AE and SAE Information .......74 
8.3.8.2. 
Method of Detecting AEs and SAEs ...........................................................74 
8.3.8.3. 
Follow-up of AEs and SAEs .......................................................................74 
8.3.8.4. 
Regulatory Reporting Requirements for SAEs ...........................................74 
8.3.8.5. 
Pregnancy in a Participant or Participant’s Partner During the Study ........75 
8.3.8.6. 
AEs of Special Interest ................................................................................75 
8.4 
 ................................................................................................................................76 
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8.4.1. 
 ....................................................................76 
8.5 
Genetics........................................................................................................................76 
8.5.1. 
 .............................................................................76 
8.6 
 ...............................................................................................77 
8.7 
Immunogenicity Assessments ......................................................................................77 
9. 
STATISTICAL CONSIDERATIONS...............................................................................77 
9.1 
Statistical Hypotheses ..................................................................................................78 
9.1.1. 
Primary Endpoint .................................................................................................78 
9.1.2. 
Secondary Endpoints ...........................................................................................78 
9.2 
Analysis Sets ................................................................................................................78 
9.2.1. 
Safety Set .............................................................................................................78 
9.2.2. 
 ..................................................................................................................78 
9.2.3. 
Full Analysis Set ..................................................................................................78 
9.3 
Efficacy Analyses ........................................................................................................78 
9.3.1. 
Primary Efficacy Endpoint ..................................................................................78 
9.3.2. 
Secondary Efficacy Endpoint ..............................................................................79 
9.3.3. 
 ......................................................................................79 
9.4 
Safety Analyses ............................................................................................................79 
9.5 
Other Analyses .............................................................................................................79 
9.5.1. 
 ........................................................................................................79 
9.5.2. 
 ..................................................................................................79 
9.6 
 .....................................................................................80 
9.7 
 .....................................................................................80 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ....80 
10.1 
Regulatory, Ethical, and Study Oversight Considerations...........................................80 
10.1.1. Regulatory and Ethical Considerations ...............................................................80 
10.1.2. Financial Disclosure ............................................................................................80 
10.1.3. Informed Consent Process ...................................................................................81 
10.1.4. Data Protection ....................................................................................................82 
10.1.4.1. Notice Regarding the Use and Transfer of the Investigator’s Personal 
Information ..................................................................................................83 
10.1.5. Committees Structure ..........................................................................................85 
10.1.5.1. IRB and/or IEC Approval ...........................................................................85 
10.1.5.2. Other Committees .......................................................................................86 
10.1.6. Dissemination of Clinical Study Data .................................................................86 
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10.1.6.1. Study Results Disclosure.............................................................................86 
10.1.7. Data Quality Assurance .......................................................................................86 
10.1.7.1. Protocol Deviations .....................................................................................87 
10.1.7.2. Study-Site Monitoring Visits ......................................................................87 
10.1.7.3. Audits ..........................................................................................................87 
10.1.8. Source Documents ...............................................................................................87 
10.1.8.1. eCRFs ..........................................................................................................88 
10.1.8.2. Documentation and Retention of Records ..................................................89 
10.1.8.3. Data Handling .............................................................................................89 
10.1.8.4. Record Retention .........................................................................................90 
10.1.9. Study and Site Start and Closure .........................................................................91 
10.1.9.1. First Act of Recruitment..............................................................................91 
10.1.9.2. Study/Site Termination ...............................................................................91 
10.1.9.3. Optional Study Participant Interviews ........................................................92 
10.1.10. Publication Policy ................................................................................................92 
10.1.11. Responsibilities of the Sponsor and the Investigator ..........................................93 
10.1.11.1. Sponsor Responsibilities .............................................................................93 
10.1.11.2. Investigator Responsibilities .......................................................................94 
10.2 
Clinical Laboratory Tests .............................................................................................96 
10.2.1. Clinical Laboratory Assessments and Other Safety Assessments .......................97 
10.2.2. 
 ....................................................98 
10.3 
AEs and SAEs: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting ...............................................................................................................98 
10.3.1. Definition of AE ..................................................................................................98 
10.3.2. Definition of SAE ..............................................................................................100 
10.3.3. Additional Considerations in Identifying and Defining AEs ............................101 
10.3.3.1. Defining Discrete AEs ..............................................................................101 
10.3.3.2. AEs of Special Interest ..............................................................................102 
10.3.4. Recording and Follow-Up of AE and/or SAE ...................................................103 
10.3.4.1. Frequency ..................................................................................................103 
10.3.4.2. Intensity .....................................................................................................103 
10.3.4.3. Causality/Relatedness ...............................................................................104 
10.3.4.4. Action Taken .............................................................................................104 
10.3.4.5. Outcome ....................................................................................................105 
10.3.4.6. Follow-Up .................................................................................................105 
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10.3.5. Expedited Reporting of SAEs and Selected AEs ..............................................106 
10.3.5.1. 
 ............................107 
10.3.5.2. Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities .................................................................................................107 
10.4 
Contraceptive and Barrier Guidance ..........................................................................107 
10.4.1. Definitions .........................................................................................................107 
10.4.2. Contraception Guidance ....................................................................................108 
10.4.3. Pregnancy ..........................................................................................................110 
10.5 
...111 
10.6 
Country-Specific Requirements .................................................................................112 
10.7 
Abbreviations and Definitions ...................................................................................113 
10.7.1. Abbreviations ....................................................................................................113 
10.8 
Protocol Amendment History ....................................................................................115 
11. 
REFERENCES ................................................................................................................116 
 
LIST OF TABLES 
Table 1.a 
 ............................................................................................21 
Table 1.b 
 ..........................29 
Table 6.a 
Study Intervention(s) Administered: Drug ............................................................52 
Table 6.b  
 .............................................57 
Table 8.a 
 ................................................................................62 
Table 10.a 
Protocol-Required Laboratory Tests ......................................................................97 
Table 10.b 
Acceptable Contraception Methods and Lactation Guidance for this Study .......109 
Table 10.c 
Unacceptable Contraception Methods .................................................................110 
Table 10.d 
 ...........................................................................................112 
 
LIST OF FIGURES 
Figure 1.a 
.........................................................................................................20 
 
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LIST OF APPENDICES 
Appendix 1 
 
 ....................................................117 
Appendix 2 
 .....................................118 
Appendix 3 
ICSD-3 Criteria for NT2 ......................................................................................119 
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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-861-2002 
Phase: 
2 
IND No.: 
154232 
EudraCT No.: 
2022-002966-34 
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 Without Cataplexy (Narcolepsy Type 2) 
Short Title: 
A Study to Evaluate the Efficacy, Safety, and Tolerability of TAK-861 in the Treatment for Narcolepsy Without 
Cataplexy 
Number of Participants (Total and per Treatment Arm): 
A total of approximately 60 participants (20 per arm) 
Investigator(s): Multicenter global study 
Site(s) and Region(s): Up to approximately 60 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 evaluate the safety and tolerability of
TAK-861.
•
Occurrence of at least 1 treatment-emergent
adverse event (TEAE).
Additional/Exploratory 
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Rationale: 
This study is designed to evaluate the efficacy, safety, and tolerability of multiple oral doses of TAK-861 in 
participants with narcolepsy without cataplexy (narcolepsy type 2 [NT2]).  
Narcolepsy without cataplexy, or NT2, has been defined in the International Classification of Sleep Disorders, 
3rd Edition (ICSD-3) criteria as having EDS with mean sleep latency of ≤8 minutes and 2 or more sleep onset 
REM periods (SOREMPs) on Multiple Sleep Latency Test (MSLT) (or with 1 SOREMP on preceding 
polysomnography (PSG) replacing 1 SOREMP on MSLT). Patients with NT2 do not have cataplexy, and 
cerebrospinal fluid (CSF) levels of orexin (OX) are greater than 110 pg/mL, or greater than one-third of the 
normal average. The presumed pathophysiology of NT2 is unclear. However, as many as 30% of patients with 
narcolepsy without cataplexy are found to have CSF OX levels that are lower than normal. 
TAK-861 is a selective agonist of OX2R that has demonstrated wake-promoting effects even in the absence of 
OX deficiency. Nonclinical pharmacology studies showed wake-promoting effects of TAK-861 in a murine 
narcolepsy model and also in mice and nonhuman primates with no known OX deficiency. 
 
 
. The 
available nonclinical information and emerging clinical 
 
 support this study. 
Study Intervention, Dose, and Mode of Administration: 
The following treatments will be administered orally: 
• 
TAK-861 Dose Regimen 1: 2 mg twice daily 
 
• 
TAK-861 Dose Regimen 2: 7 mg once daily (QD) or 2 mg followed by 5 mg 
 
• 
Matching placebo  
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Dose Regimen 2 (7 mg total daily dose) will be administered as either 7 mg QD or 2 mg followed by 5 mg; the 
decision will be made before randomization of the first participant.  
Study treatment will be administered 
. (Participants assigned to a QD dose 
regimen will receive placebo for the second dose.) Study treatment will be administered for 8 weeks. 
Overall Design and Methodology: 
This is a randomized, double-blind, placebo-controlled, multicenter, 8-week parallel group study to evaluate the 
efficacy, safety, and tolerability of 2 oral dose regimens of TAK-861.  
Approximately 60 (male and female) participants with NT2, who satisfy the inclusion and exclusion criteria, will 
be randomized such that a participant has an equal chance of being assigned to any 1 of 3 arms: 2 TAK-861 dose 
regimens or matching placebo. 
. Starting on 
 Day 1, the 
study drug will be administered at approximately the same time each day for 8 weeks.  
Participants who have provided informed consent will complete a screening period of up to 45 days (see protocol 
body, Section 6.8.1 for different washout periods) to washout any NT2 medication (if applicable). Participants 
will be asked to complete an eDiary, starting from the initial screening visit, no later than 
  
 
 
 
 
 
 
 
After the Week 8 visit, participants will have the option to participate in a long-term extension (LTE) study under 
a separate protocol (assuming protocol is open for enrollment). Participants who enroll in the LTE study will not 
have follow-up visits captured under this study protocol.  
 
 
 
 
 
 
 
Inclusion and Exclusion Criteria:  
Note that the site’s principal investigator (PI) may determine if there is a need to repeat any screening 
assessments to ensure participant suitability. 
Inclusion Criteria 
Informed Consent 
1. The participant is willing and able to understand and fully comply with study procedures and requirements 
(including digital tools and applications), in the opinion of the investigator. 
2. The participant has provided informed consent (that is, in writing, documented via a signed and dated 
informed consent form [ICF] and/or electronic consent) and any required privacy authorization before the 
initiation of any study procedures.  
Age and Body Mass Index 
3. The participant is aged 18 to 70 years, inclusive, at the time of signing the ICF. 
Note: In Japan, participants aged 16 to 70 years, inclusive, may be included. 
4. The participant has body mass index within the range 18 to 40 kg/m2 (inclusive)  
Type of Participant and Disease Characteristics 
5. The participant has an ICSD-3 diagnosis of NT2 by PSG/MSLT, performed within the past 5 years 
 
  
 
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7. The participant is judged by the investigator to be sufficiently healthy to participate in the study, on the basis 
of clinical evaluations including laboratory safety tests, medical history, physical examination, 12-lead ECG, 
and vital sign measurements performed at the screening visit and before the first dose of study drug.  
Note: Screening laboratory assessments may be repeated; the sponsor or designee should be informed. 
Contraception  
8. The participant agrees to follow the birth control requirements (see protocol body, Section 10.4). 
Exclusion Criteria 
Medical Conditions 
1. 
The participant has a current medical disorder, other than narcolepsy without cataplexy, associated with 
EDS. For example, the following are exclusionary: 
 
 
  
 
 
  
 
 
 
 
  
2. 
The participant has a current medical condition such as unstable cardiovascular, pulmonary, renal, or 
gastrointestinal disease, that would preclude enrollment in the view of the investigator.  
3. 
The participant has medically significant hepatic or thyroid disease. 
4. 
The participant has current or recent (within 6 months) gastrointestinal disease that is expected to influence 
the absorption of drugs (ie, a history of malabsorption, esophageal reflux, peptic ulcer disease, erosive 
esophagitis, frequent [more than once per week] occurrence of heartburn, or any surgical intervention). 
 
 
 
  
5. 
The participant has a history of cancer in the past 5 years (does not apply to participants with carcinoma in 
situ that has been resolved without further treatment or basal cell cancer; these participants may be included 
after approval by the sponsor or designee). 
6. 
The participant has clinically significant coronary artery disease, a history of myocardial infarction, 
clinically significant angina, clinically significant cardiac rhythm abnormality, or heart failure. 
7. 
The participant has a clinically significant history of head injury or head trauma. 
8. 
The participant has a history of epilepsy, seizure, or convulsion, or has a family history of inherited 
disorders associated with seizure (except for a single febrile seizure in childhood). 
9. 
The participant has one or more of the following psychiatric disorders: 
a. 
Any current unstable psychiatric disorder. 
b. 
Current or history of manic or hypomanic episode, schizophrenia or any other psychotic disorder, 
including schizoaffective disorder, major depression with psychotic features, bipolar depression with 
psychotic features, obsessive compulsive disorder, mental retardation, organic mental disorders, or 
mental disorders due to a general medical condition as defined in the Diagnostic and Statistical 
Manual of Mental Disorders, 5th Edition (DSM-5). 
c. 
Current diagnosis or history of substance use disorder as defined in the DSM-5. 
Note: If the history of substance use disorder is more than 12 months before baseline, the participant 
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may be allowed to enroll in the study after consultation with the sponsor or designee. (Participant 
must also have negative urine drug screen at the screening and Day -2 visit.) 
d. 
Current active major depressive episode (MDE) or who have had an active MDE in the past 
6 months. 
 
 
 
10. The participant has a history of cerebral ischemia, transient ischemic attack (<5 years ago), intracranial 
aneurysm, or arteriovenous malformation. 
11. The participant has a current history of significant multiple or severe allergies (eg, food, drug, latex allergy) 
or has had an anaphylactic reaction or significant intolerance to prescription or nonprescription drugs or 
food. 
12. The participant has a known hypersensitivity to any component of the formulation of TAK-861 or related 
compounds. 
13. The participant had major surgery or donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks 
before the screening visit.  
Prior/Concomitant Therapy 
14. The participant is unable to refrain from or anticipates using excluded food products (see protocol body, 
Section 5.3), beginning by 
 and continuing 
, or prohibited medication (as 
described in protocol body, Section 6.8.1).  
15. The participant has participated in another investigational drug study, in which they received the 
investigational drug, within 
 
 The interval window from the previous study will be derived from the date of the last 
study procedure in the previous study to the screening visit of the current study. 
Note: This does not apply to approved drugs, for which rules are laid out in protocol body, Section 6.8.1. 
 
 
Diagnostic Assessments 
 
 
 
 
 
 
18. The participant has a resting HR 
 beats per minute during screening, confirmed on repeat testing 
within a maximum of 
 minutes. 
19. The participant’s screening ECG reveals a QT interval with Fridericia correction method >
 milliseconds 
(genetically male) or >
 milliseconds (genetically female). 
20. The participant has a positive test result for hepatitis B surface antigen, hepatitis C virus antibody, or HIV 
antibody/antigen at screening. 
21. The participant’s renal creatinine clearance (Cockcroft-Gault Equation) is ≤50 mL/min at screening. 
22. The participant has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values >1.5 times 
the upper limit of normal (ULN) 
 
 
23. The participant has a positive pregnancy test at screening or Day -2 or is lactating/breastfeeding. 
 
 
 
 
  
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25. The participant is considered by the investigator to be at imminent risk of suicide or injury to self, others, or 
property, or the participant has attempted suicide within the past year before screening, or has positive 
answers on item number 4 or 5 on the C-SSRS (based on the past year) before randomization. 
Other Exclusion Criteria  
26. The participant is a study site employee or an immediate family member of or in a dependent relationship 
with a study site employee (eg, spouse, parent, child, sibling) who is involved in the conduct of this study, 
or may consent under duress. 
27. The participant consumes excessive amounts of caffeine, defined as greater than 
. (1 cup of 
coffee is approximately 120 mg.) 
28. The participant currently consumes alcohol exceeding 
 on average (1 standard 
drink is approximately equivalent to the following: beer [354 mL/12 oz], wine [118 mL/4 oz], or distilled 
spirits [29.5 mL/1 oz] per day). 
29. The participant has a nicotine dependence that is likely to have an effect on sleep (eg, a participant who 
routinely awakens at night to smoke) 
 
 
 
 
 
  
31. The participant has a usual bedtime later than 12:00 AM (midnight), an occupation requiring nighttime shift 
work or variable shift work within the past 6 months, travel with significant jet lag within 14 days before 
Day -2, or plans for travel with significant jet lag during the study. 
32. The participant, in the opinion of the investigator or subinvestigator is unlikely to comply with the protocol 
or is unsuitable for any other reason. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Maximum Duration of Participation in the Study: 
The total duration of study participation for each participant includes:  
• 
Planned duration of screening period: up to 45 days 
• 
Planned duration of treatment period: 8 weeks 
• 
Planned duration of follow-up period: 0 or 4 weeks (0 if immediately enrolling in LTE study) 
Statistical Analysis: 
Safety: 
TEAEs will be summarized by treatment group. Observed values and change from baseline in safety clinical 
laboratory measurements, vital signs, and ECG parameters will be summarized by treatment group. 
 
 
  
Efficacy: 
The change from baseline in mean sleep latency from the MWT will be analyzed using a linear mixed model for 
repeated measures (MMRM), with visit, treatment, and treatment-by-visit interaction. as the fixed effects. 
Baseline age and mean sleep latency will be used as covariates. The estimated change from baseline in the mean 
sleep latency for each treatment and the associated SE and 95% CIs will be extracted from the model, along with 
all estimated treatment differences from placebo and associated SEs, 95% CIs, and p-values. 
The change from baseline in ESS total score will also be evaluated using a similar linear MMRM as for MWT 
with the baseline value as a covariate. 
  
 
 
 
 
 
 
 
 
Data Monitoring/Other Committee: Yes 
 
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1.3 
Schedule of Activities  
Table 1.a 
 
 
 
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Table 1.a 
 
 
 
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Table 1.a 
 
 
 
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Table 1.a 
 
 
 
 
 
 
 
 
 
 
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Table 1.a 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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Table 1.a 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 1.a 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
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Table 1.a 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
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Table 1.b 
 
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Table 1.b 
 
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Table 1.b 
 
 
 
 
 
 
 
 
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2. 
Introduction 
2.1 
Study Rationale  
This study is designed to evaluate the efficacy, safety, and tolerability of multiple oral doses of 
TAK-861 in participants with narcolepsy without cataplexy (narcolepsy type 2 [NT2]).  
Narcolepsy without cataplexy, or NT2, has been defined in the International Classification of 
Sleep Disorders, 3rd Edition (ICSD-3) criteria as having excessive daytime sleepiness (EDS) 
with mean sleep latency of ≤8 minutes and 2 or more sleep onset REM periods (SOREMPs) on 
Multiple Sleep Latency Test (MSLT) (or with 1 SOREMP on preceding polysomnography 
(PSG) replacing 1 SOREMP on MSLT). Patients with NT2 do not have cataplexy, and CSF 
levels of OX are greater than 110 pg/mL, or greater than one-third of the normal average 
(American Academy of Sleep Medicine, 2014). The presumed pathophysiology of NT2 is 
unclear. However, as many as 30% of patients with narcolepsy without cataplexy are found to 
have cerebrospinal fluid (CSF) orexin (OX) levels that are lower than normal (Tabuchi et al., 
2014). 
TAK-861 is a selective agonist of orexin type-2 receptor (OX2R) that has demonstrated 
wake-promoting effects even in the absence of OX deficiency. Nonclinical pharmacology studies 
showed wake-promoting effects of TAK-861 in a murine narcolepsy model and also in mice and 
nonhuman primates with no known OX deficiency. 
 
 
 
The available nonclinical information and 
 
 
 
Additional rationale relating to the study design, TAK-861 dose administered, and study 
endpoints is provided in Section 4.2. 
2.2 
Background  
Narcolepsy is a rare, acquired, chronic neurologic disorder that alters the sleep-wake cycle. A 
cardinal symptom of narcolepsy is EDS, described as a sudden overpowering need to sleep 
during the day. Intrusion of rapid eye movement (REM) sleep phenomena into wakefulness also 
occurs. These REM phenomena may include cataplexy (sudden loss of muscle tone triggered by 
strong emotions), hypnagogic/hypnopompic hallucinations (sensory events that occur at the 
transition from wakefulness to sleep/sleep to wakefulness), and sleep paralysis (Thorpy and 
Dauvilliers, 2015, Abad and Guilleminault, 2017). Disturbed nighttime sleep (DNS) is frequent, 
with difficulty maintaining continuous sleep. Together, these 5 clinical features (EDS, cataplexy, 
hypnagogic/hypnopompic hallucinations, sleep paralysis, and DNS) comprise the narcolepsy 
symptom pentad (Thorpy and Dauvilliers, 2015, Abad and Guilleminault, 2017). It has been 
estimated that only 20% to 30% of patients have all components of the pentad (Billiard et al., 
1983). 
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Narcolepsy has been classified by the ICSD-3 diagnostic criteria (American Academy of Sleep  
Medicine, 2014) as narcolepsy type 1 (NT1) or NT2, on the basis of the presence or absence of 
cataplexy and on levels of OX in the CSF (if measured). NT1 is characterized by EDS and the 
presence of cataplexy. Both patients with NT1 and NT2 have sleep onset REM periods on 
PSG/MSLT of <8 minutes averaged over 5 naps (American Academy of Sleep  Medicine, 2014). 
Approximately 30% of those with narcolepsy are classified as having NT2 (Thorpy and 
Dauvilliers, 2015). 
The orexinergic system is a major wake-promoting system of the brain. It is comprised of 2 types 
of wake-promoting OX (also known as hypocretin) neurons, localized in a specific region of the 
lateral and posterior hypothalamus and have excitatory projections to wide areas of the central 
nervous system including the basal forebrain and brainstem nuclei involved in maintaining 
wakefulness (ie, cholinergic neurons if the reticular activating system, histaminergic 
tuberomammillary nucleus, noradrenergic locus coeruleus, dopaminergic ventral lateral area, and 
the serotonergic dorsal raphe nucleus). The OX system acts to coordinate and synchronize the 
wake-promoting centers of the brain and when absent (ie, in patients with NT1), sleep/wake 
instability results. The orexinergic system is also involved in several other functions, such as 
feeding, reward, and sympathetic activity. 
2.2.1. 
Summary of Nonclinical Data  
Nonclinical information is provided in the TAK-861 investigator’s brochure (IB). 
2.2.2. 
Summary of Effects in Humans  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.3 
Benefit-Risk Assessment  
This phase 2, randomized, double-blind, placebo-controlled, parallel group study includes 
efficacy, safety, and tolerability evaluations in participants with NT2 receiving repeated oral 
doses of TAK-861. 
2.3.1. 
Potential Benefits 
An OX2R agonist is the first approach to directly address the loss of OX peptide in the brain 
(Thannickal et al., 2000). An OX2R agonist may restore OX2R signaling at the postsynaptic 
receptors and may be more effective than current therapies in treating the entire NT1 pentad and 
especially EDS and cataplexy. While patients with NT2 by definition do not have cataplexy and 
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do not have CSF OX levels less than one-third of the normal average, as many as 30% are found 
to have CSF OX levels that are lower than normal (Tabuchi et al., 2014). As such, the use of an 
OX2R agonist would likely be efficacious in supplementing the intrinsic activity of the OX 
system.  
Furthermore, TAK-861 has demonstrated wake-promoting effects even in the absence of OX 
deficiency. Nonclinical pharmacology studies showed wake-promoting effects of TAK-861 in a 
murine narcolepsy model and also in mice and nonhuman primates with no known OX 
deficiency. 
 
 
  
For these reasons, TAK-861 has potential to be efficacious in treating the EDS in subjects with 
NT2.  
2.3.2. 
Potential Risks  
Based on nonclinical data and clinical results for TAK-861, clinical data of other compounds 
with the same mechanism of action, literature information on the association between OX2R 
agonism and cardiovascular effects, as well as effects on wakefulness in nonclinical models 
(Huang et al., 2010), potential risks for this product are: 
• Increases in BP and HR. 
• Insomnia. 
• Bladder events (eg, micturition urgency, pollakiuria). 
The principal mitigation strategy for risks related to BP increase, HR increase, insomnia, and 
bladder events includes appropriate selection of the study population; use of the inpatient clinical 
research unit setting and home health visits, which permits close monitoring and rapid institution 
of appropriate care as needed; appropriate specified monitoring procedures; and use of 
experienced staff trained in study procedures. To mitigate cardiovascular risks, BP and HR will 
be measured frequently in this study; cardiovascular effects will be evaluated by using BP and 
HR assessments and electrocardiographic (ECG) assessments. Stopping rules for individual 
participants and the overall study have been established and are noted in Section 7.  
 
 
 
 
 
 
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Finally, there is minimal risk associated with the noninvasive procedures planned for this study. 
Potential risks related to noninvasive study procedures include the following: 
• Acute hypersensitivity and/or anaphylactic reactions to new chemical entities are always 
a possible risk in any clinical study. Appropriate procedures will be used to manage such 
possible risks. 
• Study procedure-specific risks include issues related to blood collection for safety 
 
 (eg, venipuncture may cause bruising). 
Review of available nonclinical and clinical data, 
 
, supports a favorable benefit-risk ratio for 
this study with TAK-861. Refer to the latest version of the TAK-861 IB for the overall 
benefit/risk assessment and the most current information regarding drug metabolism, PK, 
efficacy, and safety of TAK-861. 
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3. 
Objectives, Endpoints 
3.1 
Objectives and Endpoints 
The following are the objectives and endpoints of this study: 
Objectives 
Endpoints 
Primary 
 
• 
To assess the effect of TAK-861 on EDS as 
measured by sleep latency from the 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 evaluate the safety and tolerability of TAK-
861. 
• 
Occurrence of at least 1 TEAE. 
Additional/Exploratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
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Objectives 
Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.2 
 
 
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4. 
Study Design  
4.1 
Overall Design  
This is a randomized, double-blind, placebo-controlled, multicenter, 8-week parallel group study 
to evaluate the efficacy, safety, and tolerability of 2 oral dose regimens of TAK-861.  
Approximately 60 (male and female) participants with NT2, who satisfy the inclusion and 
exclusion criteria, will be randomized such that each participant has an equal chance of being 
assigned to any of 3 treatment arms: 2 TAK-861 dose regimens or matching placebo. 
. Starting on 
 Day 1, the study drug will 
be administered at approximately the same time each day for 8 weeks.  
Participants who have provided informed consent will complete a screening period of up to 
45 days (see Section 6.8.1 for different washout periods) to washout any NT2 medication (if 
applicable). Participants will be asked to complete an eDiary, starting from the initial screening 
visit, no later than 
  
 
 
 
 
 
 
 
Information on the timing of the assessments is provided in the schedule of activities (SOA) 
(Table 1.a).  
After the Week 8 visit, participants will have the option to participate in an LTE study under a 
separate protocol (assuming protocol is open for enrollment). Participants who enroll in the LTE 
study will not have follow-up visits captured under this study protocol.  
 
 
 
 
 
 
 
 
For a schematic of the study design, see Section 1.2. For the SOA, see Section 1.3. 
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4.2 
Scientific Rationale for Study Design 
4.2.1. 
Rationale for Study Population 
The participants included in the study will be participants with NT2 who are otherwise generally 
healthy.  
A general rationale for the inclusion of participants with NT2 is provided in Section 2.1. 
4.2.2. 
Rationale for Study Design 
This study is a randomized, double-blind, placebo-controlled study investigating the efficacy, 
safety, and tolerability of TAK-861 in participants with NT2. Approximately 60 participants with 
NT2 will be randomized with equal probability to 1 of 3 arms: 2 TAK-861 dose regimens or 
matching placebo (dose rationale in Section 4.3). This dose-ranging study is designed to inform 
dose selection and further development of TAK-861 as a potential treatment for NT2. 
The duration of the dosing in the study (56 days) is chosen to allow enough time to evaluate all 
study endpoints and provide insight into TAK-861 efficacy and safety in participants with NT2 
in conjunction with an acceptable duration of treatment with placebo. Considering the half-life of 
TAK-861, the 56-day treatment and 28-day follow-up period are of sufficient duration to collect 
data about potential effects. 
Participants will be confined to an inpatient facility for specified periods throughout the conduct 
of the study. This confinement ensures adherence to study procedures and permits monitoring of 
safety and tolerability. 
4.2.3. 
Rationale for Endpoints 
4.2.3.1. 
Safety Endpoints 
Standard safety endpoints (eg, TEAEs, physical examination findings, vital signs, 12-lead ECG 
measures, clinical laboratory results) for early clinical investigation are included. 
 
 
 
 
 
 
 
 
 
 
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Finally, adequate measures have been taken regarding the methodology of this study to assess 
suicide risk. The selection criteria exclude the participation of participants at significant risk for 
suicide. Throughout the study, signs of suicide risk will be assessed both by rating scale 
assessment and by investigator’s clinical judgment. Participants will be withdrawn from the 
study in case of such risk. Furthermore, participants will be screened for the history of suicidal 
behavior to enter the study and then regularly screened during the study for suicidal behavior and 
thinking via the C-SSRS
 
 The C-SSRS will be administered 
, and during the follow-up visits in this study (if applicable) as indicated in the 
SOA 
 (Posner et al., 2007b, Posner et al., 2007a). 
4.2.3.2. 
Efficacy Endpoints 
To evaluate the effect of TAK-861 on symptoms of narcolepsy after multiple dosing, this study 
includes well-established objective and subjective primary and secondary efficacy endpoints for 
narcolepsy symptom measures. Major narcolepsy symptoms include EDS measured by objective 
endpoints such as sleep latency from the MWT assessment, and subjective endpoints such as the 
ESS total score.  
Further, several efficacy endpoints including parameters from 
 
 will be evaluated. In addition disturbance in nighttime sleep is also collected from 
the eDiary. 
4.2.4. 
Participant Input into Design  
Takeda consults patients and patient organizations throughout the development of TAK-861. 
4.3 
Justification for Dose  
 
 
 
 
 
 
 
 
  
As observed in nonclinical studies, the sensitivity in OX deficient and OX normal participants is 
expected to be different. Previously developed systems pharmacology and population PK/PD 
models were used to leverage dose/exposure-response relationships from prior OX2R agonists in 
humans. 
 
 is expected to achieve adequate wake promoting effects like 
those observed with prior OX2R agonists in the NT2 population. 
 
 
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 The planned highest daily dose does not exceed the 
highest daily dose being evaluated in previous clinical studies. Proposed doses will help 
characterize the dose/exposure-response relationships for key efficacy and safety endpoints in 
NT2 and help support dose selection for future pivotal studies in OX normal participants. 
Twice daily dosing of TAK-861 in this study will further evaluate maintenance of wakefulness 
during daytime by maintaining drug exposures throughout the day. Doses will be taken 
 apart to not interfere with the four 40-minute MWT sessions 
 
, to ease management of 
dosing and mealtimes while at home, and to minimize sleep disturbances. 
4.4 
End of Study/Study Completion Definition 
The end of study is defined as the final date on which data were or are expected to be collected, 
ie, the last visit of the last participant in the study. 
The participant’s maximum duration of participation is expected to be up to 19 weeks (including 
a screening period of up to 45 days, a 8-week treatment period and 4-week follow-up period). 
Participants immediately rolling over to the LTE study will not have a follow-up period. 
5. 
Study Population 
Investigators must account for all individuals who sign informed consent forms (ICFs), 
regardless of the outcome of the screening, by completing the required electronic case report 
forms (eCRFs).  
Rescreening will be allowed under circumstances described in Section 5.4. 
5.1 
Inclusion Criteria  
Participants must meet all of the following criteria to be eligible for inclusion in the study: 
Informed Consent 
1. The participant is willing and able to understand and fully comply with study procedures and 
requirements (including digital tools and applications), in the opinion of the investigator. 
2. The participant has provided informed consent (that is, in writing, documented via a signed 
and dated ICF and/or electronic consent [eConsent]) and any required privacy authorization 
before the initiation of any study procedures.  
Age and Body Mass Index  
3. The participant is aged 18 to 70 years, inclusive, at the time of signing the ICF. 
Note: In Japan, participants aged 16 to 70 years, inclusive, may be included. 
4. The participant has body mass index (BMI) within the range 18 to 40 kg/m2 (inclusive).  
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Type of Participant and Disease Characteristics 
5. The participant has an ICSD-3 diagnosis of NT2 by PSG/MSLT, performed within the past 
5 years 
 
  
 
 
  
 
 
7. The participant is judged by the investigator to be sufficiently healthy to participate in the 
study, on the basis of clinical evaluations including laboratory safety tests, medical history, 
physical examination, 12-lead ECG, and vital sign measurements performed at the screening 
visit and before the first dose of study drug.  
Note: Screening laboratory assessments may be repeated; the sponsor or designee should be 
informed. 
Contraception  
8. The participant agrees to follow the birth control requirements detailed in Section 10.4. 
5.2 
Exclusion Criteria  
The participant will be excluded from the study if any of the following exclusion criteria are met:  
Medical Conditions 
1. The participant has a current medical disorder, other than narcolepsy without cataplexy, 
associated with EDS. For example, the following are exclusionary: 
 
 
  
 
 
 
 
 
 
 
 
 
 
2. The participant has a current medical condition such as unstable cardiovascular, pulmonary, 
renal, or gastrointestinal disease, that would preclude enrollment in the view of the 
investigator.  
3. The participant has medically significant hepatic or thyroid disease. 
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4. The participant has current or recent (within 6 months) gastrointestinal disease that is 
expected to influence the absorption of drugs (ie, a history of malabsorption, esophageal 
reflux, peptic ulcer disease, erosive esophagitis, frequent [more than once per week] 
occurrence of heartburn, or any surgical intervention). 
 
 
 
  
5. The participant has a history of cancer in the past 5 years (does not apply to participants with 
carcinoma in situ that has been resolved without further treatment or basal cell cancer; these 
participants may be included after approval by the sponsor or designee). 
6. The participant has clinically significant coronary artery disease, a history of myocardial 
infarction, clinically significant angina, clinically significant cardiac rhythm abnormality, or 
heart failure. 
7. The participant has a clinically significant history of head injury or head trauma. 
8. The participant has history of epilepsy, seizure, or convulsion, or has a family history of 
inherited disorders associated with seizure (except for a single febrile seizure in childhood). 
9. The participant has one or more of the following psychiatric disorders: 
a. 
Any current unstable psychiatric disorder. 
b. 
Current or history of manic or hypomanic episode, schizophrenia or any other 
psychotic disorder, including schizoaffective disorder, major depression with 
psychotic features, bipolar depression with psychotic features, obsessive compulsive 
disorder, mental retardation, organic mental disorders, or mental disorders due to a 
general medical condition as defined in the Diagnostic and Statistical Manual of 
Mental Disorders, 5th Edition (DSM-5). 
c. 
Current diagnosis or history of substance use disorder as defined in the DSM-5. 
Note: If the history of substance use disorder is more than 12 months before baseline, 
the participant may be allowed to enroll in the study after consultation with the 
sponsor or designee. (Participant must also have negative urine drug screen at the 
screening and Day -2 visit.) 
d. 
Current active major depressive episode (MDE) or who have had an active MDE in 
the past 6 months. 
 
 
 
10. The participant has a history of cerebral ischemia, transient ischemic attack (<5 years ago), 
intracranial aneurysm, or arteriovenous malformation. 
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11. The participant has a current history of significant multiple or severe allergies (eg, food, 
drug, latex allergy) or has had an anaphylactic reaction or significant intolerance to 
prescription or nonprescription drugs or food. 
12. The participant has a known hypersensitivity to any component of the formulation of 
TAK-861 or related compounds. 
13. The participant had major surgery or donated or lost 1 unit of blood (approximately 500 mL) 
within 4 weeks before the screening visit.  
Prior/Concomitant Therapy 
14. The participant is unable to refrain from or anticipates using excluded food products (see 
Section 5.3) beginning by 
 and continuing 
, or prohibited 
medication (as described in Section 6.8.1). 
15. The participant has participated in another investigational drug study, in which they received 
the investigational drug, within 
 
 The interval window from the previous study will be 
derived from the date of the last study procedure in the previous study to the screening visit 
of the current study. 
Note: This does not apply to approved drugs, for which rules are laid out in Section 6.8.1. 
 
 
Diagnostic Assessments 
 
 
 
 
 
 
18. The participant has a resting HR 
 beats per minute during screening, confirmed 
on repeat testing within a maximum of 
 minutes. 
19. The participant’s screening ECG reveals a QT interval with Fridericia correction method 
(QTcF) >
 milliseconds (genetically male) or >
 milliseconds (genetically female). 
20. The participant has a positive test result for hepatitis B surface antigen, hepatitis C virus 
antibody, or HIV antibody/antigen at screening. 
21. The participant’s renal creatinine clearance (Cockcroft-Gault Equation) is ≤50 mL/min at 
screening. 
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22. The participant has ALT or AST values >1.5 times the upper limit of normal (ULN)  
 
 
23. The participant has a positive pregnancy test at screening or Day -2 or is 
lactating/breastfeeding. 
 
 
 
  
 
 
 
 
 
  
25. The participant is considered by the investigator to be at imminent risk of suicide or injury to 
self, others, or property, or the participant has attempted suicide within the past year before 
screening, or has positive answers on item number 4 or 5 on the C-SSRS (based on the past 
year) before randomization. 
Other Exclusion Criteria  
26. The participant is a study site employee or an immediate family member of or in a 
dependent relationship with a study site employee (eg, spouse, parent, child, sibling) who is 
involved in the conduct of this study, or may consent under duress. 
27. The participant consumes excessive amounts of caffeine, defined as greater than 
 
 (1 cup of coffee is approximately 120 mg.). 
28. The participant currently consumes alcohol exceeding 
 on average 
(1 standard drink is approximately equivalent to the following: beer [354 mL/12 oz], wine 
[118 mL/4 oz], or distilled spirits [29.5 mL/1 oz] per day). 
29. The participant has a nicotine dependence that is likely to have an effect on sleep (eg, a 
participant who routinely awakens at night to smoke) 
 
 
 
 
 
  
31. The participant has a usual bedtime later than 12:00 AM (midnight), an occupation requiring 
nighttime shift work or variable shift work within the past 6 months, travel with significant 
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jet lag within 14 days before Day -2, or plans for travel with significant jet lag during the 
study. 
32. The participant, in the opinion of the investigator or subinvestigator is unlikely to comply 
with the protocol or is unsuitable for any other reason. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
5.3 
Lifestyle Considerations  
5.3.1. 
Meals and Dietary Restrictions  
 
 
 
 
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On days of 
 MWT assessments (Table 1.a), participants will follow the 
/MWT 
manual. Caffeine will not be allowed on these days. At all other times, caffeinated beverages 
(including caffeinated tea) or xanthine-containing products will be limited to amounts of no more 
than 
 
Participants may smoke during the study outside the confines of the center, 
 
. 
For a comprehensive list of prohibited medications and procedures, see Section 6.8.1 and 
Table 6.b. 
Information on when to take the study drug in relation to meal times is provided in Section 6.2.4. 
5.3.2. 
Activity  
 
 
 
 
 
 
 
 
5.3.3. 
Contraception for Participants of Childbearing Potential or Capable of 
Producing Viable Sperm 
Participants who are of childbearing potential (that is, capable of producing viable ova and/or 
becoming pregnant) or capable of producing viable sperm must use highly effective 
contraception as agreed to in Inclusion Criterion 10. Section 10.4 lists acceptable methods of 
contraception. 
5.4 
Screening 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The site PI may determine if there is a need to repeat any screening 
assessments to ensure participant suitability. 
5.4.1. 
Screen Failures  
An individual who has provided informed consent to participate in the study may be categorized 
as a screen failure for any of the following reasons:  
• screen failure (did not meet entrance criteria). 
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• AE. 
• Lost to follow-up. 
• Pregnancy. 
• Withdrawal by participant. 
• Met eligibility criteria but not needed. 
• Study terminated by sponsor. 
• Other (specify). 
Participants are not considered screen failures if they were randomized but not treated. See 
Section 7.2.  
Information about screen failures should be collected via the eCRFs, including participant 
identification, screening disposition (including the reason for screen failure), demography, 
inclusion/exclusion criteria, and AEs (if applicable). If a potential participant experiences an 
SAE during screening, all of the participant’s screening eCRFs must be available for collection. 
The interactive response technology (IRT) should be contacted as a notification of screen failure. 
Participant identification numbers assigned to participants who fail screening should not be 
reused. 
An individual who has been designated a screen failure may be rescreened.  
5.5 
Criteria for Temporarily Delaying Randomization 
Randomization may be delayed for any of the following reasons:  
 
 
 
 
 
 
• Coronavirus disease 2019 (COVID-19) infection. 
• Self-quarantine requirement. 
• Site closure. 
• Pretreatment AE before randomization/treatment. 
For participants who were randomized, but not treated, the reason(s) should be captured on the 
eCRF. 
5.6 
Enrollment 
A participant is defined as enrolled when the participant has been randomized. 
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6. 
Study Intervention(s) and Concomitant Therapy  
6.1 
Study Interventions Administered 
In this study, the interventions includes: 
• Investigational product(s): TAK-861. The following dose regimens will be included: 
– Dose Regimen 1: 2 mg followed by 2 mg 
.  
– Dose Regimen 2: 2 mg followed by 5 mg 
 or 7 mg QD. 
• Other products required for the study: placebo. 
Dose regimens include QD or twice daily 
 dosing. Study treatment 
will be administered at 
 (Participants assigned to a QD dose 
regimen will receive placebo for the second dose.) 
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. 
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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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Proper drug accountability includes, but is not limited to: 
• The investigator or designee must maintain records of all sponsor-supplied study 
interventions delivery to the site, current site inventory, dispensing for use by each 
participant, and return to the sponsor or designee.  
• The investigator or designee must record this inventory on a sponsor (or designee)-
approved drug accountability log.  
• Based on entries in the log, it must be possible to reconcile study products delivered with 
those used and returned.  
• All study products must be accounted for and all discrepancies investigated and 
documented to the sponsor’s satisfaction.  
• If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately. 
6.2.2. 
Receiving Product at the Site 
Investigators will be provided with sufficient amounts of the study intervention to carry out this 
protocol for the agreed number of participants.  
On receipt of sponsor-supplied study drug, the investigator or designee must verify the contents 
of the shipments against the packing list. The verifier should ensure that the quantity is correct, 
and the medication is in good condition.  
Refer to the pharmacy manual for details related to the receipt of study drug. 
6.2.3. 
Labeling 
Study drug containers will be affixed with a clinical label in accordance with local regulatory 
requirements. 
6.2.4. 
Dispensing/Administration 
6.2.4.1. 
Dispensing 
Participants will be assigned to receive their treatment according to the randomization schedule. 
Information on study drug dispensing is provided in the pharmacy manual. 
6.2.4.2. 
Administration 
Each participant in this study will be instructed to take study drug twice daily: 
 
 
 
 
 
 
. Participants assigned to a QD dose regimen will receive 
placebo for the second dose. Participants assigned to placebo will receive placebo for both doses. 
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During the confinement periods (as indicated in Table 1.a), the 
 of TAK-861 or 
matched placebo will be administered 
 
 
 
with 240 mL of water 
; participants will then be allowed 
to have a 
 after study drug administration. Participants 
may consume water ad libitum. Participants will be instructed to take 
 
 Standardized meals (approximately 30% fat 
content relative to total calories) will be administered 
 
 On discharge days, lunch or 
dinner may be taken at home.  
 
 
 
 
 
 
 
 
 
 
  
While at home, participants will be instructed to take the 
 of TAK-861/matched 
placebo in the 
 with a large glass of water 
(approximately 240 mL total) 
 
. Participants will be instructed to take the 
 
 
 
 Participants will be provided 
written instructions by the site on how to take study drug at home. 
Participants should swallow the study drug whole and not chew it or manipulate it in any way 
before swallowing. Participants should be instructed not to take more than the prescribed dose at 
any time. If a dose window is missed, the dose should be skipped and no drug should be taken 
until the next scheduled dose. Under no circumstance should a participant repeat a dose or 
double-up doses.  
Participants will be instructed to record their intake of TAK-861/matched placebo each day in 
their eDiary (Section 8.2.2.3.9). Additional steps may be taken to ensure participants understand 
the dosing instructions and that they follow the correct TAK-861 dosing regimen, such as 
additional site communication with the participant throughout the treatment course, ie, on-site 
visits or phone calls. 
Participants will adhere to the dietary and medication restrictions described in Sections 5.3 
and 6.8. 
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Within the source documents, site personnel should document instruction of and understanding 
by the participant of the safe, responsible storage and administration of study intervention to the 
study participant. 
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 eDiary. 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 eDiary (a component of the eDiary). 
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). 
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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 
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 without cataplexy (NT2) 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. 
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Table 6.b  
 
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Table 6.b  
 
 
 
 
 
 
 
 
 
 
 
 
6.8.2. 
Permitted Concomitant Medications 
If medications are required to treat an AE, certain medications, including supplements, may be 
allowed after discussion and agreement between the sponsor or designee and PI, unless the 
investigator or investigator’s designee considers immediate administration necessary. 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
This section describes the circumstances under which individual participants would withdraw or 
be discontinued from the study intervention or from the study itself.  
Section 10.1 describes circumstances in which specific sites or the study itself would be 
discontinued. 
7.1 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. For participants who early terminate the study, every effort should be deployed to 
have them complete an early termination visit as soon as possible and a follow-up visit (in-clinic 
visit or home healthcare visit if available) approximately 28 days after the last dose of study drug 
(see Table 1.a). 
The primary reason for discontinuation or withdrawal of the participant from the study or study 
drug should be recorded in the eCRF using the following categories.  
• AE. An AE may require a participant to discontinue the study drug if continued 
participation would impose an unacceptable risk to the participant’s health or the 
participant is unwilling to continue because of the AE. 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
– Suicidality: Study drug should be discontinued for participants at imminent risk of 
suicide per the C-SSRS (endorsement of Item 4 with the investigator’s clinical 
judgement or Item 5) or per the investigator’s clinical judgment. Once 
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discontinued, the participants should be followed up as described in 
Section 8.3.8.3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Death. 
• Protocol deviation. The discovery after randomization that the participant did not meet 
protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the participant’s health. 
• Lost to follow-up. The participant did not attend visits and 3 attempts to contact the 
participant were unsuccessful. Attempts to contact the participant must be documented in 
the participant’s source documents. A certified letter can be sent as a last attempt.  
• Withdrawal by participant. The participant wishes to withdraw from the study. The 
reason for withdrawal, if provided, should be recorded in the eCRF.  
Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (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 
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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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Table 8.a 
 
 
 
 
8.1 
Demographics, Medical History, Medication History and Administrative 
Procedures 
8.1.1. 
Demographics 
Participant demographic information will be collected before the participant receives the first 
dose of study intervention. 
Demographic information to be obtained will include: date of birth or age (as permitted by local 
regulations), sex, race (reported by the participant), caffeine consumption, alcohol consumption, 
substance use, smoking status. 
 
 
 
 
8.1.2. 
Medical History 
Medical and medication history, including concurrent medical conditions, will be collected and 
recorded in the participant’s source documents and in the eCRF.  
Medical history to be obtained will include determining whether the participant has any 
significant conditions or diseases relevant to the disease under study that resolved before the 
participant signed the ICF. Ongoing conditions are considered concurrent medical conditions. 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present when informed consent is provided. This includes clinically significant laboratory, ECG, 
physical examination, and/or vital signs abnormalities noted at screening/baseline examination, 
according to the judgment of the investigator.  
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8.1.3. 
Prior and Concomitant Treatments/Medications 
Prior and concomitant treatments and medications will be collected and recorded in the 
participant’s source document. 
Such treatments/medications include but are not limited to: 
• Medications or vaccines. 
• Over-the-counter or prescription medicines. 
• Recreational drugs. 
• Vitamins. 
• Herbal supplements. 
• Medications relevant to the eligibility criteria. 
• Other specific categories of interest. 
Prior medications/treatments are defined as those that were received 
 
 
 
Concomitant medications/treatments are defined as those given in addition to the study 
intervention between the signing of the ICF and participant completion.  
Concomitant medications may be prescribed by a physician or obtained by the participant over-
the-counter. Concomitant medication is not provided by the sponsor.  
At each study visit, participants will be asked whether they have taken any medication or 
received any treatment other than the study intervention. 
Information to be recorded will include: 
• Identification of the medication or treatment. 
• Reason for use. 
• Dates of treatment/medication administration: start and end dates. 
• Dosage information including dose and frequency. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
8.1.4. 
Diagnostic Criteria/Disease Classification  
8.1.4.1. 
Diagnostic Criteria for NT2 
ICSD-3 criteria for NT2 are provided in Appendix 3. 
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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. 
– 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 
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. 
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• 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. 
8.2 
Efficacy Assessments  
Planned time points for all efficacy assessments are provided in the SOA (Table 1.a). 
8.2.1. 
Primary Efficacy Measurement  
The MWT is a validated, objective measure that evaluates a person’s ability to remain awake 
under soporific conditions for a defined period of time. Because there is no biological measure of 
wakefulness, wakefulness is measured indirectly by the inability or delayed tendency to fall 
asleep. This tendency to fall asleep is measured via electroencephalography-derived sleep 
latency in the MWT. One session, that includes four 40-minute MWTs, will be done on each day 
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specified in the SOA. Sleep latency in each session will be recorded. Participants will be 
required to stay awake in between the 4 MWT tests in each session. 
During each MWT, participants will be instructed to sit in a bed or reclining chair and remain 
awake for as long as possible in a dimly lit room. Sessions are ended after 40 minutes if no sleep 
occurs. If no sleep has been observed according to these rules, then the latency is defined as 
40 minutes. Specific instructions are located in the study procedure manual. 
8.2.2. 
Other 
8.2.2.1. 
 
 
 
 
 
 
 
 
 
8.2.2.2. 
 
8.2.2.2.1. 
 
 
 
 
 
 
 
 
8.2.2.2.2. 
 
 
 
 
 
 
 
 
 
 
 
 
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8.2.2.2.3. 
 
 
 
 
 
 
 
 
 
8.2.2.2.4. 
 
 
 
 
 
 
 
 
 
 
8.2.2.3. 
Clinical Outcome Assessments  
8.2.2.3.1. ESS 
The ESS is a subjective, self-administered scale that has been validated and used extensively as a 
key endpoint in studies in patients with narcolepsy to measure EDS. The ESS provides 
individuals with 8 different situations of daily life and asks them how likely they are to fall 
asleep in those situations (scored 0 to 3) and to try to imagine their likelihood of dozing even if 
they have not actually been in the identical situation; the scores are summed to give an overall 
score of 0 to 24. Higher scores indicate stronger subjective daytime sleepiness, and scores below 
10 are considered to be within the reference range. 
In this study, the ESS will be administered to assess sleep propensity on selected days after 
TAK-861 administration. Participants will be asked to evaluate their subjective sleepiness based 
on recalling their most recent daily life experiences.  
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8.2.2.3.2. 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
8.2.2.3.3. 
  
 
 
 
 
 
 
 
 
 
 
  
8.2.2.3.4. 
 
 
 
 
 
 
 
 
 
 
 
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8.2.2.3.5. 
 
 
 
  
 
 
8.2.2.3.6. 
 
 
 
 
 
 
 
 
 
 
 
  
8.2.2.3.7. 
 
 
 
 
 
 
 
.  
8.2.2.3.8. 
 
 
 
 
 
 
  
8.2.2.3.9. Daily eDiary 
Participants will complete a daily eDiary to record self-reported narcolepsy symptoms. In cases 
where the eDiary becomes unavailable, a site may use alternative methods to collect these data 
with approval from sponsor or designee. 
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Participants will record alcohol consumption in the eDiary. 
 
 
 
Dates and time of dosing will also be recorded. Additional details on dose administration are 
provided in Section 6.2.4.2. 
8.3 
Safety Assessments  
Planned time points for all safety assessments are provided in the SOA (see Table 1.a). 
8.3.1. 
Physical Examinations  
At screening and at the first follow-up visit, a full physical examination will consist of the 
following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; 
(4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; (7) extremities; 
(8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) other. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
All subsequent physical examinations should assess clinically significant changes from the 
baseline physical examination. 
 
 
 
 
 
 
 
8.3.2. 
Vital Signs  
When vital signs are scheduled at the same time as blood sample collection, the blood sample 
collection will take priority, and vital signs will be obtained within 1.0 hour before the scheduled 
blood draw. 
Vital signs will include: body temperature (oral or tympanic measurement), respiratory rate, BP 
(systolic and diastolic, with the participant resting more than  minutes), and pulse (in beats 
per minute). 
The participant should be resting for a minimum of  minutes sitting or lying in a bed with the 
head of the bed at 30 degrees. 
For BP assessment, the same method (ie, the same size cuff, manual or automated, sitting or 
lying) must be used for all measurements for each individual participant and should be the same 
for all participants at the study site. 
 
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Body temperature will be measured with an oral thermometer (with the temperature taken at the 
floor of the mouth) or a tympanic thermometer. The same method (ie, oral or tympanic) must be 
used for all subsequent measurements for each individual participant and should be the same for 
all participants at the study site. 
The investigator will assess whether a change in vital signs from baseline may be deemed 
clinically significant on the Vital Signs eCRF and whether the change should be considered and 
recorded as an AE on the AE eCRF. 
8.3.2.1. 
Weight, Height, and BMI  
Weight, height, and BMI will be measured and recorded. 
A participant should have weight and height measured while wearing indoor clothing and with 
shoes off. Weight is collected in kilograms (kg). Height is recorded in centimeters (cm).  
8.3.3. 
ECG 
Participants should be resting in a semirecumbent position for at least  minutes before each 
ECG measurement. The PI should arrange to have a study cardiologist available as needed to 
review ECG tracings with abnormalities. 
A standard 12-lead ECG will be recorded and interpretation of the ECG will be made using 1 of 
the following categories: within normal limits, abnormal but not clinically significant, or 
abnormal and clinically significant. The time that the ECG was performed will be recorded.  
The investigator will assess whether a change in ECG from baseline may be deemed clinically 
significant and whether the change should be considered and recorded as an AE on the AE 
eCRF. 
The eligibility of the participant will be based on the assessment of the ECG by the investigator.  
A baseline ECG will be obtained within approximately  hour before dosing of study drug. If a 
participant has an 
 compared with a predose baseline 
measurement, the ECG will be repeated within  minutes. 
 
. If the 
 
, the participant will 
continue to be monitored by repeat 12-lead ECGs every 
 minutes for at least  hours or until 
the 
 of the baseline value. If 
 
 persists, a consultation with a study cardiologist may be appropriate, 
and the sponsor should be notified. 
If the 
, the sponsor should be notified and the ECG should be 
reviewed by a cardiologist. The participant should be monitored by telemetry (
 
), or the participant should be considered for transfer to a location 
where closer monitoring is available. 
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If the participant has unstable hemodynamics or has any clinically significant dysrhythmias 
noted by telemetry, the participant should be immediately transferred to an acute care setting for 
definitive therapy. 
8.3.4. 
Clinical Safety Laboratory Tests  
All protocol-required laboratory tests, as defined in Section 10.2, must be conducted in 
accordance with the laboratory manual and the SOA. Details about these procedures and required 
safety monitoring will be given in the laboratory manual.  
The central laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis.  
The clinical laboratory will return these results, along with their reference ranges, to the 
investigator. The investigator is responsible for reviewing the laboratory report, documenting 
this review, and filing the laboratory report with the source documents.  
Abnormal laboratory findings associated with the underlying disease should not be considered 
clinically significant unless judged by the investigator to be more severe than expected for the 
participant’s condition.  
Clinically significant abnormal laboratory values obtained during participation in the study or 
within 
 of study intervention should be repeated until the values return 
to normal or the baseline value or are no longer considered clinically significant by the 
investigator or medical monitor. The investigator should evaluate whether the laboratory result 
meets the AE criteria in Section 10.3. 
 
 
  
If clinically significant values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the sponsor notified. 
Investigators must document their review of each laboratory safety report. 
The investigator must record the following types of laboratory test results on the laboratory 
eCRF and if applicable on the AE eCRF: 
• 
Any changes that are considered clinically significant by the investigator (eg, SAE or AE or 
dose modification). 
• 
Any laboratory test results (central laboratory, local laboratory, non-protocol specific local 
laboratory) that are used to make a study intervention decision, that require a change in 
participant management, or that are used to make a response evaluation. 
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8.3.5. 
Pregnancy Testing  
A serum human chorionic gonadotropin (β-HCG) pregnancy test will be performed at screening 
for all participants of child-bearing potential. Urine pregnancy test will be performed on all 
participants of child-bearing potential at times described in the SOA and if pregnancy is 
suspected. 
If a participant or a participant’s partner becomes pregnant during the study, the pregnancy must 
be followed as described in Section 10.4.3. 
8.3.6. 
Suicidal Ideation and Behavior Risk Monitoring  
Two versions of C-SSRS will be used to assess suicidal ideation in this study: the 
Screening/Baseline C-SSRS Lifetime and the Since-Last-Visit C-SSRS. 
 
. The 
investigator will ensure that any suicidal ideation or behavior is medically addressed, including 
assessment and treatment by qualified medical personnel. 
8.3.7. 
Other  
8.3.7.1. 
 
 
 
  
8.3.7.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
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8.3.8. 
AEs, SAEs, and Other Safety Reporting  
The definitions of AEs and SAEs are provided in Section 10.3. 
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 
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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 
regulatory requirements relating to safety reporting to the regulatory authority, IRBs/IECs, and 
investigators. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it 
along with similar documents containing safety information and will notify the IRB/IEC, if 
appropriate according to local requirements. 
8.3.8.5. 
Pregnancy in a Participant or Participant’s Partner During the Study 
Details about all unplanned/accidental pregnancies in female participants will be collected after 
the start of study intervention and until 
 (ie, 
) after the last dose 
of study drug. For partners of participants, this information will be collected after the start of 
study intervention and until 
 (ie,
) after the last dose of study 
drug. Collection of pregnancy data from a participant’s partner requires the partner’s informed 
consent.  
To the extent possible, the investigator will collect follow-up information on the outcome of the 
pregnancy and the neonate, and the information will be forwarded to the sponsor.  
Once a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours. 
Pregnancy itself is not considered to be an AE or SAE; however, AEs or SAEs associated with 
pregnancy must be reported as such, including:  
• Any pregnancy complication or elective termination of a pregnancy for medical reasons (to 
be reported as an AE or SAE). 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) (to be reported as SAEs). 
Any poststudy pregnancy-related SAE considered reasonably related to the study intervention by 
the investigator will be reported to the sponsor as described in Section 10.3.4.6. Although the 
investigator is not obligated to actively seek post study pregnancy-related SAE information from 
former study participants or their partners, he or she may learn of an SAE through spontaneous 
reporting. 
Any participant who becomes pregnant while participating in the study will be withdrawn from 
the study. 
8.3.8.6. 
AEs of Special Interest  
See Section 10.3.3.2. 
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8.4 
 
 
 
 
 
 
 
 
8.4.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
8.5 
Genetics 
8.5.1. 
 
 
 
 
 
 
 
 
 
 
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8.6 
  
 
 
 
 
 
 
 
8.7 
Immunogenicity Assessments 
Not applicable. 
9. 
Statistical Considerations 
A statistical analysis plan will be prepared and finalized before database lock. The statistical 
analysis plan will provide further details regarding the definition of analysis variables and the 
statistical analysis methodology to address all study objectives. 
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9.1 
Statistical Hypotheses  
9.1.1. 
Primary Endpoint 
TAK-861 is superior to placebo as measured by the change from baseline to Week 8 in the mean 
sleep latency (minutes) from the 4 sessions of a 40-minute MWT. The statistical null hypothesis 
is that the mean change from baseline to Week 8 in the mean sleep latency for each TAK-861 
treatment group is the same as the mean change from baseline to Week 8 in the mean sleep 
latency for the placebo treatment group. 
9.1.2. 
Secondary Endpoints 
TAK-861 is superior to placebo as measured by the change from baseline to Week 8 in the total 
ESS score. The statistical null hypothesis is that the mean change from baseline to Week 8 in the 
total ESS score for each TAK-861 treatment group is the same as the mean change from baseline 
to Week 8 for the placebo treatment group. 
9.2 
Analysis Sets 
9.2.1. 
Safety Set 
The safety set will consist of all participants who received at least 1 dose of study drug. This 
analysis set will be used for demographic, baseline characteristic, and safety summaries. 
9.2.2. 
 
 
 
9.2.3. 
Full Analysis Set  
The full analysis set will consist of all participants who were randomized and received at least 
1 dose of study drug. The full analysis set will be used for summaries of efficacy endpoints. 
9.3 
Efficacy Analyses 
9.3.1. 
Primary Efficacy Endpoint 
The change from baseline in mean sleep latency from the MWT will be analyzed using a linear 
mixed model for repeated measures (MMRM), with visit, treatment, and treatment-by-visit 
interaction as the fixed effects. Baseline age and mean sleep latency will be included as 
covariates. The estimated change from baseline in the mean sleep latency for each treatment and 
the associated SE and 95% CIs will be extracted from the model, along with all estimated 
treatment differences from placebo and associated SEs, 95% CIs, and p-values. 
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9.3.2. 
Secondary Efficacy Endpoint 
The change from baseline in ESS total score will also be evaluated using the similar linear 
MMRM as for MWT with only the baseline value as a covariate. 
9.3.3. 
 
 
9.4 
Safety Analyses 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The 
number and percentage of TEAEs will be presented by System Organ Class and Preferred Term. 
TEAEs will be further summarized by severity and relationship to the intervention(s). AEs 
related to the intervention(s), AEs leading to study drug discontinuation, SAEs, and deaths will 
be similarly summarized. 
TEAEs will be summarized by treatment group. Observed values and change from baseline in 
safety clinical laboratory measurements, vital signs, and ECG parameters will be summarized by 
treatment group. 
 
 
9.5 
Other Analyses 
9.5.1. 
 
 
 
 
 
 
 
 
 
 
 
 
9.5.2. 
 
 
 
 
 
 
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9.6 
 
 
9.7 
 
 
 
 
 
 
 
 
 
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. 
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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 
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. 
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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 
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. 
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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. 
− 
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. 
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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) 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 
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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 
required by country or regional regulations or procedures, approval from the competent 
regulatory authority will be obtained before commencement of the study or implementation of a 
substantial amendment. The sponsor will notify the site once the sponsor has confirmed the 
adequacy of site regulatory documentation Until the site receives notification no protocol 
activities, including screening may occur. 
Study sites must adhere to all requirements stipulated by their respective IRB/IEC. This may 
include notification to the IRBs/IECs regarding protocol amendments, updates to the ICF, 
recruitment materials intended for viewing by participants, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRBs/IECs, and submission of the investigator’s final status report to IRBs/IECs. All 
IRBs/IECs approvals and relevant documentation for these items must be provided to the 
sponsor or designee. 
Participant incentives should not exert undue influence for participation. Payments to 
participants must be approved by the IRBs/IECs and sponsor. 
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10.1.5.2. Other Committees 
A data monitoring committee (DMC) is present at the programmatic level for this study. A DMC 
charter will provide full guidance on the function and practices to be followed by the DMC. 
10.1.6. 
Dissemination of Clinical Study Data 
10.1.6.1. Study Results Disclosure  
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations and guidance, Takeda will, at a minimum, register all 
interventional clinical trials and disclose the results of those trials in a manner and time frame 
compliant with Takeda policy and all applicable laws and regulations. Clinical trial registration 
and results disclosures will occur on ClinicalTrials.gov, other clinical trial registries/databases as 
required by law, and on Takeda’s corporate website(s). 
10.1.7. 
Data Quality Assurance  
All participant data relating to the study will be recorded on electronic CRFs unless transmitted 
to the sponsor or designee electronically (eg, laboratory data). The sponsor will supply the 
eCRFs. The investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the eCRF before transmitting it to the sponsor. 
Guidance on completion of eCRFs will be provided in CRF completion guidelines. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
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 
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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/or designee 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. 
Alternative approaches may be used to ensure data quality, data integrity, and participant safety 
(eg, remote source data review/source data verification via phone or video) as permitted by 
regional and local regulations. See the monitoring plan for additional details. 
10.1.7.3. Audits 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments. If the study site is contacted for an inspection by a 
regulatory body, the sponsor should be notified immediately.  
The investigator and/or designee study site guarantee access for quality assurance auditors to all 
study documents as described in Section 10.1.8. 
10.1.8. 
Source Documents  
All key data must be recorded in the participant’s source documents unless otherwise noted in 
the protocol. Source documents may be paper or electronic, including data obtained using 
electronic devices and associated technologies. Original source data to be reviewed during this 
study will include, but are not limited to: participant’s medical file, appointment books, diaries, 
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clinical outcome assessments, original clinical laboratory reports, histology reports, pathology 
reports, x-rays. The investigator is responsible for maintaining adequate and accurate source 
documents.  
The investigator must provide direct access to inspect facilities, including original source records 
relevant to this study (regardless of media), to: the sponsor or its authorized representatives; the 
respective national, local, or foreign regulatory authorities; the IRB/IEC; and auditors. These 
records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency or an auditor. The 
eConsent form includes a statement granting this access to source data.  
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor. 
10.1.8.1. eCRFs 
Completed eCRFs are required for each participant who has completed the consent process. The 
eCRFs are designed to record all observations and other data pertinent to the clinical 
investigation unless otherwise noted in the protocol. Laboratory data, 
 
, electronic clinical outcome assessment, MWT, 
, ECG, 
 
data is collected electronically and will be transmitted directly via secure transfer.  
The sponsor or its designee will supply study sites with access to eCRFs. The sponsor or 
designee will train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor and regulatory 
authorities. 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 
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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. 
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. 
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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. 
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). 
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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 
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 
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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. 
 
  
 
 
  
 
 
 
 
 
 
 
10.1.9.3. Optional Study Participant Interviews 
Participants who complete the TAK-861-2002 Phase 2 study may be asked whether they are 
interested in participating in a separate qualitative interview study to share their clinical trial 
experience. The qualitative interview study would have a separate protocol and ICF.  
10.1.10. 
Publication Policy 
Both during and after this study, all public disclosures containing data/information from this 
study must undergo review and receive written approval by the appropriate Takeda 
representative(s) before any public disclosure (including but not limited to submission, 
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presentation, posting on online platforms for archiving, and distribution of unpublished 
preprints).  
This policy applies to all publication types, including: abstracts and presentations (oral and 
poster, including invited presentations) for scientific congresses; articles (original research 
manuscripts, review articles, invited articles), letters to the editor, and editorials, in scientific 
peer-reviewed journals; print, electronic and enhanced multimedia publications associated with 
traditional congress and journal publishing (such as, but not limited to, audio, visual/graphical or 
video abstracts or manuscript summaries; video or animated posters; augmented reality); books 
and book chapters.  
Authorship will be determined in line with the requirements of the International Committee of 
Medical Journal Editors Recommendation for the Conduct, Reporting, Editing and Publication of 
Scholarly Work in Medical journals, unless otherwise required by the journal or forum where the 
publication appears. 
Publications derived from this study may never contain participants’ direct identifiers (such as 
participant identification number, initials) but may contain indirect/quasi identifiers (for example 
sex/gender, age/birth date, geographic indicators). Publications derived from this study may not 
include products’ direct identifiers (lot numbers or batch numbers) unless specifically required 
by the journal or conference guidelines and if approved by Takeda.  
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. 
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• 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 
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 
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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 
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, 
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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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Table 10.a 
Protocol-Required Laboratory Tests 
Laboratory Tests 
Parameters 
Hematology 
 
Platelet count  
Hemoglobin 
Hematocrit 
 
 
RBC count 
 
WBC count with absolute 
differential  
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical Chemistry 
BUN 
Creatinine 
Creatine kinase 
Triglycerides 
Lipid panel (HDL, LDL, 
total cholesterol) 
Potassium 
Sodium 
Chloride 
Calcium 
Glucose 
Bicarbonate 
AST  
ALT  
Alkaline 
phosphatase  
 
Total bilirubina 
Total protein 
Albumin 
Routine Urinalysis 
Specific gravity, glucose, protein, blood, nitrites 
Microscopic examination (if blood or protein is abnormal) 
Pregnancy Testing 
For participants of childbearing potential only: highly sensitive serum or urine hCG 
pregnancy test  
Other Screening 
Tests 
If menopause is suspected: FSH and estradiol  
Serology (HIV antibody, HBsAg, and HCV)  
Alcohol screen 
Drug screen 
All study-required laboratory tests should be performed by a central laboratory. A local 
laboratory may be used for special circumstances after discussion with sponsor. 
ALT: alanine aminotransferase; 
; AST: aspartate aminotransferase; 
BUN: blood urea nitrogen; CSF: cerebrospinal fluid; FSH: follicle stimulating hormone; 
 
; hBsAg: hepatitis B surface antigen; hCG: human chorionic gonadotropin; HCV: hepatitis C virus; HDL: 
high density lipoprotein; 
; LDL: low density lipoprotein; 
; 
RBC: red blood cell; ULN: upper limit of normal; WBC: white blood cell.  
 
 
 
 
  
 
10.2.1. 
Clinical Laboratory Assessments and Other Safety Assessments 
A change in the value of a clinical laboratory parameter, physical examination finding, vital sign 
measure, or ECG assessment can represent an AE if the change is clinically relevant or if, during 
administration of study intervention, a shift of a parameter is observed from a value in the 
normative range to a value that is outside the reference range and considered clinically 
significant, or a further waning of an already clinically significant value. When evaluating such 
changes, the extent of deviation from the reference range, the duration until return to the 
reference range, either while continuing administration or after the end of administration with the 
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10.3.3. 
Additional Considerations in Identifying and Defining AEs  
10.3.3.1. Defining Discrete AEs 
Each reported AE should represent a single diagnosis, if the diagnosis is known. Accompanying 
signs (including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs UNLESS the diagnosis is unknown. Specific examples are as 
follows: 
Laboratory values and ECG findings: 
• If abnormal laboratory values or ECG findings are the result of pathology for which there 
is an overall diagnosis (eg, increased creatinine in renal failure), the diagnosis should be 
reported as the AE. 
Worsening of a condition: 
If the participant experiences a worsening or complication of a medical condition, the worsening 
or complication should be recorded as an AE. Investigators should ensure that the event term 
recorded captures the change in the condition (eg, “worsening of…”). This includes: 
• Pre-existing conditions present at the time of signing of informed eConsent. 
• Pre-existing episodic concurrent medical conditions (eg, asthma, epilepsy): An episode 
should only be recorded as an AE if the condition becomes more frequent, serious, or 
severe in nature.  
• A degenerative concurrent medical condition (eg, cataracts, rheumatoid arthritis): 
Worsening of the condition should only be recorded as an AE if it occurs to a greater 
extent than expected.  
• Worsening or complication of an AE after any change in study drug: The worsening or 
complication should be recorded as a new AE. 
Complications associated with preplanned procedures: 
• Changes in plan and surgical complications associated with preplanned or elective 
surgeries, therapies, or procedures should be recorded as AEs.  
• If a preplanned procedure is performed early (eg, as an emergency) due to a worsening of 
the pre-existing condition, the worsening of the condition should be recorded as an AE.  
• Complications resulting from an elective surgery should be recorded as AEs. 
Changes in intensity of AEs: 
• If the participant experiences changes in intensity of an AE, the event should be recorded 
once with the maximum intensity recorded. 
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10.3.3.2. AEs of Special Interest 
An AE of special interest (serious or non-serious) is one of scientific and medical concern 
specific to the compound or program, for which ongoing monitoring and rapid communication 
by the investigator to Takeda may be appropriate. Such events may require further investigation 
in order to characterize and understand them. 
On the basis of nonclinical data for TAK-861, clinical data for the compounds with the same 
mechanism of action and literature information on the association between OX2R agonism and 
cardiovascular effects, as well as effects on wakefulness in nonclinical models, the following are 
identified as potential risks and AEs of special interest for the study drug: 
• BP increases. 
• HR increases. 
• Insomnia. 
• Bladder events. 
BP and HR are monitored throughout the study at every planned visit. The participant should be 
promptly discontinued from the study if they meet the BP/HR specific discontinuation criteria as 
specified in Section 7.1. 
 
 
There are no special monitoring requirements for insomnia and bladder events other than routine 
AE monitoring. However every attempt should be made to get more clarity on the type of 
bladder event and insomnia the participant experienced. 
AEs of special interest must be recorded as AEs/SAEs in the eCRF. They will follow the same 
reporting procedures for AEs/SAEs as mentioned in Section 10.3.4. All AEs of special interest 
must be followed up until resolution. 
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10.3.5.1. 
 
 
 
 
 
10.3.5.2. Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The sponsor will be responsible for identifying and reporting all suspected unexpected serious 
adverse reactions (SUSARs) and any other applicable SAEs to regulatory authorities, 
investigators, and IRBs or IECs in accordance with national regulations in North America, 
Europe, and Asia Pacific. AEs that are already classified as expected (and therefore are not 
SUSARs) are listed in the RSI (see Section 10.3.4.6.1 for the location of the RSI).  
• SUSARs will be submitted to the regulatory authorities as an expedited report within 
7 days for fatal and lifethreatening events and 15 days for other serious events, relative to 
the first awareness of an event by/or further provision to the sponsor or sponsor’s 
designee, unless otherwise required by national regulations.  
• The sponsor will prepare an expedited reports for other safety issues that might materially 
alter the current benefit-risk assessment of a study drug/sponsor supplied drug, or that 
would be sufficient to consider changes in the study drug/sponsor supplied drug 
administration or in the overall conduct of the 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 
• Female 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 
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(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 postbilateral 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. 
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 
 (ie, 
) 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 drug (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  
 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 
 
(ie, 
) 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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All pregnancies in participants on study intervention(s) including/excluding the comparator or 
their partners will be followed up to final outcome, using the pregnancy form. Pregnancies will 
remain blinded to the study team. The outcome, including any premature termination, must be 
reported to the sponsor. An evaluation after the birth of the child will also be conducted. 
10.5 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 10.d 
 
10.6 
Country-Specific Requirements  
Not applicable. 
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10.7 
Abbreviations and Definitions 
10.7.1. 
Abbreviations 
 
 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
 
 
 
 
 
BMI 
body mass index 
BP 
blood pressure 
 
 
 
 
 
 
COVID-19 
coronavirus disease 2019 
 
 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia Suicide Severity Rating Scale 
 
 
DMC 
data monitoring committee 
DNS 
disturbed nighttime sleep 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
ECG 
electrocardiogram 
eConsent 
electronic consent 
eCRF 
electronic case report form  
eDiary 
electronic diary 
EDS 
excessive daytime sleepiness 
 
 
ESS 
Epworth Sleepiness Scale 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
 
 
GCP 
Good Clinical Practice 
 
 
hCG 
human chorionic gonadotropin 
HR 
heart rate 
IB 
investigator’s brochure 
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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 
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 
 
 
SOA 
schedule of activities 
SOREMP 
sleep onset REM period 
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SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
 
 
 
 
ULN 
upper limit of normal 
 
 
10.8 
Protocol Amendment History  
Date 
Document 
Global/Country/Site Specific 
13 September 2022 
Original Protocol 
Global  
 
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11. 
References 
ABAD, V. C. & GUILLEMINAULT, C. 2017. New developments in the management of 
narcolepsy. Nat Sci Sleep, 9, 39-57. 
AMERICAN ACADEMY OF SLEEP  MEDICINE 2014. International classiﬁcation of sleep 
disorders. 3rd ed. (ICSD-3), Rochester, MN, American Academy of Sleep  Medicine. 
AMERICAN ACADEMY OF SLEEP MEDICINE 2014. International classiﬁcation of sleep 
disorders (ICSD-3), Rochester, MN, American Academy of Sleep Medicine. 
 
 
. 
BILLIARD, M., BESSET, A. & CADILHAC, J. 1983. The clinical and polygraphic 
development of narcolepsy. In: GUILLEMINAULT, C. & LUGARESI, E. (eds.) 
Sleep/Wake Disorders: Natural History, Epidemiology, and Long-Term Evolution. New 
York, NY: Raven Press. 
 
 
 
 
 
 
HUANG, S. C., DAI, Y. W., LEE, Y. H., CHIOU, L. C. & HWANG, L. L. 2010. Orexins 
depolarize rostral ventrolateral medulla neurons and increase arterial pressure and heart 
rate in rats mainly via orexin 2 receptors. J Pharmacol Exp Ther, 334, 522-9. 
 
 
 
 
POSNER, K., MELVIN, G. A., STANLEY, B., OQUENDO, M. A. & GOULD, M. 2007a. 
Factors in the assessment of suicidality in youth. CNS Spectr, 12, 156-62. 
POSNER, K., OQUENDO, M. A., GOULD, M., STANLEY, B. & DAVIES, M. 2007b. 
Columbia Classification Algorithm of Suicide Assessment (C-CASA): classification of 
suicidal events in the FDA's pediatric suicidal risk analysis of antidepressants. Am J 
Psychiatry, 164, 1035-43. 
TABUCHI, S., TSUNEMATSU, T., BLACK, S. W., TOMINAGA, M., MARUYAMA, M., 
TAKAGI, K., MINOKOSHI, Y., SAKURAI, T., KILDUFF, T. S. & YAMANAKA, A. 
2014. Conditional ablation of orexin/hypocretin neurons: a new mouse model for the 
study of narcolepsy and orexin system function. J Neurosci, 34, 6495-509. 
THORPY, M. J. & DAUVILLIERS, Y. 2015. Clinical and practical considerations in the 
pharmacologic management of narcolepsy. Sleep Med, 16, 9-18. 
 
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Appendix 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 2 
 
 
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Appendix 3 
ICSD-3 Criteria for NT2 
The criteria for NT2 (narcolepsy without cataplexy) are as follows:  
Criteria a) to e) 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) A mean sleep latency of ≤8 minutes and 2 or more SOREMPs are found on an MSLT 
performed according to standard techniques. A SOREMP (within 15 minutes of sleep onset) 
on the preceding nocturnal polysomnogram may replace one of the SOREMPs on the MSLT. 
c) Cataplexy is absent.1 
d) Either CSF hypocretin-1 concentration has not been measured or CSF hypocretin-1 
concentration measured by immoreactivity is either >110 pg/mL or >1/3 of mean values 
obtained in normal subjects with the same standardized assay.2 
e) Ther hypersomnolence and/or MSLT findings are not better explained by other causes such 
as insufficient sleep, obstructive sleep apnea, delayed sleep phase disorder, or the effect of 
medication or substances or their withdrawal. 
 
1. If cataplexy develops later, then the disorder should be reclassified as NT1. 
2. If the CSF Hert-1 concentration is tested at a later stage and found to be either ≤110 pg/mL of 
<1/3 of mean values obtained in normal subjects with the same assay, then the disorder should 
be reclassified as NT1. 
 
Source: (American Academy of Sleep Medicine, 2014) 
 
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