Conditions: Narcolepsy Type 1 (NT1) Narcolepsy Type 2 (NT2)
Keywords: Drug therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 97
Healthy volunteers: no

Brief summary:
The main aims of the study are:

* To check for side effects from TAK-994 and check what dose of TAK-994 participants can tolerate.
* To check what dose range provides adequate relief of narcolepsy symptoms.
* To check how much TAK-994 stays in the blood of participants, over time.

The study will have 4 parts. Participants can only join 1 of the parts.

A. Participants with type 1 narcolepsy will take either TAK-994 or placebo tablets for 28 days. A placebo looks just like TAK-994 but will not have any medicine in it.

B. Participants with type 1 narcolepsy will take 1 of 3 doses of TAK-994 or placebo tablets for 56 days.

C. Participants with type 1 narcolepsy in China only will take TAK-994 or placebo tablets for 56 days.

D. Participants with type 2 narcolepsy will take either TAK-994 or placebo tablets for 28 days.

Detailed description:
The drug being tested in this study is called TAK-994. TAK-994 is being tested in participants with NT1 and NT2.

The study will enroll up to approximately 202 participants. The study has 4 Parts: Parts A, B, C (China only) and D. Part A - Part A has 2 cohorts \[Cohorts (A1a and A1b) A2\] In both of these Cohorts, participants will be randomly assigned (by chance, like flipping a coin) in a 2:1 ratio to receive TAK-994 or placebo up to 28 days:

* Part B: In Part B, participants will be randomized in 1:1:1:1 ratio in four parallel arms to receive TAK-994 Dose 1, 2 or 3 or placebo for 56 days. Depending upon their eligibility participants completing Part B of the study treatment will be enrolled to participate in an Extension study.
* Part C: In Part C, participants only from China will be enrolled and randomized in a 2:1 ratio to receive TAK-994 and placebo for 56 days.
* Part D: Participants will be included in two cohorts \[Cohorts (D1a and D1b) and D2\] and will be randomized in 2:1 ratio to receive TAK-994 or placebo for 28 days. The dose will be selected based on the safety and tolerability in Part A.

This multi-center trial will be conducted in the United States, Japan, China, Italy, France, and European Union. The overall duration of the study is 63 days. Participants will be followed up for 7 days after the last dose of study drug.

Arms:
arm 1: TAK-994 placebo-matching tablets, orally, twice daily (BID) for 28 days, in participants with NT1. arm 2: TAK-994 120 mg, orally, BID for 28 days, in participants with NT1. arm 3: TAK-994 180 mg, orally, BID for 28 days, in participants with NT1. arm 4: TAK-994 placebo-matching tablets, orally, BID for 56 days, in participants with NT1. arm 5: TAK-994 30 mg tablets, orally, BID for 56 days, in participants with NT1. arm 6: TAK-994 90 mg tablets, orally, BID for 56 days, in participants with NT1. arm 7: TAK-994 180 mg tablets, orally, BID for 56 days, in participants with NT1. arm 8: TAK-994 180 mg tablets, orally, BID for 56 days, in Chinese participants with NT1.

Interventions: intervention 1: TAK-994 intervention 2: Placebo
Intervention descriptions: intervention 1: TAK-994 tablets. intervention 2: TAK-994 placebo-matching tablets.

Protocol document:
Prot_000.pdf: 
 
TAKEDA PHARMACEUTICALS
PROTOCOL
A Randomized, Double-Blind, Placebo-Controlled, Multiple Rising Oral Dose Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-994 in 
Patients With Narcolepsy With or Without Cataplexy (Narcolepsy Type 1 or Narcolepsy 
Type 2)
Sponsor:
Takeda Development Center Americas, Inc. 
95 Hayden Avenue
Lexington MA 02421
USA
Study Number:
TAK-994-1501
Study Phase
2
IND Number:
142658
EudraCT Number:
2020-000777-24
Compound:
TAK-994
Date:
15 January 2021 
Version/Amendment 
Number:
Amendment 3
Amendment History: 
Date
Amendment Number
Region
15 January 2021
Amendment 3
Global
05 June 2020
Amendment 2
Global
13 March 2020
Amendment 1
Global
26 November 2019
Initial version
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 2 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................8
1.1
Protocol Amendment 3 Summary of Changes..........................................................17
2.0
STUDY SCHEMATICS................................................................................................25
3.0
SCHEDULES OF STUDY PROCEDURES..................................................................30
3.1
NT1: PART A-Cohorts A1-A2 ................................................................................30
3.1.1
Screening Through Day 15 (PART A, Cohorts A1-A2)......................................30
3.1.2
Day 16 Through Day 35 (PART A, Cohorts A1-A2)..........................................35
3.2
NT1: PART B and PART C.....................................................................................39
3.2.1
Screening Through Day 15 (PART B and PART C)...........................................39
3.2.2
Day 16 Through Day 32 (PART B and PART C)...............................................44
3.2.3
Day 33 Through Day 63 (PART B and PART C)...............................................48
3.3
NT2: PART D (Cohorts D1 and D2)........................................................................53
3.3.1
Screening Through Day 15 (Part D, Cohorts D1 and D2) ...................................53
3.3.2
Day 16 Through Day 35 (PART D, Cohorts D1 and D2)....................................58
4.0
INTRODUCTION.........................................................................................................62
4.1
Background .............................................................................................................62
4.1.1
Disease Background...........................................................................................62
4.1.2
Summary of Nonclinical Data ............................................................................63
4.1.3
Clinical Study Experience..................................................................................69
4.2
Rationale for the Proposed Study Design .................................................................70
4.3
Benefit/Risk Profile .................................................................................................71
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................73
5.1
Study Objectives......................................................................................................73
5.1.1
Primary Objective--PART A and PART D.........................................................73
5.1.2
Secondary Objective--PART A and PART D.....................................................73
5.1.3
Additional/ Exploratory Objectives--PART A and PART D...............................73
5.1.4
Primary Efficacy Objective--PART B and PART C ...........................................74
5.1.5
Secondary Objective--PART B and PART C .....................................................74
5.1.6
Additional/ Exploratory Objectives--PART B and PART C ...............................74
5.2
Endpoints.................................................................................................................75
5.2.1
Primary Endpoints- PART A and PART D.........................................................75
5.2.2
Secondary Endpoint- PART A and PART D ......................................................75
5.2.3
Additional/Exploratory Endpoints-PART A and PART D..................................75
5.2.4
Primary Endpoint- PART B and PART C...........................................................76
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 3 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
5.2.5
Secondary Endpoints- PART B and PART C .....................................................76
5.2.6
Additional/Exploratory Endpoints- PART B and PART C .................................76
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................77
6.1
Study Design ...........................................................................................................77
6.2
Dose Selection and Cohort Progression....................................................................82
6.2.1
Dose Selection Rules .........................................................................................82
6.2.2
Data Review and Interim Analysis .....................................................................82
6.3
Rationale for Study Design, Dose, and Endpoints ....................................................83
6.3.1
Rationale of Study Design..................................................................................83
6.3.2
Rationale for Dose .............................................................................................85
6.3.3
Rationale for Endpoints......................................................................................86
6.3.4
Critical Procedures Based on Study Objectives: Timing of Procedures...............87
6.4
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................87
6.5
Study Beginning and End/Completion .....................................................................88
6.5.1
Definition of Beginning of the Study..................................................................88
6.5.2
Definition of End of the Study ...........................................................................88
6.5.3
Definition of Study Completion .........................................................................88
6.5.4
Definition of Study Discontinuation...................................................................88
6.5.5
Criteria for Premature Termination or Suspension of the Study..........................88
6.5.6
Criteria for Premature Termination or Suspension of a Site................................90
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............90
7.1
Inclusion Criteria .....................................................................................................90
7.2
Exclusion Criteria ....................................................................................................92
7.3
Excluded Medications, Supplements, and Dietary Products .....................................97
7.3.1
Concomitant Medications...................................................................................99
7.3.2
Fruit Juice and Fruit ...........................................................................................99
7.3.3
Alcohol..............................................................................................................99
7.3.4
Caffeine .............................................................................................................99
7.3.5
Smoking ............................................................................................................99
7.4
Dosing Instructions, and Activity...........................................................................100
7.4.1
Dosing Instructions ..........................................................................................100
7.4.2
Activity............................................................................................................101
7.5
Criteria for Discontinuation or Withdrawal of a Subject.........................................101
7.6
Procedures for Discontinuation or Withdrawal of a Subject....................................103
7.7
Subject Replacement..............................................................................................103
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 4 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
8.0
CLINICAL STUDY MATERIAL MANAGEMENT...................................................103
8.1
Clinical Study Drug ...............................................................................................103
8.1.1
Clinical Study Drug Labeling...........................................................................103
8.1.2
Clinical Study Drug Inventory and Storage ......................................................103
8.1.3
Clinical Study Drug Blinding...........................................................................104
8.1.4
Randomization Code Creation and Storage ......................................................104
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure.................................104
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs.............................104
8.2
Ancillary Supplies .................................................................................................104
9.0
STUDY PROCEDURES.............................................................................................105
9.1
Administrative Procedures.....................................................................................107
9.1.1
Informed Consent Procedure............................................................................107
9.1.2
Inclusion and Exclusion ...................................................................................107
9.1.3
Medical History/Demography ..........................................................................108
9.1.4
Concomitant Medications.................................................................................108
9.2
Clinical Procedures and Assessments.....................................................................108
9.2.1
Physical Examination.......................................................................................108
9.2.2
Height and Weight ...........................................................................................108
9.2.3
BMI .................................................................................................................108
9.2.4
Vital Signs .......................................................................................................109
9.2.5
12-Lead ECGs .................................................................................................109
9.2.6
Wearable Devices (ABPM 
)..............................................110
9.2.7
Study Drug Administration ..............................................................................110
9.2.8
C-SSRS............................................................................................................110
9.2.9
......................................................................................110
9.2.10 AE Monitoring.................................................................................................111
9.2.11 Laboratory Procedures and Assessments ..........................................................111
9.3
PK, 
 
 Measurements..................................................................114
9.3.1
PK Measurements............................................................................................115
9.3.2
Efficacy Measurements........................................................................116
9.3.3
Biomarker Measurements.................................................................................120
9.4
Confinement ..........................................................................................................122
9.5
Childbearing Status and Methods of Contraception................................................122
9.5.1
Women of Childbearing Potential ....................................................................122
9.5.2
Women of Nonchildbearing Potential...............................................................122
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 5 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
10.0
ADVERSE EVENTS ..................................................................................................123
10.1
Definitions and Elements of AEs ...........................................................................123
10.1.1 SAEs................................................................................................................125
10.1.2 Special Interest AEs.........................................................................................126
10.2
AE Procedures.......................................................................................................126
10.2.1 Assigning Severity/Intensity of AEs.................................................................126
10.2.2 Assigning Causality of AEs..............................................................................126
10.2.3 Start Date.........................................................................................................126
10.2.4 End Date..........................................................................................................127
10.2.5 Pattern of AE (Frequency) ...............................................................................127
10.2.6 Action Taken With Study Treatment................................................................127
10.2.7 Outcome ..........................................................................................................127
10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs ................................................................................................................128
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...130
11.0
STATISTICAL METHODS........................................................................................130
11.1
Statistical and Analytical Plans ..............................................................................130
11.1.1 Analysis Sets....................................................................................................131
11.1.2 Analysis of Demography and Other Baseline Characteristics ...........................132
11.1.3 PK Analysis .....................................................................................................132
11.1.4 Efficacy
 Analysis.......................................................................................132
11.1.5
....................................................................................133
11.1.6 Safety Analysis ................................................................................................134
11.2
IA..........................................................................................................................135
11.3
Determination of Sample Size................................................................................135
12.0
QUALITY CONTROL AND QUALITY ASSURANCE.............................................136
12.1
Study Site Monitoring Visits..................................................................................136
12.2
Protocol Deviations................................................................................................136
12.3
Quality Assurance Audits and Regulatory Agency Inspections ..............................137
13.0
ETHICAL ASPECTS OF THE STUDY......................................................................137
13.1
IRB and/or IEC Approval ......................................................................................137
13.2
Subject Information, Informed Consent, and Subject Authorization .......................138
13.3
Subject Confidentiality ..........................................................................................139
13.4
Publication, Disclosure, and Clinical Study Registration Policy .............................140
13.4.1 Publication and Disclosure...............................................................................140
13.4.2 Clinical Study Registration...............................................................................140
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 6 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
13.4.3 Clinical Study Results Disclosure.....................................................................140
13.5
Insurance and Compensation for Injury..................................................................140
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.......................................141
14.1
Administrative Information....................................................................................141
14.1.1 Study Contact Information ...............................................................................141
14.1.2 Investigator Agreement....................................................................................142
14.1.3 Study-Related Responsibilities.........................................................................143
14.1.4 List of Abbreviations .......................................................................................144
15.0
DATA HANDLING AND RECORDKEEPING..........................................................146
15.1
CRFs (Electronic and Paper)..................................................................................146
15.2
Record Retention ...................................................................................................147
16.0
REFERENCES............................................................................................................148
LIST OF IN-TEXT TABLES
Table 3.a
Schedule of Study Procedures for Screening Through Day 15 (PART A, 
Cohort A1-A2)...................................................................................................30
Table 3.b
Applicable PK, 
 and Safety Assessment Timing for Screening Through 
Day 15 (PART A, Cohorts A1-A2) ....................................................................34
Table 3.c
Schedule of Study Procedures for Day 16 Through Day 35 (PART A, Cohorts 
A1-A2) ..............................................................................................................35
Table 3.d
Applicable PK, 
 and Safety Assessment Timing for Day 16 Through Day 
35 (PART A, Cohorts A1-A2)............................................................................38
Table 3.e
Schedule of Study Assessment for Screening Through Day 15 (PART B and 
PART C [Cohort C1])........................................................................................39
Table 3.f
Applicable 
 Efficacy and Safety Assessment Timing: Screening 
Through Day 15 (PARTs B-C)...........................................................................43
Table 3.g
Schedule of Study Procedures for Day 16 Through Day 32 (PART B and 
PART C)............................................................................................................44
Table 3.h
Applicable 
 Efficacy and Safety Assessment Timing for Day 16 
Through Day 32 (PARTs B-C)...........................................................................47
Table 3.i
Schedule of Study Procedures for Day 33 Through Day 63 (PARTs B-C)..........48
Table 3.j
Applicable 
 and Safety Assessment Timing for Day 33 Through Day 
63 (PARTs B-C) ................................................................................................52
Table 3.k
Schedule of Study Procedures for Screening Through Day 15 (Cohorts D1 and 
D2) ....................................................................................................................53
Table 3.l
Applicable PK, 
 and Safety Assessment Timing for Screening Through 
Day 15 (PART D, Cohorts D1 and D2)..............................................................57
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 7 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Table 3.m
Schedule of Study Procedures for Day 16 Through Day 35 (PART D, Cohorts 
D1 and D2) ........................................................................................................58
Table 3.n
Applicable PK, 
 and Safety Assessment Timing for Day 16 Through Day 
35 (PART D, Cohorts D1 and D2)......................................................................61
Table 6.a
Planned Study Cohorts and Dose Levels ............................................................78
Table 6.b
Relative Timing for Initiation of Study Parts......................................................79
Table 6.c
Overview of the Study Schedule ........................................................................81
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................97
Table 9.a
Primary Specimen Collections .........................................................................114
Table 10.a
Takeda Medically Significant AE List..............................................................125
LIST OF IN-TEXT FIGURES
Figure 2.a
Study Schematic (PART A) ...............................................................................25
Figure 2.b
Study Schematic (PARTs B-C) ..........................................................................27
Figure 2.c
Study Schematic (PART D) ...............................................................................29
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator...................................................................150
Appendix B
Elements of the Subject Informed Consent.......................................................152
Appendix C
Investigator Consent to the Use of Personal Information ..................................155
Appendix D
Pregnancy and Contraception...........................................................................156
Appendix E
ICSD-3 Diagnostic Criteria for Narcolepsy ......................................................160
Appendix F
List of Inhibitors and Inducers of CYP3A ........................................................161
Appendix G
Criteria for Identification of Markedly Abnormal Laboratory 
Values-Hematology and Serum Chemistry.......................................................162
Appendix H
Criteria for Identification of Markedly Abnormal Laboratory Values for Vital 
Signs................................................................................................................163
Appendix I
Criteria for Identification of Markedly Abnormal Laboratory Values for ECGs
........................................................................................................................164
Appendix J
Protocol History...............................................................................................165
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 8 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc.,
95 Hayden Avenue 
Lexington, MA 02421, 
United States
Compound: TAK-994
Protocol Title: A Randomized, Double-Blind, 
Placebo-Controlled, Multiple Rising Oral Dose Study to Evaluate 
the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of TAK-994 in Patients With Narcolepsy 
With or Without Cataplexy (Narcolepsy Type 1 or Narcolepsy 
Type 2)
IND No.: 142658
EudraCT Number: 2020-000777-24
Study Identifier: TAK-994-1501
Phase: 2
Study Design:
This is a phase 2, randomized, double-blind, placebo-controlled study to assess the safety, tolerability, 
pharmacokinetics (PK), 
 of multiple oral doses of TAK-994 administered to subjects 
with narcolepsy type 1 (NT1) or type 2 (NT2). The study will be conducted in 4 parts (A, B, C, and D) as follows:
Part A: Part A will include subjects with NT1 only. 
In Cohort A1 subjects will receive TAK-994 or matching placebo twice daily (BID) (with randomization ratio of 2:1) 
orally as a tablet formulation for 28 days; Cohort A1 will enroll 18 subjects. Sentinel dosing on the first 9 subjects 
(Cohort A1a) will be performed. Dosing for the next 9 subjects (Cohort A1b) may be adjusted based on the safety 
and/or efficacy data from the first 9 subjects. Overall randomization ratio for the 18 subjects in Cohort A1 will remain 
at 2:1. Based on Cohort A1 data, decision to enroll Cohort A2 will be made.
Cohort A2 is an optional cohort that, if executed, may enroll 9 to 18 subjects. Based on the Cohort A1 data, if 
additional data are needed, 9 subjects will be randomized in a 2:1 ratio to receive oral TAK-994 at the determined dose 
level or placebo in a double-blinded fashion. Based on the data from these first 9 subjects, an additional 9 subjects may 
be enrolled in this cohort in a 2:1 ratio. In both cohorts, subjects will be enrolled to receive TAK-994 BID or matching 
placebo orally as a tablet formulation for 28 days. 
Part B: Part B will enroll approximately 112 subjects with NT1 for 56 days of treatment. Part B will have 4 parallel 
arms with subjects randomized to 1 of 3 different TAK-994 dose levels (dose 1, 2 or 3) or placebo in 1:1:1:1 ratio, to 
receive TAK-994 or matching placebo BID for 56 days. In each arm, approximately 21 to 28 subjects will be enrolled. 
Doses will be determined based on the available and emerging safety, tolerability, PK, 
 data from Part A. See 
Section 6.1 for details.
Part C (China-specific): Part C will enroll 12 to 18 subjects with NT1 in a single Cohort (C1) with a ratio of 2:1 to 
receive TAK-994 BID or matching placebo for 56 days. See Section 6.1 for details.
Part D: Part D will include subjects with NT2. Subjects will be randomized in a ratio of 2:1 to receive TAK-994 BID 
or matching placebo orally for 28 days. Sentinel dosing on the first 9 subjects (Cohort D1a) will be performed. Dosing 
for the next 9 subjects (Cohort D1b) may be adjusted based on the safety and/or efficacy data from the first 9 subjects. 
Overall randomization ratio for the 18 subjects in Cohort D1 will remain at 2:1. See Section 6.1 for details.
Cohort D2 is an optional cohort that, if executed, may enroll 9 to 18 subjects. Based on the Cohort D1 data, if 
additional data are needed, Cohort D2 will enroll 9 subjects, which will be randomized with a ratio of 2:1 to receive 
oral TAK-994 at the determined dose level or placebo in a double-blinded fashion. Based on the data from these first 9 
subjects, an additional 9 subjects may be enrolled in this cohort in a 2:1 ratio. In both cohorts, subjects will be enrolled 
to receive TAK-994 BID or matching placebo) orally as a tablet formulation for 28 days. 
For Part B, the randomization will be stratified by baseline weekly cataplexy rate (WCR) (<8 vs ≥8) and 
regions/countries (ie, North America, Japan, South Korea, and Europe). 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 9 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
For Part C, the randomization will be stratified by baseline WCR (<8 vs ≥8). 
For other parts, the randomization will be stratified by regions/countries (North America, Japan, South Korea, and 
Europe.
Both blinded and unblinded data review will be performed by the sponsor at the end of each cohort for those cohorts 
that will be run sequentially. In these data reviews, available safety, tolerability, and PK 
 data will be used to 
determine the dosing regimen for the subsequent cohort(s). 
Part A and Part D:
For subjects in Parts A and D, there will be 3 periods including screening (up to 45 days, including a baseline period), 
study treatment (Days 1-28), and follow-up (Day 29 to 35, ±2 days). During the screening period, subjects will 
undergo screening assessments to determine eligibility. 
After the initial screening visit, eligible subjects must discontinue prior medication following the guidelines below (as 
applicable for each subject):
1.
Stimulant medications: minimum of 7 days or 5 half-lives before Day -2 check-in.
2.
Anticataplexy medications (Part A subjects only): The anticataplexy medication washout should start at least 21 
days before Day -2 to allow for confirmation of cataplexy eligibility criterion. See Section 9.3.2.7 for details.
3.
Sodium, and/or multisalt oxybate: at least 4 weeks before Day -2 check-in.
For subjects in Part A not taking any medications that require washout at screening, the 14 consecutive days of 
recording of daily cataplexy may commence at any time after the screening visit.
Subjects will check-in and remain as inpatients between Days -2 to 2. Baseline assessments will occur on Days -2 to 
Day 1 before randomization and dose. Subjects who met all selection criteria will be randomized on Day 1 to receive 
TAK-994 or matching placebo for 28 days. Randomized subjects will stay overnight in clinic on days as indicated in 
Section 3.0, Schedule of Study Procedures. Subjects will need to travel to the clinic for the fitting of ABPM device. 
Alternatively, the site staff may consider confining the subject the evening before fitting of the ABPM device 
according to subject and site preferences. The second scenario may require additional stays at the clinic (see Section 
3.0 and Section 9.2.6 for details). 
On other days during the treatment period, subjects will continue TAK-994 or placebo at home. Study assessments and 
visits will be conducted throughout the study as described in the Schedule of Study Procedures. A follow-up visit will 
be conducted at Day 35 (±2 days). Blood samples for PK assessment will be collected at specified timepoints over the 
duration of treatment. 
Part B and Part C:
For subjects in Part B and C, the study will consist of 3 periods including screening (up to 45 days, including a baseline 
period), study treatment (Days 1-56), and follow-up (Day 57-63 ±2 days). During the screening period, subjects will 
undergo screening assessments to determine eligibility. After the initial screening visit, eligible subjects must 
discontinue prior medication following the guidelines below (as applicable for each subject):
1.
Stimulant medications: minimum of 7 days or 5 half-lives before Day -2 check-in
2.
Anticataplexy medications: The anticataplexy medication washout should start at least 21 days before Day -2 to 
allow for confirmation of cataplexy eligibility criterion. See Section 9.3.2.7 for details. 
3.
Sodium, and/or multisalt oxybate: at least 4 weeks before Day -2 check-in.
For subjects not taking any medications at screening that require washout, the 14 consecutive days of recording of 
daily cataplexy may commence at any time after the screening visit.
Subjects will then check-in and remain as inpatient between Days -2 to 2. Baseline assessments will occur on Days -2 
to Day 1 prior to randomization. Subjects who meet all selection criteria will be randomized on Day 1 to receive 
TAK-994 or matching placebo for 56 days. Randomized subjects will stay overnight in clinic on the days indicated in 
the schedule of assessments in Section 3.0 of this protocol. On other days during the treatment period, subjects will 
continue TAK-994 or placebo at home. Study assessments and visits will be conducted throughout the study period 
according to Section 3.0, Schedule of Study Procedures. A follow-up visit will be conducted at Day 63 (±2 days).
Blood samples for PK assessment will be collected at specified timepoints over the duration of treatment and 
follow-up. Safety and tolerability will be evaluated in all study parts by adverse events (AEs), clinical laboratory 
For non-commercial use only


For non-commercial use only


For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 12 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Main Criteria for Inclusion:
To be eligible for randomization on Day 1, subjects must:

Be male or female, aged 18 to 65 years (inclusive), at the time of informed consent.

Be judged in good health by the investigator based on clinical evaluations including laboratory safety tests. See 
Section 7.1 for details. 

Have a body mass index ≥17.0 and ≤40.0 kg/m2 at the screening visit).

Have a diagnosis of NT1 (Parts A, B, and C) or NT2 (Part D) (as per International Classification of Sleep 
Disorders-3rd Edition) made by
multiple sleep latency test (MSLT) performed within the past 10 years 
meeting the minimal acceptable criteria for the proper performance of the 
MSLT as outlined by ICSD-3 
criteria. Note: If there is a potential subject with a diagnosis of NT1 or NT2 whose diagnostic
MSLT was 
performed more than 10 years ago or is not available, special exemptions, ie, ability of the site to repeat the 
diagnostic
MSLT will be considered on a case-by-case basis after discussions between the investigator and 
the sponsor or designee.

Have ≥10 ESS score at Day -1. 

Part A: The human leukocyte antigen (HLA) genotype should test positive for HLA-DQB1*06:02 - (positive 
results for either homozygous or heterozygous alleles will be considered "positive" and acceptable). However, if 
the HLA test is negative (ie, negative for the heterozygous allele) and the PI feels strongly that the subject has 
narcolepsy with cataplexy (NT1) then a discussion should be initiated between the PI and the sponsor or 
designee about the advisability of doing a spinal tap to determine the subject’s cerebrospinal fluid (CSF) orexin-1 
(OX-1) level. If the CSF result shows the OX-1 concentration is either less than or equal to 110 pg/mL, or less 
than one-third of mean values obtained in normal subjects with the same standardized assay, then the diagnosis of 
NT1 is established allowing the subject to be enrolled and randomized. If the CSF OX-1 concentration is >110 
pg/mL then the subject will not be allowed to continue in the study. Subjects previously excluded in Part A for 
being HLA negative will not be included in Part B.

Parts B and C: HLA genotyping will be done for these subjects as well; however, HLA test results are not a study 
entry criteria. Subjects who present with CSF testing results indicating OX-1 concentration either less than or 
equal to 110 pg/mL, or less than one-third of mean values obtained in normal subjects with the same standardized 
assay, may be considered for enrollment into Parts B and C after a discussion with the sponsor or designee. For all 
subjects in Parts B and C, site staff will complete the cataplexy questionnaire during screening. This questionnaire 
along with a copy of the most recent
MSLT report will be submitted to the sponsor for adjudication by a 
committee of experts in the field of narcolepsy/cataplexy to be chosen by the sponsor. This committee will to 
determine eligibility for the study and the committee’s determination will be final for study entry criteria. 
Additional documentation may be requested by the sponsor.

For Parts A, B, and C, during the screening period, the subject must have ≥4 partial or complete episodes of 
cataplexy/week (WCR), averaged over 2 weeks (14 consecutive days) minimum. WCR recording taken during 
the following period will be considered for study eligibility: after the patient has stopped taking anticataplexy 
medications for at least 7 days (minimum 7-day washout) and completed before study Day -2. Refer to Section 
9.3.2.7 for details.

Be willing to discontinue all medications used for the treatment of NT1 or NT2.

BP <140 mmHg (systolic) and <90 mmHg (diastolic). The subject may have a history of hypertension and be on 
antihypertensive medication treatment as long as the BP meets these criteria. BP measurements should be 
obtained after the subject has been resting for a minimum of 10 minutes and will be repeated 3 times. The median 
BP obtained will be used.
Main Criteria for Exclusion:
A subject must be excluded from participating in the study if the subject:

Has a positive pregnancy test or is a lactating/nursing female subject.

Has a known hypersensitivity to any component of the formulation of TAK-994 or related compounds.

Has a risk of suicide according to endorsement of Item 4 or 5 of the screening/baseline visit Columbia Suicide 
Severity Rating Scale and/or has made a suicide attempt in the previous 12 months.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 13 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL

Has a screening ECG with a QT interval with Fridericia’s correction method >450 ms (men) or >470 ms 
(women).

Has a resting pulse rate outside of the range of 40 to 100 beats per minute, confirmed on repeat testing within a 
maximum of 30 minutes. 

Has renal creatinine clearance ≤50 mL/min.

Has LFTs (alanine aminotransferase, aspartate aminotransferase) higher than 1.5× ULN at screening. 

Is an excessive (>600 mg/day) caffeine user 1 week before the study screening.

Has a history of cancer (does not apply to carcinoma in situ that has been resolved without further treatment or 
basal cell skin cancer); these subjects may be included after approval by the sponsor or designee.

Has past or current epilepsy or seizure, except for febrile seizure in childhood.

Has a lifetime history of major psychiatric disorder (such as bipolar disorder or schizophrenia), a current active 
major depressive disorder (MDD), or has had active MDD in the past 6 months.

Has a clinically significant history of head injury or head trauma per the judgment of the investigator.

Has a history of cerebral ischemia, transient ischemic attack, intracranial aneurysm, or arteriovenous 
malformation; known coronary artery disease, a history of myocardial infarction, angina, cardiac rhythm 
abnormality, or heart failure.

Has current or recent (within 6 months) gastrointestinal disease expected to influence the absorption of drugs. See 
Section 7.2 for details.

Subjects on fluoxetine (any dose) or on ≥300 mg per day of venlafaxine will be excluded due to the drug’s long 
elimination half-life or clinically significant tapering/washout difficulties. See Section 7.3 for a complete list of 
medications that are not allowed during the treatment period and the guidelines for washout for stimulant, 
anticataplexy, antidepressant medications and sodium, and/or multisalt oxybate, when applicable. 

Be unwilling to abstain from driving and operating dangerous or hazardous machinery during study participation, 
starting from when narcolepsy medications are discontinued and extending until after the follow-up visit (Day 35 
±2 days or Day 63 ±2 days as applicable).

Has a medical disorder (including moderate to severe sleep apnea syndrome with or without treatment with 
mandibular advanced device hypoglossal nerve stimulation and/or positive airway pressure therapy), other than 
narcolepsy, associated with excessive daytime sleepiness, or has any other medical condition (eg, anxiety, 
depression, epilepsy, heart disease, or significant hepatic, pulmonary, or renal disease) that requires the subject to 
take excluded medications or at the time of screening the subject is being treated with nasal /oro-nasal positive 
airway pressure for any reason. See Section 7.2 for details.

Has a usual bedtime later than 2400 (12:00 AM, midnight) or an occupation requiring nighttime shift work or 
variable shift work within the past 6 months or travel within more than 3 time zones, within 14 days before Study 
Day -2.

The subject has a nicotine dependence that is likely to have an effect on sleep (eg, a subject who routinely 
awakens at night to smoke) and/or an unwillingness to discontinue all smoking and nicotine use during the 
confinement portions of the study.
Main Criteria for Evaluation and Analyses:
PART A and PART D
Primary Endpoints
The primary endpoints assessing safety and tolerability are:

Number of subjects with at least 1 treatment-emergent AE (TEAE) during the study.

Number of subjects with at least 1 markedly abnormal value (MAV) for post dose laboratory values during the 
study.

Number of subjects with at least 1 MAV for vital signs during the study.

Number of subjects with at least 1 MAV for ECGs during the study.
Secondary Endpoints
The secondary endpoints assessing the PK of TAK-994 are:
For non-commercial use only


For non-commercial use only


For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 16 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Sample Size Justification:
PARTS A, C and D:
In Parts A, C and D, the number of subjects planned are not based on statistical hypothesis testing consideration. They 
are considered sufficient for dose selection under a typical multiple rising dose design. 
PART B: 
In Part B, change from baseline in the mean sleep latency, change from baseline in the total ESS score and postdose 
WCR will be used to evaluate the true TAK-994 effect on delaying the sleep onset (>14 minutes prolongation over 
placebo), reducing ESS (>8 points reduction over placebo) and reducing WCR (>50% reduction over placebo) at a 
dose level.
A sample size of 21 in each group will have 98% power to detect a 14-minute difference in means of change from 
baseline between a TAK-994 dose group and placebo in sleep latency using a 2-sample t-test with a 5% 2-sided 
significance level. The power to detect an 8-point reduction in means of change from baseline between a TAK-994 
dose group and placebo in the total ESS score is estimated to be approximately 95% using a 2-sample t-test with a 5% 
2-sided significance level. The power to detect a 50% reduction in WCR from that of placebo group is estimated to be 
approximately 93% using a 2-incidence-rate ratio test using Poisson model with a 5% 2-sided significance level.
A fixed sequence of tests with MWT at high and middle doses first followed by ESS at high and middle doses and 
WCR at high and middle doses will be applied. The overall power for the entire testing procedure is approximately 
75% (the square of the product of the power of each individual test at a dose level, 98%, 95%, and 93% respectively) 
under the assumption that these 3 endpoints are independent at difference dose levels. The overall power may be 
higher or lower than 75% depending on the assumed correlation structure of these 3 endpoints. There is no known 
reliable data to support any particular assumption on the correlation structure.
To allow for a 25% dropout rate, 28 subjects per group will be enrolled for Part B. The enrollment can be stopped once 
the number of evaluable 21 subjects is reached. A blinded sample size re-estimation will be performed before Part B 
starts. The change in the sample size of Part B after the re-evaluation, along with justification, will be documented in 
the clinical study report. 
The SD for the change from baseline in the sleep latency is assumed to be 11 minutes. The SD for the change from 
baseline in the ESS score is assumed to be 7 points. The incidence rate of WCR at baseline is assumed to be 3.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 17 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
1.1
Protocol Amendment 3 Summary of Changes
Protocol Amendment 3 Summary and Rationale:
This section describes the changes in reference to the protocol incorporating Amendment 3. The 
primary reasons for this amendment are to:

Updated to include recent clinical and nonclinical study data. 

Change the study eligibility criteria to better define how the presence of cataplexy is 
established for participants in Part B and C cohorts.

Clarify and revise several protocol sections, including the Schedule of Study Procedures to 
allow more flexibility for the study participants and the site personal.

Revise the statistical analysis strategy to reduce the number of times the sponsor  unblinded 
team reviews the data.
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only.
Protocol Amendment 03
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
1.
Throughout the document
Text has been edited to provide 
additional guidelines.
To provide more guidance to 
the site, so that data can be 
collected consistently, 
allowing for some flexibility 
for the subject’s travel etc.
2.
Section 1.0 STUDY SUMMARY
Section 6.0 Study Design
Section 8.1.4 Randomization Code 
Creation and Storage
Overall study description changed 
to provide clarity around start of 
each part and cohort in relation to 
the first cohort in Part A.
For Cohort A1, new term Cohort 
A1a and Cohort A1b have been 
added for clarity.
For Cohort D1, new term Cohort 
D1a and Cohort D1b have been 
added for clarity.
South Korea has been added to the 
list of countries where this study 
will be conducted. 
To provide further guidance 
about sentinel cohorts dosing. 
New country has been added 
where this study will enroll 
subjects.
For non-commercial use only


For non-commercial use only


For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 20 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Protocol Amendment 03
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 5.1.6 Additional/ 
Exploratory Objectives--
 
Section 5.2.3
Additional/Exploratory 
Endpoints-
Section 5.2.6
Additional/Exploratory Endpoints-
Section 11.1.6.4 Other Safety 
Parameters
10.
Section 1.0 STUDY SUMMARY
Section 11.1.4 Efficacy
 
Analysis
Section 11.3 Determination of 
Sample Size
Change in statistical 
consideration has been explained.
Part B is a dose-ranging part 
designed to better 
characterize the efficacy and 
safety of TAK-994 to inform 
late phase development. A 
fixed sequence statistical 
hypothesis testing procedure 
will be applied to evaluate the 
efficacy of TAK-994 at 3 
dose levels via key efficacy 
endpoints, MWT, ESS, & 
WCR, while maintaining the 
overall family-wise type 1 
error rate at 0.05 level.
11.
Section 1.0 STUDY SUMMARY
Section 6.0 STUDY DESIGN AND 
DESCRIPTION
Section 8.1.4 Randomization Code 
Creation and Storage
Randomization in Part B and 
stratification criteria has been 
added.
Update has been made
12.
Section 1.0 STUDY SUMMARY
Section 3.0 SCHEDULES OF 
STUDY PROCEDURES ABPM 
footnotes in Table 3.a, Table 3.c, 
Table 3.e, Table 3.g, Table 3.i, 
Table 3 k, Table 3 m
Section 7.4.1 Dosing Instructions
Section 9.2.6.1 ABPM
Ambulatory blood pressure 
monitoring guidance text has been 
revised. 
ABPM guideline text has
been modified to clarify 
procedure that should be used 
for this study and because of 
these modifications additional 
flexibility was added for the 
subjects and the sites.
For non-commercial use only


For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 22 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Protocol Amendment 03
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
18.
Section 3.0 SCHEDULES OF 
STUDY PROCEDURES
Table 3.a, Table 3.c, Table 3.e, 
Table 3.i, Table 3.k, Table 3.m
Text has been added to further 
clarify timing of alcohol screens 
when overnight stay does not 
occur.
To further clarify timing of 
alcohol screens when 
overnight stay does not occur.
19.
Section 3.0 SCHEDULES OF 
STUDY PROCEDURES
Table 3.a, Table 3.c, 
Table 3.e,Table 3.i, Table 3.k, 
Table 3 m
Text has been added to further 
clarify timing of urine drug screen 
when overnight stay does not 
occur.
20.
Section 3.0 SCHEDULES OF 
STUDY PROCEDURES
Table 3 f, Table 3.l, 
A practice assessment of 
cognitive testing has been added 
on Day -2 to familiarize the 
subjects with the task 
requirements.
Update has been made
21.
Section 4.1.3 Clinical Study 
Experience
Text has been revised with 
recently completed phase 1 study 
(TAK-994-1001) unblinded data.
Update has been made
22.
Section 6.1 Study Design
Section 6.2 Dose Selection and 
Cohort Progression
Section 6.3.2 Rationale for Dose
Text have been revised regarding 
the dose selection rules, and dose 
rationale, 
Revision and update
23.
Section 2.0 STUDY 
SCHEMATICS Figure 2.b
Section 3.0 SCHEDULES OF 
STUDY PROCEDURES
Table 3.e (PARTs B and C)
Section 6.1 Study Design
Section 9.3.3.2 CSF Orexin 
Measurements (FOR Subjects with 
NT1 only)
Additional text has been added to 
clarify that cerebrospinal fluid 
(CSF) testing will not be offered if 
such testing is not approved by 
local health authorities.
Update has been made
24.
Section 6.5.5.1 Criteria for 
Premature Termination or 
Suspension
This revision was done to revise
stopping criteria for Part B to 
account for the multiple arm, 
parallel nature of Part B which 
includes 112 subjects.
Update has been made
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 23 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Protocol Amendment 03
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
25.
Section 1.0 STUDY SUMMARY
Section 7.1 Inclusion Criteria
Inclusion criterion #13:
Lower limit of BMI for study 
entry has been changed from 18 to 
17 kg/m2 to consider the patient 
population in Asia.
Lower limit of BMI for study 
entry has been changed from 
18 to 17 kg/m2 to consider 
patient population in Asia.
26.
Section 7.2 Exclusion Criteria
Exclusion criterion #1:
Study entry criteria have been 
clarified for subjects who have 
recently participated in other 
studies that may be 
noninterventional or have 
required a participant to take an 
investigational medicinal product.
Update has been made
27.
Section 1.0 STUDY SUMMARY
Section 7.2 Exclusion Criteria
Exclusion criterion #11:
Based on the safety results from 
Study TAK-994-1001, study 
entry criteria for liver function 
tests (alanine aminotransferase, 
aspartate aminotransferase) have 
been adjusted.
Update has been made
28.
Section 7.2 Exclusion Criteria
Exclusion criterion #22:
Clarity added to criteria regarding 
“surgical interventions” that are 
exclusionary for this study.
Clarification has been added
29.
Section 7.2 Exclusion Criteria
Exclusion criterion #26:
Flexibility added to allow 
clinician discretion in cases where 
a change in clinical status would 
yield different results.
Update has been made
30.
Section 7.2 Exclusion Criteria
Exclusion criterion #42:
Revised to clarify that the site 
may need to draw a laboratory 
sample (prothrombin time 
[PT]/international normalized 
ratio [INR], activated partial 
thromboplastin time) during the 
screening period to allow subject 
time to read the informed consent 
and to think about agreeing to the 
procedure.
Clarification has been added
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 24 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Protocol Amendment 03
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
31.
Section 7.3.3 Alcohol
Guidance text related to alcohol 
consumption (Parts B and C) has 
been updated.
Update has been made
32.
Section 8.1.6 Accountability and 
Destruction of Sponsor-Supplied 
Drugs
Clarification has been provided 
for unused drug to be returned to 
the site.
Clarification has been added
33.
Section 10.2.8.1 Collection Period
AE collection timepoint has been 
revised to ensure all AEs are 
collected until 30 days or 5.5 
half-lives, whichever is longer, 
because after 5.5 half-lives no 
significant investigational product 
should be circulating for the 
product to be linked to an AE.
Update has been made
34.
Section 4.1.2 Summary of 
Nonclinical Data
New data has been added
Update has been made
35
Appendices G, H and I have been 
added
Appendix G: Criteria for
Identification of Markedly
Abnormal Laboratory
Values-Hematology and Serum 
Chemistry
Appendix H: Criteria for
Identification of Markedly
Abnormal Laboratory Values for 
Vital Signs
Appendix I: Criteria for
Identification of Markedly
Abnormal Laboratory Values for 
ECGs
Clarification has been added
For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 28 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
cFor MWT, confinement will start on evening of Days -2 with MWT done on Days -1 and 1, again on Day 27 with MWT performed on Day 28, and on Day 55 with 
MWT done on Day 56 with discharge on Day 57.
e For subjects participating in the optional CSF sampling, these samples may be collected any day prior to Day -5 so long as they are not collected within 24 hours 
in advance of another study procedure ie APBM. Optional CSF sampling substudy, may not be available in every region. See Section 9.3.3.2 for details.
P
I


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 62 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
4.0
INTRODUCTION
4.1
Background
4.1.1
Disease Background
The orexinergic system is a major wake-promoting system of the brain. It is comprised of 2 types 
of wake promoting orexin (OX) neurons, localized in a specific region of the lateral and posterior 
hypothalamus and have excitatory projections to wide areas of the central nervous system (CNS) 
including the basal forebrain and brainstem nuclei involved in maintaining wakefulness (ie, 
cholinergic neurons if the reticular activating system [RAS], 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.
Two orexinergic neuropeptides, OX-A and OX-B, have been identified to date. These 
neuropeptides exert effects via 2 types of G-protein coupled OX receptors: orexin type-1 receptor
(OX1R) and orexin type-2 receptor (OX2R). OX-A has a high affinity to OX1R and OX2R, and 
OX-B has a high affinity to OX2R. The 2 types of OX receptors have a distinct distribution in the 
arousal network: the locus coeruleus contains only OX1Rs, the tuberomammillary nucleus
contains only OX2Rs, and both receptor types occur in the dorsal raphe nucleus and ventral 
tegmental area. The 2 types of OX receptors also make distinct contributions to the regulation of 
arousal. OX2Rs in the tuberomammillary nucleus are essential for the maintenance of 
wakefulness, whereas both receptor types are required for the inhibition of rapid eye movement 
(REM) sleep [1].
The pathological loss of orexinergic neurons is associated with the development of NT1 [2].
Narcolepsy is a rare, acquired, chronic neurologic disorder that alters sleep-state stability. The 
cardinal symptom of narcolepsy is excessive daytime sleepiness (EDS), described as a sudden 
overpowering need to sleep during the day normal periods of alertness. Intrusion of REM sleep 
phenomena into wakefulness also can also occur. These REM-like phenomena may include 
cataplexy (sudden loss of muscle tone triggered by strong emotions), hypnagogic/hypnopompic 
hallucinations (hallucinatory phenomenon that can include mental, auditory, tactile or uncinate 
events typically occurring during at the transitions into and out of sleep), and sleep paralysis 
(similar to cataplexy, ie, acute onset of muscle atonia accompanied by a somatic feeling of general 
paralysis, usually occurring during the transition from wakefulness into sleep). Disturbed
nighttime sleep (DNS) is a common narcolepsy related symptom, with difficulty maintaining 
continuous nocturnal sleep manifested by frequent awakenings with prompt return back into sleep. 
Together, these 5 clinical features (EDS, cataplexy, hypnagogic/hypnopompic hallucinations, 
sleep paralysis, and DNS) comprise the narcolepsy symptom pentad. It has been estimated that 
only 20% to 30% of patients have all components of the pentad at any one time. NT2 or narcolepsy 
without cataplexy accounts for 20% to 40% of all cases of narcolepsy but it is important to know 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 63 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
that cataplexy onset can occur many years after the onset of EDS (cases of 10- to 20-year delay 
have been described).
Narcolepsy has been classified by the International Classification of Sleep Disorders, 3rd edition 
(ICSD-3) diagnostic criteria [3,4] as either NT1 or NT2, on the basis of the presence or absence of 
cataplexy and on levels associated with demonstrably absent or low levels of OX1 in the 
cerebrospinal fluid (CSF) (if measured). NT1 is characterized by EDS and the presence of 
cataplexy. CSF levels of OX are absent or less than one-third of normal (typically <110 pg/mL). In 
contrast, patients with NT2 do not have cataplexy, and CSF levels of OX1 are greater than 
one-third the normal value (above 110 pg/mL) for the laboratory doing the assay. Both in NT1 and 
NT2, patients have exhibit sleep-onset REM periods on polysomnography/multiple sleep latency 
test (MSLT) testing and have average sleep onset latencies of the MSLT of <8 minutes averaged 
over 5 naps. Approximately 70% of those with narcolepsy are classified as having NT1.
The pathophysiology of NT1 has a presumed, though unproven, autoimmune basis in individuals 
with a specific genetic predisposition, the most common of which is the HLA DQB1*06:02 [5,6]. 
The proposed etiology involves T-cell-mediated destruction of OX-producing neurons in the 
hypothalamus [6-8]. Loss of OX-producing neurons is reflected by low CSF OX levels [9]. The
pathophysiology of NT2 is not well understood.
Based on the aforementioned data demonstrating that partial or complete OX deficiency plays an 
important role in the development of EDS, OX replacement therapy is expected to improve EDS 
through a pathophysiology-directed mechanism of action. A novel drug that acts to help address 
the deficiency of OX may address the spectrum of narcolepsy symptoms and may have greater 
efficacy than currently approved drugs for EDS and cataplexy.
TAK-994 is a first-in-class, orally available, highly selective OX2R agonist being developed by 
Takeda for the treatment of narcolepsy with or without cataplexy (NT1 or NT2).
4.1.2
Summary of Nonclinical Data
In both OX/ataxin-3 transgenic (Tg) mice and non-Tg mice, oral administration of TAK-994 (1, 3, 
and 10 mg/kg) during the sleep phase (daytime) dose-dependently increased wakefulness time for 
1 hour after dosing. Statistically significant effects in OX/ataxin-3 Tg and non-Tg mice were 
observed at 3 and 10 mg/kg, respectively, with the minimum effective dose approximately 3 times 
lower in OX/ataxin-3 Tg than non-Tg mice. In addition, TAK-994 (3 and 10 mg/kg) administered 
orally to OX/ataxin-3 Tg mice significantly improved fragmentation of wakefulness, decreased the 
number of wakefulness episodes, and increased the duration of wakefulness episodes for 1 hour 
after dosing. The statistically significant effects were observed at 10 mg/kg for the number of 
wakefulness episodes (p≤0.01) and 3 and 10 mg/kg for the duration of wakefulness episodes 
(p≤0.05 at 3 mg/kg, p≤0.01 at 10 mg/kg). TAK-994 (3 mg/kg) also significantly suppressed 
cataplexy-like episodes for 3 hours after administration in OX/ataxin-3 Tg mice in active phase. 
TAK-994 at 30 mg/kg significantly increased wakefulness time for 1 hour after administration in 
wild-type mice in sleep phase (p≤0.05). In contrast, TAK-994 at 30 mg/kg did not significantly 
increase wakefulness time for 1 hour after administration in OX2R knockout mice. These results 
suggest that TAK-994 shows an arousal effect through OX2R activation in mice. In addition, the 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 64 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
arousal effect of TAK-994 was not diminished after 14 days subchronic administration in 
OX/ataxin-3 Tg mice. Thus, TAK-994 may have a low risk of OX2R desensitization. TAK-994 
(3 and 10 mg/kg) was administered orally to monkeys, diurnal animals with monophasic 
sleep/wake patterns, during their sleep phase. TAK-994 at 10 mg/kg significantly increased 
wakefulness time for 8 hours after administration.
In safety pharmacology studies, no CNS effects were observed in a CNS observational battery in 
rats at 50 mg/kg, although biting or licking of the chamber floor or ceiling and/or biting or licking 
of the tail were observed during respiratory measurements at 1 and 2 hours postdose at ≥50 mg/kg. 
Decreased body temperature was noted at ≥200 mg/kg. A decrease in locomotor activity was 
observed in 1 animal at 1000 mg/kg at 4 hours postdose; this animal exhibited the lowest body 
temperature. These behavioral changes were considered due to the pharmacological action of 
TAK-994 because OX2R agonists have been reported to increase locomotor activity and bursts of 
stereotypy in rats [10].
In vitro cardiovascular assessments revealed an inhibitory effect of TAK-994 on the human 
ether-à-go-go-related gene (hERG) current at 5 and 50 µg/mL; the half-maximal inhibitory 
concentration was 37.47 µg/mL in hERG-transfected HEK293 cells. In vivo cardiovascular 
studies revealed blood pressure (BP) increases at ≥20 mg/kg (10 mg/kg twice daily [BID]) in 
conscious telemeterized monkeys. Prolongation of the PR interval and shortening of the 
QT/corrected QT intervals observed at ≥100 mg/kg and 1000 mg/kg, respectively, were deemed to 
be of no toxicological importance because of the low magnitude of these changes. During a
1-week study of repeated oral administration of TAK-994 (100 mg/kg) in conscious telemeterized 
monkeys, increased BP and heart rate were observed on the first day of dosing; these findings were 
attenuated on the second dosing day and had disappeared by the final dosing day. Evaluation of 
respiratory function in rats revealed an increased respiratory rate at ≥50 mg/kg, an increased 
minute volume and decreased enhanced pause ([Penh], an index of airway constriction) at 
≥200 mg/kg, and an initially decreased and then increased Penh at 1000 mg/kg.
Plasma protein binding rates for TAK-994 ranged from 94.2% to 98.5% in rats, monkeys, and 
humans. TAK-994 was a substrate for P-glycoprotein (Pgp) but was not a substrate for breast 
cancer resistance protein (BCRP).
Metabolite profiling from in vitro studies showed that TAK-994 is mainly metabolized via 
cytochrome P-450 (CYP)3A4; no human-specific metabolites have been identified from early 
in vitro screening in hepatocytes. Treatment of cryopreserved human hepatocyte cultured 
preparations with TAK-994 (up to 30 μmol/L) showed that TAK-994 has little or no induction 
potency for CYP1A2 but does have induction potency for CYP2B6, CYP2C8, CYP2C9, and 
CYP3A4. TAK-994 inhibited CYP3A4/5 activities with a half-maximal inhibitory concentration 
value of 14 µmol/L (without preincubation) and 9.0 µmol/L (with preincubation) but had little or 
no inhibition for other CYP isoforms (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and 
CYP2D6). A study in human liver microsomes revealed that TAK-994 had direct inhibitory 
effects and some time-dependent inhibitory effects on CYP3A4/5 activity.
Based on in vitro transporter studies, TAK-994 inhibited the Pgp- and BCRP-mediated transport 
of typical substrates with the 50% inhibitory concentrations (IC50) of 11.3 and 30.1 μmol/L. 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 65 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
TAK-994 inhibited the organic anion transporting polypeptide (OATP)1B1-, organic anion
transporter (OAT)3-, organic cation transporter (OCT)1-, multidrug and toxin extrusion 
transporter (MATE)1-, and bile salt export pump-mediated transport of typical substrates with the 
IC50s of from 33.8 to 58.3 μmol/L. TAK-994 also inhibited the OATP1B1- and 
OATP1B3-mediated transport of typical substrates after pre-incubation with TAK-994 for 30 
minutes with the IC50s of 3.28 and 22.7 μmol/L. TAK-994 did not inhibit the OAT1-, OCT2-, and 
MATE2-K-mediated transport of typical substrates up to the maximum concentration of 100 
μmol/L (IC50 >100 μmol/L). 
At a mean Cmax value of 756 ng/mL in plasma (1.61 μM; unbound Cmax ~ 0.061 μM) following oral 
administration of TAK-994 200 mg BID in human subjects, the potential exists for drug-drug 
interactions when TAK-994 is coadministered with drugs that are inhibitors or inducers of 
CYP3A or Pgp or substrates of CYP3A, Pgp, BCRP or OATP1B1 based on Food and Drug 
Administration (FDA) Guidance for Industry “In Vitro Drug Interaction Studies - Cytochrome 
P450 Enzyme- and Transporter-Mediated Drug Interactions”. 
A 13-week repeat dose toxicity in rats at dose levels of 0, 50, 150, and 1500 mg/kg/day with a 
4-week recovery period was conducted. No deaths or moribundities occurred. Adverse fluorosis 
was observed at 1500 mg/kg/day with evidence of increased fluoride levels in the incisors and 
plasma. Fractures and whitening of the incisors were observed from Weeks 9 and 11, respectively 
and throughout the recovery period in both sexes at 1500 mg/kg/day, and single cell necrosis 
and/or degeneration of the ameloblasts in both sexes and pulp stone in males were observed at the 
end of the dosing period at 1500 mg/kg/day. Basophilic granules were also observed in the femur 
at 1500 mg/kg/day as a fluoride-related precipitation; however, it was not considered to be adverse 
because there was no associated morphological abnormality in the bone. Slight decreases in body
weight gain and food consumption were observed at 150 mg/kg/day and in females at 50 
mg/kg/day with more noticeable decreases at 1500 mg/kg/day that corresponded with the 
fracturing of incisors in the latter part of the dosing period. Nonadverse minimal increased diffuse 
vacuolation was observed in the adrenal gland with no organ weight changes or indication of 
adrenal dysfunction and minimal diffuse hypertrophy of the acinar cells in the submandibular 
gland was observed and considered secondary to the fractured incisors. In the liver, hypertrophy of 
the centrilobular hepatocytes was observed in both sexes at ≥150 mg/kg/day and it was 
accompanied by increased liver weight in females, indicative of an induction of hepatic 
drug-metabolizing enzymes and was considered to be nonadverse.
There were no clinical signs or decreased body weights suggestive of withdrawal signs/symptoms 
during the recovery period, and the adverse findings including the abnormalities in the incisors 
partially or fully recovered following a 4-week recovery period.
Based on the adverse fluorosis of incisors at 1500 mg/kg, the no-observed-adverse-effect level
(NOAEL) of TAK-994 was 150 mg/kg for both sexes. The Cmax and area under the 
concentration-time curve from time 0 to 24 hours (AUC24) mean values at 150 mg/kg/day were 
6030 ng/mL and 78,900 h*ng/mL and 13,200 ng/mL and 198,000 h*ng/mL in males and females, 
respectively, on Day 91.
For non-commercial use only
rac
50, 150, 
0, 150
oribundi
ribun
creased 
reased
re obser
e obse
es at 150
 at 15
th sexes
h sexe
ay. Baso
y. Bas
d precipit
recip
rpholog
phol
n were 
n wer
le decre
e dec
atter pa
atter p


TAK-994
Study No. TAK-994-1501
Page 66 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
A 13-week repeat-dose oral toxicity study in monkeys at dose levels of 0, 30, 100, and 500 mg/kg 
BID (0, 60, 200, and 1000 mg/kg/day) with a 4-week recovery period was conducted. 
Yellow-green stool was observed in males and females at 500 mg/kg BID throughout the dosing 
period that was considered nonadverse because there were no findings suggesting damage to the 
digestive tract. Vomiting was observed several times per animal at 500 mg/kg BID that was 
considered nonadverse because of low frequency and lack of abnormalities (eg, dehydration) in 
the general condition or an imbalance of plasma electrolytes. Slightly low body weight gain was
noted in males at 500 mg/kg BID. Low food consumption was sporadically noted in females at 
≥100 mg/kg BID with no corresponding effects on the body weight. There were observations of 
high ALP in females at 500 mg/kg BID, high triglycerides in males at ≥30 mg/kg BID and females 
at 500 mg/kg BID, low total cholesterol in males at ≥30 mg/kg BID and females at 500 mg/kg 
BID, and low creatine phosphokinase in females at 500 mg/kg BID. These changes were 
considered to be nonadverse because they were slight changes and there were no microscopic 
correlates. Hypertrophy of hepatocytes with an increased liver weight in males and females was 
observed at 500 mg/kg BID and was considered to be associated with the induction of hepatic 
drug-metabolizing enzymes. The analysis of hepatic microsomal drug-metabolizing enzyme 
activity revealed increases in 7-ethoxyresorufin O-deethylase activity (males at ≥30 mg/kg BID 
and females at ≥100 mg/kg BID), aminopyrine N-demethylase activity (males at 500 mg/kg BID 
and females at ≥100 mg/kg BID), and p-nitrophenol uridine 
5ʹ-diphosphate-glucuronosyltransferase activity (females at ≥100 mg/kg BID). Diffuse 
hypertrophy of the follicular cells of the thyroid gland was observed in males at 500 mg/kg BID, 
which might be associated with the induction of hepatic drug-metabolizing enzymes. These 
findings were considered to be nonadverse. There were no clinical signs or body weight changes 
suggestive of withdrawal symptoms during the recovery period, and all TAK-994-related changes 
observed during the dosing period recovered after a 28-day recovery period. Based on these 
results, the NOAEL was 500 mg/kg BID for both sexes. The plasma Cmax of 21,700 and 15,100 
ng/mL, and plasma AUC24 of 307,000 and 155,000 h*ng/mL in males and females, respectively, at 
500 mg/kg BID on Day 91. TAK-994 was not genotoxic in vitro or in vivo. A definitive 
embryo-fetal development study of TAK-994 in pregnant Sprague-Dawley rats at doses of 0 (0.5% 
[w/v] methylcellulose), 30, 100, and 1000 mg/kg/day by once daily (QD) oral gavage was 
completed. Decreases in body weights and food consumption were observed dose-dependently at 
≥100 mg/kg/day, and these changes were especially marked at 1000 mg/kg/day in dams. 
Decreases in body weights and the number of ossified bones were noted in male and female fetuses 
at 1000 mg/kg/day. Based on these results, the NOAEL was 30 mg/kg/day for maternal toxicity 
(Cmax and AUC24 of 3760 ng/mL and 51,600 h*ng/mL, respectively, on gestational day 17) and 
100 mg/kg/day for embryo-fetal toxicity (Cmax and AUC24 of 6990 ng/mL and 103,000 h*ng/mL, 
respectively, on gestational day 17). 
A definitive embryo-fetal development study of TAK-994 in pregnant New Zealand white rabbits 
at doses of 0 (0.5% [w/v] methylcellulose), 20, 50, and 150 mg/kg/day by QD oral gavage was 
completed. Decreased body weights, body weight gain, and food consumption, as well as scant or 
no feces, were noted in does at 150 mg/kg/day. The changes were considered to be the cause of 
abortion observed in 6 does at this dose. At 50 and 20 mg/kg/day, body weight gain between GDs 
7 and 9 was low compared to the control group. However, because these were transient and 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 67 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
minimal changes and there were no TAK-994- related effects on body weight gain throughout the 
dosing period (GDs 7 to 21), they were not considered to be adverse. Adequate evaluation was not 
achieved in embryos/fetuses at 150 mg/kg/day because the number of does decreased to 12 due to 
abortion in 6 does at 150 mg/kg/day. However, at this dose, slightly decreased numbers of ossified 
middle phalanges of the forelimbs and hindlimbs were noted in fetuses of the 12 does with 
sustained pregnancy. Based on these results the NOAEL was 50 mg/kg/day for maternal and 
embryo-fetal toxicity (Cmax and AUC24 of 3310 ng/mL and 15,200 h*ng/mL, respectively, on 
gestational day 20).
In a 1-week, non-pregnant rabbit oral toxicokinetic/tolerability study, decreases in food 
consumption, body weight, and feces were noted at 1000 mg/kg; 1 animal died, and 1 animal was 
euthanized at this dose level. The maximum tolerable dose in this study was 300 mg/kg/day. 
TAK-994 absorption of ultraviolet-visible light at 290 to 700 nanometers was below the threshold 
for direct phototoxicity; thus, no direct phototoxicity is anticipated.
A 4-week repeat-dose toxicity study with TAK-994 was conducted in non-Tg littermates of 
CByB6F1-Tg(HRAS)2Jic (nonTg rasH2) mice (10/sex/group, 8 weeks of age at the start of 
dosing) [Study report B-8529]. TAK-994 was administered by oral gavage at doses of 0 QD, 
300 QD, 2000 QD, and 4000 (2000 BID) mg/kg/day. The purpose of this study was to establish a 
suitable dose range for the 6-month carcinogenicity study in Tg-rasH2 mice. No deaths occurred, 
and no TAK-994-related abnormal clinical signs were observed. At 2000 and 4000 mg/kg/day, 
body weights and food consumption were transiently decreased on Week 1 and/or 2. However, the 
body weights later increased and at the end of the study there were no differences between the 
control group and the 2000 mg/kg/day group although body weights at 4000 mg/kg/day were still 
lower than the control group values. An adverse hepatocellular injury (single cell necrosis of the 
periportal hepatocytes) associated with elevated aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), ALP, and glutamate dehydrogenase (GLDH) in the clinical chemistry 
were observed at ≥300 mg/kg/day. While the single cell necrosis of the periportal hepatocytes was 
observed in several animals in both sexes at 300 mg/kg QD at a minimal grade, increased 
incidences and/or severity (minimal to mild grade) were noted in both sexes at ≥2000 mg/kg QD. 
Additionally, atrophy of hepatocytes and hyperplasia of oval cells which was considered to be a 
regenerative response to the hepatocellular injury were observed in the periportal area at 
≥300 mg/kg QD and at ≥2000 mg/kg/day, respectively. A low blood urea nitrogen, which was 
possibly related to impaired urea cycle function in the liver, was observed in males at 
≥2000 mg/kg/day, suggesting a deteriorated hepatocellular function at ≥2000 mg/kg/day. Other 
than the above, macroscopically large liver size in both sexes at 4000 mg/kg/day, increased liver 
weight in males at ≥2000 mg/kg/day and in females at ≥300 mg/kg/day, and hypertrophy of the 
centrilobular hepatocytes at ≥300 mg/kg/day were observed, which were indicative of induction of 
drug metabolizing enzymes. In the female reproductive organs, atrophy of the ovary, uterus and 
vagina was observed microscopically at ≥2000 mg/kg/day, and these findings indicate the 
disruption of the estrus cycle and are considered adverse. In conclusion, hepatocellular injury 
including single cell necrosis of the periportal hepatocytes at ≥300 mg/kg/day and adverse atrophic 
changes in the female reproductive organs at ≥2000 mg/kg/day were observed; therefore, a 
NOAEL was not established in this study. An additional 4-week repeat-dose toxicity study of 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 68 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
TAK-994 was conducted in nonTg rasH2 mice with a 7-day sacrifice to investigate the effects of 
shorter dose period on TAK-994-induced hepatotoxicity. TAK-994 was administered QD by oral 
gavage to male and female nonTg rasH2 mice (4/group/sex for the 7-day dosing groups and 
10/group/sex for the 4-week dosing groups) at doses of 0, 300, and 2000 mg/kg/day for the 7-day 
dosing groups and 0, 50, 100, and 300 mg/kg/day for the 4-week dosing groups. No deaths 
occurred, and no TAK-994-related abnormal clinical signs were observed in any group. There 
were slight decreases of body weight gain, which resulted in -6%, -8%, and -8% of mean body 
weights in females at 50, 100, and 300 mg/kg/day, respectively, compared to the control value. In 
the liver, atrophy of periportal hepatocytes in males at 300 mg/kg/day and hypertrophy of 
centrilobular hepatocytes in both sexes at 300 mg/kg/day were observed. The hypertrophy of 
centrilobular hepatocytes was in correlation with increased liver weights, which were indicative of 
induction of drug metabolizing enzymes.
No adverse hepatocellular injury such as single cell necrosis of hepatocytes was observed at any 
dose in the 4-week dosing although atrophy of periportal hepatocytes at 300 mg/kg/day was in the 
same direction as that of the previous 4-week study, and thus 300 mg/kg/day was considered to be 
marginal to induce the hepatotoxicity in mice. Therefore, based on the findings in both studies, 
overall NOAEL of TAK-994 for mice was concluded to be 100 mg/kg/day (AUC24 of 17,000 and 
30,600 h*ng/mL in males and females, respectively).
Plasma levels of free fluoride ion were determined in a 1-week repeat-dose study in mice, which 
revealed not only remarkably high concentrations of plasma fluoride in TAK-994 groups on Day 1 
(Cmax [µmol/L] on Day 1: 10.9 for males and 5.9 for females at 0 mg/kg/day, 65.5 for males and 
66.7 for females at 300 mg/kg/day, and 77.2 for males and 85.7 for females at 1000 mg/kg/day), 
but also they were increased after repeated dosing of TAK-994 (Cmax [µmol/L] on Day 7: 5.2 for 
males and 5.1 for females at 0 mg/kg/day, 106.0 for males and 122.5 for females at 300 mg/kg/day, 
and 210.9 for males and 213 for females at 1000 mg/kg/day). Repeated dosing of TAK-994 to 
mice also caused a decrease of plasma TAK-994 exposure concomitantly with findings that were 
indicative of induction of hepatic drug-metabolizing enzymes such as a dose dependent increase of 
liver weights; therefore, the increased fluoride level after the repeated dosing was considered to be 
the result of increased metabolic defluorination of TAK-994 by the induction of hepatic 
drug-metabolizing enzymes.
The in vitro and in vivo metabolic profiles of TAK-994 in humans (in vitro only), mice, rats and 
monkeys suggest marked qualitative and quantitative species differences in TAK-994 metabolism. 
Thus, in mice the proportion of TAK-994 that undergoes the reactive metabolic pathway of 
defluorination/arene oxide formation followed by glutathione conjugation appears to be 
considerably larger than in other species, especially if compared to monkey and human. Based on 
the results of the rat and monkey toxicology studies, in vitro and in vivo metabolite profiling, the
hepatotoxicity observed in non-Tg rasH2 mice appears to be related to species-specific metabolic 
conversion of TAK-994 via a reactive metabolite pathway. In addition, the TAK-994 exposure 
decrease was noted in mice suggesting some enzyme induction involved in the TAK-994 
metabolism. The induction is also considered to involve in the increase of the reactive metabolite 
formation in mice. Therefore, the hepatotoxicity observed in non-Tg rasH2 mice is likely of 
limited relevance to human safety assessment. The human risk of hepatocellular injury is further 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 69 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
mitigated by the fact that there was no liver toxicity detected in either rat or non-human primate 
13-week studies at equal plasma exposures; the mouse liver findings were of minimal severity at 
plasma exposure levels approximately 10-fold above anticipated therapeutically efficacious 
levels; accompanied by monitorable liver enzyme (potentially also free fluoride) changes; and 
would be expected to be readily reversible upon cessation of treatment. 
Please refer to the TAK-994 Investigator’s Brochure (IB) for more information on the 
investigational product.
4.1.3
Clinical Study Experience
Study TAK-994-1001 was the first-in-human (FIH), randomized, double-blind, 
placebo-controlled, single and multiple rising oral dose study to evaluate the safety, tolerability, 
PK, 
 of TAK-994 that was conducted in healthy subjects. Male and female subjects of 
nonchildbearing potential, aged 18 to 55 years (inclusive) were enrolled in Parts A, B, C, E, 
whereas, subjects ≥65 years were enrolled in Part D. 
The data from study TAK-994-1001 reveal no major safety concerns. 
TAK-994 was considered to be safe and well tolerated up to 450 mg single dose and 200 mg BID 
repeat dose both in healthy adults and elderly. The maximum repeated dose tested in healthy 
volunteers was 200 mg twice daily and it was well tolerated. There were no deaths or serious 
adverse events (SAEs) in the study. All reported treatment-emergent adverse events (TEAEs) were 
mild or moderate in severity, except 1 severe TEAE syncope, that was not related to study drug. 
Two subjects discontinued due to TEAEs (1 due to presyncope/near syncope and the other due to 
ALT increased/elevated ALT). 
A higher frequency of renal and urinary TEAEs were reported in subjects receiving TAK-994 
compared with subjects receiving placebo. Renal and urinary adverse events (AEs) were reported 
(incontinence, pollakiuria, micturition urgency, dysuria) in 24 subjects (only 1 subject in the 
placebo group); however, no subjects discontinued due to these AEs. These were mild or moderate 
in intensity and all events resolved. Frequency of these TEAEs was not dose dependent. Therefore, 
the sponsor is including a bladder questionnaire to monitor these symptoms in the current 
amendment. 
A total of 24 subjects (only 2 subjects in placebo group and rest in the TAK-994 group) also 
reported insomnia within the first 2 to 3 days of first dose; however, no subjects discontinued due 
to these AEs. These were mild or moderate in intensity and all events resolved. Higher number of 
insomnias were noted in the TAK-994 treated group compared with the placebo, in a 
dose-independent manner.
BP elevation (approximately 4 to 12 mm Hg on average in systolic BP) was observed on Day 1 at 
some dose levels; however, the elevations were not sustained beyond Day 4. There appears to be 
no clear dose response relationship for BP elevation. 
Pooled aggregate summaries of all cohorts in the healthy volunteer study (TAK-994-1001) of 
GLDH and fluoride assessed change from baseline by visit date. The analysis showed that there 
was no clinically meaningful difference between the active and placebo arms. Three subjects 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 70 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
exposed to TAK-994 had ALT elevations. All events were mild, related, and resolved without 
treatment. One subject in Part E who received TAK-994 200 mg experienced TEAEs of ALT 
increased/elevated ALT (MedDRA PT = Transaminitis) according to liver function test (57 U/L) 
on Day 1. This event was continuous, mild in intensity and considered related to study drug by the 
investigator. The subject did not receive any other dose and discontinued from the study on Day 7.
Following single- and multiple-dose oral administration of TAK-994 to healthy subjects under 
fasted conditions, TAK-994 was readily absorbed into the systemic circulation, with most median 
tmax at 2 hours. After single-dose administration, peak exposure increased near dose 
proportionally, while total exposure increased slightly greater than dose proportionally. At 
steady-state, peak and total exposure of TAK-994 appeared to increase dose proportionally when 
comparing the BID dose regimens where TAK-994 was administered at the same amount for 14 
consecutive days.
After single-dose administration, TAK-994 displayed a multiexponential disposition phase with 
an estimated mean terminal elimination half-life ranging from 3 to 12.5 hours across doses. 
Additionally, there were no apparent dose-related trends in TAK-994 clearance across the groups 
assessed.
TAK-994 exposure does not appear to accumulate after QD or BID dosing in any of the dose 
groups and study parts (≤9%). The only exception was the 120 mg AM/60 mg PM dose group in 
study Part B where it appears to marginally accumulate (≤18%).
Urinary excretion of TAK-994 was less than 0.62% in all dose groups and study parts. Overall, 
urinary excretion of TAK-994 was minimal and not impacted by dose level.
Ingesting a high-fat, high-calorie meal immediately before administering TAK-994, significantly 
increases the mean peak concentration by 53% and total exposure of TAK-994 by 25%. Ingesting 
a standardized, non–high-fat meal with TAK-994, increased mean peak concentration by 42% but 
had no effect on total exposure.
The estimated CSF to plasma concentration ratios for TAK-994 Cmax and AUC at steady-state 
were 2.92% and 2.05%, respectively, which are similar to the previously reported mean plasma 
free fraction of TAK-994, thus indicating TAK-994 readily crosses the blood brain barrier.
Given 120 mg BID TAK-994, healthy elderly subjects appear to have slightly higher TAK-994 
exposure (Cmax and AUCs) by approximately 20% to 60%, compared with healthy subjects of the 
same dose regimen in study Part B.
TAK-994 exposure in Japanese subjects appears similar to those in non-Japanese subjects treated 
with a single dose and repeated doses of TAK-994.
The approximate 50% increase of 4β-hydroxycholesterol to cholesterol ratio in TAK-994–treated 
subjects suggests TAK-994 is a weak CYP3A4/5 inducer.
4.2
Rationale for the Proposed Study Design
Nonclinical pharmacology studies showed that wake-promoting effects of TAK-994 were 
observed following chronic dosing for up to 14 days. The available nonclinical information; 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 71 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
emerging clinical safety, tolerability, and PK profiles of single doses of TAK-994; and results 
from TAK-994-1001 study in healthy subjects support this study, which is designed to evaluate the 
safety, tolerability, PK, 
 of multiple oral doses of TAK-994 in subjects with NT1 and NT2.
Additional rationale relating to the study design, TAK-994 dose administered, and study endpoints 
is provided in Section 6.3.
4.3
Benefit/Risk Profile
This randomized, double-blind, placebo-controlled study will include safety/tolerability, PK, 
 
 evaluations in subjects with NT1 or NT2 after multiple dose oral administration of TAK-994.
Patients with NT1 are deficient in OX and hence are the first individuals who would most benefit
from treatment with an OX2R agonist. If TAK-994 is efficacious for EDS and catalepsy, subjects 
receiving the drug may benefit during the period of study drug administration. Subjects will also
receive medical examinations and information about their overall health. Results of the study are
critical in planning future clinical studies with TAK-994, and it is possible that the information 
obtained in the study will be beneficial to patients with narcolepsy in the future.
In non-clinical pharmacology studies, TAK-994 showed strong wakefulness promoting effects in 
wild type animals who have normal OX levels. This observation, and preliminary 
safety/tolerability data from the recently completed TAK-994-1001 study in healthy subjects 
further support evaluating TAK-994 
 in the NT2 patient population. The NT2 population has 
OX levels that may range from 30% to 100% of normal values.
Safety data informing the risk profile for TAK-994 are limited to the mode of action, data from 
nonclinical toxicology studies, and current and emerging safety and tolerability data from 
TAK-994-1001. Based on nonclinical safety pharmacology data, the primary potential risk is 
increased BP. A safety pharmacology study of TAK-994 in monkeys found mild to moderate 
degrees of transient elevated BP at all doses tested on initial dosing, although effects on BP and 
heart rate were no longer observed at 7 days of dosing. The cardiovascular effects noted in 
preclinical models with OX2R agonists are considered potentially on-mechanism based on 
published literature [11]. To mitigate this risk, BP will be measured frequently in this study;
stopping rules for individual subjects, cohorts, and the overall study as well as the treatment of 
increased BP have been established and are noted in Section 6.5.5.1 and Section 7.5, respectively.
The AEs that have occurred in TAK-994-1001 FIH study have primarily been graded as mild. AEs 
generally increased in number with increasing dose or exposure. The tolerability of 200 mg BID in 
the MRD cohort was acceptable although there were urinary System Organ Class TEAEs. AEs of 
urinary frequency and urgency have been reported, and this will be monitored in the current study.
Other effects in nonclinical studies included vomiting at high doses and minor changes in ECG 
parameters. ECG findings in the study were considered nonadverse and monitoring for these 
events is a standard part of clinical studies. Additionally, it is possible that a long half-life may 
result in insomnia, which has been seen in healthy subjects in Study TAK-994-1001. Though 
insomnia is thought less likely to occur in NT1 patients due to their marked OX deficiency, 
stopping rules have been created for severe and/or persistent insomnia (Section 6.5.5).
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 72 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
The TAK-994-related hepatocellular injury observed in the initial non-Tg rasH2 mice is thought to 
be of limited relevance to human safety risk assessment. A subsequent 1-month study in non-Tg 
rasH2 mice at lower doses provided a NOAEL for the liver findings, which for AUC was 4-fold 
over the maximum expected clinical exposures (120 mg BID). Moreover, there were no adverse 
liver findings in the 13-week Good Laboratory Practice toxicology studies in rats and nonhuman 
primates at plasma exposures vastly exceeding the levels at which the minimal single cell necrosis 
was seen in non-Tg rasH2 mice, thus providing further evidence that the liver toxicity observed in 
mice was likely species-specific. Liver function tests will be monitored throughout the study. 
Proposed monitoring in the Schedule of Assessments are felt to be sufficient to adequately monitor 
for evidence of injury. See Section 7.5 and Section 6.5.5.1 for individual and cohort stopping rules 
related to LFT changes. 
This study has been designed to mitigate potential safety risks based on clinical and nonclinical 
findings. The principal mitigation strategy for these risks includes appropriate selection of the 
study population; intermittent use of the inpatient clinical research unit setting, which permits 
close monitoring and rapid institution of appropriate care as needed; appropriate specified 
monitoring procedures; periodic laboratory tests, ECGs, and vital signs assessments; and 
utilization of experienced staff trained in study procedures. In addition, ambulatory monitoring of 
BP will occur before baseline and at steady state in order to evaluate the effects of TAK-994 on BP 
in the ambulatory setting.
Overall, there is manageable risk associated with the proposed study. Potential risks relating to the 
study include the following:

Study procedure-specific risks, including issues relating to blood collection for safety and PK 
assessments (eg, venipuncture may cause bruising). 

Acute hypersensitivity/anaphylactic reactions to new chemical entities, which is always a 
possible risk in any clinical study. Appropriate procedures will be used to manage such 
possible risks.

This study also includes an optional CSF collection (single sample) for assessment of CSF OX 
levels. CSF OX levels are of interest as the level may potentially correlate with the 
 
 for a given drug level. CSF 
collection is an established procedure with the typical risks associated with lumbar puncture. 
There is a very low risk of CNS infection. Subjects may experience low back pain during 
needle insertion and for a brief time after the procedure and postural headache after the 
procedure. Very rare risks include the risk of meningitis, nerve root injury, and hematoma 
resulting in spinal cord compression. These risks will be detailed in the informed consent 
documentation.
Review of data supports a favorable benefit/risk ratio for this study of TAK-994. To date, the 
observed nonclinical and clinical safety data for TAK-994, including mild and manageable AEs, 
are acceptable considering its potential clinical benefit.
For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 78 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
for additional details). Subjects will receive BID dosing of TAK-994 or matching placebo for 
28 days or 56 days, as applicable).
Table 6.a
Planned Study Cohorts and Dose Levels
PART/Cohort Number
Daily Dose Level (mg) a
Dosing Regimen b
Randomization and design
PART A-Cohort A1a and 
A1b
240 mg (A1a), TBD (A1b)
Oral, 120 mg twice daily 
for 28 days (A1a),
Approximately 18 subjects 
randomized 2:1 to TAK-994 vs 
placebo, double-blind
PART A-Cohort A2 
(optional)
TBD
Oral, twice daily for 
28 days
Approximately 9-18 subjects 
randomized 2:1 to TAK-994 vs 
placebo, double-blind
PART B
TBD
Oral, twice daily for 
56 days
Approximately 112 subjects in a 
4-arm parallel group design: 
TAK-994 Dose 1, Dose 2, and 
Dose 3 vs Placebo. 28/group with 
a randomization of 1:1:1:1
PART C (China-specific)
TBD
Oral, twice daily for 
56 days
Approximately 12-18 subjects 
randomized 2:1 to TAK-994 vs 
placebo, double-blind
PART D, Cohort D1a and 
D1b
TBD
Oral, twice daily for 
28 days
Approximately 18 subjects 
randomized 2:1 to TAK-994 vs 
placebo, double-blind
PART D, Cohort D2 
(optional)
TBD
Oral, twice daily for 
28 days
Approximately 9-18 subjects 
randomized 2:1 to TAK-994 vs 
placebo, double-blind
PK: pharmacokinetic; NT1: narcolepsy type 1 (narcolepsy with cataplexy); NT2: narcolepsy type 2 (narcolepsy without cataplexy); 
TBD: to be determined.
a Doses will be determined based on the available and emerging safety/tolerability, PK, 
 data from prior study 
TAK-994-1001 and/or previous cohorts in the current study.
b Doses will be administered approximately 5 hours apart.
c. Parts A to C include subjects with NT1 and part D will include subjects with NT2.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 79 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Table 6.b
Relative Timing for Initiation of Study Parts
Study Part/ 
Description
Relative Timing of Cohort Initiation and Rationale
Part A, Cohort A1a 
(sentinel)
This will start first
The dosing regimen, 120 mg BID, used in Cohort A1a, is 
supported by the predicted range of pharmacologically 
active plasma exposure from animal studies, and available 
clinical safety and PK data from the completed 
TAK-994-1001 FIH study. See Section 6.2.1 for details.
Part A, Cohort A1b 
This will start after 9 sentinel 
subjects in Cohort A1a are dosed 
for at least 2 weeks 
The dose level for Cohort A1b will be determined based on 
the available safety, tolerability, PK, 
 data from 
Cohort A1a. See Section 6.2.1 for details.
Part A, Cohort A2 
(optional)
This will start after Cohort A1b, 
if deemed necessary based on A1 
data
The totality of Cohort A1 data will be used to determine 
whether Cohort A2 is needed to further evaluate safety, 
efficacy, PK, 
 in NT1 before initiating Part B. The 
dose level for Cohort A2 will be determined based on the 
available Cohort A1 data. See Section 6.2.1 for details.
Part B
After the last cohort in Part A.
Doses in Part B will be determined using all available data 
from Part A. See Section 6.2.1 for details. 
Part C
This will start after Part A
The dose for Part C will be selected based on all available 
data. See Section 6.2.1 for details.
Part D, Cohort D1
This will begin after Cohort A1 
The dose for Cohort D1a will be determined based on the 
available clinical safety and PK data from the completed 
TAK-994-1001 FIH study and available safety, 
tolerability, PK, 
 data from Cohort A1. See Section 
6.2.1 for details.
Part D, Cohort D2 
(optional)
Based on the Cohort D1 data, if 
additional data are needed
The dose level for Cohort D2 will be determined based on 
the available safety, tolerability, PK 
 from Cohort 
D1, if the sponsor decides that D2 is needed to further 
evaluate safety, PK, 
 in NT2. See Section 6.2.1 for 
details.
BID: twice daily; FIH: first-in-human; NT1: narcolepsy type 1 (narcolepsy with cataplexy); NT2: narcolepsy type 2 
(narcolepsy without cataplexy); 
 PK: pharmacokinetic.
PART A (Cohorts A1 and A2):
Cohort A1: Cohort A1 will enroll 18 subjects with the sentinel 9 subjects to be randomized 2:1 to 
receive treatment with oral TAK-994 120 mg BID versus placebo in a double-blinded fashion. The 
starting dose level in the first cohort of subjects, Cohort A1a, is 120 mg BID, which was based on 
the preliminary safety, tolerability, and PK data from the FIH Study TAK-994-1001 
(Section 6.3.2.1), as well as nonclinical data. Sentinel dosing on the first 9 subjects (Cohort A1a) 
(with randomization ratio of 2:1) will be performed. The second cohort of 9 subjects (Cohort A1b) 
will be randomized 2:1 to receive treatment with oral TAK-994 versus placebo in a double-blinded 
fashion. 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 80 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Optional Cohort A2: Based on the Cohort A1 data, if an additional dosing cohort is needed, Cohort 
A2 will be enrolled and started with 9 subjects. They will be randomized in a 2:1 ratio to receive 
TAK-994 or placebo in a double-blinded fashion. Based on the emerging data from these first 9 
subjects, 9 additional subjects may be enrolled in this cohort in a 2:1 ratio. 
PART B:
Part B will start after Part A is completed. In order to initiate Part B, 3 dose levels of TAK-994 will 
be selected based on unblinded safety 
 data from the previous Part A cohort(s). A 
total of 112 subjects will be randomized to either placebo or 1 of the 3 selected TAK-994 dose 
levels in a 1:1:1:1 ratio administered for 56 days. Subjects completing Part B study treatment will 
be invited to participate in an open-label extension study, if they are eligible. Details of that 
open-label extension (OLE) study design will be communicated via a separate protocol.
PART C (Cohort C1):
PART C, Cohort C1 is a China-specific cohort and is planned to consist of 12 to 18 subjects who 
will be randomized 2:1 to receive treatment with oral TAK-994 versus placebo in a double-blinded 
fashion. 
PART D (Cohorts D1 and D2):
Cohort D1 will start with sentinel dosing in a cohort of 9 subjects with NT2 (Cohort D1a) who will 
receive TAK-994 BID or placebo in a randomization ratio of 2:1. Dosing for the next 9 subjects 
(Cohort D1b) may be adjusted based on the safety and/or efficacy data from the first 9 subjects. 
Overall randomization ratio for the 18 subjects in Cohort D1 will remain at 2:1.
Based on the Cohort D1 data, if an additional dosing cohort is needed, optional Cohort D2 will 
start. Cohort D2 will enroll 9 subjects randomized in a ratio of 2:1 to receive TAK-994 or placebo 
in a double-blinded fashion. Based on the emerging data from these first 9 subjects, 9 additional 
subjects may be enrolled in this cohort in a 2:1 ratio.
Subjects who are active in screening in Parts A or B and found to not meet the criteria for NT1, 
may be considered for Part D, if they are eligible. These subjects will not be assigned a new subject 
number (in these cases when they have not screen-failed), must sign the Part D ICF and will not be 
required to undergo another screening visit (in these cases where they are still active in screening 
within the 45-day screening window). 
ALL PARTS:
After the screening visit, eligible subjects will participate in study activities as shown in the 
overview of the study schedule (Table 6.c and Section 2.0). The full Schedules of Study 
Procedures are shown in Table 3.a, Table 3.b, Table 3.c, Table 3.d, Table 3.e, Table 3.f, Table 3.g, 
Table 3.h, Table 3.i, Table 3.j, Table 3.k, Table 3.l, Table 3.m, Table 3.n.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 81 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Table 6.c
Overview of the Study Schedule
Screening, Check-In and Baseline
Treatment Period
Follow-Up Visit
Dose
Sample Collection
Days -45 to -3
Day -2 and Day -1
PART A and PART D: Day 1 to 
Day 28
Study drug administration twice 
daily
Day 1 to Day 30 (See 
Section 3.1 and 
Section 3.3)
Day 35 ±2 days
PART B and 
PART C: 
Day 63 ±2 days
Day 1 to Day 57
(See Section 3.2)
PART B and PART C: Day 1 to 
Day 56
Study drug administration twice 
daily
In- and outpatient setting 
After screening, eligible subjects must discontinue their medication used for treatment of 
NT1/NT2, including medications used for EDS and cataplexy (valid for NT1 only). Medications 
that must be discontinued before Day -2 are listed in Section 7.3. Subjects in Parts A, B and C may 
undergo optional CSF sampling (single time point) for OX assessment during screening. (NOTE: 
optional CSF testing at a country-level is dependent upon local regulations [either health authority 
or other government’s] and guidelines and site capacity. See Section 9.3.3.2 for details.)
During confinement, study drug will be administered orally twice every day per the schedule of 
study procedures. For detailed dosing instructions see Section 7.4.1. Study assessments will be 
obtained per the schedules of study procedures in accordance with the priority specified in 
Section 6.3.4. Subjects will remain as inpatient from check-in at Day -2 until Day 2; after 
completion of the scheduled test procedures on Day 2, they will be discharged.
While at home, subjects will take TAK-994 orally BID at approximately the same times each day, 
with the first dose given in the morning and the second dose approximately 5 hours later and will 
continue to complete the daily electronic patient-reported outcome (ePRO) diary. See Section 
7.4.1 for complete dosing instructions. Subjects will return to the clinic for safety, PK, 
 
assessments on in-clinic visit days. Subjects will return home on the discharge day after each 
in-clinic period. A final follow-up is also required approximately a week after the discharge days. 
See Section 3.0 for details.
After the treatment period, a follow-up visit will be done, after which subjects may resume the use 
of their prior medication for the treatment of narcolepsy.
Sites should see subjects at the study site to conduct the in-clinic study procedures. In unavoidable 
circumstances (eg, a widespread disease outbreak or natural disaster) that impact the study site’s 
ability to conduct study procedures according to the Schedule of Procedures, contingency 
measures may be implemented. Restrictions of human activities or institution activities placed by 
hospitals, local, state and national governments may prevent conduct of study procedures 
according to the Schedule of Procedures. Alternative approaches to study procedures and data 
collection for the current study are described in Section 9.1.1.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 82 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
6.2
Dose Selection and Cohort Progression
6.2.1
Dose Selection Rules
The dose range to be explored in this study is anticipated to bracket the predicted human 
efficacious concentration range in order to characterize the dose/exposure-response relationship of 
TAK-994 in subjects with NT1 or NT2. The starting dose of this study (Part A, Cohort A1a) is 120 
mg administered BID with the first dose given in the morning and the second dose given 
approximately 5 hours later. This dose regimen is supported by the predicted range of 
pharmacologically active plasma exposure associated with wake-promoting effects in humans 
from animal studies, and available clinical safety and PK data from the completed TAK-994-1001 
FIH study. Refer to Section 6.3.2.1 for starting dose rationale and Section 6.3.2.2 for dose 
decisions.
The 3 doses for Part B will be determined using all available data from Part A. 
The dose for Part C will be selected on the basis of the review of all available data before it starts.
Cohort D1 will start when a dose has been chosen based on emerging safety/tolerability, PK, 
 
 data from Cohort A1. Dose levels in subsequent (sub)cohorts in Part D may be higher than, 
lower than, or the same as the preceding dose level. However, doses in Part D should not exceed 
200 mg BID (Section 6.3.2.2). 
6.2.2
Data Review and Interim Analysis
Ongoing medical monitoring will occur during the study. Stopping rules are in Sections 6.5
and 7.5.
Part A and Part D have a design of multiple rising dose study, including different dose cohorts as 
described in the study design. After completion of each cohort, a data review is needed to decide 
the dose for the next cohort.
An unblinded sponsor’s team (internal review committee [IRC]), composed of members who do 
not have contact with investigators or sites, will perform the unblinded data reviews to select the 
dose(s) for upcoming (sub)cohort and study parts to make informed dosing recommendations to 
the blinded team. Unblinded data reviews will be done at the following times:
Unblinded data review for Part A:
1. When the sentinel cohort (first 9 subjects) in Cohort A1 complete at least 14 days of dosing. 
2. At the end of Cohort A1.
3. If the optional Cohort A2 is conducted, when the first 9 subjects in Cohort A2 complete at least 
14 days of dosing.
4. If the optional Cohort A2 is conducted, at the end of Cohort A2.
Based on all available data in Part A, the doses for Part B will also be selected. 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 83 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Unblinded data review for Part D:
1. When the sentinel cohort (first 9 subjects) in Cohort D1 complete at least 14 days of dosing.
2. At the end of Cohort D13. If the optional Cohort D2 is conducted, when the first 9 subjects in 
Cohort D2 complete at least 14 days of dosing.
An IRC charter will be prepared and approved before the first unblinding event. Access to the 
unblinded analysis results at the end of each part will also be described in the IRC charter.
Planned Interim Analysis:
In addition, there is one preplanned interim analysis (IA) at the end of Cohort A1 in Part A. For 
details regarding the end-of-part unblinded analyses, see Section 11.2.
6.3
Rationale for Study Design, Dose, and Endpoints
6.3.1
Rationale of Study Design
6.3.1.1
Rationale for Study Population
The subjects included in the study will be subjects with NT1 (Parts A, B and C) or NT2 (Part D) 
who are otherwise generally healthy. Subjects with NT1 are deficient in OX, and hence, are the 
first candidates who are likely to benefit from treatment with an OX2R agonist. In nonclinical 
pharmacology studies, wake-promoting effects as well as improvement of cataplexy-like 
syndrome by TAK-994 were observed in a murine narcolepsy model; these effects were confirmed 
after chronic dosing for up to 14 days. The efficacious dose of TAK-994 was approximately 
3 times lower in the narcolepsy model than in wild-type mice, suggesting that there may be a 
difference in sensitivity to TAK-994 between subjects with narcolepsy and healthy subjects. Based 
on these data, subjects with NT1 are expected to be more sensitive to TAK-994 than healthy 
subjects, and hence, the starting dose of TAK-994 needed for safety in NT1 are expected to be 
lower in NT1 patients than those tested in healthy normal subjects. 
6.3.1.2
Rationale for Study Design
Several key considerations were taken into account when designing the study, as the information 
generated will inform the design and dose selection for the further development of TAK-994 as a 
potential treatment for NT1 and NT2. These considerations are described below.
Since this is the first study of TAK-994 in NT1 and NT2 subjects, Parts A and D of the study are 
designed to evaluate the safety, tolerability, PK, 
 effects of TAK-994 after repeat oral 
dosing for 1 month in subjects with NT1 and NT2. Cohorts (up to 2 in each population) will be 
enrolled in a sequential manner after data review at the end of each cohort. In each cohort, 18 
subjects will be randomized in a ratio of 2:1 to receive TAK-994 and placebo for 28 days. 
Sentinel dosing in the first 9 subjects will also be performed in the first cohorts of NT1 and NT2 
subjects, Cohort A1 and Cohort D1, respectively. 
For non-commercial use only


For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 85 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
6.3.2
Rationale for Dose
6.3.2.1
Starting Dose
The starting dose of this study (Cohort A1a, sentinel dosing) is 120 mg administered BID (240 mg 
total daily dose) with the first dose given in the morning and the second dose given approximately 
5 hours later.
Single doses of TAK-994 30, 90, 180, 360, and 450 mg and multiple doses of TAK-994 180 mg 
QD for 7 days, and 120 or 200 mg BID (6-hour dosing interval) for 14 days have been safe and 
generally well tolerated in healthy subjects in the recently completed TAK-994-1001 FIH study 
(see Section 4.1.3). None of the TEAEs were considered serious, and all TEAEs were mild or 
moderate in severity, except for 1 severe AE of syncope reported in the CSF cohort at 180 mg QD, 
which the investigator considered related to study procedure but not study drug. AEs increased in 
number with increasing dose. One subject discontinued from the study due to AE after repeat 
dosing up to 14 days.
The concentration threshold for wake-promoting effect of TAK-994 in humans is predicted to be 
253 ng/mL based on nonclinical pharmacology studies. At the proposed starting dose of 120 mg 
BID, the predicted mean concentration-time profile of TAK-994 at steady state is expected to 
produce and maintain TAK-994 plasma concentrations above this efficacy threshold for about 
6 hours. Preliminary PK results showed approximate dose-proportional increases in Cmax after 
single oral doses up to 450 mg in healthy subjects, while some slight deviation from linearity was 
observed for AUC∞at the highest dose studied. Following 120 mg BID given 6 hours apart, mean 
Cmax values were 409/609 and 365/462 ng/mL after the first/second dose on Day 1 and Day 14, 
respectively. TAK-994 daily systemic exposures (AUC24) were on average 5220 and 4320 
h*ng/mL on Days 1 and 14, respectively. Both the higher plasma peak concentrations observed 
after the second dose and total daily systemic exposures on Day 1 fell well within the range of 
those observed after single doses of 180 and 360 mg. Of note, all doses and dose regimens studied 
to date in healthy subjects have resulted in systemic exposures of TAK-994 that are well below the 
NOAEL exposures of 1000 mg/kg/day in rats (Day 28 mean values for both sexes: Cmax = 9765 
ng/mL and AUC24 = 156,500 h*ng/mL).
Taken altogether, 120 mg BID is deemed appropriate as the starting dose for the Cohort A1 
sentinel dose group to initiate evaluation of the clinical safety, PK, and efficacy profile of 
TAK-994 in patients with NT1. The BID dose regimen is supported by the relatively short 
elimination half-life of TAK-994 and allows for blunted peak concentrations, lower 
peak-to-trough fluctuations, and sustained wakefulness during daytime. Both doses will be taken 
approximately 5 hours apart to not interfere with the four 40-min MWT sessions planned at 2, 4, 6, 
and 8 hours after the morning dose during the confinement periods, to ease management of dosing 
and meal times while at home, and to minimize sleep disturbances.
6.3.2.2
Maximum Dose/Exposure for This Study
The maximum daily dose will not exceed 200 mg BID (400 mg/day). 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 86 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
In Parts A, B and C, dose decisions and subsequent dose levels will be determined based on a full 
review of all available safety, tolerability, PK, 
 data (see Section 6.2.2). For example, dose 
selection for Part B will be based on the outcome of Part A-cohort A1 and optional cohort A2. The 
emerging 
 effects and time above the efficacy threshold will also be considered. Subsequent 
dose levels may be higher than, lower than, or the same as the preceding dose level.
In Part D, dose for Cohort D1 will be selected based on available data from Cohort A1. Doses for 
the subsequent subcohort or cohort will be determined based on previous data from Part D. 
Dosing will continue as long as the following conditions are met:
1. Based on the adverse fluorosis of incisors at 1500 mg/kg/day, the NOAEL of TAK-994 was 
150 mg/kg/day for both sexes. The mean Cmax and AUC24 at 150 mg/kg/day were 6030 ng/mL 
and 78,900 h*ng/mL and 13,200 ng/mL and 198,000 h*ng/mL in males and females, 
respectively, on Day 91. The mean AUC and Cmax of the maximal dose are predicted to not 
exceed the mean AUC24 and Cmax values in rats (the more conservative species) at the NOAEL 
of 150 mg/kg/day from the 13-week toxicology study (Day 91 mean values for both sexes: 
Cmax = 9600 ng/mL [average of 6030 ng/mL and 13,200 ng/mL] and AUC24 = 139,000 
h*ng/mL [average of 78,900 h*ng/mL and 198,000 h*ng/mL]).
2. Adequate safety and tolerability are present.
Specific criteria for cohort and study termination are provided in Section 6.5.5.1.
6.3.3
Rationale for Endpoints
6.3.3.1
Safety Endpoints
Standard safety endpoints (eg, TEAEs, physical examinations, vital signs [BP, pulse rate, 
respiratory rate], 12-lead ECGs, clinical laboratory evaluations) for early clinical investigation are 
included in this study.
Ambulatory blood pressure monitoring (ABPM) is also being obtained to assess BP in the
outpatient setting in a rigorous manner.
The Columbia Suicide Severity Rating Scale (C-SSRS) will be used as a standard tool for 
monitoring any signs of suicidal ideation or behavior.
LFTs will include ALT and AST at the minimum.
6.3.3.2
PK Endpoints
Standard noncompartmental PK analyses will provide measures of drug exposure in the plasma 
following multiple oral dose administration of TAK-994 in subjects. Metabolites may also be 
evaluated, as deemed appropriate.
6.3.3.3
Efficacy 
 Endpoints
To evaluate the effect of TAK-994 on symptoms of narcolepsy after multiple dosing, this study 
includes well-established objectives and subjective efficacy endpoints for narcolepsy symptom 
For non-commercial use only


For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 88 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL

Dose adjustments may be made based on the sentinel dosing results, and review of safety, 
tolerability, and efficacy data as described in Section 6.2.1.
It is understood that the current study may employ some or none of the alterations described above. 
Any alterations described above made to this protocol to meet the study objectives must be 
detailed by the sponsor in a letter to the Trial Master File and forwarded to the investigator for 
retention. The letter will be forwarded to the institutional review board (IRB)/independent ethics 
committee (IEC).
6.5
Study Beginning and End/Completion
6.5.1
Definition of Beginning of the Study
The overall study begins when the first subject signs the study informed consent form.
6.5.2
Definition of End of the Study
The overall study ends when the last subject completes the last planned or follow-up 
visit/interaction associated with a planned visit (this can be a phone contact), withdraws from the 
study, or is lost to follow-up (ie, the investigator is unable to contact the subject).
6.5.3
Definition of Study Completion
For an individual subject, study completion is defined as when the subject is examined after 
receiving all planned intervention/treatment to collect final data for all primary, secondary, and 
exploratory endpoints.
6.5.4
Definition of Study Discontinuation
Study discontinuation is defined as cessation of the overall study due to nonsafety or safety 
reasons.

For the overall study and individual cohorts, criteria and procedures for premature termination 
or suspension are described in Section 6.5.5.

For study sites, criteria and procedures for premature termination or suspension are described 
in Section 6.5.6.

For individual subjects, criteria and procedures for discontinuation or withdrawal are described 
in Section 7.5 and Section 7.6, respectively.
6.5.5
Criteria for Premature Termination or Suspension of the Study
6.5.5.1
Criteria for Premature Termination or Suspension
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of a study cohort or the overall study:
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 89 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL

New information or other evaluation regarding the safety or efficacy of the study drug
indicates a change in the known risk/benefit profile for the product, such that the risk is no
longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) compromises the ability to achieve the
primary study objectives or compromises subject safety.

A finding (eg, PK, 
) from another nonclinical or clinical study using the study treatment
results in the study being stopped for a nonsafety-related reason.

Data from drug(s) of the same class or methodology(ies) used in this study become available
and result in the study being stopped for a nonsafety-related reason.

The study is stopped because of nonscientific and nonsafety reasons, such as slow enrollment.

Unanticipated concerns of safety to the study subjects arise from this clinical study or
additional nonclinical or clinical studies with TAK-994 or drug(s) of the same class.

Study-specific stopping criteria are met by any of the following criteria, after unblinded
review:
–
BP increase: If 4 or more subjects in the same cohort (Parts A, C, D) or in the same arm
(Part B) meet the individual subject stopping criteria for BP increases defined in Section
7.5, then further dosing in the cohort will be stopped. In this case, no human dosing will be
performed at this and any higher dose levels in the planned clinical study.
–
Insomnia: If 4 or more subjects in the same cohort (Parts A, C, D) or in the same arm (Part
B) meet the individual subject stopping criteria for severe insomnia defined in Section 7.5,
then further dosing in the cohort will be stopped. No further dose escalation will occur if
the cases are assessed as causally related to the investigational product by the sponsor.
–
LFT: If 3 or more subjects in the same cohort meet (Parts A, C, D) or in the same arm (Part
B) the individual subject stopping criteria for abnormalities, as defined in Section 7.5, then
further dosing in the cohort will be stopped. No further dose escalation will occur.
–
SAE: If 3 or more subjects in the same cohort (Parts A, C, D) or in the same arm (Part B)
meet the individual subject stopping criteria or 3 or more experience a similar SAE that is
drug-related in investigator’s and sponsor’s opinions, then further dosing in the cohort will
be stopped. No further dose escalation will occur.
–
For Part B, there will be an unblinded review by the sponsor’s unblinded safety physician
who will make the final decision to either stop part B or the dosing arm in which the
SAE/AE occurred, or continue with further dosing.

The study will be paused for further evaluation if any of the following criteria are met:
–
≥10% or 3 subjects, whichever is higher, in the same cohort (Parts A, C, D) or in the same
arm (Part B) experience a similar SAE.
–
≥10% or 3 subjects, whichever is higher, in the same cohort (Parts A, C, D) or in the same
arm (Part B) experience a similar severe AE, with the exception of insomnia.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 90 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
–
≥10% or 3 subjects, whichever is higher, in the same cohort (Parts A, C, D) or in the same 
arm (Part B) discontinue study for safety reasons.
–
≥1 death determined by the investigator and the sponsor to be related to study medication.

Subject may be withdrawn from the study at any time, due to disease progression or any other 
safety reason, if it is in the best interest of the subject. 

The sponsor terminates or suspends the study, or any study cohort, at any time for any other 
clinical or administrative reasons.
6.5.5.2
Procedures for Premature Termination or Suspension of the Study
If the sponsor, an IRB/IEC, or a regulatory authority elects to terminate or suspend the study, a 
study-specific procedure for early termination or suspension will be provided by the sponsor; the 
procedure will be followed by applicable investigational site(s) during the course of termination or 
study suspension.
6.5.6
Criteria for Premature Termination or Suspension of a Site
6.5.6.1
Criteria for Premature Termination or Suspension
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, the study protocol, or contractual agreement; if the site 
(including the investigator) is unable to ensure adequate performance of the study; or as otherwise 
permitted by the contractual agreement.
6.5.6.2
Procedures for Premature Termination or Suspension
If the sponsor, an IRB/IEC, or a regulatory authority elects to terminate or suspend the 
participation of an investigational site, a study-specific procedure for early termination or 
suspension will be provided by the sponsor; the procedure will be followed by applicable 
investigational site(s) during the course of termination or study suspension. If the site closure is 
due to COVID-19, this should be captured on the CRF, end of treatment disposition page.
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria
Subject eligibility will be determined according to the following criteria before administration of 
the first dose in the study:
1. The subject must be aged 18 to 65 years, inclusive, at the time of informed consent.
2. The subject must understand the study procedures and agree to participate by providing written 
informed consent.
3. The subject must be willing and able to comply with all study procedures and restrictions.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 91 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
4. The subject must be judged to be in good health by the investigator to participate in the study, 
based on 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 or first study assessment.
Note: Screening labs may be repeated once, after consultation with the Medical Monitor.
5. The subject must have a diagnosis of NT1 (Parts A-C) or NT2 (Part D) by 
 MSLT 
performed within the past 10 years meeting the minimal acceptable criteria for the proper 
performance of 
MSLT as outlined by the ICSD-3 criteria (Appendix E). 
Note: If there is a potential subject with a diagnosis of NT1 or NT2 whose diagnostic 
MSLT was performed more than 10 years ago or is not available, special exemptions, ie, 
ability of the site to repeat the diagnostic 
MSLT will be considered on a case-by-case 
basis after discussions between the investigator and the sponsor or designee.
6. The subject’s ESS score must be ≥10 at Day -1. 
7. The subject must be willing to discontinue all medications used for the treatment of NT1/NT2.
8. The human leukocyte antigen (HLA) genotype:
–
Part A: The HLA genotype should test positive for HLA-DQB1*06:02 - (positive results 
for either homozygous or heterozygous alleles will be considered “positive” and 
acceptable). However, if the HLA test is negative (ie, negative for the heterozygous allele) 
and the PI feels strongly that the subject has narcolepsy with cataplexy (NT1) then a 
discussion should be initiated between the PI and the sponsor or designee about the 
advisability of doing a spinal tap to determine the subject's cerebrospinal fluid (CSF) 
orexin-1 (OX-1) level. If the CSF result shows the OX-1 concentration is either less than or 
equal to 110 pg/mL, or less than one-third of mean values obtained in normal subjects with 
the same standardized assay, then the diagnosis of NT1 is established allowing the subject 
to be enrolled and randomized, If the CSF OX-1 concentration is >110 pg/mL then the 
subject will not be allowed to continue in the study. See Section 9.2.11.2.4 for details. 
Subjects previously excluded in Part A for being HLA negative will not be included in Part 
B.
Parts B and C: HLA genotyping will be done for these subjects as well; however, HLA test 
results are not a study entry criteria. Subjects who present with CSF testing results 
indicating OX-1 concentration either less than or equal to 110 pg/mL, or less than one-third 
of mean values obtained in normal subjects with the same standardized assay, may be 
considered for enrollment into Parts B and C after a discussion with the sponsor or 
designee. For all subjects in Parts B and C, site staff will complete the cataplexy 
questionnaire during screening. This questionnaire along with a copy of the most recent 
MSLT report will be submitted to the sponsor for adjudication by a committee of 
experts in the field of narcolepsy/cataplexy to be chosen by the sponsor. This committee 
will determine eligibility for the study and the committee’s determination will be final for 
study entry criteria. Additional documentation may be requested by the sponsor.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 92 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
9. For Parts A, B, and C, during the screening period, the subject must have ≥4 partial or 
complete episodes of cataplexy/week (WCR), averaged over 2 weeks (14 consecutive days) 
minimum. WCR recording taken during following period will be considered for study 
eligibility: after the patient has stopped taking anticataplexy medications for at least 7 days 
(minimum 7-day washout) and study Day -2. Refer to Section 9.3.2.7 for details.
10. For a male subject who is not sterilized and sexually active with a female partner of 
childbearing potential, the subject must meet the following birth control requirements:

Agrees to use an appropriate method of contraception, including a condom with 
spermicidal cream or jelly, from the first dose of study drug until 5 half-lives (1 day) plus 
90 days after the last dose of study drug. No restrictions are required for a vasectomized 
male subject, provided the subject is at least 1-year post-bilateral vasectomy procedure 
before the first dose of study drug. A male subject whose vasectomy procedure was 
performed less than 1 year before the first dose of study drug must follow the same 
restrictions as a non-vasectomized man. Appropriate documentation of surgical procedure 
should be provided.

Agrees to not donate sperm from the first dose of study drug until 5 half-lives plus 90 days 
after the last dose of study drug.
11. For a female subject of childbearing potential who is sexually active with a male partner who is 
not sterilized, the subject must agree to use highly effective methods of contraception from 
signing of the informed consent throughout the duration of the study and for 5 half-lives of 
TAK-994 plus 30 days. Additional guidance for contraception before the study start, 
definitions and procedures for adequate contraception, pregnancy avoidance, and reporting 
responsibilities are defined in Appendix D. 
12. Subjects who smoke must be willing to abstain from smoking while confined in the inpatient 
unit.
13. The subject must have a body mass index (BMI) ≥17.0 and ≤40 kg/m2 at the screening visit. 
14. The subject must have BP <140 mmHg (systolic) and <90 mmHg (diastolic). The subject may 
have a history of hypertension and be on antihypertensive medication treatment as long as the 
BP meets these criteria. BP measurements should be obtained after the subject has been resting 
for a minimum of 10 minutes and will be repeated 3 times. The median BP obtained will be 
used.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
All Subjects
1. The subject has participated in another investigational study within 60 days (or based on local 
regulations) before the screening visit. The 60-day window will be derived from the date of the 
last study procedure and/or AE related to the study procedure in the previous study to the 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 93 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
screening visit of the current study. (Exceptions may be made for observational, natural 
history, and nonintervention type studies with sponsor or designee approval).
2. The subject is an employee of the sponsor or study site or an immediate family member 
(eg, spouse, parent, child, sibling) of an employee of the sponsor or study site who is directly 
involved in the conduct of the study.
3. The subject has a history of cancer (does not apply to subjects with carcinoma in situ that has 
been resolved without further treatment or basal cell skin cancer; these subjects may be 
included after approval by the sponsor or designee i.e. medical monitor [MM]).
4. The subject has a history of significant multiple and/or severe allergies (eg, food, drug, latex 
allergy) or has had an anaphylactic reaction or significant intolerance to prescription or 
nonprescription drugs or food.
5. The subject has a known hypersensitivity to any component of the formulation of TAK-994 or 
related compounds.
6. The subject has a positive pregnancy test or is a lactating/nursing female subject.
7. The subject has a positive test result for hepatitis B surface antigen, hepatitis C virus antibody 
at the screening visit or has a history of human immunodeficiency virus.
Note: Subjects with positive hepatitis B virus or hepatitis C virus serology may be enrolled if 
quantitative polymerase chain reaction for hepatitis B virus or hepatitis C virus ribonucleic 
acid is negative.
8. The subject had major surgery or donated or lost 1 unit of blood (approximately 500 mL) 
within 4 weeks before the screening visit.
9. The subject is unable to refrain from or anticipates using excluded medications, including food 
products and grapefruit juice (see Section 7.3), beginning approximately 7 days (14 days for 
anticataplexy medications) before baseline, throughout the study, and until the follow-up visit.
10. The subject’s renal creatinine clearance is ≤50 mL/min.
11. Has LFTs (ALT, AST) higher than 1.5× ULN at screening. 
12. The subject has poor peripheral venous access, as assessed by the investigator.
13. The subject has a risk of suicide according to endorsement of Item 4 or 5 of the 
screening/baseline visit C-SSRS and/or has made a suicide attempt in the previous 12 months.
14. The subject has past or current epilepsy or seizure, except for a single febrile seizure in 
childhood.
15. The subject has a lifetime history of major psychiatric disorder, such as bipolar disorder or 
schizophrenia. Subjects who have history of major depressive disorder (MDD) may be 
included, but subjects who have current active MDD or who have had active MDD in the past 
6 months are excluded.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 94 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
16. The subject has a clinically significant history of head injury or head trauma per the judgment 
of the investigator.
17. The subject has a history of cerebral ischemia, transient ischemic attack, intracranial 
aneurysm, or arteriovenous malformation.
18. The subject has known coronary artery disease, a history of myocardial infarction, angina, 
cardiac rhythm abnormality, or heart failure.
19. The subject has a screening ECG with a QT interval with Fridericia’s correction method 
(QTcF) >450 ms (men) or >470 ms (women).
20. The subject has a resting heart rate outside of the range of 40 to 100 beats per minute, 
confirmed on repeat testing within a maximum of 30 minutes at screening.
21. The subject has medical condition other than narcolepsy, such as medically significant 
unstable cardiovascular, pulmonary, hepatic, renal, or gastrointestinal disease, that would 
preclude enrollment in the view of the investigator.
22. The subject has current or recent (within 6 months) gastrointestinal disease that is expected to 
influence the absorption of drugs (ie, a history of malabsorption, esophageal reflux, peptic 
ulcer disease, erosive esophagitis, frequent [more than once per week] occurrence of 
heartburn, or any surgical intervention). Any history of Roux-en-Y gastric bypass is 
considered exclusionary and any other surgical intervention that may influence the absorption 
of drugs should be discussed and approved by the sponsor or designee before enrolling the 
subject.
23. The subject, in the opinion of the investigator, is unlikely to comply with the protocol or is 
unsuitable for any other reason. 
24. The subject is an excessive (>600 mg/day) caffeine user 1 week before the study screening.
25. Subjects on fluoxetine (any dose) or on ≥300 mg per day of venlafaxine will be excluded due 
to the drug’s long elimination half-life or clinically significant tapering/washout difficulties. 
See Section 7.3 for a complete list of medications that are not allowed during the treatment 
period and the guidelines for washout for stimulant, anticataplexy, antidepressant medications 
and sodium, and/or multisalt oxybate, that must be followed, as applicable.
26. The subject has a medical disorder, other than narcolepsy, associated with EDS. This includes 
clinically significant moderate to severe obstructive sleep apnea with or without treatment with 
mandibular advanced device hypoglossal nerve stimulation and/or positive airway pressure (PAP) 
therapy) and/or restless legs syndrome (RLS)/periodic limb movement disorder that has a 
significant impact on daytime sleepiness. This is evidenced by a clinical history of sleep apnea 
syndrome (loud snoring with observed respiratory pauses in the absence
) and/or RLS 
causing historical sleep onset/maintenance insomnia with resultant insufficient sleep as 
evaluated during the clinical interview at screening. Past 
 data demonstrating any of the 
following sleep disturbances: apnea Hypopnea Index ≥15 or apnea index ≥10, an oxygen 
saturation of <80 for >10 seconds, periodic leg movement arousal index of ≥15/h) should be 
considered exclusionary unless, based on a clinical evaluation by the investigator, a 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 95 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
meaningful change in clinical status has occurred that would impact the results. Because 
 
data is obtained on Day -2, subjects may fail screening if criteria are not met on the Day -2 
.
27. The subject has any other medical condition, such as anxiety, depression, heart disease, or 
significant hepatic, pulmonary, or renal disease, that requires the subject to take excluded 
medications (see Section 7.3) or at the time of screening the subject is being treated with nasal 
/oro-nasal positive airway pressure (PAP) for any reason.
28. The subject is unwilling to abstain from driving and operating dangerous or hazardous 
machinery during study participation, starting from when narcolepsy medication is 
discontinued and extending until after the follow-up visit (35 ±2 days or 63 ±2 days).
29. The subject has a positive urine screen for drugs of abuse and/or positive alcohol test at 
screening and Study Day -2. An exception at screening is made for stimulants or other drugs 
that the subject has been prescribed, but the drug screen must be negative at Study Day -2.
30. The subject has a history of drug or alcohol abuse within the 12 months before screening 
(Diagnostic and Statistical Manual of Mental Disorders, Edition 5 criteria).
31. The subject has a nicotine dependence that is likely to have an effect on sleep (eg, a subject 
who routinely awakens at night to smoke) and/or an unwillingness to discontinue all smoking 
and nicotine use during the confinement portions of the study.
32. The subject has a usual bedtime later than 2400 (12:00 AM, midnight) or an occupation 
requiring nighttime shift work or variable shift work within the past 6 months or travel within 
more than 3 time zones, within 14 days before Study Day -2.
Subjects Undergoing Optional CSF Collection 
33. The subject has undergone CSF collection within 30 days before check-in.
34. The subject has a known hypersensitivity to anesthesia/local anesthetics, or its derivatives used 
during CSF collection or to any medication used to prepare the area of lumbar puncture.
35. The subject has significant vertebral deformities (scoliosis or kyphosis) that, in the opinion of 
the investigator, may interfere with the lumbar puncture procedure.
36. The subject has a history of major back (lumbar) surgery, clinically significant back pain, 
and/or injury, in the opinion of the investigator.
37. The subject has a local infection at the puncture site.
38. The subject has developed signs of lumbar radiculopathy, including lower extremity pain and 
paresthesia.
39. The subject has any known focal neurological deficit that might suggest an increase in 
intracranial pressure.
40. The subject has any abnormal findings on ophthalmological/funduscopic assessment 
indicative of raised intracranial pressure (ie, optic disc swelling/edema or [uncontrolled] 
hypertension retinopathy).
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 96 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
41. The subject has a bleeding abnormality or history of bleeding abnormalities. The subject has 
thrombocytopenia or other suspected bleeding tendencies noted.
42. The subject is taking an anticoagulant (1 tablet/day of low dose aspirin [81 mg] is allowed) or 
has abnormal coagulation test results (prothrombin time [PT]/international normalized ratio 
[INR], activated partial thromboplastin time) from a sample taken during the screening period. 
Results must be received and reviewed by the investigator in advance of CSF sample 
collection. 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 97 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
7.3
Excluded Medications, Supplements, and Dietary Products
Excluded medications and dietary products are shown in Table 7.a.
Table 7.a
Excluded Medications, Supplements, and Dietary Products
Prohibited Drug Category
Drugs Restricted From 7 Days or 5 Half-Lives a
Before Dosing (Day 1) Until Follow-Up (Unless Otherwise 
Specified)
Any investigational drug
<60 days before screening or 5 half-lives – whichever is longer 
Psychostimulants
Methylphenidate hydrochloride, modafinil, armodafinil, 
methamphetamine hydrochloride, solriamfetol, and pitolisant 
need to be restricted from 7 days or 5 half-lives before Day -2 and 
through the follow-up visit.
Sodium, and/or multisalt oxybate
Should be discontinued at a minimum of 4 weeks before Day -2; 
decision to discontinue should be made after consulting with 
sponsor or designee
Antipsychotic drugs
Not allowed
Antianxiety/sleeping drugs
(tranquilizers/sleeping medications)
Including benzodiazepines, non-benzodiazepine drugs and
melatoninergic agonists
Antidepressants
1. At screening, those on fluoxetine (any dose) or venlafaxine 
≥300 mg/day will be excluded from the study.
2. Stimulant medications must be discontinued for a minimum of 
7 days or 5 half-lives before Day -2 check-in
3. Anticataplexy medications (eg, tricyclic antidepressants, SSRI,
and SNRI) washout should start at least 21 days before Day -2 to 
allow for confirmation of cataplexy eligibility criterion. (Parts A, 
B and C). 
Mood stabilizers (such as lithium or valproic acid 
or other antipsychotic drugs)
Not allowed
Anticonvulsants
Not allowed
Sleeping pills
Including Chinese medicine (Yokukansan,
Yokukansankachinpihange) used for insomnia
Anti-Parkinson’s disease drugs (completely
excluded)
Not allowed
Adrenocorticosteroids (excluded except for
inhaled and topical)
Systemic administration permissible during the study for 
purposes of treating an AE only 
Interferon, interleukin-formulation (excluded)
Not allowed
Muscle-relaxant drug (eg, baclofen)
Not allowed
Antihistamines
Only centrally acting antihistamines are prohibited.
Loratadine is also prohibited.
The use of antihistamines and steroids are allowed for the 
management of severe allergic reactions.
Antitussives with CNS action
Not allowed
Antiemetics with CNS action
Not allowed
Narcotic analgesics and non-narcotic analgesics, 
Use of over-the-counter pain medications (acetaminophen; 
excluding occasional use of ibuprofen, naproxen, and aspirin) is 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 98 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Table 7.a
Excluded Medications, Supplements, and Dietary Products
Prohibited Drug Category
Drugs Restricted From 7 Days or 5 Half-Lives a
Before Dosing (Day 1) Until Follow-Up (Unless Otherwise 
Specified)
varenicline (CHANTIX) 
prohibited unless otherwise approved by the principal 
investigator after consultation with the sponsor or designee (i.e. 
MM)
St. John’s Wort, health foods containing
melatonin
Not allowed
Known moderate and strong CYP3A inhibitors or
inducers are available in and Appendix F.
Not allowed
Known Pgp inhibitors (azithromycin, captopril, 
carvedilol, felodipine, quercetin, quinidine, 
ranolazine, ticagrelor)
Not allowed
Known CYP3A substrates with narrow
therapeutic range including but not limited to
ergot alkaloids, fentanyl, pimozide, astemizole,
terfenadine, systemic corticosteroids (dose
equivalent to ≥10 mg prednisone per day),
nisoldipine, lovastatin, simvastatin, midazolam,
triazolam, buspirone, almorexant, lemborexant,
suvorexant, lurasidone, naloxegol, tilidine,
sildenafil, vardenafil, cilostazol, and eletriptan
Not allowed
Known sensitive OATP1B1 substrates including
but not limited to pravastatin, rosuvastatin, 
pitavastatin, atorvastatin, elagolix, repaglinide, 
valsartan
Not allowed
Sensitive Pgp substrates with narrow TI: digoxin, 
dabigatran etexilate, fexofenadine
Not allowed
Sensitive BCRP substrates: sulfasalazine 
Not allowed
Chinese herbal medicine
Not allowed b
AE: adverse event; BCRP: breast cancer resistance protein; CNS: central nervous system; CYP: cytochrome P-450; 
MM: medical monitor; OATP: organic anion transporting polypeptide; OTC: over-the-counter; Pgp: P-glycoprotein; 
SNRI: serotonin and norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor.
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 principal investigator, unless the investigator or 
investigator’s designee considers immediate administration necessary.
a Whichever is longer.
b Topical use is allowed.
For non-commercial use only


For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 100 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
7.4
Dosing Instructions, and Activity
7.4.1
Dosing Instructions 
Each subject in this study will be instructed to take study drug BID: the first dose will be taken in 
the morning upon awakening, as close to 8 AM as possible (after completion of predose 
assessments if in the unit) and the second dose will be taken approximately 5 hours later. Both 
doses should be taken without food. A minimum of 4 hours apart is required between the morning 
and afternoon doses. The second dose should be taken no later than 2 PM based on the elimination 
half-life of TAK-994.
During the confinement periods (as indicated in Section 3.0), the first dose of TAK-994/matched 
placebo will be administered in the morning by mouth (at approximately 8 AM) with 240 mL of 
water after an overnight fast of at least 8 hours; subjects will then be allowed to have a morning 
meal approximately one-half to one hour after study drug administration. The second dose of 
TAK-994/matched placebo will be administered orally approximately 5 hours later at the site. 
Subjects may consume water ad libitum. Standardized meals (approximately 30% fat content 
relative to total calories) will be administered at approximately 4 (lunch) and 10 (dinner) hours 
post the morning dose. On discharge days, lunch or dinner may be taken at home.
On ABPM fitting days (as indicated in Section 3.0), because it is a requirement that the ABPM 
devices begin recording in the morning before the morning dose, site staff may opt to confine 
subjects in the evening before fitting subjects with the APBM monitoring device. If the subject is 
travelling to the site for the ABPM fitting, they should delay their morning dose of study 
medication (between 8 AM ±2 hours) and take their study drug right after the ABPM device 
begins recording the measurements in the clinic. Subjects who are confined the evening prior 
should also take their study drug right after the ABPM recording starts.
While at home, subjects will be instructed to take TAK-994/matched placebo upon arising in the 
morning as close to 8 AM as possible (± 1 hour) and have breakfast approximately one-half to one 
hour after study drug intake whenever possible. Subjects will be instructed to take the second dose 
approximately 5 hours after the morning dose and no later than 2 PM in the afternoon. The second 
dose should be taken without food on an empty stomach (approximately 1 hour before eating or 2 
hours after eating), whenever possible. Subjects are encouraged to take study drug at 
approximately the same time each day in the morning (first dose) and afternoon (second dose). 
Breakfast and lunch should be standard meals each containing approximately 30% fat (relative 
total calories). Subjects will be provided written instructions by the site on how to take study drug 
(dosing and mealtimes) at home.
Tablets should be taken with a large glass of water (approximately 240 mL total). Subjects should 
swallow the study medication whole and not chew it or manipulate it in any way before 
swallowing. Subjects should be instructed to take not more than the prescribed dose at any time. If 
a subject fails to take the TAK-994/matched placebo dose within the time frame specified, s/he 
should be instructed to take it at least 30 minutes before the next scheduled meal. Under no 
circumstance should a subject repeat a dose or double-up doses. If the second dose is missed, that 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 101 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
dose should be skipped and should not be taken again until the next morning. Both doses should 
never be taken at one time.
Subjects will be instructed to record their intake of TAK-994/matched placebo each day, or any 
skipped or mistimed doses, in their electronic dosing diary (Section 9.3.2.7). Additional steps may 
be taken to ensure subjects understand the dosing instructions and that they follow the correct 
TAK-994 dosing regimen, such as additional site communication with the subject throughout the 
treatment course, i.e. on-site visits or phone calls.
Subjects will adhere to the medication and dietary restrictions described in Section 7.3.
7.4.2
Activity
During confinement, subjects should remain upright (seated, standing, or ambulatory) for 4 hours 
as feasible, following dose administration, except as necessitated by the occurrence of an AE or 
study procedure (eg, obtaining 12-lead ECG). Please follow specific instructions for study 
assessments (eg. MWT). 
Subjects should refrain from strenuous physical activity (eg, weightlifting, running, bicycling) 
from 72 hours before check-in until check-out for scheduled study visits. Subjects may engage in 
usual activities at other times with the exception of driving or operating hazardous machinery.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of a subject from the study or study drug 
should be recorded in the electronic case report form (eCRF). The following criteria for 
discontinuation or withdrawal of a subject will apply to all parts of the study:
1. Pretreatment event (PTE), SAE, or AE: The subject has experienced a PTE, SAE, or AE that 
requires early termination because continued participation imposes an unacceptable risk to the 
subject’s health or the subject is unwilling to continue because of the PTE, SAE, or AE.

LFT abnormalities: Study drug should be discontinued immediately with appropriate 
clinical follow-up (including repeat laboratory tests until a subject’s laboratory profile has 
returned to normal/baseline status, see Section 9.2.11.1), if the following circumstances 
occur at any time during the study drug treatment:
–
ALT or AST >5 × ULN.
–
ALT or AST >3 × ULN in conjunction with elevated bilirubin >2 × ULN or 
INR >1.5 .
–
ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).
–
ALT >3 × ULN twice consecutively at least 24 to 48 hours apart.

Suicidality: Study drug should be discontinued immediately for subjects at imminent risk 
of suicide per the C-SSRS (score of 5) or per the investigator’s clinical judgment.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 102 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL

BP increase: Study drug should be discontinued immediately if the median of 3 in-clinic 
BP measurements (at least 10 minutes apart) meets any of the following criteria:
–
Systolic BP ≥160 mmHg and/or diastolic BP ≥100 mmHg.
–
Neurologic or cardiac findings associated with increases in BP.
In the event of BP values meeting the criteria above, the subject will be treated for 
elevated BP according to the best judgment of the investigator and in accordance with 
good medical practice, and, if needed, further emergency medical evaluation sought. If 
the drug is discontinued in any subject due to a BP increase, the subject will not be 
rechallenged with TAK-994.
Any subject found to have significantly elevated BP as an outpatient should be treated 
per standard to care in order to obtain BP lowering. The sponsor or designee (i.e. MM) 
should be notified and consulted.

Pulse rate increase: Increased from baseline earlier in the day and sustained pulse rate 
>100 bpm measured during the in-clinic visit will result in stopping treatment.

Insomnia: Study drug should be discontinued for subjects with sustained severe or serious 
insomnia as determined by the principal investigator after consultation with the sponsor or 
designee (i.e. MM).
2. Significant protocol deviation: The discovery post randomization that the subject failed to 
meet protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject’s health.
3. Lost to follow-up: The subject did not return to the clinic and 3 attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documents. A certified letter can be sent as a last attempt.
4. Voluntary withdrawal: The subject wishes to withdraw from the study. The reason for 
withdrawal, if provided, should be recorded in the eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE should not be recorded in the “voluntary withdrawal” category). If a subject chooses to 
withdraw from study participation due to personal concerns related to the COVID-19 
pandemic (other than a COVID-19-related AE), this should be specified as the reason for 
subject withdrawal in the eCRF.
5. Pregnancy, as described in Appendix D.
6. Other: The reason for discontinuation should be entered into the eCRF including unavoidable 
circumstances such as the COVID-19 pandemic. Subjects may withdraw from the study at any 
time at the discretion of the investigator or sponsor for safety reasons which should be entered 
into the eCRF.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 103 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
7. Study termination: The sponsor, IRB, IEC, or regulatory agency terminates the study. Criteria 
for premature cohort and/or study termination are provided in Section 6.5.5.1.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
early termination visit. The investigator should consult with the sponsor or designee (i.e. MM) 
before subject discontinuation whenever possible.
7.7
Subject Replacement
If a subject withdraws from the study, a replacement subject may be enrolled if deemed 
appropriate by the investigator and sponsor. The study site should contact the sponsor for the 
replacement.
8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug
Details regarding the dosage form description and strengths of the active drug and matching 
placebo can be found in the pharmacy manual. Study drug will be packaged to support enrollment 
and replacement subjects as required.
Tablet strengths for this study are 10, 30, and 90 mg.
On occasion in unavoidable circumstances such as the COVID-19 pandemic, additional drug 
supply may be provided to subjects (either at an in-person visit or delivered to subject’s residence) 
to cover extended periods between on-site visits. Any additional re-supply must be reviewed and 
approved in advance by the sponsor or designee.
8.1.1
Clinical Study Drug Labeling
Study drug containers will be affixed with a clinical label in accordance with local regulatory 
requirements.
8.1.2
Clinical Study Drug Inventory and Storage
Study drug at the sites must be stored in a secure, limited-access location under the storage 
conditions specified on the label and remain in the original container until dispensed. The 
temperature excursion information can be found in the pharmacy manual. Receipt and dispensing 
of study drug at the study site must be recorded by authorized personnel.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 104 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
8.1.3
Clinical Study Drug Blinding
This is a double-blind study; the investigator and subjects are blinded to treatment assignment. 
Treatment identity (name and strength or potency) will be included on the study drug container 
label; emergency randomization code access will be made available through the IRT system in 
accordance with the standard operating procedures of the clinical site.
Details on blinded/unblinded data review for determination of study drug doses and cohort 
initiation are provided in Section 6.2.2.
8.1.4
Randomization Code Creation and Storage
Randomization personnel of the sponsor or designee will generate the randomization schedule for 
the IRT system. 
For Part B, the randomization will be stratified by baseline WCR (<8 vs ≥8) and regions/countries 
(ie North America, Asia [Japan, South Korea], Europe). 
For other parts, the randomization will be stratified by regions/countries (North America, Asia 
[China, Japan, South Korea], Europe.
Details are in the IRT system specifications. The pharmacy manual includes instructions for 
emergency unblinding. Storage conditions are also specified in the pharmacy manual.
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure
The study drug blind will be maintained through a randomization schedule held by the IRT system. 
The study drug blind shall not be broken by the investigator unless information concerning the 
study drug is necessary for the medical treatment of the subject. If possible, the sponsor or 
designee (i.e. MM) should be contacted before the blind is broken. Unblinding will be performed 
per the standard operating procedures of the study site.
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs
The investigator is responsible for keeping accurate records of the study drug received from the 
sponsor or designee, the amount dispensed to and returned by the subjects, and the amount 
remaining at the end of the study. For all study sites, the local country sponsor personnel or 
designee will provide appropriate documentation that must be completed for study drug 
accountability, return, and destruction. Subjects will be instructed to return any remaining study 
drug they may have to the site for assessment of compliance
8.2
Ancillary Supplies
All ancillary supplies will be provided by either the study site or the sponsor or designee, based 
upon availability. The list of ancillary supplies and source information can be found in the 
pharmacy manual or in the referenced compounding manual when applicable. If provided by the 
sponsor, unused ancillary supplies will be accounted for and disposed of as directed by the sponsor 
or designee.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 105 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
9.0
STUDY PROCEDURES
The following sections describe the study procedures to be performed and data to be collected as 
indicated in the Schedules of Study Procedures (Section 3.0).
Alternative Approaches to Study Procedures and Data Collection Due to COVID-19 or 
Other 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 Schedule of Study Procedures 
(Section 3.0), 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 subjects active in the study, all attempts should be made to perform the assessments with 
the subject 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 COVID-19 Pandemic or similar unavoidable circumstances, must 
contact the sponsor or designee to discuss individual subject and site circumstances to 
obtain approval for use of alternative approaches to study procedures and data collection 
due to COVID-19 or other unavoidable circumstances.
–
Sites may seek approval from the sponsor or designee to continue subjects in the study 
despite departures from the Schedule of Study Procedures. The principal investigator is 
expected to evaluate the impact to the safety of the study participants and site personnel for 
subjects to continue. In evaluating such requests, the sponsor or designee will give the 
highest priority to the safety and welfare of the subjects. Subjects must be willing and able 
to continue taking study medication and remain compliant with the protocol. 
–
Other than discharge visits, alternative methods for conducting subject visits (eg, video 
conferencing, telephone visits, or in-home study visits conducted by study site personnel or 
designated medical personnel, contingent upon local regulations) may be used per approval 
by the sponsor or designee:

Under these circumstances, collection of certain study assessments may be omitted and 
visit windows may be extended. 

When approval is given for a subject to miss an in-person study visit, a study site 
physician will speak directly with the subject by telephone or other medium (e.g. a 
computer-based video communication) during each visit window to assess subject 
safety and overall clinical status. 

The study site physician or other qualified site personnel should conduct the following 
assessments within specified-visit window timeframes: AE assessments, 
documentation of concomitant medication, administration of C-SSRS (at applicable 
visits), and an assessment of clinical symptoms.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 106 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL

For this study, home nurses or other qualified clinical personnel may be deployed at the 
request of the site, when appropriate. Advance approval from the sponsor or designee 
should be obtained.

Other study assessments may be collected using an alternative method as feasible, and 
may involve audio or video recording where allowed by local regulation. This will be 
documented in the study records.

Subjects may choose to get COVID-19 vaccine at any time during this study.

In some instances, sites may need to split visits or sites may only be able to perform a 
few procedures on site and some procedures may need to be performed remotely. Sites 
should inform sponsor or designee when this occurs.

Sites may seek approval to extend a visit window in order to conduct an on-site visit. 
Assessments that cannot be completed during the protocol-specified window or within 
the visit window granted by the sponsor or designee will be considered missing data 
and such departures will be recorded in the study records. 
There will be no interval longer than 2 weeks between successive visits at which 
clinical laboratory tests are performed and vital signs are measured. Should the period 
of 2 weeks be met for a particular subject, the site should reach out to the sponsor or 
designee to discuss withdrawal of the subject.
–
Study site personnel may dispense additional IP to subjects at a visit to allow for 
potentially longer intervals between visits than originally planned per protocol, or IP may 
be supplied to subjects via delivery by site personnel or by courier.
–
Early termination visits should be performed in person. When it is not possible for the 
subject to come to the study site and the protocol specified visit window cannot be 
extended further, the preferred alternative for the early termination visit is for qualified 
study site personnel or designated clinical personnel to go to the subject’s residence and 
conduct the protocol-specified procedures in that location. Assessments collected at a 
subject’s residence should comply with applicable local regulations. If neither option is 
available with sponsor or designee approval, sites may conduct early termination 
procedures remotely as is feasible.
All subject discontinuations and alternative approaches to study procedures (ie, procedures not 
conducted per the Schedule of Procedures) due to the COVID-19 pandemic must be documented 
in the study records. Data collected using alternative methods may be handled differently in the 
final data analyses. This will be documented in the Statistical Analysis Plan.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 107 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
Informed consent must be obtained before the subject enters the study and before any 
protocol-directed procedures are performed. The requirements of informed consent (and 
e-consent, if applicable, as per local regulations) are described in Appendix B.
9.1.1.1
Assignment of Subject Numbers
All consented subjects will be given a unique subject number (site number plus a unique sequential 
number) through an IRT system that will be used to identify the subject for all procedures that 
occur during the study. Each subject will be assigned only 1 subject number except in the event of 
rescreens authorized by the sponsor. Subject numbers must not be reused for different subjects.
Rescreening may be allowed up to, but not more than, once for any one subject. Additional 
rescreening may be allowed for COVID-19 related factors. Subjects who were found to not meet 
criteria for NT1, may be re-screened to participate in Part D. Such subjects may enter screening an 
additional time with sponsor or designee approval. Rescreening of any subject must be reviewed 
with the sponsor or designee. Any subject who is screened more than once will be assigned a new 
subject number for each screening event.
9.1.1.2
Study Drug Assignment
On Day 1, subjects will be assigned a randomization number through the IRT system at the clinical 
site. The randomization number encodes the subject treatment assignment according to the 
randomization schedule generated before the study. The randomization number will be recorded 
on the CRF. Each subject will be dispensed blinded study drug assigned by the IRT system 
throughout the study.
9.1.2
Inclusion and Exclusion
Each subject will be assessed through randomization, according to the eligibility criteria provided 
in Section 7.0.
9.1.2.1
The Cataplexy Questionnaire
The cataplexy questionnaire is designed to ascertain the frequency and triggers of cataplexy 
events. It is designed to help differentiate cataplectic events, which are part of the NT1 clinical 
definition from pseudo-cataplexy which would be exclusionary from the NT1 portion of our study. 
For all subjects in Parts B and C, site staff will complete the cataplexy questionnaire. This 
questionnaire along with a copy of the most recent
MSLT report will be submitted to the 
sponsor for adjudication by a committee of experts in the field of narcolepsy/cataplexy to be 
chosen by the sponsor, to determine eligibility for the study. The committee’s determination will 
be final for study entry criteria. Additional documentation may be requested by the sponsor.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 108 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
9.1.3
Medical History/Demography
Qualified site personnel will collect subject significant medical history (past and concurrent 
medical conditions), per the site’s standard of care and appropriate clinical judgment, along with 
subject demographics (eg, date of birth, sex, race [reported by the subject], height, weight, caffeine 
consumption, alcohol consumption, smoking status). Information on the primary disease 
(narcolepsy) will also be collected including age of onset and year of diagnosis. Any prior CSF 
testing results will also be collected.
9.1.4
Concomitant Medications
Qualified site personnel will review subject’s prior and concomitant medication use. Medications 
are defined as prescription and over-the-counter drugs, vaccines, supplements, nutraceuticals, and 
herbal preparations.
Subjects will be asked whether they have taken any medications other than the study drug (during 
a period from the signing of informed consent through the end of the study), and all medications 
used by a subject must be recorded in each subject’s eCRF. The nonproprietary name, route of 
administration, dates of initial and final administrations, and reasons for use must also be recorded.
9.2
Clinical Procedures and Assessments
9.2.1
Physical Examination
Qualified site personnel will conduct full physical examinations (including neurological 
examination) at screening and final visit (final discharge)/early termination. On all other time 
points, an abbreviated PE will be done. 
Subjects undergoing optional CSF sampling during screening will undergo ophthalmological 
assessment of the retina (fundoscopy), a nondilated ophthalmoscopy exam to evaluate for any 
evidence of increased intracranial pressure. If needed, a dilated exam for fundoscopy may be 
performed by a trained person (optometrist, ophthalmologist, or neurologist) after dilatation of the 
pupil in both eyes by administration of tropicamide 0.5% eye drops. After pupil dilatation, subjects 
will be advised to wear sunglasses for the next 4 to 6 hours and avoid operating a car.
9.2.2
Height and Weight
Body weight and height will be obtained with the subject’s shoes off and jacket or coat removed at 
the times indicated in the Schedule of Study Procedures (Section 3.0).
9.2.3
BMI
BMI is defined as a subject’s weight (in kilograms) divided by height (in meters) squared 
(BMI = kg/m2). BMI will be calculated at the times indicated in the Schedules of Study Procedures 
(Section 3.0).
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 109 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
9.2.4
Vital Signs
Vital signs, including pulse rate, systolic and diastolic BP, respiratory rate, and body temperature, 
will be obtained at the times indicated in the Schedule of Study Procedures (Section 3.0).
When assessed in the clinic, BP will be checked (single measurement) with the subject lying in a 
bed resting for a minimum of 5 minutes with the head of the bed at 30 degrees. In the event of 
conflicts between scheduled BP assessment and PK blood draw times, BP assessments should be 
taken first.
For screening Days -45 (or the first screening visit, as applicable) and Day -2, blood pressure 
measurement may be checked up to 3 times and the median value should be used to assess 
eligibility. For all other visits a single measurement should be taken.
Outpatient vital signs monitoring is described in Section 9.2.6.
9.2.5
12-Lead ECGs
ECG monitoring will be obtained according to the Schedule of Study Procedures (Section 3.0).
Special care must be taken for proper lead placement by qualified personnel. Skin should be clean 
and dry before lead placement. Subjects may need to be shaved to ensure proper lead placement. 
Subjects should be resting in a semirecumbent position for at least 5 minutes before each ECG 
measurement and will remain in that position until ECG is completed. The principal investigator 
should arrange to have a study cardiologist available as needed to review ECG tracings with 
abnormalities.
If a subject demonstrates an increase in QTcF interval ≥40 milliseconds compared with a baseline 
measurement, the ECG will be repeated within 5 minutes. The average value of the QTcF interval 
from the 2 ECGs will represent the value at that time point. If the average QTcF interval increase 
from baseline for any postdose time point is ≥40 milliseconds, the subject will continue to be 
monitored by repeat 12-lead ECGs every 60 minutes for at least 4 hours or until the QTcF interval 
is within 40 milliseconds of the baseline value. If prolongation of the QTcF interval 
≥40 milliseconds persists, a consultation with a study cardiologist may be appropriate and the 
sponsor should be notified.
If the QTcF interval is ≥500 milliseconds, the sponsor should be notified and the ECGs should be 
reviewed by a cardiologist. The subject should be considered for transfer to a location where closer 
monitoring is available.
If the subject has unstable hemodynamics, or has any clinically significant dysrhythmias noted by 
telemetry, the subject should be immediately transferred to an acute care setting for definitive 
therapy.
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in place or 
mark the position of the electrodes for subsequent ECGs. To mark the position of the electrodes, 
12-lead electrode sites will be marked on the skin of each subject with an ECG skin marker pen to 
ensure reproducible electrode placement.
For non-commercial use only


For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 111 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
9.2.10
AE Monitoring
AE monitoring begins after signing of the informed consent form. Changes in subject health status 
from the baseline assessment until study drug administration should be captured in the subject’s 
medical history. A complete description of AE collection procedures is provided in Section 10.0.
9.2.11
Laboratory Procedures and Assessments
Laboratory samples will be collected in accordance with acceptable laboratory procedures. A 
discussion between the investigator and the sponsor or designee will take place to consider 
additional lab assessments or rescreening.
9.2.11.1
Safety Clinical Laboratory Tests
Samples for assessment of hematology, chemistry, and urinalysis will be taken as indicated in the 
Schedule of Study Procedures (Section 3.0).
9.2.11.1.1
Hematology
Hematology will consist of the following tests:
Erythrocytes (red blood cell count)
PT/INR b, aPTT a
Hematocrit
Leukocytes (white blood cell count) with absolute 
differential
Hemoglobin
Platelets
aPTT: activated partial thromboplastin time; CSF: cerebrospinal fluid; INR: international normalized ratio; 
PT: prothrombin time.
a For subjects undergoing CSF collection only.
b If ALT or AST >3 times the ULN and for subjects undergoing optional CSF collection.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 112 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
9.2.11.1.2
Chemistry
Chemistry evaluations will consist of the following standard chemistry panel:
Albumin
Chloride
Alkaline phosphatase
Creatinine
ALT
γ-glutamyltransferase
AST
Glucose
Bilirubin (total), if above ULN total bilirubin will be 
fractionated
FSH a
Blood urea nitrogen
Calcium
Potassium
Carbon dioxide
Protein (total)
Triglycerides
Sodium
Lipid panel (HDL, LDL, total cholesterol)
ALT: alanine aminotransferase; AST: aspartate aminotransferase; FSH: follicle-stimulating hormone; HDL: high 
density lipoproteins; LDL: low density lipoproteins; ULN: upper limit of normal.
a Optional; for postmenopausal women.
If subjects experience ALT, or AST >3 × ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, γ-glutamyltransferase, and INR) should be 
performed within 24 to 48 hours after the abnormality is noted. 
As detailed in Section 7.5, subjects with 2 consecutive ALT elevation >3x ULN should be 
withdrawn from the study. For subjects with ALT or AST elevated >3 × ULN at any occasion, the 
investigator must contact the sponsor or designee for consideration of additional testing, close 
monitoring, possible discontinuation of study drug, and discussion of the relevant subject details 
and possible alternative etiologies. The abnormality should be recorded as an AE.
Please refer to Section 7.5 for subject discontinuation criteria regarding abnormal LFTs and 
Section 10.2.8.5 for guidance on reporting abnormal LFTs.
9.2.11.1.3
Urinalysis
Urinalysis will consist of the following tests:
Blood
Nitrite
Glucose
Protein
Urine specific gravity
Urine microscopy will be performed if urinalysis is abnormal. Microscopy consists of red blood 
cell count/high-power field, white blood cell count/high-power field, and casts.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 113 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
9.2.11.2
Diagnostic Screening
Samples for serum screening, alcohol screening, urine drug screening, HLA genotyping, and 
pregnancy testing (if applicable) will be taken as indicated in the Schedule of Study Procedures 
(Section 3.0).
9.2.11.2.1
Serum
The serum diagnostic screening assessment will include the following tests:
HIV
Hepatitis screen (hepatitis B surface antigen, hepatitis C virus)
HIV: human immunodeficiency virus
9.2.11.2.2
Alcohol Screen
Subjects will undergo an alcohol breath test. A serum alcohol test may be performed at the 
discretion of the investigator.
9.2.11.2.3
Urine Drug Screen
The urine drug screening assessment will include the following tests:
Amphetamines
MDMA (3,4-methylenedioxy-methamphetamine)
Barbiturates
Methadone/metabolite
Benzodiazepines
Opiates
Buprenorphine/metabolitea
Oxycodone/oxymorphone
Cannabinoids
Phencyclidine
Cocaine/metabolites
Confirmatory UDS
UDS: Confirmatory urine drug testing will be done where available for all study parts except PART A. See clinical 
laboratory reference document for details. Confirmatory UDS will be done at PI discretion.
a In some regions testing for this substance may not be available.
9.2.11.2.4
HLA-DQB1*06:02 Genotyping
Many patients with NT1 who experience cataplectic attacks have this HLA-DQB1*06:02 
genotype (heterozygous or homozygous expression), and it has been found to correlate with low 
OX concentrations in the CSF. The HLA genotype will be determined only at screening. 
Pre-screening for HLA is allowed per the protocol and will require a separate informed consent. 
Dependent upon local regulations, informed consent for HLA testing may be administered through 
e-consent or be administered over-the-phone for participants who may not live close to the site. In 
these cases, home nurses or other qualified clinical personnel may be deployed by the site to the 
subject’s residence to collect pre-screening HLA sample (as per local regulations).
Part A
The human leukocyte antigen (HLA) genotype should test positive for HLA-DQB1*06:02 -
(positive results for either homozygous or heterozygous alleles will be considered “positive” and 
For non-commercial use only


For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 115 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
9.3.1
PK Measurements
The PK parameters of TAK-994 for each treatment group or cohort will be determined from 
plasma concentrations on study days with serial PK sampling timepoints, as data permit (See 
Table 3.b, Table 3.d, Table 3.f, Table 3.h, Table 3.j, Table 3.l, Table 3.n) using noncompartmental 
analysis methods. Actual sampling times, rather than scheduled sampling times, will be used in all 
computations involving sampling times.
Symbol/Term
Definition
Plasma
AUCτ
Area under the concentration-time curve during a dosing interval, where τ is the 
length of the dosing interval
AUClast
Area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration
Cav,ss
Average plasma concentration during a dosing interval, at steady state, calculated as 
AUCτ/τ
Cmax
Maximum observed concentration
Cmax, ss
Maximum observed concentration during a dosing interval, at steady state
Ctrough
Trough plasma concentration at steady state (observed concentration at the end of a 
dosing interval measured directly before the next study drug administration)
tmax
Time to reach Cmax
Additional PK parameters may be calculated as appropriate. A detailed PK analysis plan will be prepared before PK 
parameter computation.
9.3.1.1
Plasma for PK Measurements
Blood samples (one sample per scheduled time) for plasma TAK-994 concentration will be 
collected according to the schedules of study procedures (Section 3.0). Additional blood samples 
will be collected predose on the days specified in the Schedules of Study Procedures (Section 3.0) 
for measurement of the 4β-hydroxycholesterol/cholesterol ratio to assess CYP3A4/5 activity.
The actual time of sample collection will be recorded on the source document and eCRF. Sampling 
time points may be adjusted based on the preliminary emerging concentration data collected from 
prior subject(s), but the total number of samples collected per subject should not exceed the 
planned number.
Instructions for collecting, processing, and shipping of PK samples are provided in the Central 
Laboratory Reference Document.
9.3.1.2
PK Sample Analysis
Plasma concentrations of TAK-994 and plasma concentrations of 
4β-hydroxycholesterol/cholesterol will be measured by validated high-performance liquid 
chromatography with tandem mass spectrometry assays. Part of the archival plasma samples may 
be used for potential analysis of unknown metabolite characterization, if appropriate.
For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 123 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with the treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
retest and/or continued monitoring of an abnormal value are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation, or monitoring 
of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, X-ray) should NOT be recorded as an AE unless related 
to a study procedure. However, if the subject experiences a worsening or complication of such 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 124 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
a concurrent medical history condition, the worsening or complication should be recorded 
appropriately as an AE (worsening or complication occurs after informed consent is signed). 
Investigators should ensure that the event term recorded captures the change in the condition 
(eg, “worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious, or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change from baseline in the condition (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent 
than that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of an AE after the first administration of 
study medication or after any change in study medication, the worsening or complication 
should be recorded as a new AE. Investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Changes in severity of AEs:

If the subject experiences a change in the severity of an AE that is not associated with a change 
in study medication, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled before signing of informed 
consent are not considered AEs. However, if a preplanned procedure is performed early (eg, as 
an emergency) due to a worsening of the pre-existing condition, the worsening of the condition 
should be captured appropriately as an AE. Complications resulting from any planned surgery 
should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. It is up to the investigator or the reporting physician to decide 
whether a dose is to be considered an overdose, in consultation with the sponsor.

All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the eCRF, in order to capture this important safety information consistently in the 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 125 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
database. AEs associated with an overdose will be documented on AE eCRF(s) according to 
Section 10.0.

SAEs of overdose should be reported according to the procedure outlined in Section 10.2.8.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE-THREATENING.
–
The term “life-threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:
–
May require intervention to prevent Items 1 through 5 above.
–
May expose the subject to danger, even though the event is not immediately 
life-threatening or fatal or does not result in hospitalization.
–
Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
Table 10.a
Takeda Medically Significant AE List
Term
Acute respiratory failure/acute respiratory 
distress syndrome
Hepatic necrosis
Acute liver failure
Torsade de pointes/ventricular fibrillation/
ventricular tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizures
Pulmonary fibrosis
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Toxic epidermal necrolysis/
Stevens-Johnson syndrome
Neuroleptic malignant syndrome/malignant hyperthermia
Spontaneous abortion/stillbirth and fetal death
AE: adverse event.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 126 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Sections 10.1 and 10.1.1).
10.1.2
Special Interest AEs
Special interest AEs have not been defined for this study.
10.2
AE Procedures
10.2.1
Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
An AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort, but poses no significant or permanent risk of harm to the research 
participant.
Severe:
An AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
10.2.2
Assigning Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a 
drug (including the course after withdrawal of the drug) or study procedure or 
for which a causal relationship is at least a reasonable possibility (ie, the 
relationship cannot be ruled out), although factors other than the drug, such as 
underlying diseases, complications, concomitant drugs, and concurrent 
treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration 
of a drug or study procedure and/or that can reasonably be explained by other 
factors, such as underlying diseases, complications, concomitant medications, 
and concurrent treatments.
10.2.3
Start Date
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 127 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
10.2.4
End Date
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae, or the subject died.
10.2.5
Pattern of AE (Frequency)
Episodic AEs (eg, headache) or those that occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.6
Action Taken With Study Treatment

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a study medication was stopped for a reason other than the particular AE 
(eg, the study has been terminated, the subject died, dosing with study medication had not yet 
started, or dosing with study medication was already stopped before the onset of the AE).

Drug interrupted – the dose was interrupted due to the particular AE.
10.2.7
Outcome

Recovered/resolved – subject returned to first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by one or more stages: the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved but has not 
returned to the normal range or to the baseline value; or the subject died from a cause other 
than the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs, or symptoms; the 
intensity of the diagnosis, signs/symptoms, or laboratory value on the last day of the observed 
study period has become worse than when it started; the AE is an irreversible congenital
anomaly; or the subject died from another cause, with the particular AE state remaining “Not 
recovered/not resolved.”

Recovered/resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – an AE that is considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 128 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
10.2.8
Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal LFTs
10.2.8.1
Collection Period
Collection of AEs (ie, AEs, SAEs, Special Interest AEs, and abnormal LFTs) will commence at the 
time the subject signs the informed consent. Routine collection of AEs will continue until 
approximately 30 days or 5.5 half-lives, whichever is longer, after the last dose of investigational 
product. For subjects who discontinue before the administration of study medication, AEs will be 
followed until the subject discontinues study participation.
10.2.8.2
Reporting AEs
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question (eg, “How have you been feeling since your last visit?”) may be asked. Subjects
may report AEs occurring at any other time during the study. Subjects experiencing an SAE before 
the first exposure to investigational product must be monitored until the symptoms subside and 
any clinically relevant changes in laboratory values have returned to baseline or there is a 
satisfactory explanation for the change. Nonserious AEs that begin before the first exposure to 
investigational product, related or unrelated to the study procedure, need not be followed up for the 
purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All AEs will be documented in the AE page of the eCRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:

Event term.

Start and end date and time.

Pattern of AE (frequency).

Severity/intensity.

Causality (Investigator’s opinion of the causal relationship between the event and 
administration of study drug[s]).

Action taken with study drug.

Outcome of event.

Seriousness.
In addition, additional information regarding following AEs may be collected on CRF:

Increased urinary urgency and frequency (daily urinary frequency), urinary incontinence
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 129 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
10.2.8.3
Reporting SAEs
When an SAE occurs through the AE collection period, it should be reported according to the 
procedure outlined below:
SAEs should be reported via SAE eCRF in Rave EDC, which is the preferred method of reporting. 
A Takeda SAE form must be completed, in English, and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
If access to Rave EDC is not feasible within 24 hours of receiving the event, the paper SAE form 
should be submitted via fax. The SAE form should be completed within 24 hours of first onset or 
notification of the event, signed by the investigator, and transmitted via fax or email to the 
attention of the contact listed in Section 14.1.1. In case of fax, site personnel need to confirm 
successful transmission of all pages and include an email address on the fax cover sheet so that an 
acknowledgment of receipt can be returned via email within 1 business day.
Email submission of SAE forms (to the appropriate email address listed below) with a PDF 
attachment should only be used in the case where fax is not possible and access to Rave EDC is not 
feasible within 24 hours of receiving the event. In case of email, site personnel need to confirm 
successful transmission by awaiting an acknowledgment of the receipt via e mail within 1 business 
day.

United States and Canada: PVSafetyAmericas@tpna.com.

Rest of World: eupv@tgrd.com.
If SAEs are reported via fax or by email, Rave EDC must be updated as soon as possible with the 
appropriate information.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of SAEs that begin before the first administration of investigational product will follow 
the same procedure for SAEs occurring on treatment.
10.2.8.3.1
SAE Follow-Up
If information not available at the time of the first report becomes available at a later date, the 
investigator should update SAE eCRF in Rave EDC or complete a follow-up SAE form or provide 
other written documentation and fax it immediately within 24 hours of receipt. Copies of any 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 130 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
relevant data from the hospital notes (eg, ECGs, laboratory tests, discharge summary, postmortem 
results) should be sent to the addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.2.8.4
Reporting Special Interest AEs
No special interest AEs have been defined for this study. 
10.2.8.5
Reporting of Abnormal LFTs
If a subject is noted to have ALT or AST elevated >3 × ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE, and the subject should be withdrawn from the study. In 
addition, an LFT Increases eCRF must be completed providing additional information on relevant 
recent history, risk factors, clinical signs and symptoms, and results of any additional diagnostic 
tests performed.
If a subject is noted to have ALT or AST >3 × ULN and total bilirubin >2 × ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.8.3. The investigator must contact the sponsor or designee for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease. Follow-up laboratory tests as described in Section 9.2.11 must also be 
performed. In addition, an LFT Increases eCRF must be completed and transmitted with the 
Takeda SAE form (as per Section 10.2.9).
10.2.9
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in investigational medicinal product administration or in the overall 
conduct of the study. The investigational site will also forward a copy of all expedited reports to 
his or her IRB or IEC in accordance with national regulations.
11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized before the unblinded data review 
for the first 9 subjects in Cohort A1 (Cohort A1a). This document will provide further details 
For non-commercial use only


For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 132 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
after randomization. In full analysis set efficacy summaries and analysis, subjects will be analyzed 
by the treatment to which they were randomized.
11.1.2
Analysis of Demography and Other Baseline Characteristics
Demography and other baseline characteristics will be summarized by treatment groups and will 
be listed. Data from subjects receiving placebo will be pooled as appropriate for each part/study 
group. Descriptive statistics will be used to summarize data for continuous variables like age and 
weight (number of subjects [N], mean, median, SD, minimum, and maximum) and for categorical 
variables like sex, ethnicity, race, HLA positive/negative, and baseline WCR (≤8 vs. >8) (number 
and percentage of subjects within each category). Medical history and medication history will be 
listed by subject.
11.1.3
PK Analysis
Individual plasma concentrations of TAK-994 in subjects with NT1 or NT2 will be presented in a 
data listing and summarized by day, and nominal sampling time point using descriptive statistics 
for each treatment (arithmetic mean, SD, coefficient of variation, median, minimum, maximum, 
and geometric mean). Individual plasma noncompartmental analysis PK parameters obtained in 
NT1 and in NT2 will be tabulated and summarized descriptively by day for each treatment. As data 
permit, the 4β-hydroxycholesterol/cholesterol ratio, measured predose throughout the treatment 
period, will also be summarized descriptively for each treatment to assess CYP3A4/5 activity over 
time.
TAK-994 plasma concentration-time data collected in this study will be combined with other 
clinical study data to develop a population PK model of TAK-994 in subjects with NT1 or NT2. 
The objectives and details of this modeling approach will be described in a separate analysis plan, 
and the results of this analysis will be reported separately.
There will be no imputation of incomplete or missing PK concentration data.
11.1.4
Efficacy
 Analysis
For each study part/subject group, observed MWT, ESS, WCR, and 
, and 
change from baseline (or shift tables) will be summarized by treatment and overall. 
The efficacy analyses include the linear mixed effect models for repeated measures on change 
from baseline in the mean sleep latency from the MWT and ESS scores. In these models, baseline 
will be included as a covariate; treatment, day, and treatment by day interaction will be included as 
fixed factors. CSF orexin levels may be included as a covariate in the model. Bayesian models will 
also be used on the change from baseline in the sleep latency and change from baseline in the ESS 
score to evaluate the posterior probability of the true TAK-994 effect in delaying the sleep onset to 
>8, 14, and 20 minutes and reducing the ESS (>4 points and >8 points reduction). In addition, 
p-values and 95% CIs for pairwise comparisons between each TAK-994 dose group to placebo 
will be generated.
For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 136 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
A sample size of 21 in each group will have 98% power to detect a 14-minute difference in means 
of change from baseline between a TAK-994 dose group and placebo in sleep latency using a 
2-sample t-test with a 5% 2-sided significance level. The power to detect an 8-point reduction in 
means of change from baseline between a TAK-994 dose group and placebo in the total ESS score 
is estimated to be approximately 95% using a 2-sample t-test with a 5% 2-sided significance level. 
The power to detect a 50% reduction in WCR from that of placebo group is estimated to be 
approximately 93% using a 2-incidence-rate ratio test using Poisson model with a 5% 2-sided 
significance level. 
A fixed sequence of tests with MWT at high and middle doses first followed by ESS at high and 
middle doses and WCR at high and middle doses will be applied. The overall power for the entire 
testing procedure is approximately 75% (the square of the product of the power of each individual 
test, 98%, 95%, and 93% respectively) under the assumption that these 3 endpoints are 
independent at all dose levels. The overall power may be higher or lower than 75% depending on 
the assumed correlation structure of these 3 endpoints. There is no known reliable data to support 
any particular assumption on the correlation structure.
To allow for a 25% dropout rate, 28 subjects per group will be enrolled for Part B. The enrollment 
can be stopped once the number of evaluable 21 subjects is reached. A blinded sample size 
re-estimation will be performed before Part B starts. The change in the sample size of Part B after 
the re-evaluation, along with justification, will be documented in the clinical study report. 
The SD for the change from baseline in the sleep latency is assumed to be 11 minutes. The SD for 
the change from baseline in the ESS score is assumed to be 7 points. The incidence rate of WCR at 
baseline is assumed to be 3.
12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the sponsor or its 
designee (clinical research organization) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or the 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, study drug, subject medical records, informed consent documentation, and 
review of eCRFs and associated source documents. It is important that the investigator and other 
study personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
12.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances (such as the
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 137 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
COVID-19 pandemic), arise that will require deviation from protocol-specified procedures, the 
investigator should consult with the sponsor or designee (and IRB or IEC, as required) to 
determine the appropriate course of action. There will be no exemptions (a prospectively approved 
deviation) from the inclusion or exclusion criteria.
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment.
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency [MHRA], the Pharmaceuticals and Medical Devices Agency 
[PMDA] of Japan). If the study site is contacted for an inspection by a regulatory body, the sponsor 
should be notified immediately. The investigator guarantees access for quality assurance auditors 
to all study documents as described in Section 12.1.
13.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the International Council on Harmonisation (ICH) of Technical Requirements for 
Pharmaceuticals for Human Use for GCP. Each investigator will conduct the study according to 
applicable local or regional regulatory requirements and align his or her conduct in accordance 
with the “Responsibilities of the Investigator”. The principles of Helsinki are addressed through 
the protocol and through appendices containing requirements for informed consent and 
investigator responsibilities.
13.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the informed consent 
form, and, if applicable, subject recruitment materials and/or advertisements and other documents 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 138 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
required by all applicable laws and regulations must be submitted to a central or local IRB or IEC 
for approval. The IRB’s or IEC’s written approval of the protocol and subject informed consent 
must be obtained and submitted to the sponsor or designee before commencement of the study (ie, 
before shipment of the sponsor-supplied drug or study-specific screening activity). The IRB or 
IEC approval must refer to the study by exact protocol title, number, and version date; identify 
versions of other documents (eg, informed consent form) reviewed; and state the approval date. 
The sponsor will ship drug/notify the site once the sponsor has confirmed the adequacy of site 
regulatory documentation and, when applicable, the sponsor has received permission from 
competent authority to begin the study.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to the IRB or IEC. 
All IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
13.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and, if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor before use. When applicable, study 
participation consent may be obtained by e-consent. 
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 139 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
The subject must be given ample opportunity to: (1) inquire about details of the study and 
(2) decide whether or not to participate in the study. If the subject determines he or she will 
participate in the study, then the informed consent form and subject authorization form (if 
applicable) must be signed and dated by the subject at the time of consent and before the subject 
entering into the study. The subject should be instructed to sign using their legal names, not 
nicknames, using blue or black ballpoint ink. The investigator must also sign and date the informed 
consent form and subject authorization form (if applicable) at the time of consent and before 
subject entering into the study; however, the sponsor may allow a designee of the investigator to 
sign to the extent permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects in the same 
manner as the original informed consent. The date the revised consent was obtained should be 
recorded in the subject’s medical record, and the subject should receive a copy of the revised 
informed consent form.
Subjects who consented and provided a blood sample for DNA and RNA analysis can withdraw 
their consent and request disposal of a stored sample at any time before analysis. Notify sponsor of 
consent withdrawal.
13.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, MHRA, PMDA), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 13.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 140 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
13.4
Publication, Disclosure, and Clinical Study Registration Policy
13.4.1
Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the Clinical Study Site Agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
13.4.2
Clinical Study Registration
In order to ensure that information on clinical studies 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 studies it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with the investigator’s city, state (for Americas investigators), country, 
and recruiting status, will be registered and available for public viewing.
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting study 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the study. The investigative sites are encouraged to handle the study 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of study enrollment, they should be referred to the sponsor.
Any investigator who objects to the sponsor providing this information to callers must provide the 
sponsor with a written notice requesting that their information not be listed on the registry site.
13.4.3
Clinical Study Results Disclosure
Takeda will post the results of clinical studies on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws, and/or regulations.
13.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the Clinical Study Site Agreement regarding the sponsor’s policy on subject compensation and 
For non-commercial use only


For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 142 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
14.1.2
Investigator Agreement
I confirm that I have read and that I understand this protocol, the IB, package insert, and any other 
product information provided by the sponsor. I agree to conduct this study in accordance with the 
requirements of this protocol and also to protect the rights, safety, privacy, and well-being of study 
subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council on Harmonisation, E6 Good Clinical Practice: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.2.9 of this protocol.

Terms outlined in the study site agreement.

Responsibilities of the investigator (Appendix A).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 143 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
14.1.3
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific study-related 
activities will perform these activities in full or in partnership with the sponsor.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 144 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
14.1.4
List of Abbreviations
AE
adverse event
ALT
alanine aminotransferase
ABPM
ambulatory blood pressure monitoring
AHI
Apnea-Hypopnea Index
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC∞
area under the concentration-time curve from time 0 to infinity
AUC24
area under the concentration-time curve from time 0 to 24 hours
AUCτ
area under the concentration-time curve during a dosing interval
BCRP
breast cancer resistance protein
BID
twice daily
BMI
body mass index
BP
blood pressure
CFR
Code of Federal Regulations
Cmax
maximum observed concentration
CNS
central nervous system 
COVID-19
coronavirus disease 2019
CSF
cerebrospinal fluid
C-SSRS
Columbia Suicide Severity Rating Scale
CYP
cytochrome P-450
ECG
electrocardiogram
eCRF
electronic case report form
EDS
excessive daytime sleepiness
ePRO
electronic patient-reported outcome
ESS
Epworth Sleepiness Scale
FDA
Food and Drug Administration
FIH
first-in-human
GCP
Good Clinical Practice
GLDH
glutamate dehydrogenase
hERG
human ether-à-go-go-related gene
HLA
human leukocyte antigen
IA
interim analysis
IB
Investigator’s Brochure
IC50
50% inhibitory concentrations
ICH
International Council on Harmonisation
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 145 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
ICSD-3
International Classification of Sleep Disorders, 3rd edition
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
LFT
liver function test
MATE
multidrug and toxin extrusion transporter
MAV
markedly abnormal value
MDD
major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
MM
medical monitor
MRD
multiple-rising dose
MSLT
multiple sleep latency test
MWT
Maintenance of Wakefulness Test
NOAEL
no-observed-adverse-effect level
NT1
narcolepsy type 1 (narcolepsy with cataplexy)
NT2
narcolepsy type 2 (narcolepsy without cataplexy)
OAT
organic anion transporter
OATP
organic anion transporting polypeptide
OCT
organic cation transporter
OX
orexin
OX-1
orexin 1
OX1R
orexin type-1 receptor
OX2R
orexin type-2 receptor
Penh
enhanced pause
Pgp
P-glycoprotein
PK
pharmacokinetic(s)
PLMS
Periodic Limb Movements of Sleep
PMDA
Pharmaceuticals and Medical Devices Agency
PROMIS
Patient-Reported Outcomes Measurement Information System
PT
prothrombin time
PTE
pretreatment event
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 146 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
QD
once daily
QTcF
QT interval with Fridericia’s correction method
REM
rapid eye movement
RLS
restless leg syndrome
SAE
serious adverse event
SAP
statistical analysis plan
SOREMP
sleep onset REM period
SUSARs
suspected unexpected serious adverse reactions
t1/2z
terminal elimination half-life
TEAE
treatment-emergent adverse event
Tg
transgenic
tmax
time of first occurrence of Cmax
ULN
upper limit of normal
VAS
visual analog scale
WCR
weekly cataplexy rate
15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent conditions will be coded using MedDRA. Drugs will be 
coded using the World Health Organization Drug Dictionary.
15.1
CRFs (Electronic and Paper)
Completed eCRFs are required for each subject who signs an informed consent form.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Corrections are recorded in an audit trail that captures the old information, new information, 
identification of the person making the correction, date the correction was made, and reason for 
change. Reasons for significant corrections should additionally be included.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 147 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the eCRFs should be made by the investigator with use of change and modification records of 
the eCRFs. The principal investigator must review the data change for completeness and accuracy 
and must sign and date.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
15.2
Record Retention
The investigator agrees to keep the records stipulated in Section 15.1 and those documents that 
include (but are not limited to) the study-specific documents, identification log of all participating 
subjects, medical records, temporary media (eg, thermal-sensitive paper), source worksheets, all 
original signed and dated informed consent forms, subject authorization forms regarding the use of 
personal health information (if separate from the informed consent forms), electronic copy of 
eCRFs (including the audit trail), and detailed records of drug disposition to enable evaluations or 
audits from regulatory authorities, the sponsor, or its designees. Any source documentation printed 
on degradable thermal-sensitive paper should be photocopied by the site and filed with the original 
in the subject’s chart to ensure long-term legibility. Furthermore, ICH E6 Section 4.9.5 requires 
the investigator to retain essential documents specified in ICH E6 (Section 8) until at least 2 years 
after the last approval of a marketing application for a specified drug indication being investigated 
or, if an application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents.
For non-commercial use only


For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 149 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
17.
Janssen M, Pickard AS, Golicki D, Gudex C, Niewada M, Scalone L, et al. Measurement 
properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a 
multi-country study. Quality of Life Research 2013;22(7):1717-27.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 150 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Appendix A
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH guidelines of GCP and all the 
applicable local laws and regulations. The responsibilities imposed on investigators by the FDA 
are summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed 
and signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
study-related duties and functions, the investigator/institution should ensure that this 
individual or party is qualified to perform those study-related duties and functions and should 
implement procedures to ensure the integrity of the study-related duties and functions 
performed and any data generated.
4. Ensure that study-related procedures, including study-specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, before the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH, and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
ePROs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 151 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
contact and receive written approval from the sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
13. Report adverse reactions to the sponsor promptly. In the event of a SAE, notify the sponsor 
within 24 hours.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 152 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 153 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject may discontinue 
participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject will be informed in a timely manner if information becomes 
available that may be relevant to the subject’s willingness to continue participation in the 
study.
22. A statement that results of DNA analysis will not be disclosed to an individual, unless 
prevailing laws require the sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) That personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs.
b) It is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law.
c) That personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies.
d) That subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research.
e) That the subject’s identity will remain confidential in the event that study results are 
published.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 154 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from signing the informed consent and throughout the duration of the study, and for 5 
half-lives plus 30 days after the last dose of study drug. Regular pregnancy tests will be 
performed throughout the study for all female subjects of childbearing potential. If a subject is 
found to be pregnant during study, study drug will be discontinued and the investigator will 
offer the subject the choice to receive unblinded treatment information.
26. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study and for 5 half-lives 
plus 90 days after the last dose of study drug. If the partner or wife of the subject is found to be 
pregnant during the study, the investigator will offer the subject the choice to receive 
unblinded treatment information.
27. A statement that clinical study information from this study will be publicly disclosed in a 
publicly accessible website, such as ClinicalTrials.gov.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 155 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Appendix C
Investigator Consent to the Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
The 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 the 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 medication.

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 study registries, databases, and websites.
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.
The investigator acknowledges and consents to the use of his or her personal information by 
Takeda and other parties for the purposes described above.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 156 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Appendix D
Pregnancy and Contraception
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the study, and for 5 half-lives PLUS 
90 days after last dose of study drug, nonsterilized** male subjects who are sexually active with a 
female partner of childbearing potential* must use barrier contraception (eg, condom with 
spermicidal cream or jelly). In addition, they must be advised not to donate sperm during this 
period. Women of childbearing potential who are partners of male subjects are also advised to use 
additional contraception shown in the list of highly effective contraception below.
Female Subjects and Their Male Partners
From the signing of the informed consent throughout the duration of the study, and for 5 half-lives 
PLUS 30 days after last dose of study drug, female subjects of childbearing potential* who are 
sexually active with a nonsterilized male partner** must use:
Two highly effective methods of contraception (from the list below). 
In addition, they must not donate ova during this period.
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* A woman is considered a woman of childbearing potential (ie, fertile) following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses 
for 12 months without an alternative medical cause. A high FSH level in the postmenopausal range 
(FSH >40 IU/L) may be used to confirm a postmenopausal state in younger women (eg, those aged 
<45 years) or women who are not using hormonal contraception or hormonal replacement therapy. 
However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
** Sterilized males should be at least 1-year post-bilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as “those, alone or in combination, 
that result in a low failure rate” (ie, less than 1% failure rate per year when used consistently 
and correctly). In this study, the only acceptable methods of contraception are as follows:

Nonhormonal Methods:
–
Intrauterine device.
–
Bilateral tubal occlusion.
–
Vasectomized partner (provided that partner is the sole sexual partner of the study 
participant and that the vasectomized partner has received medical assessment of the 
surgical success).
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 157 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL

Hormonal Methods: Hormonal contraception may be susceptible to interaction with the 
investigative compound or concomitant medications, which may reduce the efficacy of the 
contraception method. Therefore, study subjects using hormonal contraception must also 
use an additional barrier method (male condom, female condom, or diaphragm) throughout 
the duration of the study, and for 5 half-lives PLUS 30 days after last dose of study drug.
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation. Contraception must be initiated at least 3 months before the 
first dose of study drug. If female subjects have been taking progestogen-only 
hormonal contraception for less than 3 months before the first dose of study drug, 
female subjects must also (or partners of male subjects are advised to) employ a barrier 
method (male condom, female condom or diaphragm) until she has been on
contraceptive for 3 months. The options below are included in the category of 
progestogen-only hormonal contraception

Oral†.

Intravaginal† (eg, ring).

Transdermal†.
–
Progestogen-only hormonal contraception associated with inhibition of ovulation. 
Important: Progestogen-only hormonal contraception must be initiated at least 3 
months before the first dose of study drug. If female subjects have been taking 
progestogen-only hormonal contraception for less than 3 months before the first dose 
of study drug, female subjects must also (or partners of male subjects are advised to) 
employ a barrier method (male condom, female condom or diaphragm) until she has 
been on contraceptive for 3 months. The options below are included in the category of 
progestogen-only hormonal contraception:

Oral†.

Injectable.

Implantable.
2. Unacceptable methods of contraception are as follows:

Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 158 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL

Declared sexual abstinence is NOT an acceptable method of contraception (unless 
approved by the investigator). 
3. Subjects will be provided with information on highly effective/effective methods of 
contraception as part of the subject informed consent process and will be asked to sign a 
consent form stating that they understand the requirements for avoidance of pregnancy, and 
not to donate ova or sperm during the course of the study. 
4. During the course of the study, regular hCG pregnancy tests will be performed only for women 
of childbearing potential, and all subjects (male and female) will receive continued guidance 
with respect to the avoidance of pregnancy and ova donation and sperm donation as part of the 
study procedures. Such guidance should include a reminder of the following:
5.
In addition to a negative hCG pregnancy test at screening, female subjects of childbearing 
potential must also have confirmed menses in the month before first dosing (no delayed 
menses). Subjects must also have a negative hCG pregnancy test within 24 hours before 
receiving the first dose of investigational drug as close as possible and before the first dose of 
investigational drug, preferably on the same day.
General Guidance With Respect to the Avoidance of Pregnancy
Such guidance should include a reminder of the following:
a) Contraceptive requirements of the study.
b) Reasons for use of barrier methods (ie, condom) in males with pregnant partners.
c) Assessment of subject compliance through questions such as
i.
Have you used the contraception consistently and correctly since the last visit?
ii.
Have you forgotten to use contraception since the last visit?
iii.
Are your menses late (even in women with irregular or infrequent menstrual cycles, a 
pregnancy test must be performed if the answer is “yes”).
iv.
Is there a chance you (or your partner) could be pregnant? It is recommended that a 
pregnancy test be performed if a pregnancy is suspected.
Pregnancy/Suspected Pregnancy
If any subject is found to be pregnant during the study, she should be withdrawn and any 
sponsor-supplied drugs should be immediately discontinued. In addition, any pregnancies in the 
partner of a male subject during the study or for 5 half-lives plus 90 days after the last dose should 
also be recorded following authorization from the subject’s partner.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of the right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
Subjects randomized to placebo need not be followed.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 159 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the female 
subject/female partner of the subject was participating in a clinical study at the time she became 
pregnant and provide details of the study drug the subject received (blinded or unblinded, as 
applicable).
All pregnancies in subjects, including female partners of male subjects, on active study drug will 
be followed up to the 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.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 160 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Appendix E
ICSD-3 Diagnostic Criteria for Narcolepsy
The criteria for NT1 (narcolepsy with cataplexy) are as follows: Criteria a) and b) must be met.
a) The subject has daily periods of irrepressible need to sleep or daytime lapses into sleep 
occurring for at least 3 months.
b) The presence of 1 and 2 or 3 of the following:
1. Cataplexy (as defined under essential features).
2. A mean sleep latency of ≤8 minutes and 2 or more sleep onset REM periods (SOREMPs) 
on a MSLT performed according to standard techniques. A SOREMP (defined as the 
appearance of REM sleep within 15 minutes of sleep onset) on the preceding nocturnal 
polysomnogram may replace 1 of the SOREMPs on the MSLT.
3. The cerebrospinal fluid hypocretin-1 concentration, measured by immunoreactivity, is 
either ≤110 pg/mL or <1/3 of the mean values obtained in normal subjects with the same 
standardized assay.
The criteria for NT2 (narcolepsy without cataplexy) are as follows: (Criteria A-E must all be met)
A. The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep 
occurring for at least three months.
B. A mean sleep latency of <8 minutes and 2 or more SOREMPs are found on a MSLT 
performed according to standard techniques. A SOREMP (REM sleep appearing 
within 15 minutes of sleep onset) on the preceding nocturnal polysomnogram may 
replace 1 of the SOREMPs on the MSLT.
C. Cataplexy is absent.
D. Either CSF orexin-1 concentration has not been measured or CSF orexin-1 
concentration measured by immunoreactivity is either >110 pg/mL or >1/3 of mean 
values obtained in normal subjects with the same standardized assay.
E. The hypersomnolence and/or MSLT finding 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. 
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 161 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Appendix F
List of Inhibitors and Inducers of CYP3A 
Known moderate and strong CYP3A inhibitors or inducers and listed below:
Strong CYP3A inhibitors: clarithromycin, troleandomycin, cobicistat, conivaptan, boceprevir, 
danoprevir, ritonavir, elevitegravir, indinavir, saquinavir, idelalisib, itraconazole, ketoconazole, 
voriconazole, posaconazole, lopinavir, nefazodone, nelfinavir, paritaprevir, ombitasvir, dasabuvir, 
telaprevir, tipranavir.
Moderate CYP3A inhibitors: amprenavir, aprepitant, atazanavir, casopitant, 
cimetidine,ciprofloxacin, clotrimazole, crizatinib, cyclosporin, diltiazem, dronadarone, 
erythromycin, fluconazole, fosamprenavir, fluvoxamine, miconazole, imatinib, istradefylline, 
tofisopam, verapamil.
Strong CYP3A inducers: carbamazepine, enzalutamide, mitotane, phenobarbital, phenytoin, 
rifabutin, rifampicin.
Moderate CYP3A inducers: bosentan, efavivenz, etravirine, modafinil.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 162 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Appendix G
Criteria for Identification of Markedly Abnormal Laboratory
Values-Hematology and Serum Chemistry
Hematology—Criteria for Markedly Abnormal Values
Parameter
Unit
Low Abnormal
High Abnormal
Hemoglobin
Both 
<0.8 × LLN
>1.2 × ULN
Hematocrit
Both
<0.8 × LLN
>1.2 × ULN
RBC count 
Both
<0.8 × LLN 
>1.2 × ULN
WBC count 
Both 
<0.5 x LLN
>1.5 x ULN
Platelet count
Conventional
<75 x 103/L
>600 x 103/L
SI
<75 x 109/L
>600 x 109/L
LLN: lower limit of normal; RBC: red blood cell; ULN: upper limit of normal: WBC: white blood cell. 
Serum Chemistry—Criteria for Markedly Abnormal Values
Parameter
Unit 
Low Abnormal
High Abnormal
ALT
Both
--
>3x ULN
AST
Both
--
>3x ULN
GGT
Both
--
>3x ULN
Alkaline phosphatase
Both
--
>3x ULN
Total bilirubin
Conventional
--
>1.5x ULN
SI
--
>1.5x ULN
Albumin
Conventional 
<2.5 g/dL
--
SI 
<25 g/L
--
Total protein
Both
<0.8x LLN
>1.2x ULN
Creatinine
Conventional 
--
>1.5x ULN 
SI
>1.5x ULN 
Blood urea nitrogen
Conventional 
>40 mg/Dl
SI
>10.7 mmol/L
Sodium
Conventional
<130 mEq/L
>150 mEq/L
SI
<130 mmol/L
>150 mmol/L
Potassium
Conventional
<3.0 mEq/L
>5.3 mEq/L
SI
<3.0 mmol/L
>5.3 mmol/L
CPK
Both
--
>3x ULN
Glucose
Conventional
<50 mg/dL
>300 mg/dL
SI
<2.8 mmol/L
>19.4 mmol/L
Calcium
Conventional
<7.7 mg/dL
>11.1 mg/dL
SI
<1.92 mmol/L
>2.77 mmol/L
ALT: alanine aminotransferase; AST: aspartate aminotransferase; CPK: creatine phosphokinase; GGT: -glutamyl 
transferase; LLN: lower limit of normal; ULN: upper limit of normal.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 163 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Appendix H
Criteria for Identification of Markedly Abnormal Laboratory Values for 
Vital Signs
Parameter
Unit
Lower Criteria 
Upper Criteria
Pulse
bpm
<40 
>115
Systolic blood pressure
mm Hg
<90 
≥ 160 
Diastolic blood pressure
mm Hg
<50 
≥100
Systolic blood pressure change
mm Hg
>20, >30 
Diastolic blood pressure change
mm Hg 
>20, >30
Body temperature
oC
>38.5 
Respiratory Rate
Breath/min
>21
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 164 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Appendix I
Criteria for Identification of Markedly Abnormal Laboratory Values for 
ECGs
Parameter
Lower Criteria 
Upper Criteria
Heart rate
<40 beats per minute
>115 beats per minute
PR
≤80 milliseconds
≥200 milliseconds
QTcF Interval
≤300 milliseconds
>500 milliseconds OR 
≥30 milliseconds change from baseline and >450 
milliseconds
QRS
≤80 milliseconds
≥180 milliseconds
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 165 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Appendix J
Protocol History
Date
Amendment Number
Region
15 January 2021
Amendment 3
Global
05 June 2020
Amendment 02
Global
13 March 2020
Amendment 01
Global
26 November 2019
Initial version
Global
Rationale for Amendment 02:
This document describes the changes to the protocol incorporating Amendment 02.
In addition to the overview of changes provided below, in this amendment minor grammatical,
editorial, formatting, and administrative changes not affecting the conduct of the study are
included for clarification and administrative purposes only.
The primary reason for amending this study design is that the information generated will inform 
the design and dose selection for the further development of TAK-994 as a potential treatment for 
narcolepsy with cataplexy (NT1) and narcolepsy without cataplexy (NT2) and to further the phase 
3 program development. Changes have also been made also to address the Food and Drug 
Administration (FDA) feedback (on liver enzyme testing criteria for study inclusion and 
pharmacokinetics [PK]) on the prior Amendment 01. 
These considerations are described below.
Since this is the first study of TAK-994 in NT1 and NT2 subjects, Parts A and D of the study have 
a multiple-rising dose (MRD) design to evaluate the safety, tolerability, PK, 
 
 effects of TAK-994 after repeated oral, twice daily (BID) dosing in 
subjects with NT1 and NT2. 
Part B is a dose ranging design that characterizes the efficacy and safety of 8-week treatment of 
TAK-994 in 3 different dose levels or placebo, a total of 4 parallel arms. This will be performed 
after the MRD Part A in NT1 subjects is completed and appropriate dose levels are identified. 
Another major reason for this amendment is to describe management of study procedures (eg, 
alternative strategies for collecting data, conducting study visits and distributing investigational 
product) during unexpected, unavoidable circumstances (eg, a widespread disease outbreak or 
natural disaster) such as the coronavirus disease 2019 (COVID-19) pandemic. 
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only.
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 166 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Protocol Amendment 02
Summary of Changes Since the Last Version of the Approved Protocol
Description of Each Change and Rationale
Section(s) Affected by Change
Description
Rationale
Location(s)
1. Organization address has been updated.
To document a legal change in the 
sponsor address.
Title page
2. Overall study description changed due to 
the study design.
Overall number of subjects to be enrolled 
has increased.
Schematics for different parts of the study 
have been updated according to the updated 
design.
Additional schedule of assessment tables 
have been added for clarification purposes.
Previous cohort #3 (Amendment 
01) has now been changed to a 
4-arm parallel group dose ranging 
part (Part B) to evaluate 3 dose 
levels of TAK-994 versus 
placebo. Part B evaluates efficacy 
as the primary endpoint. Duration 
of dosing in Part B has also been 
increased to 56 days to support the 
longer duration of treatment in 
future Phase 3 studies. The 
number of subjects per arm is 
hence increased to allow for 
higher drop rate because of a 
longer treatment duration while 
maintaining the original power of 
the study. Doses to be evaluated in 
this part will be selected based on 
the emerging safety, tolerability 
 data in Part A.
Because of these changes, the 
study phase has been changed to 
Phase 2.
The increase in the treatment 
duration also necessitated 
inclusion of additional schematics 
and additions to the schedule of 
assessments. 
The study has now been divided in 
to 4 parts: Parts A – D to make it 
easier for the investigators to 
understand differences between 
parts because the study includes 
NT1 and NT2 subjects; dosing 
duration of 28 and 56 days; and a 
Chinese cohort.
Section 1.0: STUDY 
SUMMARY
Section 2.0: STUDY 
SCHEMATICS
Section 3.0: SCHEDULE OF 
STUDY PROCEDURES
Section 6.1: Study Design
Section 6.3: Rationale for Study 
Design, Dose, and Endpoints
Section 11.0: Statistical Methods
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 167 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Protocol Amendment 02
Summary of Changes Since the Last Version of the Approved Protocol
Description of Each Change and Rationale
Section(s) Affected by Change
Description
Rationale
Location(s)
3. Inclusion criterion related to body mass 
index (BMI) has been revised to align with 
study population: 
Acceptable upper range of BMI for study 
inclusion criterion has been revised to be 
≤40 kg/m2. to allow patient participation.
Other editorial changes have been made for 
consistency and clarity.
BMI criteria was updated to in 
acknowledgment of the 
comorbidity of obesity in this 
patient population. 
Section 1.0: STUDY 
SUMMARY
Section 7.1: Inclusion Criteria
4. Exclusion criterion related to liver 
function tests (LFTs) has been revised as 
follows:
Has LFTs (alanine aminotransferase [ALT], 
aspartate aminotransferase [AST]) higher 
than 1.0 times the upper limit of normal 
(ULN) at screening. At the baseline visit, 
any increase in LFT by more than 50% of the 
screening value as well as exceeding ULN 
will prevent randomization. If there is 
sufficient time in the screening window, 
ALT assessment may be repeated; if the 
second ALT value reduces to less than the 
50% increase seen at baseline, the subject 
may be randomized.
The timeline for follow-up for abnormal 
LFTs was changed to “within 24 to 48 
hours from “within 7 days”
Based on recent FDA feedback 
and sponsor decision, subjects 
will be excluded if the upper limit 
of transaminase (ALT and/or 
AST) values is >1.0× ULN 
(instead of the previous cut-off 
of >1.5× ULN) and the timeline 
for follow-up of abnormal LFTs 
was changed to “within 24 to 48 
hours from “within 7 days”.
Section 1.0: STUDY 
SUMMARY
Section 7.2: Exclusion Criteria
Section 9.2.10.1: Safety Clinical 
Laboratory Tests
5. Exclusion criteria for patient who is a 
relative or family members of a study related 
personnel has been revised to allow patient 
participation.
Other editorial changes have been made for 
consistency and clarity.
In acknowledgement that some 
sites may be large research 
facilities or associated with 
academic research facilities, this 
exclusion language was updated 
to clarify that relatives of site staff 
or site staff directly involved with 
the study are to be excluded due to 
potential conflict of interest and 
also to protect vulnerable subject 
populations.
Section 1.0: STUDY 
SUMMARY
Section 7.2: Exclusion Criteria
For non-commercial use only


For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 169 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Protocol Amendment 02
Summary of Changes Since the Last Version of the Approved Protocol
Description of Each Change and Rationale
Section(s) Affected by Change
Description
Rationale
Location(s)
9. Provision of e-consent has been added. 
In acknowledgement of outbreaks 
of COVID 19 or other unexpected 
circumstances that may disrupt 
the sites ability to carry out the 
study as planned, contingency 
measures for executing certain 
study activities have been 
included in this amendment.
Section 3.0: SCHEDULE OF 
STUDY PROCEDURES
Section 9.1.1: Informed Consent 
Procedure
Section 13.2: Subject 
Information, Informed Consent, 
and Subject Authorization
10. Clinical information has been updated 
based on emerging data from the study 
TAK-994-1001, including the blinded safety 
and preliminary PK data.
To include the most recent 
available clinical information.
Section 4.1.3: Clinical Study 
Experience
11. Nonclinical section has been updated 
based on recently available data including 
the 13-week repeat dose Good Laboratory 
Practice toxicity studies in rats and monkeys.
To include the most recent 
nonclinical information to support 
the longer treatment period 
proposed in this amendment.
Section 4.1.2: Summary of 
Non-clinical Data
Section 4.3: Benefit/Risk Profile
12. Instructions related to excluded 
medications have been revised to 
accommodate revised study population.
Based on emerging nonclinical 
data on transporter substrates and 
inhibitor studies, the excluded 
medication list is being revised.
Section 7.3: Excluded 
Medications, Supplements, and 
Dietary Products
13. Instruction for allowable limit for 
alcohol consumption has been revised for 
subjects in Parts B and C.
Based on the longer treatment 
duration in PARTs B and C, the 
instruction for abstaining for 
alcohol during the treatment 
period has been removed. 
Instructions for moderation of 
alcohol intake has been provided 
instead.
Section 7.3.3 Alcohol
14. Text has been revised for criteria for 
discontinuation or withdrawal of a subject. 
Some changes have been made 
according to FDA feedback, and 
also to clarify that the criteria for 
each part of the study.
Instructions has been added to 
address how study discontinuation 
related or unrelated to COVID-19 
should be handled. 
Section 7.5: Criteria for 
Discontinuation or Withdrawal 
of a Subject
For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 170 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
Protocol Amendment 02
Summary of Changes Since the Last Version of the Approved Protocol
Description of Each Change and Rationale
Section(s) Affected by Change
Description
Rationale
Location(s)
15. Text has been revised for study drug 
supply, randomization, blinding and storage.
Instructions have been added to 
address how drug supply should 
be accessible to the patients to 
cover extended periods between 
on-site visits due to COVID-19 or 
other unavoidable circumstances.
Section 8.1: Clinical Study Drug
16. Alternative approaches for study 
procedure and data collection guidelines 
have been included 
Instructions have been added to 
address how, in unavoidable 
circumstances (eg, a widespread 
disease outbreak or natural 
disaster) that impact the study 
site’s ability to conduct study 
procedures according to the 
Schedule of Study Procedures 
(Section 3.0), contingency 
measures may be implemented.
Section 9.9: STUDY 
PROCEDURES
17. Physical examination
Clarification regarding full versus 
abbreviated physical 
examinations have been added.
Section 9.2.1: Physical 
Examination
Section 3.0: SCHEDULE OF 
STUDY PROCEDURES
Tables 3a-3n
18. Changes in the safety section 
Based on the emerging clinical 
data from study TAK-994-1001, 
additional data regarding urinary 
AEs being collected in the 
electronic case report form.
Section 10.2.8: Collection and 
Reporting of AEs, SAEs, Special 
Interest AEs, and Abnormal 
LFTs
19. Changes in Appendix D- Contraception
Guideline for male contraception 
has been changed based on 
regulatory feedback.
Appendix D: Pregnancy and 
Contraception
20. New Appendix F has been added
New appendix F has been added 
to list of inhibitors and inducers of 
cytochrome p-450(CYP)3A and 
P- glycoprotein.
Section 7.3: Excluded 
Medications, Supplements, and 
Dietary Products
Appendix F: List of Inhibitors 
and Inducers of CYP3A and PgP
21. Editorial changes
For better flow and clarification
Throughout the protocol.
Rationale for Amendment 01
This document describes the changes to the protocol incorporating Amendment 01.
For non-commercial use only


For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 172 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
15. It was clarified in the schedule of study procedures that the electrocardiogram (ECG) taken on 
Day 29 was not predose.
16. The information on disease background was updated.
17. The statement saying the information on the 4-week repeat-dose toxicity study was not yet 
included in the investigator’s brochure (IB) was deleted.
18. Data from ongoing Study TAK-994-1001 were updated.
19. “other exploratory objectives” were removed.
20. Three additional cohorts were included, 1 consisting of 12 to 18 Chinese subjects with NT1 
(Cohort 4) and 2, each consisting of 18 subjects with NT2 (Cohorts 5 and 6). 
21. Dose selection rules were clarified.
22. The type of confinement facility that will be used was clarified.
23. In the inclusion criteria, it was specified that screening labs may be repeated once.
24. In the inclusion criteria, glutamate dehydrogenase (GLDH) was removed as a selection 
criterion. In the same criterion, a note was added to clarify that rescreening for labs may be 
repeated once.
25. In the inclusion criteria and Appendix E, the diagnosis for subject selection was updated and 
the acceptability criteria clarified.
26. In the inclusion criteria, it was clarified that subjects’ Epworth Sleepiness Scale (ESS) score 
should be ≥10 at Day -1.
27. In the inclusion criteria, it was clarified that in order to be eligible for study participation, 
subjects need to have a human leukocyte antigen (HLA) DQB1*06:02 genotype (Cohorts 
1-4).
28. In the inclusion criteria, the separate weight criterion was removed.
29. In the inclusion criteria, it was clarified that the subject must have ≥4 partial or complete 
episodes of cataplexy/week by history when off of anticataplexy medications and ≥4 partial or 
complete episodes of cataplexy/week during the screening period when off of anticataplexy 
medications, averaged over 2 weeks minimum, with a ≥80% compliance rate in completion of 
the self-reported electronic diary for cataplexy episodes (Cohorts 1-4).
30. In the exclusion criteria, it was clarified that subjects with basal cell skin cancer were eligible 
for study participation.
31. In the exclusion criteria, it was clarified that in order to be eligible for study participation, 
subjects could have had 1 single febrile seizure in childhood.
32. In the exclusion criteria, the criterion related to medical disorders in general was clarified.
33. In the exclusion criteria, the period subjects need to abstain from driving and operating 
dangerous or hazardous machinery was clarified.
For non-commercial use only


For non-commercial use only


TAK-994
Study No. TAK-994-1501
Page 174 of 174
Protocol Incorporating Amendment No. 3
15 January 2021
CONFIDENTIAL
54. It was added to the protocol that for adverse events (AEs), the causality to the study procedure 
should be determined.
55.
56. The procedure on collecting and reporting of serious adverse events (SAEs) was clarified.
57. The analysis methods for Cohorts 1 to 6 were updated.
58. The description of the planned interim analyses was updated.
59. The determination of sample size was updated enumerating the range of subjects and 
randomization ratio (study drug: placebo) in Cohorts 4 (China-specific), 5, and 6.
60. The instructions related to pregnancy and contraception were updated.
For non-commercial use only


For non-commercial use only

SAP_001.pdf: 
For non-commercial use only


TAK-994_1501
Page 2 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
2.0
TABLE OF CONTENTS.................................................................................................2
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objective--PART A and PART D.................................................................7
4.2
Secondary Objective--PART A and PART D.............................................................7
4.3
Additional/ Exploratory Objectives--PART A and PART D.......................................7
4.4
Primary Efficacy Objective--PART B and PART C ...................................................8
4.5
Secondary Objective--PART B and PART C .............................................................8
4.6
Additional/ Exploratory Objectives--PART B and PART C .......................................8
4.7
Study Design .............................................................................................................9
5.0
ANALYSIS ENDPOINTS.............................................................................................14
5.1
Primary Endpoints- PART A and PART D ..............................................................14
5.2
Secondary Endpoints- PART A and PART D...........................................................14
5.3
Additional/Exploratory Endpoints- PART A and PART D.......................................14
5.4
Primary Endpoints- PART B and PART C...............................................................15
5.5
Secondary Endpoints- PART B and PART C...........................................................15
5.6
Additional/Exploratory Endpoints- PART B and PART C .......................................16
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................16
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................17
7.1
General Principles....................................................................................................17
7.1.1
Study Definitions.............................................................................................18
7.1.2
Definition of Study Days .................................................................................18
7.1.3
Definition of Study Visit Windows..................................................................18
7.1.4
Conventions for Missing Adverse Event Dates ................................................21
7.1.5
Conventions for Missing Concomitant Medication Dates.................................22
7.1.6
Conventions for Missing PK Data....................................................................23
7.1.7
Conventions for Missing Efficacy Data............................................................23
7.2
Major Protocol Violation .........................................................................................23
7.3
Analysis Sets ...........................................................................................................24
7.4
Disposition of Subjects ............................................................................................25
7.5
Demographic and Other Baseline Characteristics.....................................................25
7.6
Medical History and Concurrent Medical Conditions...............................................26
7.7
Medication History and Concomitant Medications...................................................26
For non-commercial use only


TAK-994_1501
Page 3 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
7.8
Study Drug Exposure and Compliance.....................................................................27
7.9
Efficacy Analysis.....................................................................................................27
7.9.1
Sleep Latency and other MWT Parameters ......................................................28
7.9.2
Epworth Sleepiness Scale (ESS) ......................................................................30
7.9.3
Weekly Cataplexy Rate (WCR) 
...................32
7.9.4
Efficacy Evaluation at the Low Dose ...............................................................35
7.10
Pharmacokinetic Analysis........................................................................................36
7.11
7.11.1
7.11.2
7.11.3
7.11.4
7.11.5
7.11.6
7.11.7
7.11.8
7.11.9
7.12
Safety Analysis........................................................................................................44
7.12.1
Adverse Events................................................................................................44
7.12.2
Clinical Laboratory Evaluations.......................................................................45
7.12.3
Vital Signs.......................................................................................................46
7.12.4
Analysis for ABPM .........................................................................................47
7.12.5
12-Lead ECGs.................................................................................................51
7.12.6
Other Observations ..........................................................................................51
7.12.7
Group Analyses for Selected Safety Endpoints ................................................51
7.13
7.14
Unblinded Data Reviews and Interim Analysis ........................................................53
7.14.1
Unblinded Data Reviews .................................................................................53
7.14.2
Interim Analysis ..............................................................................................54
8.0
APPENDIX...................................................................................................................55
8.1
Changes From the Previous Version of the SAP.......................................................55
9.0
REFERENCES..............................................................................................................63
For non-commercial use only


For non-commercial use only


TAK-994_1501
Page 5 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
3.0
LIST OF ABBREVIATIONS
ABPM 
ambulatory blood pressure monitoring
AE
adverse event
ALT
alanine aminotransferase
ANCOVA 
analysis of covariance
AUC 
area under the concentration-time curve
AUClast
area under the plasma concentration-time curve from time 0 to time of the last 
quantifiable concentration
AUCτ
area under the plasma concentration-time curve during a dosing interval
BID 
twice daily
BLO
below the lower limit of quantification
BP
blood pressure
CI
confidence interval
Cmax
maximum observed plasma concentration
CRF
case report form
CSF
cerebrospinal fluid
C-SSRS
Columbia - Suicide Severity Rating Scale
ECG
electrocardiogram
ESS
Epworth Sleepiness Scale
eCRF
electronic case report form
FDA
Food and Drug Administration
IA
interim analysis
IRC
internal review committee
IRT
interactive response technology
LLN
lower limit of normal
LLOQ
lower limit of quantification
MAV
markedly abnormal value
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed-models for repeated measures
MWT
Maintenance of Wakefulness Test
NT1
narcolepsy type 1
NT2
narcolepsy type 2
PA3
Protocol Amendment 3
For non-commercial use only


TAK-994_1501
Page 6 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
PK
pharmacokinetic(s)
TEAE
treatment-emergent adverse event
tmax
time of first occurrence of Cmax
ULN
upper limit of normal
WCR
weekly cataplexy rate
WE
weekly episodes
For non-commercial use only


For non-commercial use only


For non-commercial use only


TAK-994_1501
Page 9 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
4.7
Study Design
This is a phase 2 randomized, double-blind, placebo-controlled study to assess the safety, 
tolerability, PK, 
 of multiple rising oral doses of TAK-994 administered to subjects with 
NT1 or NT2. An interactive response technology (IRT) system will be utilized for the 
randomization of subjects to treatment.
Approximately 202 (male and female) subjects, aged 18 to 65 years (inclusive) who satisfy the 
inclusion and exclusion criteria will be enrolled in the study in 4 study parts (Table 4.a). The 
same subjects will not be allowed to be enrolled or randomized into different parts of the study; 
therefore, these 4 study parts are considered distinct from each other. However, subjects in 
Part B will have the opportunity to participate in an extension study.
Subjects recruited for the study are expected to be generally healthy, other than having 
narcolepsy.
For Part B, the randomization will be stratified by baseline WCR (<8 vs ≥8) and 
regions/countries (ie, North America, Japan, South Korea, and Europe). 
For Part C, the randomization will be stratified by baseline WCR (<8 vs ≥8).
For other parts, the randomization will be stratified by regions/countries (North America, Japan, 
South Korea, and Europe).
Subjects who were in the screening period at the time that coronavirus disease 2019 (COVID-19) 
related factors resulted in discontinuation may be rescreened with approval (Refer to Section 9.0 
in PA3 for additional details). Subjects will receive BID dosing of TAK-994 or matching 
placebo for 28 days or 56 days, as applicable).
For non-commercial use only


TAK-994_1501
Page 10 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
Table 4.a
Planned Study Cohorts and Dose Levels
PART/Cohort Number
Daily Dose 
Level (mg) a
Dosing Regimen b
Randomization and design
PART A-Cohort A1a and 
A1b
240 mg (A1a),
TBD (A1b)
Oral, 120 mg twice daily
for 28 days (A1a)
Approximately 18 subjects, 9 subjects 
each in Cohort A1a and A1b, 
randomized 2:1 to TAK-994 vs 
placebo, double-blind
PART A-Cohort A2 
(optional)
TBD
Oral, twice daily for 28 
days
Approximately 9-18 subjects 
randomized 2:1 to
TAK-994 vs placebo, double-blind
PART B
TBD
Oral, twice daily for 56 
days
Approximately 112 subjects in a 4-arm 
parallel group 
design: TAK-994 Dose 1, Dose 2, and
Dose 3 vs Placebo. 28/group with a 
randomization of 1:1:1:1
PART C (China-specific)
TBD
Oral, twice daily for 56 
days
Approximately 12-18 subjects 
randomized 2:1 to
TAK-994 vs placebo, double-blind
PART D, Cohort D1a and 
D1b
TBD
Oral, twice daily for 28 
days
Approximately 18 subjects 
randomized 2:1 to
TAK-994 vs placebo, double-blind
PART D-Cohort D2 
(optional)
TBD
Oral, twice daily for 28 
days
Approximately 9-18 subjects 
randomized 2:1 to
TAK-994 vs placebo, double-blind
PK: pharmacokinetic; NT1: narcolepsy type 1 (narcolepsy with cataplexy); NT2: narcolepsy type 2 (narcolepsy 
without cataplexy).
TBD: to be determined.
a: Doses will be determined based on the available and emerging safety/tolerability, PK, 
 data from prior 
study TAK-994-1001 and/or previous cohorts in the current study.
b: Doses will be administered approximately 5 hours apart.
c: Parts A to C include subjects with NT1 and part D will include subjects with NT2.
For non-commercial use only


TAK-994_1501
Page 11 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
Table 4.b
Relative Timing for Initiation of Study Parts
Study Part/
Description
Relative Timing of Cohort Initiation and Rationale
Part A, Cohort A1a
(sentinel)
This will start first
The dosing regimen, 120 mg BID, used in 
Cohort A1a, is supported by the predicted 
range of pharmacologically active plasma 
exposure from animal studies, and available 
clinical safety and PK data from the completed 
TAK-994-1001 FIH study. See Section 6.2.1 
in PA3 for details.
Part A, Cohort A1b
This will start after 9 sentinel 
subjects in Cohort A1a are dosed for 
at least 2 weeks
The dose level for Cohort A1b will be 
determined based on the available safety, 
tolerability, PK, 
 data from Cohort 
A1a. See Section 6.2.1 in PA3 for details.
PART A, Cohort A2 
(optional)
This will start after Cohort A1b, if 
deemed necessary based on A1 data
The totality of Cohort A1 data will be used to 
determine whether Cohort A2 is needed to 
further evaluate safety, efficacy, PK, 
 
in NT1 before initiating Part B. The dose level 
for Cohort A2 will be determined based on the 
available Cohort A1 data. See Section 6.2.1 in 
PA3 for details.
PART B
After the last cohort in Part A
Doses in Part B will be determined using all 
available data from Part A. See Section 6.2.1 
in PA3 for details.
PART C 
This will start after Part A
The dose for Part C will be selected based on 
all available data. See Section 6.2.1 in PA3 for 
details.
PART D, Cohort D1
This will begin after Cohort A1
The dose for Cohort D1a will be determined 
based on the available clinical safety and PK 
data from the completed TAK-994-1001 FIH 
study and available safety, tolerability, PK, 
 data from Cohort A1. See Section 
6.2.1 in PA3 for details.
PART D-Cohort D2 
(optional)
Based on the Cohort D1 data, if 
additional data are needed
The dose level for Cohort D2 will be 
determined based on the available safety, 
tolerability, PK 
 from Cohort D1, if the 
sponsor decides that D2 is needed to further 
evaluate safety, PK, 
 in NT2. See 
Section 6.2.1 in PA3 for details.
a: Doses will be determined based on the available and emerging safety/tolerability, PK, 
 data from prior 
study TAK-994-1001 and/or previous cohorts in the current study.
b: Doses will be administered approximately 5 hours apart.
PK: pharmacokinetic; NT1: narcolepsy type 1 (narcolepsy with cataplexy); NT2: narcolepsy type 2 (narcolepsy 
without cataplexy).
TBD: to be determined.
c: Parts A to C include subjects with NT1 and part D will include subjects with NT2.
For non-commercial use only


TAK-994_1501
Page 12 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
PART A (Cohorts A1 and A2):
Cohort A1: Cohort A1 will enroll 18 subjects with the sentinel 9 subjects to be randomized 2:1 to 
receive treatment with oral TAK-994 120 mg BID versus placebo in a double-blinded fashion. 
The starting dose level in the first cohort of subjects, Cohort A1a, is 120 mg BID, which was 
based on the preliminary safety, tolerability, and PK data from the FIH Study TAK-994-1001 
(Section 6.3.2.1 in PA3), as well as nonclinical data. Sentinel dosing on the first 9 subjects 
(Cohort A1a) (with randomization ratio of 2:1) will be performed. The second cohort of 
9 subjects (Cohort A1b) will be randomized 2:1 to receive treatment with oral TAK- 994 versus 
placebo in a double-blinded fashion.
Optional Cohort A2: Based on the Cohort A1 data, if an additional dosing cohort is needed, 
Cohort A2 will be enrolled and started with 9 subjects. They will be randomized in a 2:1 ratio to 
receive TAK-994 or placebo in a double-blinded fashion. Based on the emerging data from these 
first 9 subjects, 9 additional subjects may be enrolled in this cohort in a 2:1 ratio.
PART B:
Part B will start after Part A is completed. In order to initiate Part B, 3 dose levels of TAK-994 
will be selected based on unblinded safety 
 data from the previous Part A 
cohort(s). A total of 112 subjects will be randomized to either placebo or 1 of the 3 selected 
TAK-994 dose levels in a 1:1:1:1 ratio administered for 56 days. Subjects completing Part B 
study treatment will be invited to participate in an extension study, if they are eligible. Details of 
that extension study design will be communicated via a separate protocol.
PART C (Cohort C1):
PART C, Cohort C1 is a China-specific cohort and is planned to consist of 12 to 18 subjects who 
will be randomized 2:1 to receive treatment with oral TAK-994 versus placebo in a double-
blinded fashion.
PART D (Cohorts D1 and D2):
Cohort D1 will start with sentinel dosing in a cohort of 9 subjects with NT2 (Cohort D1a) who 
will receive TAK-994 BID or placebo in a randomization ratio of 2:1. Dosing for the next 
9 subjects (Cohort D1b) may be adjusted based on the safety and/or efficacy data from the first 
9 subjects. Overall randomization ratio for the 18 subjects in Cohort D1 will remain at 2:1.
Based on the Cohort D1 data, if an additional dosing cohort is needed, optional Cohort D2 will 
start. Cohort D2 will enroll 9 subjects randomized in a ratio of 2:1 to receive TAK-994 or 
placebo in a double-blinded fashion. Based on the emerging data from these first 9 subjects, 
9 additional subjects may be enrolled in this cohort in a 2:1 ratio.
Subjects who are active in screening in Parts A or B and found to not meet the criteria for NT1, 
may be considered for Part D, if they are eligible. These subjects will not be assigned a new 
subject number (in these cases when they have not screen-failed), must sign the Part D ICF and 
will not be required to undergo another screening visit (in these cases where they are still active 
in screening within the 45-day screening window).
For non-commercial use only


TAK-994_1501
Page 13 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
ALL PARTS:
After the screening visit, eligible subjects will participate in study activities as shown in the 
overview of the study schedule (Table 6.c and Section 2.0 in PA3). The full Schedules of Study 
Procedures are shown in Table 3.a, Table 3.b, Table 3.c, Table 3.d, Table 3.e, Table 3.f, 
Table 3.g, Table 3.h, Table 3.i, Table 3.j, Table 3.k, Table 3.l, Table 3.m, Table 3.n in PA3. 
Table 4.c
Overview of the Study Schedule
Screening, Check-In and Baseline
Treatment Period
Follow-Up Visit
Dose
Sample Collection
Days -45 to -3
Day -2 and Day -
1
PART A and PART D: Day 
1 to
Day 28
Study drug administration 
twice
daily
Day 1 to Day 30
Day 35 ±2 days
PART B and PART C: Day 
1 to (See Section 3.2)
Day 56
Study drug administration 
twice
daily
Day 1 to Day 56
PART B and
PART C:
Day 63 ±2 days
------------ In- and outpatient setting ----------
After screening, eligible subjects must discontinue their medication used for treatment of 
NT1/NT2, including medications used for EDS and cataplexy (valid for NT1 only). Medications 
that must be discontinued before Day -2 are listed in PA3 Section 7.3. Subjects in Parts A, B and 
C may undergo optional CSF sampling (single time point) for OX assessment during screening. 
(NOTE: optional CSF testing at a country-level is dependent upon local regulations [either health 
authority or other government’s] and guidelines and site capacity.)
During confinement, study drug will be administered orally twice every day per the schedule of 
study procedures. For detailed dosing instructions see PA3 Section 7.4.1. Study assessments will 
be obtained per the schedules of study procedures in accordance with the priority specified in 
PA3 Section 6.3.4. Subjects will remain as inpatient from check-in at Day -2 until Day 2; after 
completion of the scheduled test procedures on Day 2, they will be discharged.
While at home, subjects will take TAK-994 orally BID at approximately the same times each 
day, with the first dose given in the morning and the second dose approximately 5 hours later and 
will continue to complete the daily electronic patient-reported outcome (ePRO) diary. See PA3 
Section 7.4.1 for complete dosing instructions. Subjects will return to the clinic for safety, PK, 
 assessments on in-clinic visit days. Subjects will return home on the discharge day 
after each in-clinic period. A final follow-up is also required approximately a week after the 
discharge days. See PA3 Section 3.0 for details.
For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


TAK-994_1501
Page 17 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
A sample size of 21 in each group will have 98% power to detect a 14-min difference in means 
of change from baseline between a TAK-994 dose group and placebo in sleep latency using a 
two-sample t-test with a 5% two-sided significance level. The power to detect an 8-point 
reduction in means of change from baseline between a TAK-994 dose group and placebo in the 
total ESS score is estimated to be approximately 95% using a two-sample t-test with a 5% 
two-sided significance level. The power to detect a 50% reduction in WCR from that of placebo 
group is estimated to be approximately 93% using a two-incidence-rate ratio test using Poisson 
model with a 5% two-sided significance level.
A fixed sequence of tests with MWT at high and low doses first followed by ESS at high and 
low doses and WCR at high and low doses will be applied. The overall power for the entire 
testing procedure is approximately 75% (the square of the product of the power of each 
individual test at a dose level, 98%, 95% and 93% respectively) under the assumption that these 
three endpoints are independent. The overall power for the above 6 tests combined may be 
higher or lower than 75% depending on the correlation structure of these three endpoints. There 
is no known reliable data to support any particular assumption on the correlation structure.
To allow for a 25% dropout rate, 28 subjects per group will be enrolled for Part B. The 
enrollment can be stopped once the number of evaluable 21 subjects is reached. A blinded 
sample size re-estimation will be performed before Part B starts. The change in the sample size 
of Part B after the re-evaluation, along with justification, will be documented in the clinical study 
report. 
The SD for the change from baseline in the sleep latency is assumed to be 11 min. The SD for 
the change from baseline in the ESS score is assumed to be 7. The WCR at baseline is assumed 
to be 3. 
7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
Unless otherwise described, general principles, definitions, and summaries described in 
Section 7.1 to 7.7 will be applied to each part of the study as well as the subgroups defined in 
Section 7.1.1.
Randomized subjects are the subjects who are enrolled and received a randomization number.
For Parts A and D, placebo subjects from different cohorts will be grouped into the “placebo” 
group in the summaries and inferential analyses for each part, respectively.
For integrated group analysis that include subjects from different parts with NT1 subjects, 
subject receiving the same treatment (same TAK-994 dose levels or placebo) will be pooled 
together. 
Continuous data will be summarized using the following descriptive statistics: number of 
subjects (N), mean, standard deviation (SD), median, minimum, and maximum, where 
appropriate. Where indicated, the coefficient of variation (%CV) and geometric mean will also 
be included in the summary of continuous data. Categorical data will be summarized using the 
For non-commercial use only


TAK-994_1501
Page 18 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
number and percent of subjects for each category, where appropriate. When presenting summary 
statistics by treatment groups, the treatment groups include placebo, each of TAK-994 dose 
groups, and TAK-994 overall. The “overall” group will also be presented for specific summaries. 
All p-values will be rounded to 3 decimal points (eg, 0.123) before comparing to the specific α 
level (for example, 0.05). Posterior probabilities will be presented in % and rounded to one 
decimal points (eg, 12.3%).
Unless otherwise stated, baseline value is defined as the last observed value before the first dose 
of study drug.
All data analyses and figures will be generated using SAS System® Version 9.4 or higher.
7.1.1
Study Definitions
In addition to each part described in Section 4, the following groups for NT1 subjects in this 
study are defined: 

Group 1 (NT1): All NT1 subjects. 

Group 2 (NT1- Japan): All NT1 subjects from the sites in Japan. 

Group 3 (NT1-Asia): NT1 subjects from China, Japan and other Asian countries/places.

Group 4 (NT1- HLA positive) and Group 5 (NT1- HLA negative): Baseline HLA test 
positive and HLA test negative subjects, respectively. Subjects may come from Parts A, B 
and Part C.

Group 6 (NT1- low baseline WCR): Subjects with baseline WCR≤8.

Group 7 (NT1- high baseline WCR): Subjects with baseline WCR>8.
Analyses using above groups will be described in Sections 7.11.9 and 7.12.7. 
7.1.2
Definition of Study Days
Study day will be calculated relative to the date of the first dose of the study drug for each 
subject. Study days prior to the first dose of study drug will be calculated as: (date of 
assessment/event – date of first dose of study drug of the subject). Study days on or after the first 
dose of study drug will be calculated as: (date of assessment/event – date of first dose of study 
drug of the subject + 1).
7.1.3
Definition of Study Visit Windows
For each visit, a window is defined; this window establishes a time interval around which data 
will be considered for the analysis of the scheduled visit pertaining to that window. The lower 
and upper bounds of each window are the approximate midpoints between the scheduled days for 
the current visit and its adjacent scheduled visits. The value used in analysis for by-visit 
summaries is the value within the specified window that is the closest to the scheduled study day. 
If two observations are equidistant from the scheduled visit date, the observation with a later date 
For non-commercial use only


For non-commercial use only


For non-commercial use only


TAK-994_1501
Page 21 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
Table 7.d
Visit Windows (Days) for ABPM for Scheduled Visits During the Treatment 
Period---Part B and C
Visit
Scheduled Day
ABPM
Screen/Baseline
-45 to -3
<1b
Week 2
3-12
3-13
Week 3
15-25
15 – 25
Week 6
43-54
43-54
a. ABPM readings will be obtained over 24 hours at home before Day -2 check-in. 
b. last non-missing value prior to the first dose is defined as Baseline.
For other efficacy and safety data, data that are obtained more than 3 days after the last dose of 
study medication (start date – last dose date +1 >3) will be listed but excluded from summaries 
and analyses. Adverse events that start more than 30 days after the last dose of study medication 
(start date – last dose date +1>30) will be listed but excluded from the summaries and analyses.
7.1.4
Conventions for Missing Adverse Event Dates
Adverse events with start dates that are completely or partially missing will be imputed as 
follows:

If month and year are known but day is missing.
–
If month and year are the same as month and year of first dose date, then impute to first 
dose date.
–
If month and year are different than month and year of first dose date, then impute to first 
date of the month 

If year is known but day and month are missing.
–
If year is same as year of 1st dose date, then 1st dose date will be used instead.
–
If year is different than year of 1st dose date, then 1st of January of the year will be 
imputed. 

If start date is completely missing, using first dosing date to impute it. 
Imputing missing AE start date is mandatory. After the imputation, all imputed dates are checked 
against the start dates to ensure the stop date does not occur before start date. 
Adverse events with stop dates that are completely or partially missing will be imputed as 
follows:

If “ongoing” is checked, no imputation is necessary.

If month and year are known but day is missing, the last day of the month will be imputed.
For non-commercial use only


TAK-994_1501
Page 22 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL

If year is known, but day and month are missing.
–
If YYYY ≤year of last dose, then 31st of December will be imputed.
–
If YYYY >year of last dose, then 1st of January will be imputed. 

If all are missing, no imputation is necessary. The event will be considered “ongoing.” 
If an AE is ongoing, AE stop date could be missing. Otherwise, AE stop date could be imputed 
per above rules. If a subject dies during the study and AE stop date is missing, then the death 
date will be used for AE stop date. After the imputation, all the imputed stop dates are compared 
with the start dates to ensure the stop date does not occur before the start date. If the imputed 
stop date occurs prior to the start date, then the imputed stop date will be the same as the start 
date. 
The imputed dates will not be populated on the data listing, they are used for derivation purpose 
only. The actual and incomplete date will be on the data listing.
7.1.5
Conventions for Missing Concomitant Medication Dates
Concomitant medications with start date that are completely or partially missing will be analyzed 
as follows:

If month and year are known, but day is missing, then impute day to first of the month.

If year is known, but day and month are missing, then 1st of January of the year will be 
imputed.
Concomitant medications with stop dates that are completely or partially missing will be 
analyzed as follows:

If “ongoing” is checked, no imputation is necessary.

If month and year are known but day is missing, the last day of the month will be imputed.

If year is known, but day and month are missing.
–
If YYYY ≤year of last dose, then 31st of December will be imputed. 
–
If YYYY >year of last dose, then 1st of January will be imputed. 

If all are missing, no imputation is necessary. Concomitant medication will be considered as 
“ongoing”.
If a concomitant medication is ongoing, the stop date could be missing. Otherwise, concomitant 
medications stop date could be imputed per above rules. If a subject dies during the study and the 
concomitant medication stop date is missing, then the death date will be used for the stop date. 
After the imputation, all the imputed stop dates are compared with the start dates to ensure the 
stop date does not occur before the start date. If the imputed stop date occurs prior to the start 
date, then the imputed stop date will be the same as the start date.
For non-commercial use only


For non-commercial use only


For non-commercial use only


TAK-994_1501
Page 25 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
7.4
Disposition of Subjects
All summaries in this section will be performed for Part A, B, C, and D, as well as subgroups 
defined in Section 7.1.1, respectively. 
Disposition of all screened subjects will be tabulated (count and percent); there will be no 
inferential analysis of subject disposition data. 

All subjects who signed informed consent form.

All subjects who were randomized.

All subjects who were not randomized.
The primary reasons for subjects who were not randomized will be summarized.
Disposition of randomized subjects will be tabulated as below by corresponding treatment 
groups and overall: 

All subjects who randomized but did not receive any study drug.

All subjects who received at least one dose of study drug.

Subjects who completed the study drug.

Subjects who prematurely discontinued study drug. 

Subjects who completed all study visits.

Subjects who prematurely discontinued study visits.
Primary reasons for discontinuation of study drug/visits, as entered on the electronic case report 
form (eCRF), will be tabulated. The primary reasons for premature discontinuation of study 
drug/study visit will be presented for each subject in listings. 
7.5
Demographic and Other Baseline Characteristics
All summaries in this section will be performed for Part A, B, C, and D, as well as subgroups 
defined in Section 7.1.1, respectively. 
Demographics of the screening failures collected on the eCRF will be summarized. 
For subjects in the Safety Set, demographics and other baseline characteristics will be 
summarized by treatment groups and will be listed. Data from subjects receiving the same dose, 
including placebo, will be pooled across cohorts or parts as appropriate. Descriptive statistics 
will be used to summarize data for continuous variables like age and weight (number of subjects 
[N], mean, median, SD, minimum, and maximum) and for categorical variables like sex, 
ethnicity, race, HLA positive/negative, and baseline WCR (≤8 vs. >8) (number and percentage of 
subjects within each category). 
Individual subject demographic and baseline characteristic data will be listed. Study part and/or 
cohorts will be included in the listing.
For non-commercial use only


TAK-994_1501
Page 26 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
7.6
Medical History and Concurrent Medical Conditions
Medical history includes any significant conditions or diseases relevant to the disease under 
study that stopped at or prior to signing of informed consent. Concurrent medical conditions are 
those significant ongoing conditions or diseases present at signing of informed consent. Medical 
history and concurrent medical conditions will be coded using the Medical Dictionary for Drug 
Regulatory Activities (MedDRA, Version 23 or higher) coding system.
All summaries in this section will be performed for Part A, B, C, and D, as well as subgroups 
defined in Section 7.1.1, respectively. 
Medical history and concurrent medical conditions will be summarized using the Safety Set by 
treatment group and overall using system organ class (SOC) and preferred term (PT). The table 
will include number and percentages of subjects. The denominator used for calculating the 
percentages will be the total number of subjects included in each treatment group. SOC will be 
sorted in alphabetical order and the PT will be sorted in decreasing frequency based on the total 
number of subjects. A subject will only be counted once within a particular class even if he/she 
has multiple conditions/symptoms.
All medical history and concurrent medical condition data will be listed by subject. The listing 
will contain study part, cohort, subject identifier, treatment, system organ class (SOC), preferred 
term (PT), whether there was any medical history or concurrent condition, and, if yes, a detail of 
the medical history or concurrent condition. 
7.7
Medication History and Concomitant Medications
Medication history information obtained includes any medication stopped at or within 28 days 
prior to signing of informed consent. Medications used from signing of informed consent 
through the end of study will be considered as concomitant medications.
All summaries in this section will be performed for Part A, B, C, and D, as well as subgroups 
defined in Section 7.1.1, respectively. 
Medication history and concomitant medications will be coded using World Health Organization 
Drug Dictionary (WHO Drug) and summarized by treatment groups and overall by giving the 
number and percentage of subjects by preferred term within each therapeutic class, with 
therapeutic class and medications in each class sorted in alphabetical order. If a subject reports 
taking 2 drugs belonging to the same class, he/she will only be counted once within that class. 
The Safety Set will be used for the summaries of medication history and concomitant 
medication. For concomitant medications, the above summaries will be provided for the 
concomitant medication that started or continued from informed consent and stopped prior to the 
first dose of study drug, that started or continued during the screening period and continued into 
the treatment period, and started after the first dose of the study drug. All medication history and 
concomitant medications data will be listed by subject including the duration of concomitant 
condition. Study part and/or cohorts will be included in the listing.
For non-commercial use only


TAK-994_1501
Page 27 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
7.8
Study Drug Exposure and Compliance
All summaries in this section will be performed for Part A, B, C, and D, as well as subgroups 
defined in Section 7.1.1, respectively. 
The date and time of each dose for each subject will be reported in the data listing. Listings and 
summary statistics for TAK-994 plasma concentrations and pharmacokinetic parameters will 
also be provided. 
The summary of study drug exposure and compliance will be based on the Safety Set. Duration 
of exposure to study medication for each subject is defined as (date of last dose – date of first 
dose +1). In the event that the date of last dose is missing, the last dose date will be estimated as 
described in Section 7.1.3.
Treatment duration (days) will be summarized using descriptive statistics (n, mean, SD, median, 
minimum, and maximum) for each treatment group and overall. 
For each Part, percent of study drug compliance associated with the dose for each bottle (10 mg 
or 10 mg placebo, 30 mg or 30 mg placebo, 90 mg or 90 mg placebo) is defined as:
(           !  ) 
   # $! ! ∗&∗(       '() ∗100%
If a value for the number of returned tablets is missing or the return date is missing, then 100% 
compliance will be assigned for each day up to the number of tablets dispensed or up to the date 
of return or the date of completion if the date of return is missing, whichever is earlier. The 
overall compliance for a treatment group will be the average of these percentages. 
For each treatment group, study medication compliance will be summarized by the dose 
associated with the bottles (ie, 10 mg or 10 mg placebo, 30 mg or 30 mg placebo, 90 mg or 
90 mg placebo) and overall using the number of subjects and the frequency in each compliance 
category (<70%, 70 to 130%, and ≥130%). Study medication compliance will also be 
summarized as a continuous variable using descriptive statistics (n, mean, SD, median, 
minimum, and maximum) for each treatment group. 
All study drug administration and accountability data will be listed by treatment, study site, and 
subject number. The following variables will be listed: study part, subject identifier, site number, 
visit number, first and last dose dates, medication bottle identification number, dose associated 
with the medication bottle, date dispensed and returned, number of tablets dispensed and 
returned, and compliance percentage.
7.9
Efficacy Analysis 
The analyses described in this section will be performed for Part B and the subgroups defined in 
Section 7.1.1, respectively. Sensitivity analyses for the primary efficacy endpoint will also be 
described. All summary statistics described will be performed for both Parts B and C. If there are 
sufficient number of subjects in Part C, inferential statistical analyses might be performed for 
Part C. 
The planned summaries and analyses for other efficacy endpoints are described in Section 7.11.
For non-commercial use only


TAK-994_1501
Page 28 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
The analysis is focused on the following efficacy endpoints: 

Sleep latency from MWT;

Epworth sleepiness scale total scores;

Weekly cataplexy rate and 
 
A fixed-sequence hypothesis testing procedure will be used for the primary efficacy endpoints 
and key secondary endpoints. The following testing order in comparison to placebo will be of 
change from baseline to Week 8 (Day 56) in: sleep latency at TAK-994 high dose, sleep latency 
at TAK-994 middle dose, ESS at TAK-994 high dose, ESS at TAK-994 middle dose, WCR at 
TAK-994 high dose, and WCR at TAK-994 middle dose. If the p-value from the last 
comparison, WCR between TAK-994 middle dose and placebo is <0.05, then the test will 
continue to sleep latency at TAK-994 low dose, ESS at TAK-994 low dose, and WCR at 
TAK-994 low dose. If p-value>0.05 at any of these steps, the hypothesis test will be stopped. 
Superiority of TAK-994 over placebo will be considered established at 0.05 in all comparisons 
between TAK-994 and placebo conducted before this step. No superiority of TAK-994 over 
placebo is established for the comparisons at this step and thereafter. Details will be described in 
the following subsection of 7.9.1, 7.9.2, 7.9.3 and 7.9.4 by Step 1 to Step 9. 
7.9.1
Sleep Latency and other MWT Parameters 
Sleep latency and other MWT parameters will be derived for each of the 4 MWT sessions on 
Day -1 and post dose days as described in the protocol. The mean of a parameter from the 
4 MWT sessions on a given day will be calculated for each subject. If there are 2 or more 
missing values, the mean will be assigned as missing for that day. In addition, change from 
time-matched baseline for each MWT parameter and the change from baseline for the mean of 
the 4 MWT sessions will be derived for each subject. 
All summary statistics (N, mean, median, SD, minimum, and maximum) will be prepared for the 
each MWT parameters for each MWT session and the mean of the 4 MWT sessions by treatment 
at baseline and post dose days. Summary statistics will also be prepared for the change from 
baselines to post dose days by treatment. FAS will be used for these summaries.
7.9.1.1
Analysis of the Primary Efficacy Endpoint – Change from Baseline in Mean Sleep 
Latency to Week 8
The primary efficacy endpoint, change from baseline in mean sleep latency to Week 8, will be 
analyzed using the linear mixed-effect models for repeated measures (MMRM). Change from 
baseline in mean sleep latency will be the response. The models will contain fixed effects for 
baseline, treatment, visit (Day 1, 
 and Week 8), and the treatment-by-visit interaction. 
Visit will be a repeated factor. The least squares means of change from baseline in mean sleep 
latency for each treatment and the associated SE and 95% CI will be calculated for each week, 
along with all pairwise differences from placebo and associated SEs, 95% CIs, and p-values.
For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


TAK-994_1501
Page 33 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
WCR will be summarized by treatment at baseline and post dose weeks (
 
 Week 8). In addition to the means, geometric means for the observed WCR will be 
presented. The change and % change in the WCR from baseline to post dose weeks will also be 
summarized. FAS will be used.
For the inferential analyses in the following Section 7.9.3.1 to Section 7.9.3.4, post dose WCR at 
 Week 8 will be calculated using Study Days 
 and Study Days 29 to 56, 
respectively:
,-. = 012345 6789:; 2< =434>5:?@ 2A:; 4 6789:; 2< 626 −8DEED6F GD4;@ G4@E <2; 4 FDA:6 G7;43D26
6789:; 2< 626 −8DEED6F GD4;@ G4@E D6 3ℎ43 G7;43D26
K ∗7
A minimum of 70% non-missing diary days are required for the calculation of the WCR at 
 
 Week 8. Otherwise, the WCR will be considered missing for that week.
7.9.3.1
Analysis of the Key Secondary Endpoints – Weekly Cataplexy Rate at Week 8
A generalized linear-mixed model for repeated measures featuring Poisson regression will be 
used to evaluate the drug effect on the WCR. The response variable will be the total number of 
cataplexy for Weeks 4 and 8. The model will include treatment, weeks and treatment by weeks 
interaction as fixed factors, and adjusted for baseline WCR, and exposure time (as in weeks) as 
offset variables. In case of overdispersion (the estimated scale parameter >2), a negative 
binomial regression will be used. An unstructured variance-covariance structure will be used 
initially in these models. Other variance-covariance structures will be evaluated if there are 
convergence issues with the model. If lack-of-convergence still exist, the analysis will be done 
for Week 4 and Week 8 separately. The estimated incident rate ratio (IRR) of weekly cataplexy 
comparing treatment groups to placebo for each week, and the associated SEs, 95% CIs, and 
p-values will be estimated from the model. If lack-of-convergence still exists, then 
non-parametric analysis described in Section 7.9.3.2 will be performed. 
The FAS will be used for this analysis. Following fixed hierarchical testing order using the 
p-values from the convergent model will be used to control the overall type 1 error rate of 0.05 if 
the p-value for Step 4 in Section 7.9.2.1 is ≤0.05:
Step 5: A test for significant difference between TAK-994 high dose vs. placebo will be 
performed at 5% level. If the p-value is ≤0.05, then proceed to Step 6. Otherwise, the test 
will be stopped.
Step 6: A test for significant difference between TAK-994 middle dose vs. placebo will 
be performed at 5% level. If the p-value is >0.05, then the test will be stopped.
Sensitivity analysis using PPS will be performed. In addition, evaluation of the impact of missing 
data will be performed as described in Section 7.1.7. 
For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


TAK-994_1501
Page 45 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL

Most Frequent (≥2 subjects or ≥5% based on total number of safety set subjects in any 
treatment group, whichever larger) Non-Serious Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term.

Relationship of Treatment-Emergent Adverse Events to Study Drug by System Organ Class 
and Preferred Term.

Drug-Related Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term.

Drug-Related Treatment-Emergent Adverse Events by Preferred Term.

Intensity of Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term. 

Intensity of Drug-Related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term. 

Treatment-Emergent Adverse Events by alcohol consumption status (Yes or No) and 
treatment group (for Part B, C and D only)
In addition, the details of urinary TEAEs symptom will be listed (the listing will include all the 
item in the urinary symptoms form as well as the corresponding TEAE onset time, duration, and 
treatment group). The number of subjects with at least one urinary symptom, the number of 
subjects with >=1 increased urinary frequency reported, and descriptive statistics (N, mean, SD, 
median, minimum and maximum) for each symptom in the form of urinary event caused by 
TEAE will be provided for each treatment group. 
Data listings will be provided for all AEs including: TEAEs, AEs leading to death, AEs leading 
to study drug or study visit discontinuation, SAEs and death.
7.12.2
Clinical Laboratory Evaluations
Clinical safety laboratory tests include clinical chemistry, hematology, and urinalysis. A list of 
all the clinical laboratory evaluations can be found in Protocol Section 9.2.1.1.
Descriptive statistics (N, mean, SD, median, minimum and maximum) of clinical laboratory 
variables will be summarized for baseline and post-dose values, as well as change from baseline 
to post dose values by study visits and treatment. Only the scheduled measurements will be 
included in the summary. No statistical tests will be performed.
Individual results for clinical laboratory tests will be evaluated against the Takeda predefined 
laboratory markedly abnormal values (MAV) criteria (Appendix A) using the result and criteria 
in SI units. All subjects with at least 1 post-dose laboratory result that meets the MAV criteria 
will be presented in a data listing.
The number and percentage of subjects with at least 1 post-dose markedly abnormal laboratory 
test result will also be summarized by treatment. Subjects who meet the MAV criteria will be 
mapped to their respective qualifying laboratory result. All post-dose clinical lab MAV results, 
including scheduled and unscheduled measurements, will be included in the MAV summaries.
For non-commercial use only


TAK-994_1501
Page 46 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
Listings of all clinical safety laboratory data will be provided in the listings and will be presented 
in both SI and conventional units (and CV units, if available). Laboratory data outside of the 
normal reference range will be indicated in the listings. 
7.12.3
Vital Signs
Vital sign measurements include blood pressure (SBP and DBP), pulse, respiratory rate, and 
body temperature.
SBP, DBP and pulse will be summarized (N, mean, SD, median, minimum and maximum) for 
baseline, postdose, and change from baseline (or change from time-matched baseline to 
postdose, if appropriate) by treatment. Only the scheduled measurements will be included in the 
summary. 
Summary statistics (N, mean, SD, median, minimum and maximum) of vital sign measurements 
will be provided for those scheduled pre dose measurements.
Respiratory rate, weight and temperature will be summarized for baseline, postdose, and change 
from baseline at each time point by treatment. 
All individual vital signs that meet Takeda’s predefined criteria for MAVs (Appendix B) will be 
listed. The number and percentage of subjects with at least 1 post-dose markedly abnormal vital 
sign measurement will be summarized by treatment. Time-matched baselines should be used 
when they are available for blood pressure and pulse. Subjects who meet the MAV criteria will 
be mapped to their respective qualifying vital sign result. All post-dose MAV vital signs, 
including both scheduled and unscheduled measurements, will be included in the MAV 
summaries. Listings of all vital signs data will be provided in the listings, and vital sign MAVs 
will be flagged. 
In addition, the drug effect on clinic BP and pulse at pre and post treatment time points will be 
analyzed by post dose visit using a linear mixed effects model for repeated measures (MMRM). 
In this model, change from time-matched baseline to the post dose visit will be the response; 
baseline will be the covariate, treatment, time points, and treatment by time point interaction will 
be the fixed effects. The estimated change from baseline in SBP, DBP and pulse for each 
treatment and the associated SE and 95% CI will be extracted from the model at each time, along 
with all pairwise differences from placebo and associated SEs, 95% CIs, and p-values. 
Unstructured variance-covariance structure will be used initially in these models. Other variance-
covariance structures will be evaluated if there are convergence issues with the model.
For non-commercial use only


TAK-994_1501
Page 47 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
The post dose visit with matched timepoint is summarized in Table 7.h. 
Table 7.h
Summary of VS Post Dose Visit and Matched Timepoint
Visit
Post Dose Timepoints
Baseline Time-matched Timepoints
Day 1
Predose, hour 1, 3, 5, 7, 9, 12, 
14 and 24
Study Day -1 measures at 1, 3, 5, 7, 9, 12, 14 hour will 
be used to match timepoints of 1, 3, 5, 7, 9, 12, 14 h 
post Study Day 1 AM dose; Study Day 1 pre-dose 
measure will be used to match Study Day 1 24 post 
dose 
Week 2 (Part A and D 
only)
Predose, hour 1, 3, 5, 7, 9 and 
12
Study Day -1 measures at 1, 3, 5, 7, 9, 12, 14 hour will 
be used to match timepoints of 1, 3, 5, 7, 9, 12, 14 h 
post Study Day 14 AM dose; Study Day 1 pre-dose 
measure will be used to match Study Day 14 24 post 
dose
Week 4/ET
Predose, hour 1, 3, 5, 7, 9, 12, 
14 and 24
Study Day -1 measures at 1, 3, 5, 7, 9, 12, 14 hour will 
be used to match timepoints of 1, 3, 5, 7, 9, 12, 14 h 
post Study Day 28 AM dose; Study Day 1 pre-dose 
measure will be used to match Study Day 28 24 post 
dose
Week 8/ET (Part B 
and C only)
Predose, hour 1, 3, 5, 7, 9, 12, 
14 and 24
Study Day -1 measures at 1, 3, 5, 7, 9, 12, 14 hour will 
be used to match timepoints of 1, 3, 5, 7, 9, 12, 14 h 
post Study Day 56 AM dose; Study Day 1 pre-dose 
measure will be used to match Study Day 56 24 post 
dose
7.12.4
Analysis for ABPM
7.12.4.1
Derivation of ABPM Parameters
The analysis of ambulatory BP will be based on the following variables that are obtained by 
summarizing the individual ambulatory BP measurements (SBP, DBP and HR), namely: hourly 
mean ABPM (baseline and post dose), 0- to 24-hour post dose mean ambulatory BP, 0- to 
12-hour post dose mean ambulatory BP, daytime mean ambulatory BP, and nighttime mean 
ambulatory BP. The derived parameters will be: 

The hourly mean ABPM values will be calculated by taking the average of all observations 
in each hour post dose. 

The baseline 0- to 24-hour mean ambulatory BP will consist of the average (arithmetic mean) 
of ABPM measurements over the time period beginning with the first ABPM observation 
and including all observations recorded over the subsequent 24 hours (any observations that 
are recorded ≥24 hours after the first observation will be excluded).

The Day 5 0- to 24-hour mean ambulatory BP will consist of the average (arithmetic mean) 
of ABPM measurements over the time period beginning with the Day 5 study medication 
dose and including all observations recorded over the 24-hour period following that dose. 
For non-commercial use only


TAK-994_1501
Page 48 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL

The Day 19 0- to 24-hour mean ambulatory BP will consist of the average (arithmetic mean) 
of ABPM measurements over the time period beginning with the Day 19 study medication 
dose and including all observations recorded over the 24-hour period following that dose. 

The baseline 0- to 12-hour mean ambulatory BP will consist of the average (arithmetic mean) 
of ABPM measurements over the time period beginning with the first ABPM observation 
and including all observations recorded over the subsequent 12 hours.

The Day 5 0- to 12-hour mean ambulatory BP will consist of the average (arithmetic mean) 
of ABPM measurements over the time period beginning with the Day 5 study medication 
dose and including all observations recorded over the 12-hour period following that dose.

The Day 19 0- to 12-hour mean ambulatory BP will consist of the average (arithmetic mean) 
of ABPM measurements over the time period beginning with the Day 19 study medication 
dose and including all observations recorded over the 12-hour period following that dose.

The baseline 12- to 24-hour mean ambulatory BP will consist of the average (arithmetic 
mean) of ABPM measurements over the time period beginning at 12-hour first ABPM 
observation and over the subsequent 12 hours. 

The Day 5 12- to 24-hour mean ambulatory BP will consist of the average (arithmetic mean) 
of ABPM measurements over the time period beginning with the 12-hr post the Day 5 study 
medication dose and up to the 24-hr post the Day 6 dosing.

The Day 19 12- to 24-hour mean ambulatory BP will consist of the average (arithmetic 
mean) of ABPM measurements over the time period beginning with the 12-hr post the 
Day 19 study medication dose and up to the 24-hr post the Day 19 dosing.

The Day 54 0- to 24-hour mean ambulatory BP will consist of the average (arithmetic mean) 
of ABPM measurements over the time period beginning with the Day 54 study medication 
dose and over the 24-hour period following that dose. (for Part B and C only)

The Day 54 0- to 12-hour mean ambulatory BP will consist of the average (arithmetic mean) 
of ABPM measurements over the time period beginning with the Day 54 study medication 
dose and over the 12-hour period following that dose. (for Part B and C only)

The Day 54 12- to 24-hour mean ambulatory BP will consist of the average (arithmetic 
mean) of ABPM measurements over the time period beginning with the 12-hr post the 
Day 54 study medication dose and up to the 24-hr post the Day 54 dosing. (for Part B and C 
only)

The daytime mean ambulatory BP will consist of the average of those ABPM measurements 
that were included in the respective 24-hour mean ambulatory BP calculations and were also 
recorded between the hours of 6 AM (inclusive) and 10 PM (exclusive).

The nighttime mean ambulatory BP will consist of the average of those ABPM 
measurements that were included in the respective 24-hour mean ambulatory BP calculations 
and were also recorded between the hours of 12 AM (inclusive) and 6 AM (exclusive).
For non-commercial use only


TAK-994_1501
Page 49 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
Those parameters are summarized in the Table 7.i below: 
Table 7.i
Summary of ABPM Derived Parameters
ABPM Parameters 
(apply for SBP, DBP and HR)
Applied Parts 
Hour mean of ambulatory BP
Part A, B, C and D
The baseline 0- to 24-hour mean ambulatory BP 
Part A, B, C and D
The Day 5 0- to 24-hour mean ambulatory BP
Part A, B, C and D
The Day 19 0- to 24-hour mean ambulatory BP
Part A, B, C and D
The baseline 0- to 12-hour mean ambulatory BP 
Part A, B, C and D
The Day 5 0- to 12-hour mean ambulatory BP
Part A, B, C and D
The Day 19 0- to 12-hour mean ambulatory BP
Part A, B, C and D
The baseline 12- to 24-hour mean ambulatory BP
Part A, B, C and D
The Day 5 12- to 24-hour mean ambulatory BP
Part A, B, C and D
The Day 19 12- to 24-hour mean ambulatory BP
Part A, B, C and D
The Day 54 0- to 24-hour mean ambulatory BP
Part B and C
The Day 54 0- to 12-hour mean ambulatory BP
Part B and C
The Day 54 12- to 24-hour mean ambulatory BP
Part B and C
The daytime mean ambulatory BP
Part A, B, C and D
The nighttime mean ambulatory BP
Part A, B, C and D
7.12.4.2
Summary Statistics of ABPM Parameters
The ABPM parameters listed above will be presented in summary tables by descriptive statistics 
(including mean, SD, median, minimum, and maximum). Change from Baseline for the ABPM 
variables will also be summarized in this fashion.
Only observed data will be used for the summary and analyses of ABPM parameters. No 
imputation will be performed for missing data. ABPM parameters and ABPM related data 
collected on the eCRF will be included in the data listings. Raw 24-hour ABPM recordings will 
not be presented in a listing.
Following figures will be prepared:

Average baseline ambulatory BP values by hour for the 0- to 24-hour interval, final ABPM 
values by hour for the 0- to 24-hour interval and change from baseline in ABPM values by 
hour for the 0- to 24-hour interval.

Average baseline ambulatory BP values by hour for day-time interval, final ABPM values by 
hour for the daytime interval, and change from baseline in ABPM values by hour for the 
daytime interval.
For non-commercial use only


TAK-994_1501
Page 50 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL

Average baseline ambulatory BP values by hour for the night time interval, final ABPM 
values by hour for the night time interval, and change from baseline in ABPM values by hour 
for the night-time interval.
7.12.4.3
Bayesian Analysis of ABPM Parameters
A generalized linear Bayesian model will be used on change from baseline in 24-hour mean SBP 
by ABPM to estimate the posterior probability of the true TAK-994 effect on the difference in 
systolic blood pressure between treatment and placebo to be <2, < 5, and <10 mmHg at each 
visit. The model includes effects of baseline, treatment, visit (Day 5, Day 19 and Day 54 (Part B 
and C only)), and treatment-by-visit interaction. The posterior mean, SD, and the 95% credible 
interval for the change from baseline in SBP for each treatment, along with those for the 
differences between TAK-994 and placebo, will be estimated using the model. The posterior 
probabilities of the true effect on the SBP being <2 mmHg, < 5 mmHg and < 10 mmHg will be 
calculated for each of the TAK-994 doses given the difference from placebo at each visit. A non-
informative prior will be used for TAK-994 and placebo. This analysis will also be performed for 
change from baseline in 24-hour mean ABPM DBP. 
7.12.4.4
MMRM Analysis of ABPM Parameters
Linear mixed effect model for repeated measures (MMRM) will be performed on change from 
baseline in 24-hour mean SBP by ABPM. In this model, change from baseline will be the 
response, baseline will be a covariate, treatment, post dose visit, and treatment by post dose visit 
interaction will be the fixed effects. The LS means of change from baseline in 24-hour mean 
ABPM SBP for each treatment and the associated SE and 95% CI will be extracted from the 
model at each time, along with all pairwise differences from placebo and associated SEs, 95% 
CIs, and p-values. This analysis will also be performed for change from baseline in 24-hour 
mean ABPM DBP and 24-hour mean HR. Similar analyses will be performed for the following 
ABPM parameters: Mean daytime (6 AM to 10 PM) SBP, Mean daytime DBP and Mean 
daytime HR.
7.12.4.5
Dipper Analysis
The following blood pressure dipping categories [3] will be defined using the ratio of mean 
daytime and night-time ABPM SBP (daytime defined as (0900 to 2100h) and nighttime defined 
as (0100 to 0600h):

Non-dipping or riser: Night-time/Day-time ≥1.0.

Mild dipper: 0.9 <Night-time/Day-time 1.0<1.0.

Dipper: 0.8< Night-time/Day-time ≤0.9.

Extreme Dipping: Night-time/Day-time ≤0.8.
The dipper ratio will be summarized by treatment for each visit. 
For non-commercial use only


For non-commercial use only


TAK-994_1501
Page 52 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
will be performed for clinic BP and pulse as well as ABPM parameters only. Safety Sets will be 
used for the summaries and analysis. Details are provided in Table 7.j.
Table 7.j
Group Analysis for Selected Safety Endpoints
Groups
Safety Endpoints
Data Source
Inferential Statistics and Data Time 
Frame
Group 1: All 
NT1 subjects

TEAEs

MAVs for safety labs, 
vital signs and 12-lead 
ECGs 

Time-matched clinic 
BP and pulse

ABPM parameters
Parts A, B and C
Only for time-matched clinical BP and 
pulse with Data up to Week 4
Parts B and C
Only for time-matched clinical BP and 
pulse and ABPM parameters with data up 
to Week 8
Group 2: All 
NT1 Japanese 
subjects

TEAEs

MAVs for safety labs, 
vital signs and 12-lead 
ECGs 

Time-matched clinic 
BP and pulse

ABPM parameters
Part A and B
Only for time-matched clinic BP and pulse 
and if N>20% of the total number of 
subjects in Parts A and B with data up to 
Week 4
Group 3: All 
NT1 subjects 
from sites in 
Asia

TEAEs

MAVs for safety labs, 
vital signs and 12-lead 
ECGs 

Time-matched clinic 
BP and pulse

ABPM parameters
Parts A, B and C
Only for time-matched clinical BP and 
pulse and if N>20% of the total number of 
subjects in Parts A, B and C; with data up 
to Week 4
Parts B and C
Only for time-matched clinical BP and 
pulse and ABPM parameters and if 
N>20% of the total number of subjects in 
Parts B and C; with data up to Week 8
Group 4 All 
NT1 subjects 
with HLA 
positive results

TEAEs

MAVs for safety labs, 
vital signs and 12-lead 
ECGs 

Time-matched clinic 
BP and pulse

ABPM parameters
Parts A, B and C
Only for time-matched clinical BP and 
pulse and if N>20% of the total number of 
subjects in Parts A, B and C; with data up 
to Week 4
Parts B and C
Only for time-matched clinical BP and 
pulse and ABPM parameters and if 
N>20% of the total number of subjects in 
Parts B and C; with data up to Week 8
Group 5 All 
NT1 subjects 
with HLA 
negative results

TEAEs

MAVs for safety labs, 
vital signs and 12-lead 
ECGs 

Time-matched clinic 
BP and pulse

ABPM parameters
Parts A, B and C
Only for time-matched clinical BP and 
pulse and if N>20% of the total number of 
subjects in Parts A, B and C; with data up 
to Week 4
Parts B and C
Only for time-matched clinical BP and 
pulse and ABPM parameters and if 
N>20% of the total number of subjects in 
Parts B and C; with data up to Week 8
For non-commercial use only


For non-commercial use only


TAK-994_1501
Page 54 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
committee (IRC) after each sentinel dose cohort or cohort. All available safety, 
 data will 
be used for dose selection. Details will be described in the IRC charter.
7.14.2
Interim Analysis
At the end of Part A Cohort A1, an IA will be performed. The purpose of this IA is to have 
an early look of TAK-994 efficacy and safety. The selected analyses defined in the SAP will be 
used for the IA and will be specified in IRC charter. 
The four parts in this study are independent of each other. They are included in one protocol for 
administrative purposes. With this in mind, data cleaning and database lock will be performed 
for each of these 4 parts. Unblinded analyses described below may be performed thereafter.

End-of-Part A: At the end of Part A, a final unblinded analyses will be performed to evaluate 
the safety and efficacy of TAK-994 for Part A only.

End-of-Part B: Final unblinded analyses will be performed after Part B completes to evaluate 
the safety, PK and efficacy of TAK-994 for NT1 subjects in Part B only, 
 
.

End-of-Part D: The final unblinded analyses for NT2 may be performed to evaluate the 
safety, PK, and efficacy at the end of Part D using Part D subjects only.

End-of-Part C: the final unblinded analysis for sites in China may be performed at the end of 
Part C using subjects in Part C only.
Unblinded data and interim analyses result reviews will be performed by TAKEDA Internal 
Review Committee (IRC). The IRC consists of members that will not be involved with study 
level activities. Details will be presented in the IRC Charter. 
For non-commercial use only


TAK-994_1501
Page 55 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
8.0
APPENDIX
8.1
Changes From the Previous Version of the SAP
Changes made from the original version of SAP (Approved on June 15 2020) that have a 
material impact to the planned statistical analysis methods are described below. In addition, 
there were textual changes purely to improve the flow, organization and clarity. As these 
represent cosmetic changes with no impact to the planned statistical analyses, they are not 
included in the table below. 
SAP Section (Previous 
SAP)
Impacted Text (Previous 
SAP)
Change 
(Current SAP)
Rationale for Change
7.1 General Principles
All summaries and
analyses described in this 
document will be 
performed for: Cohorts 1 
to 3 together (Group 1), 
and Cohorts 5 and 6
together (Group 5). In 
addition, some of the 
summaries and analyses 
might be performed for 
other subgroups in NT1 
subjects (such as China 
alone, Japan alone, and/or 
China and Japan combined 
[Groups 2, 3, and/or 4, if 
applicable]) if deemed
appropriate.
A section to define 
different subgroups is 
added as Section 7.1.1. In 
addition to the previously 
defined subgroups, 
subgroups based on HLA 
results and based on the 
baseline WCR are added.
Group analyses description 
and definition has been 
changed due to PA3.
7.1.3 Definition of Study 
Visit Windows
Table 7.a visit windows 
for scheduled visits during 
treatment period for 
MWT, ESS, lab, VS, ECG 
and PK. 
Table 7.b visit windows 
for scheduled visits during 
treatment period for 
ABPM.
Visit windows are 
redefined and new visit 
windows are added in 
Section 7.1.3, including 
Visit windows for re-
designed Part B and new 
procedures.
Table 7.a. defines the visit 
windows for Part A and D 
for MWT, ESS, lab, VS, 
ECG and PK.
Table 7.b1. defines the 
visit windows for ABPM 
for Part A. 
Table 7.b2 defines the visit 
windows for ABPM for 
Part D. 
Changes of the overall 
study design and treatment 
duration in PA3. 
For non-commercial use only


For non-commercial use only


For non-commercial use only


TAK-994_1501
Page 58 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
SAP Section (Previous 
SAP)
Impacted Text (Previous 
SAP)
Change 
(Current SAP)
Rationale for Change
7.10.3.1 Analysis for 
ABPM
For NT1 subject, an 
ANCOVA model is 
planned for ABPM 
parameters as those 
cohorts only have one post 
dose visit (Study Day 19) 
for ABPM.
In Section 7.12.4.3, a
generalized linear 
Bayesian model is planned 
to estimate posterior 
probability of the true 
TAK-994 effect on the 
ABPM parameters 
comparing between 
treatment and placebo.
In Section 7.12.4.4, a 
linear mixed effect model 
for repeated measures 
(MMRM) is planned to 
estimate TAK-994 effect 
on the ABPM parameters 
comparing to placebo for 
each visit.
In Section 7.12.4.5, 
analyses for dipper 
categories are add. 
More ABPM were added 
in PA3. The planned
inferential analyses were 
changed accordingly. 
7.10.5 Other Observations
Only data listings are 
planned for other 
observations. 
Alcohol consumption, 
 are 
added in Section 7.12.6 
Other Observations.
Additional to data listing, 
summary statistics are 
added for those 
parameters. 
CYP3A4/5 activity 
analysis is moved to PK 
section (7.10). 
Due to the change in PA3.
Safety analyses for groups 
were not planned.
Section 7.12.7 was added 
to described the 
summaries for selected 
safety endpoints
Due to the change in PA3.
7.10.6 
 
PK/Safety Analysis
The plot of TAK-994 
plasma concentration 
versus the post treatment 
SL on the MWT was 
planned. 
The plot of PK 
concentration vs. SL in 
MWT is removed from 
Section 7.13
 
PK/Safety Analysis
The plots will be generated 
and described in a separate 
. 
For non-commercial use only


TAK-994_1501
Page 59 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
SAP Section (Previous 
SAP)
Impacted Text (Previous 
SAP)
Change 
(Current SAP)
Rationale for Change
7.11 Interim Analysis
End-of-population 
analyses were planned at 
the end of each part. 
As database lock is 
planned for each part in 
PA3, End-of-Population 
analyses were replaced 
with final analyses and 
described in Section 
7.14.2.
In PA3, each partis 
considered an independent 
study. A formal database 
lock is planned at the end 
of each part. End-of-
population analyses are 
replaced with formal 
analyses for clinical study 
reports after database lock. 
For non-commercial use only


TAK-994_1501
Page 60 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values
Hematology—Criteria for Markedly Abnormal Values
Parameter
Unit
Low Abnormal
High Abnormal
Hemoglobin
Both 
<0.8 × LLN
>1.2 × ULN
Hematocrit
Both
<0.8 × LLN
>1.2 × ULN
RBC count 
Both
<0.8 × LLN 
>1.2 × ULN
WBC count 
Both 
<0.5 x LLN
>1.5 x ULN
Platelet count
Conventional
<75 x 103/L
>600 x 103/L
SI
<75 x 109/L
>600 x 109/L
LLN=lower limit of normal, RBC=red blood cell, ULN=upper limit of normal, WBC=white blood cell. 
Serum Chemistry—Criteria for Markedly Abnormal Values
Parameter
Unit 
Low Abnormal
High Abnormal
ALT
Both
--
>3x ULN
AST
Both
--
>3x ULN
GGT
Both
--
>3x ULN
Alkaline phosphatase
Both
--
>3x ULN
Total bilirubin
Conventional
--
>1.5x ULN
SI
--
>1.5x ULN
Albumin
Conventional 
<2.5 g/dL
--
SI 
<25 g/L
--
Total protein
Both
<0.8x LLN
>1.2x ULN
Creatinine
Conventional 
--
>1.5x ULN 
SI
>1.5x ULN 
Blood urea nitrogen
Conventional 
>40 mg/Dl
SI
>10.7 mmol/L
Sodium
Conventional
<130 mEq/L
>150 mEq/L
SI
<130 mmol/L
>150 mmol/L
Potassium
Conventional
<3.0 mEq/L
>5.3 mEq/L
SI
<3.0 mmol/L
>5.3 mmol/L
CPK
Both
--
>3x ULN
Glucose
Conventional
<50 mg/dL
>300 mg/dL
SI
<2.8 mmol/L
>19.4 mmol/L
Calcium
Conventional
<7.7 mg/dL
>11.1 mg/dL
SI
<1.92 mmol/L
>2.77 mmol/L
ALT=alanine aminotransferase, AST=aspartate aminotransferase, CPK=creatine phosphokinase, GGT=-glutamyl 
transferase, LLN=lower limit of normal, ULN=upper limit of normal.
For non-commercial use only


TAK-994_1501
Page 61 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
Appendix B
Criteria for Markedly Abnormal Values for Vital Signs
Parameter
Unit
Lower Criteria 
Upper Criteria
Pulse
bpm
<40 
>115
Systolic blood pressure
mm Hg
<90 
≥160 
Diastolic blood pressure
mm Hg
<50 
≥100
Systolic blood pressure change
mm Hg
>20, >30 
Diastolic blood pressure change
mm Hg 
>20, >30
Body temperature
oC
>38.5 
Respiratory Rate
Breath/min
>21
For non-commercial use only


TAK-994_1501
Page 62 of 63
Statistical Analysis Plan 
12 May 2021
CONFIDENTIAL
Appendix C
Criteria for Markedly Abnormal Values for Electrocardiograms
Parameter
Lower Criteria 
Upper Criteria
Heart rate
<40 beats per minute
>115 beats per minute
PR
≤80 milliseconds
≥200 milliseconds
QTcF Interval
≤300 milliseconds
>500 milliseconds OR 
≥30 milliseconds change from baseline and >450 
milliseconds
QRS
≤80 milliseconds
≥180 milliseconds
For non-commercial use only


For non-commercial use only


For non-commercial use only