Clinical trial NCT03990649
Conditions: Complex Regional Pain Syndrome
Keywords: Drug Therapy Soticlestat TAk-935
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2019-07-23; Completion date: 2020-10-28
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to investigate the effect of soticlestat (TAK-935) on calculated 24-hour average pain intensity by the numeric pain scale (NPS).

Detailed description:
The drug being tested in this study is called soticlestat (TAK-935). Soticlestat is being tested to treat people with chronic complex regional pain syndrome (CRPS). This study will look at the efficacy, safety, and tolerability of soticlestat as an adjunctive therapy in participants with CRPS.

The study will enroll approximately 24 patients. Participants will be randomly assigned (by chance, like flipping a coin) in 2:1 ratio to one of the two treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

Soticlestat 100 mg tablets, 100, 200 or 300 mg twice daily (BID) Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient

Participants will receive 100 mg soticlestat tablets or soticlestat matching placebo tablets, BID for Week 1, 2x100 mg soticlestat tablets or soticlestat matching placebo tablets, BID for Week 2 and followed by 3x100 mg soticlestat tablets or soticlestat matching placebo tablets, BID for Week 3. Dose will be uptitrated based on safety and tolerability in titration period. Participants will continue to receive the same dose in maintenance period. Dose adjustments during maintenance period may take place due to safety and tolerability.

Participants will then enter Part B (optional) or taper period. In Part B all participants will receive soticlestat 2x100 mg tablets, BID for 1 Week, followed by soticlestat 3x100 mg tablets, BID for 1 Week. Dose will be uptitrated/downtitrated based on safety and tolerability in titration period (Part B), participants will continue to receive the same dose in maintenance period (Part B) and followed by a taper period.

This multi-center trial will be conducted in United Kingdom. The overall time to participate in this study is approximately 36 weeks. Participants will make multiple visits to the clinic and will be contacted by telephone 15 days after last dose of study drug for a follow-up assessment.

Arms: arm 1: Soticlestat matching placebo tablets, orally, twice daily (BID) for Weeks 1, 2 and 3 in Double blind Titration Period. Soticlestat matching placebo tablets, orally BID for 12 weeks in Double blind Maintenance Period. Taper period (if participant did not continue to Part B): Dose of soticlestat matching placebo tablets was reduced to next lower dose every 3 days (maximum 6 days) until discontinuation. arm 2: Soticlestat, tablet, orally, 100 mg BID for Week 1, followed by 2×100 mg tablets, soticlestat, orally BID for Week 2, further followed by 3×100 mg tablets, soticlestat, orally BID for Week 3. Dose was uptitrated every week based on safety and tolerability. Part A (Double blind Maintenance Period): 3×100 mg tablets, soticlestat, orally BID for 12 weeks. Dose was adjusted during Maintenance Period due to safety and tolerability. Taper Period (if participant did not continue to Part B): Dose of soticlestat was reduced to next lower dose every 3 days (maximum 6 days) until soticlestat was discontinued. arm 3: Soticlestat, 2×100 mg tablets, orally, BID for Week 1, followed by 3×100 mg tablets, soticlestat, orally, BID for Week 2. Dose was uptitrated every week based on safety and tolerability. Part B (Open label extension: Maintenance Period): 3×100 mg tablets, soticlestat, orally, BID for 12 weeks. Dose was adjusted during Maintenance Period due to safety and tolerability. Taper Period: Dose of soticlestat was reduced to next lower dose every 3 days (maximum 6 days) until soticlestat was discontinued.
Interventions: intervention 1: Soticlestat intervention 2: Placebo
Intervention descriptions: intervention 1: Soticlestat tablets intervention 2: Soticlestat matching placebo tablets

Protocol documents:
Prot_000.pdf: 



Title: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, 
Safety, and Tolerability of TAK-935 as an Adjunctive Therapy in Adult Subjects With Chronic 
Complex Regional Pain Syndrome
NCT Number: NCT03990649
Protocol Approve Date: 16 December 2019
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


1.0 TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, 
Safety, and Tolerability of TAK-935 as an Adjunctive Therapy in Adult Subjects With Chronic 
Complex Regional Pain Syndrome
Study of TAK-935 as an Adjunctive Therapy in Adult Subjects With Complex Regional 
Pain Syndrome
Sponsor:
Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda 
Pharmaceuticals Company Limited
40 Lansdowne Street
Cambridge, MA 02139, USA
Study Number:
TAK-935-2008
EudraCT Number:
2018-004750-21
Compound:
TAK-935
Date:
16 December 2019
Amendment 
Number:
03
Amendment History:
Date
Amendment Number
Region
30 January 2019
Initial protocol
Global
08 May 2019
01
Global
01 July 2019
02
Global
16 December 2019
03
Global
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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided to each site.
Takeda Pharmaceuticals Company Limited (TDC) sponsored investigators per individual country 
requirements will be provided with emergency medical contact information cards to be carried by 
each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
The names and contact information for the medical monitor and responsible medical officer are in 
the study manual.
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1.2
Approval
REPRESENTATIVES OF TAKEDA
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this study protocol and also in accordance with the following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Council for Harmonisation (ICH) E6 Good Clinical Practice (GCP): 
Consolidated Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer and other signatories, as applicable, can 
be found on the signature page.
Electronic Signatures are provided on the last page of this document.
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
dance
ance
GCP):
GCP):
a privac
priva
ther sig
her sig
his docu
is doc
For Non-Commercial Use Only an


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1.3
Protocol Amendment 03 Summary of Changes
Rationale for Amendment 03
This document describes the changes to the protocol incorporating Amendment No. 03. The 
primary reason for this amendment is to update the dose selection rationale based on new data 
from the TAK-935-2001 study.
Minor grammatical, editorial, and formatting changes are included for clarification purposes only.
For specific descriptions of text changes and where the changes are located, see Appendix F.
Changes in Amendment 03:
1. Updated the dose selection rationale.
2. Clarified the schematic of study design.
3. Replaced ‘dosing card’ with ‘electronic diary’.
4. Moved a secondary objective to an exploratory objective to align with endpoints.
5. Modified Figure 4.a.
6. Clarified the rationale for the study.
7. Moved the detail on pharmacogenomic analysis.
8. Revised contraceptive requirements.
9. Modified the detail regarding blood volumes collected during the study.
10. Clarified the ECG procedures for specific visits.
11. Clarified the efficacy analysis.
12. Clarified the exploratory analysis.
13. Clarified the interim analysis.
14. Clarified when blood samples for plasma protein binding assessment will be collected.
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INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 
prescribing information and any other product information provided by the sponsor. I agree to 
conduct this study in accordance with the requirements of this protocol and also to protect the 
rights, safety, privacy, and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

ICH, E6 GCP: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events (SAEs) defined in Section 10.2
of this protocol.

Terms outlined in the clinical study site agreement.

Responsibilities of the investigator. (Appendix B)
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 03 Summary of Changes ..........................................................4
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................18
3.1
Study-Related Responsibilities.................................................................................18
3.2
Coordinating Investigator.........................................................................................18
3.3
List of Abbreviations ...............................................................................................19
3.4
Corporate Identification...........................................................................................20
4.0
INTRODUCTION.........................................................................................................21
4.1
Background .............................................................................................................21
4.2
Rationale for the Proposed Study.............................................................................23
4.3
Benefit-Risk Profile .................................................................................................23
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................25
5.1
Objectives................................................................................................................25
5.1.1
Primary Objective ..............................................................................................25
5.1.2
Secondary Objectives.........................................................................................25
5.1.3
Exploratory Objectives.......................................................................................25
5.1.4
Safety Objective.................................................................................................25
5.2
Endpoints.................................................................................................................25
5.2.1
Primary Endpoint...............................................................................................25
5.2.2
Secondary Endpoints..........................................................................................25
5.2.3
Exploratory Endpoints .......................................................................................26
5.2.4
Safety Endpoints................................................................................................26
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................27
6.1
Study Design ...........................................................................................................27
6.2
Justification for Study Design, Dose, and Endpoints ................................................31
6.2.1
Study Design......................................................................................................31
6.2.2
Dose ..................................................................................................................32
6.2.2.1
Clinical Safety.........................................................................................33
6.2.3
Endpoints...........................................................................................................34
6.3
Premature Termination or Suspension of Study or Study Site...................................35
6.3.1
Criteria for Study Termination related to Drug-Related Events...........................35
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6.3.2
Criteria for Premature Termination or Suspension of the Study..........................35
6.3.3
Criteria for Premature Termination or Suspension of Study Sites .......................35
6.3.4
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s)..............................................................................35
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............36
7.1
Inclusion Criteria .....................................................................................................36
7.2
Exclusion Criteria ....................................................................................................37
7.3
Excluded Medications, Procedures, and Treatments.................................................39
7.4
Diet, Fluid, Activity Control ....................................................................................40
7.5
Withdrawal of a Subject...........................................................................................40
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................41
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................42
8.1
Study Drug and Materials ........................................................................................42
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................42
8.1.1.1
Study Drug ..............................................................................................42
8.1.1.2
Rescue Medication ..................................................................................42
8.1.1.3
Sponsor-Supplied Drug............................................................................42
8.1.2
Storage...............................................................................................................42
8.1.3
Dose and Regimen .............................................................................................43
8.1.4
Overdose............................................................................................................43
8.2
Study Drug Assignment and Dispensing Procedures ................................................44
8.3
Randomization Code Creation and Storage..............................................................44
8.4
Unblinding Procedure..............................................................................................45
8.5
Accountability and Destruction of Sponsor-Supplied Drugs.....................................45
9.0
STUDY PLAN ..............................................................................................................47
9.1
Study Procedures.....................................................................................................47
9.1.1
Informed Consent Procedure..............................................................................47
9.1.2
Demographics, Medical History, and Medication History Procedure..................47
9.1.3
Physical Examination Procedure ........................................................................47
9.1.4
Neurological Examination Procedure.................................................................48
9.1.5
9.1.6
Weight, Height, and BMI...................................................................................48
9.1.7
Vital Sign Procedure..........................................................................................48
9.1.8
Primary Efficacy Measurements.........................................................................48
9.1.8.1
NPS.........................................................................................................48
9.1.8.2
PROMIS-29.............................................................................................49
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9.1.8.3
PGIC .......................................................................................................49
9.1.8.4
CSS .........................................................................................................49
9.1.9
Documentation of Concomitant Medications......................................................49
9.1.10 Documentation of Concurrent Medical Conditions.............................................49
9.1.11 Procedures for Clinical Laboratory Samples.......................................................50
9.1.12 PK Sample Collection........................................................................................52
9.1.13 PD Sample Collection........................................................................................52
9.1.14 Plasma Protein Binding Collection.....................................................................52
9.1.15 Pharmacogenomics Sample Collection...............................................................53
9.1.16 Contraception and Pregnancy Avoidance Procedure...........................................53
9.1.17 Pregnancy ..........................................................................................................55
9.1.18 ECG Procedure..................................................................................................55
9.1.19 Clinical Assessment of Suicidal Ideation and Behavior ......................................56
9.1.20 Documentation of Screen Failure .......................................................................56
9.1.21 Documentation of Randomization......................................................................56
9.2
Monitoring Subject Treatment Compliance..............................................................57
9.3
Schedule of Observations and Procedures................................................................57
9.3.1
Screening...........................................................................................................57
9.3.2
Randomization...................................................................................................57
9.3.3
Part A ................................................................................................................57
9.3.4
End of Part A or Early Termination....................................................................58
9.3.5
Part B.................................................................................................................58
9.3.6
End of Part B or Early Termination....................................................................58
9.3.7
Final Follow-up .................................................................................................59
9.3.8
Unscheduled Visit..............................................................................................59
9.3.9
Poststudy Care ...................................................................................................59
10.0
PRETREATMENT EVENTS AND AES ......................................................................60
10.1
Definitions...............................................................................................................60
10.1.1 Pretreatment Events ...........................................................................................60
10.1.2 AEs....................................................................................................................60
10.1.3 Additional Points to Consider for AEs................................................................60
10.1.4 SAEs..................................................................................................................61
10.1.5
10.1.5.1
10.1.5.2
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10.1.5.3
10.1.6 Intensity of AEs .................................................................................................63
10.1.7 Causality of AEs ................................................................................................63
10.2
Procedures...............................................................................................................63
10.2.1 Collection and Reporting of AEs........................................................................63
10.2.1.1
AE Collection Period...............................................................................63
10.2.1.2
AE Reporting...........................................................................................63
10.2.1.3
10.2.2 Collection and Reporting of SAEs......................................................................65
10.2.3 Reporting of Abnormal Liver Tests....................................................................65
10.3
Follow-up of SAEs ..................................................................................................65
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities..................66
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................67
12.0
DATA HANDLING AND RECORDKEEPING............................................................68
12.1
eCRFs......................................................................................................................68
12.2
Record Retention .....................................................................................................68
13.0
STATISTICAL METHODS..........................................................................................70
13.1
Statistical and Analytical Plans ................................................................................70
13.1.1 Analysis Sets......................................................................................................70
13.1.2 Analysis of Demographics and Other Baseline Characteristics...........................70
13.1.3 Efficacy Analysis...............................................................................................70
13.1.4 Exploratory Analysis..........................................................................................71
13.1.5 Safety Analysis ..................................................................................................72
13.2
Interim Analysis and Criteria for Early Termination ................................................72
13.3
Determination of Sample Size..................................................................................72
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................73
14.1
Study-Site Monitoring Visits ...................................................................................73
14.2
Protocol Deviations..................................................................................................73
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................73
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................74
15.1
IRB..........................................................................................................................74
15.2
Subject Information, Informed Consent, and Subject Authorization .........................74
15.3
Subject Confidentiality ............................................................................................75
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................76
15.4.1 Publication and Disclosure.................................................................................76
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15.4.2 Clinical Trial Registration..................................................................................76
15.4.3 Clinical Trial Results Disclosure ........................................................................77
15.5
Insurance and Compensation for Injury....................................................................77
16.0
REFERENCES..............................................................................................................78
LIST OF IN-TEXT TABLES
Table 7.a
 
Table 8.a
Table 9.a
Table 10.a
LIST OF IN-TEXT FIGURES
Figure 4.a
Figure 6.a
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................80
Appendix B
Responsibilities of the Investigator.....................................................................83
Appendix C
Elements of the Subject Informed Consent.........................................................85
Appendix D
Investigator Consent to Use of Personal Information..........................................88
Appendix E
Opioid Conversion Calculator............................................................................89
Appendix F
Detailed Description of Amendments to Text.....................................................91
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2.0
STUDY SUMMARY
Name of Sponsor:
Millennium Pharmaceuticals, a wholly owned 
subsidiary of Takeda Pharmaceuticals Company 
Limited
40 Lansdowne Street
Cambridge, MA 02139, USA
Compound:
TAK-935
Title of Protocol: A Phase 2a, Randomized, Double-Blind, 
Placebo-Controlled Study to Evaluate the Efficacy, Safety, 
and Tolerability of TAK-935 as an Adjunctive Therapy in 
Adult Subjects With Chronic Complex Regional Pain 
Syndrome
EudraCT No.:
2018-004750-21
Study Number: TAK-935-2008
Phase: 2a
Study Design:
This is a phase 2a randomized, double-blind, placebo-controlled, parallel-group study in adult subjects (≥18 years) 
with chronic (symptoms ≥6 months) complex regional pain syndrome (CRPS). The objective will be to evaluate the 
ability of TAK-935 as adjunctive therapy to reduce pain as measured by the Numeric Pain Scale ([NPS], an 11-point 
scale by electronic pain diary). The study will also evaluate efficacy of TAK-935 as measured by the 29-item 
Patient-Reported Outcomes Measurement Information System (PROMIS-29, version 2.1), Patient Global Impression 
of Change (PGIC) scale, and CRPS Severity Score (CSS).
Approximately 24 subjects will be randomized to ensure 21 completers in the double-blind phase of the study. 
Randomization will be 2:1 (16 treatment: 8 placebo).
This study consists of 2 parts:
Part A: Double-Blind Treatment 
2- to 4-week screening period.
3-week titration period.
12-week maintenance period.
Taper period (maximum 6 days)/Follow-up (to occur 15 days after last dose of study drug) if the subject does not 
continue into the open label extension).
Part B: Open-Label Extension
2-week titration period.
12-week open label period.
Taper period (maximum 6 days)/Follow-up (to occur 15 days after last dose of study drug).
Part A: Double-Blind Treatment (19-21 weeks including the screening period and follow- up if the subject does not 
continue into the open label extension)
At Visit 1 (Screening), after obtaining informed consent, subjects will undergo screening procedures to assess subject 
eligibility in accordance with study entry criteria. Subjects who fulfill the CRPS Budapest Criteria, have symptoms for 
≥6 months and meet all inclusion criteria and none of the exclusion criteria at the screening visit will be eligible for 
entry into the study. For a minimum of 6 of the last 7 screening days before randomization at Visit 2 (Day 1) into the 
study, baseline current pain intensity will be collected 3 times a day to provide an average daily 24-hour pain intensity 
(NPS, an 11-point scale by electronic pain diary). The baseline will be defined as the mean of the average screening 
24-hour pain intensity score for the last 7 days before the first dose. During Part A, average 24-hour pain intensity will 
be calculated as the mean of 3 measurements collected during a day. The average pain intensity score will be 
calculated as the mean of the average 24-hour pain intensity score collected during the last 7 days prior to Visit 5 (Day 
21, Week 3) and Visit 8 (Day 105, Week 15) (or the last dose in Part A), which will be used for the primary endpoint 
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analysis.
At the end of the prospective screening period, subjects will return to the clinic (Visit 2, Day 1) and if a subject does 
not meet the eligibility criteria the subject will be discontinued from the study and considered a screen failure.
On Visit 2 (Day 1), subjects who meet the entry criteria will be randomized in a 2:1 ratio to double-blind treatment 
with investigational product (IP), either TAK-935 (100 mg tablets) or matching placebo, for 15 weeks (3-week 
titration period and 12-week maintenance period).
All screening/baseline assessments will be collected prior to initiating treatment.
At Visit 2 (Day 1), after randomization and all predose procedures have been performed, subjects will be started on 
100 mg twice daily (BID) IP (either TAK-935 100 mg tablets or matching placebo) for approximately 1 week. The 
first dose on Day 1 will be taken in the clinic. The subject will take the second dose on Day 1 and the rest of the doses 
at home (except for Visit 4 [Day 14], Visit 6 [Day 49], and Visit 13 (Day 203), when subjects will be instructed to take 
their dose on site at their study visit). The site will contact the subject by telephone on Day 4 to determine safety and 
tolerability.
At Visit 3 (Day 7, Week 1), safety and tolerability will be assessed and if the drug is well tolerated, the dose will be 
increased to 200 mg BID. The site will contact the subject by telephone on Day 10 to determine safety and tolerability 
of this dose. Any subjects who continue with 100 mg BID and still cannot tolerate the minimum daily dose of 100 mg 
BID, will be withdrawn from the study.
At Visit 4 (Day 14, Week 2), safety and tolerability will be assessed and if the drug is well tolerated with no continuing 
pain, the subject will remain at 200 mg BID. If the subject continues to need a higher dose, in the PI’s opinion, the dose 
will be increased to 300 mg BID. The site will contact the subject via phone on Day 17 to determine the safety and 
tolerability of this dose. Subjects that do not require the dose to be increased to 300 mg BID will still be required to 
complete a 21-day titration period in order to confirm the tolerated dose prior to entering the maintenance phase. After 
completing 1 week for each dose adjustment at 100 mg BID increment to 300 mg BID depending on tolerance, the 
3-week titration period will be completed and the subject will return to the site for Visit 5 (Day 21, Week 3) to begin 
the 12-week maintenance period.
After Visit 5 (Day 21, Week 3), subjects will visit the clinic approximately every 4 weeks (Visit 6 [Day 49, Week 7] 
and Visit 7 [Day 77, Week 11]). The current pain intensity will be collected 3 times a day using the electronic pain 
diary. From this data an average 24-hour pain intensity score can be calculated.
If at any time during either the titration or the maintenance period the subject cannot tolerate the dose, the dose may be 
decreased to the previous tolerated dose. The subject may return to the clinic for an unscheduled visit at any time 
during either the titration period or the maintenance period if dose adjustments are needed between scheduled visits. If 
the subject cannot tolerate the minimum daily dose of 100 mg BID, the subject will be withdrawn from the study. If the 
dose has been decreased due to inability to tolerate the dose, based on the investigator’s review, the dose may be 
increased to the next highest dose 1 time during the titration. Dose modifications during the maintenance period 
should be discussed with the medical monitor.
The subject should be instructed not to alter their dose without prior approval from the investigator. Any change in 
dose will be documented in the subject’s clinic chart and electronic diary.
Pain medications and nondrug treatments must be stable (regimented per prescription) for 1 month prior to screening 
and should remain stable throughout Part A. Pain medication use may be adjusted under supervision during Part B. 
Concurrent treatment regimen data will be collected throughout the study.
A single effective rescue medication must be identified for each subject for use during the study. The prescribed 
maximum dose must remain stable during Part A. The use of rescue pain medications will be assessed at each visit; 
subjects requiring significant increase of rescue medication (frequency or dose 50% over pre-enrollment levels or over 
the prescribed maximum) during Part A will be considered for withdrawal from the study at the investigator’s and 
sponsor’s discretion.
During Part A, all subjects will continue to enter the current pain intensity score as described 3 times a day using the 
NPS in the electronic pain diary. This data will be captured daily during Part A.
An unblinded interim analysis will be conducted when all subjects have completed Part A (Double-Blind Treatment)
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Following completion of Part A, subjects will have the option to continue into Part B, a 14-week open-label drug 
extension, or to enter a double-blind taper period (maximum 6 days).
For all subjects that choose not to enter into Part B (Open-Label Extension), the IP dose will be reduced to the next 
lower dose every 3 days (or less frequently based on the investigator’s discretion) until IP dose is discontinued. After 
tapering, the subjects will complete a safety follow-up phone call approximately 15 days after the last dose of IP.
Part B Open-Label Extension (14 weeks):
Because the Part A treatment assignments will remain blinded, all subjects who choose to continue into Part B will 
start at 200 mg BID TAK-935 (100 mg tablets), regardless of the treatment they were on in Part A at Visit 8 (Day 105, 
Week 15). Subjects will remain at this dose for 1 week. The site will contact the subject by telephone, 3 days after 
initiation of this dose, on Day 108 to determine safety and tolerability.
At Visit 9 (Day 112, Week 16), safety and tolerability will be assessed and if the drug is well tolerated and the subject 
continues to need a higher dose in the PI’s opinion, the dose will be increased to 300 mg BID. The dose may also be 
decreased to 100 mg BID based on tolerability at Visit 9 (Day 112, Week 16). If the subject tolerates the 200 mg BID 
dose without continuing pain, the dose will remain at 200 mg BID. The site will contact the subject on Day 115 to 
determine the safety and tolerability of this dose.
After completing 1 week at 300 mg BID, the 2-week titration period will be completed and the subject will return to 
the site for Visit 10 (Day 119, Week 17) to begin the 12-week maintenance period.
If at any time during either the titration period or the maintenance period the subject cannot tolerate the dose, the dose 
may be decreased to the previous tolerated dose. The subject may return to the clinic for an unscheduled visit at any 
time during either the titration period or the maintenance period if dose adjustments are needed between scheduled 
visits. If the subject cannot tolerate the minimum daily dose of 100 mg BID, the subject will be withdrawn from the 
study.
The subject should be instructed not to alter their dose without prior approval from the investigator. Any change in 
dose will be documented in the subject’s clinic chart and electronic diary.
After Visit 10 (Day 119, Week 17), the subjects will visit the clinic approximately every 4 weeks (Visit 11 [Day 147, 
Week 21] and Visit 12 [Day 175, Week 25]). The current pain intensity will be collected daily, 3 times a day, using the 
electronic pain diary until the end of the study. From these data an average 24-hour pain intensity score can be 
calculated. In addition, using the data collected in the last 7 days prior to Visit 11 (Day 147, Week 21) and Visit 13 
(Day 203, Week 29) (or the last dose in Part B), the average pain score prior to these visits will be derived.
During the taper period, the IP dose will be reduced to the next lower dose every 3 days (or less frequently based on the 
investigator’s discretion) until IP dose is discontinued. After tapering, the subjects will complete a safety follow-up 
phone call approximately 15 days after the last dose of IP and exit the study.
The total period of evaluation from screening to the final follow-up in Part B will be approximately 34-36 weeks.
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BID: twice daily.
Primary Objective:
!
To investigate the effect of TAK-935 on calculated 24-hour average pain intensity by the NPS (an 11-point 
scale).
Secondary Objectives:
!
To investigate the effect of TAK-935 on overall function using the PGIC and the PROMIS-29 scale.
!
To investigate the effect of TAK-935 on the CRPS CSS score.
!
To investigate the effect of TAK-935 on responder rate (responder is defined as ≥30% improvement in the 
24-hour pain intensity).
Exploratory Objectives:
Safety Objective: To evaluate safety and tolerability of TAK-935 in subjects with CRPS.
Subject Population: Adult subjects aged ≥18 to75 years with chronic (symptoms ≥6 months) of CRPS.
Number of Subjects: Total of approximately 24 subjects 
randomized in Part A: 2 (TAK-935): 1 (placebo).
Number of Sites: Approximately 10 sites
Dose Levels:
Part A: TAK-935 100 mg BID to 300 mg BID 
(100 mg tablets) or matching placebo
Part B: TAK-935 100 mg BID to 300 mg BID 
(100 mg tablets)
Route of Administration:
Oral
Duration of Treatment:
Part A: 15 weeks (Titration and Maintenance)
Part B: 14 weeks (Titration and Maintenance) and 
Period of Evaluation: ~36 weeks (including up to 
4-week screening/baseline period, 15-week 
double-blind treatment period [3-week titration and 
12-week maintenance periods], 14-week open-label 
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maximum 6 days (Taper period).
period [2-week titration and 12-week maintenance 
periods]), and 3-week taper/follow-up period.
Main Criteria for Inclusion (see Section 7.1 for full inclusion criteria):
!
The subject is a male or female aged ≥18 to 75 years inclusive at the time of informed consent.
!
The subject meets the Budapest clinical diagnosis of CRPS at the screening visit, and is at least 6 months since 
onset of symptoms.
!
The subject has a history of failure of one or more standard of care therapies for the treatment of CRPS, as judged 
by the investigator.
!
The subject’s pain medications and nondrug treatments must be stable (regimented per prescription) for 1 month 
prior to screening and should remain stable throughout Part A.
!
The subject agrees to use a single previously prescribed rescue medication within the prescribed dose during Part 
A of the trial and to record the daily use of these medications.
!
The subject must have an average 24-hour pain intensity score ≥4 and ≤9 on the 24-hour average pain intensity 
NPS during screening/baseline. This score will be calculated by averaging the daily 24-hour pain intensity scores 
for the past seven days prior to randomization. The subject must have daily 24-hour pain intensity scores 
recorded for at least 6 of the past 7 days.
Main Criteria for Exclusion (see Section 7.2 for full exclusion criteria):
!
Currently receiving intravenous (IV) or oral ketamine or other infusion therapy, history of IV or oral ketamine 
use within the past 6 weeks prior to screening, or planned use of IV or oral ketamine during the study.
!
The subject has any unstable, clinically significant neurologic (other than the disease being studied), psychiatric, 
cardiovascular, ophthalmologic, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, 
hematopoietic, or endocrine disease or other abnormality which may impact the ability to participate in the study 
or that may potentially confound the study results. It is the responsibility of the investigator to assess the clinical 
significance.
!
.
!
The subject has any history of alcohol, opioid, or other moderate to severe substance use disorder (except 
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nicotine), as per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, within the 2 years 
immediately prior to the screening visit (Visit 1).
!
Subject is receiving chronic opioid treatment at a dose that has not been stable over the past 28 days.
!
Subject is receiving chronic opioid treatment >160 mg of morphine equivalent per day.
!
The subject is considered by the investigator to be at imminent risk of suicide or injury to self, others, or property, 
or the subject has attempted suicide within the past year prior to screening. Subjects who have positive answers 
on item number 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS), based on the past year, prior to 
randomization are excluded.
!
!
Main Criteria for Evaluation and Analyses:
Primary Endpoints:
!
Change in mean 24-hour pain intensity NPS from baseline to the end of Part A (Week 15).
Secondary Endpoints:
!
Percent change in mean 24-hour pain intensity NPS score from baseline to the end of Part A (Week 15).
!
Percent of responders (defined as ≥30% improvement on the 24-hour pain intensity NPS) by the end of Part A 
(Week 15).
!
Change and percent change from baseline of mean total score of the PROMIS-29 version 2 to the end of Part A 
(Week 15).
!
Change and percent change from baseline of mean PGIC to the end of Part A (Week 15).
!
Change and percent change from baseline of mean CSS to the end of Part A (Week 15).
Exploratory Endpoints:
Safety Endpoints:
!
Percentage of subjects with at least 1 treatment-emergent adverse event in Part A and Part B.
!
Percentage of subjects with at least 1 markedly abnormal value for clinical laboratory evaluations, vital signs, 
body weight/body mass index, and electrocardiogram parameters after treatment in Part A and Part B.
!
Change from baseline in clinical laboratory evaluations, vital signs, body weight, C-SSRS, and 
electrocardiogram parameter values after treatment in Part A and Part B.
Statistical Considerations:
Efficacy Analysis:
For the primary efficacy endpoint, only subjects with a baseline and at least 1 postdose value will be included in the 
summary and analyses. The data from the last 7 days prior to the visits on Day 21 (Week 3), Day 105 (Week 15) (or the 
last dose in Part A, whichever is earlier), Day 147 (Week 21), and Day 203 (Week 29) (or the last dose in Part B, 
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whichever is earlier) will be used to derive the mean 24-hour pain intensity for the corresponding visits.
For Part A, summary statistics will be provided for the observed values of the efficacy measures at baseline and each 
of postdose visits by treatment group. Change from baseline and percent change from baseline will also be 
summarized with descriptive statistics by treatment group.
For Part B, summary statistics will be provided for the observed values of the efficacy measures at each of the 
postdose visits for all subjects, as well as by treatment group in Part A. Change from baseline and percent change from 
baseline will also be summarized with descriptive statistics. Baseline will be the baseline for Part A.
For the mean 24-hour pain intensity derived above in Part A, linear mixed models for repeated measurements will be 
used to evaluate the effect of TAK-935 on the primary and secondary endpoints. The change from baseline in the 
24-hour mean pain intensity to the scheduled visits (Day 21, Week 3) and Day 105, Week 15) will be the response in 
the model; baseline, site, visit (Day 14 (Week 2) and Day 105 (Week 15), treatment, and treatment by visits interaction 
will be the fixed effects; and a completely unstructured covariance matrix will be assumed. The treatment effect at 
each visit will be evaluated using the difference in the least-square means of the change from baseline between 
TAK-935 and placebo. 95% confidence intervals for the differences and p-values will also be provided. Percent of 
responders will be summarized and compared between treatment arms in Part A.
Safety Analyses: Descriptive statistics will be used to summarize all safety endpoints, by treatment group. Data 
summaries will be displayed for incidence of adverse events, clinical laboratory variables, vital signs, body weight and 
body mass index, and electrocardiogram parameters.
Interim Analysis: An unblinded interim analysis will be conducted after all subjects have completed Part A. All 
planned efficacy analysis for the primary and secondary endpoints will be performed for the data collected during Part 
A. Safety and PK/PD summaries will also be performed for Part A. Since this analysis will be conducted at the end of 
the double-blind period, this analysis will be considered as the primary efficacy assessment of TAK-935 on CRPS 
relative to placebo. No alpha spending or adjustment to sample size will be needed based on the results of this analysis.
Sample Size Justification: Assuming a standard deviation of 2 and a 12% drop-out rate, a sample size of 24 subjects 
in total with randomization ratio of 2:1 is sufficient to achieve at least 65% power to detect a difference of 2 between 
TAK-935 and placebo by a 2-sample t-test on the change from baseline to Week 15 in mean 24-hour pain intensity 
NPS score at 0.10 2-sided significance level. A difference of 2 is within the accepted range of minimally clinically 
important difference for the 11-point NPS [1,2].
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
clinical supplier list in the study manual. The identified vendors will perform specific 
study-related activities either in full or in partnership with the sponsor.
3.2
Coordinating Investigator
Takeda will select a signatory coordinating investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study drug, their expertise in the therapeutic area and the conduct of clinical research, 
and study participation. The signatory coordinating investigator will be required to review and 
sign the clinical study report and by doing so agrees that it accurately describes the results of the 
study.
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3.3
List of Abbreviations
24HC
24S-hydroxycholesterol
AAP
alpha-1-acid glycoprotein
Ab
antibody
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC24
area under the concentration-time curve from time 0 to 24 hours
BID
twice daily
BMI
body mass index
CH24H
cholesterol 24-hydroxylase
Cmax
maximum observed concentration
CNS
central nervous system
CPIP
chronic postischemic pain
CRPS
complex regional pain syndrome
CRPS-I
CRPS, presenting as reflex sympathetic dystrophy
CRPS-II
CRPS, with clinical and/or electrodiagnostic evidence of nerve damage
CSS
CRPS Severity Score
C-SSRS
Columbia-Suicide Severity Rating Scale
DEE
developmental and epileptic encephalopathy
ECG
electrocardiogram
eCRF
electronic case report form
EO
enzyme occupancy
FAS
full analysis set
FDA
[United States] Food and Drug Administration
GCP
Good Clinical Practice
hCG
human chorionic gonadotropin
ICF
informed consent form
ICH
International Council for Harmonisation
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
ID
identification 
IV
intravenous
IWRS
interactive web response system
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare Products Regulatory Agency
MRD
multiple-rising dose
NMDA
N-methyl-D-aspartate
NPS
Numeric Pain Scale
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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PD
pharmacodynamic(s)
PET
positron emission tomography
PGIC
Patient Global Impression of Change scale
PGx
pharmacogenomics
PK
pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Devices Agency, Japan
PROMIS-29
29-item Patient-Reported Outcomes Measurement Information System, version 2.1
PTE
pretreatment event
PTZ
pentylenetetrazol
PWT
paw withdrawal threshold
QD
once daily
QTcF
QT interval with Fridericia’s correction method
RO
receptor occupancy
SAE
serious adverse event
SOP
standard operating procedure
SRD
single-rising dose
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
UK
United Kingdom
US
United States
3.4
Corporate Identification
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
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4.0
INTRODUCTION
4.1
Background
Complex regional pain syndrome (CRPS) was initially identified by Claude Bernard (1813-1878) 
when he noted that extreme pain could be associated with abnormalities in the autonomic nervous 
system. Mitchell (1829-1914) coined the term ‘causalgia’ to describe this constellation occurring 
in veterans of the American Civil War. The term ‘reflex sympathetic dystrophy’ was used until 
recently when CRPS was agreed upon. CRPS can be subdivided into 3 types: (1) CRPS-I: 
previously known as reflex sympathetic dystrophy; (2) CRPS-II, previously known as causalgia 
and defined as CRPS with clinical and/or electrodiagnostic evidence of nerve damage; and (3) 
CRPS (not otherwise specified) which only partially meets diagnostic criteria, but no better 
diagnosis can be discerned [3]. CRPS-I and CRPS-II have similar outcomes and response to pain 
medication. Autonomic changes are often required for the diagnosis and may distinguish between 
acute CRPS (‘hot’ limb with edema and red coloration) and chronic (‘cold’ limb with atrophy and 
blue coloration). Although there is significant involvement of the peripheral nervous system, 
chronic CRPS is thought to be a central neurological disease with demonstrated alterations in both 
central nervous system (CNS) function as well as structural changes including alterations in 
cortical representations in both sensory and motor cortex [4]. CRPS is known as one of the most 
painful disorders and the risk of suicide is significantly higher in patients with CRPS with one 
study demonstrating that 75% of patients had a high risk for suicide [5]. Due to the severity of the 
pain, amputation is rarely being considered as a therapeutic option [6]. Although the 
pathophysiology has not been established, overactivity of the N-methyl-D-aspartate (NMDA) 
receptors are thought to play a role [7] and while no drugs are approved for CRPS, ketamine, a 
NMDA receptor antagonist, has established efficacy in a randomized control trial [8]. Use of an 
NMDA antagonist along with morphine, decreased pain and cerebral pain representation 
consistent with brain involvement in CRPS [9].
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TAK-935 is also being evaluated for the treatment of rare pediatric epilepsies.
For further information, refer to the TAK-935 Investigator’s Brochure.
4.2
Rationale for the Proposed Study
In phase 1 studies in healthy adult subjects and in a phase 1b/2a study in adult subjects with DEEs, 
acceptable pharmacokinetic (PK) and safety characteristics have been observed.
This study will be the first phase 2a study to test the efficacy, safety, and tolerability of TAK-935 
in adults with CRPS. Based on the mechanism of action, preclinical data on a pertinent model to 
CRPS and the safety characteristics of the completed and ongoing studies, we propose this phase 
2a study that will test the efficacy, safety and tolerability of TAK-935 in adults with CRPS, a 
highly impacted population with great unmet need.
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
!
To investigate the effect of TAK-935 on calculated 24-hour average pain intensity by the 
Numeric Pain Scale (NPS) (an 11-point scale).
5.1.2
Secondary Objectives
!
To investigate the effect of TAK-935 on overall function using the Patient Global Impression 
of Change (PGIC) and the Patient-Reported Outcomes Measurement Information System 
(PROMIS-29) scale.
!
To investigate the effect of TAK-935 on the CRPS Severity Score (CSS).
!
To investigate the effect of TAK-935 on responder rate (responder is defined as ≥30% 
improvement in the 24-hour pain intensity).
5.1.3
Exploratory Objectives
5.1.4
Safety Objective
!
To evaluate safety and tolerability of TAK-935 in subjects with CRPS.
5.2
Endpoints
5.2.1
Primary Endpoint
!
Change in mean 24-hour pain intensity NPS from baseline to the end of Part A (Week 15).
5.2.2
Secondary Endpoints
!
Percent change in mean 24-hour pain intensity NPS score from baseline to the end of Part A 
(Week 15).
!
Percent of responders (defined as ≥30% improvement on the 24-hour pain intensity NPS) by 
the end of Part A (Week 15).
!
Change and percent change from baseline of mean total score of the PROMIS 29 version 2.1 to 
the end of Part A (Week 15).
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!
Change and percent change from baseline of mean PGIC to the end of Part A (Week 15).
!
Change and percent change from baseline of mean CSS in subjects to the end of Part A (Week 
15).
5.2.3
Exploratory Endpoints
5.2.4
Safety Endpoints
!
Percentage of subjects with at least 1 treatment-emergent adverse event (TEAE) in Part A and 
Part B.
!
Percentage of subjects with at least 1 markedly abnormal value for clinical laboratory 
evaluations, vital signs, body weight/body mass index (BMI), and electrocardiogram (ECG) 
parameters after treatment in Part A and Part B.
!
Change from baseline in clinical laboratory evaluations, vital signs, body weight, 
Columbia-Suicide Severity Rating Scale (C-SSRS), and ECG parameter values after treatment 
in Part A and Part B.
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 2a randomized, double-blind, placebo-controlled, parallel-group study in adult 
subjects (≥18-75 years inclusive) with chronic (symptoms ≥6 months) CRPS. The objective will 
be to evaluate the ability of TAK-935 as adjunctive therapy to reduce pain as measured by the NPS 
(an 11-point scale by electronic pain diary). This study will also evaluate efficacy of TAK-935 as 
measured by PROMIS-29 version 2.1, PGIC, and CSS.
Approximately 24 subjects will be randomized to ensure 21 completers in the double-blind phase 
of the study. Randomization will be 2:1 (16 treatment: 8 placebo).
This study consists of 2 parts:

Part A: Double-Blind Treatment
–
2- to 4-week screening period.
–
3-week titration period.
–
12-week maintenance period.
–
Taper period (maximum 6 days)/Follow-up (15 days after last dose of study drug) if the 
subject does not continue into the open-label extension (see Section 9.3.4 for details).

Part B: Open-Label Extension
–
2-week titration period.
–
12-week open label.
–
Taper period (maximum 6 days)/Follow-up (15 days after last dose of study drug).
Part A: Double-Blind Treatment (19-21 weeks including the screening period and follow-up if the 
subject does not continue into the open label extension)
At Visit 1 (screening), after obtaining informed consent, subjects will undergo screening 
procedures to assess subject eligibility in accordance with study entry criteria. Subjects who fulfill 
the CRPS Budapest Criteria, have symptoms for ≥6 months and meet all inclusion criteria and 
none of the exclusion criteria at the screening visit will be eligible for entry into the study. For a 
minimum of 6 of the last 7 screening days prior to randomization at Visit 2 (Day 1) into the study, 
baseline current pain intensity will be collected 3 times a day to provide an average daily 24-hour 
pain intensity (NPS; an 11-point scale by electronic pain diary). The baseline will be defined as the 
mean of the average screening 24-hour pain intensity score for the last 7 days before the first dose. 
During Part A, average 24-hour pain intensity will be calculated as the mean of 3 measurements 
collected during a day. The average pain intensity score will be calculated as the mean of the 
average 24-hour pain intensity score collected during the last 7 days before Visit 5 (Day 21, 
Week 3) and Visit 8 (Day 105, Week 15) (or the last dose in Part A), which will be used for the 
primary endpoint analysis.
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At the end of the prospective screening period, subjects will return to the clinic (Visit 2, Day 1) and 
if a subject does not meet the eligibility criteria the subject will be discontinued from the study and 
considered a screen failure.
On Visit 2 (Day 1), the subjects who meet the entry criteria will be randomized in a 2:1 ratio to 
double-blind treatment with investigational product (IP), either TAK-935 100 mg tablets or 
matching placebo, for 15 weeks (3-week titration period and 12-week maintenance period).
All screening/baseline assessments will be collected prior to initiating treatment.
At Visit 2 (Day 1), after randomization and all predose procedures have been performed, subjects 
will be started on 100 mg BID IP (either TAK-935 100 mg tablets or matching placebo) for 
approximately 1 week. The first dose on Day 1 will be taken in the clinic (except for Visit 4 
[Day 14], Visit 6 [Day 49], and Visit 13 (Day 203), when subjects will be instructed to take their 
dose on site at their study visit). The subject will take the second dose on Day 1 and the remaining 
daily doses at home. The site will contact the subject by telephone on Day 4 to determine safety 
and tolerability.
At Visit 3 (Day 7, Week 1), safety and tolerability will be assessed and if the drug is well tolerated, 
the dose will be increased to 200 mg BID. The site will contact the subject by telephone on Day 10 
to determine safety and tolerability of this dose. Any subjects who continue with 100 mg BID and 
still cannot tolerate the minimum daily dose of 100 mg BID, will be withdrawn from the study.
At Visit 4 (Day 14, Week 2), safety and tolerability will be assessed and if the drug is well 
tolerated with no continuing pain, the subject will remain at 200 mg BID. If the subject continues 
to need a higher dose in the PI’s opinion, the dose will be increased to 300 mg BID. The site will
contact the subject via phone on Day 17 to determine the safety and tolerability of this dose. 
Subjects that do not require the dose to be increased to 300 mg BID will still be required to 
complete a 21-day titration period in order to confirm the tolerated dose prior to entering the 
maintenance phase. After completing 1 week for each dose adjustment at 100 mg BID increments 
to 300 mg BID depending on tolerance, the 3-week titration period will be completed and the 
subject will return to the site for Visit 5 (Day 21, Week 3) to begin the 12-week maintenance 
period.
After Visit 5 (Day 21, Week 3), subjects will visit the clinic approximately every 4 weeks (Visit 6 
[Day 49, Week 7] and Visit 7 [Day 77, Week 11]). The current pain intensity will be collected 3
times a day using the electronic pain diary. From this data, an average 24-hour pain intensity score 
can be calculated.
If at any time during either the titration period or the maintenance period the subject cannot 
tolerate the dose, the dose may be decreased to the previous tolerated dose. The subject may return 
to the clinic for an unscheduled visit at any time during either the titration period or the 
maintenance period if dose adjustments are needed between scheduled visits. If the subject cannot 
tolerate the minimum daily dose of 100 mg BID, the subject will be withdrawn from the study. If 
the dose is decreased due to inability to tolerate the dose based on the investigator’s review, the 
dose may be increased to the next highest dose 1 time during the titration. Dose modifications 
during the maintenance period should be discussed with the medical monitor.
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The subject should be instructed not to alter their dose without prior approval from the 
investigator. Any change in dose will be documented in the subject’s clinic chart and electronic 
diary.
Pain medications and nondrug treatments must be stable (regimented per prescription) for 1 month 
prior to screening and should remain stable throughout Part A. Pain medication use may be 
adjusted under supervision during Part B. Concurrent treatment regimen data will be collected 
throughout the study.
A single effective rescue medication must be identified for each subject for use during the study. 
The prescribed maximum dose must remain stable during Part A. The use of rescue pain 
medications will be assessed at each visit; subjects requiring significant increase of rescue 
medication (frequency or dose 50% over pre-enrollment levels or over the prescribed maximum) 
during Part A will be considered for withdrawal from the study at the investigator’s and sponsor’s 
discretion.
During Part A, all subjects will continue to enter the current pain intensity score as described 
3 times a day using the NPS in the electronic pain diary.
An unblinded interim analysis will be conducted when all subjects have completed Part A 
(Double-Blind Treatment).
Following completion of Part A, subjects will have the option to continue into Part B, a 14-week 
open-label drug extension, or to enter a double-blind taper period (maximum 6 days).
For all subjects that choose not to enter into Part B (Open-Label Extension), the IP dose will be 
reduced to the next lower dose every 3 days (or less frequently based on the investigator’s 
discretion) until IP dose is discontinued. After tapering, the subjects will complete a safety 
follow-up phone call approximately 15 days after the last dose of IP.
Part B Open-Label Extension (14 weeks):
Because the Part A treatment assignments will remain blinded, all subjects who choose to continue 
into Part B will start at 200 mg BID TAK-935 (100 mg tablets), regardless of the treatment they 
were on in Part A at Visit 8 (Day 105, Week 15). Subjects will remain at this dose for 1 week. The 
site will contact the subject by telephone, 3 days after initiation of this dose, on Day 108 to 
determine safety and tolerability.
At Visit 9 (Day 112, Week 16), safety and tolerability will be assessed and if the drug is well 
tolerated and the subject continues to need a higher dose in the PI’s opinion, the dose will be 
increased to 300 mg BID. The dose may also be decreased based on tolerability at Visit 9 
(Day 112, Week 16). The site will contact the subject on Day 115 to determine the safety and 
tolerability of this dose.
After completing 1 week at 300 mg BID, the 2-week titration period will be completed and the 
subject will return to the site for Visit 10 (Day 119, Week 17) to begin the 12-week maintenance 
period.
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If at any time during either the titration period or the maintenance period the subject cannot 
tolerate the dose, the dose may be decreased to the previous tolerated dose. The subject may return 
to the clinic for an unscheduled visit at any time during either the titration period or the 
maintenance period if dose adjustments are needed between scheduled visits.
The subject should be instructed not to alter their dose without prior approval from the 
investigator. Any change in dose will be documented in the subject’s clinic chart and electronic 
diary.
After Visit 10 (Day 119, Week 17), the subjects will visit the clinic approximately every 4 weeks 
(Visit 11 [Day 147, Week 21] and Visit 12 [Day 175, Week 25]). The current pain intensity will be 
collected daily, 3 times a day, using the electronic pain diary until the end of the study. From these 
data an average 24-hour pain intensity score can be calculated. In addition, using the data collected 
in the last 7 days before Visit 11 (Day 147, Week 21) and Visit 13 (Day 203, Week 29) (or the last 
dose in Part B), the average pain score prior to these visits will be derived.
During the taper period, the IP dose will be reduced to the next lower dose every 3 days (or less 
frequently based on the investigator’s discretion) until IP dose is discontinued. After tapering, the 
subjects will complete a safety follow-up phone call approximately 15 days after the last dose of IP 
and exit the study.
The total period of evaluation from screening to the final follow-up in Part B will be approximately 
34-36 weeks.
A schematic of the study design in shown in Figure 6.a. A schedule of study procedures is listed in 
Appendix A.
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Figure 6.a
Schematic of Study Design
BID: twice daily.
During the titration periods of both Part A and Part B, safety and tolerability will be assessed at each visit and if the 
drug is well tolerated and the subject continues to need a higher dose (ie, the subject still has pain), the dose will be 
increased to a maximum dose of 300 mg BID.
Starting doses for Part A and optional open-label extension Part B are shown.
Following completion of Part A, subjects will have the option to continue into Part B, a 14-week open-label drug 
extension study part or to enter a double-blind taper period.
All subjects will undergo dose taper procedures and will then proceed to the follow-up period. During the taper period, 
IP dose will be reduced to the next lower dose every 3 days (or less frequently based on the investigator’s discretion) 
until IP dose is discontinued. Subjects who are on the lowest administered dose of IP will not undergo dose taper.
6.2
Justification for Study Design, Dose, and Endpoints
6.2.1
Study Design
This is a randomized, double-blind, placebo-controlled, parallel-group study with an open-label 
extension part to further examine the safety, tolerability, and preliminary efficacy of TAK-935 as 
adjunctive therapy in the treatment of subjects with chronic CRPS (symptoms ≥6 months, 
diagnosed using the Budapest criteria). Since in a majority of CRPS subjects, symptoms resolve 
within the first 6 months, the large unmet need is for those subjects with chronic disease.
As this is proof of concept study, statistical power of 65% was considered adequate with an alpha 
level of 0.10.
During this study, subjects will continue their current medications; therefore, placebo was chosen 
as the control group to provide maximum difference between the treatment and control arms.
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6.2.2
Dose
Dose selection is based on a comprehensive analysis of the safety, tolerability, PK and 
pharmacodynamic (PD) data from 4 completed single- and multiple-dose phase 1 studies in 
healthy subjects, and a safety, tolerability, and PK data from the phase 1b/2a study of TAK-935 as 
adjunctive therapy in adult subjects with DEEs.
The up-titration scheme and target dose regimen were chosen to maximize target engagement 
(ie, CH24H enzyme occupancy) and downstream changes in plasma 24HC levels for optimal drug 
response, while ensuring an acceptable clinical safety profile in the target patient population. A 
population PK/enzyme occupancy (EO)/PD model, using the totality of the information available 
in healthy subjects was built to characterize TAK-935 PK, and describe its relationships with brain 
CH24H EO and subsequent reduction in plasma 24HC levels (PD). This integrated model consists 
of a 2-compartment PK model with (1) transit compartments to account for the delayed absorption 
of the new tablet formulation (to be used in this study) relative to the oral solution (used in 
previous phase 1 studies) and (2) dose as a covariate on clearance parameters and peripheral 
volume of distribution to describe TAK-935 nonlinear PK. A sigmoid Emax (maximum 
drug-induced effect) model using an effect-site compartment described the temporal relationship 
between TAK-935 concentrations and brain EO, while the relationship between 24HC plasma 
levels and TAK-935 concentrations was characterized by an indirect inhibitory response PK/PD 
model. Standard goodness-of-fit diagnostics, parameter precision and visual predictive checks 
demonstrated the appropriateness of the population PK and PK/EO/PD models.
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6.2.2.1
Clinical Safety
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6.2.3
Endpoints
The safety-related endpoints of TEAEs, clinical laboratory test results, vital sign measurements, 
C-SSRS, and ECG parameters selected for this study are standard methods for assessing safety and 
tolerability in clinical studies.
The primary endpoint (24-hour average pain intensity scale as measured on an 11-point scale 
[0-10]), and secondary endpoints (PROMIS-29 version 2.1, PGIC, and CSS) are 
well-characterized and accepted endpoints for pain studies.
Measurements of plasma 24HC levels will be included in this study as a PD biomarker related to 
the mechanism of action of TAK-935. The conversion of cholesterol to 24HC is a critical process 
in maintaining cholesterol homeostasis in the brain and its release into the cerebrospinal fluid and 
plasma. Evidence suggests that plasma 24HC levels are correlated with brain 24HC levels in 
healthy subjects and are largely derived from the CNS. Data from SRD and MRD studies showed 
a decrease in plasma 24HC levels after administration of TAK-935 in healthy subjects, which was 
correlated with the changes in EO% measured in the brain using the PET radioligand displacement 
approach (Study TAK-935-1003).
 
 
Pharmacogenomic analysis may be conducted to investigate the contribution of genetic variance 
on drug response, for example, its efficacy and safety. Participation of study subjects in 
pharmacogenomic sample collection is optional.
As pharmacogenomics is an evolving science, currently many genes and their function are not yet 
fully understood. Future data may suggest a role of some of these genes in drug response or 
diseases, which may lead to additional hypothesis-generating exploratory research on stored 
samples.
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6.3
Premature Termination or Suspension of Study or Study Site
6.3.1
Criteria for Study Termination related to Drug-Related Events
6.3.2
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied that 
require temporary suspension or early termination of the study.
!
New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a change in the known risk/benefit profile for the TAK-935, such that the risk is no 
longer acceptable for subjects participating in the study.
!
Significant violation of GCP that compromises the ability to achieve the primary study
objectives or compromises subject safety.
6.3.3
Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.4
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s)
In the event that the sponsor, an institutional review board (IRB), or regulatory authority elects to 
terminate or suspend the study or the participation of a study site, a study-specific procedure for 
early termination or suspension will be provided by the sponsor; the procedure will be followed by 
applicable study sites during the course of termination or study suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to first dose of study drug.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study:
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject signs and dates a written, informed consent form (ICF) and any required privacy 
authorization prior to the initiation of any study procedures, including requesting that a subject 
fast for any clinical laboratory evaluations.
3. The subject is a male or female aged ≥18 to 75 years inclusive at the time of informed consent.
4. The subject meets the Budapest clinical diagnosis of CRPS at the screening visit, and is at least 
6 months since onset of symptoms.
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d. No other diagnosis that better explains the signs and symptoms.
5. The subject has a history of failure of one or more standard of care therapies for the treatment 
of CRPS as judged by the investigator.
6. The subject’s pain medications and nondrug treatments must be stable (regimented per 
prescription) for 1 month prior to screening and remain stable throughout Part A.
7. The subject agrees to use a single previously prescribed rescue medication within the 
prescribed dose during Part A of the study and to record the daily use of these medications.
8. The subject must have an average 24-hour pain intensity score ≥4 and ≤9 on the 24-hour 
average pain intensity NPS during screening/baseline. This score will be calculated by 
averaging the daily 24-hour pain intensity scores for the past seven days prior to 
randomization. The subject must have daily 24-hour pain intensity scores recorded for at least 
6 of the past 7 days.
9. The subject is not involved in active litigation related to CRPS.
10.
11.
12.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
1. Currently receiving intravenous (IV) or oral ketamine, history of IV or oral ketamine use 
within the past 6 weeks prior to screening, or planned use of IV or oral ketamine during this 
study.
2. The subject has received any excluded medications, procedures, or treatments during the time 
periods listed in Section 7.3.
3. The subject has any unstable, clinically significant neurologic (other than the disease being 
studied), psychiatric, cardiovascular, ophthalmologic, pulmonary, hepatic, renal, metabolic, 
gastrointestinal, urologic, immunologic, hematopoietic, or endocrine disease or other 
abnormality which may impact the ability to participate in the study or that may potentially 
confound the study results. It is the responsibility of the investigator to assess the clinical 
significance.
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4.
5. The subject has any history of alcohol, opioid, or moderate to severe substance use disorder 
(except nicotine and cannabis), as per the Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition, within the 2 years immediately prior to the screening visit (Visit 1).
6. Subject is receiving chronic opioid treatment at a dose that has not been stable 28 days prior to 
screening.
7. Subjects is receiving chronic opioid treatment >160 mg of morphine equivalent per day (refer 
to Appendix E for conversion table).
8. The subject has a positive drug screen for phencyclidine, amphetamine/ methamphetamine, or 
cocaine at screening. Cannabis is allowed.
9. The subject is considered by the investigator to be at imminent risk of suicide or injury to self, 
others, or property, or the subject has attempted suicide within the past year prior to screening. 
Subjects who have positive answers on item number 4 or 5 on the C-SSRS (based on the past 
year) prior to randomization are excluded.
10.
11.
12. The subject is positive for hepatitis B or hepatitis C infection at screening. (Note that subjects 
who have been vaccinated against hepatitis B [hepatitis B surface antibody {Ab}-positive] 
who are negative for other markers of prior hepatitis B infection [eg, negative for hepatitis B 
core Ab] are eligible. Also, note that subjects who are positive for hepatitis C Ab are eligible if 
they have a negative hepatitis C viral load by quantitative polymerase chain reaction).
13. The subject has abnormal and clinically significant ECG abnormality at screening as 
determined by the investigator. Subject has a QT interval with Fridericia’s correction method 
(QTcF) >450 ms (males) or >470 ms (females), confirmed with 1 repeat testing, at screening.
14. The subject has abnormal clinical laboratory test results at screening that suggest a clinically 
significant underlying disease that would compromise the well-being of the subject (if the 
subject has alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST] >2.5 × 
the upper limit of normal [ULN], the medical monitor should be consulted).
15. The subject has a known hypersensitivity to any component of the formulation of TAK-935.
16. The subject has been part of a clinical study involving another investigational product in the 
previous 3 months prior to screening or subject is currently receiving an investigational 
product.
17. The subject has received TAK-935 in a previous clinical study or as a therapeutic agent.
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18. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in conduct of this study (eg, spouse, 
parent, child, sibling) or may consent under duress.
19. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 30 days after participating in this study; or intending to donate ova during such time 
period.
20. If male, the subject intends to donate sperm during the course of the study or within 90 days
after the last dose of study drug.
7.3
Excluded Medications, Procedures, and Treatments
Ketamine use is excluded from the screening until the end of the follow-up visit.
The subject may be currently receiving nondrug interventions (eg, physical therapy, 
occupational/physical therapy, biofeedback, cognitive behavioral therapy, and/or 
yoga/meditation), which must have been started 90 days prior to randomization and continue 
throughout the duration of the study.
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Subjects should be advised to not consume alcohol or illicit drugs during the study. Cannabis is 
allowed. Subjects must be instructed not to take any medications including over-the-counter 
products, without first consulting with the investigator.
Elective procedures for CRPS are not allowed during the study, by consent.
7.4
Diet, Fluid, Activity Control
There are no restrictions on diet, fluids, or activity during this study. Subjects should continue their 
current nondrug interventional therapies (eg, physical/occupational therapy, pain management, 
etc.).
7.5
Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the electronic case report form (eCRF) using the following categories. For 
screen failure subjects, refer to Section 9.1.20.
1. AE. The subject has experienced an 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 AE.

Liver test 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 9.1.11), if the following circumstances occur at any 
time during study drug treatment:
–
ALT or AST >8 × ULN, or
–
ALT or AST >5 × ULN and persists for more than 2 weeks, or
–
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or
–
ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).
2. Subjects who cannot tolerate the 100 mg BID dosing will be withdrawn from the study and 
should undergo all procedures scheduled for the final visit at the time of withdrawal.
3. Drug-related SAE or drug-related significant non-serious AE, which in the opinion of the 
study physician or principal investigator, warrants discontinuation of the study for the 
subject’s wellbeing.
4. 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.
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5. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documents.
6. Withdrawal by subject. 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. Similarly, lack of efficacy 
should not be recorded in the “voluntary withdrawal” category.
7. Study termination. The sponsor, IRB, or regulatory agency terminates the study.
8. Pregnancy. The subject is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.17. 
9. Lack of efficacy. The investigator has determined that the subject is not benefiting from study 
treatment; and, continued participation would pose an unacceptable risk to the subject. 
10. The subject has received ketamine therapy during the study.
11. Other. Subjects requiring significant increase of rescue medication (frequency or dose 50% 
over pre-enrollment levels or over prescribed maximum) will be considered for withdrawal 
from the study at the investigator’s discretion.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
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. Subjects who withdraw early from the study should undergo 
dose tapering and complete all procedures scheduled for the final visit (at time of withdrawal). The 
investigator in consultation with the medical monitor will evaluate the possible effects of rapid 
withdrawal from the study drug versus the risk of continuing the drug. Discontinued or withdrawn 
subjects may be replaced.
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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
This section contains information regarding all medications and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of study material.
8.1
Study Drug and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term study drug refers to all or any of the drugs defined below.
8.1.1.1
Study Drug
The sponsor will supply the study sites with TAK-935 100 mg tablets and matching placebo 
tablets. TAK-935 100 mg tablets and matching placebo tablets are manufactured by Takeda 
Pharmaceutical Company, Ltd, Osaka, Japan. Study drug will be supplied in high-density 
polyethylene bottles with induction seal and child-resistant caps. Each bottle will contain a label 
that includes pertinent study information and caution statements.
8.1.1.2
Rescue Medication
A single effective rescue medication must be identified for each subject for use during the study. 
The prescribed maximum dose must remain stable during Part A. The use of rescue pain 
medications will be assessed at each visit; subjects requiring significant increase of rescue 
medication (frequency or dose 50% over pre-enrollment levels or over the prescribed maximum) 
in Part A will be considered for withdrawal from the study at the investigator’s discretion.
Rescue medication will not be supplied by the sponsor.
8.1.1.3
Sponsor-Supplied Drug
Sponsor-supplied drugs referenced in other sections of the protocol include the following:
!
TAK-935 100 mg tablets.
!
Matching placebo tablets.
8.1.2
Storage
Study drug must be kept in an appropriate, limited-access, secure place until it is dispensed and 
after returned to the sponsor or designee for destruction. Study drug must be stored under the 
conditions specified on the label, and remain in the original container until dispensed. A daily 
temperature log of the drug storage area must be maintained every day.
CCI
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8.1.3
Dose and Regimen
Each subject will be instructed to administer study drug, orally, at the same time each day with or 
without food. The study site personnel will indicate how many tablets should be taken per day on 
the bottle label, per information provided by the Interactive Web Response System (IWRS).
The investigator or designee will instruct the subject on the dosing procedures and study drug 
storage requirements. Subjects should return unused study drug at each study visit to allow the 
investigator or designee to evaluate subjects’ compliance with the dosing instructions. Number of 
dispensed and returned tablets will be recorded on the eCRF.
The planned daily dose and tablet count to be administered to subjects in each part of the study is 
shown in Table 8.a.
Table 8.a
Dose and Regimen
Study Part
Dose
Treatment Description a
Part A
(double-blind)
TAK-935 100 mg BID
or matching placebo BID
1 TAK-935 100 mg tablet BID for 7 days
or 1 placebo tablet BID for 7 days
TAK-935 200 mg BID
or matching placebo BID
2 TAK-935 100 mg tablets BID for 7 days
or 2 placebo tablets BID for 7 days
TAK-935 100, 200, or 300 mg BID
or matching placebo BID
1, 2, or 3 TAK-935 100 mg tablets BID for 7 days 
(titration period), followed by 84 days (maintenance 
period)
or 1, 2, or 3 placebo tablets BID for 7 days (titration 
period), followed by 84 days (maintenance period)
Part B
(open-label extension)
TAK-935 100, 200, or 300 mg BID Initiate with 2 TAK-935 100 mg tablets BID for 7 days. 
Dose may be adjusted per investigator’s discretion to a 
maximum of 3 TAK-935 100 mg tablets BID.
BID: twice daily; IP: investigational product.
a Planned dose titration is presented. If at any time during Part A titration or maintenance period the subject cannot 
tolerate the dose, the dose may be decreased to the previous tolerated dose. During the titration period, safety and 
tolerability will be assessed at each visit and if the drug is well tolerated and the subject continues to need a higher dose 
(ie, the subject still has pain), the dose will be increased to a maximum dose of 300 mg BID.
During the taper period, the IP dose will be reduced to the next lower dose every 3 days (or less frequently based on the 
investigator’s discretion) until IP dose is discontinued.
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of study drug, to or by a 
study subject, at a dose above that which is assigned to that individual subject according to the 
study protocol.
All cases of overdose (with or without associated AEs) will be documented in the eCRF. Cases of 
overdose without manifested signs or symptoms are not considered AEs. AEs associated with an 
overdose will be documented on AE CRF(s) according to Section 10.0.
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2.
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In the event of drug overdose, the subject should be treated symptomatically.
8.2
Study Drug Assignment and Dispensing Procedures
Sites should follow the IWRS manual for specific instructions (IWRS manual provided 
separately). For Part A, subjects will be assigned to receive their treatment according to the 
randomization schedule. The investigator or investigator’s designee will access the IWRS at the 
Visit 1 (screening) to obtain the subject number. At Visit 2 (Day 1, Randomization), the 
investigator or the investigator’s designee will use the IWRS to randomize eligible subjects into 
the study. During this contact, the investigator or designee will provide the necessary 
subject-identifying information, including the subject number assigned at screening. The 
medication identification (ID) number of the study drug to be dispensed will then be provided by 
the IWRS. At subsequent drug-dispensing visits, the investigator or designee will again contact the 
IWRS to request additional study drug for a subject. The medication ID number of the study drug 
to be dispensed will again be provided by the IWRS. The medication ID number will be entered 
onto the eCRF. If sponsor-supplied drug (TAK-935 100 mg or matching placebo tablets) is lost or 
damaged, the site can request a replacement from the IWRS (refer to the IWRS manual provided 
separately).
Each subject should be instructed as follows:

Keep sponsor-supplied drugs in original containers until the time of dosing.

Administer study drug as instructed. If the subject misses a dose, he or she should not be given 
twice the dose the next day. 

Store sponsor-supplied drugs according to the label and keep them out of the reach of children.

Return unused sponsor-supplied drugs at each clinic visit.

Record the number of tablets taken (AM and PM) in the electronic diary.
8.3
Randomization Code Creation and Storage
For Part A, the randomization will be stratified by the investigation site. The dummy 
randomization schedules will be developed by IWRS and approved by the sponsor. All 
randomization information will be stored in IWRS.
Study drug will be administered in a double-blind manner in Part A. The study drug blind will be 
maintained by IWRS. The principal investigator at each study site will receive instructions for 
obtaining the study drug assignment through the IWRS. During regularly scheduled monitoring 
visits, a study monitor from the sponsor or a designee will perform an inventory of assigned and 
unassigned bottles of study drug. All assigned/unassigned study drug bottles will be reconciled 
before destroying at site (permitted if internal standard operating procedure [SOP] is in place) or 
returning to the sponsor or a designee before study closure.
Study drug will be administered in an open-label manner in Part B. During regularly scheduled 
monitoring visits, a study monitor from the sponsor or a designee will perform an inventory of 
assigned and unassigned bottles of study drug. All assigned/unassigned study drug bottles will be 
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reconciled before destroying at site (permitted if internal SOP is in place) or returning to the 
sponsor or a designee before study closure.
8.4
Unblinding Procedure
If the investigator deems it necessary to unblind the study drug used by the subject to determine the 
dosage administered for the medical treatment of the subject in case of emergency, for example, 
the occurrence of SAEs, the investigator must complete the unblinding process within the IWRS as 
outlined in the IWRS manual. The sponsor/designee must be notified immediately if the study 
drug blind is broken. The date, time, and reason the blind was broken must be recorded in the 
source documents and on the appropriate eCRF.
If any site personnel is unblinded, it is recommended that the study drug be tapered down in 
consultation with the medical monitor, and the subject must be withdrawn from the study. 
However, the investigator in consultation with the medical monitor will evaluate the possible 
effects of rapid withdrawal from the study drug versus the risk of continuing the drug.
The reason for withdrawal should be recorded as, “Protocol Deviation.” Subjects who are 
withdrawn early from the study should undergo all procedures scheduled for the final visit at the 
time of withdrawal.
Only the responsible investigator or delegate and the respective subject’s code will be unblinded. 
Other study site personnel and sponsor personnel directly associated with the conduct of the study 
should not be unblinded. The investigator will follow the early termination procedures and 
withdraw the subject from the study.
8.5
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being destroyed at site or returned 
to the sponsor or designee. NOTE: Destruction at site is permitted if internal SOP is in place by 
providing copy of certificate of destruction or memo confirming the destruction to be stored in the 
trial master file.
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance with 
the protocol and is dispensed only to subjects enrolled in the study. To document appropriate use 
of sponsor-supplied drug (TAK-935 100 mg or matching placebo tablets), the investigator or 
designee must maintain records of all sponsor-supplied drug delivery to the site, site inventory, 
dispensation and use by each subject, destruction at site and/or return to the sponsor or designee.
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, and the 
medication is in good condition. If quantity and conditions are acceptable, investigator or designee 
should acknowledge the receipt of the shipment by recording in IWRS. If there are any 
discrepancies between the packing list versus the actual product received, Takeda must be 
contacted to resolve the issue. The packing list should be filed in the investigator’s essential 
document file.
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The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to:

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the drug lot (or medication ID number) used to prepare 
each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The IWRS will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
The investigator or designee must record the current inventory of all sponsor-supplied drugs 
(TAK-935 100 mg and matching placebo tablets) on a sponsor-approved drug accountability log. 
The following information will be recorded at a minimum: protocol number and title, name of 
investigator, site identifier and number, description of sponsor-supplied drugs, expiry date, date 
and amount dispensed including initials, seal, or signature of the person dispensing the drug, and 
the date and amount returned to the site by the subject, including the initials, seal, or signature of 
the person receiving the sponsor-supplied drug. The log should include all required information as 
a separate entry for each subject to whom sponsor-supplied drug is dispensed.
All study drug not returned to the site by a subject must be investigated by the site and 
appropriately documented on the drug accountability log.
Before site closure or at appropriate intervals, a representative from the sponsor or its designee will 
perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied drugs 
are destroyed at site, or returned to the sponsor or its designee for destruction. The investigator or 
designee will retain a copy of the documentation regarding sponsor-supplied drug accountability, 
return, and/or destruction, and originals will be sent to the sponsor or designee.
In the event of expiry date extension of sponsor-supplied drug already at the study site, Takeda or 
its designee will provide a memo stating the new extended expiry date.
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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
schedule of study procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed.
A unique subject ID number (subject number) will be assigned to each subject at the time that 
informed consent is obtained; this subject number will be used throughout the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth, sex, Hispanic ethnicity, race as 
described by the subject, and smoking status of the subject at screening.
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that resolved at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.10).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and the efficacy or safety evaluations stopped or started within 6 months prior to signing of 
informed consent.
Subjects will be asked if they have used ketamine therapy within the past 6 weeks prior to 
screening, how long ago was the therapy provided, what formulation was used, whether the 
therapy provided relief, and why the therapy was stopped. Subjects will be asked if they 
experience flare-ups in their pain and, if so, how frequently.
9.1.3
Physical Examination Procedure
A baseline physical examination (defined as the assessment prior to first dose of study drug) will 
consist of a general examination of the following body systems: (1) ears, nose, throat; 
(2) cardiovascular system; (3) respiratory system; (4) gastrointestinal system; (5) dermatologic 
system; (6) extremities; (7) musculoskeletal system; (8) lymph nodes; and (9) other. All 
subsequent physical examinations should assess clinically significant changes from the assessment 
prior to first dose examination. The physical examination must be captured in the source document 
and eCRF. 
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9.1.4
Neurological Examination Procedure
A separate neurological examination will be performed and collected in the eCRF. This will 
include testing mental status, gait, cerebellar function, cranial nerves, motor function (including 
strength and reflexes), and sensation. As part of the neurological exam, vision testing is 
recommended to include fundoscopy and best corrected visual acuity using a pocket vision 
screening card, if possible.
9.1.6
Weight, Height, and BMI
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The BMI is calculated using metric units with the formula provided below. Height is recorded 
in centimeters without decimal places. Weight is collected in kilograms (kg) with 1 decimal place. 
BMI should be derived as:
Metric:
BMI = weight (kg)/height (m)2
Note that although height is reported in centimeters, the formula uses meters for height; meters can 
be determined from centimeters by dividing by 100. Thus, for example, if height = 176 cm 
(1.76 meters) and weight = 79.2 kg, then BMI = 79.2/1.762 = 25.56818 kg/m2, which will be 
rounded to 25.6 kg/m2.
9.1.7
Vital Sign Procedure
Vital signs will include oral body temperature, respiratory rate, blood pressure (systolic and 
diastolic, resting more than 5 minutes), and pulse (bpm).
9.1.8
Primary Efficacy Measurements
9.1.8.1
NPS
The 24-hour average pain intensity (NPS, an 11-point scale) will be calculated from current pain 
intensity scores collected 3 times a day as measured by the electronic pain diary daily during Parts 
A and B. Pain intensity will be evaluated on the affected limb. If more than 1 limb is involved, the 
subject and the investigator will determine which limb is the most problematic and the pain 
intensity will be evaluated for that limb throughout the study. For both Parts A and B, average 
24-hour pain intensity will be calculated as the mean of 3 measurements collected during a day. 
The average pain intensity score will be calculated as the mean of the average 24-hour pain 
intensity score collected during the last 7 days before Day 21(Week 3), Day 105 (Week 15) (or the 
last dose in Part A), which will be used for the primary endpoint analysis, as well as Day 147 
(Week 21) and Day 203 (Week 29) (or the last dose in Part B).
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In addition to collecting the pain intensity at the time of recording, the electronic pain diary will 
collect number of flare-ups experienced that day.
9.1.8.2
PROMIS-29
The PROMIS-29 (version 2.1), a generic health-related quality of life survey, assesses each of the 
7 PROMIS domains (depression, anxiety, physical function, pain interference, fatigue, sleep 
disturbance, and ability to participate in social roles and activities) with 4 questions per domain. 
The questions are ranked on a 5-point Likert scale.
9.1.8.3
PGIC
The PGIC is a 7-point Likert scale to address the following question: Since beginning treatment at 
this clinic would you describe any changes (if any) in activity, limitations, symptoms, emotions 
and overall quality of life related to your painful condition compared to before treatment? Very 
much improved; moderately improved; slightly improved; no change; slightly worse; moderately 
worse; very much worse.
9.1.9
Documentation of Concomitant Medications
Concomitant medication is any drug ongoing at the time the informed consent, as well as given in 
addition to the study drug during the study. These may be prescribed by a physician or obtained by 
the subject over the counter. Concomitant medication is not provided by the sponsor. At each study 
visit, subjects will be asked whether they have taken any medication other than the study drug 
(used from signing of informed consent through the end of the study), and all medication including 
vitamin supplements, over-the-counter medications, and oral herbal preparations, must be 
recorded in the eCRF. Documentation will include generic medication name, dose, unit, 
frequency, route of administration, start and end dates, and reason for use.
9.1.10
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, ECG, or physical 
examination abnormalities noted at screening/baseline examination, according the judgment of the 
investigator. The condition (ie, diagnosis) should be described and recorded on the medical history 
form.
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9.1.11
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. Details of these 
procedures and required safety monitoring will be given in the laboratory manual. The 
approximate volume of blood collected at any single visit and the approximate total volume of 
blood collected in the study will be given in the laboratory and/or study manual.
Table 9.a lists the tests that will be obtained for each laboratory specimen.
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The local laboratory will perform all laboratory tests including hematology, serum chemistries, 
and urinalysis. The results of laboratory tests will be provided to the investigator, who is 
responsible for reviewing and filing these results. The investigator will maintain a copy of the 
laboratory accreditation and the reference ranges for the laboratory used.
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If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, gamma-glutamyl transferase, and international 
normalized ratio) should be performed preferably within 48 to 72 hours and no later than 5 days 
after the abnormality was noted.
(Refer to Section 7.5 for discontinuation criteria and Section 10.2.3 for requirements related to 
ALT or AST >3 ×ULN in conjunction with total bilirubin >2 ×ULN.)
If ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions the investigator must 
contact the medical monitor for consideration of additional testing, close monitoring, possible 
discontinuation of study drug, discussion of the relevant subject details and possible alternative 
etiologies. The abnormality should be recorded as an AE (please refer to Section 10.2.3 for 
reporting requirements).
For female subjects, the results of the serum pregnancy test obtained at Visit 1 must be confirmed 
to be negative by the investigator prior to randomization.
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9.1.16
Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, and for up to 90 days after 
last dose of study drug, nonsterilized** male subjects who are sexually active with a female 
partner of childbearing potential* must use barrier contraception (eg, condom with or without 
spermicidal cream or jelly). In addition, they must be advised not to donate sperm during the 
course of the study and for 90 days after the last dose of study drug. Females of childbearing 
potential who are partners of male subjects are also advised to use additional contraception as 
shown in the list containing highly effective contraception below. From signing of informed 
consent, throughout the duration of the study, and for 30 days after last dose of study drug, female 
subjects of childbearing potential* who are sexually active with a nonsterilized male partner**
must use a highly effective method of contraception (from the list below). In addition, they must be 
advised not to donate ova during this period.
* Females NOT of childbearing potential are defined as those who have been surgically 
sterilized (hysterectomy, bilateral oophorectomy, or tubal ligation) or who are postmenopausal 
(eg, defined as ≥1 year since last regular menses with a follicle-stimulating hormone level 
>40 IU/L or ≥5 years since last regular menses, confirmed before any study drug is 
administered).
**Sterilized males should be ≥1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate.
A highly effective method of contraception is defined as one that has no higher than a 1% failure 
rate per year when used consistently and correctly. In this study, the only acceptable methods of 
contraception are as follows:
Hormonal contraception:
!
Combined (estrogen and progesterone containing) hormonal contraception associated with the 
inhibition of ovulation:
–
Oral.
–
Intravaginal.
–
Transdermal.
!
Progestogen-only hormonal contraception associated with the inhibition of ovulation:
–
Oral.
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–
Injectable.
–
Implantable.
Double-barrier methods (each time the subject has intercourse):

Sponge (plus spermicidal cream or jelly) PLUS male condom with or without spermicidal 
cream or jelly.

Cap (plus spermicidal cream or jelly) PLUS male condom with or without spermicidal cream 
or jelly.

Diaphragm (plus spermicidal cream or jelly) PLUS male condom with or without spermicidal 
cream or jelly.
Intrauterine devices:

Copper T PLUS condom.

Intrauterine hormone-releasing system.
Sterilization:

Bilateral tubal occlusion.

Vasectomized partner (provided that the partner is the sole sexual partner of the study 
participant and the absence of sperm in the ejaculate has been confirmed).
Abstinence:

Sexual abstinence, if it is the preferred and usual lifestyle of the subject, will be considered an 
acceptable method of contraception on a case-by-case basis upon prior approval by the medical 
monitor. Subjects practicing abstinence as a method of contraception must refrain from 
heterosexual intercourse throughout the duration of the study (for female and male subjects)
and for 30 (female subjects) or 90 (male subjects) days after last dose of study drug.
Subjects will be provided with information on acceptable 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 (during the course of the study and for 30 (female subjects) or 90 
(male subjects) days after the last dose of study drug).

donation of ova (during the course of the study and for 30 days after the last dose of study 
drug).

sperm donation (during the course of the study and for 90 days after the last dose of study 
drug).
All female subjects of childbearing potential must have a negative serum human chorionic 
gonadotropin (hCG) pregnancy test at screening (Visit 1). During the study, subjects will receive 
continued guidance with respect to the avoidance of pregnancy and sperm donation as part of the 
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study procedures. An additional serum hCG pregnancy test will be performed at the end of Part 
A/start of Part B (Visit 4).
9.1.17
Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued. In addition, any pregnancies in the 
partner of a male subject during the study or for 90 days after the last dose, should also be recorded 
following authorization from the subject’s partner.
If the pregnancy occurs during administration of active study drug, eg, after Visit 2 or within 
90 days for a male subject OR within 30 days for a female subject, of the last dose of active study 
drug, the pregnancy should be reported immediately, using a pregnancy notification form, to the 
contact listed in Section 1.1.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
Subjects randomized to placebo need not be followed.
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the female 
subject/female partner of the subject was participating in a clinical study at the time she became 
pregnant and provide details of the study drug the subject received (blinded or unblinded, as 
applicable).
All pregnancies, including female partners of male subjects, in subjects on active study drug will 
be followed up to final outcome, using the pregnancy form. Pregnancies will remain blinded to the 
study team. The outcome, including any premature termination, must be reported to the sponsor. 
An evaluation after the birth of the child will also be conducted.
9.1.18
ECG Procedure
A standard 12-lead ECG will be recorded at Visit 1 (Screening) to evaluate subject’s eligibility. A 
standard 12-lead ECG will be recorded in triplicate at predose at Visit 2, and at predose and 
between 30 to 45 min postdose (~Tmax) at Visits 5, 8, and 13. The investigator (or a qualified 
observer at the study site) will interpret the ECG using 1 of the following categories: within normal 
limits, abnormal but not clinically significant, or abnormal and clinically significant. The 
interpretation of the ECG will be recorded in the source documents and in the eCRF. The time that 
the ECG was performed will be recorded. The following parameters will be recorded on the eCRF 
from the subject’s ECG trace: heart rate, RR interval, PR interval, QT interval, QRS interval with 
QTcF, and corrected QT interval. ECG traces recorded on thermal paper will be photocopied to 
avoid degradation of trace over time.
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9.1.19
Clinical Assessment of Suicidal Ideation and Behavior
Suicidal ideation and behavior will be assessed using the C-SSRS. The C-SSRS is a 3-part scale 
that measures suicidal ideation (eg, subject endorses thoughts about a wish to be dead or has other 
thoughts of suicide), intensity of ideation (frequency, duration, controllability, deterrents, and 
reasons for ideation), and suicidal behavior (actually, interrupted, and aborted attempts at suicide) 
[20].
Two versions of the C-SSRS will be used in this study: the Screening/Baseline C-SSRS Lifetime 
and the Since-Last-Visit C-SSRS.
9.1.20
Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent. If the subject is withdrawn 
at the screening visit, the investigator should complete the eCRF. The IWRS should be contacted 
as a notification of screen failure.
The primary reason for screen failure is recorded in the eCRF using the following categories:

AE.

Did not meet entrance criteria (specify reason).

Significant protocol deviation.

Lost to follow-up.

Withdrawal by subject.

Study terminated by sponsor.

Other (specify reason).
Subjects may be rescreened after consultation with the medical monitor.
Subject ID numbers assigned to subjects who fail screening should not be reused. If a subject fails 
screening, but is later successfully rescreened, the data for the subject will be entered as if these 
were 2 separate subjects. Therefore, the data should be entered as follows:
1. The screen failure data should be entered as a screen failure subject.
2. Rescreened subjects should be assigned a new subject ID number and treated as a stand-alone 
subject.
9.1.21
Documentation of Randomization
Only subjects who meet all the inclusion criteria and none of the exclusion criteria are eligible for 
randomization into the Part A double-blind treatment period.
Following completion of Part A, subjects will have the option to continue into Part B, an 
open-label extension study part or to enter a double-blind taper period (maximum 14 days).
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If the subject is found to be not eligible, the investigator should record the primary reason for 
failure on the applicable eCRF.
9.2
Monitoring Subject Treatment Compliance
Subjects will be required to bring study drug containers/unused study drug and the daily recording 
in the electronic diary to each dispensing site visit. All subjects should be reinstructed about the 
dosing requirements during study contacts. The authorized study personnel conducting the 
re-education must document the process in the subject source records.
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s). Sequencing of visits per the 
schedule of assessments shall not be adjusted and must be maintained in order despite the 
allowance for visit window creating the ability to overlap.
9.3.1
Screening
Eligibility of subjects will be assessed in accordance with predefined inclusion and exclusion 
criteria as described in Section 7.0 at the screening visit (Visit 1). See Section 9.1.20 for 
procedures for documenting screening failures. At the screening visit, subjects will be trained on 
how to use the electronic pain diary. Subjects will be instructed to record pain 3 times a day for a 
minimum of 6 of the last 7 screening days prior to enrollment into the study and daily (3 times a 
day) throughout the study after the consent has been signed. 
Eligible subjects will be notified by phone of their study entry, after completing the baseline 
period.
9.3.2
Randomization
Randomization for eligible subjects will take place on Day 1 in Part A (Visit 2), before subjects 
take the first dose of study drug in the clinic.
If the subject has satisfied all the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized using the IWRS, as described in Section 8.2.
9.3.3
Part A
On Day 1 (Visit 2), after randomization and all predose procedures have been performed, subjects 
will receive the first dose of double-blind IP (TAK-935 100 mg or matching placebo tablets). The 
site will contact the subject by phone on Days 4, 10, and 17 to assess safety and tolerability, and 
discuss adjusting the study drug dosing as needed. The subject will return to the clinic on Visits 3 
(Day 7, Week 1), 4 (Day 14, Week 2), 5 (Day 21, Week 3), 6 (Day 49, Week 7), and 7 (Day 77, 
Week 11) to complete all scheduled assessments, assess safety and tolerability, and adjust study 
drug dosing as needed.
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Pain medications and nondrug treatments must be regimented per prescription for 1 month prior to 
screening, and prescriptions should not be altered during Part A. Concurrent treatment regimen 
data will be collected throughout the study. The use of rescue pain medications will be assessed at 
each visit.
During Part A, all subjects will continue to enter the current pain intensity score 3 times a day 
using the NPS in the electronic pain diary. This data will be captured daily during Part A.
9.3.4
End of Part A or Early Termination
At the end of Part A, subjects will return to the clinic on Day 105 (Week 15, Visit 8) to complete all 
scheduled assessments.
Subjects will have the option to continue into Part B, a 14-week open-label extension study, or to 
enter a follow-up period which includes a double-blind taper period (maximum 6 days) followed 
by a 2-week follow-up period off IP.
In all subjects choosing the taper period, the IP dose will be reduced to the next lower dose every 3 
days (or less frequently based on the investigator’s discretion) until IP dose is discontinued.
Subjects who withdraw early from Part A of the study will undergo dose tapering and complete all 
procedures scheduled for the end of Part A/early termination visit (Visit 8) at time of withdrawal. 
The investigator in consultation with the medical monitor will evaluate the possible effects of 
rapid withdrawal from the study drug versus the risk of continuing the drug.
9.3.5
Part B
Because treatment assignment in Part A will remain blinded, all subjects who choose to continue 
into Part B will start at 200 mg BID TAK-935 (100 mg tablets). Subjects should remain at this dose 
for 1 week. The site will contact the subject by phone on Day 108 to determine safety and 
tolerability. The subject will return to the clinic on Day 112 (Week 16, Visit 9) to complete all 
scheduled assessments, assess safety and tolerability, and adjust study drug dosing as needed. The 
dose may be decreased from 200 mg BID to 100 mg BID based on tolerability at Visit 9 (Day 112, 
Week 16). After Visit 9, subjects will visit the clinic approximately every 4 weeks (Visit 10 [Day 
119, Week 17], Visit 11 [Day 147, Week 21], Visit 12 [Day 175, Week 25], and Visit 13 [Day 203, 
Week 29]). The current pain intensity will be collected 3 times a day using the electronic pain diary 
daily. From this data an average 24-hour pain intensity score can be calculated.
9.3.6
End of Part B or Early Termination
The end of Part B (Visit 13) is on Day 203 (Week 29), at which time the appropriate dose 
de-escalation schedule begins. Subjects return to the clinic to complete all scheduled assessments.
During the taper period, the IP dose will be reduced to the next lower dose every 3 days (or less 
frequently based on the investigator’s discretion) until IP dose is discontinued.
Subjects who withdraw early from Part B of the study should undergo dose tapering and complete 
all procedures scheduled for the final follow-up visit (Visit 13) at time of withdrawal. The 
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investigator in consultation with the medical monitor will evaluate the possible effects of rapid 
withdrawal from the study drug versus the risk of continuing the drug.
9.3.7
Final Follow-up
After tapering, the subjects will complete a safety follow-up phone call approximately 15 days 
after the last dose of IP.
9.3.8
Unscheduled Visit
Subjects may return to the study center for unscheduled visits as needed. Unscheduled study visits 
can be performed when the subject has a study related issue in between regular study visits. 
The following procedures should be performed during this visit:

Concomitant medications.

AE assessment.

Other procedures, including dose adjustments, as deemed appropriate by the investigator.
9.3.9
Poststudy Care
Study drug will not be available upon completion of the subject’s participation in the study. The 
subject should be returned to the care of a physician and standard therapies as required.
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10.0
PRETREATMENT EVENTS AND AEs
10.1
Definitions
10.1.1
Pretreatment Events 
A pretreatment event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed informed consent to participate in a study but prior to 
administration of any study drug; it does not necessarily have to have a causal relationship with 
study participation.
10.1.2
AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory value), symptom, or disease temporally associated with the use of a drug whether or not 
it is considered related to the drug. This includes any newly occurring event or a previous 
condition that has increased in severity or frequency since the administration of study drug.
10.1.3
Additional Points to Consider for AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study drug or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Changes in intensity of AEs:

If the subject experiences changes in intensity of an AE, the event should be captured once 
with the maximum intensity recorded.
Preplanned procedures (surgeries or interventions):

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
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early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of 
the condition should be recorded as an AE. Complications resulting from 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. Procedures for 
CRPS are not allowed during the study, by consent. 

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing illness 
and lack of therapeutic efficacy.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
AEs, but instead will be documented on the appropriate eCRF page. Any manifested side 
effects will be considered AEs and will be recorded on the AE page of the eCRF.
10.1.4
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires subject HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
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AEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5
AEs of Special Interest
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10.1.6
Intensity of AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.7
Causality of AEs
The relationship of each AE to study drug(s) will be assessed using the following categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant medications and concurrent treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant medications and concurrent treatments.
10.2
Procedures
10.2.1
Collection and Reporting of AEs
10.2.1.1
AE Collection Period
Collection of AEs will commence from the time informed consent is provided at screening 
(Visit 1) and continue until early termination or until the follow-up visit (Visit 13, Week 29). For 
subjects who discontinue prior to study drug administration, AEs are collected until the subject 
discontinues study participation.
10.2.1.2
AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing an 
SAE 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.
All subjects experiencing AEs, whether considered associated with the use of the study drug or 
not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All 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.
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The electronic pain diary will not be used as a primary means to collect AEs. However, should the 
investigator become aware of a potential AE through the information collected with this 
instrument, proper follow-up with the subject for medical evaluation should be undertaken. 
Through this follow-up if it is determined that an AE not previously reported has been identified, 
normal reporting requirements should be applied (see Section 10.1.2).
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
A urine sample for illicit drug use and a blood alcohol level should be obtained as soon as 
possible after the convulsion has occurred.

Document any electrolyte abnormalities or other signs of systemic illness not otherwise 
evident. Other pertinent laboratory values that should be recorded include the subject’s 
electrolyte panel results, blood urea nitrogen, creatinine, and complete blood count with 
differential.
AEs of special interest have to be recorded as AEs in the eCRF. An evaluation form along with all 
other required documentation must be submitted to the sponsor.
10.2.2
Collection and Reporting of SAEs
All AEs spontaneously reported by the subject or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will be 
recorded on the appropriate page of the eCRF (see Section 10.2.1 for the period of observation). 
Any clinically relevant deterioration in laboratory assessments or other clinical finding is 
considered an AE. When possible, signs and symptoms indicating a common underlying 
pathology should be noted as a single comprehensive event.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
10.2.3
Reporting of Abnormal Liver Tests
If a subject had ALT or AST elevations >3 × ULN on 2 consecutive occasions, as specified in 
Section 9.1.11, the abnormality should be recorded as an AE. In addition, a relevant eCRF(s) must 
be completed providing additional information on relevant recent history, risk factors, clinical 
signs, symptoms, and results of any additional diagnostic tests performed. 
If a subject has elevated ALT or AST >3 × ULN and total bilirubin >2 × ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the medical monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.11 must also be performed. The relevant eCRF(s) must be 
completed and transmitted with the SAE form (as per Section 10.2.2).
10.3
Follow-up of SAEs
If information not available at the time of the first report becomes available later, then the 
investigator will transmit a follow-up electronic data capture SAE report (or paper-based SAE 
form if an electronic data capture SAE report is not feasible) or provide other written 
documentation and transmit it immediately within 24 hours of receipt. Copies of any relevant data 
from the hospital notes (eg, ECGs, laboratory tests, discharge summary, postmortem results) 
should be sent to the addressee, if requested.
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All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.3.1
Safety Reporting to Investigators, IRBs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
and any other applicable SAEs to regulatory authorities, including investigators and IRBs, as 
applicable. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, suspected unexpected serious adverse reactions will be submitted to the 
regulatory authorities as an expedited report within 7 days for fatal and life-threatening events and 
15 days for other serious events, unless otherwise required by national regulations. The sponsor 
will also prepare an expedited report for other safety issues where these might materially alter the 
current benefit-risk assessment of a study drug/sponsor supplied drug or that would be sufficient to 
consider changes in the study drug/sponsor supplied drug administration or in the overall conduct 
of the trial. The study site also will forward a copy of all expedited reports to his or her IRB.
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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.
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12.0
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 medical conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization Drug Dictionary.
12.1
eCRFs
Completed eCRFs are required for each subject who signs an ICF.
The sponsor or its designee will supply study 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.
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.
The principal investigator must review the eCRFs for completeness and accuracy and must e-sign
the appropriate eCRFs as indicated. Furthermore, the investigator must retain full responsibility 
for the accuracy and authenticity of all data entered on the eCRFs.
After submission of the CRFs to the sponsor, any change of, modification of or addition to the data 
on eCRFs should be made by the investigator with use of change and modification records of 
eCRFs (Data Clarification Form) provided by the sponsor. The principal investigator must review 
the Data Clarification Form for completeness and accuracy, and must sign and date the form.
After the lock of the study database, any change of, modification of, or addition to the data on the 
eCRFs should be made by the investigator with the approval from the sponsor. 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 the sponsor or its designee. 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.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
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worksheets, all original signed and dated ICFs, subject authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copy of eCRFs, including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from regulatory 
authorities, the sponsor or its designees. Any source documentation printed on degradable thermal 
sensitive paper should be photocopied by the site and filed with the original in the subject’s chart 
to ensure long term legibility. Furthermore, ICH E6 Section 4.9.5 requires the investigator to retain 
essential documents specified in ICH E6 (Section 8) until at least 2 years after the last approval of 
a marketing application for a specified drug indication being investigated or, if an application is 
not approved, until at least 2 years after the investigation is discontinued and regulatory authorities 
are notified. In addition, ICH E6 Section 4.9.5 states that the study records should be retained until 
an amount of time specified by applicable regulatory requirements or for a time specified in the 
study site agreement between the investigator and sponsor.
Refer to the study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
The investigator and the head of the study site are required to retain essential relevant documents 
until the day specified as 1) or 2) below, whichever comes later. However, if the sponsor requests 
a longer time period for retention, the head of the study site should discuss how long and how to 
retain those documents with the sponsor. 
1. The day on which marketing approval of the study drug is obtained (or the day 3 years after the 
date of notification in the case that the investigation is discontinued.)
2. The day 3 years after the date of early termination or completion of the study.
In addition, the investigator and the head of the study site should retain the essential relevant 
documents until the receipt of a sponsor-issued notification to state the retention is no longer 
required.
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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan will be prepared and finalized prior to unblinding of subject’s treatment 
assignment in Part A. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives.
A blinded data review will be conducted prior to unblinding of subject’s treatment assignment. 
This review will assess the accuracy and completeness of the study database, subject evaluability, 
and appropriateness of the planned statistical methods.
13.1.1
Analysis Sets
The randomized set will include all subjects who were randomly assigned to treatment through the 
IWRS.
The full analysis set (FAS) for Parts A and B will include all subjects who were randomized. In 
efficacy analyses, FAS subjects with both baseline and at least 1 valid postbaseline value will be 
used for appropriate analyses in Parts A and B. In FAS efficacy summaries, subjects will be 
analyzed according to the treatment to which they were randomized.
The safety analysis set for Parts A and B will include all subjects who received at least 1 dose of 
study drug. In safety summaries, subjects will be analyzed according to the treatment they 
received.
The PK analysis sets for Parts A and B will include all subjects who received at least 1 dose of 
study drug and have at least 1 measurable TAK-935 or M-1 plasma concentration.
The PD analysis set for Parts A and B will include all subjects who received at least 1 dose of study 
drug and have at least 1 measurable plasma 24HC concentration. 
13.1.2
Analysis of Demographics and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized and listed for enrolled 
subjects by treatment group and overall. Descriptive statistics will be used to summarize data for 
continuous variables such as age and weight (eg, number of subjects, mean, median, standard 
deviation, and range) and for categorical variables such as sex, ethnicity, and race (number and 
percentage of subjects within each category). Medical history and medication history will be listed 
by subject.
13.1.3
Efficacy Analysis
For the primary efficacy endpoint, only subjects with a baseline and at least 1 postdose value will 
be included in the summary and analyses. The data from the last 7 days prior to the visits on 
Day 21 (Week 3), Day 105 (Week 15) (or the last dose in Part A, whichever is earlier), Day 147 
(Week 21), and Day 203 (Week 29) (or the last dose in Part B, whichever is earlier) will be used to 
derive the mean 24-hour pain intensity for the corresponding visits.
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For Part A, summary statistics will be provided for the observed values of the efficacy measures at 
baseline and each of the postdose visits by treatment group. Change from baseline and percent 
change from baseline will also be summarized with descriptive statistics by treatment group.
For Part B, summary statistics will be provided for the observed values of the efficacy measures at 
each of the postdose visits for all subjects, as well as by treatment group in Part A. Change from 
baseline and percent change from baseline will also be summarized with descriptive statistics. 
Baseline will be the baseline for Part A.
For the mean 24-hour pain intensity in Part A derived above, linear mixed models for repeated 
measurements will be used to evaluate the effect of TAK-935 on the primary and secondary 
endpoints. The change from baseline in the 24-hour mean pain intensity to the scheduled visits 
(Day 21, Week 3, Day 105, Week 15) will be the response in the model; baseline, site, visit 
(Day 21, Week 3, or Day 105, Week 15), treatment, and treatment by visit interaction will be the 
fixed effects; and a completely unstructured covariance matrix will be assumed. The treatment 
effect at each visit will be evaluated using the difference in the least-square means of the change 
from baseline between TAK-935 and placebo; 95% confidence intervals for the differences and 
p-values will also be provided. Percent of responders will be summarized and compared between 
treatment arms in Part A.
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13.1.5
Safety Analysis
Descriptive statistics will be used to summarize all safety endpoints, by treatment group as 
appropriate. Data summaries will be displayed for incidence of AEs, clinical laboratory variables, 
vital signs, body weight and BMI, and ECG parameters.
Safety data summaries will be using the safety analysis set.
All AEs will be coded using MedDRA. Data will be summarized using preferred term and primary 
system organ class.
13.2
Interim Analysis and Criteria for Early Termination
An unblinded interim analysis will be conducted after all subjects have completed Part A. Subject 
treatment will be unblinded for this interim analysis. The interim analysis will include the primary 
and secondary efficacy analysis as well as safety and PK/PD summaries for the data collected 
during Part A. Because this analysis will be conducted at the end of the double-blind period, this 
analysis will be considered as the primary efficacy assessment of TAK-935 on CRPS relative to 
placebo. No alpha spending or adjustment to sample size will be needed based on the results of this 
analysis.
13.3
Determination of Sample Size
Assuming a standard deviation of 2 and a 12% drop-out rate, a sample size of 24 subjects in total 
with randomization ratio of 2:1 is sufficient to achieve at least 65% power to detect a difference of 
2 between TAK-935 and placebo by a 2-sample t-test on the change from baseline to Week 15 in 
mean 24-hour pain intensity NPS score at 0.10 2-sided significance level. A difference of 2 is 
within the accepted range of minimally clinically important difference for the 11-point NPS [1,2].
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and the study site guarantee access to source documents by the sponsor or its 
designee and by the IRB.
All aspects of the study and its documentation will be subject to review by the sponsor or the 
sponsor’s designee (if blinding is not jeopardized), including but not limited to the Investigator’s 
Binder, study drug, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the ICFs, and review of 
eCRFs and associated source documents. It is important that the investigator and other study 
personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB, as required) to determine the appropriate course of action. There will be no 
exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB, as required). 
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment.
The sponsor will assess any protocol deviation; if it is likely to affect to a significant degree the 
safety and rights of a subject or the reliability and robustness of the data generated, it may be 
reported to regulatory authorities as a serious breach of GCP and the protocol.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the United States [US] Food and Drug Administration [FDA], 
the United Kingdom [UK] 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 and study site guarantee access for quality assurance 
auditors to all study documents as described in Section 14.1.
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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonized Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB
IRBs must be constituted according to the applicable 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. If any member of the IRB 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 for 
the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of the ICF, 
and, if applicable, subject recruitment materials and/or advertisements and other documents 
required by all applicable laws and regulations, must be submitted to a central or local IRB for 
approval. The IRB’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. The IRB 
approval must refer to the study by exact protocol title, number, and version date; identify versions 
of other documents (eg, ICF) reviewed; and state the approval date. The sponsor will notify site 
once the sponsor has confirmed the adequacy of site regulatory documentation and, when 
applicable, the sponsor has received permission from competent authority to begin the study.
Study sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the ICF, 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, and 
submission of the investigator’s final status report to IRB. All IRB 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 and sponsor.
15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, subject authorization form (if applicable), and subject 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
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disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF 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 ICF 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 ICF 
and if applicable, the subject authorization form. The ICF, subject authorization form (if 
applicable), and subject information sheet (if applicable) must be approved by both the IRB and 
the sponsor prior to use.
The ICF, 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 ICF, 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.
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, or the subject’s legally 
acceptable representative, determines he or she will participate in the study, then the ICF and 
subject authorization form (if applicable) must be signed and dated by the subject, or the subject’s 
legally acceptable representative, at the time of consent and prior to the subject entering into the 
study. The subject should be instructed to sign using their legal names, not nicknames, using a 
ballpoint pen with either blue or black ink. The investigator must also sign and date the ICF and 
subject authorization (if applicable) at the time of consent and before the subject enters 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 ICF, 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 ICF, the signed subject authorization form (if applicable), and subject information sheet (if 
applicable) shall be given to the subject.
All revised ICFs 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 ICF.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical trial database or documentation via a subject ID 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 ID number.
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To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit the monitor or the sponsor’s designee, representatives from any 
regulatory authority (eg, US FDA, UK MHRA, Japan PMDA), the sponsor’s designated auditors, 
and the appropriate IRBs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the study site agreement, any public disclosure 
(including publicly accessible websites) related to the protocol or study results other than study 
recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the study site agreement. In the event of any discrepancy between the protocol and 
the study site agreement, the study site agreement will prevail.
15.4.2
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing.
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
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Any investigator who objects to the sponsor providing this information to callers must provide the 
sponsor with a written notice requesting that their information not be listed on the registry site.
15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov and/or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the sponsor 
or sponsor’s designee.
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16.0
REFERENCES
1. Goebel A, Bisla J, Carganillo R, Frank B, Gupta R, Kelly J, et al. Low-dose intravenous 
immunoglobulin treatment for long-standing complex regional pain syndrome: a randomized 
trial. Ann Intern Med 2017;167(7):476-83.
2. Maughan EF, Lewis JS. Outcome measures in chronic low back pain. Eur Spine J 
2010;19(9):1484-94.
3. Lascombes P, Mamie C. Complex regional pain syndrome type I in children: What is new? 
Orthop Traumatol Surg Res 2017;103(1S):S135-S42.
4. Urits I, Shen AH, Jones MR, Viswanath O, Kaye AD. Complex regional pain syndrome, 
current concepts and treatment options. Curr Pain Headache Rep 2018;22(2):10.
5. Lee DH, Noh EC, Kim YC, Hwang JY, Kim SN, Jang JH, et al. Risk factors for suicidal 
ideation among patients with complex regional pain syndrome. Psychiatry Investig 
2014;11(1):32-8.
6. Midbari A, Suzan E, Adler T, Melamed E, Norman D, Vulfsons S, et al. Amputation in 
patients with complex regional pain syndrome: a comparative study between amputees and 
non-amputees with intractable disease. Bone Joint J 2016;98-B(4):548-54.
7. Goh EL, Chidambaram S, Ma D. Complex regional pain syndrome: a recent update. Burns 
Trauma 2017;5:2.
8. Schwartzman RJ, Alexander GM, Grothusen JR, Paylor T, Reichenberger E, Perreault M. 
Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a 
double-blind placebo controlled study. Pain 2009;147(1-3):107-15.
9. Gustin SM, Schwarz A, Birbaumer N, Sines N, Schmidt AC, Veit R, et al. NMDA-receptor 
antagonist and morphine decrease CRPS-pain and cerebral pain representation. Pain 
2010;151(1):69-76.
10. Paul SM, Doherty JJ, Robichaud AJ, Belfort GM, Chow BY, Hammond RS, et al. The major 
brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of 
N-methyl-D-aspartate receptors. J Neurosci 2013;33(44):17290-300.
11. Alexandrov P, Cui JG, Zhao Y, Lukiw WJ. 24S-hydroxycholesterol induces inflammatory 
gene expression in primary human neural cells. Neuroreport 2005;16(9):909-13.
12. Raccosta L, Fontana R, Maggioni D, Lanterna C, Villablanca EJ, Paniccia A, et al. The 
oxysterol-CXCR2 axis plays a key role in the recruitment of tumor-promoting neutrophils. J 
Exp Med 2013;210(9):1711-28.
13. de Mos M, de Bruijn AG, Huygen FJ, Dieleman JP, Stricker BH, Sturkenboom MC. The 
incidence of complex regional pain syndrome: a population-based study. Pain 
2007;129(1-2):12-20.
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14. Sandroni P, Benrud-Larson LM, McClelland RL, Low PA. Complex regional pain syndrome 
type I: incidence and prevalence in Olmsted county, a population-based study. Pain 
2003;103(1-2):199-207.
15. Savas S, Baloglu HH, Ay G, Cerci SS. The effect of sequel symptoms and signs of complex 
regional Pain syndrome type 1 on upper extremity disability and quality of life. Rheumatol Int 
2009;29(5):545-50.
16. Aronoff GM, Harden N, Stanton-Hicks M, Dorto AJ, Ensalada LH, Klimek EH, et al. 
American Academy of Disability Evaluating Physicians (AADEP) position paper: complex 
regional pain syndrome I (RSD): impairment and disability issues. Pain Med 
2002;3(3):274-88.
17. O'Connell NE, Wand BM, McAuley J, Marston L, Moseley GL. Interventions for treating pain 
and disability in adults with complex regional pain syndrome. Cochrane Database Syst Rev 
2013(4):CD009416.
18. Harden RN, Oaklander AL, Burton AW, Perez RS, Richardson K, Swan M, et al. Complex 
regional pain syndrome: practical diagnostic and treatment guidelines, 4th edition. Pain Med 
2013;14(2):180-229.
19. Marchettini P, Lacerenza M, Formaglio F. Sympathetically maintained pain. Curr Rev Pain 
2000;4(2):99-104.
20. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from 
three multisite studies with adolescents and adults. Am J Psychiatry 2011;168(12):1266-77.
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CONFIDENTIAL
Appendix A
Schedule of Study Procedures
Study Period
Screening
Part A, Double-Blind Treatment
Part B, Optional Open-Label Extension
Day
-28 to -1
1
Rand-
omization
4
(±2)
7
(±2)
10
(±2)
14 
(±2)
17 
(±2)
21 
(±2)
49 
(±2)
77 
(±2)
105
(±5) a
Start 
Part B
108
(±2)
112
(±2) b 115
(±2)
119
(±2)
147
(±7)
175
(±2)
203
(±7)
218
(±7)
Final 
Follow-up 
(Part B) c
Week
-4 to -1
1
2
3
7
11
15
16
17
21
25
29
31
Study Visit
1
2
PC d
3
PC d
4
PC d
5
6
7
8
PC d
9
PC 
d
10
11
12
13 
(ET)
PC
Informed consent
X
Inclusion/
Exclusion criteria
X
X (pre
dose)
Demographics and medical 
history
X
Medication history
X
Physical examination
X
X (pre
dose)
X
X
X
X
X
X
Neurological examination, 
including fundoscopy and visual 
acuity (if possible)
X
X (pre
dose)
X
X
X
X
X
X
Vital signs
X
X (pre
dose)
X
X
X
X
X
X
X
X
X
X
X
Height e, weight, and BMI
X
X (pre
dose)
X
X
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Part B, O
Part B
plic
±2)
2)
05
(±5) 
(±5) a
Start
Sta
Pa
P
App
to
A p
11
11
ct
6
jec
ubj
Su
d
u
d
y a
nly
On
e
n
X
e O
U e
X
l U
l U
e
al U
n Commer


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Protocol Incorporating Amendment No. 03
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CONFIDENTIAL
Study Period
Screening
Part A, Double-Blind Treatment
Part B, Optional Open-Label Extension
Day
-28 to -1
1
Rand-
omization
4
(±2)
7
(±2)
10
(±2)
14 
(±2)
17 
(±2)
21 
(±2)
49 
(±2)
77 
(±2)
105
(±5) a
Start 
Part B
108
(±2)
112
(±2) b 115
(±2)
119
(±2)
147
(±7)
175
(±2)
203
(±7)
218
(±7)
Final 
Follow-up 
(Part B) c
Week
-4 to -1
1
2
3
7
11
15
16
17
21
25
29
31
Study Visit
1
2
PC d
3
PC d
4
PC d
5
6
7
8
PC d
9
PC 
d
10
11
12
13 
(ET)
PC
Concomitant medications
X-------------------------------------------------------------------------------------------------------------------------------------------------------------------------
12-lead ECG f
X
X (pre
dose)
X
X
X
24-hour pain intensity NPS g
X
X---------------------------------------------------------------------------------------------------------------------------------------------------------X
PROMIS-29
X
X
X
PGI-C
X
X
CRPS Severity Scale
X
X
X
C-SSRS
X
X (pre
dose)
X
X
X
X
X
X
X
X
X
X
X
Safety/tolerability assessment h
X-------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Clinical laboratory evaluations i
X
X (pre
dose)
X
X
X
Urine drug screen
X
X
Serum pregnancy test (hCG) for 
females of childbearing potential
X
X
X
PD (24HC), PK j
X (pre
dose)
X
X
X
Plasma protein binding 
assessment k
X
PGx assessment l
X
Access IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug dispensing and 
accountability
X
X
X
X
X
X
X
X
X
X
X
X
AE assessment
X-------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Footnotes are on the following page.
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CONFIDENTIAL
AE: adverse event; BID: twice daily; BMI: body mass index; CRPS: complex regional pain syndrome; C-SSRS: Columbia-Suicide Severity Rating Scale; ECG: electrocardiogram; 
ET: early termination; hCG: human chorionic gonadotropin; ID: identification; IWRS: interactive web response system; NPS: Numeric Pain Scale; PC: Phone Call; PGIC: Patient 
Global Impression of Change; PGx: Pharmacogenomics; PROMIS-29: 29-item Patient-Reported Outcomes Measurement Information System, version 2.1.
a Subjects who do not continue into Part B will undergo the dose taper procedures and will then proceed to the follow-up period. The timing of the follow-up phone call and follow-up 
period will be 15 days after the last dose of study medication. Subjects who are on the lowest administered dose of TAK-935 during the taper period will not undergo dose taper.
b Dosing of TAK-935 will be started at 200 mg BID when subjects enter Part B. After 7 days, doses may be increased to a maximum of 300 mg BID. If at any time during either the 
titration period or the maintenance period subjects cannot tolerate the dose, the dose may be decreased to the previous tolerated dose. If subjects cannot tolerate the minimum daily 
dose of 100 mg BID, then subjects will be withdrawn from the study.
c All subjects will undergo dose taper procedures and will then proceed to the follow-up period. The timing of the follow-up phone call and follow-up period will depend on the dose 
taper procedures followed. In all subjects choosing the taper period, the IP dose will be reduced to the next lower dose every 3 days (or less frequently based on the investigator’s 
discretion) until IP dose is discontinued. After tapering, the subjects will complete a safety follow-up phone call approximately 15 days after the last dose of IP. Subjects who are on 
the lowest administered dose of TAK-935 at the end of Part B will not undergo dose taper. The follow-up visit may be eliminated for subjects enrolled in the open-label extension.
d The phone call should be made by an experienced healthcare provider who can review study drug dosing.
e Height will only be measured at Screening (Visit 1).
f A standard 12-lead ECG will be recorded at Screening to evaluate subject’s eligibility. A standard 12-lead ECG will be recorded in triplicate at predose at Visit 2, and predose and 
between 30 to 45 min postdose (~Tmax) at Visit 5, 8, and 13.
g For a minimum of 6 of the last 7 screening days prior to enrollment into the study, baseline average daily 24-hour pain intensity will be collected (NPS; an 11-point scale by
electronic pain diary). During the study, 24-hour pain intensity will be collected 3 times a day.
h Safety and tolerability will be continuously evaluated throughout the study. A formal documented safety and tolerability analysis will be conducted at Visit 4 before advancing 
subjects from 200 mg BID to 300 mg BID.
i Blood samples for clinical safety laboratory tests including hematology and chemistry, will be collected at Visit 1, Visit 2 (predose), Visit 4 during Part A, Visit 8 (end of Part A/early 
CCI
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up visit m
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TAK-935
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Page 83 of 102
Protocol Incorporating Amendment No. 03
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations.
The investigator agrees to assume the following responsibilities:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-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, prior to 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 
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 local requirements or regulations for informed consent, 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 ICF 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 ICF does not include 
such a subject authorization, then the investigator must obtain a separate subject authorization 
form from each subject or the subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
(e)CRFs, 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 
contact and receive written approval from the sponsor before disposing of any such 
documents.
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11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix C
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written ICF, the subject or the subject’s 
legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject may discontinue 
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participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject will be informed in a timely manner if information becomes 
available that may be relevant to the subject’s willingness to continue participation in the 
study.
22. A statement that results of pharmacogenomic 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 ICF or provided as a separate 
document) describing to the subject the contemplated and permissible uses and disclosures of 
the subject’s personal information (including personal health information) for purposes of 
conducting the study. The subject authorization must contain the following statements 
regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study drug(s), studying other therapies for subjects, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
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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 screening throughout the duration of the study, and for 30 days after last dose. 
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 a highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study, and for 90 days after 
last dose. If the partner or wife of the subject is found to be pregnant during the study, the 
investigator will offer the subject the choice to receive unblinded treatment information.
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.
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Appendix D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study drug.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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In summary, the selected dose up-titration over time and the fractionated dosing 
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trough; T(EO≥65%): time above EO threshold of at least 65%; P(EOtrough<65%): percentage of 
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wording:
!
To investigate the effect of TAK-935 on overall function using the Patient Global 
Impression of Change (PGIC) and the Patient-Reported Outcomes Measurement 
Information System (PROMIS-29) scale.
!
To investigate the effect of TAK-935 on the CRPS Severity Score (CSS).
!
To investigate the effect of TAK-935 on responder rate (responder is defined as 
≥30% improvement in the 24-hour pain intensity).
Exploratory Objectives
Amended or 
new 
wording:
Secondary Objectives
!
To investigate the effect of TAK-935 on overall function using the Patient Global 
Impression of Change (PGIC) and the Patient-Reported Outcomes Measurement 
Information System (PROMIS-29) scale.
!
To investigate the effect of TAK-935 on the CRPS Severity Score (CSS).
!
To investigate the effect of TAK-935 on responder rate (responder is defined as 
≥30% improvement in the 24-hour pain intensity).
Exploratory Objectives
Rationale for Change: Align bulleting/numbering of objectives for consistency with the 
numbers/bulleting in the endpoints section.
The following sections also contain this change:
CCI
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
Section 2.0 STUDY SUMMARY
Change 5: Modified Figure 4.a.
The change occurs in Section 4.1 Background Figure 4.a:
Description 
of change:
The horizontal axis Day 0 timepoint was changed from ‘Day 0’ to ‘6hr post ischemia 
(Day 0)’.
Rationale for Change: Update information on the CPIP model for better representation of study 
design.
Change 6: Clarified the rationale for the study.
The primary change occurs in Section 4.2 Rationale for the Proposed Study:
Added text: This study will be the first phase 2a study to test the efficacy, safety, and tolerability 
of TAK-935 in adults with CRPS. Based on the mechanism of action, preclinical 
data on a pertinent model to CRPS and the safety characteristics of the 
completed and ongoing studies, we propose this phase 2a study that will test the 
efficacy, safety and tolerability of TAK-935 in adults with CRPS, a highly 
impacted population with great unmet need.
Rationale for Change: Update the study rationale with a summary of available preclinical and 
clinical data.
Change 9: Moved the detail on pharmacogenomic analysis.
The primary change occurs in Section 6.2.3 Endpoints:
Added text: Pharmacogenomic analysis may be conducted to investigate the contribution of 
genetic variance on drug response, for example, its efficacy and safety. 
Participation of study subjects in pharmacogenomic sample collection is 
optional.
As pharmacogenomics is an evolving science, currently many genes and their 
function are not yet fully understood. Future data may suggest a role of some of 
these genes in drug response or diseases, which may lead to additional 
hypothesis-generating exploratory research on stored samples.
Rationale for Change: Move pharmacogenomic analysis paragraphs from Rationale for the 
Proposed Study to the Endpoint section.
The following sections also contain this change:

Section 4.2 Rationale for the Proposed Study
Change 8: Revised contraceptive requirements.
The primary change occurs in Section 9.1.16 Contraception and Pregnancy Avoidance Procedure:
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Initial 
wording:
From signing of informed consent, throughout the duration of the study, and for up to 
30 days after last dose of study drug, nonsterilized** male subjects who are sexually 
active with a female partner of childbearing potential* must use barrier contraception 
(eg, condom with or without spermicidal cream or jelly). In addition, they must be 
advised not to donate sperm during this period. Females of childbearing potential 
who are partners of male subjects are also advised to use additional contraception as 
shown in the list containing highly effective/effective contraception below. From 
signing of informed consent, throughout the duration of the study, and for 30 days 
after last dose of study drug, female subjects of childbearing potential* who are 
sexually active with a nonsterilized male partner** must use a highly 
effective/effective method of contraception (from the list below). In addition, they 
must be advised not to donate ova during this period.
…
•
Sexual abstinence, if it is the preferred and usual lifestyle of the subject, will 
be considered an acceptable method of contraception on a case-by-case basis upon 
prior approval by the medical monitor. Subjects practicing abstinence as a method of 
contraception must refrain from heterosexual intercourse throughout the duration of 
the study and for 30 days after last dose of study drug.
Subjects will be provided with information on acceptable methods of contraception 
as part of the subject informed consent process and will be asked to sign a consent 
form stating that they understand the requirements for avoidance of pregnancy, 
donation of ova, and sperm donation during the course of the study and for 30 days 
after the last dose of study drug.
Amended or 
new 
wording:
From signing of informed consent, throughout the duration of the study, and for up to 
30 90 days after last dose of study drug, nonsterilized** male subjects who are 
sexually active with a female partner of childbearing potential* must use barrier 
contraception (eg, condom with or without spermicidal cream or jelly). In addition, 
they must be advised not to donate sperm during this periode course of the study 
and for 90 days after the last dose of study drug. Females of childbearing potential 
who are partners of male subjects are also advised to use additional contraception as 
shown in the list containing highly effective/effective contraception below. From 
signing of informed consent, throughout the duration of the study, and for 30 days 
after last dose of study drug, female subjects of childbearing potential* who are 
sexually active with a nonsterilized male partner** must use a highly 
effective/effective method of contraception (from the list below). In addition, they 
must be advised not to donate ova during this period.
…
•
Sexual abstinence, if it is the preferred and usual lifestyle of the subject, will 
be considered an acceptable method of contraception on a case-by-case basis upon 
prior approval by the medical monitor. Subjects practicing abstinence as a method of 
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contraception must refrain from heterosexual intercourse throughout the duration of 
the study (for female and male subjects) and for 30 (female subjects) or 90 (male 
subjects) days after last dose of study drug.
Subjects will be provided with information on acceptable 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 (during the course of the study and for 30 (female 
subjects) or 90 (male subjects) days after the last dose of study drug),

donation of ova (during the course of the study and for 30 days after the 
last dose of study drug),

and sperm donation (during the course of the study and for 3090 days after 
the last dose of study drug).
Rationale for Change: Correct a typographical error.
The following sections also contain this change:

Section 7.1 Inclusion Criteria

Section 7.2 Exclusion Criteria

Section 9.1.17 Pregnancy

Appendix C Elements of the Subject Informed Consent
Change 9: Modified the detail regarding blood volumes collected during the study.
The primary change occurs in Section 9.1.11 Procedures for Clinical Laboratory Samples:
Initial 
wording:
All samples will be collected in accordance with acceptable laboratory procedures. 
The maximum volume of blood at any single visit is approximately 5 mL, and the 
approximate total volume of blood for the study is 15 mL. Details of these procedures 
and required safety monitoring will be given in the laboratory manual.
Amended or 
new 
wording:
All samples will be collected in accordance with acceptable laboratory procedures. 
The maximumDetails of these procedures and required safety monitoring will be 
given in the laboratory manual. The approximate volume of blood collected at any 
single visit is approximately 5 mL, and the approximate total volume of blood for the 
study is 15 mL. Details of these procedures and required safety monitoring will be 
given in the laboratorycollected in the study will be given in the laboratory and/or 
study manual.
Rationale for Change: Update to reflect that all blood volumes are included in the laboratory 
and/or study manual (local lab is utilized in this study).
The following sections also contain this change:
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!
Appendix A Schedule of Study Procedures, footnote ‘i’.
Change 10: Clarified the ECG procedures for specific visits.
The primary change occurs in Section 9.1.18 ECG Procedure:
Initial 
wording:
A standard 12-lead ECG will be recorded in triplicate at predose and between 30 to 
45 min postdose (~Tmax).
Amended or 
new 
wording:
A standard 12-lead ECG will be recorded at Visit 1 (Screening) to evaluate 
subject’s eligibility. A standard 12-lead ECG will be recorded in triplicate at predose 
at Visit 2, and at predose and between 30 to 45 min postdose (~Tmax). at Visits 5, 8, 
and 13.
Rationale for Change: Provide clarification on ECG procedures, as per study manual.
The following sections also contain this change:
!
Appendix A Schedule of Study Procedures, footnote ‘f’.
Change 11: Clarified the efficacy analysis.
The primary change occurs in Section 13.1.3 Efficacy Analysis:
Added text: Percent of responders will be summarized and compared between treatment 
arms in Part A.
Rationale for Change: Provide additional detail regarding responder rate analysis.
The following sections also contain this change:
!
Section 2.0 STUDY SUMMARY
Change 12: Clarified the exploratory analysis.
The primary change occurs in Section 13.1.4 Exploratory Analysis:
Initial 
wording:
Amended or
new 
wording:
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TAK-935
Study No. TAK-935-2008
Page 102 of 102
Protocol Incorporating Amendment No. 03
16 December 2019
Rationale for Change: Correct a typographical error and provide additional detail regarding 
rescue medication analysis.
Change 13: Clarified the interim analysis.
The primary change occurs in Section 13.2 Interim Analysis and Criteria for Early Termination:
Initial 
wording:
An unblinded interim analysis will be conducted after all subjects have completed 
Part A. Subject treatment will be unblinded for this interim analysis. The interim 
analysis will include the primary efficacy analysis as well as safety summaries for the 
data collected during Part A.
Amended or 
new 
wording:
An unblinded interim analysis will be conducted after all subjects have completed 
Part A. Subject treatment will be unblinded for this interim analysis. The interim 
analysis will include the primary and secondary efficacy analysis as well as safety
and PK/PD summaries for the data collected during Part A.
Rationale for Change: Clarify the analysis planned, including secondary and PK/PD summaries.
The following sections also contain this change:
!
Section 2.0 STUDY SUMMARY
Change 14: Clarified when blood samples for plasma protein binding assessment will be 
collected.
The primary change occurs in Appendix A Schedule of Study Procedures:
Description 
of change:
Added a separate row for plasma protein binding assessment and added a footnote ‘k’ 
to clarify when these samples will be collected.
Rationale for Change: Update blood sample collection recommendations for better clarity to the 
investigators and site staff.
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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy, Safety, and Tolerability of TAK-935 as an Adjunctive Therapy in Adult Subjects With 
Chronic Complex Regional Pain Syndrome
NCT Number: NCT03990649
SAP Approve Date: 10 February 2021
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-935-2008
A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy,
Safety, and Tolerability of TAK-935 as an Adjunctive Therapy in Adult Subjects with Chronic
Complex Regional Pain Syndrome
Study of TAK-935 as an Adjunctive Therapy in Adult Subjects with Complex Regional 
Pain Syndrome
PHASE 1b/2a
Version: 1.0 
Date: 10 February 2021
Prepared by:
Based on:
Protocol Version: Amendment 03
Protocol Date:  16 December 2019
PPD
Property of Takeda: For N
ocol
ocol Ve
V
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ommercial Use Only and Subject to the Applicable Terms of Use
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Adul
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TAK-935-2008
Page 2 of 35
Statistical Analysis Plan Final 
10 February 2021
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
Study Title:
Study of TAK-935 as an Adjunctive Therapy in Subjects with Complex 
Regional Pain Syndrome
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
t to the Applicable Te


TAK-935-2008
Page 3 of 35
Statistical Analysis Plan Final 
10 February 2021
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objective......................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Exploratory Objectives ..............................................................................................7
4.4
Safety Objectives.......................................................................................................7
4.5
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS.............................................................................................11
5.1
Primary Endpoint.....................................................................................................11
5.2
Secondary Endpoints ...............................................................................................11
5.3
Exploratory Endpoints .............................................................................................12
5.4
Safety Endpoints......................................................................................................12
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................12
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................13
7.1
General Principles....................................................................................................13
7.1.1
Definition of Study Day and Baseline ..............................................................13
7.1.2
Conventions for Missing Data..........................................................................14
7.1.3
Conventions for Missing Adverse Event Dates ................................................14
7.1.3.1
Imputation of missing or partial dates of AE start dates............................14
7.1.3.2
Imputation of missing or partial dates of AE end dates.............................15
7.1.4
Conventions for Missing Concomitant Medication Dates.................................15
7.1.4.1
Imputation of missing or partial dates of concomitant medication start 
dates........................................................................................................16
7.1.4.2
Imputation of missing or partial dates of concomitant medication end 
dates........................................................................................................16
7.2
Analysis Sets ...........................................................................................................16
7.3
Disposition of Subjects ............................................................................................17
7.4
Demographic and Other Baseline Characteristics.....................................................17
7.5
Medical History and Concurrent Medical Conditions...............................................18
7.6
Medication History and Concomitant Medications...................................................18
7.7
Study Drug Exposure and Compliance.....................................................................18
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-935-2008
Page 4 of 35
Statistical Analysis Plan Final 
10 February 2021
7.8
Efficacy Analysis.....................................................................................................20
7.8.1
Primary Efficacy Endpoint...............................................................................20
7.8.2
Secondary Efficacy Endpoints .........................................................................21
7.8.3
Exploratory Endpoints .....................................................................................22
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................24
7.9.1
Pharmacokinetic Analysis................................................................................24
7.9.1.1
Pharmacokinetic Concentrations..............................................................24
7.9.2
Pharmacodynamic Analysis.............................................................................24
7.9.2.1
Pharmacodynamic Concentrations ...........................................................24
7.10
Other Outcomes.......................................................................................................25
7.11
Safety Analysis........................................................................................................25
7.11.1
Adverse Events................................................................................................26
7.11.2
Clinical Laboratory Evaluations.......................................................................27
7.11.3
Vital Signs.......................................................................................................28
7.11.4
12-Lead ECGs.................................................................................................28
7.12
Interim Analysis ......................................................................................................29
8.0
REFERENCES..............................................................................................................29
LIST OF IN-TEXT FIGURES
Figure 4.a
Schematic of Study Design ................................................................................11
LIST OF APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values .................30
Appendix B
Criteria for Markedly Abnormal Vital Signs.......................................................32
Appendix C
Criteria for Markedly Abnormal 12-Lead ECG Parameters ................................33
Appendix D
PROMIS 29 – PROFILE V2.1 Scoring Tables ...................................................34
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-935-2008
Page 5 of 35
Statistical Analysis Plan Final 
10 February 2021
3.0
LIST OF ABBREVIATIONS
24HC
24S-hydroxycholesterol
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BA
bioavailability
BID
twice daily
BMI
body mass index
Cav,ss
average concentration during a dosing interval at steady-state
CFR
Code of Federal Regulations
CH24H
Cholesterol 24-hydroxylase
CNS
central nervous system
C-SSRS
Columbia-Suicide Severity Rating Scale
ECG
electrocardiogram
eCRF
electronic case report form 
EEG
electroencephalogram
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
-glutamyl transferase
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
ICH
International Conference on Harmonisation
ID
identification
IEC
Independent Ethics Committee
INR
international normalized ratio
IP
investigational product
IRB
Institutional Review Board
IVRS
interactive voice response system
IWRS
interactive web response system
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
M-I
metabolite of TAK-935
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PPS
per-protocol set
PTZ
pentylenetetrazol
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-935-2008
Page 6 of 35
Statistical Analysis Plan Final 
10 February 2021
QD
once daily
SAE
serious adverse event
SAP
statistical analysis plan
SRD
single-rising dose
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
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TAK-935-2008
Page 7 of 35
Statistical Analysis Plan Final 
10 February 2021
4.0
OBJECTIVES
4.1
Primary Objective
∀
To investigate the effect of TAK-935 on calculated 24-hour average pain intensity by the 
Numeric Pain Scale (NPS), an 11-point scale.
4.2
Secondary Objectives
∀
To investigate the effect of TAK-935 on overall function using the Patient Global Impression 
of Change (PGIC) and the PROMIS-29 scale.
∀
To investigate the effect of TAK-935 on the CRPS Severity Scale (CSS).
∀
To investigate the effect of TAK-935 on responder rate (responder is defined as ≥30% 
improvement in the 24-hour pain intensity).
4.3
Exploratory Objectives
4.4
Safety Objectives
∀
To evaluate safety and tolerability of TAK-935 in subjects with CRPS
4.5
Study Design
This is a randomized, double-blind, placebo-controlled, parallel-group study with an open-label 
extension period in adult subjects aged ≥18 and ≤75 years with chronic CRPS (symptoms ≥6 
months, diagnosed using the Budapest criteria). The primary objective will be to evaluate the 
efficacy of TAK-935 as an adjunctive therapy in the treatment of chronic CRPS as measured by 
the reduction in the NPS (an 11-point scale by electronic pain diary (e-diary)). This study will 
also evaluate efficacy of TAK-935 as measured by PROMIS-29 version 2.1, PGIC, CSS version 
2, responder rate and the use of rescue medications.
Approximately 24 subjects will be randomized to ensure 21 completers in the double-blind phase 
of the study. The randomization ratio will be 2:1 (16 treatment: 8 placebo).
This study consists of 2 parts:
∀
Part A: Double-Blind Treatment.
–
2- to 4-week screening period.
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TAK-935-2008
Page 8 of 35
Statistical Analysis Plan Final 
10 February 2021
–
3-week titration period.
–
12-week maintenance period.
–
Taper period (maximum 6 days)/Follow-up (15 days after last dose of study drug if the
subject does not continue into the open-label extension.

Part B: Open-Label Extension.
–
2-week titration period.
–
12-week open label.
–
Taper period (maximum 6 days)/Follow-up (15 days after last dose of study drug)
Part A: Double-Blind Treatment (19-22 weeks including screening, titration, maintenance, and,
if the subject does not continue into the open-label extension period, taper if needed and follow-
up periods):
At Visit 1 (screening), after obtaining informed consent, subjects will undergo screening
procedures to assess subject eligibility in accordance with study entry criteria. Subjects who meet 
all inclusion criteria and none of the exclusion criteria at the screening visit will be asked to enter 
pain score daily in an electronic pain diary. For a minimum of 6 of the last 7 screening days prior 
to randomization at Visit 2 (Day 1) into the study, baseline current pain intensity will be 
collected 3 times a day to provide an average daily 24-hour pain intensity in NPS; The average 
24-hour pain intensity score for a given day will be calculated as the mean of the 3 
measurements collected for the day. 
The baseline pain intensity is defined as the mean of the average screening 24-hour pain intensity 
score for the last 7 days before the first dose. Missing pain score entries will not be imputed. At 
the end of the prospective screening period, subjects will return to the clinic (Visit 2, Day 1) and
if a subject does not meet the eligibility criteria the subject will be discontinued from the study 
and considered a screen failure.
On Visit 2 (Day 1), the subjects who meet the entry criteria will be randomized in a 2:1 ratio to
double-blind treatment with investigational product (IP), either TAK-935 100 mg tablets or
matching placebo. At the same visit, after randomization and all pre-dose procedures have been 
performed, subjects will be started on 100 mg BID IP (either TAK-935 100 mg tablets or 
matching placebo) for approximately 1 week. The first dose on Day 1 will be taken in the clinic. 
The subject will take the second dose on Day 1 and the remaining daily doses at home. The site 
will contact the subject by telephone on Day 4 to determine safety and tolerability.
At Visit 3 (Day 7, Week 1), safety and tolerability will be assessed and if the drug is well 
tolerated, the dose will be increased to 200 mg BID. The site will contact the subject by 
telephone on Day 10 to determine safety and tolerability of this dose. Any subjects who continue 
with 100 mg BID and still cannot tolerate the minimum daily dose of 100 mg BID, will be 
withdrawn from the study.
At Visit 4 (Day 14, Week 2), safety and tolerability will be assessed and if the drug is well
tolerated with no continuing pain, the subject will remain at 200 mg BID. If the subject continues
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-935-2008
Page 9 of 35
Statistical Analysis Plan Final 
10 February 2021
to need a higher dose in the PI’s opinion, the dose will be increased to 300 mg BID. The site will
contact the subject via phone on Day 17 to determine the safety and tolerability of this dose.
Subjects that do not require the dose to be increased to 300 mg BID will still be required to
complete a 21-day titration period in order to confirm the tolerated dose prior to entering the
maintenance phase. After the 3-week titration period, the subject will return to the site for Visit 5 
(Day 21, Week 3) to begin the 12-week maintenance period.
After Visit 5 (Day 21, Week 3), subjects will visit the clinic approximately every 4 weeks (Visit 
6 [Day 49, Week 7] and Visit 7 [Day 77, Week 11]). The daily pain intensity will be collected 3
times a day using the electronic pain diary throughout Part A. Dosing information will also be 
entered using the same device.
The average pain intensity score for Visit 5 (Day 21, Week 3) and Visit 8 (Day 105, Week 15) 
(or the last dose in Part A) will be calculated as the mean of the average 24-hour pain intensity 
score collected during the last 7 days before the corresponding visit. No imputation will be 
performed for missing pain score entries.
If at any time during either the titration period or the maintenance period, the subject cannot
tolerate the dose, the dose may be decreased to the previous tolerated dose. The subject may 
return to the clinic for an unscheduled visit at any time during either the titration period or the
maintenance period if dose adjustments are needed between scheduled visits. If the subject 
cannot tolerate the minimum daily dose of 100 mg BID, the subject will be withdrawn from the 
study. If the dose is decreased due to inability to tolerate the dose based on the investigator’s 
review, the dose may be increased to the next highest dose 1 time during the titration. Dose 
modifications during the maintenance period should be discussed with the medical monitor.
Any change in dose will be documented in the subject’s clinic chart and dosing card. Pain 
medications and nondrug treatments must be stable (regimented per prescription) for 1 month
prior to screening and should remain stable throughout Part A. Pain medication use may be
adjusted under supervision during Part B. Concurrent treatment regimen data will be collected
throughout the study. A single effective rescue medication must be identified for each subject for 
use during the study. The prescribed maximum dose must remain stable during Part A. The use 
of rescue pain medications will be assessed at each visit; subjects requiring significant increase 
of rescue medication (frequency or dose 50% over pre-enrollment levels or over the prescribed 
maximum) during Part A will be considered for withdrawal from the study at the investigator’s 
and sponsor’s discretion.
An unblinded interim analysis will be conducted when all subjects have completed Part A
(Double-Blind Treatment).
Following the completion of Part A, subjects will have the option to continue into Part B, a 
14-week open-label drug extension, or to enter a double-blind taper period (maximum 6 days).
For all subjects that choose not to enter Part B (Open-Label Extension), the IP dose will be
reduced to the next lower dose every 3 days (or less frequently based on the investigator’s
discretion) until IP dose is discontinued. After tapering, the subjects will complete a safety
follow-up phone call approximately 15 days after the last dose of IP.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-935-2008
Page 10 of 35
Statistical Analysis Plan Final 
10 February 2021
Part B Open-Label Extension (16-17 weeks, including titration, maintenance, taper if needed, 
and follow-up periods):
Because the Part A treatment assignments will remain blinded, all subjects who choose to 
continue into Part B will start at 200 mg BID TAK-935 (100 mg tablets), regardless of the 
treatment received in Part A at Visit 8 (Day 105, Week 15). Subjects will remain at 200 mg BID 
for 1 week. The site will contact the subject by telephone on Day 108 (3 days after initiation of 
this dose) to determine safety and tolerability.
At Visit 9 (Day 112, Week 16), safety and tolerability will be assessed and if the drug is well
tolerated and the subject continues to need a higher dose in the PI’s opinion, the dose will be
increased to 300 mg BID. The dose may also be decreased based on tolerability at Visit 9 
(Day 112, Week 16). The site will contact the subject on Day 115 to determine the safety and 
tolerability of this dose.
After completing 1 week at the assigned dose, the 2-week titration period will be completed and 
the subject will return to the site for Visit 10 (Day 119, Week 17) to begin the 12-week 
maintenance period.
If at any time during either the titration period or the maintenance period the subject cannot
tolerate the dose, the dose may be decreased to the previous tolerated dose. The subject may 
return to the clinic for an unscheduled visit at any time during either the titration period or the
maintenance period if dose adjustments are needed between scheduled visits.
Any change in dose will be documented in the subject’s clinic chart and dosing card. After Visit 
10 (Day 119, Week 17), the subjects will visit the clinic approximately every 4 weeks (Visit 11 
[Day 147, Week 21] and Visit 12 [Day 175, Week 25]). The current pain intensity will be
collected daily, 3 times a day, using the electronic pain diary until the end of the study. 
The average pain intensity score for Visit 11 (Day 147, Week 21) and Visit 13 (Day 203, Week 
29) (or the last dose in Part B) will be calculated as the mean of the average 24-hour pain 
intensity score collected during the last 7 days before the corresponding visit. No imputation will 
be performed for missing pain score entries.
During the taper period, the IP dose will be reduced to the next lower dose every 3 days (or less
frequently based on the investigator’s discretion) until IP dose is discontinued. After tapering, 
the subjects will complete a safety follow-up phone call approximately 15 days after the last dose 
of IP and exit the study.
The total period of evaluation from screening to the final follow-up in Part B will be 
approximately 34-36 weeks.
A schematic of the study design in shown in Figure 4.a. A schedule of study procedures is listed 
in Appendix A of the protocol.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-935-2008
Page 11 of 35
Statistical Analysis Plan Final 
10 February 2021
Figure 4.a
Schematic of Study Design
BID: twice daily.
During the titration periods of both Part A and Part B, safety and tolerability will be assessed at 
each visit and if the drug is well tolerated and the subject continues to need a higher dose (i.e., 
the subject still has pain), the dose will be increased to the next higher level. The maximum dose 
is 300 mg BID.
Following completion of Part A, subjects will have the option to continue into Part B, a 14-week 
open-label drug extension study or to enter a double-blind taper period.
All subjects will undergo dose taper procedures and will then proceed to the follow-up period. 
During the taper period, IP dose will be reduced to the next lower dose every 3 days (or less 
frequently based on the investigator’s discretion) until IP dose is discontinued. Subjects who are 
on the lowest administered dose of IP will not undergo dose taper.
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
Change in mean 24-hour pain intensity NPS from baseline to the end of Part A (Week 15). 
5.2
Secondary Endpoints

Percent change in mean 24-hour pain intensity NPS score from baseline to the end of Part A 
(Week 15).

Percent of responders (defined as ≥30% improvement on the mean 24-hour pain intensity 
NPS) by the end of Part A (Week 15).
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TAK-935-2008
Page 12 of 35
Statistical Analysis Plan Final 
10 February 2021
∀
Change and percent change of the PROMIS-29 version 2.1 total score from baseline to the 
end of Part A (Week 15).
∀
PGIC at the end of Part A (Week 15).
∀
Change and percent change of CSS from baseline to the end of Part A (Week 15).
5.3
Exploratory Endpoints
5.4
Safety Endpoints
∀
Percentage of subjects with at least 1 treatment-emergent adverse event in Part A and Part B.
∀
Percentage of subjects with at least 1 markedly abnormal value for clinical laboratory 
evaluations, vital signs, body weight/body mass index, and electrocardiogram parameters 
after treatment in Part A and Part B.
∀
Change from baseline in clinical laboratory evaluations, vital signs, body weight, and
electrocardiogram parameter values after treatment in Part A and Part B.
6.0
DETERMINATION OF SAMPLE SIZE
Assuming a common standard deviation of 2 in the change of 7-day average pain score and a 12% 
drop-out rate, a sample size of 24 subjects in total with a randomization ratio of 2:1 is sufficient 
to achieve at least 65% power to detect a difference of 2 between TAK-935 and placebo using a 
2-sample t-test on the change from baseline to Week 15 in mean 24-hour pain intensity NPS 
score at 0.10 2-sided significance level. A difference of 2 in the 11-point NPS is within the 
accepted range of minimally clinically important difference in treating complex regional pain 
syndrome1,2.
CCI
Property of Takeda: For Non-Commercial Use Only
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TAK-935-2008
Page 13 of 35
Statistical Analysis Plan Final 
10 February 2021
7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
The Statistical Analysis Plan (SAP) should be read in conjunction with the study protocol and 
electronic case report forms (eCRFs).
All study-related raw data and derived data will be presented in data listings. Continuous 
variables will be summarized using the number of subjects with non-missing values, mean, 
median, standard deviation (SD), minimum, and maximum values. Where indicated, coefficient 
of variation (CV%) and geometric mean will also be included in the summary of continuous data. 
Categorical data will be summarized using the number and percentage of subjects for each 
category where appropriate. The denominator for the percentages will be based on the number of 
subjects who provide non-missing responses to the categorical variable.
Where applicable, variables will be summarized descriptively by study visit. 
All confidence intervals (CI) and the p-values in statistical tests will be reported as 2-sided and 
the statistical significance will be assessed at a type-I error rate, α, of 0.10 significance level 
unless otherwise stated. The p-values will be rounded to 4 decimal places prior to assessment of 
statistical significance. 
The means and medians will be presented in 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented in 2 more decimal places than the recorded data. The 
confidence interval of a parameter estimate will be presented using the same number of decimal 
places as the parameter estimate.
7.1.1
Definition of Study Day and Baseline 
Study day will be calculated relative to the date of the first dosing in Part A. Study day prior to 
the first dosing will be calculated as: date of assessment/event – date of first dosing; study day on 
or after the date of first dose of treatment will be calculated as: date of assessment/event – date of 
first dosing + 1.
In general, the baseline characteristics for the entire study will be defined as the last non-missing 
measurements prior to first dose of study drug in Part A. The baseline pain intensity for both Part 
A and Part B will be the screening average pain score, defined as the mean of the daily average 
screening 24-hour pain intensity score in the last 7 days before the first dose in Part A. The 
baseline reference values for clinical laboratory test results, vital sign measurements, C-SSRS, 
and ECG parameters in both Parts A and B will be the last non-missing measurements prior to 
the first dose of study drug in Part A. The baseline values in the exploratory endpoints for Part B 
will also be the corresponding values before the first dose of study drug in Part A.
Both date and time of the measurement and the dosing date and time should be used when 
determining the baseline if possible. In the case where the last non-missing measurement (except 
AE and concomitant medications) and the first dose in Part A coincide at the same time, or the 
same date if time of the measurement is not collected, that measurement will be considered as 
baseline value. 
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7.1.2
Conventions for Missing Data
There will be no imputation of incomplete or missing data other than the AE and concomitant 
medication dates mentioned in the two sections below. 
Plasma concentrations that are below the limit of quantification (BLQ) will be treated as zero in 
the summarization of concentration values. These values will be flagged in the data listings and 
deviations from this convention may be considered on a case-by-case basis as deemed 
appropriate.
7.1.3
Conventions for Missing Adverse Event Dates
Adverse events with completely or partially missing dates will be imputed as follows in order to 
determine the associated period. The listings will only display dates as entered.
7.1.3.1
Imputation of missing or partial dates of AE start dates

Month/year available and day missing:
–
If the month and year are the same as those in the first dose date in Part A and the event 
is not indicated as a pre-treatment event, the first dose date in Part A is to be used to 
impute the start date. 
–
If the month and year are the same as those in the first dose date in Part A and the event 
is indicated as a pre-treatment event, the date prior to the day of the first dose in Part A is 
to be used to impute the AE start date. If the date prior to the day of the first dose in Part 
A is in previous month/year, set the AE start month/year to the previous month/year. 
–
If the month and year are after the first dose date in Part A and the same as or before the 
last dose date in Part A plus 15 days for patients who do not continue to Part B or before 
the first dose date in Part B, the first of the month will be used for the start date.
–
If the month and year are the same as the first dose date in Part B and the same as the last 
dose date in Part A, the first of the month will be used for the start date.
–
If the month and year are the same as the first dose date in Part B and after the last dose 
date in Part A, then the event is considered as a treatment emergent for Part B and the 
first dose date in Part B is to be used to impute the start date.
–
If the month and year are after the first dose date in Part B, the first day of the month will 
be used for the start date. 

Year available and month/day missing:
–
If the year is the same as the year of the first dose date in Part A and same as or before 
the first dose in Part B and the event is not indicated as a pre-treatment event, the first 
dose date in Part A is to be used to impute the AE start date.
–
If the year is the same as the year of the first dose date in Part A and same as or before 
the first dose in Part B and the event is indicated as a pre-treatment event, the date prior 
to the day of the first dose in Part A is to be used to impute the AE start date. If the date 
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Statistical Analysis Plan Final 
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prior to the day of the first dose in Part A is in previous month/year, set the start 
month/year to the previous month/year.
–
If the year is the same as the year of the first dose in Part B and after the year of the last 
dose in Part A, the first dose date in Part B is to be used to impute the AE start date.
–
If the year is not the same as the year of the first dose date in Part A or the year of first 
dose date in Part B, set the start date as January 1.

Year/month/day all missing:
–
If the event is not indicated as a pre-treatment event, the first dose date in Part A is to be 
used to impute the AE start date.
–
If the event is indicated as a pre-treatment event, the date prior to the first dose date in 
Part A is to be used to impute the AE start date. 
7.1.3.2
Imputation of missing or partial dates of AE end dates
If the event is indicated as ongoing at the end of the study, no imputation is needed.
If the event is not indicated as ongoing:

Month/year available and day missing:
–
Use the last day of the month to impute the AE end date. If the imputed end date is before 
the AE start date, keep the end date same as the start date. If the subject died, use the date 
of death to impute the end date. 

Year available and month/day missing:
–
If the year is the same as or before the year of the last dose in Part B, set the end date as 
December 31.
–
If the year is after the year of the last dose in Part B, set the end date as January 1.

Year/month/day all missing:
–
Impute the end date as December 31 of the Part B last dose year. If the imputed end date 
is before the AE start date, keep the end date same as the start date. If the subject died, 
use the date of death to impute the end date.
7.1.4
Conventions for Missing Concomitant Medication Dates
Concomitant medications with completely or partially missing dates will be imputed as follows. 
Note the imputed dates are used in determining the associated period. The listings will only 
display dates as entered.
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Statistical Analysis Plan Final 
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7.1.4.1
Imputation of missing or partial dates of concomitant medication start dates 

Month/year available and day missing:
–
The first day of the month will be used for the start date.

Year available and month/day missing:
–
Set the start date as January 1.

Year/month/day all missing:
–
If date of birth is available, use the date of birth as the start date.
–
If date of birth is not available, estimate date of birth using the screening date and age, 
and use the estimated date of birth as the start date.
7.1.4.2
Imputation of missing or partial dates of concomitant medication end dates 
If the concomitant medication is indicated as ongoing, no imputation is needed.
If the concomitant medication is not indicated as ongoing, use the same algorithm in Section 
7.1.2.2 to impute.
7.2
Analysis Sets
The randomized set will include all subjects who were randomly assigned to planned treatment 
through the IVRS/IWRS.
The PK analysis set for Parts A and B will include all subjects who received at least 1 dose of 
study drug and have at least 1 post-dose measurable TAK-935 or M-I plasma concentration. PK 
analysis performed for Part B separately will include subjects who have received at least 1 dose 
of TAK-935 in Part B and have at least one post-dose measurable TAK-935 or M-I plasma 
concentration in Part B.
The PD analysis set for Parts A and B will include all subjects who received at least 1 dose of 
study drug and have at least 1 measurable plasma 24HC concentration. PD analysis performed 
for Part B separately will include subjects who have received at least 1 dose of TAK-935 in Part 
B and have at least one measurable plasma 24HC concentration.
The full analysis set (FAS) for Parts A and B will include all subjects who were randomized, 
received at least 1 dose of study drug, and have at least 1 valid post-baseline value for the 
assessment of average 24-hour pain score in Part A or Part B. Efficacy analyses performed for 
Part B separately will include subjects who have received at least 1 dose of TAK-935 in Part B 
and have at least one valid 7-day NPS assessment during Part B. In FAS efficacy summaries, 
subjects will be analyzed according to the treatment they received. 
The safety analysis set for Parts A and B will include all subjects who received at least 1 dose of 
study drug. In safety summaries, subjects will be analyzed according to the actual treatment they 
received. Safety analysis performed for Part B separately will include subjects who have 
received at least 1 dose of TAK-935 in Part B.
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7.3
Disposition of Subjects
Study information will be presented, including date first subject signed the Informed Consent 
Form, date of first dose of study drug, date of last subject’s last visit/contact in Part A and Part B, 
date of last subject’s last procedure for collection of data for primary endpoint, Medical 
Dictionary for Regulatory Activities (MedDRA) Version, World Health Organization Drug 
Dictionary Version (WHODRUG), and SAS Version.
Disposition of all screened subjects (denominator) will be tabulated (count and percent); there 
will be no inferential analysis of subject disposition data. 
The number of randomized subjects in each study site will be summarized by treatment group 
(placebo or TAK-935) and overall.
Among randomized subjects, the number and percentage of subjects who complete study drug 
and all study visits in Part A of the study, prematurely discontinue study drug and study visits in 
Part A will be summarized by treatment group (placebo or TAK-935), final maintenance dose 
regimen (100, 200, or 300 mg BID), and overall for all randomized subjects in the double-blind 
period. For all the subjects who continue in Part B of the study, the number and percentage of 
subjects who complete study drug and all study visits in Part B, prematurely discontinue study 
drug and study visits in Part B will be summarized for Part B overall. The number of patients 
who prematurely discontinue study drug does not include those who have completed the study 
drug in the maintenance period but not the taper period. The number of patients who prematurely 
discontinue study visits does not include those who have completed visits in the maintenance 
period but not the safety follow-up phone call. For each study Part, the primary reason for 
discontinuation of study drug/visits, as entered on the electronic case report form (eCRF), will be 
tabulated. The date of first dose, date of last dose, duration of treatment and the reason for 
premature discontinuation of study drug/study visit will be presented for each subject in listings. 
Disposition of screen failure subjects in Part A will be summarized descriptively. Primary 
reasons for failure will be summarized and will be presented in a data listing. 
The number and percentage of subjects who comprised each analysis set will be summarized by 
treatment group, final maintenance dose regimen, overall in Part A, and overall in Part B.
Details for important (significant) protocol deviations for subjects in Safety analysis set will be 
summarized in a table and provided in a data listing. 
7.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics (e.g., age, sex, ethnicity, race as described by the 
subject, smoking status at screening, disease characteristics and substance use) will be 
summarized and listed for subjects by treatment group (placebo or TAK-935) and overall using 
the safety analysis set in Part A. Summary statistics (number of subjects, mean, SD, median, 
minimum, and maximum) will be presented for continuous variables (e.g., age, and weight), and 
the number and percentage of subjects within each category will be presented for categorical 
variables (e.g., sex, ethnicity, race). No inferential statistics will be presented. Individual subject 
demographic and baseline characteristic data will be listed.
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Statistical Analysis Plan Final 
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Demographic variables of screen failure subjects and reasons for screen failure will be 
summarized overall for subjects who are screened but not enrolled in the study. Individual 
demographic characteristics, date of informed consent, any available safety data and reason for 
screen failure will also be presented in the data listing. 
7.5
Medical History and Concurrent Medical Conditions
Medical history refers to the significant conditions or diseases relevant to the disease under study 
that resolved 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 latest version of 
Medical Dictionary for Regulatory Activities (MedDRA, version 19.0) and will be summarized 
by treatment group and overall in Part A, using System Organ Class (SOC) and MedDRA 
preferred term. The table will include number and percentages of subjects and will be sorted in 
alphabetical order by system organ class and preferred term. A subject will only be counted once 
within a class even if he/she has multiple conditions/symptoms. Summaries will be based on the 
safety analysis set and presented for Part A only. 
Part A period will begin with the signing of the informed consent. Part B period will begin with 
the first dose in Week 15 visit.
All medical history and concurrent medical condition data will also be presented in listings.
7.6
Medication History and Concomitant Medications
Medication history to be obtained includes any medication relevant to eligibility criteria and the 
efficacy or safety evaluations stopped or started within 6 months prior to signing informed 
consent. The timeframe for medication history for Part A will be within 6 months prior to 
signing the informed consent. Medications used anytime from the signing of the informed 
consent to right before the first dose in Part B if enrolled in Part B, or, if not enrolled in Part B, 
the last dose (including taper period if applicable) in Part A, will be considered concomitant 
medications for Part A. Medications used anytime from the first dose in Part B to the last dose 
(including taper period if applicable) will be considered concomitant medications for Part B.
Summaries of medication history and concomitant medications will be based on the safety 
analysis set. Summaries of medication history will be presented for Part A only. Concomitant 
medications that started and ended prior to the first dose will be summarized for Part A. 
Concomitant medications started prior to the first dose and ongoing on the day of the first dose, 
or started after the first dose will be summarized for Part A and Part B. 
No inferential statistics will be presented. All prior and concomitant medications data will be 
summarized by treatment group and overall and presented in listings. 
7.7
Study Drug Exposure and Compliance
The start and end dates and time of each dose for each subject in the safety analysis set will be 
reported in a data listing. Summaries of study drug exposure data will be provided by treatment 
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Statistical Analysis Plan Final 
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received (TAK-935 or placebo) and overall using the safety analysis set. No inferential statistics 
will be presented.
The duration of exposure (days) to the double-blind study medication in Part A is defined as 
(date of the last dose of double-blind study drug – date of first dose of double-blind study drug + 
1). For patients who do not enter Part B, the date of last dose of study drug will be the date of last 
dose before tapering where applicable, and the overall duration of exposure to the TAK-935 will 
be the same as the duration of exposure in Part A. The duration of exposure to the open-label 
study medication in Part B is defined as (date of last dose of open-label study drug before 
tapering – date of first dose of open-label study drug + 1). For patients who are on placebo in 
Part A and dosed in Part B, the overall duration of exposure to the TAK-935 will be the same as 
the duration of exposure in Part B. For patients who have been treated in both Parts A and B with 
active drug (TAK-935), the overall duration of exposure to the TAK-935 is defined as (date of 
last dose of open-label study drug before tapering – date of first dose of double-blind study drug 
+1).
The date of last dose of study drug in Part A and Part B will be obtained from the e-diary and 
derived from drug accountability data where available. The date of the last dose of study drug in 
a study period will be the date of the last non-missing dose date before the tapering period in the 
corresponding study period. The date of the last dose of study drug based on drug accountability 
will be estimated as the last drug dispense date plus the number of days the drug was taken based 
on the last drug accountability form. When the two derived dates are different, the date based on 
drug accountability data, if available, will be used.
The duration of double-blind treatment in Part A will be summarized by treatment group as a 
continuous variable and, additionally, classified by the following categories: 1 to 21 days, 22 to 
97, 98 to 119, 120-189, and 190 days or more. The intervals are calculated based on the actual 
recorded study days and the treatment termination date.
In Part A of the study, subjects are to take 100 mg/200 mg/300 mg of TAK-935 or matching 
placebo twice each day. In Part B, subjects are to take 100 mg/200 mg/300 mg TAK-935 twice 
daily. Overall percent study drug compliance for each period (Part A and Part B) will be 
calculated as: 
Drug compliance (%) based on e-diary = 100 ∙
	
  
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	
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  
Drug compliance (%) based on pill count = 100 
	
   
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where expected number of tablets to be taken = [number of tablets to be taken daily*(date of last 
dose of medication – date of first dose of medication + 1)]. 
e-diary pain score entry compliance (%) = 100 ∙
	
  
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×	
     	   
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Statistical Analysis Plan Final 
10 February 2021
e-diary dosing entry compliance (%) = 100 ∙
	
  
  
     
×	
     	   
All compliance measures will be presented to 1 decimal place in the derived dataset and Table, 
Figures, and Listings (TFLs) outputs.
All measures of study drug compliance and e-diary compliance in Part A and Part B will be 
summarized separately using descriptive statistics. and by the number of subjects in each of the 
following compliance categories: <70%, ≥70 to <85%, and ≥85 to ≤100%. For drug compliance 
by pill count, two additional categories, >100%, and missing, might be necessary.
All study drug administration (double-blind placebo in Part A, double-blind active (TAK-935) 
drug in Part A, and open-label study drug in Part B) and accountability data will be listed by 
subject number. The following variables will be listed for drug accountability: subject identifier, 
drug category, date and number of tablets dispensed and returned, and Drug compliance in Part 
A and Part B by pill count. 
7.8
Efficacy Analysis
Efficacy analysis on numeric pain score, PROMIS-29, Patient Global Impression of Change 
(PGIC) and CPRS Severity Scale (CSS) will be performed based on FAS.
The weekly NPS for the visits on Weeks 3, 15, and 29 is the average of 24-hour pain scores in 
the last 7 days prior to the corresponding visit. The 24-hour pain score is the average of the pain 
scores recorded for the day. The 24-hour pain score is missing for a day when no pain score is 
recorded for the day. The 7-day average NPS is the average of the non-missing 24-hour pain 
score during the 7 days. 
7.8.1
Primary Efficacy Endpoint
For the primary efficacy endpoint, only subjects with a screening baseline and at least 1 post-
dose efficacy measurement will be included in the summary and analyses. The average 24-hour 
pain intensity score is defined as the mean of the recorded NPS (morning, afternoon and evening) 
of the day. The weekly NPS of a week is defined as the mean of the average 24-hour pain 
intensity score of the week. Summary statistics and plots of the mean and standard deviation of 
weekly average daily pain score for baseline and each subsequent week from Week 1 to Week 15 
will be provided by treatment group. The baseline NPS is defined as the mean of the average 
screening 24-hour pain intensity score for the last 7 screening days before the first dose of study 
drug in Part A. The weekly NPS is defined as the mean of the average 24-hour pain intensity 
score in each week following the first dose, with Study Visit 2 (Day 1) as the first day in the first 
week. All subsequent weeks in Part A will be defined relative to Day 1. The change and percent 
change from baseline for each week from Week 1 to Week 15 will also be summarized and the 
change from baseline will be plotted. For subjects with no more than one day of NPS records for 
a week, the weekly NPS will be considered missing for the week. 
For the mean 24-hour pain intensity in Part A, linear mixed models for repeated measurements 
will be used to evaluate the effect of TAK-935 on the primary endpoint. The change from 
baseline in the weekly average daily pain intensity to the scheduled visits (Day 21/Week 3, Day 
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Statistical Analysis Plan Final 
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105/Week 15) will be the response in the model; baseline NPS, site, visit (Day 21/Week 3, or 
Day 105/Week 15), treatment, and treatment by visit interaction will be the fixed effects, and 
subject the random effect. A completely unstructured covariance matrix will be assumed. In case 
a model does not converge, AR(1) or compound symmetry covariance matrix may be assumed. 
The week 3 NPS will be based on the records from the last 7 days prior to the visits on Day 21
(Week 3), or the last dose in Part A, whichever is earlier. The week 15 NPS will be based on the 
records from the last 7 days prior to the visits on Day 105 (Week 15), or the last dose in Part A if 
it is after 3 weeks, whichever is earlier, The treatment effect at each visit will be evaluated using 
the difference in the least-square means of the change from baseline between TAK-935 and 
placebo; 95% confidence intervals for the differences and p-values will also be provided.
As a sensitivity analysis, a linear mixed model based on all weekly average daily pain intensity 
from Week 3 to Week 15, where available, will also be used to assess the efficacy of TAK-935 
compared to Placebo. The baseline and weekly NPS are as defined as those used for weekly 
summary statistics. The model will be similar to the one used for primary analysis except all the 
available weekly mean 24-hour NPS scores from Week 3 to Week 15 will be included.
An additional sensitivity analysis will be performed using the same linear mixed model based on 
all weekly average NPS but including only subjects in the Placebo arm and subjects with at least 
70% drug compliance in TAK-935 arm.
7.8.2
Secondary Efficacy Endpoints
Percentage change in mean 24-hour pain intensity will be analyzed similarly as in the primary 
analysis. Percentage change will be calculated based on the baseline and weekly NPS as defined 
in the summary statistics for the weekly NPS. Summary statistics of percentage change for each 
week will be summarized by treatment group from Week1 to Week 15. 
Percent of responders will be summarized weekly from Week 1 to Week 29 by treatment group 
based on the baseline and weekly NPS as described in the summary statistics for weekly NPS. In 
a given week, a responder is defined as a subject with ≥30% improvement in the weekly average 
24-hour pain intensity for the week compared to baseline. The proportion is calculated based on 
the number of subjects with average NPS for the week.
Summary statistics will be provided for other efficacy measures at baseline (PROMIS-29 and 
CSS) and the Week 15 and Week 29 visits (PROMIS-29, CSS and PGIC) by treatment received 
in Part A and overall. The PGIC scale at the end of Week 15 and Week 29 will be summarized as 
a categorical variable. Change from baseline and percent change from baseline for PROMIS-29 
(T-score for each domain) and CSS total score will also be summarized with descriptive statistics 
by treatment received. CSS total score is the number of “Yes” answers to the questions on the 8 
symptoms and 8 signs when all 16 questions are answered. The change in mean CSS total score 
from baseline to the end of Week 15 will be compared between treatment and placebo using a 
two-sample t-test. In addition to the overall CSS score, the number and proportion of subjects 
with a “Yes” answer to each of the 16 questions will be summarized for baseline and Weeks 15 
and 29 by treatment received in Part A and overall. 
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Statistical Analysis Plan Final 
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The PROMIS-29 instrument consists of seven domains (short forms) related to physical, mental 
and social health with 4 questions in each domain as well as one 11-point rating scale (0-10) for 
pain intensity. The scoring of each of the seven domains (physical functioning, anxiety, 
depression, fatigue, pain interference, sleep disturbance, and satisfaction with social role 
participation) in PROMIS-29 will depend on whether a respondent has answered all items in the 
domain. If a respondent skips an item, the scoring will be based on the response pattern scoring 
provided by the Health Measures Scoring Service 
(https://www.assessmentcenter.net/ac_scoringservice). For patients who have answered all 
questions, the scoring will be based on the score conversion table in Appendix D. First, find the 
total raw score for a short form with all questions answered by summing the scores of the 
response to each question. Then locate the applicable score conversion table in Appendix 1 and 
convert the total raw score into a T-score for the domain for each participant. The summary 
statistics will be provided for each of the seven domains separately.
7.8.3
Exploratory Endpoints
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Statistical Analysis Plan Final 
10 February 2021
CCI
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Statistical Analysis Plan Final 
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7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
7.9.2
Pharmacodynamic Analysis
7.9.2.1
Pharmacodynamic Concentrations
Blood samples for the measurement of 24HC levels in plasma will be collected according to the 
schedule shown in Appendix A of the protocol.
The PD measures of the plasma 24HC levels will be listed for each subject and summarized (N, 
mean, SD, median, minimum, and maximum) by each time point for each dose regimen and 
study period.
A population PK/PD analysis approach will be used to determine the population estimates for 
TAK-935. The PK and PD analysis will be described in a separate analysis plan, and the 
parameters for TAK-935 will be summarized in a separate population PK/PD report where data 
allow.
Correlation between 7-day average daily pain score and plasma 24HC levels during the double-
blind and open-label treatment periods will also be evaluated. At each post-baseline visit where 
24HC data are available, scatterplot of change in average weekly pain score from baseline 
against change in trough plasma 24HC levels will also be generated. 
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Statistical Analysis Plan Final 
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7.10
Other Outcomes
7.11
Safety Analysis
Safety analyses include adverse events (AEs), clinical laboratory parameters, vital sign
parameters, 12-lead ECG results, and other safety parameters. The safety analysis set will be 
used for all summaries of safety parameters. The safety endpoints will be summarized by Part A 
and Part B separately, and additionally for Part A and B combined. For each period, summary 
statistics will be provided by treatment received at the start datetime of the AE (Placebo and 
TAK-935 for Part A and TAK-935 for Part B) and overall. The listings will include treatment 
and dose level at the start datetime of the corresponding AE. 
For the analyses of AEs, for subjects who did not enter Part B, the Part A period will be from the 
first dose in Part A up to 15 days (onset date – last date of dose + 1 ≤15) after the last dose of 
study drug in Part A, including the taper period. For subjects who entered Part B, the Part A 
period is from the first dose in Part A up to right before the first dose in Part B, and the Part B 
period will be from the first dose in Part B up to 15 days (onset date –date of last dose + 1 ≤15) 
after the last dose of study drug in Part B including the taper period.
For the analyses of safety laboratory parameters, vital signs and ECG, week 15 will be 
summarized in part A. Otherwise, the data handling should be same as how it is described in the 
context of analyses of AEs above.
CCI
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TAK-935-2008
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Statistical Analysis Plan Final 
10 February 2021
The safety endpoints include:

Percentage of subjects with at least 1 treatment-emergent adverse event in Part A and Part B.

Percentage of subjects with at least 1 markedly abnormal value for clinical laboratory 
evaluations, vital signs, body weight/body mass index, and electrocardiogram parameters 
after treatment in Part A and Part B.

Change from baseline in clinical laboratory evaluations, vital signs, body weight, and
electrocardiogram parameter values after treatment in Part A and Part B.
7.11.1
Adverse Events
A Pre-Treatment Event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed informed consent to participate in a study, but prior to 
administration of any study medication; a causal relationship with study participation is not 
required.
A treatment-emergent adverse event (TEAE) is defined as any untoward medical occurrence in a 
clinical investigation subject after the administration of a study drug; it does not necessarily have 
to have a causal relationship with this treatment. PTE and TEAE verbatim terms will be coded 
by SOC and PT using MedDRA (version 19 or later).
TEAEs for Part A will be defined as any sign, symptom, syndrome, or new illness, regardless of 
relationship to study drug, that occurs after the first dose of study drug received in Part A and, 
for those not enrolled in Part B, up to 15 days (onset date – last date of dose + 1 ≤ 15) after the 
last dose of study drug in Part A, or for those enrolled in Part B, before the first dose of study 
drug in Part B. AEs that occur on the same day as the first dose of study drug in Part A but with 
missing time will be considered as TEAEs for Part A.
TEAEs for Part B will be defined as any sign, symptom, syndrome, or new illness, regardless of 
relationship to study drug, that occurs after the first dose of study drug received in Part B and up 
to 15 days (onset date –date of last dose + 1 ≤ 15) after the last dose of study drug in Part B. AEs 
that occur on the same day as the first dose of study drug in Part B but with missing time will be 
considered as TEAEs for Part B.
TEAEs for Part A and B combined will be defined as any sign, symptom, syndrome, or new 
illness, regardless of relationship to study drug, that occur after the first dose of study drug 
received in Part A and up to 15 days (onset date –date of last dose + 1 ≤ 15) after the last dose of 
study drug in Part B. AEs that occur on the same day as the first dose of study drug in Part A but 
with missing time will be considered as TEAEs for Part A and B.
TEAEs will be presented by severity (mild, moderate, and severe). Serious TEAEs, TEAEs 
leading to study drug discontinuation, and TEAEs leading to death will also be summarized 
using SOC and PT. 
When calculating the frequency and percentage of subjects who reported TEAEs, a subject will 
be counted only once for each SOC or PT when multiple TEAEs under the same treatment or 
TAK-935 dose level in the same study period are coded to the same SOC or PT. For the intensity 
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Statistical Analysis Plan Final 
10 February 2021
or relatedness summaries, if a subject reports multiple TEAEs coded to the same SOC or PT, the 
TEAE with maximum intensity or strongest relationship will be included in the summary.
AEs with missing severity will be listed as such in the AE listings, however, will be summarized 
as severe in summary tables. Similarly, if the relationship of an event is missing, the event will 
be considered as related but in listings it will be presented as missing.
In general, TEAEs will be tabulated at the following levels: overall summary (subjects with at 
least 1 AE in any dose or treatment), the MedDRA SOC, and the MedDRA PT. The tables will 
include the number and percentage (N (%)) of subjects. The following summary tables will be 
generated for each study part (Part A, Part B, and Parts A and B combined) and summarized by 
treatment received Part A and overall: 
∀
Overview of Treatment-Emergent Adverse Events.
∀
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term.
∀
Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term.
∀
Most Frequent (>5%) 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.
∀
Severity of Treatment-Emergent Adverse Events by System Organ Class and Preferred Term.
∀
Pretreatment Adverse Events by System Organ Class and Preferred Term (Part A only).
In addition, subject mappings for the TEAEs by SOC and PT will be generated.
Data listings will be provided for PTEs, TEAEs, TEAEs leading to study drug discontinuation, 
SAEs, 
, and AEs 
that resulted in death. 
7.11.2
Clinical Laboratory Evaluations
Clinical laboratory tests (hematology, serum chemistry and urinalysis) will be analyzed using the 
safety analysis set and will be evaluated and presented using International System of Units (SI) 
unless otherwise stated. Table 9.a in the protocol shows a list of all clinical laboratory tests. 
All laboratory test parameters will be displayed in individual subject data listings in both SI units 
and conventional (CV) units. For test results not in SI units, the conversion to SI units will be 
done in derived analysis data sets using the known conversion factors. If necessary, SI units from 
the central laboratory may be converted to Takeda’s preferred SI units in the derived dataset. All 
summaries and analyses will be based on the values using these preferred SI units.
CCI
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Statistical Analysis Plan Final 
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Only observations within 15 days of the last dose of study drug will be included in the tables. No 
inferential statistics will be presented unless otherwise stated.
Descriptive statistics (N, mean, SD, median, minimum, and maximum) for the observed and 
change from baseline values will be presented for Parts A and B. Study baseline defined in 
Section 7.1.1 will be used for change from baseline in each part of the study. Note that character 
urinalysis tests will only be listed.
Laboratory Markedly Abnormal Values (MAVs), identified by the criteria defined in 
Appendix A, will be tabulated. If a subject has a MAV for a particular laboratory test, all visits 
for that subject for that parameter will be listed. The number and percentage of subjects with at 
least 1 post-dose markedly abnormal laboratory test result will be summarized. The mapping of 
the subjects who meet the MAV criteria will be listed as a table. All observations, including ones 
at unscheduled visits, will be included in the MAV evaluation and summaries if MAV criteria 
are satisfied.
All clinical laboratory data will be presented in both SI and conventional units in data listings.
7.11.3
Vital Signs
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be used to 
summarize vital sign parameters (body temperature, respiratory rate, systolic BP, diastolic BP, 
and pulse) at baseline, each post-baseline visit, and change from baseline to each post-baseline 
visit for both Parts A and B. Study baseline defined in Section 7.1.1 will be used. Only 
observations within 7 days of the study drug will be included in the tables.
Vital sign MAVs, identified by the criteria defined in Appendix B, will be tabulated. If a subject 
has a MAV for a particular vital sign parameter, all visits for that subject for that parameter will 
be listed. The number and percentage of subjects with at least 1 post-dose markedly abnormal 
vital signs measurement will be summarized. The mapping of the subjects who meet the MAV 
criteria will be listed as a table. All observations, including ones at unscheduled visits, will be 
included in the MAV evaluation and summaries if MAV criteria are satisfied.
All vital signs will be listed in a data listing.
7.11.4
12-Lead ECGs
Descriptive statistics (N, mean, SD, median, minimum, and maximum) of ECG parameters, 
including heart rate, PR interval, RR interval, QRS interval, QT interval, and QTc interval 
(Fridericia’s corrections), will be presented for baseline, each post-baseline visit, and change 
from baseline to each post-baseline visit for both Parts A and B. Study baseline defined in 
Section 7.1.1 will be used. All measurements, including those during unscheduled visits, will be 
provided in data listings, but only the scheduled measurements will be included in the summary. 
Only observations within 7 days of the study drug will be included in the tables. No inferential 
statistics will be presented.
ECG MAVs, identified by the criteria defined in Appendix C, will be tabulated. If a subject has a 
MAV for a particular 12-lead ECG parameter, all visits for that subject for that parameter will be 
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TAK-935-2008
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Statistical Analysis Plan Final 
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listed. The number and percentage of subjects with at least 1 post-dose markedly abnormal 12-
lead ECG measurement will be summarized. The mapping of the subjects who meet the MAV 
criteria will be listed as a table. All observations, including ones at unscheduled visits, will be 
included in the MAV evaluation and summaries.
Overall ECG interpretation category (normal, abnormal not clinically significant, abnormal 
clinically significant, not evaluable) is collected by eCRF at baseline and at each scheduled post-
baseline visit. Shifts in ECG interpretation will be presented as cross-tabulations (baseline versus 
each post-baseline visit) of numbers of subjects with normal, abnormal not clinically significant, 
and abnormal clinically significant interpretations, not evaluable, with missing, if applicable, and 
total categories by each treatment (placebo, TAK-935).
All ECG parameters will be listed in a data listing.
7.12
Interim Analysis 
An unblinded interim analysis will be conducted after all subjects have completed Part A but 
prior to the completion of Part B of the study. An unblinded team not involved in the study 
conduct or the program will perform the unblinded analysis in order not to introduce bias to the 
conduct or analysis of the study. No modification of sample size will be made based on the 
analysis. The investigators and study sites will not have access to the results of the interim 
analysis until the final unblinding of the study.
The interim analysis will include the primary and secondary efficacy analysis, safety summaries, 
as well as descriptive summary statistics of TAK-935 plasma concentration and 24HC for each 
dose regimen based on the data collected during Part A. If the preparation and analysis of PK and 
PD data takes significantly longer than the clinical and safety data, the results can be delivered 
separately. Because this analysis will be conducted at the end of the double-blind period, this 
analysis will be considered as the primary efficacy assessment of TAK-935 on CRPS relative to 
placebo. No alpha spending will be needed.
8.0
REFERENCES
1. Goebel A, Bisla J, Carganillo R, Frank B, Gupta R, Kelly J, et al. Low-dose intravenous 
immunoglobulin treatment for long-standing complex regional pain syndrome: a randomized 
trial. Ann Intern Med 2017;167(7):476-83.
2. Maughan EF, Lewis JS. Outcome measures in chronic low back pain. Eur Spine J 
2010;19(9):1484-94.
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rcial Use Only and Subject to the Applicable Terms of Use


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CCI
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plicable Terms of Use


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Appendix D
PROMIS 29 – PROFILE V2.1 Scoring Tables
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