A Phase 2a, Randomized, Double-Blind Placebo-controlled, Parallel-group Study to Assess the Analgesic Efficacy and Safety of ASP0819 in Patients With Fibromyalgia
Phase: PHASE2
Conditions: Fibromyalgia
Sponsor: Astellas Pharma Global Development, Inc.

Sponsor: APGD
ISN/Protocol 0819-CL-0201
- CONFIDENTIAL -
19 Dec 2016
Astellas
Page 1 of 103
Version 2.0 Incorporating Substantial Amendment 1
A Phase 2a, Randomized, Double-Blind Placebo-controlled,
Parallel-group Study to Assess the Analgesic Efficacy and Safety 
of ASP0819 in Patients with Fibromyalgia
The Field Study
ISN/Protocol 0819-CL-0201
Version 2.0
Incorporating Substantial Amendment 1 [ See Attachment 1]
19 December 2016
IND 127248
Sponsor:
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062
Protocol History:
Version 1.0 [20Oct2016]
-------------------------------------------------------------------------------------------------------------------------
The information contained in this document is supplied as a background for clinical investigations. 
This document contains confidential information which is the intellectual property of Astellas. By 
accepting or reviewing this document, you agree to hold this information in confidence and not copy 
or disclose it to others or use it for unauthorized purposes except (1) as otherwise agreed to in writing; 
(2) where required by applicable law; (3) where disclosure is directly related to the care and safety of
the research participant; and (4) where disclosure of such information is made to a member of the
investigator’s team who agrees to hold this information in confidence.
NCT03056690

Sponsor: APGD
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Table of Contents
I.
SIGNATURES ······················································································ 7
II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL····························10
III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················11
IV.
SYNOPSIS··························································································15
1
INTRODUCTION·················································································32
1.1
Background ····················································································32
1.2
Nonclinical and Clinical Data ·······························································34
1.3
Summary of Key Safety Information for Study Drugs ···································35
1.4
Risk Benefit Assessment ·····································································35
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ··································35
2.1
Study Objective(s) ············································································35
2.1.1
Primary Objectives······································································35
2.1.2
Secondary Objectives···································································35
2.1.3
Exploratory Objectives ·································································35
2.2
Study Design and Dose Rationale···························································36
2.2.1
Study Design·············································································36
2.2.2
Dose Rationale···········································································38
2.3
Endpoints·······················································································39
2.3.1
Primary Endpoints·······································································39
2.3.2
Secondary Endpoints····································································39
2.3.3
Exploratory Endpoints··································································40
3
STUDY POPULATION··········································································41
3.1
Selection of Study Population ·······························································41
3.2
Inclusion Criteria··············································································41
3.3
Exclusion Criteria·············································································43
4
TREATMENT(S)··················································································45
4.1
Identification of Investigational Product(s) ················································45
4.1.1
Study Drug ···············································································45
4.1.2
Comparative Drug·······································································45
4.1.3
Rescue Medication ······································································45
4.2
Packaging and Labeling······································································46

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4.3
Study Drug Handling ·········································································46
4.4
Blinding ························································································47
4.4.1
Blinding Method·········································································47
4.4.2
Confirmation of the Indistinguishability of the Study Drugs ······················47
4.4.3
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking ··················································································47
4.4.4
Breaking the Treatment Code for Emergency ·······································47
4.4.5
Breaking the Treatment Code by the Sponsor ·······································47
4.5
Assignment and Allocation ··································································48
5
TREATMENTS AND EVALUATION························································48
5.1
Dosing and Administration of Study Drug(s) and Other Medication(s)················48
5.1.1
Dose/Dose Regimen and Administration Period ····································48
5.1.2
Increase or Reduction in Dose of the Study Drug(s)································49
5.1.3
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy) ··················································································49
5.1.4
Treatment Compliance··································································51
5.2
Demographics and Baseline Characteristics ···············································51
5.2.1
Demographics············································································51
5.2.2
Medical History··········································································51
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease··············51
5.2.4
Mini-International Neuropsychiatric Interview······································52
5.2.5
Hospital Anxiety and Depression Scale ··············································53
5.3
Efficacy and Pharmacokinetics Assessments··············································53
5.3.1
Daily Average Pain Numerical Rating Scale·········································53
5.3.2
Fibromyalgia Sleep Diary ······························································54
5.3.3
Fibromyalgia Impact Questionnaire Revised ········································54
5.3.4
Patient Global Impression of Change  and Patient Global Impression of 
Severity···················································································54
5.3.5
Neuropathic Pain Symptom Inventory················································55
5.3.6
European Quality of Life-5 Dimensions-5 Levels Questionnaire ·················55
5.3.7
Modified Irritable Bowel Syndrome-Diarrhea Predominant ·······················55
5.3.8
Pharmacokinetics········································································56
5.4
Safety Assessment ············································································56
5.4.1
Vital Signs················································································56
5.4.2
Adverse Events ··········································································56

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5.4.3
Laboratory Assessments································································56
5.4.4
Physical Examination···································································58
5.4.5
Electrocardiogram·······································································59
5.4.6
Colombia Suicide Severity Rating Scale ·············································59
5.5
Adverse Events and Other Safety Aspects ·················································59
5.5.1
Definition of Adverse Events ··························································59
5.5.2
Definition of Serious Adverse Events ················································60
5.5.3
Special Situations········································································60
5.5.4
Criteria for Causal Relationship to the Study Drug ·································61
5.5.5
Criteria for Defining the Severity of an Adverse Event ····························61
5.5.6
Reporting of Serious Adverse Events·················································62
5.5.7
Follow-up of Adverse Events··························································63
5.5.8
Monitoring of Common Serious Adverse Events ···································63
5.5.9
Procedure in Case of Pregnancy·······················································63
5.5.10
Emergency Procedures and Management of Overdose ·····························64
5.5.11
Supply of New Information Affecting the Conduct of the Study··················64
5.6
Test Drug Concentration ·····································································64
5.7
Other Measurements, Assessments or Methods ···········································65
5.7.1
Blood Sample for Future Pharmacogenomics Analysis (Retrospective 
Pharmacogenomics Analysis) (Optional)·············································65
5.7.2
Subject Training Materials ·····························································65
5.8
Total Amount of Blood·······································································65
6
DISCONTINUATION············································································66
6.1
Discontinuation of Individual Subject(s)···················································66
6.2
Discontinuation of the Site···································································66
6.3
Discontinuation of the Study ································································67
7
STATISTICAL METHODOLOGY ···························································67
7.1
Sample Size····················································································67
7.2
Analysis Sets···················································································67
7.2.1
Full Analysis Set ········································································68
7.2.2
Per Protocol Set··········································································68
7.2.3
Safety Analysis Set······································································68
7.3
Demographics and Baseline Characteristics ···············································68
7.3.1
Subject Disposition······································································68

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7.3.2
Previous and Concomitant Medications ··············································68
7.3.3
Medical History··········································································69
7.4
Analysis of Efficacy ··········································································69
7.4.1
Analysis of Primary Endpoint ·························································69
7.4.2
Analysis of Secondary Endpoints ·····················································70
7.4.3
Analysis of Exploratory Endpoints····················································71
7.5
Analysis of Safety·············································································73
7.5.1
Adverse Events ··········································································73
7.5.2
Laboratory Assessments································································73
7.5.3
Vital Signs················································································73
7.5.4
Physical Examination···································································73
7.5.5
Electrocardiograms······································································74
7.5.6
Columbia Suicide Severity Rating Scale ·············································74
7.5.7
Analysis of Pharmacokinetics··························································74
7.6
Protocol Deviations ···········································································74
7.7
Interim Analysis (and Early Discontinuation of the Clinical Study)····················74
7.8
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········74
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················75
8.1
Procedure for Clinical Study Quality Control ·············································75
8.1.1
Data Collection ··········································································75
8.1.2
Electronic Patient Reported Outcomes ···············································75
8.1.3
Specification of Source Documents···················································76
8.1.4
Clinical Study Monitoring······························································76
8.1.5
Direct Access to Source Data/Documents············································76
8.1.6
Data Management ·······································································77
8.1.7
Protocol Deviations ·····································································77
8.1.8
End of Trial in All Participating Countries···········································77
8.2
Ethics and Protection of Subject Confidentiality··········································78
8.2.1
Institutional Review Board/Competent Authorities·································78
8.2.2
Ethical Conduct of the Study···························································78
8.2.3
Informed Consent of Subjects ·························································78
8.2.4
Subject Confidentiality and Privacy···················································79
8.3
Administrative Matters ·······································································80
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ·····80

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8.3.2
Documents and Records Related to the Clinical Study ·····························80
8.3.3
Protocol Amendment and/or Revision················································81
8.3.4
Signatory Investigator for Clinical Study Report····································81
9
QUALITY ASSURANCE········································································82
10
STUDY ORGANIZATION······································································82
10.1
Data Monitoring Committee·································································82
10.2
Other Study Organization ····································································82
11
REFERENCES ····················································································83
12
APPENDICES ·····················································································86
12.1
List of Excluded Concomitant Medications - Excluded Medications with 
Efficacy or Potential Efficacy in Fibromyalgia Pain······································86
12.2
List of Allowed Anti-depressants and Sleep Aids·········································89
12.3
Liver Safety Monitoring and Assessment··················································90
12.4
Common Serious Adverse Events···························································93
12.5
Retrospective Pharmacogenomics Sub-Study ·············································94
12.6
Questionnaires·················································································96
13
ATTACHMENT 1:  SUBSTANTIAL AMENDMENT 1 ··································97
14
COORDINATING INVESTIGATOR’S SIGNATURE·································· 102
15
SPONSOR’S SIGNATURES·································································· 103

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I.
SIGNATURES
1. SPONSOR’S SIGNATURES
Required signatures (e.g., Protocol authors and contributors, etc.) are located in [Section 15
Sponsor’s Signatures]; located at the end of this document.

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2. COORDINATING INVESTIGATOR’S SIGNATURE 
The Coordinating Investigator’s signature can be found in [Section 14 Coordinating 
Investigator’s Signature].

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3. INVESTIGATOR’S SIGNATURE
A Phase 2a, Randomized, Double-Blind, Placebo-controlled, Parallel-group Study 
to Assess the Analgesic Efficacy and Safety of ASP0819 in Patients with 
Fibromyalgia
ISN/Protocol 0819-CL-0201
Version 2.0 Incorporating Substantial Amendment 1
19 December 2016
I have read all pages of this clinical study protocol for which Astellas is the Sponsor. I agree to 
conduct the study as outlined in the protocol and to comply with all the terms and conditions set out 
therein. I confirm that I will conduct the study in accordance with International Council for
Harmonisation (ICH) Good Clinical Practice (GCP) guidelines and applicable local regulations. I will 
also ensure that subinvestigator(s) and other relevant members of my staff have access to copies of 
this protocol and the ICH GCP guidelines to enable them to work in accordance with the provisions 
of these documents.
Principal Investigator:
Signature:
Printed Name:-------------------------------------------------------------------
Date (dd Mmm yyyy)
<Insert name and qualification of the Investigator>
Address:

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III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
ACR
American College of Rheumatology
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase (GPT)
ANCOVA
Analysis of covariance
anti-HAV (IgM)
Hepatitis A virus antibodies (immunoglobulin M)
anti-HCV
Hepatitis C virus antibodies
APGD
Astellas Pharma Global Development, Inc.
AST
Aspartate aminotransferase (GOT)
ATC
Anatomical Therapeutic Chemical
AUC
Area under the concentration-time curve
BMI
Body mass index
BOCF
Baseline observation carried forward
CCSI
Company core safety information
CI
Confidence interval
Cmax
Maximum concentration
CMSI
Complex Medical Symptoms Inventory
CPAP
Continuous positive airway pressure
CRF
Case report form
CRO
Contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP3A
Cytochrome P450 3A
DBP
Diastolic blood pressure
DSM-V
Diagnostic and Statistical Manual of Mental Disorders
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EOS
End of study
EOT
End of treatment
ePRO
Electronic patient reported outcome
EQ-5D-5L
European Quality of Life-5 Dimensions-5 Levels
EU
European Union
FAS
Full analysis set
FDA
Federal Drug Administration
FIQ
Fibromyalgia Impact Questionnaire
FIQR
Fibromyalgia Impact Questionnaire Revised
FMSD
Fibromyalgia Sleep Diary
GABAB
y-aminobutyric acid
GCP
Good clinical practice
GMP
Good manufacturing practices
HADS
Hospital Anxiety and Depression Scale
HBsAg
Hepatitis B surface antigen
HIPAA
Health Insurance Portability and Accountability Act
IAP
Interim Analysis Plan
IB
Investigator’s brochure

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Abbreviations
Description of abbreviations
ICD-10
International Statistical Classification of Diseases and Related Health Problems
ICF
Informed consent form
ICH 
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IDMC
Independent Data Monitoring Committee
IND
Investigational New Drug
INR
International normalized ratio
IUD
Intrauterine device
IUS
Intrauterine system
IRB
Institutional review board
ISN
International study number
LA-CRF
Liver abnormality case report form
LFT
Liver function tests
LOAEL
Lowest-observed-adverse-effect level
LOCF
Last observation carried forward
mBOCF
Modified Baseline Observation Carried Forward
M.I.N.I.
Mini-International Neuropsychiatric Interview
MedDRA
Medical Dictionary for Regulatory Activities
mIBS-D
Modified irritable bowel syndrome - diarrhea predominant
MMRM
Mixed model repeated measures
NDA
New Drug Application
NPSI
Neuropathic Pain Symptom Inventory
NRS
Numerical rating scale
NSAID
Nonsteroidal anti-inflammatory drug
PGIC
Patient global impression of change
PGIS
Patient global impression of severity
PGx
Pharmacogenomics
PI
Prediction interval
PKAS
Pharmacokinetic analysis set
PPS
Per protocol set
PRO
Patient reported outcome
qd
Quaque die (once daily)
QT
time from electrocardiogram Q wave to the end of the T wave
SAE
Serious adverse event
SAF
Safety analysis set
SBP
Systolic blood pressure
SOP
Standard operating procedure
SS
Symptom severity
SUSAR
Suspected unexpected serious adverse reactions
TBL
Total bilirubin level
TEAE
Treatment emergent adverse event 
tmax
Time of maximum concentration 
TSH
Low thyroid stimulating hormone
ULN
Upper limit of normal
US
United States
WPI
Widespread pain index

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Definition of Key Study Terms
Terms
Definition of terms
Baseline
Assessments of subjects as they enter a trial before they receive any treatment. 
Baseline Diary Run-
In
7-day period in which subject completes numerical rating scale (NRS) and 
Fibromyalgia Sleep Diary (FMSD) on handheld device daily beginning at 
Day -7 through Day -1.
Double-Blind
The study subjects, investigator(s), site staff and Astellas study team will be 
blinded to treatment.
Early
Discontinuation
(ED)
The act of concluding participation prior to completion of all protocol-required 
elements in a trial by an enrolled subject. Four categories of discontinuation 
are distinguished as follows: a) dropout: Active discontinuation by a subject 
(also a noun referring to such a discontinued subject); b) Investigator-initiated 
discontinuation (e.g., for cause); c) loss to follow-up: cessation of participation 
without notice or action by the subject; d) Sponsor-initiated discontinuation. 
Note that subject discontinuation does not necessarily imply exclusion of 
subject data from analysis. “Termination” has a history of synonymous use, 
but it is now considered non-standard.
Endpoint 
Variable that pertains to the efficacy or safety evaluations of a trial.
Enroll
The process of registering or entering a subject into a clinical trial. NOTE: 
Once a subject has signed the informed consent form (ICF), the clinical trial 
protocol applies to the subject. 
End of Study
(EOS)
End of study for each subject has occurred when the final protocol-defined 
assessment has been completed. In this study, the last protocol defined 
assessment is approximately 4 weeks after last study drug dose.
End of Treatment 
(EOT)
The date the last dose of study drug was taken by the enrolled subject.
Electronic Patient
Reported Outcomes
(ePRO)
An ePRO is a patient-reported outcome that is collected by electronic methods.
Follow-up Period
The weeks following the final dose of study drug for all subjects. This includes 
a Follow-up visit and an End of Study Phone Call.
Independent Data 
Monitoring
Committee
(IDMC)
The Independent Data Monitoring Committee (IDMC) is responsible for the 
interim futility evaluation of efficacy data defined in the IDMC Charter. 
Participants in the IDMC include, but may not be limited to an Independent 
Astellas Statistician who is not on the study team and does not communicate 
with study team or Site staff. The IDMC will evaluate unblinded data and 
provide conclusion of futility analysis to Astellas Management.
Intervention
The drug, device, therapy or process under investigation in a clinical study that 
is believed to have an effect on outcomes of interest in a study. (e.g., health-
related quality of life, efficacy, safety and pharmacoeconomics). 
Randomization
The process of assigning trial subjects to treatment or control groups using an 
element of chance to determine assignments in order to reduce bias.
Randomization will occur after predose assessments and eligibility criteria 
have been confirmed at Visit 3.

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Terms
Definition of terms
Screening
A process of active consideration of potential subjects for enrollment in a trial.
Screen failure
Potential subject who did not meet 1 or more criteria required for participation 
in a trial.
Screening period
Period of time before entering the treatment period, usually from the time 
when a subject signs the ICF until just before the test drug or comparative drug 
is given to a subject.
Study period
Period of time from the first site initiation date to the last site completing the 
study.
Treatment Period
Time from Day 1, after first study drug administration and through time of last 
study drug dose. Period of time where major interests of protocol objectives 
are observed, and where the test drug or placebo is given to a subject, and 
continues until the last assessment after completing administration of the test 
drug or placebo.
Washout
Time (post review of safety laboratory assessments) when a subject 
discontinues use of prohibited medications, as medically indicated and based 
upon the Investigator’s recommendation, to allow for medication to be 
eliminated from the body. Completed prior to Diary Run-In.

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IV.
SYNOPSIS
Date and Version No of Protocol Synopsis:
19 December 2016, Version 2.0
Sponsor:  
Astellas Pharma Global Development Inc (APGD)
Protocol Number:
0819-CL-0201
Name of Study Drug:
ASP0819
Phase of Development:  
2a
Title of Study:  
A Phase 2a, Randomized, Double-Blind, Placebo-controlled, Parallel-group Study to Assess the 
Analgesic Efficacy and Safety of ASP0819 in Patients with Fibromyalgia
Planned Study Period: 
From 1Q2017 to 3-4Q2018 
Study Objective(s):
The objectives of the study, conducted in patients with fibromyalgia, are the following:
Primary Objectives

Assess analgesic efficacy of ASP0819 relative to placebo. 

Assess the safety and tolerability of ASP0819 relative to placebo.
Secondary Objectives 

Assess treatment differences in physical function of ASP0819 relative to placebo.

Assess the improvements in overall subject status (e.g., fibromyalgia symptoms and global 
functioning) of ASP0819 relative to placebo. 
Exploratory Objectives

Assess the time course of efficacy of ASP0819. 

Assess treatment differences in sleep disturbance.

Assess treatment differences in depression. 

Assess treatment differences in quality of life.

Assess the use of rescue medication.

Assess treatment differences in responder rate based on composite endpoint definition. 

Assess treatment differences in gastrointestinal symptoms.

Assess relationship between gastrointestinal symptoms and analgesic effect.

Assess relationship between neuropathic pain symptoms and analgesic effect.
Planned Total Number of Study Centers and Location(s):  
Up to approximately 35 sites in 1 country (United States only)
Study Population:  
Male and female subjects between 18 and 80 years of age with fibromyalgia
Number of Subjects to be Enrolled and Randomized:  
Approximately 323 subjects are planned to be screened for 178 randomized subjects (89 per arm) 
(45% screen fail rate).

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Study Design Overview:  
This is a phase 2a, randomized, double-blind, placebo-controlled parallel group study to assess 
analgesic efficacy and safety of ASP0819 in subjects with fibromyalgia. 
The study will consist of the following study periods:

Screening period (Day -42 to Day -1) 
Up to 42 days, which includes the completion of screening procedures (Visit 1), wash-out of 
prohibited medications (if applicable), and a 7-day Baseline Diary Run-In. The wash-out of 
prohibited medications should be completed prior to the initiation of the Baseline Diary 
Run-In. The Baseline Diary Run-In may be extended up to 2 days if necessary in the 
Investigator’s opinion. In general, the Screening period should not exceed 42 days. The 
Investigator should contact the medical monitor if there are circumstances that would cause 
the subject to exceed 42 days.

Double-blind randomized treatment period (Day 1 to Day 57 [End of Treatment (EOT)]) 
Eight-weeks of treatment with study drug and site visits at Day 1, 15, 29 and 57.

Follow-up period (Day 58 to Day 85 [End of Study (EOS)]) 
Includes a follow-up site visit on Day 71 and an (EOS) phone call on Day 85.
Screening Period: 
After signing the informed consent, screening procedures for the subject will start (Visit 1). 
Subjects will be required to meet both the 1990 and 2010 American College of Rheumatology 
(ACR) criteria for fibromyalgia. The Investigator or other qualified individual at the site will 
confirm the diagnosis of fibromyalgia. 
Subjects who meet the eligibility criteria [see Section 3.2 Inclusion Criteria] will be instructed, if 
medically appropriate, to wash-out of any prohibited medications via phone call. At Visit 2 all 
subjects who continue to meet eligibility criteria will be provided with an electronic diary (e-
diary). Subjects will enter a 1-week Baseline Diary Run-In, and during this period, they will 
record their daily average pain score (0 - 10 Numerical Rating Scale [NRS]) and sleep quality 
information with the Fibromyalgia Sleep Diary (FMSD) in the e-diary. They will receive 
instructions regarding its use and begin entering daily scores. Upon awakening, subjects are to rate 
their sleep quality during the previous night using the e-diary. Each evening before bed, subjects 
are to rate their average pain during the previous 24 hours using the e-diary. Subjects will need to 
have a mean daily average pain score ≥4 and ≤9, and meeting pre-specified criteria for daily 
average pain scores.
A subject who does not meet the required mean daily average pain score or who is not compliant 
with e-diary entries by completing at least 5 of 7 days in the baseline run-in, will be considered a 
screen failure and will not be allowed to repeat the pain assessments nor rescreen for the study.
After confirmation of eligibility at Visit 3 (Randomization), subjects who meet the mean daily 
average pain score eligibility requirements at this visit will be randomized. For subjects that meet 
the entry criteria at Visit 3 (Randomization), additional baseline assessments will be obtained (see 
Schedule of Assessments). 
Double-Blind Randomized Treatment Period (treatment period):
Subjects will enter the treatment period and will be randomized in a 1:1 ratio to receive either 
ASP0819 or placebo once per day for a period of 8 weeks. Acetaminophen may be used as rescue 
therapy for intolerable pain due to fibromyalgia during the baseline period and in all subsequent 
study periods (see rescue medication section). Nonsteroidal anti-inflammatory drugs (NSAIDs) 
may be used (with the exception of celecoxib) as needed for non-fibromyalgia pain (e.g., 
headache).

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Throughout the treatment period, beginning on Day 1 (Randomization) through Visit 6/Week 8, 
subjects will record all daily average pain scores (NRS) and any acetaminophen use in the e-diary. 
Sleep quality scores (FMSD) will be recorded through Visit 6/Week 8. Subjects will take study 
drug once per day (qd). Subjects randomized to ASP0819 will receive 15 mg (3 capsules of 5 mg 
each). In order to maintain the study blind, ASP0819 and placebo treated subjects will receive 
matching capsules. 
During the treatment period, subjects will return to the clinic per schedule for safety and efficacy 
procedures (see Schedule of Assessments for details). Subjects who do not complete the treatment 
period will be requested to complete EOT visit procedures.
Follow-up Period:
Subjects are encouraged to abstain from any concomitant medications for the treatment of pain 
prior to Visit 7/Week 10. Rescue medication is allowed during the follow-up period. Subjects will 
continue to enter their daily average pain score (NRS), sleep quality scores (FMSD) and 
acetaminophen use into their e-diary and return diaries at Visit 7/Week 10. All subjects will return 
to the site for a follow-up visit at Day 71, 2 weeks following the EOT visit (Day 57). A follow-up 
safety phone call will take place approximately 4 weeks post study drug discontinuation 
(Day 85/EOS).
Inclusion/Exclusion Criteria: 
Inclusion
A subject is eligible for the study if all of the following apply:
1.
Institutional Review Board (IRB)-approved written informed consent and privacy language as 
per national regulations (e.g., Health Insurance Portability and Accountability Act [HIPAA]
Authorization for United States [US] sites) must be obtained from the subject prior to any 
study-related procedures (including withdrawal of prohibited medication, if applicable).
2.
A male or female subject between 18 and 80 years of age at the signing of the informed 
consent. 
3.
Subject has a body mass index (BMI) ≤45 kg/m2.
4.
Female subject must either:
Be of nonchildbearing potential:
o Postmenopausal (defined as at least 1 year without any menses) prior to Screening, 
or, 
o Documented as surgically sterile (e.g., hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy).
Or, if of childbearing potential:
o Agree not to try to become pregnant during the study and for 28 days after the final 
study drug administration,
o Have a negative blood pregnancy test at Screening and negative urine test on Day 1,
and
o If heterosexually active, agree to consistently use 1 form of highly effective birth 
control* starting at Screening and throughout the study period and for 28 days after 
the final study drug administration.
5.
Female subject must agree not to breastfeed at Screening and throughout the study period and 
for 28 days after the final study drug administration.
6.
Female subject must not donate ova starting at Screening, throughout the study period, and for 
28 days after the final study drug administration.

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7.
Male subject must not donate sperm starting at Screening and throughout the study period and
for 28 days after the final study drug administration.
8.
Male subject with a partner of child-bearing potential, or a pregnant or breastfeeding partner(s)
must agree to remain abstinent or use a condom throughout the study period and for 28 days 
after the final study drug administration.
9.
Subject meets the ACR 1990 fibromyalgia diagnostic criteria at Screening: 
Widespread pain for at least 3 months, defined as the presence of all of the following:
o pain on right and left sides of the body,
o pain above and below the waist, and
o pain in the axial skeleton (cervical spine or anterior chest or thoracic spine or low 
back) must be present.
Pain in at least 11 of 18 tender point sites on digital palpation.
o Digital palpation should be performed with an approximate force of 4 kg. 
10. Subject meets the ACR 2010 fibromyalgia diagnostic criteria at Screening:
Widespread pain index (WPI) ≥7 and symptom severity (SS) scale score ≥5 or WPI 3-6
and SS scale score ≥9.
Symptoms have been present at a similar level for at least 3 months.
The subject does not have a disorder that would otherwise explain the pain. 
11. Subject has a pain score ≥ 4 on the revised fibromyalgia impact questionnaire (FIQ) pain item 
at Screening.
12. Subject is compliant with daily pain recordings during the Baseline Diary Run-In period, as 
defined by the completion of a minimum of 5 of 7 daily average pain ratings and agrees to 
complete daily diaries throughout the duration of the study.
13. Subject has a mean daily average pain score ≥4 and ≤9 on an 11-point 0 to 10 NRS as 
recorded in the subject e-diary during the Baseline Diary Run-In period, and meeting pre-
specified criteria for daily average pain scores.
14. Subject agrees to use only acetaminophen as rescue medication for fibromyalgia pain 
throughout the course of the trial (up to 1000 mg per dose and not to exceed 3000 mg/day). 
15. Subject agrees not to initiate or change any non-pharmacologic interventions (including 
normal daily exercise routines, chiropractic care, physical therapy, psychotherapy, and 
massage therapy) during the course of the study. Non-pharmacologic interventions must be 
stable for a minimum of 30 days prior to Screening. Subject agrees to maintain usual level of 
activity for the duration of the study.
16. Subject is capable of completing study assessments and procedures, in the opinion of the 
Investigator.
17. Subject agrees not to participate in another interventional study from Screening through the 
EOS visit.
* Highly effective forms of birth control include the following:
Consistent and correct usage of established hormonal contraceptives that inhibit 
ovulation,
Established intrauterine device (IUD) or intrauterine system (IUS),
Vasectomy (A vasectomy is a highly effective contraception method if the absence of 
sperm has been confirmed. If not, an additional highly effective method of contraception 
should be used).
Male is sterile due to a bilateral orchiectomy.

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NOTE: The reliability of sexual abstinence for male and/or female subject enrollment 
eligibility needs to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the subject. The investigator is responsible for confirming the 
subject is continuing to use the protocol-stated contraception requirements.
Waivers to the inclusion criteria will NOT be allowed.
Exclusion  
Subject will be excluded from participation if any of the following apply:
1.
Subject has received an investigational therapy within 28 days or 5 half-lives, whichever is 
longer, prior to Screening. 
2.
Subject has had no meaningful improvement, in the Investigator’s opinion, from 2 or more 
prior treatments (commercially available) for fibromyalgia (in at least 2 pharmacologic 
classes). 
3.
Subject has had known hypersensitivity or intolerance to the use of acetaminophen or
associated formulation components; known hypersensitivity to the formulation components 
of ASP0819.
4.
Subject has pain due to diabetic peripheral neuropathy, post-herpetic neuralgia, traumatic 
injury, prior surgery, complex regional pain syndrome, or other source of pain that, in the 
Investigator’s opinion, would confound or interfere with the assessment of the subject’s 
fibromyalgia pain or require excluded therapies during the subject’s study participation. 
5.
Subject has infectious or inflammatory arthritis (e.g., rheumatoid arthritis, ankylosing 
spondylitis, psoriatic arthritis or gout), autoimmune disease (e.g., systemic lupus 
erythematosus), or other widespread rheumatic disease other than fibromyalgia.
6.
Subject has a current, untreated moderate or severe major depressive disorder as assessed by 
the Mini-International Neuropsychiatric Interview (M.I.N.I.). Subject with current, treated 
major depressive disorder can be included provided that, in the investigator’s opinion, it is 
without clinically significant changes in symptoms while on the same dose of a protocol 
allowed antidepressant for greater than 60 days prior to Screening.
7.
Subject has initiated any non-pharmacologic interventions for the treatment of fibromyalgia or 
depression within 30 days prior to Screening or during the Screening period. 
8.
Subject has a history of any psychotic and/or bipolar disorder as assessed by the M.I.N.I.
9.
Subject has a Hospital Anxiety and Depression Scale (HADS) score > 14 on the Depression 
subscale at Screening or at the time of Visit 3 (Randomization).
10. Subject has a history of suicide attempt or suicidal behavior within the last 12 months, or has 
suicidal ideation within the last 12 months (a response of “yes” to questions 4 or 5 on the 
suicidal ideation portion of the Columbia-Suicide Severity Rating Scale [C-SSRS]), or who is 
at significant risk to commit suicide, as assessed by the investigator at Screening and at the 
time of Visit 3 (Randomization).
11. Subject has clinically significant abnormalities in clinical chemistry, hematology, or 
urinalysis, or a serum creatinine > 1.5 times the upper limit of normal (ULN) at Screening. 
These assessments may be repeated once, after a reasonable time period at the investigator’s 
discretion (but within the Screening period).

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12. Subject has aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 1.5 times 
the upper limit of the reference range at Screening. These assessments may be repeated once, 
after a reasonable time period at the Investigator’s discretion (but within the Screening
period).
13. Subject has a positive test for hepatitis B surface antigen (HBsAg), hepatitis A virus antibodies 
(immunoglobulin M) (anti-HAV [IgM]), or hepatitis C virus antibodies (anti-HCV)) at 
Screening or has history of a positive test for human immunodeficiency virus type 1(HIV-1) 
and/or type 2 (HIV-2). 
14. Subject has a resting systolic blood pressure (SBP) > 180 mmHg or < 90 mmHg, and/or a 
resting diastolic blood pressure (DBP) > 100 mmHg at Screening. These assessments may be 
repeated once after a reasonable time period at the investigator’s discretion (but within the 
Screening period).
15. Subject has a clinically significant abnormality on 12-lead electrocardiogram (ECG) at 
Screening or Visit 3 (Randomization). If the ECG is abnormal, based on the investigator’s 
judgment, an additional ECG can be carried out. If this also gives an abnormal result, the
subject must be excluded.
16. Subject has a history of myocardial infarction (within 6 months of Screening), unexplained 
syncope, cardiac arrest, unexplained cardiac arrhythmias or torsade de pointes, structural heart 
disease or a family history of Long QT Syndrome.
17. Subject has evidence of any clinically significant, uncontrolled cardiovascular, 
gastrointestinal, endocrinologic (low thyroid stimulating hormone [TSH], but euthyroid is 
allowed), hematologic, hepatic, immunologic, infectious, metabolic, urologic, pulmonary 
(including obstructive sleep apnea not controlled by a continuous positive airway pressure 
[CPAP] device), neurologic, dermatologic, psychiatric, renal and/or other major disease 
(exclusive of fibromyalgia), as assessed by the investigator.
18. Subject has planned surgery during the study participation.
19. Subject has an active malignancy or a history of malignancy (except for treated non-melanoma 
skin cancer) within 5 years of Screening.
20. Subject has a positive drug or alcohol test at Screening, Baseline Diary Run-In or prior to 
Randomization. However, a positive test for tetrahydrocannabinol (THC) and/or opioids is 
allowed at the Screening visit, but must be confirmed negative prior to Baseline Diary Run-In
and Randomization. 
21. Subject has a current or recent (within 12 months of Screening) history of a substance use 
disorder including cannabinoid and/or alcohol abuse disorder. Patient has used opioids for pain 
for more than 4 days during the week preceding the Screening visit.
22. Subject is currently using protocol-specified prohibited medications and is unable to wash-out 
[see Section 5.1.3 for Concomitant Medication Restrictions].
23. Subject has filed or is awaiting judgment on a disability claim or has any pending worker’s 
compensation litigation or related monetary settlements. 
24. Subject has any condition which, in the investigator’s opinion, makes the subject unsuitable 
for study participation.
25. Subject is an employee of the Astellas Group, the Contract Research Organization (CRO) 
involved, or the investigator site personnel directly affiliated with this study and/or their 
immediate families (spouse, parent, child, or sibling, whether biological or legally adopted). 
Waivers to the exclusion criteria will NOT be allowed.

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Investigational Product(s):
ASP0819 15 mg
Dose(s):  
15 mg/3 capsules of 5 mg each
Mode of Administration:
As a single oral dose to be taken preferably in the morning with or without food.
Comparative Drug(s):
Matching placebo for ASP0819 capsules.
Dose(s):
3 placebo capsules to match ASP0819 capsules.
Mode of Administration:
As a single oral dose to be taken preferably in the morning with or without food.
Rescue Therapy: 
If a subject experiences intolerable pain due to fibromyalgia during the baseline, treatment or 
follow-up periods, the subject should be instructed to use acetaminophen (for non-fibromyalgia 
pain, NSAIDs may be used as needed, refer to [Section 5.1.3 Concomitant medication]). 
Subjects are instructed to document all acetaminophen use in the e-diary under rescue medication.
Dose(s):
The maximum amount of acetaminophen is up to 1000 mg per dose, not to exceed 3000 mg/day.
Mode of Administration:
Oral
Concomitant Medication Restrictions or Requirements:
Medications taken for fibromyalgia during the 12 months prior to Screening and other medication 
taken 28 days prior to the Screening visit and up to the first dose of study medication (treatment 
period) will be documented in the appropriate case report form (CRF) as prior medication. 
Subjects taking prohibited medications who are willing to discontinue these medications as 
medically indicated and based upon the investigator’s recommendation, may wash-out over a 
period of 5 half-lives on a schedule determined by the investigator. 
Medications taken after the first dose of study medication and up to EOS will be documented on 
the appropriate CRF as concomitant medication. 
Prior and concomitant medications to be documented include but are not limited to: vitamins, 
herbal remedies (e.g., St. John’s wort, valerian), OTCs and prescription medications. Any 
medications taken for treatment of pain symptoms will be documented as such on the CRF.
Subjects are instructed not to take any concomitant medication without first consulting the 
investigator or study coordinator (SC) throughout the duration of the study.
Concomitant Medication for Treatment of Non-Fibromyalgia Pain Symptoms:
NSAIDs will be allowed (with the exception of celecoxib), as needed, for treatment non-
fibromyalgia pain, such as headache.

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Prohibited Therapies:
Concomitant use of the following medications, therapies or surgical procedures could influence 
the evaluation of the study drug’s efficacy and safety and are prohibited throughout the study 
(wash-out through the EOS):
●
Medications that may have efficacy in reducing pain in fibromyalgia (except for allowed 
rescue medication), are as follows: gabapentinoids, antidepressants (except for selective 
serotonin reuptake inhibitors), ketamine, y-aminobutyric acid (GABAB) receptor agonists 
(including sodium oxybate), opioids, celecoxib, chronic non-narcotic analgesics (with the 
exception of low dose aspirin for cardioprophylaxis, up to 325 mg daily) and topical pain 
medications.
●
Medications that are sensitive Cytochrome P450 3A (CYP3A) substrates or CYP3A 
substrates that have a narrow therapeutic range. 
●
Use of cannabinoids from the Screening visit and throughout the study. 
●
Procedures that may have efficacy in reducing pain in fibromyalgia (e.g., nerve block, 
iontophoresis, laser therapy, acupuncture, tender point injections, dry needle injections, spinal 
cord stimulation therapy and transcutaneous electrical nerve stimulation).
●
Hypnotics, other than those specified with restrictions, are listed in the section below, 
Permitted Medications.
●
Tranquilizers, sedating antihistamines (non-sedating antihistamines are permitted), 
benzodiazepines for sedative, anxiolytic, or sleep aid. In contrast, non-benzodiazepines such 
as zolpidem are allowed for insomnia as discussed in the Permitted Medications list below.
Permitted Medications:
This list is not all inclusive and the Medical Monitor should be contacted to discuss medications 
not listed below.
●
The following serotonin reuptake inhibitors will be allowed if the patient is on a stable dose 
60 days prior to Screening and no changes are anticipated during the course of the study: 
sertraline, paroxetine, fluoxetine, citalopram, escitalopram, fluvoxamine, vilazodone and 
vortioxetine. 
●
The following medications will be allowed if they are stable for at least 30 days prior to 
Screening and no additional medication is taken for insomnia: zolpidem up to10 mg, 
eszopiclone up to 1 mg, zaleplon up to 10 mg, zopiclone up to 2 mg and melatonin for sleep.
●
Allowed stable medications (i.e., stable dose 30 days prior to Screening and with no changes 
anticipated during the course of the study): anti-diabetic medications, anti-hypertensive 
medications, non-sedating antihistamines, lipid-lowering agents, asthma medications, low 
dose aspirin for cardioprophylaxis, non-sedating treatments for allergic rhinitis, triptans, 
multivitamins, short-term use of nasal, inhaled and topical corticosteroids.
●
NSAIDs will be allowed (with the exception of celecoxib), as needed, for non-fibromyalgia 
pain, such as headache. However, chronic use of NSAIDs is not allowed (with the exception 
of low dose aspirin for cardioprophylaxis, up to 325 mg daily)
Permitted Non-Medication Therapy:
The following therapies must be stable for at least 30 days prior to Screening and with no changes 
anticipated during the course of the study: exercise routines, chiropractic care, physical therapy, 
psychotherapy and massage therapy.

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Duration of Study and Treatment:  
Subjects will be treated for a period of up to 8 weeks. Total study duration for a subject is 
approximately 18 weeks, including a Screening period of up to 6 weeks, an 8-week double-blind 
treatment period, and a 4-week follow-up period.
Endpoints for Evaluation:  
Primary Efficacy
●
Change from baseline to Week 8 in mean daily average pain score assessed by NRS 
(0 to 10 scale) in the subject’s daily e-diary.
Secondary Efficacy
●
Subject’s response defined as achieving ≥ 30 % reduction from baseline to Week 8 and EOT 
in mean daily average pain score assessed by NRS (0 to 10 scale) in the subject’s daily diary.
●
Subjects response defined as achieving ≥ 50 % reduction from baseline to Week 8 and EOT 
in mean daily average pain score assessed by NRS (0 to 10 scale) in the subject’s daily diary.
●
Change from baseline to Weeks 2, 4, 8, and EOT in the FIQR Physical Function, Symptoms, 
and Overall Impact subscales.
●
Overall subject improvement assessed by Patient Global Impression of Change (PGIC) at 
Weeks 2, 4, 8, and EOT. 
Exploratory Efficacy
Treatment Period
●
Change from baseline to Weeks 1, 2, 3, 4, 5, 6, 7 and EOT in mean daily average pain score. 
●
Subject’s response defined as achieving various reduction levels (> 0%, ≥ 10%, ≥20%, 
≥40%, ≥ 60%, ≥ 70%, ≥ 80%, ≥ 90%, 100%) from baseline to Week 8 and EOT in mean 
daily average pain score assessed by NRS (0 to 10 scale) in the subject’s daily diary.
●
Change from baseline to Weeks 2, 4, 8 and EOT in FIQR Total Score. 
●
Change from baseline to Weeks 2, 4, 8 and EOT in PGIS.
●
Subject’s response defined as PGIC of very much or much improved at Week 8 and EOT.
●
Subject’s response defined as achieving ≥ 30 % reduction from baseline in FIQR total score 
at Week 8 and EOT. 
●
Subject’s composite pain response defined as achieving ≥ 30% reduction from baseline in 
mean daily average pain score and PGIC of very much or much improved at Week 8 and 
EOT. 
●
Subject’s composite syndrome response defined as achieving ≥ 30% reduction from baseline 
in mean daily average pain score and PGIC of very much or much improved and ≥30% 
reduction from baseline in FIQR total score at Week 8 and EOT.
●
Change from baseline to Weeks 1, 2, 3, 4, 5, 6, 7, 8 and EOT in daily in the FMSD, which 
captures all critical sleep disturbance features of fibromyalgia (8 items).
●
Change from baseline to Week 8 and EOT in the HADS depression subscale.
●
Change from baseline to Week 8 and EOT in European Quality of Life-5 Dimensions-
5 Levels (EQ-5D-5L)  
●
Proportion of days with rescue medication use at Weeks 1, 2, 3, 4, 5, 6, 7, 8 and EOT.
●
Incidence of subjects using rescue medication at Weeks 1, 2, 3, 4, 5, 6, 7, 8 and EOT.
●
Average daily dosage of rescue medication at Weeks 1, 2, 3, 4, 5, 6, 7, 8 and EOT.

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●
Change from baseline to Weeks 2, 4, 8 and EOT in Modified Irritable Bowel Syndrome -
Diarrhea Predominant (mIBS-D) Symptom Summary Score and abdominal pain, stomach 
pain, abdominal cramps, abdominal pressure, and bloating as assessed by the mIBS-D Daily 
Symptom Diary. 
●
Change from baseline to Week 8 and EOT in neuropathic pain symptoms as assessed by the 
Neuropathic Pain Symptom Inventory (NPSI).
Follow-Up Period
●
Change from baseline and EOT to Week 10 in mean daily average pain score. 
●
Change from baseline and EOT to Week 10 in FIQR Physical Function subscale, Symptoms 
subscale, Overall Impact subscale and total score.
●
Overall patient improvement assessed by PGIC to Week 10.
●
Change from baseline and EOT to Week 10 in PGIS.
●
Patient’s response defined as achieving ≥ 30 % reduction from baseline to Week 10 in mean 
daily average pain score assessed by NRS (0 to 10 scale) in the patient’s daily diary.
●
Patient’s response defined as achieving ≥ 50 % reduction from baseline to Week 10 in mean 
daily average pain score assessed by NRS (0 to 10 scale) in the patient’s daily diary.
●
Change from baseline to Week 10 in EQ-5D-5L. 
●
Proportion of days with rescue medication use at Week 10.
●
Incidence of patients using rescue medication at Week 10.
●
Average daily dosage of rescue medication at Week 10.
Safety and Tolerability Endpoints
●
Treatment-emergent adverse events (TEAEs)/serious adverse events (SAEs) from Screening
until EOS.
●
Safety laboratory tests at Weeks 2, 4, 8 and 10.
●
Vital sign measurements at Weeks 2, 4, 8 and 10.
●
12-lead ECG parameters at Weeks 8 and 10.
●
Physical examination at Weeks 8 and 10.
●
C-SSRS (evaluation of suicidal ideation and behavior) at Weeks 2, 4, 8 and 10.
Statistical Methods:
Sample size justification: 
The sample size calculations are based on the primary efficacy endpoint of change from baseline 
to Week 8 in mean daily average pain NRS. A meta-analysis of the change from baseline in mean 
daily average pain NRS for pregabalin or duloxetine vs placebo in studies for fibromyalgia 
indicated an effect size of approximately 0.30.
Using an effect size of 0.39 (30% larger than the meta-analysis result) for the primary efficacy 
endpoint for the comparison of ASP0819 vs placebo, 84 subjects in the ASP0819 and placebo 
groups would be required to provide 80% power to demonstrate statistical significance using a 
1-sided 5% significance level (based on the assumption of normally distributed data, and taking 
into account the interim analysis for futility).
The total number of subjects required for the analysis would be 168 (84:84 subjects in ASP0819: 
placebo). Assuming approximately 5% of randomized subjects will not contribute to the analysis, 
and then a total of 178 subjects would be required for randomization using a 1:1 randomization 
ratio (89:89) subjects for the ASP0819 group and placebo group.

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Efficacy:
The primary endpoint is the change from baseline to Week 8 in the mean daily average pain NRS. 
The baseline mean daily average pain score will be derived from the daily average pain scores 
(based on the daily NRS recorded in the 7 days before the first day of dosing). The primary 
analysis population will be the Full Analysis Set (FAS), which will include all randomized 
subjects who received at least 1 dose of study medication. Unless otherwise stated, all assessments 
of statistical significance will be one-sided at the 5% significance level, and as such one-sided p-
values will be shown.
The primary analysis for the primary endpoint of change from baseline to Week 8 in the mean 
daily average pain NRS will use a mixed model repeated measures (MMRM) analysis, where the 
model will include the effects for treatment group, center (pooled where necessary), time (study 
Week 1 to 8) and treatment-by-time interaction, as well as the covariates of baseline mean daily 
average pain NRS and baseline pain-by-treatment interaction and subject as a random effect. The 
unconstrained between-time-point covariance structure will be used. This analysis will utilize 
observed data, and there will be no imputation for missing data. Least squares estimates for the 
primary endpoint will be shown for both treatment groups, and for the treatment comparisons of 
ASP0819 vs placebo (together with 2-sided 90% confidence intervals [CI]). A one-sided 5% 
significance level will be used for the comparison of ASP0819 vs placebo. This analysis will also 
display the same estimates for the exploratory endpoints of change from baseline to each Week
from Week 1 to 7 in the mean daily average pain NRS. The analysis of change from baseline to 
EOT in mean daily average pain will use analysis of covariance (ANCOVA), with covariates of 
baseline average pain NRS score and center (pooled where necessary).
A sensitivity analysis for the primary endpoint will use the same MMRM model as described 
previously. However, for this secondary analysis, multiple imputation will be used for imputation 
of any missing data, using the ‘Jump to Reference’ algorithm (where placebo is the reference 
group) for subjects who discontinue due to lack of efficacy or AEs and standard regression-based 
multiple imputation for subjects with missing data for other reasons. An additional sensitivity 
analysis for the primary endpoint will use modified baseline observation carried forward 
(mBOCF) for missing data with analysis using ANCOVA, with covariates of baseline mean daily 
average pain NRS score and center (pooled where necessary). mBOCF is defined as imputation by 
baseline observation carried forward (BOCF) for subjects who discontinue due to lack of efficacy 
or AEs, and imputation by last observation carried forward (LOCF) for subjects with missing data 
at Week 8 for other reasons.
The primary analysis for the secondary endpoints, of mean daily average pain response (≥30% 
and 50% reduction from baseline to Week 8 and to EOT) will be carried out with the Fisher’s 
Exact Test (with one-sided p-value). In addition the percentage of subjects who meet cumulative 
response levels of > 0% to = 100% will be shown. For the Week 8 analysis subjects with missing 
data will be classified as non-responders (BOCF), and an additional analysis will use mBOCF. For 
the EOT analysis, LOCF will be used.
The primary analysis for the change from baseline to Weeks 2, 4 and 8 for the FIQR subscales of 
Physical Function, Symptoms and Overall Impact will use the same MMRM analysis as described 
above for the mean daily average pain score. 
The primary analysis for the change from baseline to EOT for the FIQR subscales will use the 
same ANCOVA model as described above.
The primary analysis for the PGIC secondary endpoint will use the proportional odds model for 
ordinal data, with model term for treatment group. In addition, the percentage of subjects who 
achieve PGIC response (Improved, Very Much Improved) will be carried out with the Fisher’s 
Exact Test (with one-sided p-value) for binary data.

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Safety:  
The safety variables will be summarized by descriptive statistics.
Interim analyses:
Two interim analyses for futility based on the primary efficacy endpoint will be conducted. The 
timing of these analyses will be at approximately 35% and 55% of all subjects with Week 8/EOT 
data. The plan for the interim analysis may be modified based on speed of recruitment. These 
analyses will be conducted by an Astellas statistician, with results reviewed by an Astellas IDMC. 
The Astellas statistician and other members of the Astellas IDMC are external to the study team. 
No one within the study team will be unblinded to the treatment allocation or interim results. 
Details of the interim analysis procedure, steps to maintain treatment blind in the study team and 
criteria for stopping the study will be described in an Interim Analysis Plan (IAP).

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V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS
Flow Chart

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Table 1
Schedule of Assessments
Schedule of Assessments 
Screening Period
Randomization
Treatment Period
Follow-Up Perioda
Screening
Wash-
out
Baseline 
Diary
Run-In
Treatment
Follow-up 
Visit 
End of Study 
(EOS)
Phone Call
Visit 
1
NA
2
3
4
5
6
7
N/A
Week
-6 through -1
2
4
8/EOT
10
12
Day (and Window)
-42 to -8
-7 to -1
1
15 ± 2
29 ± 2
57± 2
71± 2
85± 2
ASSESSMENTS
Informed Consent
X
Demographics
X
Height and Weightb
X
X
X
Medical/Surgical History
X
Medication History and Concomitant 
Medication
X
X
X
X
X
X
X
X
X
Fibromyalgia Diagnosis (ACR 1990 
and 2010)c
X
Verify Eligibility Criteria (and 
duplicate subject database check)
X
Xd
Xd
X
Phone Call to Patiente
X
X
e-diary Distribution/Return
X
X
Physical Examination (including 
tender point exam at Screening)
X
X
X
X
Drug and Alcohol Screenf
X
X
X
Randomizationg
X
Vital Signsh
X
X
X
X
X
X
Laboratory Tests (Hematology, 
Biochemistry, Urinalysis)i
X
X
X
X
X
X
Electrocardiogramj
X
X
X
X
Pregnancy Test
Xk
Xl
Xl
Xl
Blood Sample for
Pharmacogenomicsm
X
Blood sampling for
Pharmacokineticsn
X
X
X
X
Complex Medical Symptoms 
Inventory (CMSI)o
X
Table continued on next page

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Schedule of Assessments 
Screening Period
Randomization
Treatment Period
Follow-Up Perioda
Screening
Wash-
out
Baseline 
Diary
Run-In
Treatment
Follow-up 
Visit 
End of Study 
(EOS)
Phone Call
Visit 
1
NA
2
3
4
5
6
7
N/A
Week
-6 through -1
2
4
8/EOT
10
12
Day (and Window)
-42 to -8
-7 to -1
1
15 ± 2
29 ± 2
57± 2
71± 2
85± 2
M.I.N.I.p
X
Hospital Anxiety and Depression 
Scale (HADS)q
X
X
X
NRS e-diary Collectionr
NPSIs
X
X
PGICt
X
X
X
X
PGISu
X
X
X
X
X
EQ-5D-5Lv
X
X
X
FMSD e-diary Collectionw
FIQRx
X
X
X
X
X
X
mIBS-D Symptoms Diaryy
X
X
X
X
C-SSRSz
X
X
X
X
X
X
Subject Training Materialsaa
X
X
Study Drug Dispensed
X
X
X
Study Drug Dosingbb
X
X
X
X
Study Drug Returned
X
X
X
Adverse Eventscc
X
X
X
X
X
X
X
X
X
Rescue Medication (if applicable)
a) Follow-up visit and phone call will be planned relative to date of last dose (14 and 28 days post last dose).
b) Height will be measured at Screening only. Weight will be collected at Screening, prior to Randomization and Week 8/End of Treatment (EOT). 
c) Tender point examination training of the principal investigator and/or designated site study physician must be documented.
d) Continued subject eligibility to be confirmed based on laboratory results prior to having the subject wash-out of current pain medications (site to contact subject via phone 
call). Continued subject eligibility to be confirmed based on completion of wash-out prior to having the subjects start Baseline Diary Run-In (Visit 2).
e) During Screening period (wash-out): study staff to contact the subject, if necessary, to initiate wash-out of current pain medications after continued eligibility has been 
confirmed. During follow-up: follow-up phone call 4 weeks (Day 85) post study drug will be required.
Footnotes continued on next page

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f) Subjects will be tested for drugs and alcohol at Screening, Baseline Diary Run-In, and prior to Randomization. A positive screen for tetrahydrocannabinol (THC) and/or 
opioids is allowed at the Screening visit, however must be confirmed negative prior to Baseline Diary Run-In and Randomization. 
g) Continued subject eligibility to be assessed and confirmed based on daily average pain scores recorded in the e-diary prior to subject being randomized.
h) Sitting or supine resting blood pressure and pulse rate values will be obtained at each visit (except for Visit 2) and should be conducted prior to blood draws. Body temperature 
will be assessed at Screening, Randomization and Week 8/EOT only.
i) Blood specimens for scheduled clinical chemistry laboratory tests do not need to be fasted samples.
j) Electrocardiograms are to be conducted prior to blood draws. A single electrocardiogram (ECG) will be obtained at the specified visits, unless, in the investigator’s 
judgment, additional ECG’s are required for safety reasons.
k) Serum for females of childbearing potential.
l) Urine for females of childbearing potential. Samples are to be collected prior to Randomization, Week 8/EOT, and the Week 10/FU visits.
m) Sample to be collected 1 time, preferably prior to first dose on Day 1; however, the sample can be collected at any time during the course of the study. A separate 
pharmacogenomics ICF will need to be obtained from subject prior to collecting.
n) Pharmacokinetic sampling will occur on Day 1 in the clinic at approximately 1-4 hour(s) after dosing and once at Weeks 2, 4 and 8 at any time point. Date and time of the 
dose taken prior to collecting the PK sample, as well as the date and time of the last meal in relation to that dose will be captured in the electronic case report form 
(eCRF). 
o) Complex Medical Symptom Inventory (CMSI). Questionnaire will be completed by the subject at Baseline Diary Run-in.
p) Mini-International Neuropsychiatric Interview (M.I.N.I.) will be completed by trained personnel at Screening.
q) Hospital Anxiety and Depression Scale (HADS). Questionnaire will be completed by the subject at Screening, Randomization and the Week 8/EOT visits.
r) Numeric Rating Scale (NRS). Subject is to rate average pain on a daily basis (24-hour recall) by entering pain score (0 - 10) in the e-diary. The NRS should be completed 
prior to bedtime at a consistent time of day throughout the study starting daily at Diary Run-In until Week 10/FU.
s) Neuropathic Pain Symptom Inventory (NPSI). Questionnaire will be completed by the subject at Randomization and Week 8/EOT visits.
t) Patient Global Impression of Change (PGIC). Questionnaire will be completed by the subject at the Week 2, 4, 8/EOT and Week 10/FU visits.
u) Patient Global Impression of Severity (PGIS) Questionnaire will be completed by the subject at Randomization and the Week 2, 4, 8/EOT and Week 10/FU visits.
v) European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L). Questionnaire will be completed by the subject at Randomization, Week 8/EOT and Week 10/FU visits.
w) Fibromyalgia Sleep Diary (FMSD) during the study starting daily at Baseline Diary Run-In (Visit 2) until Week 10/FU visit. Upon awakening, subject is to rate their 
quality of sleep (FMSD) during the previous night using the e-diary.
x) Fibromyalgia Impact Questionnaire Revised (FIQR) will be completed by the subject at Screening, Randomization and at the Week 2, 4, 8/EOT and Week 10 visits. At 
Screening, subject only completes pain item of FIQR.
y) Modified irritable bowel syndrome - diarrhea predominant (mIBS-D) Symptoms Diary will be completed by the subject at Randomization and at Weeks 2, 4 and 8/EOT
visits.
Footnotes continued on next page 

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z) Columbia Suicide Severity Rating Scale (C-SSRS). Questionnaire will be facilitated by the primary investigator/Site staff, as appropriately trained, at Screening, 
Randomization and the Weeks 2, 4, 8/EOT and Week 10/FU visits.
aa)Subject training materials are to be distributed and reviewed during the Screening period.
bb)Subjects will begin study drug dosing on Day 1 of the Randomization visit. 
cc) Serious Adverse Events (AEs, TEAEs, SAEs and SUSARs) will be collected from the time of signing the ICF through 4 weeks post-last dose.

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1
INTRODUCTION
Protocol 0819-CL-0201 is a proof-of-concept study to examine the effects of ASP0819 for 
the treatment of pain in subjects with fibromyalgia.
1.1
Background
Background on Target Indication
Fibromyalgia is a complex syndrome characterized by chronic widespread musculoskeletal 
pain often occurring with symptoms of depression, fatigue, sleep disturbances and/or cognitive 
complaints. Fibromyalgia pain typically includes deep musculoskeletal pain with tender points 
in the shoulder, girdle, torso, hips and extremities. Fibromyalgia may include various somatic 
symptoms, such as headache and irritable bowel syndrome. The core diagnostic criteria for 
fibromyalgia are defined by the 1990 American College of Rheumatology (ACR) [Wolfe et al, 
1990]. While the ACR has published new, as well as subsequent amended criteria [Wolfe et al, 
2011; Wolfe et al, 2010], the 1990 version is still commonly utilized in clinical trials. The 
overall prevalence of fibromyalgia in the general population was estimated to be 2.2% in the 
United States (3.4% and 0.5% in females and males, respectively) [Queiroz, 2013].
Drugs used to treat fibromyalgia (e.g., pregabalin and duloxetine) provide, at best, only 
modest relief of symptoms and are accompanied by various side effects including sedation, 
dizziness, cognitive complaints, weight gain, edema and headaches. The approved 
medications for the treatment of fibromyalgia (United States [US]: pregabalin, duloxetine
and milnacipran; Japan: pregabalin) result in only an incremental increase in the percent of 
subjects (~8% to 13%) with a 30% pain reduction compared to 28% to 34% of subjects with 
a similar level of improvement on placebo in randomized clinical trials [Häuser et al, 2014]. 
Despite the available approved medications, novel medications to treat pain, fatigue, sleep 
disturbances and impaired cognition without intolerable AEs are required to address an 
unmet medical need for subjects with fibromyalgia.
A pathophysiological mechanism for fibromyalgia has not yet been established. The concept 
of altered central processing of nociceptive information has dominated the fibromyalgia 
literature [Woolf, 2011; Staud, 2011]. However, accumulating evidence suggests an 
abnormality in both peripheral nerve fibers, as well as central pain processing in subjects 
with fibromyalgia [Serra et al, 2014; Staud & Smitherman, 2002]. Studies have suggested 
that peripheral abnormalities in sensory nerves may be important in contributing to and/or 
possibly maintaining fibromyalgia symptoms [Staud, 2006]. Increased spontaneous and 
evoked firing was observed in fibromyalgia subjects [Serra et al, 2014]; while lidocaine was 
shown to improve hyperalgesia in fibromyalgia subjects [Staud et al, 2014]. Abnormal 
(increased) peripheral sensory afferent input may be amplified in the presence of central 
sensitization (decreased inhibition) [Staud et al, 2014; Staud, 2006].
Furthermore, specific C-fiber abnormalities have been reported in fibromyalgia subjects. 
Skin biopsies obtained from fibromyalgia subjects showed distinct ultrastructural 
abnormalities in C-fibers including ballooned Schwann cells (concentrated in tender areas) 

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and peripheralized small axons of Remak bundles [Kim et al, 2008]. Serra et al. [2014] 
reported hyperexcitability, as well as structural changes in peripheral nociceptive C-fibers of 
fibromyalgia subjects, suggesting abnormal peripheral C nociceptor ongoing activity and 
increased mechanical sensitivity could contribute to the pain and tenderness suffered by 
fibromyalgia subjects [Serra et al, 2014].
In addition, studies have reported that small-fiber pathology is a contributor to the widespread 
pain in fibromyalgia subjects [Oaklander et al, 2013; Üçeyler et al, 2013]. Oaklander et al 
[2013] demonstrated that subjects diagnosed with fibromyalgia have evidence of a neurological 
cause of their chronic pain and other symptoms, specifically small-fiber polyneuropathy. 
Further, Üçeyler et al [2013] challenged the concept of fibromyalgia being a form of depression 
or a psychological disorder, illustrating small-fiber impairment on a psychophysical, 
neurophysiological and morphological level in fibromyalgia and postulating that small-fiber 
pathology may be a peripheral nervous system contributor to the complex pathophysiology of 
pain in fibromyalgia.
Taken together, these findings suggest that some fibromyalgia subjects may have underlying 
peripheral nerve damage that may contribute to pain symptoms. Given the significant unmet 
medical need and emerging understanding of peripheral pathophysiology, targeting 
peripheral mechanisms may be helpful in the treatment of fibromyalgia.
Background on Pharmacological Concept
Ca2+-activated K+ channels are classified according to their single channel conductance: large 
conductance channel (K+ large conductance Ca2+-activated channel, subfamily M, alpha 1 
[KCNMA1]), intermediate conductance channel (KCa3.1) and small conductance channel 
(SK). KCa3.1 is voltage-insensitive and requires only a small increase in intracellular Ca2+ to 
open, subsequently maintaining a negative membrane potential through K+ efflux [Bradding 
and Wulff, 2009]. Opening of KCa3.1 results in a period of reduced excitability after each 
action potential called afterhyperpolarization. The physiological role of KCa3.1 is considered 
to be regulation of cellular excitability, which suggests it is a potential therapeutic target for 
various diseases associated with abnormal nerve excitation [Wulff et al, 2007]. For example, 
the activation of KCa3.1 appears not only to have an analgesic effect on visceral 
hypersensitivity [McHugh et al, 2008], but also to be involved in the analgesic action of 
peroxisome proliferator-activated receptor agonists [LoVerme et al, 2006]. The channel is 
represented in A-delta and C-fiber dorsal root ganglion and axons [Tsantoulas and
McMahon, 2014]. Thus, the regulation of KCa3.1 may be a novel target for the treatment of 
painful disorders associated with neuronal hyperactivity.
Rationale for Clinical Trial with ASP0819
ASP0819 is predicted to lead to hyperpolarization of primary sensory afferent nerves and 
subsequent decreased firing. This pharmacological action of ASP0819 should reduce 
peripheral nerve hyperexcitability, thus normalizing the frequency of action potentials and 
reducing the pain experienced by fibromyalgia subjects. 

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1.2
Nonclinical and Clinical Data
ASP0819 is an orally available, new molecular entity discovered by Astellas Pharma Inc. 
ASP0819 has KCa3.1 opening activity that targets peripheral sensory nerves. 
ASP0819 pharmacokinetics have been assessed across single doses (1 to 55 mg) and 14-days 
of multiple once-daily dose (1 to 18 mg) in the same tablet formulation as that tested in the 
current study. ASP0819 was rapidly absorbed with median tmax ranging from 1.03 to 
3.03 hours postdose following single and multiple doses. Cmax, AUCinf and AUCtau increased 
in a dose-proportional manner showing a low to moderate between-subject variability (12.3% 
to 41.5%). The average terminal elimination half-life ranged from 38.9 to 54.5 hours with a 
mean apparent oral clearance varying from 0.196 to 0.285 L/h. Drug accumulation was on 
average 2.82- to 3.45-fold higher (AUCtau) at steady-state compared to single dose with no 
clear differences across dose levels. Most of the subjects with once daily doses of ASP0819 
appeared to be at steady-state after 8 to 10 days of dosing. The peak to trough ratio was low 
(1.57 - 1.87 on average), thus suggesting a low degree of fluctuation in the plasma 
concentrations over the dosing period. The analysis of urine concentrations collected at 
steady-state showed, that after repeat dosing, ASP0819 excretion in urine was very low 
(≤2%) and not dose dependent. Overall, no sex effect could be observed and the effect of 
food was clinically insignificant (approximately 20-36% lower following a high-fat meal).
In the phase 1 study, 
, where single and multiple ascending doses of ASP0819 
were assessed, ASP0819 was well tolerated in healthy males and females. There were no 
deaths, other serious treatment emergent adverse events (TEAEs), or TEAEs leading to 
discontinuation during the study. In general, the most commonly reported adverse events 
(AEs) observed across the single ascending dose and multiple ascending dose parts of the 
study, were constipation and other Gastrointestinal Disorder SOC events; the majority of 
these events were mild. There were no clinically significant abnormalities in any of the liver 
or hematologic parameters or other clinical laboratory test results considered related to 
ASP0819. There were no clinically significant abnormalities in vital signs or 
electrocardiograms (ECGs); there were no cardiac repolarization (QTcF) intervals greater 
than 450 msec and no change greater than 30 msec from baseline. There were no clinically 
significant abnormalities on orthostatic blood pressure changes, with the exception of 1
report of a single brief, mild presyncope following a 55 mg single dose, which was 
accompanied by a positive orthostatic challenge test (at 18:00 hour, a decrease in DBP of 
10.3 mmHg after 3 min standing, and approximately 8 hours post-dosing). Based on a 
concentration vs change from baseline analysis, ASP0819 showed no clinically significant 
effects on QTcF.
Please refer to the IB for detailed information from nonclinical and clinical studies.
PPD

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1.3
Summary of Key Safety Information for Study Drugs
Given the early stage of development, there are currently no expected AEs for ASP0819.
ASP0819 may be associated with TEAEs based on the nonclinical studies. The following 
were key nonclinical observations: signs of liver abnormality; gastrointestinal atrophy, 
inflammation; changes in hemoglobin, hematocrit and other red blood cell parameters (Refer 
to the IB for detailed information). 
1.4
Risk Benefit Assessment
No clinical efficacy studies have been conducted to evaluate ASP0819 in the treatment of pain 
associated with fibromyalgia; therefore, the actual benefit of ASP0819 in the treatment of pain 
associated with fibromyalgia is unknown. There are no known risks identified with this 
mechanism of action, as ASP0819 is a first-in-class compound. Based on the safety profile 
from the phase 1 clinical data, the risks appear to be justified from a risk benefit assessment. 
An overview of the risk benefit of ASP0819 can be found in the IB, including monitoring and 
mitigation steps taken to maintain safety of the subjects while on study treatment. Routine risk 
minimization procedures are planned in this study. Overall, the fibromyalgia subjects that will 
meet the inclusion and exclusion criteria will be relatively healthy; therefore increased risk is 
not expected in this population. [See Section 2.2.2 Dose Rationale for safety margins relative 
to non-clinical toxicology].
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS
2.1
Study Objective(s)
The objectives of the study, conducted in subjects with fibromyalgia, are the following:
2.1.1
Primary Objectives

Assess analgesic efficacy of ASP0819 relative to placebo. 

Assess the safety and tolerability of ASP0819 relative to placebo.
2.1.2
Secondary Objectives 

Assess treatment differences in physical function of ASP0819 relative to placebo.

Assess the improvements in overall subject status (e.g., fibromyalgia symptoms, global 
functioning) of ASP0819 relative to placebo. 
2.1.3
Exploratory Objectives

Assess the time course of efficacy of ASP0819. 

Assess treatment differences in sleep disturbance.

Assess treatment differences in depression. 

Assess treatment differences in quality of life.

Assess the use of rescue medication.

Assess treatment differences in responder rate based on composite endpoint definition. 

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
Assess treatment differences in gastrointestinal symptoms.

Assess relationship between gastrointestinal symptoms and analgesic effect. 

Assess relationship between neuropathic symptoms and analgesic effect.
2.2
Study Design and Dose Rationale
2.2.1
Study Design
This is a phase 2a, randomized, double-blind, placebo-controlled parallel group study to 
assess analgesic efficacy and safety of ASP0819 in subjects with fibromyalgia. 
The study will be conducted in the US in up to approximately 35 sites. Approximately 323 
subjects are planned to be screened for 178 randomized subjects (89/arm) (45% screen fail 
rate).
The study will consist of the following study periods:

Screening period (Day -42 to Day -1) 
Up to 42 days, which includes the completion of screening procedures (Visit 1), wash-out 
of prohibited medications (if applicable), and a 7-day Baseline Diary Run-In. The wash-
out of prohibited medications should be completed prior to the initiation of the Baseline 
Diary Run-In. The Baseline Diary Run-In may be extended up to 2 days if necessary in 
the investigator’s opinion. In general, the Screening period should not exceed 42 days. 
The investigator should contact the medical monitor if there are circumstances that would 
cause the subject to exceed 42 days.

Double-blind randomized treatment period (Day 1 to Day 57 [End of Treatment (EOT)]) 
Eight-weeks of treatment with study drug and site visits at Day 1, 15, 29 and 57.

Follow-up period (Day 58 to Day 85 [End of Study (EOS)]) 
Includes a follow-up site visit on Day 71, and an (EOS) phone call on Day 85.
Screening Period: 
After signing the ICF, screening procedures for the subject will start (Visit 1). Subjects will 
be required to meet both the 1990 and 2010 ACR criteria for fibromyalgia. The investigator
or other qualified individual at the site will confirm the diagnosis of fibromyalgia. 
After signing informed consent and during the screening period, study site personnel will 
check that potential subjects have not already been pre-screened, initiated or completed 
screening or have been randomized into this study, or another clinical trial, using an 
independent subject participation database.  Independent subject participation databases seek 
to reduce duplicate enrollment by identifying duplicates before they randomize into the study, 
and this measure is consistent with exclusion requirement of not participating in another 
interventional clinical trial during the conduct of the study (inclusion criterion 17).  In order 
to complete this check and per the informed consent, study personnel will request that the 
subject present a valid picture identification (e.g. driver’s license, passport, state issued ID 
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that could potentially be used to identify study subjects identifiers (e.g. date of birth, initials, 
etc.) so that the match algorithms can be run. 
Subjects that meet the inclusion criteria, none of the exclusion criteria, and are not identified 
as a duplicate subject (e.g. certainly, possible, probably), will be enrolled into the study. 
Appropriate documentation reflecting the subject’s eligibility according to these criteria will 
be reflective in the subject’s source documents.
Subjects who meet the eligibility criteria will be instructed, if medically appropriate, to wash-
out of any prohibited medications via phone call from the site. At Visit 2, all subjects who 
continue to meet eligibility criteria will be provided with an electronic diary (e-diary). 
Subjects will enter a 1-week Baseline Diary Run-In, and during this period, they will record 
their daily average pain score (0 – 10 Numerical Rating Scale [NRS]) and sleep quality 
information with the Fibromyalgia Sleep Diary (FMSD) in the e-diary. They will receive 
instructions regarding its use and begin entering daily scores. Upon awakening, subjects are 
to rate their sleep quality during the previous night using the e-diary. Each evening before 
bed, subjects are to rate their average pain during the previous 24 hours using the e-diary. 
Subjects will need to have a mean daily average pain score ≥ 4 and ≤ 9 (0-10 NRS), and meet
pre-specified criteria for daily average pain scores. 
A subject who does not meet the required mean daily average pain score or who is not 
compliant with e-diary entries by completing at least 5 of 7 days in the baseline run-in, will 
be considered a screen failure and will not be allowed to repeat the pain assessments nor 
rescreen for the study.
Weight, medication history and concomitant medication, physical examination, drug and 
alcohol screen, vital signs, ECG, pregnancy test, Hospital Anxiety and Depression Scale
(HADS), Columbia-Suicide Severity Rating Scale (C-SSRS), Patient Global Impression of 
Severity (PGIS), European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L), Fibromyalgia 
Impact Questionnaire Revised (FIQR) and Modified irritable bowel syndrome - diarrhea 
predominant (mIBS-D) Symptoms Diary should all be obtained and reviewed before 
Randomization at Visit 3. After confirmation of eligibility, subjects who meet the mean daily 
average pain score eligibility requirements at this visit will be randomized. For subjects that 
meet the entry criteria blood samples for laboratory tests and pharmacogenomics will be taken 
after Randomization and prior to dosing. Pharmacokinetics will be obtained approximately 1 to 
4 hour(s) after the first dose.
Rescreening is not allowed. Repeat of screening assessments as mentioned in exclusion 
criteria 11, 12, 14 and 15 may be done once, after a reasonable timed period at the 
Investigator’s discretion but within the Screening period. 
Double-Blind Randomized Treatment Period (treatment period):
Subjects will enter the treatment period and will be randomized in a 1:1 ratio to receive either 
ASP0819 or placebo once per day for a period of 8 weeks. 

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Acetaminophen may be used as rescue therapy for intolerable pain due to fibromyalgia 
during the baseline period and in all subsequent study periods [see Section 4.1.3 Rescue 
Medication]. Nonsteroidal anti-inflammatory drugs (NSAIDs) will be allowed (with the 
exception of celecoxib), as needed, for non-fibromyalgia pain, such as headache.
Throughout the treatment period, beginning on Day 1 (Randomization) through 
Visit 6/Week 8, subjects will record all daily average pain scores (NRS) and any 
acetaminophen use in the e-diary. FMSD sleep quality scores will be recorded through 
Visit 6/Week 8. Subjects will take study drug once per day (qd). Subjects randomized to 
ASP0819 will receive 15 mg (3 capsules of 5 mg each). In order to maintain the study blind,
placebo treated subjects will receive matching capsules. 
During the treatment period, subjects will return to the clinic per schedule for safety and 
efficacy procedures (see Schedule of Assessments for details). Subjects who do not complete 
the treatment period will be requested to complete EOT visit procedures.
Follow-up Period:
Subjects are encouraged to abstain from any concomitant medications for the treatment of 
fibromyalgia pain prior to Visit 7/Week 10. Rescue medication is allowed during the follow-
up period. Subjects will continue to enter their daily average pain score (NRS), FMSD sleep 
quality scores and acetaminophen use into their e-diary and return diaries at Visit 7/Week 10. 
All subjects will return to the site for a follow-up visit at Day 71, 2 weeks following the 
EOT visit (Day 57). A follow-up safety phone call will take place approximately 4 weeks 
post study drug discontinuation (Day 85/EOS).
Interim Analyses:
Two interim analyses for futility based on the primary efficacy endpoint will be conducted. 
The timing of these analyses will be at approximately 35% and 55% of all subjects with 
Week 8/EOT data [see Section 7.7 Interim Analysis]. The plan for the interim analysis may 
be modified based on the speed of recruitment.
2.2.2
Dose Rationale
The analgesic efficacy of ASP0819 will be assessed at a dose of 15 mg qd over a period of 
8 weeks.
Target exposures assessed in this proof-of -concept study are based on efficacious exposures 
from the rat vagotomy model, which showed significant signs of analgesia with an EC50 (Ceff) 
at 119 ng/mL, and rat reserpine induced myalgia nerve firing model, which showed significant 
signs of pharmacology at tested exposures ranging from approximately 90 ng/mL to 
5000 ng/mL. Based on the Phase 1 human PK data, the predicted mean Ctrough (95% Prediction 
Interval [PI]) following 15 mg qd is 2610 ng/mL (1450-3850 ng/mL). All subjects are 
predicted to have Ctrough concentrations above the target efficacious exposure (Ceff 119 ng/mL).
The predicted mean Cmax (95%PI) and AUCtau (95%PI) for a 15 mg qd dose of ASP0819 
in subjects are 4380 ng/mL (2790–6090 ng/mL) and 76200 ng*hr/mL 

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(44700-109800 ng*hr /mL), respectively. These predicted mean exposures are below the 
previously established mean exposure limits; and they are approximately 3-fold or more below 
the 13-wk rat and dog no-observed-adverse-effect-level Cmax and AUC24.
The 13-wk lowest-observed-adverse-effect level (LOAELs; 10 mg/kg/day in rat and dog 
studies) are based on the observations of atrophy in mucosal epithelium in both rats and dogs 
and necrosis or degeneration in parietal cells in dogs. All findings were reversible. There is 
approximately a 9-fold safety margin based on the LOAELs from the 13-wk rat and dog 
toxicology studies to the predicted upper 95% PI for Cmax and AUC24 from a 15 mg qd dose.
Thus, a dose of 15 mg qd should provide exposure within an efficacious target range and 
below exposures associated with toxicity in nonclinical studies.
2.3
Endpoints 
2.3.1
Primary Endpoints
Primary Efficacy Endpoint
●
Change from baseline to Week 8 in mean daily average pain score assessed by NRS 
(0 to 10 scale) in the subject’s daily e-diary.
Safety and Tolerability Endpoints
●
TEAEs/serious adverse events (SAEs) from Screening until EOS.
●
Safety laboratory tests at Weeks 2, 4, 8 and 10
●
Vital sign measurements at Weeks 2, 4, 8 and 10.
●
12-lead ECG parameters at Weeks 8 and 10.
●
Physical examination at Weeks 8 and 10.
●
C-SSRS (evaluation of suicidal ideation and behavior) at Weeks 2, 4, 8 and 10.
2.3.2
Secondary Endpoints 
Secondary Efficacy Endpoints
●
Subject’s response defined as achieving ≥ 30 % reduction from baseline to Week 8 and 
EOT in mean daily average pain score assessed by NRS (0 to 10 scale) in the subject’s 
daily diary.
●
Subject’s response defined as achieving ≥ 50 % reduction from baseline to Week 8 and 
EOT in mean daily average pain score assessed by NRS (0 to 10 scale) in the subject’s 
daily diary.
●
Change from baseline to Weeks 2, 4, 8, and EOT in the FIQR Physical Function, 
Symptoms, and Overall Impact subscales.
●
Overall subject improvement assessed by PGIC at Weeks 2, 4, 8, and EOT. 

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2.3.3
Exploratory Endpoints
Exploratory Efficacy Endpoints
Treatment Period
●
Change from baseline to Weeks 1, 2, 3, 4, 5, 6, 7 and EOT in mean daily average pain 
score. 
●
Subject’s response defined as achieving various reduction levels (> 0%, ≥ 10%, ≥20%, ≥ 
40%, ≥ 60%, ≥ 70%, ≥ 80%, ≥ 90%, 100%) from baseline to Week 8 and EOT in mean 
daily average pain score assessed by NRS (0 to 10 scale) in the subject’s daily diary.
●
Change from baseline to Weeks 2, 4, 8 and EOT in FIQR Total Score. 
●
Change from baseline to Weeks 2, 4, 8 and EOT in PGIS.
●
Subject’s response defined as PGIC of very much or much improved at Week 8 and EOT.
●
Subject’s response defined as achieving ≥ 30 % reduction from baseline in FIQR total 
score at Week 8 and EOT. 
●
Subject’s composite pain response defined as achieving ≥ 30% reduction from baseline in 
mean daily average pain score and PGIC of very much or much improved at Week 8 and 
EOT. 
●
Subject’s composite syndrome response defined as achieving ≥ 30% reduction from 
baseline in mean daily average pain score and PGIC of very much or much improved and
≥ 30 % reduction from baseline in FIQR total score at Week 8 and EOT.
●
Change from baseline to Weeks 1, 2, 3, 4, 5, 6, 7, 8 and EOT in daily in the FMSD, which 
captures all critical sleep disturbance features of fibromyalgia (8 items).
●
Change from baseline to Week 8 and EOT in the HADS depression subscale.
●
Change from baseline to Week 8 and EOT in EQ-5D-5L.
●
Proportion of days with rescue medication use at Weeks 1, 2, 3, 4, 5, 6, 7, 8 and EOT.
●
Incidence of subjects using rescue medication at Weeks 1, 2, 3, 4, 5, 6, 7, 8 and EOT.
●
Average daily dosage of rescue medication at Weeks 1, 2, 3, 4, 5, 6, 7, 8 and EOT.
●
Change from baseline to Weeks 2, 4, 8 and EOT in Irritable Bowel Syndrome Symptom 
Summary Score and abdominal pain, stomach pain, abdominal cramps, abdominal 
pressure, and bloating as assessed by the Irritable Bowel Syndrome-diarrhea predominant 
(IBS-D) Daily Symptom Diary. 
●
Change from baseline to Week 8 and EOT in neuropathic pain symptoms as assessed by 
the Neuropathic Pain Symptom Inventory (NPSI).
Follow-Up Period
●
Change from baseline and EOT to Week 10 in mean daily average pain score. 
●
Change from baseline and EOT to Week 10 in FIQR Physical Function subscale, 
Symptoms subscale, Overall Impact subscale, and total score.
●
Overall subject improvement assessed by PGIC to Week 10.
●
Change from baseline and EOT to Week 10 in PGIS.
●
Subject’s response defined as achieving ≥ 30 % reduction from baseline to Week 10 in 
mean daily average pain score assessed by NRS (0 to 10 scale) in the subject’s daily diary.

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●
Subject’s response defined as achieving ≥ 50 % reduction from baseline to Week 10 in 
mean daily average pain score assessed by NRS (0 to 10 scale) in the subject’s daily diary.
●
Change from baseline to Week 10 in EQ-5D-5L. 
●
Proportion of days with rescue medication use at Week 10.
●
Incidence of subjects using rescue medication at Week 10.
●
Average daily dosage of rescue medication at Week 10.
3
STUDY POPULATION
3.1
Selection of Study Population 
Male and female subjects between 18 and 80 years of age with fibromyalgia.
3.2
Inclusion Criteria
A subject is eligible for the study if all of the following apply:
1.
Institutional Review Board (IRB)-approved written ICF and privacy language as per 
national regulations (e.g., Health Insurance Portability and Accountability Act [HIPAA]
Authorization for US sites) must be obtained from the subject prior to any study-related 
procedures (including withdrawal of prohibited medication, if applicable).
2.
A male or female subject between 18 and 80 years of age at the signing of the informed 
consent. 
3.
Subject has a body mass index (BMI) ≤ 45 kg/m2.
4.
Female subject must either:
●Be of nonchildbearing potential:
o
postmenopausal (defined as at least 1 year without any menses) prior to 
Screening, or
o
documented surgically sterile (e.g., hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy).
●Or, if of childbearing potential:
o
agree not to try to become pregnant during the study and for 28 days after the 
final study drug administration,
o
have a negative blood pregnancy test at Screening and negative urine test on 
Day 1, and
o
if heterosexually active, agree to consistently use 1 form of highly effective birth 
control* starting at Screening and throughout the study period and for 28 days 
after the final study drug administration.
5.
Female subject must agree not to breastfeed at Screening and throughout the study 
period, and for 28 days after the final study drug administration.
6.
Female subject must not donate ova starting at Screening, throughout the study period, 
and for 28 days after the final study drug administration

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7.
Male subject must not donate sperm starting at Screening and throughout the study 
period, and for 28 days after the final study drug administration.
8.
Male subject with a partner of child-bearing potential, or a pregnant or breastfeeding 
partner(s) must agree to remain abstinent or use a condom throughout the study period 
and for 28 days after the final study drug administration. 
9.
Subject meets the ACR 1990 fibromyalgia diagnostic criteria at Screening: 
●Widespread pain for at least 3 months, defined as the presence of all of the following:
o
pain on right and left sides of the body,
o
pain above and below the waist, and
o
pain in the axial skeleton (cervical spine or anterior chest or thoracic spine or low 
back) must be present.
●Pain in at least 11 of 18 tender point sites on digital palpation.
o
Digital palpation should be performed with an approximate force of 4 kg. 
10. Subject meets the ACR 2010 fibromyalgia diagnostic criteria at Screening:
●Widespread pain index (WPI) ≥ 7 and SS scale score ≥ 5 or WPI 3-6 and SS scale 
score ≥ 9.
●Symptoms have been present at a similar level for at least 3 months.
●The subject does not have a disorder that would otherwise explain the pain. 
11. Subject has a pain score ≥ 4 on the revised fibromyalgia impact questionnaire revised 
(FIQR) pain item at Screening.
12. Subject is compliant with daily pain recordings during the Baseline Diary Run-In period, 
as defined by the completion of a minimum of 5 of 7 daily average pain ratings and 
agrees to complete daily diaries throughout the duration of the study.
13. Subject has a mean daily average pain score ≥ 4 and ≤ 9 on an 11-point 0 to 10 NRS as 
recorded in the subject e-diary during the Baseline Diary Run-In period, and meeting 
pre-specified criteria for daily average pain scores.
14. Subject agrees to use only acetaminophen as rescue medication for fibromyalgia pain 
throughout the course of the trial (up to 1000 mg per dose and not to exceed 3000 
mg/day). 
15. Subject agrees not to initiate or change any non-pharmacologic interventions (including 
normal daily exercise routines, chiropractic care, physical therapy, psychotherapy, and 
massage therapy) during the course of the study. Non-pharmacologic interventions must 
be stable for a minimum of 30 days prior to Screening. The subject agrees to maintain 
usual level of activity for the duration of the study.
16. Subject is capable of completing study assessments and procedures, in the opinion of the 
investigator.
17. Subject agrees not to participate in another interventional study from Screening through 
the EOS visit.

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* Highly effective forms of birth control include:
●
Consistent and correct usage of established hormonal contraceptives that inhibit 
ovulation,
●
Established intrauterine device (IUD) or intrauterine system (IUS),
●
Vasectomy (A vasectomy is a highly effective contraception method if the 
absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used).
●
Male is sterile due to a bilateral orchiectomy.
NOTE: The reliability of sexual abstinence for male and/or female subject enrollment 
eligibility needs to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the subject. The investigator is responsible for confirming 
the subject is continuing to use the protocol stated contraception requirements.
Waivers to the inclusion criteria will NOT be allowed.
3.3
Exclusion Criteria
Subject will be excluded from participation if any of the following apply:
1.
Subject has received an investigational therapy within 28 days or 5 half-lives, whichever 
is longer, prior to Screening. 
2.
Subject has had no meaningful improvement, in the investigator’s opinion, from 2 or 
more prior treatments (commercially available) for fibromyalgia (in at least 
2 pharmacologic classes). 
3.
Subject has had known hypersensitivity or intolerance to the use of acetaminophen or 
associated formulation components; known hypersensitivity to the formulation 
components of ASP0819.
4.
Subject has pain due to diabetic peripheral neuropathy, post-herpetic neuralgia, 
traumatic injury, prior surgery, complex regional pain syndrome, or other source of pain 
that, in the investigator’s opinion, would confound or interfere with the assessment of 
the subject’s fibromyalgia pain or require excluded therapies during the subject’s study 
participation. 
5.
Subject has infectious or inflammatory arthritis (e.g., rheumatoid arthritis, ankylosing 
spondylitis, psoriatic arthritis and gout), autoimmune disease (e.g., systemic lupus 
erythematosus), or other widespread rheumatic disease other than fibromyalgia.
6.
Subject has a current, untreated moderate or severe major depressive disorder as 
assessed by the Mini-International Neuropsychiatric Interview (M.I.N.I.). Subject with 
current, treated major depressive disorder can be included provided that, in the 
investigator’s opinion, it is without clinically significant changes in symptoms while on 
the same dose of a protocol allowed antidepressant for greater than 60 days prior to 
Screening.

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7.
Subject has initiated any non-pharmacologic interventions for the treatment of 
fibromyalgia or depression within 30 days prior to Screening or during the Screening
period. 
8.
Subject has a history of any psychotic and/or bipolar disorder as assessed by the M.I.N.I.
9.
Subject has a HADS score > 14 on the Depression subscale at Screening or at the time of 
Visit 3 (Randomization).
10. Subject has a history of suicide attempt or suicidal behavior within the last 12 months, or 
has suicidal ideation within the last 12 months (a response of “yes” to questions 4 or 5 
on the suicidal ideation portion of the C-SSRS), or who is at significant risk to commit 
suicide, as assessed by the investigator at Screening and at the time of Visit 3 
(Randomization).
11. Subject has clinically significant abnormalities in clinical chemistry, hematology, or 
urinalysis, or a serum creatinine > 1.5 times the ULN at Screening. These assessments 
may be repeated once, after a reasonable time period at the investigator’s discretion (but 
within the Screening period).
12. Subject has aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
≥1.5 times the upper limit of the reference range at Screening. These assessments may 
be repeated once, after a reasonable time period at the investigator’s discretion (but 
within the Screening period).
13. Subject has a positive test for hepatitis B surface antigen (HBsAg), hepatitis A virus 
antibodies (immunoglobulin M) (anti-HAV [IgM]) or hepatitis C virus antibodies (anti-
HCV) at Screening or has history of a positive test for human immunodeficiency virus 
type 1(HIV-1) and/or type 2 (HIV-2).
14. Subject has a resting systolic blood pressure (SBP) > 180 mmHg or < 90 mmHg, and/or 
a sitting diastolic blood pressure (DBP) > 100 mmHg at Screening. These assessments 
may be repeated once, after a reasonable time period at the investigator’s discretion (but 
within the Screening period).
15. Subject has a clinically significant abnormality on 12-lead ECG at Screening or Visit 3 
(Randomization). If the ECG is abnormal, based on the investigator’s judgment, an 
additional ECG can be carried out. If this also gives an abnormal result, the subject must 
be excluded.
16. Subject has a history of myocardial infarction (within 6 months of Screening), 
unexplained syncope, cardiac arrest, unexplained cardiac arrhythmias or torsade de 
pointes, structural heart disease or a family history of Long QT Syndrome.
17. Subject has evidence of any clinically significant, uncontrolled cardiovascular, 
gastrointestinal, endocrinologic (low thyroid stimulating hormone [TSH], but euthyroid 
is allowed), hematologic, hepatic, immunologic, infectious, metabolic, urologic, 
pulmonary (including obstructive sleep apnea not controlled by a CPAP device) 

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neurologic, dermatologic, psychiatric, renal and/or other major disease (exclusive of 
fibromyalgia), as assessed by the investigator or designee.
18. Subject has planned surgery during the study participation.
19. Subject has an active malignancy or a history of malignancy (except for treated non-
melanoma skin cancer) within 5 years of Screening.
20. Subject has a positive drug or alcohol test at Screening, Baseline Diary Run-In or prior 
to Randomization. However, a positive test for tetrahydrocannabinol (THC) and/or 
opioids is allowed at the Screening visit, but must be confirmed negative prior to 
Baseline Diary Run-In and Randomization. 
21. Subject has a current or recent (within 12 months of Screening) history of a substance 
use disorder including cannabinoid and/or alcohol abuse disorder. Subject has used 
opioids for pain for more than 4 days during the week preceding the Screening visit.
22. Subject is currently using protocol specified prohibited medications and is unable to 
wash-out [see Section 5.1.3 for Concomitant Medication Restrictions].
23. Subject has filed or is awaiting judgment on a disability claim or has any pending 
worker’s compensation litigation or related monetary settlements. 
24. Subject has any condition which, in the investigator’s opinion, makes the subject
unsuitable for study participation.
25. Subject is an employee of the Astellas Group, the Contract Research Organization 
(CRO) involved or the investigator site executing the study. 
Waivers to the exclusion criteria will NOT be allowed. 
4
TREATMENT(S)
4.1
Identification of Investigational Product(s)
4.1.1
Study Drug
The test drug, ASP0819, will be supplied as 5 mg capsules. The ASP0819 capsules are hard 
gelatin capsules with a Swedish orange body and yellow cap and contain white powder. For 
storage conditions, see label text.
4.1.2
Comparative Drug
Matching placebo capsules will be supplied. For storage conditions, see label text.
4.1.3
Rescue Medication
If a subject experiences intolerable pain due to fibromyalgia during the Screening, treatment 
or follow-up periods, the subject should be instructed to use acetaminophen as a rescue 
medication for fibromyalgia. Rescue medication use will be captured in the e-diary. NSAIDs 

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will be allowed, as needed for non-fibromyalgia pain [see Section 5.1.3 Concomitant 
Medications].
Access to acetaminophen will be arranged by the site according to the local regulations and 
requirements.
Doses:
The maximum amount of acetaminophen is up to 1000 mg per dose and not to exceed 
3000 mg/day. 
4.2
Packaging and Labeling
All study drug(s) used in this study will be prepared, packaged, and labeled under the 
responsibility of qualified staff at API/APEBV or Sponsor’s designee in accordance with 
API/APEBV or Sponsor’s designee Standard Operating Procedures (SOPs), Good 
Manufacturing Practice (GMP) guidelines, International Council for Harmonisation (ICH)
Good Clinical Practice (GCP) guidelines, and applicable local laws/regulations.
Each carton will bear a label conforming to regulatory guidelines, GMP and local laws and 
regulations that identifies the contents as investigational drug.
4.3
Study Drug Handling 
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries 
from the Sponsor are received by the investigator/or designee and that:
●
Such deliveries are recorded,
●
Study drug is handled and stored according to labeled storage conditions,
●
Study drug with appropriate expiry/retest and is only dispensed to study subjects in 
accordance with the protocol, and
●
Any unused study drug is returned to the Sponsor.
Study drug inventory and accountability records will be kept by the investigator, head of 
study site or designee. Study drug accountability throughout the study must be documented 
and reconciled. The following guidelines are therefore pertinent:
●
The investigator, head of study site or designee agrees not to supply study drugs to any 
persons except the eligible subjects in this study in accordance with the protocol.
●
The investigator, head of study site or designee (i.e., study drug manager) will keep the 
study drugs in a pharmacy or other locked and secure storage facility under controlled 
storage conditions, accessible only to those authorized by the investigator to dispense 
these study drugs.
●
A study drug inventory will be maintained by the investigator, head of study site or 
designee (i.e, study drug manager). The inventory will include details of material 
received and a clear record of when they were dispensed and to which subject.
●
At the conclusion or termination of this study, the investigator, head of study site or 
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to record the results of this inventory on the Drug Accountability Record. It must be 
possible to reconcile delivery records with those of used and/or returned study drug. Any 
discrepancies must be accounted for and documented. Appropriate forms of deliveries 
and returns must be signed by the site staff delegated this responsibility.
●
The site staff must return study drug to the Sponsor or designee at the end of the study or 
upon expiration unless otherwise approved by the Sponsor.
4.4
Blinding
4.4.1
Blinding Method 
This is a double blind study. Subjects will be randomized to receive ASP0819 or Placebo in a 
blinded fashion such that neither the investigator, Sponsor’s study management team, clinical 
staff, nor the subject will know which agent is being administered. The randomization
number will be assigned based on information obtained from the Interactive Response 
Technology (IRT).
4.4.2
Confirmation of the Indistinguishability of the Study Drugs 
The appearance and the form of both the drug and packaging are identical to those of their 
matching placebo. 
4.4.3
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking 
The randomization list and study medication blind will be maintained by the Interactive 
Response Technology (IRT) system. Details of steps to maintain treatment blind in the study 
team during the interim analysis will be described in an Interim Analysis Plan (IAP).
4.4.4
Breaking the Treatment Code for Emergency 
The treatment code for each randomized subject will be provided by the IRT in the event of a
medical emergency requiring knowledge of the treatment assigned to the subject. The time,
date, subject number and reason for obtaining any of these codes, and therefore breaking the
blind, must be documented in the study file. They must only be requested by the investigator
or other persons designated as sub-investigators. No subjects or other study personnel will be
made aware of the treatment given to any subject unless a medical emergency necessitates
such disclosure. Unblinding of the study drug should only be considered for subject safety or 
when critical therapeutic decisions are contingent upon knowing the blinded study drug 
assignment. Any unblinding by the investigational staff must be reported immediately to the 
Sponsor and must include an explanation of why the study drug was unblinded. If possible, 
the Sponsor should be contacted prior to unblinding of the study drug.
4.4.5
Breaking the Treatment Code by the Sponsor
The Sponsor may break the treatment code for subjects who experience a Suspected 
Unexpected Serious Adverse Reaction (SUSAR), in order to determine if the individual case 
or a group of cases requires expedited regulatory reporting. Individual Emergency Codes will 

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be provided to the limited staff who are responsible to break the codes for all SUSAR cases 
for reporting purposes.
4.5
Assignment and Allocation
All subject numbers will be assigned using the IRT starting at Screening. Randomization will 
be stratified by site. All subjects will have a unique, 10-digit subject number. The first 
5 digits of this number will be the investigator’s site number. The second 5 digits assigned 
will represent the subject’s accession number. This will be the number that identifies a 
subject during the course of the study.
All subjects who meet the eligibility criteria will be randomized. Subjects will be randomized 
in a 1:1 ratio to ASP0819 or placebo according to the randomization schedule through IRT. 
The site personal will dispense the treatment according to the IRT system’s assignment.
If a subject is assigned a randomization number, but does not receive study drug, the 
randomization number will not be used again. The randomization schedules that determine 
subject treatment will be computer-generated by IRT before the beginning of the study.
Specific procedures for randomization through the IRT are contained in the study-specific 
IRT manual.
5
TREATMENTS AND EVALUATION
5.1
Dosing and Administration of Study Drug(s) and Other 
Medication(s)
5.1.1
Dose/Dose Regimen and Administration Period
Subjects randomized to the ASP0819 group will receive ASP0819 15 mg (3 capsules of 
5 mg) qd for the duration of 8 weeks. Subject randomized to the placebo group will receive 
placebo to match ASP0819 (3 capsules) qd for the duration of 8 weeks. 
Doses should be taken in the morning with or without food. In case a subject forgets a dose, 
the dose should be taken as soon as they remember but prior to bedtime that day. The next 
day's dose should still be taken as planned. Two doses should not be taken in the same day.
At Randomization and at Visit 4 (Week 2), subjects will receive the assigned treatment 
sufficient for a period of 2 weeks (including morning dose on the day of the next visit). At 
Visit 5 (Week 4) subjects will receive the assigned treatment sufficient for a period of 4 weeks. 
Pharmacokinetic sampling will occur on Day 1 in the clinic at approximately 1 to 4 hour(s) 
after dosing and once (anytime during the visit) at Weeks 2, 4 and 8. There are no fasting 
requirements for the pharmacokinetic samples but date and time of the dose taken prior to 
collecting the pharmacokinetic sample, as well as the date and time of the last meal in 
relation to that dose will be captured in the eCRF. 

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5.1.2
Increase or Reduction in Dose of the Study Drug(s)
The dose of 15 mg qd of ASP0819 is less than the highest dose assessed in the phase 1 
multiple dose study (18 mg qd). This highest multiple dose of 18 mg was well tolerated and 
no maximum tolerated dose was determined. Stopping criteria are presented in [Section 6.1
Discontinuation of Subjects]. Study 0819-CL-0201 is a fixed dose, proof-of-concept study. In 
order to adequately evaluate the hypothesis, it is important to assess efficacy and safety 
across a common dose; therefore, dose increases and decreases are not allowed. 
5.1.3
Previous and Concomitant Treatment (Medication and Non-Medication Therapy)
Concomitant Medication Restrictions or Requirements:
Medications taken for fibromyalgia during the 12 months prior to Screening and other 
medication taken 28 days prior to the Screening visit and up to the first dose of study
medication (treatment period) will be documented in the appropriate CRF as prior fibromyalgia 
medications or other prior medication. Subjects taking prohibited medications who are willing 
to discontinue these medications, as clinically indicated and based upon the investigator’s 
recommendation, may wash-out over a period of 5 half-lives on a schedule determined by the 
investigator. 
Medications taken after the first dose of study medication and up to EOS will be documented 
on the appropriate CRF as concomitant medication. 
Prior and concomitant medications to be documented include but are not limited to the 
following: vitamins, herbal remedies (e.g., St. John’s wort, valerian), over-the-counter and 
prescription medications. Any medications taken for treatment of pain symptoms will be 
documented as such on the CRF.
Subjects are instructed not to take any concomitant medication without first consulting the 
investigator or study coordinator throughout the duration of the study.
Concomitant Medication for Treatment of Non-Fibromyalgia Pain Symptoms:
NSAIDs will be allowed (with the exception of celecoxib), as needed, for non-fibromyalgia 
pain, such as headache. Use in chronic treatment is not allowed (with the exception of low 
dose aspirin for cardioprophylaxis, up to 325 mg daily). NSAIDs are not to be used as rescue 
medication for the treatment of pain associated with fibromyalgia. Dosing should be 
consistent with approved labeling. NSAID use will be captured on the eCRF. 
Prohibited Therapies:
Concomitant use of the following medications, therapies or surgical procedures could 
influence the evaluation of the study drug’s efficacy and safety and are prohibited throughout 
the study (wash-out through the EOS):
●
Medications that may have efficacy in reducing pain in fibromyalgia (except for allowed 
rescue medication), are as follows: gabapentinoids, antidepressants (except for serotonin 
reuptake inhibitors), ketamine, GABAB receptor agonists (including sodium oxybate), 

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opioids, celecoxib, chronic non-narcotic analgesics (with the exception of low dose 
aspirin for cardioprophylaxis, up to 325 mg daily) and topical pain medications.
●
Medications that are sensitive CYP3A substrates or CYP3A substrates that have a 
narrow therapeutic range. 
●
Use of cannabinoids from the Screening visit and throughout the study. 
●
Procedures that may have efficacy in reducing pain in fibromyalgia, for example: nerve 
block, iontophoresis, laser therapy, acupuncture, tender point injections, dry needle 
injections, spinal cord stimulation therapy and transcutaneous electrical nerve 
stimulation.
●
Hypnotics other than those specified with restrictions in the following section on 
Permitted Medications. Tranquilizers, sedating antihistamines (non-sedating 
antihistamines are permitted), benzodiazepines for sedative, anxiolytic, or sleep aid. In 
contrast, non-benzodiazepines such as zolpidem are allowed for insomnia as discussed 
below in the section, Permitted Medication.
Refer to [Appendix 12.1 List of Excluded Concomitant Medications] for a list of drug classes 
and specific medications that are prohibited during participation in the study. 
Permitted Medications:
This list is not all inclusive and the Medical Monitor should be contacted to discuss medications 
not listed below.
●
The following serotonin reuptake inhibitors will be allowed if the subject is on a stable 
dose 60 days prior to Screening and no changes are anticipated during the course of the 
study: sertraline, paroxetine, fluoxetine, citalopram, escitalopram, fluvoxamine, 
vilazodone and vortioxetine. 
●
The following medications will be allowed if the subject is on a stable dose for at least 
30 days prior to Screening and no additional medication is taken for insomnia: zolpidem 
up to10 mg, eszopiclone up to 1 mg, zaleplon up to 10 mg, zopiclone up to 2 mg and
melatonin for sleep.
●
Allowed stable medications (i.e., stable dose 30 days prior to Screening and with no 
changes anticipated during the course of the study):  anti-diabetic medications, anti-
hypertensive medications, non-sedating antihistamines, lipid-lowering agents, asthma 
medications, low dose aspirin for cardioprophylaxis, non-sedating treatments for allergic 
rhinitis, triptans, multivitamins, short-term use of nasal, inhaled and topical 
corticosteroids. NSAIDs will be allowed (with the exception of celecoxib), as needed,
for non-fibromyalgia pain, such as headache. However, chronic use of NSAIDs is not 
allowed (with the exception of low dose aspirin for cardioprophylaxis, up to 325 mg 
daily). 
Refer to [Appendix 12.2 List of Allowed Anti-depressants and Sleep Aids] for a list of the
medications that are permitted during participation in the study. 

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Permitted Non-Medication Therapy:
The following therapies must be stable for at least 30 days prior to Screening and with no 
changes anticipated during the course of the study: exercise routines, chiropractic care, 
physical therapy, psychotherapy, massage therapy. Non-Medication Therapy for 
fibromyalgia during the 12 months prior to Screening will be documented in the appropriate 
case report.
5.1.4
Treatment Compliance
Study subjects should be counseled on the need to meet 100% compliance with study drug. 
Investigator or designee should ensure that study subjects meet this goal throughout the study 
period. Compliance will be verified by the accounting of study drug at each visit after 
Randomization. When study drug is administered at the research facility, it will be 
administered under the supervision of study personnel.
Compliance of the study drug will be monitored by the accounting of unused medication 
returned by the subject at visits. Compliance will be documented.
If compliance is less than 80%, or over 100%, the investigator or designee is to counsel the 
subject and ensure steps are taken to improve compliance. 
5.2
Demographics and Baseline Characteristics
5.2.1
Demographics
Date of birth, sex, race, ethnicity, height, weight, and BMI will be recorded at Screening
(Visit 1). Height will be measured at Screening only. Weight will also be collected prior to 
Randomization and at Week 8/EOT.
5.2.2
Medical History
A detailed medical history (including psychiatric history) for each subject will be obtained at 
Screening, including prior medication and contraception use. All relevant past and present 
conditions, as well as prior surgical procedures will be recorded. Presence of current and/or 
past major depressive disorder will be captured in the eCRF. Any history of diagnosis of the 
following disorders will be captured in the eCRF: temporomandibular disorders, irritable 
bowel syndrome, chronic tension type headache, migraine, chronic low back pain, myalgic 
encephalomyelitis/chronic fatigue syndrome, interstitial cystitis/painful bladder syndrome, 
endometriosis, and vulvodynia.
Details on family history of fibromyalgia, depression, bipolar disorder, and Long QT 
Syndrome will be obtained for each subject.
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease 
The diagnosis fibromyalgia must be confirmed by the investigator and documented in the 
subject’s medical notes (meeting both the 1990 and 2010 American College of 
Rheumatology clinical classification criteria for fibromyalgia). Duration of fibromyalgia, 

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date of onset of fibromyalgia symptoms and date of fibromyalgia diagnosis will be recorded 
in the eCRF. 
The number of tender points, WPI and SS score will be completed by the clinician on a tablet 
device during the Screening visit. Subjects should have a WPI ≥7 and SS score ≥ 5 or WPI 
of 3 to 6 and SS scale score ≥ 9. Tender point examination training of the principal
investigator and/or designated site study physician must be documented.
Severity of pain due to fibromyalgia will be assessed through the PGIS and the FIQR and 
subjects will use a tablet device for completion. Subjects should have a FIQR pain score of 
≥4 at Visit 1 to be eligible for participation in this study. In addition, the NPSI will be used 
to characterize the presence of neuropathic pain symptoms.
In order to be eligible for Randomization (Visit 3), subjects will be required to have a mean 
daily average pain score of ≥ 4 and ≤9 on the NRS during the Baseline Diary Run-In period 
and meeting pre-specified criteria for daily average pain scores. 
The Complex Medical Symptoms Inventory (CMSI) is designed to aid clinicians in 
collecting information from fibromyalgia patients regarding their disease-specific symptoms 
and to characterize the diagnosis. The inventory contains 2 parts: a symptom checklist to be 
completed by patients, and a diagnostic inventory completed by the clinician. In this study, 
only the symptom checklist will be utilized.
The symptom checklist contains 39 items (males) or 41 items (females). For each symptom 
question, patients mark a box to indicate if the symptom: 1) has occurred for at least 
3 months in the past year, and/or 2) has occurred for a 3-month period during their lifetime. 
Only the boxes that apply should be checked. 
The CMSI will be completed on the tablet device by the subject at Baseline Diary Run-In
(Visit 2).
5.2.4
Mini-International Neuropsychiatric Interview
The M.I.N.I. International Neuropsychiatric Interview (M.I.N.I. 7.0) is a short, structured 
diagnostic interview administered by trained personnel. The instrument captures the major 
Axis I psychiatric disorders in Diagnostic and Statistical Manual of Mental Disorders 
(DSM-V) and International Statistical Classification of Diseases and Related Health 
Problems (ICD-10), and has demonstrated equivalent reliability, validity, and decreased 
interview time when compared to the Structured Clinical Interview for DSM diagnoses 
(SCID-P). Each module begins with screening questions that are answered yes or no. A
negative response in the screening algorithm advances the interview to the next module, 
whereas a positive response will prompt additional questions that ask patients to characterize 
behavior with “yes” or “no” responses. Some questions contain a recall period (e.g., “Past 
Two Weeks,” “Past Episode” and “Current Episode”). After completion of the additional 
questions, the clinician indicates whether or not the diagnostic criteria have been met, based 
on the instrument scoring criteria [Sheehan et al, 1998; Amorim et al, 1998; Sheehan et al, 
1997; Lecrubier et al, 1997].

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The M.I.N.I. 7.0 will be completed at Screening by trained site personnel, in accordance with 
the structured interview requirements.
5.2.5
Hospital Anxiety and Depression Scale
HADS is a 14-item self-report scale developed for the assessment of anxiety and depression 
in non-psychiatric populations. Each item is rated on a 4-point Likert-type scale with varying 
level descriptors specific to each item. For the purposes of this study, only the 7-item 
depression subscale will be administered to monitor subjects for moderate to severe 
symptoms of depression [Snaith, 2003; White et al, 1999; Hermann, 1997; Zigmond & 
Snaith, 1983].
The HADS depression subscale will be recorded on a tablet device at Screening and at
Randomization before dosing. Subjects will be excluded in case they have a score of > 14 at
Screening or Randomization. The HADS depression subscale will also be administered at
Week 8/EOT.
5.3
Efficacy and Pharmacokinetics Assessments
The subjects will use a handheld device, e-diary, to report daily average pain NRS scores, 
enter FMSD data and to capture rescue medication use. Data will be automatically 
transmitted to a central database.
The questionnaires on efficacy to be performed during the clinic visits (FIQR, PGIC, PGIS, 
EQ-5D-5L and mIBS-D Symptoms Diary) will be reported on a tablet device [see also 
Appendix 12.6]. Efficacy will also be assessed using the HADS depression subscale [see 
Section 5.2.5 Hospital Anxiety and Depression Scale].
Subjects will receive instructions on how to complete the e-diary/tablet and will be counseled
on the importance of completing the e-diary daily and should be retrained on the use of the 
diary as needed. During the start of Baseline Diary Run-In (Visit 2), the subject will be given 
sufficient time to practice e-diary completion, supervised by trained site personnel.
Questionnaires need to be completed by the subject prior to any other study assessment.
During the Baseline Diary Run-In period, subjects must record daily average pain ratings on
a minimum of 5 of 7 days in order to be randomized in the study.
5.3.1
Daily Average Pain Numerical Rating Scale
The NRS is a generic instrument for the assessment of pain, consisting of a single question 
that asks subjects to record their daily average pain on an 11- point scale, where 0 anchors 
“no pain” and 10 “pain as bad as you can imagine.” The recall period is the last 24 hours. To 
be eligible for the study subjects should be compliant with daily pain recordings during the 
Baseline Diary Run-In period, as defined by the completion of a minimum of 5 of 7 daily 
average pain ratings and agrees to complete daily diaries throughout the duration of the 
study.
The NRS should be completed by the subject daily for the duration of the study, in the 
evening and at a consistent time each day. Throughout the study, the subjects should be 

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counseled on completion of daily e-diary entries and should be retrained on the use of the 
diary as needed.
The NRS will be collected from the start of the baseline run-in period through Week 10.
5.3.2
Fibromyalgia Sleep Diary
The Fibromyalgia Sleep Diary (FMSD) is an 8-item patient reported outcome (PRO) measure 
of sleep disturbance specific to fibromyalgia patients, covering the hypothesized domains of 
Falling Asleep, Staying Asleep, and Sufficient Sleep. Each item is rated on an 11-pt NRS
anchored by “0 - not at all” and “10 – extremely.” The subject completes the FMSD to rate 
their quality of sleep during the previous night. The instrument has completed qualitative 
development in accordance with the Federal Drug Administration (FDA) PRO guidance and 
ISPOR recommendations, and has established content validity [Kleinman et al, 2014]. 
The FMSD will be completed on the electronic patient reported outcome (ePRO) device by 
the subject, daily upon awakening, starting at Baseline Diary Run-In (Visit 2) until Week 10 
(Visit 7).
5.3.3
Fibromyalgia Impact Questionnaire Revised
FIQR was developed to capture the total spectrum of problems related to fibromyalgia and 
the responses to therapy. The original FIQ and FIQR have been extensively used as an index 
of disease activity and therapeutic efficacy. The 21-item FIQR contains 3 domains: activities 
of daily living, overall impact, and symptoms. Subjects answer each question on an 11-pt 
NRS, with anchors appropriate to each question. The recall period is the last 7 days or, for 
the physical function domain, the last time the activity was performed if not within the 7 day 
recall period [Bennett et al, 2009].
The FIQR will be completed by the subject on the tablet device at Randomization and at the 
Week 2, 4, 8/EOT and Week 10 visit. At Screening, the subject only completes the pain item 
of the FIQR. 
5.3.4
Patient Global Impression of Change and Patient Global Impression of 
Severity
PGIC and PGIS are adaptable global indices that capture the patient’s perspective on a 
defined condition. The PGIC is a self-administered 7-pt Likert scale that asks subjects to 
evaluate their fibromyalgia relative to baseline. The PGIC is anchored by “very much 
improved” and “very much worse.” The PGIS is a self-administered 6-pt Likert scale that 
asks subjects to evaluate how their fibromyalgia is now. The PGIS is anchored by “no 
symptoms” to “very severe”. 
Both the PGIC and the PGIS will be completed by the subject on the tablet device at the site. 
The PGIC will be completed at Weeks 2, 4, 8 and 10. The PGIS will be completed at 
Randomization, Weeks 2, 4, 8 and 10. 

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5.3.5
Neuropathic Pain Symptom Inventory
The NPSI is a self-report questionnaire specifically designed to evaluate the different
symptoms of neuropathic pain [Bouhassira et al, 2004]. The questionnaire comprises a list of 
10 descriptors (plus 2 temporal items) reflecting spontaneous, paroxysmal and evoked pain 
(i.e., mechanical and thermal allodynia/hyperalgesia) and paresthesia/dysesthesia. Each of 
these items is quantified on a (0–10) numerical scale, with 0 = none and 10 = worst 
imaginable. The NPSI discriminates and quantifies 5 distinct clinically relevant dimensions 
of neuropathic pain syndromes. The instrument is being used to understand neuropathic pain 
symptoms that the subjects may have at study entry, and to evaluate any change in symptoms 
during the study.
The NPSI will be completed by the subject on the tablet device at the site at Randomization 
and Week 8/EOT.
5.3.6
European Quality of Life-5 Dimensions-5 Levels Questionnaire
The subjects’ general health status will be assessed by the EQ-5D-5L. The EQ-5D-5L is an 
international and standardized nondisease specific (i.e., generic) instrument for describing 
and valuing health status. It is a multidimensional measure of Health-Related Quality of Life, 
capable of being expressed as a single index value and specifically designed to complement 
other health status measures. The EQ-5D-5L has 5 dimensions: Mobility, Self-Care, Usual 
Activities, Pain/Discomfort, and Anxiety/Depression. In the newest version, each dimension 
has 5 response levels (e.g., no problems, slight problems, moderate problems, severe 
problems and unable to perform the activity). In addition, it has a vertical visual analog scale 
that elicits a self-rating by the respondent of his/her health status on a scale from 0 (bottom: 
“The worst health you can imagine”) to 100 (top: “The best health you can imagine”).
The EQ-5D-5L will be completed on the tablet device by the subject at Randomization
(predose), Week 8 and Week 10.
5.3.7
Modified Irritable Bowel Syndrome-Diarrhea Predominant
The mIBS-D is a 5-item questionnaire that assesses the predominant symptoms of IBS-D 
(abdominal pain, stomach pain, abdominal pressure, bloating, abdominal cramping) on an 11-
pt NRS (0 - absence of symptoms to 10- severe symptoms). The items in the mIBS-D are
derived from the 7-item IBS-D. The instrument is being used to understand IBS-like 
symptoms that the subjects may have at study entry, and to evaluate any change in symptoms 
during the study [Delgado-Herrera et al, 2016; Rosa et al, 2016; Marquis et al, 2014].
Subjects will be asked to complete the questionnaire items while considering 2 distinct recall 
periods (previous 24 hours and last 7 days).
The mIBS-D Symptoms Diary (5 items) will be completed by the subject on the tablet device 
at Randomization and at Weeks 2, 4 and 8/EOT.

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5.3.8
Pharmacokinetics
Pharmacokinetic sampling will occur on Day 1 in the clinic at approximately 1 to 4 hour(s) 
after dosing and once (anytime during the visit) at Weeks 2, 4 and 8. Date and time of the 
dose taken prior to collecting the PK sample, as well as the date and time of the last meal in 
relation to that dose will be captured in the eCRF. 
Details on sample collection, processing, labeling, storage and shipment procedures are 
provided in the laboratory manual. Analysis of ASP0819 and any metabolites (if applicable) 
will be performed using a validated method at a bioanalytical laboratory specified by the 
Sponsor.
5.4
Safety Assessment
Safety will be assessed through AEs, safety laboratory tests (chemistry, hematology and
urinalysis), physical examination, vital signs, 12-lead ECGs and the C-SSRS. Unscheduled 
assessments will be performed if clinically warranted.
5.4.1
Vital Signs
Single measures of sitting resting blood pressure (SBP and DBP) and pulse rate values will 
be obtained at each visit (except for Visit 2) and should be conducted prior to blood draws. 
Blood pressure should always be measured on the same arm of the subject and preferably in 
the same position (sitting or supine).
Body temperature will be assessed at Screening, Randomization and Week 8/EOT only. The 
method of recording body temperature must be the same between visits (acceptable methods 
are oral or tympanic temperature).
Vital signs should be taken before scheduled blood draws.
5.4.2
Adverse Events
See [Section 5.5 Adverse Events and Other Safety Aspects] for information regarding AE
collection and data handling. 
5.4.2.1 Adverse Events of Possible Hepatic Origin
See [Appendix 12.3 Liver Safety Monitoring and Assessment] for detailed information on 
liver abnormalities, monitoring and assessment, if the AE for a subject enrolled in a study 
and receiving study drug is accompanied by increases in liver function test (LFT) values
(e.g., AST, ALT, bilirubin, etc.) or is suspected to be due to hepatic dysfunction. 
Subjects with AEs of hepatic origin accompanied by LFT abnormalities should be carefully 
monitored. 
5.4.3
Laboratory Assessments
Below is a table of the laboratory tests that will be performed during the conduct of the study. 
See also the [Table 1 Schedule of Assessments] for study visit collection dates.

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Clinical significance of out-of-range laboratory findings is to be determined and documented
by the investigator/sub-investigator who is a qualified physician.
Panel
Visits
Parameters to be analyzed
Hematology
and
Coagulation
Screening, Randomization, 
Weeks 2, 4, 8/EOT and 10
Hemoglobin
Hematocrit
Erythrocytes (red blood cell [RBC])
Leukocytes (white blood cell [WBC])
Differential WBC
Platelets
TSH (only at Screening)
PT and INR
MCV
MCH
Reticulocytes
Biochemistry
Screening, Randomization, 
Weeks 2, 4, 8/EOT and 10
Sodium
Potassium
Calcium
Chloride
Magnesium
Glucose
Creatine Kinase
Creatinine
Alkaline Phosphatase (ALP)
Lactate dehydrogenase (LDH)
Aspartate transaminase (AST)
Alanine transaminase (ALT)
Gamma glutamyl transpeptidase
Total bilirubin (direct and indirect)
Total protein
Albumin
Total cholesterol
Triglycerides
Uric Acid
Blood Urea Nitrogen
Inorganic phosphate
Serology
Screening
Hepatitis B surface antigen (HBsAg)
Hepatitis A virus antibodies
(immunoglobulin M) (anti-HAV [IgM])
Hepatitis C (HCV) Antibody
Urinalysis
Screening, Randomization, 
Weeks 2, 4, 8/EOT and 10
Leucocytes
Nitrite
Protein
Glucose
pH
Table continued on next page

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Panel
Visits
Parameters to be analyzed
Urinalysis
(continued)
Screening, Randomization, 
Weeks 2, 4, 8/EOT and 10
Blood
Urobilinogen
Bilirubin
Ketones
Potassium
Drug Screen
(urine collection/ 
urine dip stick)
Screening*, Baseline Diary Run-
In (Visit 2), Randomization
Amphetamines
Barbituates
Benzodiazepines
Cannibinoids
Cocaine
Opioids
Alcohol screen
(urine)
Screening, Baseline Diary Run-
In (Visit 2), Randomization
Alcohol
Pregnancy test
(for applicable
females only)
Screening (serum),
Randomization (urine), 
Week 8/EOT (urine), and 
Week 10 (urine)
β-HCG
*A positive test for tetrahydrocannabinol (THC) and/or opioids is allowed at the Screening visit, but must be 
confirmed negative prior to Baseline Diary Run-In and Randomization.
Drug and alcohol screen will be analyzed by central lab at Screening.
Central laboratory will provide kits to perform urinary drug and alcohol screening tests to be 
performed locally at Baseline Diary Run-In and Visit 3 (prior to Randomization). 
Results of the urinary drug and alcohol screen tests will be noted in the patient files.
A serum pregnancy test will be performed for all female subjects of child-bearing potential at 
Screening, A urine pregnancy test will be performed for female subjects of child-bearing 
potential prior to Randomization and at Week 8/EOT and the Week 10/FU visits. 
If the clinical laboratory results are outside the normal range, the investigator will document 
his/her assessment as clinically significant or not clinically significant. 
Unscheduled tests or a repeat of abnormal laboratory test(s) may be performed if clinically 
indicated and to follow-up on suspected AEs.
5.4.4
Physical Examination 
The subject will be examined by a medical doctor or other allied professional at Screening, 
Randomization (predose), Week 8 and Week 10. Physical examination may also be 
performed at unscheduled visits if necessary. It includes examination of main body systems, 
such as cardiovascular system, chest/lungs, abdomen, neurological state and musculoskeletal 
system.
At the Screening visit (Visit 1) the physical examination will include a tender point exam.
For the tender point examination, an incremental pressure with a maximum force of 
approximately 4 kg will be applied to the 18 possible tender point sites. A positive tender 

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point count is a response from the subject indicating a subjective feeling of discomfort 
following pressure ≤ 4 kg. 
The medical doctor will conduct the exam, determine findings and assess any abnormalities 
as to clinical significance and whether any exclusion criteria have been met. After study drug 
administration, new abnormal findings or a worsening of an ongoing abnormal condition 
must be recorded as an AE.
5.4.5
Electrocardiogram 
A 12-lead ECG will be performed at Screening, Randomization, EOT and FU visits. All 
ECGs should be taken before any scheduled blood draws. ECGs will be recorded with the 
subject in the supine position, after the subject has been lying down for approximately 5 
minutes. There should be at least 5 minutes between ECG measurements in case a repeat is 
needed. Any clinically significant adverse changes on the ECG will be reported as AEs.
Printouts of all ECGs, marked with the subject number and initials, visit date and visit 
number should be stored in the subject’s source data.
5.4.6
Colombia Suicide Severity Rating Scale
The C-SSRS was developed as a screening tool to identify suicide risk. The interview asks 
subjects detailed questions regarding suicidal ideation, behaviors, intensity of ideation, and 
attempts. Response options and recall periods vary in accordance with the nature of the 
question. The scale requires training to ensure appropriate administration. 
The C-SSRS will be performed by trained site staff via interview at Screening, 
Randomization, and at Weeks 2, 4, 8 and 10. At Screening, the “Screening /baseline” version 
is to be used to determine eligibility. During all subsequent visits, the “Since last visit” 
version is used to monitor on-study suicidal ideation and behavior after the initial assessment. 
Responses will be reported on the tablet device. 
Subjects who have a history of suicide attempt or suicidal behavior within the last 12 months, 
or has suicidal ideation within the last 12 months (a response of “yes” to questions 4 or 5 on 
the suicidal ideation domain), will be excluded.
5.5
Adverse Events and Other Safety Aspects
5.5.1
Definition of Adverse Events
An AE is any untoward medical occurrence in a subject, temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product. An AE 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a 
medicinal product.
In order to identify any events that may be associated with study procedures and could lead 
to a change in the conduct of the study, Astellas collects AEs even if the subject has not 
received treatment. AE collection begins after the signing of the informed consent and will be 
collected until 4 weeks after the last dose of study drug. 

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An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG 
data, physical examination) should be defined as an AE only if the abnormality meets 1 of 
the following criteria:

Induces clinical signs or symptoms

Requires active intervention

Requires interruption or discontinuation of study drug

The abnormality or test value is clinically significant in the opinion of the investigator.
5.5.2
Definition of Serious Adverse Events
An AE is considered “serious” if, in the view of either the investigator or Sponsor, it results 
in any of the following outcomes: 

Results in death

Is life-threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or Sponsor, its occurrence places the subject at immediate risk of death. It does 
not include an AE that, had it occurred in a more severe form, might have caused death)

Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 

Results in congenital anomaly, or birth defect

Requires inpatient hospitalization (except for planned procedures as allowed per study) or 
leads to prolongation of hospitalization (hospitalization for 
treatment/observation/examination caused by AE is to be considered as serious) 

Other medically important events (defined in paragraph below)
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent 1 of the other outcomes listed in the definition 
above. These events, including those that may result in disability/incapacity, should also 
usually be considered serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that 
do not result in hospitalization; or development of drug dependency or drug abuse. 
The Sponsor has a list of events that they classify as “always serious” events. If an AE is 
reported that is considered to be an event per this classification as “always serious,” 
additional information on the event may be requested. 
5.5.3
Special Situations
Special Situations observed in association with the study drug(s) (e.g., test drug, comparator, or 
background therapy) administered to the subject as part of the study are collected as described 
in the table below. These Special Situations are not considered AEs but can be associated with 
or result in an AE. An AE that may be associated with or result from a Special Situation is to 
be assessed separately from the Special Situation and captured in the eCRF or electronic data 
source. If the AE meets the definition of serious, these SAEs are to be collected via the 

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SAE/Special Situation worksheet together with the details of the associated Special Situation 
and reported as described in [Section 5.5.6 Reporting of Serious Adverse Events].
Special Situation
Collected
SAE/Special Situation worksheet
eCRF
Uses other than what is stated in the protocol 
X
Overdose* of the medicinal product(s) [see 
Section 5.5.10 Emergency Procedures and 
Management of Overdose]
X**
X
Suspected misuse/abuse of the investigational 
medicinal product(s)
X
X
*Overdose refers to the administration of a quantity of a study drug given per administration or cumulatively, 
which is above that specific in the protocol. This may be either an accidental or intentional overdose. 
**In the event of an intentional overdose, the Special Situation worksheet must be filled out. 
5.5.4
Criteria for Causal Relationship to the Study Drug
AEs that fall under either "Possible" or "Probable" should be defined as "AEs whose 
relationship to the study drugs could not be ruled out".
Causal relationship
to the study drug
Criteria for causal relationship
Not Related
A clinical event, including laboratory test abnormality, with a 
temporal  relationship to study drug administration, which makes a 
causal relationship improbable, and/or in which other drugs, 
chemicals or underlying disease provide plausible explanations.
Possible
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the study drug, but 
which could also be explained by concurrent disease or other drugs 
or chemicals. Information on drug withdrawal may be lacking or 
unclear.
Probable
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the study drug, 
unlikely to be attributed to concurrent disease or  other drugs or 
chemicals, and which follows a clinically reasonable response on re-
administration (rechallenge) or withdrawal (dechallenge).
5.5.5
Criteria for Defining the Severity of an Adverse Event
The investigator will use the following definitions to rate the severity of each AE:

Mild: No disruption of normal daily activities

Moderate: Affects normal daily activities

Severe: Inability to perform daily activities

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5.5.6
Reporting of Serious Adverse Events
The collection of AEs and the expedited reporting of SAEs will start following receipt of the 
informed consent and will continue to 30 days after the last dose of study drug. 
In the case of a SAE, the investigator must contact the Sponsor by fax or email immediately
(within 24 hours of awareness), and the study team (CRA and Medical Monitor) should be 
notified as well within 24 hours of awareness.
The investigator should complete and submit an SAE/Special Situation Worksheet containing 
all information that is required by local and/or regional regulations to the Sponsor by email or 
fax immediately (within 24 hours of awareness). 
For contact details, see [Section II Contact Details of Key Sponsor's Personnel]. Fax or email 
the SAE/Special Situations Worksheet to:
Astellas Pharma Global Development – United States
Pharmacovigilance
Fax number (888) 396-3750
Alternate fax number: (847) 317-1241
Email: safety-us@astellas.com
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
Sponsor's Medical Monitor/Study Physician or his/her designee [Section II Contact Details of 
Key Sponsor’s Personnel]. 
Follow-up information for the event should be sent promptly (within 7 days of the initial 
notification).
Full details of the SAE should be recorded on the medical records, SAE/Special Situation 
Worksheet and on the (e)CRF.
The following minimum information is required:

International Study Number (ISN)/study number, 

subject number, sex and age,

the date of report,

a description of the SAE (event, seriousness criteria), and

causal relationship to the study drug.
The Sponsor or Sponsor's designee will submit expedited safety reports (e.g., IND Safety 
Reports and Council for International Organizations of Medical Sciences-I) to the regulatory 
agencies (e.g., FDA, European Medicines Agency) per current local regulations, and will 
inform the investigators of such regulatory reports as required. Investigators must submit 
safety reports as required by their IRB within timelines set by regional regulations (e.g.,
European Union [EU], electronic Common Technical Document, FDA) where required. 
Documentation of the submission to and receipt by the IRB of expedited safety reports 
should be retained by the site.

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The Sponsor will notify all investigators responsible for ongoing clinical studies with the 
study drug of all SUSARs, which require submission per local requirements IRB.
The investigators should provide written documentation of IRB notification for each report to 
the Sponsor.
The investigator may contact the Sponsor's Medical Monitor/Study Physician for any other 
problem related to the safety, welfare, or rights of the subject.
5.5.7
Follow-up of Adverse Events
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized by the investigator. 
If during AE follow-up, the AE progresses to an "SAE," or if a subject experiences a new 
SAE, the investigator must immediately report the information to the Sponsor. 
Please refer to [Appendix 12.3 Liver Safety Monitoring and Assessment] for detailed 
instructions on Drug-Induced Liver Injury.
5.5.8
Monitoring of Common Serious Adverse Events
No common SAEs have been identified at this time. Common SAEs are SAEs commonly 
anticipated to occur in the study population independent of drug exposure. SAEs classified as 
“common” are provided in [Appendix 12.4 Common Serious Adverse Events] for reference. 
The list does NOT change the investigator’s reporting obligations or prevent the need to 
report an AE meeting the definition of an SAE as detailed above. The purpose of this list is to 
alert the investigator that some events reported as SAEs may not require expedited reporting 
to the regulatory authorities based on the classification of “common SAEs” as specified in 
[Appendix 12.4 Common Serious Adverse Events]. The Sponsor will monitor these events 
throughout the course of the study for any change in frequency. Any changes to this list will 
be communicated to the participating investigational sites. Investigators must report 
individual occurrences of these events as stated in [Section 5.5.6 Reporting of Serious 
Adverse Events]. 
5.5.9
Procedure in Case of Pregnancy
If a female subject becomes pregnant during the study dosing period or within 28 days from 
the discontinuation of dosing, the investigator is to report the information to the Sponsor
according to the timelines in [Section 5.5.6 Reporting of a Serious Adverse Event] using the 
pregnancy reporting form and the SAE/Special Situation Worksheet. 
The investigator will attempt to collect pregnancy information on any female partner of a 
male subject who becomes pregnant during the study dosing period or within 28 days from 
the discontinuation of dosing and report the information to Sponsor according to the 
timelines in [Section 5.5.6 Reporting of a Serious Adverse Event] using the pregnancy 
reporting form and the SAE/Special Situation Worksheet. 

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The expected date of delivery or expected date of the end of the pregnancy, last menstruation, 
estimated conception date, pregnancy result and neonatal data etc., should be included in this 
information.
When the outcome of the pregnancy falls under the criteria for SAEs (spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly [including anomaly in a 
miscarried fetus]), the investigator should respond in accordance with [Section 5.5.6
Reporting of Serious Adverse Event]. Additional information regarding the outcome of a 
pregnancy (which is categorized as an SAE) is mentioned as follows:
●
"Spontaneous abortion" includes miscarriage, abortion and missed abortion.
●
Death of an infant within 1 month after birth should be reported as an SAE regardless of 
its relationship with the study drug.
●
If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the investigator.
●
In the case of a delivery of a living newborn, the "normality" of the infant is evaluated at 
the birth.
●
Unless a congenital anomaly is identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination.
5.5.10
Emergency Procedures and Management of Overdose
No information on overdose with ASP0819 in humans is available. Following a suspected 
overdose, study subjects should be managed with symptomatic and supportive care and 
observed in a controlled medical setting according to the current standard of care. The 
Medical Monitor/Expert should be contacted when appropriate.
5.5.11
Supply of New Information Affecting the Conduct of the Study
When new information becomes available necessary for conducting the clinical study 
properly, the Sponsor will inform all investigators involved in the clinical study, as well as 
the regulatory authorities. Investigators should inform the IRB of such information when 
needed. 
The investigator will also inform the subjects, who will be required to sign an updated 
informed consent form (ICF) in order to continue in the clinical study.
5.6
Test Drug Concentration
Test drug concentration will be measured to evaluate clinical pharmacokinetics of ASP0819 
and any metabolites (if applicable). Pharmacokinetic blood sampling will occur on Day 1 in 
the clinic at approximately 1 to 4 hour(s) after dosing and once (anytime during the visit) at 
Weeks 2, 4 and 8. Date and time of the dose taken prior to collecting the PK sample, as well 
as the date and time of the last meal in relation to that dose will be captured in the eCRF. 
Details on sample collection, processing, labeling, storage, and shipment procedures are 
provided in the laboratory manual. Analysis will be performed using a validated liquid

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chromatography with tandem mass spectrometry method at a bioanalytical laboratory 
specified by the Sponsor. The remainder of the pharmacokinetic samples might be used in the 
future to explore the absorption, distribution, metabolism and excretion profile, mode of 
action and/or safety signals of ASP0819. The samples will be destroyed a maximum of 
5 years after clinical study completion.
5.7
Other Measurements, Assessments or Methods
5.7.1
Blood Sample for Future Pharmacogenomics Analysis (Retrospective 
Pharmacogenomics Analysis) (Optional)
Pharmacogenomics (PGx) research may be conducted in the future to analyze or determine 
genes of relevance to clinical response, pharmacokinetics, and toxicity/safety issues. After 
Randomization (see schedule of assessments), a 6 mL sample of whole blood for possible 
retrospective PGx analysis will be collected. Samples will be shipped to a Sponsor 
designated banking CRO.
Details on sample collection, labeling, storage and shipment procedures will be provided in a 
separate laboratory manual.
See [Appendix 12.5, Retrospective PGx Sub-study] for further details on the banking 
procedures.
5.7.2
Subject Training Materials
During the Screening visit, booklets will be provided to the subjects for educational purposes. 
These booklets will provide the subjects with more information on what to expect while
participating in a clinical study and how to accurately report their pain. At the end of each
booklet, the subjects will be asked to answer several questions to test their knowledge. These
results are not collected in the study database.
5.8
Total Amount of Blood
Total amount of blood collected per subject for laboratory specimens is approximately 
130 mL.

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6
DISCONTINUATION
6.1
Discontinuation of Individual Subject(s) 
A discontinuation from treatment is a subject who enrolled in the study and for whom study 
treatment is permanently discontinued for any reason. 
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice. The 
investigator is also free to discontinue the subject from study treatment or to terminate a 
subject's involvement in the study at any time if the subject's clinical condition warrants it.
If a subject is discontinued from the study with an ongoing AE or an unresolved laboratory 
result that is significantly outside of the reference range, the investigator will attempt to 
provide follow-up until the condition stabilizes or no longer is clinically significant. 
Discontinuation Criteria from Treatment for Individual Subjects:
1. Subject develops unacceptable toxicity
2. Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject
3. Subject withdraws consent for further treatment
4. Female subject becomes pregnant
5. Monitoring of liver safety is done to address the potential for liver toxicity (see 
[Appendix 12.3] for details).
If an individual subject has an ALT or AST result > 3 x ULN or total bilirubin level 
(TBL) > 2 x ULN, testing should be repeated within 48 to 72 hours of notification of the 
test results; and then twice weekly liver safety tests will be performed until normalization 
or study discontinuation.
Any subject that meets the following criteria below [outlined in the FDA Guidance for
Industry, Drug-Induced Liver Injury: Pre-marketing Clinical Evaluation (July 2009)] 
should be considered for discontinuation from treatment.
●
ALT or AST > 8 x ULN
●
ALT or AST > 5 x ULN for more than 2 weeks
●
ALT or AST > 3 x ULN and (TBL > 2 x ULN or international normalized ratio 
[INR] > 1.5)
●
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%)
Even if a subject discontinues treatment the subject should be asked to continue completion 
of the EOT, follow-up and EOS visits. 
6.2
Discontinuation of the Site
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the Sponsor.

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6.3
Discontinuation of the Study
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If 
the Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination.
7
STATISTICAL METHODOLOGY
The statistical analysis will be coordinated by the responsible biostatistician of Astellas 
Pharma Global Development-United States (APGD-US). A Statistical Analysis Plan (SAP) 
will be written to provide details of the analysis, along with specifications for tables, listings 
and figures to be produced. The SAP will be finalized before the first interim lock at the 
latest. Any changes from the analyses planned in SAP will be justified in the Clinical Study 
Report (CSR).
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
SD, minimum, median and maximum) for continuous endpoints, and frequency and 
percentage for categorical endpoints.
7.1
Sample Size
The sample size calculations are based on the primary efficacy endpoint of change from 
baseline to Week 8 in mean daily average pain NRS. A meta-analysis of the change from 
baseline in mean daily average pain NRS for pregabalin or duloxetine vs placebo in studies 
for fibromyalgia indicated an effect size of approximately 0.30. 
Using an effect size of 0.39 (30% larger than the meta-analysis result) for the primary 
efficacy endpoint for the comparison of ASP0819 vs placebo, 84 subjects in the ASP0819
and placebo groups would be required to provide 80% power to demonstrate statistical 
significance using a 1-sided 5% significance level (based on the assumption of normally 
distributed data, and taking into account the interim analysis for futility).
The total number of subjects required for the analysis would be 168 (84:84 subjects in 
ASP0819:placebo groups). Assuming approximately 5% of randomized subjects will not 
contribute to the analysis, then a total of 178 subjects would be required for randomization 
using a 1:1 randomization ratio (89:89) subjects for the ASP0819:placebo groups.
7.2
Analysis Sets
Detailed criteria for analysis sets will be laid out in Classification Specifications and for the 
allocation of subjects to analysis sets, except Pharmacokinetic Analysis Set (PKAS), will be 
determined prior to database hard-lock. The allocation of subjects to PKAS will be 
determined after database hard lock.

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7.2.1
Full Analysis Set
The full analysis set (FAS) will consist of all subjects who are randomized and receive at 
least 1 dose of study drug. This will be the analysis set for demographic and baseline 
summaries and all efficacy analyses.
When the FAS is utilized in an analysis, subjects will be presented by the randomized 
treatment group, even if the treatment they received was different. 
7.2.2
Per Protocol Set
The per protocol set (PPS) will consist of a subset of subjects from the FAS who meet criteria 
based on adherence to the protocol, which may affect the primary efficacy endpoint or select 
secondary efficacy endpoints. The PPS criteria will be defined in the SAP.
The PPS will be used for demographic and baseline characteristic summaries and for 
sensitivity analyses of the primary endpoint and select secondary efficacy endpoints.
7.2.3
Safety Analysis Set
The safety analysis set (SAF) will consist of all randomized subjects who took at least 1 dose 
of study drug. The SAF will be used for demographic and baseline characteristic summaries 
and all safety analyses.
When the SAF is utilized in an analysis, subjects will be presented by the treatment actually 
received. 
7.2.3.1 Pharmacokinetic Analysis Set
The PKAS will consist of the subset of SAF for which at least 1 postdose concentration is 
available. 
7.3
Demographics and Baseline Characteristics 
Demographics and other baseline characteristics will be summarized by treatment group and 
overall for the FAS, SAF and PPS. Descriptive statistics will include number of subjects, 
mean, standard deviation, minimum, median and maximum for continuous endpoint, and 
frequency and percentage for categorical endpoint. 
7.3.1
Subject Disposition 
The number and percentage of subjects who discontinued Screening period and 
corresponding reasons for discontinuation will be presented for all subjects who signed ICFs. 
For treatment period and follow-up period, the number and percentage of subjects who 
discontinued and corresponding reasons for discontinuation will be presented for the FAS 
and SAF. 
7.3.2
Previous and Concomitant Medications
Previous and concomitant medications are coded with World Health Organization Drug 
Dictionary (WHO-DD) and will be summarized by therapeutic subgroup (Anatomical 

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Therapeutic Chemical [ATC] second level) and chemical subgroup (ATC fourth level) and 
preferred WHO name by treatment group and overall for the SAF.
All previous and concomitant medications will also be presented in a listing.
7.3.3
Medical History
Medical history is coded in Medical Dictionary for Regulatory Activities (MedDRA) and 
will be summarized by System Organ Class (SOC) and Preferred Term (PT) by treatment 
group and overall for the SAF. 
Medical history for each subject will also be presented in a listing. Any history of diagnosis 
of the following: temporomandibular disorders, irritable bowel syndrome, chronic tension 
type headache, migraine, chronic low back pain, myalgic encephalomyelitis/chronic fatigue 
syndrome, interstitial cystitis/painful bladder syndrome, endometriosis, and vulvodynia will 
be captured on eCRF and will be summarized for the SAF.
7.4
Analysis of Efficacy 
The efficacy analysis will be conducted using the FAS for all efficacy endpoints and the PPS 
for the primary efficacy endpoint and select secondary endpoints. The interpretation of 
results from statistical tests will be based on the FAS. The PPS will be used to assess the 
robustness of the results from the statistical tests based on the FAS.
Unless otherwise stated, all hypothesis testing will be one-sided at the 5% significance level 
and two-sided 90% CI will be presented when applicable. Centers will be pooled for analysis 
when necessary. The center pooling algorithm will be described in detail in the SAP.
7.4.1
Analysis of Primary Endpoint 
The primary efficacy endpoint is change from baseline to Week 8 in mean daily average pain 
score assessed by NRS (0 to 10 scale) in the subject’s daily e-diary. 
7.4.1.1 Primary Analysis
The primary analysis for the primary endpoint of change from baseline to Week 8 in the 
mean daily average pain NRS will use a MMRM analysis, where the model will include the 
effects for treatment group, center (pooled where necessary), time (study Week 1 to 8) and 
treatment-by-time interaction, as well as the covariates of baseline mean daily average pain 
NRS and baseline pain-by-treatment interaction and subject as a random effect. The 
unconstrained between-time-point covariance structure will be used. If this is not feasible, 
additional covariance structures will be considered and details will be provided in the SAP. 
This analysis will utilize observed data, and there will be no imputation for missing data. The 
treatment group contrast for change from baseline to Week 8 will be the primary statistical 
inference obtained from the MMRM analysis. Least squares estimates for the primary 
endpoint will be shown for each treatment group, and for the treatment comparisons of 
ASP0819 vs placebo with 2-sided 90% CIs. A one-sided 5% significance level will be used 
for the comparison involving ASP0819 vs placebo. 

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The hypothesis for comparisons is given as follows:
H0: The change from baseline to Week 8 in the mean daily average pain NRS for 
ASP0819 group is the same as (or worse than) the placebo group. 
H1: The change from baseline to Week 8 in the mean daily average pain NRS for 
ASP0819 group is less than the placebo group.
7.4.1.2 Sensitivity Analysis
The following sensitivity analyses will be conducted for the primary endpoint. 
●
A sensitivity analysis for the primary endpoint will use the same MMRM model as 
described in [Section 7.4.1.1 Primary Analysis]. For this sensitivity analysis, multiple 
imputation will be used for imputation of any missing data, using “Jump to Reference”
algorithm (where placebo is the reference group) [Carpenter et al. 2013] for subjects 
who discontinue due to lack of efficacy or AEs and standard regression-based multiple 
imputation for subjects with missing data for other reasons. 
●
A sensitivity analysis will use modified baseline observation carried forward (mBOCF) 
for missing data at Week 8 with analysis of covariance (ANCOVA), with covariates of 
baseline mean daily average pain NRS score and center. mBOCF is defined as 
imputation by baseline observation carried forward (BOCF) for subjects who 
discontinue due to lack of efficacy or AEs, and imputation by last observation carried 
forward (LOCF) for subjects with missing data at Week 8 for other reasons. 
●
A sensitivity analysis for the primary endpoint will use the same MMRM model as 
described in [Section 7.4.1.1 Primary Analysis] using the PPS.
7.4.1.3 Subgroup Analysis
Subgroup analysis of primary efficacy endpoint will be considered for following subgroups: 
sex, age category, category of baseline pain score, with or without depression (current vs no 
current diagnosis and current/prior diagnosis vs no current/prior diagnosis), and central or 
peripheral pain etiology (subgroups by CMSI, NPSI). Additional subgroups will be 
considered as appropriate. More details about subgroup analysis will be provided in the SAP. 
7.4.2
Analysis of Secondary Endpoints 
The secondary efficacy endpoints are defined in [Section 2.3.2 Secondary Endpoints]. 
The primary analysis for the secondary endpoints of mean daily average pain score (≥30% 
and 50% reduction from baseline to Week 8 and to EOT) will be carried out with the Fisher’s 
Exact Test. For the Week 8 analysis, subjects with missing data will be classified as non-
responders (BOCF group) and an additional analysis will use mBOCF. For the EOT analysis, 
LOCF will be used. 
The primary analysis for the change from baseline to Weeks 2, 4 and 8 for the FIQR 
subscales of Physical Function, Symptoms and Overall Impact will use the same MMRM 
analysis as described in [Section 7.4.1.1 Primary Analysis]. The primary analysis for the 
change from baseline to EOT for the FIQR subscales will use an ANCOVA model, with 

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covariates of baseline FIQR subscale score and center. An additional ANCOVA analysis will 
be conducted at Week 8 with mBOCF for subjects with missing data. 
The primary analysis for the PGIC will use the proportional odds model for ordinal data with 
model term for treatment group. The analysis will be used to assess PGIC at Weeks 2, 4, 8 
and EOT. For subjects with missing data, the analysis at Weeks 2, 4 and 8 will be conducted 
using mBOCF. An additional analysis at Weeks 2 and 4 will use LOCF. 
7.4.3
Analysis of Exploratory Endpoints 
The exploratory efficacy endpoints are defined in [Section 2.3.3 Exploratory Endpoints]. For 
the treatment period, the following analyses will be performed. 
The analysis for the change from baseline to each week from Week 1 to 7 in mean daily 
average pain is included in the primary analysis of primary endpoint as described in 
[Section 7.4.1.1 Primary Analysis], which includes data from Week 1 to 8. The change from 
baseline to EOT in mean daily average pain will be analyzed with an ANCOVA model, with 
covariates of baseline mean daily average pain and center. In addition, the percentage of 
subjects who meet cumulative response levels of > 0% to = 100% at Week 8 and EOT will be 
shown. For the analysis at Week 8, subjects with missing data will be classified as non-
responders (BOCF group) and an additional analysis will use mBOCF. 
The change from baseline to Weeks 2, 4, 8 in FIQR Total Score and PGIS will be analyzed 
using the MMRM model as described in [Section 7.4.1.1 Primary Analysis]. The change 
from baseline to EOT in FIQR total Score and PGIS will be analyzed with an ANCOVA 
model, with covariates of baseline score and center. An additional ANCOVA analysis for 
change from baseline to Week 8 will be conducted with mBOCF. 
The subject’s response defined as achieving ≥ 30% reduction from baseline in FIQR Total 
score at Week 8 and EOT will be analyzed using the Fisher’s Exact Test. For the analysis at 
Week 8, mBOCF will be used for subjects with missing data. 
The percentage of subjects who achieve PGIC response (Much Improved, Very Much 
Improved) at Week 8 and EOT will be analyzed using the Fisher’s Exact Test. The analyses 
at Week 8 will be conducted using mBOCF for subjects with missing data. 
The subject’s composite pain response is defined as achieving ≥ 30% reduction from baseline 
in mean daily average pain score and PGIC of very much or much improved. The percentage 
of subjects who achieve composite pain response at Week 8 and EOT will be analyzed using 
the Fisher’s Exact Test. The analysis at Week 8 will be conducted using mBOCF for subjects 
with missing data. 
The subject’s composite syndrome response is defined as achieving ≥ 30% reduction from 
baseline in mean daily average pain score and PGIC of very much or much improved and ≥ 
30% reduction from baseline in FIQR total score. The percentage of subjects who achieve 
composite syndrome response at Week 8 and EOT will be analyzed using the Fisher’s Exact 
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The change from baseline to each week from Week 1 to 8 in FMSD will be analyzed using 
the MMRM model as described in [Section 7.4.1.1 Primary Analysis]. The change from 
baseline to EOT in FMSD will be analyzed with an ANCOVA model, with covariates of 
baseline score and center. 
The change from baseline to Week 8 and EOT in HADS depression subscale will be 
analyzed with an ANCOVA model, with covariates of baseline score and center. The change 
from baseline to Week 8 and EOT in the EQ-5D-5L (5 dimensions and the subject’s health 
status) will be summarized with descriptive statistics.
The following analyses on rescue medication will be summarized for acetaminophen use. 
The proportion of days with rescue medication use during each week from Week 1 to 8 and 
EOT will be analyzed using Negative Binomial Regression model with terms for treatment 
and center. The incidence of subjects using rescue medication during each week from 
Week 1 to 8 and EOT will be analyzed using the Fisher’s Exact Test. The average daily dose 
of rescue medication during each week from Week 1 to 8 and EOT will be analyzed using 
analysis of variance with model terms for treatment and center.
The change from baseline to Weeks 2, 4 and 8 in IBS symptom summary score and abdominal 
pain, stomach pain, abdominal cramps, abdominal pressure, and bloating as assessed by the 
mIBS-D daily symptom diary will be analyzed using the MMRM method as described in 
[Section 7.4.1.1 Primary Analysis]. The change from baseline to EOT in these assessments will 
be analyzed with an ANCOVA model, with covariates of baseline score and center.
The change from baseline to Week 8 and EOT in the NPSI subscores of burning spontaneous 
pain, pressing spontaneous pain, paroxysmal pain, evoked pain and paresthesia/dysesthesia
will be analyzed with an ANCOVA model, with covariates of baseline score and center.
For the follow-up period, data will be summarized with descriptive statistics (number of 
subjects, mean, SD, minimum, median and maximum) for continuous endpoints, and 
frequency and percentage for categorical endpoints. The following endpoints will be 
considered and summarized by randomized treatment group. 
●
Change from baseline and EOT to Week 10 in mean daily average pain score.
●
Change from baseline and EOT to Week 10 in FIOR physical function subscale, 
symptoms subscale, overall impact subscale and total score.
●
Overall subject improvement assessed by PGIC to Week 10. 
●
Change from baseline and EOT to Week 10 in PGIS.
●
Subject’s response defined as achieving ≥ 30 % reduction from baseline to Week 10 in 
mean daily average pain score assessed by NRS (0 to 10 scale) in the subject’s daily 
diary.
●
Subject’s response defined as achieving ≥ 50 % reduction from baseline to Week 10 in 
mean daily average pain score assessed by NRS (0 to 10 scale) in the subject’s daily 
diary.
●
Change from baseline to Week 10 in EQ-5D-5L. 
●
Proportion of days with rescue medication use at Week 10.

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●
Incidence of subjects using rescue medication at Week 10.
●
Average daily dosage of rescue medication at Week 10.
7.5
Analysis of Safety
Safety analysis will be conducted using the SAF, unless otherwise specified. No hypothesis 
testing will be performed comparing treatment groups for any safety parameters. 
7.5.1
Adverse Events
AEs will be coded using the MedDRA. TEAE is defined as any AE which starts, or worsens, 
after the first dose of study drug through 30 days after the last dose of study drug.
The number and percentage of subjects with TEAEs, TEAEs leading to discontinuation, 
serious TEAEs and TEAEs related to study drug as assessed by the investigator will be 
summarized by system organ class, preferred term and treatment group. In addition, TEAEs 
will be summarized by relationship to study drug as determined by the investigator and by 
severity for each treatment group. 
All TEAEs will also be listed.
7.5.2
Laboratory Assessments
For quantitative laboratory tests, descriptive statistics will be used to summarize baseline 
value, post baseline value at each specified time point, and change from baseline to each 
specified post baseline time point by treatment group. Shifts relative to normal ranges from 
baseline to each specified post baseline time point in laboratory tests will also be tabulated. 
The number and percentage of subjects with potentially clinically significant values in liver 
enzymes: alkaline phosphatase (ALP), ALT, AST and TBL will be presented by treatment 
group. Criteria for potentially clinically significant values using the above laboratory tests 
will be provided in the SAP.
Laboratory test data will also be displayed in listings.
7.5.3
Vital Signs
Descriptive statistics will be used to summarize vital sign parameters at baseline value, post 
baseline value at each specified time point, and change from baseline to each specified post 
baseline time point by treatment group. 
The number and percentage of subjects with potentially clinically significant values in SBP, 
DBP and pulse rate will be presented by treatment group. Criteria for potentially clinically 
significant values using the above vital sign parameters tests will be provided in the SAP.
Vital sign parameter data will also be displayed in listings.
7.5.4
Physical Examination
Physical examination will be listed by treatment group.

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7.5.5
Electrocardiograms
The shift table of the finding at baseline (normal, not clinically significant normal and
clinically significant normal) to the worst finding during treatment period and follow-up 
period will be presented by treatment group. 
7.5.6
Columbia Suicide Severity Rating Scale
Descriptive statistics and listing of events will be provided for the C-SSRS for each treatment 
group by time point and for the entire study.
7.5.7
Analysis of Pharmacokinetics
A listing of sample times and concentrations will be provided.
7.6
Protocol Deviations 
Protocol deviations as defined in [Section 8.1.7 Protocol Deviations] will be summarized for 
all randomized subjects by treatment group and total as well as by site. A data listing will be 
provided by site and subject. 
The protocol deviation criteria will be uniquely identified in the summary table and listing. 
The unique identifiers will be as follows:
●
PD1 - Entered into the study even though they did not satisfy entry criteria, 
●
PD2 - Developed withdrawal criteria during the study and was not withdrawn,
●
PD3 - Received wrong treatment or incorrect dose,
●
PD4 - Received excluded concomitant treatment. 
7.7
Interim Analysis (and Early Discontinuation of the Clinical Study)
Two interim analyses for futility based on the primary efficacy endpoint will be conducted. 
The timing of these analyses will be at approximately 35% and 55% of all subjects with
Week 8/EOT data. The plan for the interim analysis may be modified based on speed of 
recruitment. These analyses will be conducted by an Astellas statistician, with results 
reviewed by an Astellas Independent Data Monitoring Committee (IDMC). The Astellas 
statistician and other members of the Astellas IDMC are external to the study team. No one 
within the study team will be unblinded to the treatment allocation or interim results. Details 
of the interim analysis procedure, steps to maintain treatment blind in the study team and 
criteria for stopping the study will be described in an IAP.
7.8
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
As a general principle, no imputation of missing data will be done. Exceptions are the start 
and stop dates of AEs, concomitant medication, last dose date of double blind study drug and 
the efficacy data below. The imputed dates will be used to allocate the concomitant 
medication and AEs to a treatment group, in addition to determining whether an AE is/is not 
treatment emergent. The imputed date of study drug will be used to calculate duration of 

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study drug exposure. Listings of the AEs and concomitant medications and study dosing will 
present the actual partial dates; imputed dates will not be shown.
For one of the sensitive analyses for the primary efficacy endpoint, multiple imputation will 
used to impute missing data, using Jump to Reference algorithm for subjects who discontinue 
due to lack of efficacy or AEs and standard regression-based multiple imputation for subjects 
with missing data for other reasons. For analyses of selected efficacy endpoints, mBOCF, 
BOCF and/or LOCF will be used to impute the missing data. More details are described in 
[Section 7.4 Analysis of Efficacy]
See the SAP for details of the definition for windows to be used for analyses by visit.
Centers that do not enroll a sufficient number of subjects will be pooled for statistical 
analyses, which includes study center according to a pre-specified algorithm in the SAP. The 
pooling decisions will be made and documented prior to study hard-lock.
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS
8.1
Procedure for Clinical Study Quality Control
8.1.1
Data Collection
The investigator or site designee will enter data collected using an Electronic Data Capture 
(EDC) system. In the interest of collecting data in the most efficient manner, the investigator 
or site designee should record data (including laboratory values, if applicable) in the eCRF 
within 5 days after the subject visit.
The investigator or site designee is responsible to ensure that all data in the eCRFs and 
queries are accurate and complete and that all entries are verifiable with source documents. 
These documents should be appropriately maintained by the site.
The monitor should verify the data in the eCRFs with source documents, as defined in the 
Monitoring Plan, and confirm that there are no inconsistencies between them.
Laboratory tests are performed at a central laboratory. Central Laboratory data will be 
transferred electronically to the Sponsor or designee at predefined intervals during the study. 
The Central laboratory will provide the Sponsor or designee with a complete and clean copy 
of the data. 
For Screen failures the demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria and Adverse Events will be collected in the eCRF.
8.1.2
Electronic Patient Reported Outcomes
Subject diaries and questionnaires will be completed by the subject on an electronic device. 
The information completed by the subject on the electronic device will be automatically 
uploaded into a central website. The investigator or site designee should review the diaries 
and questionnaire data on the website for correct completion while the subject is at the site. 
The diary and questionnaire data will be transferred electronically to Sponsor or designee at 

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predefined intervals during the study. The vendor will provide Sponsor or designee with a 
complete and clean copy of the data.
8.1.3
Specification of Source Documents
Source data must be available at the site to document the existence of the study subjects and 
to substantiate the integrity of study data collected. Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject. 
The following information should be included, but not limited to, in the source medical 
records:
●
Demographic data (age, sex, race, ethnicity, height and body weight);
●
Inclusion and exclusion criteria details;
●
Participation in main study, PGx sub-study (if applicable) and original signed and dated 
ICFs;
●
Visit dates;
●
Medical history and physical examination details;
●
Key efficacy and/or and safety data, if applicable (as specified in the protocol);
●
AEs and concomitant medication ;
●
Results of relevant examinations (e.g., ECG charts, X-ray films etc.);
●
Laboratory printouts (if applicable);
●
Details of dispensing and return of study drug;
●
Reason for premature discontinuation (if applicable);
●
Pharmacokinetic sample processing and storage history, including date/time each sample 
is transferred to the freezer, freezer identification and the temperature log for the freezer 
(if applicable);
●
Pharmacogenomic sample processing and storage history, including date/time each 
sample is transferred to the freezer, freezer identification and the temperature log for the 
freezer (if applicable).
8.1.4
Clinical Study Monitoring
The Sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
investigator/sub-investigator are accurate and complete and that they are verifiable with 
study-related records such as source documents. The Sponsor is responsible for assigning 
study monitor(s) to this study for proper monitoring. They will monitor the study in 
accordance with planned monitoring procedures. 
8.1.5
Direct Access to Source Data/Documents
The investigator and the study site must accept monitoring and auditing by the Sponsor or 
delegated CRO, as well as inspections from the IRB and relevant regulatory authorities. In 
these instances, they must provide all study-related records, such as source documents [refer 

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to Section 8.1.3 Specification of Source Documents] when they are requested by the Sponsor 
monitors and auditors, the IRB, or regulatory authorities. The confidentiality of the subject's 
identities shall be well protected consistent with local and national regulations when the 
source documents are subject to direct access.
8.1.6
Data Management
Data Management will be coordinated by the Data Science department of the Sponsor in 
accordance with the SOPs for data management. All study-specific processes and definitions 
will be documented by Data Management. eCRF completion will be described in the eCRF 
instructions. Coding of medical terms and medications will be performed using MedDRA 
and WHO-DD, respectively.
8.1.7
Protocol Deviations
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The investigator is responsible for ensuring 
the study is conducted in accordance with the procedures and evaluations described in this 
protocol and must protect the rights, safety, and welfare of subjects. The investigator should 
not implement any deviation from, or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to study subjects. 
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited.
For the purposes of this protocol, deviations requiring notification to Sponsor are defined as 
any subject who: 

entered into the study even though they did not satisfy entry criteria,

developed withdrawal criteria during the study and not withdrawn,

received wrong treatment or incorrect dose, and

received excluded concomitant treatment.
When a deviation from the protocol is identified for an individual subject, the investigator or 
designee must ensure the Sponsor is notified. The Sponsor will follow-up with the 
investigator, as applicable, to assess the deviation and the possible impact to the safety and/or 
efficacy of the subject to determine subject continuation in the study. 
If a deviation impacts the safety of a subject, the investigator must contact the Sponsor 
immediately.
The investigator will also assure that deviations meeting IRB and applicable regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IRB and applicable regulatory authorities will be provided to the 
Sponsor and maintained within the trial master file.
8.1.8
End of Trial in All Participating Countries
The end of the study is defined as the last visit or follow-up contact of the last subject in the 
study.

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8.2
Ethics and Protection of Subject Confidentiality 
8.2.1
Institutional Review Board/Competent Authorities 
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, 
the IB, the informed consent and all other forms of subject information related to the study 
(e.g., advertisements used to recruit subjects) and any other necessary documents be 
reviewed by an IRB. The IRB will review the ethical, scientific and medical appropriateness 
of the study before it is conducted. IRB approval of the protocol, informed consent and 
subject information and/or advertising, as relevant, will be obtained prior to the authorization 
of drug shipment to a study site.
Any substantial amendments to the protocol will require IRB approval prior to 
implementation of the changes made to the study design at the site. The investigator will be 
required to submit, maintain and archive study essential documents according to ICH GCP.
Any SAEs that meet reporting criteria, as dictated by local regulations, will be reported to 
both responsible ethics committees and regulatory agencies, as required. During the conduct 
of the study, the investigator should promptly provide written reports (e.g., ICH Expedited 
Reports, and any additional reports required by local regulations) to the IRB of any changes 
that affect the conduct of the study and/or increase the risk to subjects. Written 
documentation of the submission to the IRB should also be provided to Sponsor.
If required by local regulations, the investigator shall make accurate and adequate written 
progress reports to the IRB at appropriate intervals, not exceeding 1 year. The investigator 
shall make an accurate and adequate final report to the IRB within 90 days after the close-out 
visit for APGD-sponsored studies, or for APEB/APEL-sponsored studies within 1 year after 
last subject out or termination of the study.
8.2.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki. 
8.2.3
Informed Consent of Subjects
8.2.3.1 Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the subject or 
his/her guardian or legal representative, and answer all questions regarding this study. Prior 
to any study-related screening procedures being performed on the subject, the informed 
consent statement will be reviewed and signed and dated by the subject or his/her guardian or  
legal representative, the person who administered the informed consent and any other 
signatories according to local requirements. A copy of the signed ICF will be given to the 
subject and the original will be placed in the subject’s medical record. An entry must also be 
made in the subject’s dated source documents to confirm that all informed consents were
obtained prior to any study-related procedures and that the subject received signed copies.

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The signed ICFs will be retained by the investigator and made available (for review only) to 
the study monitor and auditor regulatory authorities and other applicable individuals upon 
request.
Subjects must provide separate written consent prior to providing any blood samples that 
may be used at a later time for genetic analysis as part of the PGx substudy.
8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information
1.
The investigator or his/her representative will immediately inform the subject orally 
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue to participate in the study 
(e.g., report of serious drug adverse drug reaction). The communication must be 
documented in the subject’s medical records and whether the subject is willing to remain 
in the study or not must be confirmed and documented.
2.
The investigator must update their ICF and submit it for approval to the IRB. The 
investigator or his/her representative must obtain written informed consent from the 
subject on all updated ICFs throughout their participation in the study. The investigator 
or his/her designee must reconsent subjects with the updated ICF even if relevant 
information was provided orally. The investigator or his/her representative who obtained 
the written informed consent and the subject should sign and date the ICF. A copy of the 
signed ICF will be given to the subject and the original will be placed in the subject’s 
medical record. An entry must be made in the subject’s records documenting the re-
consent process.
8.2.4
Subject Confidentiality and Privacy
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Such medical information may be 
given only after approval of the subject to the subject's physician or to other appropriate 
medical personnel responsible for the subject's well-being.
The Sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons.
Even though any individuals involved in the study, including the study monitors and auditors, 
may get to know matters related to subject's privacy due to direct access to source 
documents, or from other sources, they may not leak the content to third parties. 
The Sponsor affirms the subject's right to protection against invasion of privacy. Only a
subject identification number and/or initials will identify subject data retrieved by the 
Sponsor. However, the Sponsor requires the investigator to permit the Sponsor, Sponsor's 
representative(s), the IRB and when necessary, representatives of the regulatory health 
authorities to review and/or to copy any medical records relevant to the study.
The Sponsor agrees to comply and process personal data in accordance with all applicable 
privacy laws and regulations, including, without limitation, the Personal Information 

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Protection Law in Japan and Privacy laws in the US. If the services will involve the 
collection or processing of personal data (as defined by applicable data protection legislation) 
within the European Economic Area (EEA), then Sponsor shall serve as the controller of 
such data, as defined by the EU Data Protection Directive, and the investigator and/or third 
party shall act only under the instructions of the Sponsor in regard to personal data. If 
Sponsor is not based in the EEA, Sponsor must appoint a third party to act as its local data 
protection representative or arrange for a cocontroller established in the EU for data 
protection purposes in order to comply with the Directive.
8.3
Administrative Matters
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the IB and other pertinent information is confidential and remains the property of the 
Sponsor. Details should be disclosed only to the persons involved in the approval or conduct 
of the study. The investigator may use this information for the purpose of the study only. It is 
understood by the investigator that the Sponsor will use the information obtained during the 
clinical study in connection with the development of the drug and therefore may disclose it as 
required to other clinical investigators or to regulatory agencies. In order to allow for the use 
of the information derived from this clinical study, the investigator understands that he/she 
has an obligation to provide the Sponsor with all data obtained during the study.
Publication of the study results is discussed in the clinical study agreement.
8.3.2
Documents and Records Related to the Clinical Study
The Sponsor will provide the investigator and/or institution with the following:
●
study protocol (and amendments, where applicable),
●
IB (and amendments, where applicable),
●
eCRFs,
●
study drug with all necessary documentation and
●
study contract.
In order to start the study, the investigator and/or study site is required to provide the 
following documentation to the Sponsor: 
●
Financial disclosure in compliance with federal regulation 21CFR Part 54,
●
signed and dated FDA form 1572,
●
signed investigator's statement in this protocol and eCRF,
●
current Curricula Vitae of all investigators,
●
list of sub-investigators and collaborators,
●
IRB approval of the protocol, protocol amendments (if applicable) including a 
membership list with names and qualification (copy documents) and
●
study contract.

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The investigator will archive all study data (e.g., subject identification code list, source data, 
CRFs, and investigator's file) and relevant correspondence. These documents are to be kept 
on file for the appropriate term determined by local regulation (for US sites, 2 years after 
approval of the New Drug Application [NDA] or discontinuation of the Investigational New 
Drug [IND]). The Sponsor will notify the site/investigator if the NDA/Marketing 
Authorisation Applications/Japan-NDA is approved or if the IND/Investigational Medicinal 
Product Dossier/Clinical Trial Notification (CHIKEN TODOKE) is discontinued. The 
investigator agrees to obtain the Sponsor's agreement prior to disposal, moving, or 
transferring of any study-related records. The Sponsor will archive and retain all documents 
pertaining to the study according to local regulations.
Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes.
All data will be entered on the CRFs supplied for each subject.
8.3.3
Protocol Amendment and/or Revision
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments: substantial amendments and/or non-substantial amendments. 
Depending on the nature of the amendment, either IRB, Competent Authority approval or 
notification may be required. The changes will become effective only after the approval of 
the Sponsor, the investigator, the regulatory authority, and the IRB (if applicable).
Amendments to this protocol must be signed by the Sponsor and the investigator. Written 
verification of IRB approval will be obtained before any amendment is implemented, which 
affects subject safety or the evaluation of safety, and/or efficacy. Modifications to the 
protocol that are administrative in nature do not require IRB approval, but will be submitted 
to the IRB for their information, if required by local regulations.
If there are changes to the informed consent, written verification of IRB approval must be 
forwarded to the Sponsor. An approved copy of the new informed consent must also be 
forwarded to the Sponsor.
8.3.4
Signatory Investigator for Clinical Study Report
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study 
report which forms part of a marketing authorization application be signed by the 
representative for the coordinating investigator(s) or the principal investigator(s). The 
representative for the coordinating investigator (s) or the principal investigator(s) will have 
the responsibility to review the final study results to confirm to the best of his/her knowledge 
it accurately describes the conduct and results of the study. The representative for
coordinating investigator(s) or the principal investigator(s) will be selected from the 
participating investigators by the Sponsor prior to database lock.

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9
QUALITY ASSURANCE
The Sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that studies are conducted and data are generated, documented, 
recorded, and reported in compliance with the protocol, GCP and applicable regulatory 
requirement(s). Where applicable, the quality assurance and quality control systems and 
written SOPs of the CRO will be applied.
The Sponsor or Sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. The audit may include on-site review of regulatory 
documents, CRFs, and source documents. Direct access to these documents will be required 
by the auditors.
10
STUDY ORGANIZATION
10.1
Data Monitoring Committee
The IDMC is responsible for the interim futility evaluation of efficacy data defined in the 
IDMC Charter. Participants in the IDMC include, but may not be limited to: an Independent 
Astellas Statistician who is not on the study team, and does not communicate with study team 
or Site staff. The IDMC will evaluate unblinded data and provide conclusion of futility analysis 
to Astellas Management [see Section 7.7 Interim Analysis (and Early Discontinuation of the 
Study)].
Two interim analyses for futility based on the primary efficacy endpoint will be conducted. 
The timing of these analyses will be at approximately 35% and 55% of all subjects with 
Week 8/EOT data. The plan for the interim analysis may be modified based on speed of 
recruitment. These analyses will be conducted by an external statistician of the project team, 
with results reviewed by an IDMC also external to the study team. Details of the interim 
analysis procedure, steps to maintain treatment blind in the study team and criteria for stopping 
the study will be described in an IAP.
10.2
Other Study Organization
Not applicable.

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11
REFERENCES 
Amorim P, Lecrubier Y, Weiller E, Hergueta T, Sheehan D: DSM-III-R Psychotic Disorders: 
procedural validity of the M.I.N.I. International Neuropsychiatric Interview (M.I.N.I.). 
Concordance and causes for discordance with the CIDI. European Psychiatry. 1998;13:26-34.
Bennett RM, Friend R, Jones KD, Ward R, Han BK, Ross RL. The Revised Fibromyalgia Impact 
Questionnaire (FIQR): validation and psychometric properties. Arthritis Res Ther. 
2009;11(4):R120. Epub 2009 Aug 10. Erratum in: Arthritis Res Ther. 2009;11(5):415.
Bouhassira D, Attal N, Fermanian J, et al. Development and validation of the neuropathic pain 
symptom inventory. Pain. 2004;108:248–57.
Bradding P, Wulff H. The K+ channels KCa3.1 and Kv1.3 as novel targets for asthma therapy. Br J 
Pharmacol. 2009;157:1330-9.
Carpenter JR, Roger JH & Kenward MG (2013) Analysis of longitudinal trials with protocol 
deviation: a framework for relevant, accessible, assumptions, and inference via multiple 
imputation, Journal of Biopharmaceutical Statistics. 2013;23(6):1352-1371.
Delgado-Herrera L1, Lasch K2, Popielnicki A3, Nishida A4, Arbuckle R5, Banderas B6, Zentner S1, 
Gagainis I1, Zeiher B1. Cultural adaptation: translatability assessment and linguistic validation 
of the patient-reported outcome instrument for irritable bowel syndrome with diarrhea. Patient 
Relat Outcome Meas. 2016;Jun 22;7:81-92.
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” issued by 
FDA on July 2009. 
Häuser W, Walitt B, Fitzcharles MA, Sommer C. Review of pharmacological therapies in 
fibromyalgia syndrome. Arthritis Res Ther. 2014;16:201.
Hermann C. International experiences with the Hospital Anxiety and Depression Scale - a review of 
validation data and clinical results. Journal of Psychosomatic Research 1997;42(1):17-41.
Kim SH, Kim DH, Oh DH, Clauw DJ. Characteristic electron microscopic findings in the skin of 
patients with fibromyalgia—preliminary study. Clin Rheumatol. 2008;27:407-11.
Kleinman et al. Assessment of sleep in patients with fibromyalgia: qualitative development of the 
fibromyalgia sleep diary. Health and Quality of Life Outcomes. 2014;12:111.
Lecrubier Y, Sheehan D, Weiller E, Amorim P, Bonora I, Sheehan K, Janavs J, Dunbar G. The 
M.I.N.I. International Neuropsychiatric Interview (M.I.N.I.) A Short Diagnostic Structured 
Interview: Reliability and Validity According to the CIDI. European Psychiatry. 
1997;12:224-231. 
LoVerme J, Russo R, La Rana G, Fu J, Farthing J, Mattace-Raso G, et al. Rapid broad-spectrum 
analgesia through activation of peroxisome proliferator-activated receptor-α. J Pharmacol Exp 
Ther. 2006;319:1051-61.
Marquis P, Lasch KE, Delgado-Herrera L, Kothari S, Lembo A, Lademacher C, Spears G, Nishida A, 
Tesler WL, Piault E, Rosa K, Zeiher B. Qualitative development of a patient-reported outcome 

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symptom measure in diarrhea-predominant irritable bowel syndrome. Clin Transl 
Gastroenterol. 2014;5:59. 
McHugh D, Head V, Panesar MS, Tigani B, Fox A, Lilley E. Effect of small and intermediate 
conductance potassium channel modulators on visceral hypersensitivity and function. 
Gastroenterology. 2008;134,Suppl 1:A-544.
Oaklander AL, Herzog ZD, Downs HM, Klein MM. Objective evidence that small-fiber 
polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain.
2013;154:2310-16.
Queiroz LP. Worldwide epidemiology of fibromyalgia. Curr Pain Headache Rep. 2013;17:356.
Rosa, K., Delgado-Herrera, L., Zeiher, B. et al. Psychometric assessment of the IBS-D Daily 
Symptom Diary and Symptom Event Log. Qual Life Res. 2016;1335-1.
Serra J, Collado A, Solà R, Antonelli F, Torres X, Salgueiro M, et al. Hyperexcitable C nociceptors in 
fibromyalgia. Ann Neurol. 2014;75:196-208.
Sheehan DV, Lecrubier Y, Harnett-Sheehan K, Janavs J, Weiller E, Bonara LI, Keskiner A, Schinka J, 
Knapp E, Sheehan MF, Dunbar GC. Reliability and Validity of the M.I.N.I. International 
Neuropsychiatric Interview (M.I.N.I.): According to the SCID-P. European Psychiatry. 1997; 
12:232-241. 
Sheehan DV, Lecrubier Y, Harnett-Sheehan K, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, 
Dunbar G: The M.I.N.I. International Neuropsychiatric Interview (M.I.N.I.): The Development 
and Validation of a Structured Diagnostic Psychiatric Interview. J. Clin Psychiatry, 
1998;59(suppl 20):22-33. 
Snaith RP. The Hospital Anxiety and Depression Scale. Health and Quality of Life Outcomes. 
2003;Aug:1:29.
Staud R. Biology and therapy of fibromyalgia: pain in fibromyalgia syndrome. Arthritis Res Ther. 
2006;8:208.
Staud R. Brain imaging in fibromyalgia syndrome. Clin Exp Rheumatol. 2011;29:S109-17.
Staud R, Smitherman ML. Peripheral and central sensitization in fibromyalgia: pathogenic role. Curr 
Pain Headache Rep. 2002;6:259-66.
Staud R, Weyl EE, Bartley E, Price DD, Robinson ME. Analgesic and anti-hyperalgesic effects of 
muscle injections with lidocaine or saline in patients with fibromyalgia syndrome. Eur J Pain. 
2014;18:803-12.
Tsantoulas C, McMahon SB. Opening paths to novel analgesics: the role of potassium channels in 
chronic pain. Trends Neurosci. 2014;37:146-58.
Üçeyler N, Zeller D, Kahn AK, Kewenig S, Kittel-Schneider S, Schmid A, et al. Small fibre 
pathology in patients with fibromyalgia syndrome. Brain. 2013;136:1857-67.

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White D, Leach C, Sims R, Atkinson M, Cottrell D. Validation of the Hospital Anxiety and 
Depression Scale for use with adolescents. Br J Psychiatry. 1999;175:452-4.
Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, et al. The American 
College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the 
Multicenter Criteria Committee. Arthritis Rheum. 1990;33:160-72.
Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz RS, Mease P, et al. The American College 
of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of 
symptom severity. Arthritis Care Res. 2010;62:600-10.
Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Häuser W, Katz RS, et al. Fibromyalgia criteria 
and severity scales for clinical and epidemiological studies: a modification of the ACR 
Preliminary Diagnostic Criteria for Fibromyalgia. J Rheumatol. 2011;38:1113-22.
Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 
2011;152:S2-15.
Wulff H, Kolski-Andreaco A, Sankaranarayanan A, Jean-Marcand S, Shakkottai V. Modulators of 
small- and intermediate-conductance calcium-activated potassium channels and their 
therapeutic indications. Curr Med Chem. 2007;14:1437-57.
Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand.
1983;67:361-370.

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12
APPENDICES
12.1
List of Excluded Concomitant Medications - Excluded Medications 
with Efficacy or Potential Efficacy in Fibromyalgia Pain  
These lists are not exhaustive. Medications should be considered excluded if taken alone or 
as part of a combination product. If in doubt, please contact the Medical Monitor.
Gabapentenoids
gabapentin
miragabalin
pregabalin
Antidepressants
amitriptyline
bupropion
Monoamine oxidase inhibitors
maprotiline
reboxetine
trazodone
Tricyclic Antidepressants
venlafaxine
duloxetine
desvenlafaxine
levomilnacipran
milnacipram
mianserin
mirtazapine
Opioids
bezitramide
hydromorphone 
papaveretum
buprenorphine
ketobemidone
pentazocine 
butorphanol
meptazinol
pethidine/meperidine
dextromoramide 
methadone
phenazocine
dextropropoxyphene 
morphine 
piritramide
dezocine 
nalbuphine  
tapentadol
dihydrocodeine
nicomorphine 
tilidine
fentanyl
oxycodone
tramadol
Others
baclofen
buspirone
Cannabinoids
Herbals (e.g., St. John’s wort, 
kava kava, kratom)
ketamine
mazindol
Muscle Relaxants 
(e.g., carisoprodol,
cyclobenzaprine, tizanidine, 
metaxalone)
sodium oxybate
Stimulants
celecoxib
Topical and Injectable Pain Medications
capsaicin
menthol
methyl salicylate
Tenderpoint injections with 
anesthetics or steroids

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Excluded P450 CYP3A Substrates  
Sensitive Substrates
alfentanil
ebastine 
perospirone
almorexant
eletriptan 
quetiapine
alpha-dihydroergocryptine
elvitegravir
ridaforolimus 
aplaviroc
eplerenone
saquinavir
aprepitant
everolimus
sildenafil 
atazanavir
felodipine 
simeprevir
atorvastatin
ibrutinib
simvastatin
avanafil
indinavir
tacrolimus
bosutinib
ivacaftor
terfenadine
brecanavir
levomethadyl (LAAM)
ticagrelor 
brotizolam
lomitapide
tilidine 
budesonide
lopinavir
tipranavir
buspirone
lovastatin
tolvaptan
capravirine
lumefantrine
triazolam
casopitant
lurasidone 
ulipristal
conivaptan
Maraviroc
vardenafil
danoprevir
midazolam 
vicriviroc
darifenacin
midostaurin
voclosporin
darunavir
neratinib
dasatinib
nisoldipine
dronedarone 
Narrow Therapeutic Range Substrates
alfentanil
ergotamine
quinidin
cyclosporine
fentanyl
sirolimus
diergotamine
pimozide
tacrolimus

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Excluded Central Nervous System Agents 
Antipsychotics/Tranquilizers
amisulpride
amoxapine
aripiprazole
asenapine
brexpiprazole
cariprazine
chlorproethazine
clozapine
droperidol
fluphenazine
haloperidol
iloperidone
loxapine
lurasidone
melperone
mesoridazine
molindone
olanzapine
paliperidone
perphenazine
pimavanserin
pimozide
quetiapine
risperidone
thioridazine
thiothixene
trifluoxperazine
ziprasidone
Benzodiazepines /Sedatives/Sleep Agents
alprazolam
Barbituates
chlordiazepoxide
clobazam
clonazepam
clorazepate
diazepam
flurazepam
hydroxyzine
lorazepam
meprobamate
midazolam
oxazepam
temazepam
triazolam
Sedating Antihistamines
alimemazine
Chronic diphenhydramine or 
use for sleep
ketotifen
chlorpheniramine
cyproheptadine
promethazine
clemastine
hydroxyzine
Other CNS Medications
Anti-epileptics (e.g., 
topiramate, divalproate sodium, 
carbamazepine, lamotrigine)
Dopamine agonists
Mood stabilizers (e.g., lithium)

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12.2
List of Allowed Anti-depressants and Sleep Aids
If in doubt, please contact the Medical Monitor.
Allowed Antidepressants*
Selective Serotonin Reuptake 
Inhibitors
citalopram
fluvoxamine
vilazodone
escitalopram
paroxetine
vortioxetine
fluoxetine
sertraline
*follow prescribing information in package insert
Allowed Sleep Aids*
eszopiclone up to 1 mg 
zaleplon up to 10 mg
zopiclone up to 2 mg
melatonin 
zolpidem up to10 mg
*follow prescribing information in package insert

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12.3
Liver Safety Monitoring and Assessment 
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases to > 3 × ULN or bilirubin > 2 × ULN should undergo detailed 
testing for liver enzymes (including at least ALT, AST, ALP, and TBL). Testing should be 
repeated within 72 hours of notification of the test results. For studies for which a central 
laboratory is used, alerts will be generated by the central laboratory regarding moderate and 
severe liver abnormality to inform the investigator, study monitor and study team. Subjects 
should be asked if they have any symptoms suggestive of hepatobiliary dysfunction.
Definition of Liver Abnormalities
Confirmed abnormalities will be characterized as moderate and severe where ULN:
ALT or AST
Total Bilirubin
Moderate
> 3 × ULN 
or
> 2 × ULN
Severe*
> 3 × ULN
and
> 2 × ULN
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following:
ALT or AST > 8 × ULN.
ALT or AST > 5 × ULN for more than 2 weeks. 
ALT or AST > 3 × ULN and INR > 1.5 (If INR testing is applicable/evaluated).
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring 
and follow-up.
Follow-up Procedures
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, 
physical examination and laboratory tests. The site should complete the liver abnormality 
case report form (LA-CRF) that has been developed globally and can be activated for any 
study or an appropriate document. Subjects with confirmed abnormal liver function testing 
should be followed as described below.
Confirmed moderately abnormal LFTs should be repeated 2 to 3 times weekly then weekly 
or less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic. 
Severe hepatic liver function abnormalities as defined above, in the absence of another 
etiology, may be considered an important medical event and may be reported as a SAE. The 
Sponsor should be contacted and informed of all subjects for whom severe hepatic liver 
function abnormalities possibly attributable to study drug are observed.

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To further assess abnormal hepatic laboratory findings, the investigator is expected to do the 
following:
Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms 
and new-onset diseases is to be recorded as “AEs” within the (e)CRF. Illnesses and 
conditions such as hypotensive events and decompensated cardiac disease that may lead to 
secondary liver abnormalities should be noted. Nonalcoholic steatohepatitis is seen in obese 
hyperlipoproteinemic and/or diabetic patients and may be associated with fluctuating AT 
levels. The investigator should ensure that the medical history form captures any illness 
that predates study enrollment that may be relevant in assessing hepatic function. 

Obtain a history of concomitant drug use (including nonprescription medication, 
complementary and alternative medications), alcohol use, recreational drug use and special 
diets. Medications, including dose, is to be entered in the (e)CRF. Information on alcohol, 
other substance use and diet should be entered on the LA-CRF or an appropriate document.

Obtain a history of exposure to environmental chemical agents.

Based on the subject’s history, other testing may be appropriate including the following: 
o acute viral hepatitis (A, B, C, D, E or other infectious agents),
o ultrasound or other imaging to assess biliary tract disease,
o other laboratory tests including INR, direct bilirubin.

Consider gastroenterology or hepatology consultations.

Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document.
Subject Study Discontinuation
In the absence of an explanation for increased LFT’s, such as viral hepatitis, preexisting or 
acute liver disease, or exposure to other agents associated with liver injury, the subject may 
be discontinued from the study. The investigator may determine that it is not in the subject’s 
best interest to continue study enrollment. Discontinuation of treatment should be considered 
if the LFT results are as follows:

ALT or AST > 8 × ULN.

ALT or AST > 5 × ULN for more than 2 weeks.

ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5) (If INR testing is 
applicable/evaluated).

ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, drug should be discontinued.
*Hy’s Law Definition: Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10 to 50% mortality 
(or transplant). The 2 “requirements” for Hy’s Law are: 1) Evidence that a drug can cause 
hepatocellular-type injury, generally shown by an increase in transaminase elevations higher 
3 × ULN (“2 × ULN elevations are too common in treated and untreated patients to be 

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discriminating”). 2) Cases of increased bilirubin (at least 2 × ULN) with concurrent 
transaminase elevations at least 3 × ULN and no evidence of intra- or extra-hepatic bilirubin 
obstruction (elevated ALP) or Gilbert’s syndrome [Temple, 2006].
References
Temple R. Hy’s law: Predicting Serious Hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006 
April;15(Suppl 4):241-3.
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” issued by 
FDA on July 2009. 

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12.4
Common Serious Adverse Events
For this protocol, there is no list of common SAEs anticipated for the study population for the 
purposes of IND safety reporting. 

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12.5
Retrospective Pharmacogenomics Sub-Study 
INTRODUCTION
PGx research aims to provide information regarding how naturally occurring changes in a 
subject’s gene and/or expression based on genetic variation may impact what treatment 
options are best suited for the subject. Through investigation of PGx by technologies such as 
genotyping, gene sequencing, statistical genetics and Genome-Wide Association Studies, the 
relationship between gene profiles and a drug’s kinetics, efficacy or toxicity may be better 
understood. As many diseases may be influenced by 1 or more genetic variations, PGx 
research may identify which genes are involved in determining the way a subject may or may 
not respond to a drug.
OBJECTIVES
The PGx research that may be conducted in the future with acquired blood samples is 
exploratory. The objective of this research will be to analyze or determine genes of relevance 
to clinical response, pharmacokinetics and toxicity/safety issues.
By analyzing genetic variations, it may be possible to predict an individual subject’s response 
to treatment in terms of efficacy and/or toxicity.
SUBJECT PARTICIPATION
Subjects who have consented to participate in this study may participate in this PGx sub-
study. As part of this sub-study, subjects must provide written consent prior to providing any 
blood samples that may be used at a later time for genetic analysis.
SAMPLE COLLECTION AND STORAGE
Subjects who consent to participate in this sub-study will provide 1 approximately 6 mL tube 
of whole blood per Astellas’ instructions. Each sample will be identified by the unique 
subject number (first code). Samples will be shipped frozen to a designated banking CRO 
either directly from site or via a central laboratory as directed by Astellas.
PHARMACOGENOMICS ANALYSIS
Details on the potential PGx analysis cannot be established yet. Astellas may initiate the PGx 
analysis in case evidence suggests that genetic variants may be influencing the drug’s 
kinetics, efficacy and/or safety. 
DISPOSAL OF PHARMACOGEMONICS SAMPLES / DATA
All PGx samples collected will be stored for a period of up to 15 years following study 
database hardlock. If there is no requirement for analysis, the whole blood sample will be 
destroyed after the planned storage period. The subject has the right to withdraw consent at 
any time. When a subject’s withdraw notification is received, the PGx sample will be 
destroyed. The results of any PGx analysis conducted on a sample prior to its withdrawal will 
be retained at Astellas indefinitely.

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INFORMATION DISCLOSURE TO THE SUBJECTS
Exploratory PGx analysis may be conducted following the conclusion of the clinical study, if 
applicable. The results of the genetic analysis will not be provided to any investigators or 
subjects, nor can the results be requested at a later date. Any information that is obtained 
from the PGx analysis will be the property of Astellas. 

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12.6
Questionnaires
Questionnaire
Frequency/Visit
Daily Average Pain Numerical 
Rating Scale (NRS) Score
Daily from Visit 2 onwards, at home, until Visit 7 by subject.
Every attempt should be made by the subject to enter the daily NRS 
score at a consistent time in the evening throughout the study.
Fibromyalgia Sleep Diary 
(FMSD)
Daily from Visit 2 onwards, at home, until Visit 7 by subject. 
Every attempt should be made by the subject to enter the daily 
FMSD score upon awakening in the morning throughout the study.
Mini-International 
Neuropsychiatric Interview 
(M.I.N.I.)
Visit 1 at clinic by site personnel 
Hospital Anxiety and 
Depression Scale (HADS)
Visit 1, Visit 3 and Visit 6 at clinic by subject
Columbia-Suicide Severity 
Rating Scale (C-SSRS)
Visit 1, Visit 3, Visit 4, Visit 5, Visit 6 and Visit 7 at clinic by site 
personnel. 
Complex Medical Symptoms 
Inventory (CMSI)
Visit 2 by the subject on the electronic patient reported outcomes 
(ePRO) device
Patient Global Impression of 
Change (PGIC)
Visit 4, Visit 5, Visit 6 and Visit 7 at clinic by subject
Patient Global Impression of 
Severity (PGIS)
Visit 3, Visit 4, Visit 5, Visit 6 and Visit 7 at clinic by subject
European Quality of Life-5 
Deminsenions-5 Levels 
(EQ-5D-5L)
Visit 3, Visit 6 and Visit 7 at clinic by subject
Fibromyalgia Impact 
Questionnaire Revised (FIQR)
Visit 1, Visit 3, Visit 4, Visit 5, Visit 6 and Visit 7 at clinic by 
subject
Modified Irritable Bowel 
Syndrome – Diarrhea 
Predominant (mIBS-D)
Symptoms Diary
Visit 3, Visit 4, Visit 5 and Visit 6 at clinic by subject
Neuropathic Pain Symptom 
Inventory (NPSI)
Randomization and Week 8/End of Treatment
For the daily questionnaires the subject will receive an e-diary that can be taken home. The
subject should take the e-diary to the clinic for each study visit. For the questionnaires to be
completed at the site the subject will use the tablet that is available at the site.

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13
ATTACHMENT 1:  SUBSTANTIAL AMENDMENT 1
I.  The purpose of this amendment is:
Substantial Change
1. PoC Fibromyalgia studies  0819-CL-0201 and 
 (see separate 
submission to PAC) are pilot for including duplicate subject check
DESCRIPTION OF CHANGE:
New screening assessment added to section 2.2.1 : after signing informed consent and 
during the screening period, study site personnel will check that potential subjects have not 
already been pre-screened, initiated or completed screening or have been randomized into 
this study, or another clinical trial, using an independent subject participation database.  
Independent subject participation databases seek to reduce duplicate enrollment by 
identifying duplicates before they randomize into the study, and this measure is consistent 
with exclusion requirement of not participating in another interventional clinical trial during 
the conduct of the study.  
In order to complete this check and per the informed consent, study personnel will request 
that the subject present a valid picture identification (e.g. driver’s license, passport, state 
issued ID card, etc.)  and study personnel may be required to provide certain authorized 
information that could potentially be used to identify study subjects identifiers (e.g. date of 
birth, initials, etc.) so that the match algorithms can be run. 
Subjects that meet the inclusion criteria, none of the exclusion criteria, and are not identified 
as a duplicate subject (e.g. certainly, possible, probably), will be enrolled into the study.
Appropriate documentation reflecting the subject’s eligibility according to these criteria will 
be reflective in the subject’s source documents.
Note : Protocol wording developed in collaboration with the legal department
RATIONALE:
Proliferating problem of professional patients (recognized for a.o. US trials)- Websites 
dedicated to train people on how to get into research studies (e.g. 
Finance.youngmoney.com)
6-11% who seek entry are, on another trial, in a lock out period or are attempting to enter 
at another facility
Incidence of dual enrollment per trial ranges from 2% to 10% according to the 
therapeutic area and the phase of the study
Certain indications attract “repeat” subjects 
Recent study (3662-CL-0049) demonstrated that 3% of subjects were within study 
duplicates (screened only) at two different sites in a small POC study
Fibromyalgia is a very heterogeneous disease, lacks rigorous standardized and objective 
diagnostic criteria and relies on patient reported medical history
Implement checking prospectively in new (CNS) clinical trials to maximize the signal to 
noise ratio and increase chance of detecting effect size.A third party vendor will be used 
PPD

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who is specialized in detecting potential duplicate subjects from a trials database. 
Subjects will provide informed consent for this verification in the study’s ICF.
Non-Substantial Changes
1. Minor Administrative-type changes
DESCRIPTION OF CHANGE: 
Wording changes for 8062 protocol also implemented here in the 0819 protocol to align the 2 
FM PoC Ph2 studies.
RATIONALE:
To align with the 
 study.
2. Clarification of  the number of tender point sites
DESCRIPTION OF CHANGE:
Clarify the expectation that the patient will be eligible if she/he has pain in ‘at least’ 11 of the 
18 tender point sites.
RATIONALE:
The expectation is that a patient is eligible for study participation if he/she has pain in at least 
11 of the 18 tender point sites. The wording is only mentioning that the patient has pain in 11 
of 18 tender point sites.
3. Update collection of tender points on site tablet instead of CRF 
DESCRIPTION OF CHANGE:
The FM diagnosis is confirmed using the ACR criteria: Widespread Pain Index, Symptoms 
Severity Scale and the Tender Points. WPI and SSS are captured by the investigator on the 
site tablet. We want to include the tender point assessment here as well instead of capturing it 
separately in the CRF.  
RATIONALE:
Decreasing complexity for the site in keeping the 3 assessments together.
PPD

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Version 2.0 Incorporating Substantial Amendment 1
II  Amendment Summary of Changes:
2.1 Study Design and Dose Rationale
Section 2.2.1, Study Design
ADDED:
After signing informed consent and during the screening period, study site personnel 
will check that potential subjects have not already been pre-screened, initiated or 
completed screening or have been randomized into this study, or another clinical trial, 
using an independent subject participation database.  Independent subject 
participation databases seek to reduce duplicate enrollment by identifying duplicates 
before they randomize into the study, and this measure is consistent with exclusion 
requirement of not participating in another interventional clinical trial during the 
conduct of the study (inclusion criterion 17).  In order to complete this check and per 
the informed consent, study personnel will request that the subject present a valid 
picture identification (e.g. driver’s license, passport, state issued ID card, etc.)  and 
study personnel may be required to provide certain authorized information that could 
potentially be used to identify study subjects identifiers (e.g. date of birth, initials, etc.) 
so that the match algorithms can be run. 
Subjects that meet the inclusion criteria, none of the exclusion criteria, and are not 
identified as a duplicate subject (e.g. certainly, possible, probably), will be enrolled 
into the study. Appropriate documentation reflecting the subject’s eligibility according 
to these criteria will be reflective in the subject’s source documents.
Table 1 : Schedule of Assessements
WAS:
Verify Eligibility Criteria
IS AMENDED TO:
Verify Eligibility Criteria (and duplicate subject database check)
IV Synopsis, Inclusion Criteria and 3 Study Population
3.2 Inclusion Criterion #9
WAS:
Pain in 11 of 18 tender point sites on digital palpation.
IS AMENDED TO:

Pain in at least 11 of 18 tender point sites on digital palpation.

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1 Background
Background on Target Indication
WAS:
Despite the available approved medications, novel medications to treat pain, fatigue, sleep 
disturbances and impaired cognition without intolerable AEs present an unmet medical need for 
subjects with fibromyalgia.
IS AMENDED TO:
Despite the available approved medications, novel medications to treat pain, fatigue, sleep 
disturbances and impaired cognition without intolerable AEs are required to address an 
unmet medical need for subjects with fibromyalgia.
2.1 Study Design and Dose Rationale
2.2.1 Study Design
WAS:
The study will be conducted in the US. 
IS AMENDED TO:
The study will be conducted in the US in up to approximately 35 sites. 
5.2 Demographics and Baseline Characteristics
5.2.3 Diagnosis of the Target Disease, Severity and Duration of Disease
WAS:
The diagnosis fibromyalgia must be confirmed by the investigator and documented in the 
subject’s medical notes (meeting both the 1990 and 2010 American College of 
Rheumatology clinical classification criteria for fibromyalgia). Duration of fibromyalgia, 
date of onset of fibromyalgia symptoms date of fibromyalgia diagnosis and number of 
tenderpoints will be recorded in the eCRF. Tender point examination training of the 
principal investigator and/or designated site study physician must be documented.
The WPI and SS score will be completed by the clinician on a tablet device during the 
Screening visit. Subjects should have a WPI ≥7 and SS score ≥ 5 or WPI of 3 to 6 and 
SS scale score ≥ 9.
IS AMENDED TO:
The diagnosis fibromyalgia must be confirmed by the investigator and documented in the 
subject’s medical notes (meeting both the 1990 and 2010 American College of 
Rheumatology clinical classification criteria for fibromyalgia). Duration of fibromyalgia, 
date of onset of fibromyalgia symptoms and date of fibromyalgia will be recorded in the 
eCRF.
The number of tender points, WPI and SS score will be completed by the clinician on a 

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tablet device during the Screening visit. Subjects should have a WPI ≥7 and SS score ≥ 5 
or WPI of 3 to 6 and SS scale score ≥ 9. Tender point examination training of the 
principal investigator and/or designated site study physician must be documented.
5.8 Total Amount of Blood
WAS:
Total blood collected for laboratory specimens is approximately 144 mL.
IS AMENDED TO:
Total amount of  blood collected per subject for laboratory specimens is approximately 
144 mL.

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[GPF v5.0]
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