Clinical trial NCT03056690
Conditions: Fibromyalgia
Keywords: ASP0819 Fibromyalgia
Sponsor: Astellas Pharma Global Development, Inc.
Start date: 2017-03-20; Completion date: 2018-02-27
Enrollment: 186 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study assessed analgesic efficacy of ASP0819 relative to placebo as well as the safety and tolerability.

This study assessed treatment differences in physical function as well as the improvements in overall subject status (e.g., fibromyalgia symptoms and global functioning) of ASP0819 relative to placebo.

Detailed description:

Arms: arm 1: Participants received ASP019 15 mg capsules, orally, once daily in the morning, with or without food for 8 weeks. arm 2: Participants received ASP019 matching placebo capsules, orally, once daily in the morning, with or without food for 8 weeks.
Interventions: intervention 1: ASP0819 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral capsule intervention 2: Oral capsule

Protocol documents:
Prot_000.pdf: 
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, 
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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 
designee (i.e., study drug manager) agrees to conduct a final drug supply inventory and 


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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 
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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 
Test. The analysis at Week 8 will be conducted using mBOCF for subjects with missing data. 


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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 
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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]
15
SPONSOR’S SIGNATURES

SAP_001.pdf: 
Sponsor: Astellas Pharma Global Development, Inc. (APGD)
SAP Final Version 2.0
ISN/Protocol 0819-CL-0201
10-Apr-2018
Astellas
Page 1 of 95
STATISTICAL ANALYSIS PLAN
Final Version 2.0, dated 10-Apr-2018
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: 0819-CL-0201
IND number: 127248
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way,
Northbrook, 
IL 60062
This confidential document is the property of the sponsor.  No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor.
NCT03056690


Sponsor: Astellas Pharma Global Development, Inc. (APGD)
SAP Final Version 2.0
ISN/Protocol 0819-CL-0201
10-Apr-2018
Astellas
Page 2 of 95
Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 5
1
INTRODUCTION·················································································· 9
2
FLOW CHART AND VISIT SCHEDULE···················································10
3
STUDY OBJECTIVE(S) AND DESIGN······················································14
3.1
Study Objective(s) ············································································14
3.1.1
Primary Objectives······································································14
3.1.2
Secondary Objectives ···································································14
3.1.3
Exploratory Objectives ·································································14
3.2
Study Design···················································································14
3.3
Randomization·················································································15
4
SAMPLE SIZE·····················································································15
5
ANALYSIS SETS ·················································································16
5.1
Full Analysis Set (FAS) ······································································16
5.2
Per Protocol Set (PPS)········································································16
5.2.1
Reasons for Exclusion From PPS ·····················································16
5.3
Safety Analysis Set (SAF) ···································································19
5.4
Pharmacokinetics Analysis Set (PKAS)····················································19
6
ANALYSIS VARIABLES ·······································································19
6.1
Efficacy Endpoints············································································19
6.1.1
Primary Efficacy Endpoint(s)··························································20
6.1.2
Secondary Efficacy Endpoints·························································20
6.1.3
Exploratory Efficacy Endpoints ·······················································23
6.2
Safety Variables ···············································································32
6.2.1
Adverse Events ··········································································32
6.2.2
Clinical Laboratory Variables··························································33
6.2.3
Vital Signs················································································33
6.2.4
Electrocardiograms······································································33
6.2.5
Columbia Suicide Severity Rating Scale ·············································33
6.3
Pharmacokinetic Variables···································································34
6.4
Other Variables················································································34
6.4.1
Exposure··················································································34
6.4.2
Percent overall compliance·····························································34


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6.4.3
Previous and concomitant medication ················································35
6.4.4
Time since onset of Fibromyalgia symptoms and time since diagnosis ··········35
6.4.5
Mini-International Neuropsychiatric Interview······································36
6.4.6
Widespread Pain Index and Symptom Severity Scale score ·······················36
6.4.7
Complex Medical Symptoms Inventory··············································36
7
STATISTICAL METHODOLOGY ···························································37
7.1
General Considerations·······································································37
7.2
Study Population ··············································································39
7.2.1
Disposition of Subjects ·································································39
7.2.2
Protocol Deviations ·····································································39
7.2.3
Demographic and Other Baseline Characteristics ···································40
7.2.3.1
Demographics······································································40
7.2.3.2
Fibromyalgia and Targeted Medical History···································41
7.2.3.3
Fibromyalgia related baseline disease characteristics ·························42
7.2.3.4
Medical History····································································44
7.2.4
Previous and Concomitant Medications ··············································44
7.2.5
Previous and Concomitant Non-Medication Therapy·······························45
7.3
Study Drugs····················································································46
7.3.1
Exposure··················································································46
7.3.2
Treatment Compliance··································································47
7.4
Analysis of Efficacy ··········································································47
7.4.1
Analysis of Primary Endpoint(s) ······················································47
7.4.1.1
Primary Analysis of Primary Endpoint ·········································48
7.4.1.2
Sensitivity Analyses of Primary Endpoint······································49
7.4.2
Analysis of Secondary Endpoints ·····················································51
7.4.3
Analysis of Exploratory Endpoints····················································53
7.4.4
Analysis of Other Variables····························································59
7.5
Analysis of Safety·············································································60
7.5.1
Adverse Events ··········································································60
7.5.1.1
Adverse Events Prior to First Dose··············································60
7.5.1.2
Treatment Emergent Adverse Events ···········································60
7.5.1.3
Treatment Emergent Adverse Events by SOC and/or PT·····················61
7.5.2
Adverse Events of Interest ·····························································61
7.5.3
Clinical Laboratory Evaluation ························································62
7.5.3.1
Liver Enzymes and Total Bilirubin··············································63


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7.5.3.2
Potentially Clinically Significant Laboratory Criteria·························64
7.5.4
Vital Signs················································································64
7.5.5
Electrocardiograms······································································65
7.5.6
Physical Examination Findings························································65
7.5.7
Columbia Suicide Severity Rating Scale ·············································65
7.5.8
Pregnancies···············································································66
7.6
Analysis of PK·················································································66
7.7
Analysis of PD·················································································66
7.8
Subgroups of Interest ·········································································66
7.8.1
Subgroup Analysis for Primary Endpoint ············································66
7.8.2
Subgroup Analysis for Exploratory Endpoint FMSD·······························68
7.9
Other Analyses ················································································68
7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)····················68
7.11
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········68
7.11.1
Missing Data ·············································································68
7.11.2
Outliers ···················································································71
7.11.3
Values below limit of quantification (BLOQ) ·······································71
7.11.4
Visit Windows for Efficacy Variables ················································71
7.11.4.1
Duplicate Values···································································71
7.11.4.2
Post Dosing Efficacy Observations··············································71
7.11.4.3
Visit Windows ·····································································71
7.11.5
Visit Windows for Safety Variables···················································73
7.11.5.1
Duplicate Values···································································73
7.11.5.2
Post Dosing Safety Observations ················································74
7.11.5.3
Visit Windows ·····································································74
7.11.6
Pooling Sites Algorithm ································································75
8
DOCUMENT REVISION HISTORY ·························································76
9
REFERENCES ····················································································84
10
APPENDICES ·····················································································85
10.1
Appendix 1: Drug Abuse Related Adverse Events········································86
10.2
Appendix 2: Drug Withdrawal Related Adverse Events ·································89
10.3
Appendix 3: Potentially Clinically Significant Laboratory Criteria·····················92
10.4
Appendix 4: Key contributors and Approvers ·············································93


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I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
ACR
American College of Rheumatology
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Transaminase
ANCOVA
Analysis of Covariance
ANOVA
Analysis of Variance
APGD
Astellas Pharma Global Development, Inc.
ASCM
Analysis Set Classification Meeting 
AST
Aspartate Transaminase
ATC
Anatomical Therapeutic Chemical
BLOQ
Below the limit of quantification
BMI
Body Mass Index
BOCF
Baseline Observation Carried Forward
CI
Confidence Interval
CMSI
Complex Medical Symptom Inventory
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
CYP3A
Cytochrome P450 3A
DBP
Diastolic Blood Pressure
DSM-V
Diagnostic and Statistical Manual of Mental Disorders
e-diary
Electronic diary
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EOS
End of Study
EOT
End of Treatment
EQ-5D-5L
European Quality of Life 5 Dimensions-5 Levels
EQ-VAS
EQ Visual Analog Scale
FAS
Full Analysis Set
FIQR
Fibromyalgia Impact Questionnaire Revised
FM
Fibromyalgia
FMSD
Fibromyalgia Sleep Diary
FU
Follow-up
GABAB
γ-aminobutyric acid
GD-US
Global Development - United States
H
High


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Abbreviations
Description of abbreviations
HADS
Hospital Anxiety and Depression Scale
IAP
Interim Analysis Plan
ICD-10
International Statistical Classification of Diseases and Related Health Problems
ICF
Informed consent form
ICH
International Council for Harmonization
IDMC
Independent Data Monitoring Committee
INR
International Normalized Ratio
IRT
Interactive Response Technology
L
Low
LDH
Lactate dehydrogenase
LOCF
Last Observation Carried Forward
LS
Least squares
mBOCF
Modified Baseline Observation Carried Forward
MDD
Major Depressive Disorder
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
mIBS-D
Modified irritable bowel syndrome - diarrhea predominant
M.I.N.I.
Mini-International Neuropsychiatric Interview
MMRM
Mixed model repeated measures
N
Normal
NPSI
Neuropathic Pain Symptom Inventory
NRS
Numerical rating scale
NSAID
Nonsteroidal anti-inflammatory drug
PCS 
Potentially Clinically Significant
PD1-x
Protocol Deviation 1-x
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity
PK
Pharmacokinetic
PKAS
Pharmacokinetics Analysis Set
PPS
Per-Protocol Analysis Set
PRO
Patient reported outcome
PT
Preferred Term
RBC
Red blood cell
SAE
Serious adverse event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SAS 
Statistical Analysis Software


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Abbreviations
Description of abbreviations
SBP
Systolic Blood Pressure
SD
Standard deviation
SE
Standard error
SMQ
Standardised MedDRA Query
SOC
System Organ Class
SS
Symptom severity
TBL
Total bilirubin
TEAE
Treatment Emergent Adverse Event
THC
Tetrahydrocannabinol
TLF
Tables, Listings and Figures
ULN
Upper Limit of Normal
US
United States
WBC
White blood cell
WHO-DD
World Health Organization Drug Dictionary
WPI
Widespread pain index


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List of Key Terms
Terms
Definition of terms
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.
End of Study
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 
The date the last dose of study drug was taken by the enrolled subject.
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.
Treatment-Emergent 
Adverse Event
Any adverse event which starts, or worsens, after the first dose of study drug 
through 30 days after the last dose of study drug.


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1
INTRODUCTION
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes detailed procedures 
for executing the statistical analysis of the primary and secondary endpoints and other data. 
The SAP is finalized and signed prior to database hard lock to ensure lack of bias.  Any 
subsequent changes will be described with justification in an updated version of the SAP 
(with date of version number).
This statistical analysis is coordinated by the responsible biostatistician of GD-US.  Any 
changes from the analyses planned in the SAP will be justified in the Clinical Study Report 
(CSR).
Prior to database hard lock, a final review of data and Tables, Listings and Figures (TLFs) 
meeting will be held to allow a review of the clinical trial data and to verify the data that will 
be used for analysis set classification.  If required, consequences for the statistical analysis 
will be discussed and documented.  A meeting to determine analysis set classifications may 
also be held prior to database hard lock.


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2
FLOW CHART AND VISIT SCHEDULE
Figure 1
Study flow chart
EOS: end of study; EOT: end of treatment.


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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 Subjecte
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 principle 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.
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.
Footnotes continued on next page


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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 informed consent form (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.
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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3
STUDY OBJECTIVE(S) AND DESIGN
3.1
Study Objective(s)
The objectives of the study, conducted in subjects with fibromyalgia, are the following:
3.1.1
Primary Objectives
Assess analgesic efficacy of ASP0819 relative to placebo. 
●
Assess the safety and tolerability of ASP0819 relative to placebo.
●
3.1.2
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. 
3.1.3
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. 
●
Assess treatment differences in gastrointestinal symptoms.
●
Assess relationship between gastrointestinal symptoms and analgesic effect. 
●
Assess relationship between neuropathic symptoms and analgesic effect.
●
3.2
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 United States (US).  Approximately 323 subjects are 
planned to be screened for 178 randomized subjects (45% screen fail rate).  Subjects will be 
randomized in a 1:1 ratio to one of two treatment groups: ASP0819 15 mg or Placebo once 
per day.
The study will consist of a screening period of up to 6 weeks, which includes the completion 
of screening procedures, wash-out of prohibited medications (if applicable) followed by a 
1-week baseline diary run-in; an 8-week double-blind randomized treatment period (subjects 
randomized to the ASP0819 group will receive ASP0819 15 mg [3 capsules of 5 mg] once 
daily; subjects randomized to the placebo group will receive placebo to match ASP0819 
[3 capsules] once daily); and a 4-week follow-up period.  The total study duration for a 
subject is approximately 18 weeks.
Acetaminophen may be used as rescue therapy for intolerable pain due to fibromyalgia 
during the baseline diary run-in and in all subsequent study periods.  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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This study design includes a stopping rule for futility.  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/End of Treatment (EOT) data.  The 
plan for the interim analysis may be modified based on speed of recruitment.
The futility 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 Interim Analysis Plan (IAP).
3.3
Randomization
All subject numbers will be assigned using the interactive response technology (IRT) starting 
at screening. All subjects will have a unique, ten-digit subject number.  The first five digits 
of this number will be the investigator’s site number.  The second five digits assigned will 
represent the subject’s accession number.  This will be the number that identifies a subject 
during the course of the study.
Screening procedures, wash-out of prohibited medications (if applicable) and the baseline-
diary run-in will be completed prior to randomization.  Only subjects who meet all inclusion 
criteria and exhibit none of the exclusion criteria will be randomly assigned in a 1:1 ratio to 
ASP0819 15 mg or placebo according to the randomization schedule through IRT.  The 
randomization will be stratified by site.  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.
4
SAMPLE SIZE
In this study, a total of 178 subjects will be randomized in a 1:1 ratio to ASP0819 15 mg once 
daily (89 subjects) or placebo once daily (89 subjects).
The sample size calculations are based on the primary efficacy endpoint of change from 
baseline to Week 8 in mean daily average pain assessed by numerical rating scale (NRS).  A 
meta-analysis of the change from baseline in mean daily average pain NRS for pregabalin or 
duloxetine versus 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 versus placebo, 84 subjects each in the 
ASP0819 group and the placebo group (168 subjects in total) would be required to provide 


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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).
Assuming approximately 5% of randomized subjects will not contribute to the primary 
efficacy analysis, a total of 178 subjects are required to be randomized into the study.
5
ANALYSIS SETS
In accordance with International Council for Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses.
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.
5.1
Full Analysis Set (FAS)
The full analysis set (FAS) will consist of all randomized subjects who take at least one dose 
of study drug.
The FAS will be used for demographic and baseline characteristic summaries and primary 
summaries and analyses of efficacy variables.
When the FAS is utilized in an analysis, subjects will be presented by the randomized 
treatment group, i.e. planned treatment group, even if the treatment they received was 
different.
5.2
Per Protocol Set (PPS)
The per protocol set (PPS) will include 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 is defined in Section 5.2.1 of this 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 outlined 
in Section 7.4.2
Final judgments on exclusion of subjects from the PPS are to be made at the analysis set 
classification meeting (ASCM), which will be held prior to database hard lock and 
unblinding of the study. 
5.2.1
Reasons for Exclusion From PPS
A subject who meets any of the criteria described in Table 2 will be completely excluded 
from the PPS; there will be no partial data exclusion of a specified time point for a subject.


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Table 2
Criteria for Assessing Reasons for Exclusion From PPS
Number
Source
Criterion/Criteria
Didn’t Satisfy Diary Eligibility Criteria
1.1
Inclusion Criterion # 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.
Compliance is not met at baseline i.e. number 
of days of daily average NRS pain ratings 
during the baseline diary run-in (from study 
day -7 to -1) is < 5.
1.2
Inclusion Criterion # 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 electronic diary (e-diary) during the 
baseline diary run-in period, and meeting 
pre-specified criteria for daily average pain scores.
During the baseline diary run-in period (from 
study day -7 to -1) the subject has:

A mean daily average pain NRS of 
< 4 or > 9 and/or,

Two or more daily average pain 
scores of > 9 and/or,

Four or more daily average pain 
scores of ≤3.
Didn’t Satisfy Non-Diary Eligibility Criteria
2.1
Inclusion Criterion # 9: 
Subject meets the American College of 
Rheumatology (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 11 of 18 tender point sites on digital 
palpation.
o
Digital palpation should be performed 
with an approximate force of 4 kg.
Inclusion Criterion # 9 is No and/or pain is in 
< 11 tender point sites
2.2
Inclusion Criterion # 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.
Inclusion criterion #10 is No and/or 
WPI ≥ 7 and SS scale score < 5 or 
WPI 3-6 and SS scale score < 9 or
WPI < 3.
Table continued on next page


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Number
Source
Criterion/Criteria
2.3
Inclusion Criterion # 11:
Subject has a pain score ≥ 4 on the revised 
fibromyalgia impact questionnaire revised (FIQR) 
pain item at Screening.
Inclusion criterion #11 is No and/or FIQR 
pain item score < 4 at Screening.
Met Exclusion Criteria
3.1
Exclusion Criterion # 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.
Exclusion Criterion # 4 is Yes.
3.2
Exclusion Criterion # 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.
Exclusion Criterion # 5 is Yes.
3.3
Exclusion Criterion # 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.
Exclusion Criterion # 6 is Yes.
3.4
Exclusion Criterion # 8:
Subject has a history of any psychotic and/or 
bipolar disorder as assessed by the M.I.N.I.
Exclusion Criterion # 8 is Yes.
3.5
Exclusion Criterion # 9:
Subject has a HADS score > 14 on the Depression 
subscale at Screening or at the time of Visit 3 
(Randomization).
Exclusion Criterion #9 is Yes and/or HADS 
total score > 14 (using HADS corrected 
questionnaire) at Screening or Visit 3 
(Randomization). Subjects who completed the 
incorrect version of this questionnaire will be 
reviewed on a case by case basis.
Error in Study Drug Administration Compared to Treatment Assigned
4
Received wrong treatment during the double-blind 
treatment period
A subject will be excluded if the study drug 
taken at any time during the double-blind 
treatment period is different from the 
treatment group assigned at randomization.
Table continued on next page


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Number
Source
Criterion/Criteria
Poor Study Drug Compliance
5
Poor study drug compliance during the double-
blind treatment period.
Percent overall compliance is <70% for a 
subject, calculated over day 1 to Week 8/EOT.
Subjects with missing compliance will be 
reviewed on a case by case basis.
Unblinding of Study Drug
6
Incorrect unblinding of double-blind study drug. 
A subject’s treatment for double-blind study 
drug is incorrectly unblinded.  The decision to 
exclude the subject will be evaluated on a case 
by case basis.
Use of Prohibited Concomitant Medication
7
Subject received celecoxib, duloxetine, 
gabapentin, milnacipran or pregabalin during the 
double-blind treatment period.
Subject received at least one dose of 
celecoxib, duloxetine, gabapentin, milnacipran 
or pregabalin during the double-blind 
treatment period.
5.3
Safety Analysis Set (SAF)
The Safety Analysis Set (SAF) consists of all randomized subjects who received at least one 
dose of study drug.
The SAF will be used for summaries of demographic and baseline characteristics and all 
safety and tolerability related variables.
When the SAF is utilized in an analysis, subjects will be presented by the treatment actually 
received.  Subjects who are randomized to placebo who accidentally receive at least one dose 
of ASP0819 will be summarized in the ASP0819 treatment group in the SAF.
5.4
Pharmacokinetics Analysis Set (PKAS)
The PKAS will consist of the subset of SAF for which at least one post dose concentration is 
available. 
6
ANALYSIS VARIABLES
6.1
Efficacy Endpoints
The subjects will use a handheld device (an e-diary that will be taken home) to report daily 
average pain NRS scores, enter Fibromyalgia sleep diary (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 (Fibromyalgia Impact 
Questionnaire Revised [FIQR], Patient Global Impression of Change [PGIC], Patient Global 
Impression of Severity [PGIS], European Quality of Life 5 Dimensions-5 Levels 
[EQ-5D-5L], modified irritable bowel syndrome - diarrhea predominant [mIBS-D] 
Symptoms Diary) and the Hospital Anxiety and Depression Scale (HADS) depression 
subscale will be reported on a tablet device that is available at the site.  For FIQR, PGIS, 
EQ-5D-5L, mIBS-D and HADS baseline is defined as the last assessment on or prior to the 
first dose day (Day 1) of double-blind study drug.


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6.1.1
Primary Efficacy Endpoint(s)
The primary efficacy variable is the change from baseline to Week 8 in mean daily average 
pain score assessed by NRS (0 to 10 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.
The subject will use the e-diary to report daily average pain NRS scores from the start of the 
baseline diary run-in period through Week 10.  Subjects will be instructed to complete the 
NRS in the evening and at a consistent time each day (ideally between 6pm and midnight, 
however can be captured until 2am the next morning).  For this reason, any daily average 
pain score entered onto the e-diary up to 2am the following day will be attributed to the 
previous study day in the derivation of the mean daily average NRS pain scores. This is 
described in more detail in Section 7.11.4.3
Mean daily average NRS pain scores will be derived for each subject as follows:
Table 3
Derivation of mean daily average NRS pain score
Analysis Time point
Derivation
Baseline
Arithmetic mean of non-missing daily pain scores from the last 7 days 
prior to the randomization visit i.e., using the non-missing scores from 
Study Days -7 to -1.  If the pain score is missing on all of these 7 days, 
then the score will be set to missing.
Treatment period
Week 1, Week 2, Week 3, Week 4,
Week 5, Week 6, Week 7, Week 8, 
EOT 
Follow-up period
Week 10
Arithmetic mean of non-missing daily pain scores collected within time 
window per visit windows defined in Section 7.11.4.3  Table 21  If the 
pain score is missing on all of the days during the time window, then the 
score for that time point will be set to missing.
EOT: end of treatment
Change from baseline is defined in Section 7.1   A negative change indicates a 
reduction/improvement from baseline (i.e., a favorable outcome).
6.1.2
Secondary Efficacy Endpoints
Secondary efficacy endpoints include:
Percentage of subjects achieving ≥ 30 % (or ≥ 50%) reduction from baseline to Week 8 
●
in mean daily average pain score assessed by NRS (0 to 10 scale) in the subject’s daily 
diary.
○
A subject with at least 30% (or 50%) reduction in mean daily average pain score 
(NRS) from baseline to Week 8 will be classified as a responder; otherwise they 
will be classified as a non-responder. 
○
Subjects who do not have Week 8 data will be classified as non-responders.
○
Subjects who do not have baseline data will be classified as non-responders.


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Percentage of subjects achieving ≥ 30 % (or ≥ 50%) reduction from baseline to EOT in 
●
mean daily average pain score assessed by NRS (0 to 10 scale) in the subject’s daily 
diary.
○
A subject with at least 30% (or 50%) reduction in mean daily average pain score 
(NRS) from baseline to EOT will be classified as a responder; otherwise they will 
be classified as a non-responder. 
○
Subjects who do not have EOT data will be classified as non-responders.
○
Subjects who do not have baseline data will be classified as non-responders.
Percent change from Baseline is defined in Section 7.1  A negative percent change 
indicates a reduction/improvement from Baseline (i.e., a favorable outcome). 
Change from baseline to Weeks 2, 4, 8 and EOT in the FIQR function, symptoms and 
●
overall impact subscales. 
The 21-item FIQR contains 3 subscales: function (9 questions), overall impact 
(2 questions), and symptoms (10 questions).  Subjects answer each question on an 
11-point NRS, with anchors appropriate to each question on a tablet device during the 
clinic visit.  The recall period is the last 7 days or, for the function subscale, the last time 
the activity was performed if not within the 7-day recall period.
For each subject the items described in Table 4 will be derived. The questionnaire should 
be considered to be invalid if three or more of the individual questions are unanswered.  
In this case, all subscales and the total score would be set to missing, even if a particular 
subscale has no missing items. 
Change from baseline is defined in Section 7.1   A negative change indicates a 
reduction/improvement from baseline (i.e., a favorable outcome). 
Table 4
Derivation of FIQR subscales and total score
Analysis Time 
point
FIQR Item
Derivation 
Baseline,
Treatment period 
Week 2, Week 4, 
Week 8, EOT, 
Follow-up period
Week 10
Function subscale score
Rate the difficulty of the following 
activities:
1)
Brush or comb your hair
2)
Walk continuously for 20 mins
3)
Prepare a homemade meal
4)
Vacuum, scrub or sweep floors
5)
Lift and carry a full bag of 
groceries
6)
Climb one flight of stairs
7)
Change bed sheets
8)
Sit in a chair for 45 mins
9)
Go shopping for groceries
Sum of scores from questions 1 to 9.
In the case of missing data, unanswered 
questions should be compensated using the 
following “weighting” factor:
If only x questions from the Function 
subscale were answered, the added score of 
the x questions should be weighed by 9/x. 
The range of scores will be 0 to 90, with a 
lower score indicting better (higher) 
function.
Table continued on next page


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Analysis Time 
point
FIQR Item
Derivation 
Overall impact subscale score:
10) Fibromyalgia prevented me 
from accomplishing goals for 
the week
11) I was completely overwhelmed 
by my fibromyalgia symptoms
Sum of scores from questions 10 and 11.
In the case of missing data, unanswered 
questions should be compensated using the 
following “weighting” factor:
If only x questions from the Overall impact 
subscale were answered, the added score of 
the x questions should be weighed by 2/x.
The range of scores will be 0 to 20, with a 
lower score indicating better (lower) 
impact.
Symptoms subscale score:
Please rate:
12) Your level of pain
13) Your level of energy
14) Your level of stiffness
15) The quality of your sleep
16) Your level of depression
17) Your level of memory problems
18) Your level of anxiety
19) Your level of tenderness to 
touch
20) Your level of balance problems
21) Your level of sensitivity to loud 
noises, bright lights, odors and 
colds
Sum of scores from questions 12 to 21.
In the case of missing data, unanswered 
questions should be compensated using the 
following “weighting” factor:
If only x questions from the Symptoms 
subscale were answered, the added score of 
the x questions should be weighed by 10/x.
The range of scores will be 0 to 100, with a 
lower score indicating a better (lower) 
level of symptoms.
Total score
A normalization factor is applied to each of 
the three subscale scores: the function 
subscale score is divided by 3, the overall 
subscale score is divided by 1 (i.e. it is left 
unchanged), and the symptoms subscale 
score is divided by 2.
The total FIQR score is the sum of the 
three normalized subscale scores.  The 
range of scores will be 0 to 100, with a 
lower score indicating a better response.
EOT: end of treatment
Overall subject improvement assessed by PGIC at Weeks 2, 4, 8, and EOT.
●
The PGIC is a self-administered 7-point Likert scale that asks subjects to evaluate their 
fibromyalgia relative to baseline.  This is a single question and the grade ranges from 1 
to 7, where 1 anchors “Very Much Improved” and 7 anchors “Very Much Worse”.  
Subjects will complete the questionnaire during the clinic visits on a tablet device.


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6.1.3
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 (see Table 3) assessed by NRS (0 to 10 scale).
Percentage of subjects achieving > 0%, ≥ 10%, ≥ 20%, ≥ 40%, ≥ 60%, ≥ 70%, ≥ 80%, 
●
≥90% and =100% reduction from baseline to Week 8 and from baseline to 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 (see Table 4).
Change from baseline to Weeks 2, 4, 8 and EOT in PGIS.
The PGIS is a self-administered 6-point Likert scale that asks subjects to evaluate how 
their fibromyalgia is now.  This is a single question and the grade ranges from 1 to 6 
where 1 anchors “no symptoms” and 6 anchors “very severe”.  Subjects will complete 
the questionnaire during the clinic visits on a tablet device. 
Change from baseline is defined in Section 7.1   A negative change indicates a 
reduction/improvement from baseline (i.e., a favorable outcome). 
Percentage of subjects achieving a PGIC of “Very Much Improved” or “Much 
●
Improved” at Week 8 and at EOT.
Percentage of subjects achieving ≥ 30 % reduction from baseline in FIQR total score at 
●
Week 8 and at EOT.
Percentage of subjects achieving a composite pain response, defined as achieving ≥ 30% 
●
reduction from baseline in mean daily average pain score and PGIC of “Very Much 
Improved” or “Much Improved” at Week 8 and at EOT. 
Percentage of subjects achieving a composite syndrome response, defined as achieving 
●
≥30% reduction from baseline in mean daily average pain score and PGIC of “Very 
Much Improved” or “Much Improved” and ≥ 30 % reduction from baseline in FIQR 
total score, at Week 8 and EOT.


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Table 5
Summary of responder definition for exploratory endpoints
Analysis Time point
Responder definition
Handling of missing data
Percentage of subjects achieving > 0%, ≥ 10%, ≥20%, ≥ 40%, ≥ 60%, ≥70%, ≥ 80%, ≥90% and =100% reduction compared to baseline in mean daily average pain score
Week 8
Except for >0% and 100%, a subject will be classified as a responder if the reduction from 
baseline to Week 8 is ≥ the specified percentage; otherwise classified as a non-responder.
For >0%, a subject will be classified as a responder if the reduction from baseline to Week 8 is 
>0%; otherwise classified as a non-responder. 
For 100%, a subject will be classified as a responder if the reduction from baseline to Week 8 is 
=100%; otherwise classified as a non-responder.
Subjects with missing baseline or Week 8 data will 
be classified as non-responders.
Week 8 using mBOCFa
for imputation of missing 
data
As above.
Subjects with missing baseline or EOT data will be 
classified as non-responders.
EOT
Except for >0% and 100%, a subject will be classified as a responder if the reduction from 
baseline to EOT is ≥ the specified percentage; otherwise classified as a non-responder.
For >0%, a subject will be classified as a responder if the reduction from baseline to EOT is 
>0%; otherwise classified as a non-responder. 
For 100%, a subject will be classified as a responder if the reduction from baseline to EOT is 
=100%; otherwise classified as a non-responder.
Subjects with missing baseline or EOT data will be 
classified as non-responders
Percentage of subjects achieving a PGIC of “Very Much Improved” or “Much Improved”
Week 8 using mBOCFa
for imputation of missing 
data
A subject will be classified as a responder if they answer “Very Much Improved” or “Much 
Improved” at Week 8; whereas if they answer “Minimally Improved”, “No Change”, 
“Minimally Worse”, “Much Worse” or “Very Much Worse” they will be classified as a non-
responder.
Subjects with missing EOT data will be classified as 
non-responders.
EOT
A subject will be classified as a responder if they answer “Very Much Improved” or “Much 
Improved” at EOT; whereas if they answer “Minimally Improved”, “No Change”, “Minimally 
Worse”, “Much Worse” or “Very Much Worse” they will be classified as a non-responder.
Subjects with missing EOT data will classified as 
non-responders.
Table continued on next page


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Analysis Time point
Responder definition
Handling of missing data
Percentage of subjects achieving ≥ 30 % reduction from baseline in FIQR total score
Week 8 using mBOCFa
for imputation of missing 
data
A subject with at least 30% reduction in FIQR total score from baseline to Week 8 will be 
classified as a responder; otherwise they will be classified as a non-responder.
Subjects with missing baseline or EOT data will be 
classified as non-responders.
EOT
A subject with at least 30% reduction in FIQR total score from baseline to EOT will be classified 
as a responder; otherwise they will be classified as a non-responder.
Subjects with missing baseline or EOT data will 
classified as non-responders
Percentage of subjects achieving a composite pain response
Week 8 using mBOCFa
for imputation of missing 
data
A subject with at least 30% reduction from baseline in mean daily average pain score and PGIC 
of “Very Much Improved” or “Much Improved” at Week 8 will be classified as a responder; 
otherwise they will be classified as a non-responder.
Subjects with missing baseline or EOT data for any 
component will be classified as non-responders.
EOT
A subject with at least 30% reduction from baseline in mean daily average pain score and PGIC 
of “Very Much Improved” or “Much Improved” at EOT will be classified as a responder; 
otherwise they will be classified as a non-responder.
Subjects with missing baseline or EOT data for any 
component will classified as non-responders
Percentage of subjects achieving a composite syndrome response
Week 8 using mBOCFa
for imputation of missing 
data
A subject with at least 30% reduction from baseline in mean daily average pain score and PGIC 
of “Very Much Improved” or “Much Improved” and at least 30 % reduction from baseline in 
FIQR total score at Week 8 will be classified as a responder; otherwise they will be classified as 
a non-responder.
Subjects with missing baseline or EOT data for any 
component will be classified as non-responders.
EOT
A subject with at least 30% reduction from baseline in mean daily average pain score and PGIC 
of “Very Much Improved” or “Much Improved” and at least 30 % reduction from baseline in 
FIQR total score at EOT will be classified as a responder; otherwise they will be classified as a 
non-responder.
Subjects with missing baseline or EOT data for any 
component will classified as non-responders
AE: adverse event; EOT: end of treatment; FIQR: Fibromyalgia impact questionnaire revised; mBOCF: modified baseline observation carried forward; PGIC: Patient global 
impression of change 
amBOCF for these binary response endpoints will be implemented as follows: Subjects who discontinue early due to lack of efficacy or adverse events (AEs) will be classified as non-
responders whereas subjects who discontinue early due to other reasons will be classified using their responder status at EOT.


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Change from baseline to Weeks 1, 2, 3, 4, 5, 6, 7, 8 and EOT in mean daily FMSD item 
●
scores, which captures all critical sleep disturbance features of fibromyalgia.
The FMSD is an 8-item patient reported outcome (PRO) measure of sleep disturbance 
specific to fibromyalgia subjects, covering the hypothesized domains of Falling Asleep, 
Staying Asleep, and Sufficient Sleep.  Each item is rated on an 11-point NRS anchored 
by “0 - not at all” and “10 – extremely.”  Using the e-diary, the subject completes the 
FMSD to rate their quality of sleep during the previous night each morning at a 
consistent time (ideally between 6 am and noon however can be captured until 2 am the 
next morning).  For this reason, any FMSD item entered onto the e-diary up to 2 am the 
following day will be attributed to the previous study day.  This is described in more 
detail in Section 7.11.4.3  
Table 6
Derivation of mean daily score for each FMSD item
Analysis Time point
FMSD Item
Derivation
Baseline
Treatment period
Week 1, Week 2,
Week 3, Week 4,
Week 5, Week 6,
Week 7, Week 8 
EOT,
Follow-up period
Week 10 
Item 1: Difficulty with falling asleep
Item 2: Restlessness of sleep
Item 3: Difficulty getting comfortable
Item 4: Difficulty staying asleep
Item 5: Degree of deep sleep
Item 6: Degree of being rested when 
waking up for the day
Item 7: Difficulty with beginning the day
Item 8: Degree of having enough sleep 
during the previous night
Score from 0 to 10 for each individual 
item.
To calculate the mean daily FMSD 
item scores at each analysis timepoint:
Arithmetic mean of non-missing FMSD 
item scores collected within time 
window per visit windows defined in 
Section 7.11.4.3, Table 22   If any of 
the FMSD item scores are missing on 
all of the days during the time window, 
then the FMSD item score for that time 
point will be set to missing. 
EOT: end of treatment; FMSD: Fibromyalgia Sleep Diary
Change from baseline is defined in Section 7.1   For FMSD Item 1, Item 2, Item 3, 
Item 4 and Item 7 a negative change indicates a reduction/improvement from baseline 
(i.e., a favorable outcome); whereas FMSD Item 5, Item 6 and Item 8 a positive change 
indicates an improvement in sleep symptoms compared to baseline.
Change from baseline to Week 8 and EOT in the HADS depression subscale.
●
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 
symptoms of depression.  Higher scores indicate more severe symptoms of depression. 
Change from baseline is defined in Section 7.1   A negative change indicates a
reduction/improvement from baseline (i.e., a favorable outcome).  Change from baseline 


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to Week 8 and to EOT for the HADS depression subscale will only be calculated for 
subjects who have baseline data captured using the corrected version of the 
questionnaire. For subjects who have baseline HADS data captured using the original 
version of the questionnaire that was used at the start of the study change from baseline 
will not be derived.  Data captured using the original version of the questionnaire will be 
listed only and will not be presented in any tables.
Table 7
Derivation of HADS depression subscale
Analysis Time 
point
HADS 
Version
HADS Depression Item
Derivation
Baseline
Treatment period
Week 8
EOT
Corrected
Depression total score:

I feel as if I am slowed down

I enjoy the things I used to 
enjoy

I have lost interest in my 
appearance

I can laugh and see the funny 
side of things 

I look forward with enjoyment 
to things

I feel cheerful

I can enjoy a good book, radio 
or television program
Note: Reverse scoring has been applied 
on CRF.
Sum of the non-missing scores 
from the 7 questions used for 
depression and yields a score of 
0 to 21. The score cannot be 
calculated if the score is missing 
for 2 or more of the individual 
questions. If the score is missing 
only for 1 question, then it will 
be imputed with average of the 
remaining non-missing scores 
from the 6 questions.
Baseline
Original
Depression total score:
1)
I wake early and then sleep 
badly for the rest of the night.
3)
I feel miserable and sad.
5)
I have lost interest in things.
7)
I have a good appetite.
9)
I feel life is not worth living.
10) I still enjoy the things I used to.
13) I feel as if I have slowed down.
For items 7 and 10 the scoring is 
reversed
Sum of the non-missing scores 
from the 7 questions used for 
depression and yields a score of 
0 to 21. The score cannot be 
calculated if the score is missing 
for 2 or more of the individual 
questions. If the score is missing 
only for 1 question, then it will 
be imputed with average of the 
remaining non-missing scores 
from the 6 questions.
EOT: end of treatment; HADS: Hospital anxiety and depression scale
Change from baseline to Week 8 and EOT in EQ-5D-5L.
●
EQ-5D-5L consists of 2 parts: 1) the descriptive system and 2) the EQ visual analogue 
scale (EQ-VAS).  
The descriptive system comprises the following 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression.  In the newest version, each 
dimension has 5 response levels: no problems, slight problems, moderate problems, 
severe problems and unable to perform the activity.  There will be no imputation for
missing answers on the questions. 
The EQ-VAS is recorded by the subject of his/her health on a vertical, visual analogue 
scale where the endpoints are labeled ‘The best health you can imagine’ (=100) and ‘The 
worst health you can imagine’ (=0).  There will be no imputation for missing answer on 


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the question.  
Change from baseline is defined in Section 7.1 and only applies to the EQ-VAS.  A
positive change in the EQ-VAS indicates an improvement in health versus baseline.
Table 8
Derivation of EQ-5D-5L items
Analysis Time point
EQ-5D-5L Item
Derivation
Baseline
Treatment period
Week 8, EOT
Follow-up period
Week 10
Descriptive system dimension
1)
Mobility 
2)
Self-care 
3)
Usual activities
4)
Pain/discomfort
5)
Anxiety/depression
For each dimension, there are 5 
response levels of increasing severity:
1)
No problems
2)
Slight problems
3)
Moderate problems
4)
Severe problems
5)
Unable to perform the activity
There will be no imputation for missing 
answers on the questions.
EQ-VAS: 
Visual analogue scale from 0 to 100.
Score from 0 to 100.
There will be no imputation for missing 
answer on the question.
Proportion of days with rescue medication use at Weeks 1, 2, 3, 4, 5, 6, 7, 8, EOT and 
●
Overall double-blind treatment period.
The number and proportion of days with rescue medication use during each analysis time 
point will be derived for each subject as shown in Table 9   The number of days with 
rescue medication use will be utilized to derive the proportion of days with rescue 
medication use and will be used for summaries of raw proportions.  See Section 7.4.3 for 
formal analysis of this endpoint.  Rescue medication use will be derived for 
acetaminophen use collected from the daily e-diary only.
Incidence of subjects using rescue medication at Weeks 1, 2, 3, 4, 5, 6, 7, 8, EOT and 
●
Overall double-blind treatment period.
Average daily dosage of rescue medication at Weeks 1, 2, 3, 4, 5, 6, 7, 8, EOT and 
●
Overall double-blind treatment period.
The derivation of average daily dosage of rescue medication use (acetaminophen use 
only) during each time point for each subject is shown in Table 9.


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Table 9
Derivation of rescue medication endpoints
Analysis Time 
point
Item
Derivation
Baseline,
Treatment period
Week 1, Week 2,
Week 3, Week 4,
Week 5, Week 6,
Week 7, Week 8 
EOT, Overall 
double-blind 
treatment period
Follow-up period
Week 10, Overall 
follow-up period
Proportion of days with 
rescue medication use 
Number of days of rescue medication
Total number of days
Number of days of rescue medication:
Number of days of acetaminophen use within time window 
per visit windows defined in Section 7.11.4.3  Table 21
Total number of days:
Minimum of (upper bound of the time window, last 
assessment day from e-diary data) – lower bound of the 
time window + 1, per visit windows defined in 
Section 7.11.4.3  Table 21
If no rescue medication is taken on any of the days during 
the time window, then the proportion of days with rescue 
medication use for that time point will be zero.
Incidence of subjects 
using rescue medication
Percentage of subjects with acetaminophen use within the 
time window per visit windows defined in 
Section 7.11.4.3  Table 21
Average daily dosage of 
rescue medication (mg)
Total dose of rescue medication
Total number of days
Total dose of rescue medication:
Total dose of acetaminophen within time window per visit 
windows defined in Section 7.11.4.3, Table 21.  If no 
rescue medication (acetaminophen) is taken on any of the 
days during the time window, then the total dose will be 
zero.
Total number of days:
Minimum of (upper bound of the time window, last 
assessment day from e-dairy data) – lower bound of the 
time window + 1, per visit windows defined in in 
Section 7.11.4.3  Table 21
EOT: end of treatment
Change from baseline to Weeks 2, 4, 8 and EOT in Irritable Bowel Syndrome Symptom 
●
Summary Score and abdominal pain, stomach pain, abdominal cramping, abdominal 
pressure, and bloating individual items as assessed by the mIBS-D Daily Symptom 
Diary.
The mIBS-D is a 5-item questionnaire that assesses the predominant symptoms of IBS-D 
(abdominal pain, stomach pain, abdominal pressure, bloating, abdominal cramps) on an 
11-point NRS (0 - absence of symptoms to 10- severe symptoms).  Subjects will be 
asked to complete the questionnaire items while considering 2 distinct recall periods 
(previous 24 hours and last 7 days) and will enter their scores on a tablet device during 
their clinic visit.  The Irritable Bowel Syndrome 4-item Symptom Summary Score will 


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be derived for each subject for each of the 2 distinct recall periods (previous 24 hours 
and last 7 days) as shown in Table 10   
Change from baseline is defined in Section 7.1   A negative change indicates a 
reduction/improvement from baseline (i.e., a favorable outcome).
Table 10
Derivation of Irritable Bowel Syndrome Symptom Summary Score
Analysis Time 
point
Derivation
Baseline
Treatment period
Week 2, Week 4,
Week 8, EOT
Symptom summary score: 
(abdominal pain + abdominal pressure + abdominal cramps + bloating)/4
The score ranges between 0 to 10 with 0 indicating an absence of symptoms and 10 
indicating severe symptoms.
Apart from abdominal pain (where responses to the stomach pain item for the same time 
point & recall period may be used) there will be no imputation for missing answers on 
the questions. 
The symptom summary score cannot be calculated if data is missing in at least one of the 
items (apart from abdominal pain which can be replaced with stomach pain)
Change from baseline to Week 8 and EOT in neuropathic pain symptoms as assessed by 
●
the Neuropathic Pain Symptom Inventory (NPSI).
The NPSI is a self-report questionnaire specifically designed to evaluate the different 
symptoms of neuropathic pain and will be completed by the subject during clinic visits 
on a tablet device.  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 = no pain and 10 =  the most intense pain imaginable; 
and the total score ranges from 0 to 100.  The NPSI total score and 5 subscale scores 
including burning (superficial) spontaneous pain, pressing (deep) spontaneous pain, 
paroxysmal pain, evoked pain, and paresthesia/dysesthesia will be derived for each 
subject as shown in Table 11  


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Table 11
Derivation of Neuropathic Pain Symptom Inventory total score and 
subscores
Analysis Time point
Derivation
Baseline,
Treatment period
Week 8, EOT 
Burning (superficial) spontaneous pain: Question 1 score
Pressing (deep) spontaneous Pain: (Question 2 score + Question 3 score)/2
Paroxysmal pain : (Question 5 score + Question 6 score)/2
Evoked pain : (Question 8 score + Question 9 score + Question 10 score)/3
Paresthesia/dysesthesia : (Question 11 score + Question 12 score)/2
Total score :  (Question 1 score + Question 2 score + Question 3 score + 
Question 5 score + Question 6 score + Question 8 score + Question 9 score + 
Question 10 score + Question 11 score + Question 12 score)
The subscales where data is missing (any item) cannot be scored.
The total score cannot be calculated if data is missing in at least one of
the subscales.
Follow-Up Period
The following exploratory endpoints during the follow-up period will also be assessed.  In 
the derivation of these endpoints there will be no imputation of missing data as these will be 
summarized using descriptive summaries only.  Change from baseline and change from EOT 
are defined in Section 7.1   Apart from the EQ-VAS a negative change indicates a 
reduction/improvement from baseline or EOT.  Whereas a positive change indicates an 
increase/worsening versus baseline or EOT.
Change from baseline and EOT to Week 10 in mean daily average pain score. 
●
Change from baseline and EOT to Week 10 in FIQR 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.
●
Percentage of subjects 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.
Percentage of subjects 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 and Overall follow-up period.
●
Incidence of subjects using rescue medication at Week 10 and Overall follow-up period.
●
Average daily dosage of rescue medication at Week 10 and Overall follow-up period.
●


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6.2
Safety Variables
The schedule of safety assessments is shown in Table 1   Baseline is defined as the last 
assessment on or prior to the first dose day (Day 1) of double-blind study drug.
6.2.1
Adverse Events
Adverse events will be categorized as those which occur prior to first dose or 
treatment-emergent as follows:
Adverse events prior to first dose 
●
Adverse events prior to first dose is an adverse event which starts prior to the first dose 
of study drug.  If the adverse event occurs on Day 1 and the onset check box is marked 
“Onset before first dose of study drug”, then the adverse event will be considered as an 
AE prior to first dose.  If the adverse event occurs on Day 1 and the onset check box is 
marked “Onset after first dose of study drug” or the onset check box is left blank, then 
the adverse event will not be considered as an AE prior to first dose.
Treatment-emergent adverse events (TEAEs; frequency, severity, seriousness, and 
●
relationship to study drug).
TEAE is defined as an adverse event which starts, or worsens, after the first dose of 
study drug through 30 days after the last dose of study drug.  If the adverse event occurs 
on Day 1 and the onset check box is marked “Onset after first dose of study drug” or the 
onset check box is left blank, then the adverse event will be considered treatment 
emergent.  If the adverse event occurs on Day 1 and the onset check box is marked 
“Onset before first dose of study drug”, then the adverse event will not be considered 
treatment emergent.
TEAE (Treatment period) is an adverse event which starts, or worsens, after the first 
dose of study drug through to 4 days after the last dose of study drug.  If the adverse 
event occurs on Day 1 and the onset check box is marked “Onset after first dose of study 
drug” or the onset check box is left blank, then the adverse event will be considered 
treatment emergent.  If the adverse event occurs on Day 1 and the onset check box is 
marked “Onset before first dose of study drug”, then the adverse event will not be 
considered treatment emergent, unless it worsens in severity after Day 1 (up to day 4 
after last dose).
TEAE (Follow-up period) is an adverse event which starts, or worsens, 5 days after the 
last dose of study drug through 30 days after the last dose of study drug.
A drug-related TEAE is defined as any TEAE with a possible or probable relationship to 
study treatment as assessed by the investigator or with missing assessment of the causal 
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For each AE, duration will be calculated in days, using the following formula:
Duration of AE = End date of AE – Start date of AE +1, 
●
where the start date of AE and the end date of AE are defined as the onset date and end date 
of the AE, as captured in the eCRF.  Imputed dates for the start date or end date may be used 
to calculate duration (Section 7.11.1).
6.2.2
Clinical Laboratory Variables
Clinical laboratory variables are raw values (i.e., values at each scheduled visit) and changes 
from baseline for chemistry, hematology and urinalysis parameters at Weeks 2, 4, 8 and 
Week 10. 
6.2.3
Vital Signs
Vital signs variables are raw values (i.e., values at each scheduled visit) and changes from 
baseline in systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate at 
Weeks 2, 4, 8 and Week 10.
6.2.4
Electrocardiograms
The 12-lead electrocardiograms (ECG) scheduled assessments will be made at baseline, 
Week 8 and Week 10.  The results will be recorded as “normal”, “abnormal not clinically 
significant”, or “abnormal clinically significant”.  Electrocardiogram variables are raw values 
(categorical) at each scheduled visit and changes from baseline (shift from baseline) at 
Week 8 and Week 10. 
6.2.5
Columbia Suicide Severity Rating Scale
The Columbia suicide severity rating scale (C-SSRS) is a questionnaire used for suicide 
assessment.  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.  Analysis will mainly 
focus on two aspects: suicidal ideation and suicidal behavior and they will be derived for 
each subject as follows using the “Since Last visit” version:
Analysis Time point
C-SSRS Item
Derivation
Baseline
Treatment period 
Week 2, Week 4,
Week 8, EOT,
Overall double-blind 
treatment period
Follow-up period
Week 10,
Overall follow-up period
Suicidal 
ideation 
A “yes” answer to any one of the following five questions from 
suicidal ideation section on the C-SSRS.
1.
Wish to be dead
2.
Non-specific active suicidal thoughts
3.
Active suicidal ideation with any methods (not plan) 
without intent to act
4.
Active suicidal ideation with some intent to act, 
without specific plan
5.
Active suicidal ideation with specific plan and intent
If a subject answers “yes” to more than one suicidal ideation 
question within a visit window at an analysis time point 
(Section 7.11.5.3, Table 25), the worst case response (i.e., the 
highest) will be used in any summaries.
Table continued on next page


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Analysis Time point
C-SSRS Item
Derivation
Suicidal 
behavior
A “yes” answer to any one of the following five questions from 
suicidal behavior section on the C-SSRS.
6.
Preparatory acts or behavior
7.
Aborted attempt
8.
Interrupted attempt
9.
Actual attempt
10. Completed suicide
If a subject answers “yes” to more than one suicidal behavior 
question within a visit window (Section 7.11.5.3, Table 25), at 
an analysis time point (the worst case response (i.e., the 
highest) will be used in any summaries. 
Suicidal 
ideation or 
behavior
A “yes” answer to any one of the above ten suicidal ideation or 
behavior questions on the C-SSRS.
Self-injurious 
behavior 
without suicidal 
intent
A “yes” answer to the following question from suicidal 
behavior section on the C-SSRS: “Has subject engaged in 
Non-Suicidal Self-Injurious Behavior?”
There will be no imputation for missing answers on questions.
6.3
Pharmacokinetic Variables
Pharmacokinetic (PK) 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 electronic Case Report Form (eCRF).
Plasma concentrations for ASP0819 and any metabolites (if applicable) will be listed only.
6.4
Other Variables
6.4.1
Exposure
For each subject, duration of exposure (defined as length of time on 8 weeks of treatment 
period) will be calculated in days, using the following formula:
Duration of exposure = Date of last dose of study drug – Date of first dose of study 
●
drug +1, 
where the date of first dose of study drug and the date of last dose of study drug are defined 
as the first study drug dosing date and the last study drug dosing date, as captured in the 
eCRF.  Imputed dates for the first or last dose of study drug may be used to calculate 
exposure (Section 7.11.1). 
6.4.2
Percent overall compliance 
Subjects will be instructed to take 3 capsules once per day. 
Overall compliance (%) = 100 × (total number of capsules actually received during 
●
8 weeks of treatment period / total number of capsules planned to receive during 8 weeks 
of treatment period).


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Where 
Total number of capsules planned to receive during 8 weeks of treatment period = 
●
3 x duration of exposure.  Duration of exposure will be calculated as described in 
Section 6.4.1
Total number of capsules actually received during 8 weeks of treatment period = total 
●
number of capsules dispensed during 8 weeks of treatment period – total number of 
capsules returned during 8 weeks of treatment period.
Double-blind study drug compliance for the entire double-blind treatment period will be 
calculated for subjects whose total number of capsules taken and the complete date of the 
first dose and the last dose of double-blind study drug are known.
6.4.3
Previous and concomitant medication
Previous and concomitant non-medication therapy
●
A previous non-medication therapy (screening/wash-out) is defined as any 
non-medication therapy administered up to the last day of screening/washout (i.e. prior 
to the baseline diary run-in).
A previous non-medication therapy (baseline diary run-in) is defined as any 
non-medication therapy administered after the last day of screening/washout and before 
the first dose of double-blind study drug.
A concomitant non-medication therapy (double-blind treatment period) is defined as any 
non-medication therapy administered between the first dose (inclusive) of double-blind 
study drug and the last dose of double-blind study drug (inclusive).
A concomitant non-medication therapy (follow-up period) is defined as any 
non-medication therapy administered after the last dose of double-blind study drug.
Previous and concomitant medication
●
A previous medication (screening/wash-out) is defined as any medication taken up to the 
last day of screening/washout (i.e. prior to the baseline diary run-in).
A previous medication (baseline diary run-in) is defined as any medication taken after 
the last day of screening/washout and before the first dose of double-blind study drug.
A concomitant medication (double-blind treatment period) is defined as any medication 
taken between the first dose (inclusive) of double-blind study drug and the last dose of 
double blind study drug (inclusive).
A concomitant medication (follow-up period) is defined as any medication taken after 
the last dose day of double-blind study drug.
6.4.4
Time since onset of Fibromyalgia symptoms and time since diagnosis
Time since onset of FM symptoms (years) = (Informed consent date -date FM symptoms 
●
started + 1)/365.25
Time since FM diagnosis (years) = (Informed consent date – date of FM 
●
diagnosis + 1)/365.25. 


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Imputed dates for the date FM symptoms started and FM diagnosis may be used to calculate 
both of these endpoints as described in Section 7.11.1
6.4.5
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).  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 subjects to 
characterize behavior with “yes” or “no” responses.  The final number of YESs or NOs 
allows the coding a final evaluation per module by Yes/No answer (according to time recall) 
or severity (according to module): current, in early remission and in remission.  The 
M.I.N.I. 7.0 will be completed at Screening and any diagnosis identified from the M.I.N.I 
will be captured in the eCRF.
6.4.6
Widespread Pain Index and Symptom Severity Scale score
The Widespread Pain Index (WPI) and Symptom Severity (SS) scale score will be completed
by the clinician on a tablet device during the Screening visit.
The WPI is a checklist of 19 non-articular body parts classified in 5 body regions.  The body 
parts are checked if pain/tenderness is observed.  The WPI global score is the sum of body 
parts checked as presence of pain and ranges from 0 to 19.  
The SS Scale is comprised of two parts: 
First part: evaluation of 3 key-symptoms (fatigue, waking unrefreshed and cognitive 
●
symptoms) over the past week.  The severity of these symptoms will be measured on 
a 4-point response scale (from 0 = no problem to 3 = severe).
The score for the first part is the sum of the item scores and ranges from 0 to 9.
Second Part: presence evaluation (1=presence and 0=absence) of 3 other somatic 
●
symptoms (headaches, pain/cramps in lower abdomen and depression) during the 
previous 6 months.
The score for the second part is the sum of the item scores and ranges from 0 to 3.
The SS Scale score is the sum of the first and the second part scores and ranges from 0 to 12.
6.4.7
Complex Medical Symptoms Inventory
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, subjects mark a box to indicate if the symptom: 1) has occurred for at least 


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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). The CMSI total score is the sum of 
the number of items that the subject checks as either occurring for at least 3 months in the 
past year and/or has occurred for a 3-month period during their lifetime. The CMSI total 
score at baseline will be calculated and ranges from 0 to 39 for males and 0 to 41 for females.
Baseline is defined as the last assessment on or prior to the first dose day (Day 1) of double-
blind study drug.
7
STATISTICAL METHODOLOGY
7.1
General Considerations
For continuous variables, descriptive statistics will include the number of subjects (n), mean, 
standard deviation (SD) and/or standard error (SE), median, minimum and maximum.  When 
needed, the use of other percentiles (e.g., 10%, 25%, 75% and 90%) will be mentioned in the 
relevant section.  Frequencies and percentages will be displayed for categorical data.  
Percentages by categories will be based on the number of subjects with no missing data, i.e. 
will add up to 100%. 
Summaries based on FAS and PPS (e.g. disposition, baseline and efficacy data) will be 
presented by planned treatment group, unless specifically stated otherwise.  Safety analysis 
and other summaries based on SAF will be presented by actual treatment received. For 
summaries which present both absolute values over time and change from baseline values 
over time the number of subjects used to calculate the descriptive statistics will be those who 
have non-missing data at each analysis visit and at baseline.  For endpoints which include 
mBOCF, LOCF or mLOCF imputation the descriptive statistics will be calculated after the 
imputation has been performed. 
Unless otherwise specified, statistical comparisons will be made using one-sided tests at the 
α=0.05 significance level and two-sided 90% confidence intervals (CIs) will be presented 
when applicable.  When two-sided p-values are presented statistical comparisons will be 
made using an α=0.1 significance level. 
The pooled site will be used in all statistical models that include the “center” as a factor. The 
pooling sites algorithm is provided in Section 7.11.6.
All data, including observed and derived data, will be presented in subject data listings.
All data processing, summarization, and analyses will be performed using SAS ® Version 9.3 
or higher on Unix.  Specifications for table, figures, and data listing formats can be found in 
the TLF specifications for this study.
Calculations of change from baseline or change from EOT:
Change from baseline to post-baseline will be calculated as: post-baseline value –
●
baseline value. 
Change from EOT to Week 10 will be calculated as: Week 10 – EOT
●


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Percent change from baseline to post-baseline will be calculated as: 100 × (change / 
●
baseline value). 
Handling of baseline value of 0 in analysis involving percent change is discussed in the TLF 
Specifications for this study. 
Definition of Study Day:
The number of study days relative to the first dose date of study drug (Study Day), is 
calculated as: 
Study Day = Date of assessment – Date of first dose of study drug +1, when the date 
●
of assessment is on or after the date of first dose of study drug
Study Day = Date of assessment – Date of first dose of study drug, when the date of 
●
assessment is before the date of first dose of study drug
where the date of first dose of study drug is defined in Section 6.4.1
The day of the first dose of study drug is defined as Study Day 1, while the day before the 
date of first dose of study drug (i.e., Randomization visit) is defined as Study Day -1 (there is 
no Study Day 0). 
For daily average pain scores assessed by NRS and FMSD scores, any data captured in the 
e-diary up to 2 am in the morning of the following day will be assigned to the previous day in 
the derivation of Study Day.
Definition of Follow-up Day:
The number of study days relative to the last dose date of study drug (Follow-up Day), is 
calculated as: 
Follow-up Day = Date of assessment – Date of last dose of study drug
●
where the date of last dose of study drug up is defined in Section 6.4.1  
Follow-up Day will equal zero on the day of the last dose of study drug and positive values 
will indicate days during the follow-up period.  
For daily average pain scores assessed by NRS and FMSD scores, any data captured in the 
e-diary up to 2 am in the morning of the following day will be assigned to the previous day in 
the derivation of Follow-up Day.
Definition of Treatment Period:
Time from Study Day 1, through to Follow-up Day 4.
Definition of Efficacy Follow-up Period:
Time from Follow-up Day 5 through to Follow-up Day 28. 
Definition of Safety Follow-up Period:
Time from Follow-up Day 5 through to Follow-up Day 30. 


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7.2
Study Population
7.2.1
Disposition of Subjects
The following subject data will be presented:
Number of subjects with informed consent, discontinued during screening/wash-out, 
●
entered the baseline diary run-in, discontinued prior to randomization, randomized for all 
subjects with informed consent (‘Total’ overall only);
Number and percentage of subjects who were randomized, took study drug, did not take 
●
study drug, in the analysis sets by treatment group and ‘Total’ over all treatment groups 
for all randomized subjects;
Number and percentage of subjects who completed and discontinued the screening/wash-
●
out, and primary reason for discontinuing screening/wash-out for all subjects with 
informed consent (‘Total’ overall only);  
Number and percentage of subjects who completed and discontinued prior to 
●
randomization, and primary reason for discontinuing prior to randomization for all 
subjects who came for randomization visit (‘Total’ overall only);
Number and percentage of subjects who completed and discontinued treatment, and 
●
primary reason for treatment discontinuation by treatment group and ‘Total’ over all 
treatment groups for all randomized subjects, SAF and FAS; 
Number and percentage of subjects completed and discontinued the follow-up period, 
●
and primary reason for discontinuing the follow-up period by treatment group and ‘Total’ 
over all treatment groups for all randomized subjects and SAF; 
Number and percentage of subjects who completed and discontinued treatment at each 
●
visit, by primary reason for treatment discontinuation by treatment group and ‘Total’ 
over all treatment groups for all randomized subjects, SAF and FAS;
Number and percentage of subjects excluded from PPS by reason for exclusion defined 
●
in Section 5.2.1, by treatment group and ‘Total’ over all treatment groups for FAS; and
Number and percentage of subjects for each protocol version by treatment group and 
●
‘Total’ over all treatment groups for randomized subjects, as well as, number and 
percentage of subjects for each protocol version for screen failures (subjects who 
discontinued during screening/wash-out or prior to randomization) and Total Number of 
subjects enrolled (i.e. including Screen Failures).
A stacked bar plot of cumulative discontinuation rates (colored by primary reason for 
discontinuation) overall and at each visit by treatment group will be produced for the SAF. 
7.2.2
Protocol Deviations
Protocol deviations as defined in the study protocol (Section 8.1.6 Protocol Deviations) will 
be assessed for all randomized subjects.  The number and percentage of subjects meeting any 
criteria will be summarized for each criterion and overall, by treatment group and total as 
well as by study site.  Subjects deviating from a criterion more than once will be counted 
once for the corresponding criterion.  Any subjects who have more than one protocol 


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deviation will be counted once in the overall summary.  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. 
7.2.3
Demographic and Other Baseline Characteristics
No hypothesis testing will be performed comparing treatment groups for demographic and 
other baseline characteristics.
7.2.3.1
Demographics
Demographic characteristics will be summarized by descriptive statistics for the following 
variables listed in Table 12   This will be done for all randomized subjects, as well as for the 
SAF, FAS and PPS by treatment group and ‘Total’ over all treatment groups.
Table 12
Demographic characteristics
Characteristic
Summarized as
Categories
Age (years)
Continuous
--------
Weight (kg)
Continuous
--------
Height (cm)
Continuous
--------
BMI (kg/m2)
Continuous
--------
Sex
Categorical
Male
●
Female
●
Unknown
●
Race
Categorical
White
●
Black or African American
●
Asian
●
American Indian or Alaska Native 
●
Native Hawaiian or Other Pacific Islander
●
Other
●
Ethnicity
Categorical
Not Hispanic or Latino
●
Hispanic or Latino
●
Age group
Categorical
< 45 years
●
≥ 45 to < 65 years
●
≥ 65 years
●
EudraCT Age group
Categorical
≥ 18 to ≤ 64 years
●
≥ 65 to ≤ 84 years
●
Table continued on next page


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Characteristic
Summarized as
Categories
BMI group 1
Categorical
< 25 kg/m2
●
≥ 25 to < 30 kg/m2
●
≥ 30 kg/m2
●
BMI group 2
Categorical
< 30 kg/m2
●
≥ 30 kg/m2
●
Number and percentage of subjects randomized in each site will be presented by treatment 
group and ‘Total’ over all treatment groups for randomized subjects.  In addition, number and 
percentage of pooled sites and the combination of sites into pooled sites will be summarized 
by treatment group and overall for the FAS. 
7.2.3.2
Fibromyalgia and Targeted Medical History
Fibromyalgia and targeted medical history will be summarized by descriptive statistics for 
the following variables listed in Table 13   This will be done for all randomized subjects, the 
SAF, FAS and PPS by treatment group and ‘Total’ over all treatment groups.
Table 13
Fibromyalgia Diagnosis and Targeted Medical History
Characteristic
Summarized as
Categories
Time since FM diagnosis (years) 
Continuous
--------
Time since onset of FM symptoms 
(years)
Continuous
--------
Currently treated for FM
Categorical
Yes
●
No
●
History of Major Depressive Disorder 
(MDD) as assessed by M.I.N.I.
Categorical
Yes
●
No
●
Ongoing MDD (only for subjects with 
a History of MDD)
Categorical
Yes
●
No
●
Currently Treated with Medication for 
MDD (only for subjects with a History 
of MDD)
Categorical
Yes
●
No
●
HADS Depression total score*
Continuous
--------
HADS Depression group*
Categorical
Normal (0 to 7) 
●
Mild mood disturbance (8 to 10)  
●
Moderate mood disturbance (11 to 14)
●
Severe mood disturbance (15 to 21)
●
C-SSRS Item:

Suicidal ideation

Suicidal behavior

Suicidal ideation or behavior

Self-injurious behavior without 
suicidal intent
Categorical
For each item:
Yes
●
No
●
History of Temporomandibular 
Disorders 
Categorical
Yes
●
No
●
History of Irritable Bowel Syndrome
Categorical
Yes
●
No
●
Table continued on next page


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Characteristic
Summarized as
Categories
History of Chronic Tension Type 
Headache
Categorical
Yes
●
No
●
History of Migraine
Categorical
Yes
●
No
●
History of Chronic Low Back Pain
Categorical
Yes
●
No
●
History of Myalgic 
Encephalomyelitis/Chronic Fatigue 
Syndrome
Categorical
Yes
●
No
●
History of Interstitial Cystitis/Painful 
Bladder Syndrome
Categorical
Yes
●
No
●
History of Endometriosis (Females 
Only)
Categorical
Yes
●
No
●
History of Vulvodynia (Females Only)
Categorical
Yes
●
No
●
Alcohol History
Categorical
Never
●
Current
●
Former
●
History of Alcohol Use Disorder (only 
for subjects with current or former 
Alcohol History)
Categorical
Yes
●
No
●
History of Drug Use
Categorical
Never
●
Current
●
Former
●
History of Substance Use Disorder 
(only for subjects with current or 
former History of Drug Use)
Categorical
Yes
●
No
●
First or Second Degree Family History 
of 

Fibromyalgia

Depression

Bipolar disorder
Categorical
For each Family History:
Yes
●
No
●
C-SSRS: Columbia Suicide Severity Rating Scale, FM: Fibromyalgia, HADS: Hospital Anxiety and Depression 
Scale, MDD: Major Depressive Disorder, M.I.N.I: Mini-International Neuropsychiatric Interview
*Only for subjects with data captured using the corrected version of the HADS questionnaire.
7.2.3.3
Fibromyalgia related baseline disease characteristics
Fibromyalgia related baseline disease characteristics will be summarized by descriptive 
statistics for the following variables listed in Table 14   This will be done for all randomized 
subjects, the SAF, FAS and PPS by treatment group and ‘Total’ over all treatment groups.
Table 14
Fibromyalgia related baseline disease characteristics
Characteristic
Summarized as
Categories
Baseline mean daily average pain 
score assessed by NRS 
Continuous
--------
Baseline mean daily average pain 
score assessed by NRS group
Categorical
No pain: 0
●
Mild: > 0 to < 4
●
Moderate: ≥ 4 to < 7
●
Severe: ≥ 7 to 10
●
Table continued on next page


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Characteristic
Summarized as
Categories
WPI
Continuous
-------
SS scale score
Continuous
-------
Tender point count
Continuous
-------
PGIS
Categorical
No symptoms
●
Very mild
●
Mild
●
Moderate
●
Severe
●
Very severe
●
CMSI total score at baseline
Continuous
--------
Central pain etiology as defined by 
CMSI*
Categorical
More centrally driven FM pain
●
Non-specific FM pain
●
More peripherally driven FM pain
●
NPSI:

Burning (superficial) 
spontaneous pain subscore

Pressing (deep) 
spontaneous pain subscore

Paroxysmal pain subscore

Evoked pain subscore

Paresthesia/dysesthesia

Total score
Continuous
-------
Peripheral pain etiology as defined 
by NPSI: NPSI total score and 
relevant subscales*
Categorical
Low
●
High
●
FIQR:

Function subscale

Symptoms subscale

Overall impact subscale

Total score
Continuous
-------
mIBS-D within past 24 hours at 
baseline:

Abdominal pain 

Stomach pain

Abdominal cramps

Abdominal pressure

Bloating

Symptom summary score
Continuous
--------
mIBS-D within past 24 hours*:

Abdominal pain

Stomach pain

Abdominal cramps

Abdominal pressure

Bloating

Symptom summary score
Categorical
Low
●
Mid
●
High
●
CMSI: Complex Medical Symptom Inventory, FIQR: Fibromyalgia Impact Questionnaire Revised, 
FM: Fibromyalgia; mIBS-D: Modified irritable bowel syndrome - diarrhea predominant, NPSI: Neuropathic 
Pain Symptom Inventory, NRS: Numerical Rating Scale; PGIS: Patient Global Impression of Severity, 
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SS: Symptom severity, WPI: Widespread pain index.
*CMSI will be split into three groups using the CMSI total score at baseline: more centrally driven FM pain
(≤1st tertile); non-specific FM pain (> 1st tertile to < 3rd tertile) and more peripherally driven FM pain (≥ 3rd
tertile); NPSI total score and subscales will be split into two groups using the scores at baseline: low scores
(< median) versus high scores (≥ median); m-IBS items and symptom summary score with past 24 hours will be 
split into three groups at baseline: low (≤1st tertile); mid (> 1st tertile to < 3rd tertile) and high (≥ 3rd tertile).
These were defined during blinded data review using the methods described in Section 7.8.1
7.2.3.4
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) as well as by PT 
alone, by treatment group and “Total” over all treatment groups for the SAF. 
7.2.4
Previous and Concomitant Medications
The following will be presented using the SAF:
All previous medications prior to the baseline diary run-in, 
●
All previous medications taken for any pain (i.e., FM pain only or FM pain and Other 
●
type of pain or Other type of pain only) prior to the baseline diary run-in,
All previous medications taken for FM pain (FM pain only or FM pain and Other type of 
●
pain) prior to the baseline diary run-in,
All previous medications during baseline diary run-in,
●
All previous medications taken for any pain during baseline diary run-in,
●
All previous medications taken for FM pain during baseline diary run-in,
●
All concomitant medications during the double-blind treatment period,
●
All concomitant medications taken for any pain during the double-blind treatment 
●
period, 
All concomitant medications taken for FM pain during the double-blind treatment 
●
period, 
All concomitant medications taken during the follow-up period,
●
All concomitant medications taken for any pain during the follow-up period, and
●
All concomitant medications taken for FM pain during the follow-up period.
●
Previous and concomitant medications are coded with World Health Organization Drug 
Dictionary (WHO-DD).  Each of the above will be summarized by therapeutic subgroup 
(ATC 2nd level) and chemical subgroup (ATC 4th level) and preferred WHO name by 
treatment group and ‘Total’ over all treatment groups.  Subjects taking the same medication 
multiple times will be counted once per medication and investigational period.  A medication 
which can be classified into several chemical and/or therapeutic subgroups is presented in all 
chemical and therapeutic subgroups.  All previous medications taken for any pain prior to the 
baseline diary run-in; all previous medications taken for any pain during baseline diary run-
in; all concomitant medications taken for any pain during the double blind treatment period 
and all concomitant medications taken for any pain during the follow-up period will also be 
summarized by preferred WHO name by treatment group and ‘Total’ over all treatment 
groups.


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In addition to the above summaries, an overview of previous medications taken prior to the 
baseline diary run-in and previous medications during the baseline diary run-in taken to treat 
pain will be produced.  This will summarize the number and percentage of subjects in each of 
the following categories for each treatment group and ‘Total’ over all treatment groups:
Any pain (i.e., FM pain only; or FM pain and Other type of pain; or Other type of pain 
●
only),
FM pain (i.e., FM pain only; or FM pain and Other type of pain),
●
FM pain only,
●
FM pain and Other type of pain,
●
As with previous medication, concomitant medication (double-blind treatment period) and 
concomitant medication (follow-up period) taken to treat pain will be summarized for each 
treatment group and ‘Total’ over all treatment groups for the above categories.
The listing will only contain data of the subjects who actually used previous and concomitant 
medications.
7.2.5
Previous and Concomitant Non-Medication Therapy
The following will be presented using the SAF:
All previous non-medication therapies prior to baseline diary run-in, 
●
All previous non-medication therapies received for any pain (i.e., FM pain only or FM 
●
pain and Other type of pain or Other type of pain only) prior to baseline diary run-in,
All previous non-medication therapies received for FM pain (FM pain only or FM pain 
●
and Other type of pain) prior to baseline diary run-in,
All previous non-medication therapies received during baseline diary run-in,
●
All previous non-medication therapies received for any pain during baseline diary run-in,
●
All previous non-medication therapies received for FM pain during baseline diary run-in,
●
All concomitant non-medication therapies received during the double-blind treatment 
●
period,
All concomitant non-medication therapies received for any pain during the double-blind 
●
treatment period, 
All concomitant non-medication therapies received for FM pain during the double-blind 
●
treatment period, 
All concomitant non-medication therapies received during the follow-up period,
●
All concomitant non-medication therapies received for any pain during the follow-up 
●
period, and
All concomitant non-medication therapies received for FM pain during the follow-up 
●
period.
Each of the above will be summarized by treatment group and ‘Total’ over all treatment 
groups for:
Normal Daily Exercise Routines,
●
Chiropractic Care,
●
Physical Therapy,
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Psychotherapy,
●
Massage therapy, and
●
Other.
●
Subjects receiving the same non-medication therapy multiple times will be counted once per 
medication and investigational period. 
In addition to the above summaries an overview of previous non-medication therapies prior 
to the baseline diary run-in and previous non-medication therapies during the baseline diary 
run-in received to treat pain, the number and percentage of subjects with the following 
categories will be summarized for each treatment group and ‘Total’ over all treatment 
groups:
Any pain (i.e. FM pain only; or FM pain and Other type of pain; or Other type of pain 
●
only),
FM pain (i.e. FM pain only; or FM pain and Other type of pain),
●
FM pain only,
●
FM pain and Other type of pain,
●
As with previous non-medication therapy, concomitant non-medication therapy (double-blind 
treatment period) and concomitant non-medication therapy (follow-up period) will be 
summarized for each treatment group and ‘Total’ over all treatment groups for the above 
categories.
The listing will only contain data of the subjects who actually used previous and concomitant 
non-medication therapies.
7.3
Study Drugs
7.3.1
Exposure
Duration of exposure will be summarized by treatment group and ‘Total’ over all treatment 
groups in three ways for the SAF:
Descriptive statistics will be presented for the total number of days a subject was 
●
exposed to study drug.
Number and percentage of subjects in each of the following mutually exclusive extent of 
●
exposure categories:
○
1 to 7 days,
○
8 to 14 days, 
○
15 to 28 days, 
○
29 to 48 days,
○
49 to 64 days,
○
≥ 65 days.
Number and percentage of subjects in the following cumulative extent of exposure time 
●
categories:
○
≥ 1 day,
○
≥ 8 days;


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○
≥ 15 days,
○
≥ 29 days,
○
≥ 49 days,
○
≥ 65 days.
7.3.2
Treatment Compliance
Overall compliance with the dosing schedule will be examined for subjects in the SAF whose 
total study drug count and first and last days of treatment are known.
Percent overall compliance will be summarized by treatment group and ‘Total’ over all 
treatment groups in two ways for the SAF:
Descriptive statistics for percent overall compliance.
●
Number and percentage of subjects in the following categories of percent overall 
●
compliance:
○
< 50%,
○
≥ 50% to < 80%,
○
≥ 80% to < 100%,
○
= 100%,
○
> 100% to < 120%,
○
≥ 120%.
7.4
Analysis of Efficacy 
Efficacy analyses will be performed using the FAS and the PPS where indicated.  No formal 
hypothesis testing of comparison between treatment groups will be performed for the efficacy 
data during the follow-up period i.e., descriptive statistics will be used to summarize the 
continuous efficacy variables and frequencies and percentages will be used to summarize the 
categorical efficacy data.
7.4.1
Analysis of Primary Endpoint(s)
Analysis of the primary efficacy endpoint will be performed on the FAS and the PPS.  
Table 15 describes the primary analysis and sensitivity analyses that will be performed for 
the primary efficacy endpoint.


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Table 15
Summary of the Primary and Sensitivity Analyses for the Primary 
Efficacy Endpoint
Variable
Imputation
Analysis Set
Analysis Type
Change from baseline to Week 8 in mean daily 
average pain score assessed by NRS
(Primary Analysis)
None
FAS
MMRM analysis of 
change from 
baselinea
Change from baseline to Week 8 in mean daily 
average pain score assessed by NRS 
(Sensitivity Analysis)
Discontinuation-
reason based 
multiple 
imputationb
FAS
MMRM analysis of 
change from 
baselinea
Change from baseline to Week 8 in mean daily 
average pain score assessed by NRS 
(Sensitivity Analysis)
mBOCFc
FAS
ANCOVA analysis 
of change from 
baseline
Change from baseline to Week 8 in mean daily 
average pain score assessed by NRS
(Sensitivity Analysis)
None
PPS
MMRM analysis of 
change from 
baselinea
aMMRM analysis uses data from baseline and change from baseline data at Week 1, Week 2, Week 3, Week 4, 
Week 5, Week 6, Week 7 and Week 8 time points.
bDiscontinuation-reason based multiple imputation (MI) will use a “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 MI for subjects with missing data for other reasons.
cmBOCF is defined as imputation by baseline observation carried forward for subjects who discontinue due to 
lack of efficacy or AEs, and imputation by last observation carried forward for subjects with missing data at 
Week 8 for other reasons.
7.4.1.1 Primary Analysis of Primary Endpoint
The hypothesis for comparison of mean change from baseline between ASP0819 and placebo 
is shown below:
H0: The mean change from baseline to Week 8 in mean daily average pain score assessed by 
NRS (0 to 10 scale) for ASP0819 15 mg once daily group is same as (or higher, i.e. worse 
than) the placebo group.
H1: The mean change from baseline to Week 8 in mean daily average pain score assessed by 
NRS (0 to 10 scale) for ASP0819 15 mg once daily group is less than the placebo group.
The change from baseline in mean daily average pain score to Week 1, Week 2, Week 3, 
Week 4, Week 5, Week 6, Week 7 and Week 8 will be analyzed using a mixed-effect, 
repeated measures (MMRM) model including treatment, center (pooled where necessary), 
time (study Week 1 to 8), and treatment-by-time interaction as fixed effects, baseline mean 
daily average pain score and baseline mean daily average pain score-by-time interaction as 
covariates.  The treatment group contrasts for change from baseline to Week 8 will be the 
primary statistical inference obtained from this model.
This analysis will utilize observed data, and there will be no imputation for missing data.  
Parameters will be estimated using restricted maximum-likelihood and the Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom and adjust SEs.


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An unstructured variance-covariance structure will be used to model the within-subject 
errors.  If the fit of the unstructured covariance structure fails to converge, the following 
covariance structures will be tried in order until convergence is reached: heterogeneous 
Toeplitz (for efficacy endpoints captured in the e-diary only, i.e. mean daily average pain 
score assessed by NRS and mean daily average FMSD) followed by compound symmetry.  
Residual plots of scaled residuals will be used to check the fit of the model and assess 
whether there is any evidence of non-normality.
From the MMRM model the following results will be presented:
Least squares (LS) mean estimates, SE and 2-sided 90% confidence interval (CI) for 
●
mean change from baseline to each analysis time-point (Week 1 to Week 8) within a 
treatment group (ASP0819, placebo),
The difference in LS means for ASP0819 versus placebo, SE for the difference and 
●
2-sided 90% CI for the difference at each analysis time-point,
One-sided p-value for ASP0819 versus placebo at each analysis time-point, and
●
Two-sided p-value for treatment-by time interaction.
●
An overlay plot will be provided for LS mean change from baseline from the MMRM 
analysis and mean change from baseline from the follow-up period +/- SE vs analysis 
time-point by treatment group. 
7.4.1.2
Sensitivity Analyses of Primary Endpoint
The following sensitivity analyses will be performed for the primary efficacy endpoint to 
assess the robustness of the primary analysis.
Discontinuation-reason based multiple imputation
The MMRM analysis that will be used to perform the primary analysis of the primary 
endpoint assumes that missingness is at random.  That is, the model assumes that the 
trajectory of mean daily average pain scores over time for subjects who withdraw is similar 
to the trajectory for those observed in their own treatment arm which is valid so long as that 
assumption is reasonable.
Discontinuation-reason based multiple imputation (MI) will be used to examine the 
sensitivity of the primary analysis results to departures from that underlying assumption and 
will assess a situation where data for subjects who discontinue early follow a pattern which is 
missing not at random.  Specifically, MI 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 MI for subjects with missing data for other reasons.  The analysis will be implemented 
using the general three-step process (imputation phase, followed by analysis phase, followed 
by pooling phase) described in O’Kelly and Ratitch, 2014.
1.
The imputation phase will implement MI via sequential modelling for both the “Jump to 
Reference” algorithm and standard regression-based MI.  In particular, when 
implementing the “Jump to Reference” algorithm via sequential modelling, this means 


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that only baseline values are used in the imputation of missing values for subjects in the 
ASP0819 15 mg once daily group who discontinue due to lack of efficacy or AEs (this 
variation of the “Jump to Reference” algorithm is also referred to as the “Unconditional 
Reference” approach).  The imputation phase will generate M imputed datasets, where 
M=100.
2.
The analysis phase will perform the primary MMRM analysis model of the primary 
efficacy endpoint as described in Section 7.4.1.1 for each of the M=100 imputed datasets 
(which now contain complete data, where missing data have been filled in).
3.
Rubin’s rules will be used to generate an overall set of pooled results which combines 
the analysis results from the M=100 imputed datasets.
The overall set of pooled results will present:
Least squares (LS) mean estimates, SE and 2-sided 90% confidence interval (CI) for 
●
mean change from baseline to Week 8 within a treatment group (ASP0819, placebo),
The difference in LS means for ASP0819 versus placebo, SE for the difference and 
●
2-sided 90% CI for the difference at Week 8,
One-sided p-value for ASP0819 versus placebo at Week 8, obtained using the difference 
●
in the LS means.
Descriptive summary statistics at Week 8 will be derived using the mean of the M=100
●
imputed datasets. 
Descriptive summaries and plots will be used to explore the pattern of missingness are 
described in Section 7.2.1
Modified baseline observation carried forward
Prior to any analysis mBOCF will be used to impute any missing Week 8 data.  Modified 
baseline observation carried forward is defined as imputation by BOCF for subjects who 
discontinue due to lack of efficacy or AEs, and imputation by LOCF for subjects with 
missing data at Week 8 for other reasons.  The imputed change from baseline to Week 8 data 
will be analyzed using ANCOVA with treatment group and center (pooled site) as fixed 
effects and baseline value as a covariate.
The ANCOVA will present LS mean estimates, SE for the LS means and two-sided 90% CI 
for change from baseline to Week 8 within a treatment group (ASP0819, placebo).  For 
comparisons between ASP0819 and placebo for the change from baseline to Week 8, the 
ANCOVA model will present the difference in LS mean estimates, SE and corresponding 
2-sided 90% CI.  The differences in LS mean estimates will be used to obtain 1-sided 
p-values for ASP0819 versus placebo.
Per-protocol analysis
The same analysis of the primary efficacy endpoint as described in Section 7.4.1.1 will be 
repeated using the PPS.
Subgroup analysis
The subgroup analysis of the primary efficacy endpoint is described in Section 7.8.1


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7.4.2
Analysis of Secondary Endpoints 
Analysis of secondary efficacy endpoints will be performed on the FAS.  Analyses of select 
secondary endpoints will be performed on the PPS as specified in Table 16
Table 16
Summary of the Analyses for the Secondary Efficacy Variables
Variable
Imputation
Analysis 
Set
Analysis Type
Percentage of subjects achieving ≥ 30% (or ≥50%) 
reduction from baseline to Week 8 in mean daily 
average pain score assessed by NRS where all subjects 
with missing Week 8 data are classified as 
non-responders
BOCF
FAS
Fisher’s exact test
Percentage of subjects achieving ≥ 30% (or ≥ 50%) 
reduction from baseline to Week 8 in mean daily 
average pain score assessed by NRS 
(Sensitivity analysis)
mBOCFc
FAS
Fisher’s exact test
Percentage of subjects achieving ≥ 30% (or ≥ 50%) 
reduction from baseline to Week 8 in mean daily 
average pain score assessed by NRS where all subjects 
with missing Week 8 data are classified as non-
responders
(Sensitivity analysis)
BOCF
PPS
Fisher’s exact test
Percentage of subjects achieving ≥ 30% (or ≥ 50%) 
reduction from baseline to EOT in mean daily average 
pain score assessed by NRS
LOCF
FAS
Fisher’s exact test
Change from baseline to Week 2, Week 4 and Week 8 
for the FIQR function, symptoms and overall impact 
subscales
None
FAS
MMRM analysis of 
change from 
baselinea
Change from baseline to Week 8 for the FIQR 
function, symptoms and overall impact subscales 
(Sensitivity Analysis)
Discontinuation-
reason based 
multiple 
imputationb
FAS
MMRM analysis of 
change from 
baselinea
Change from baseline to Week 8 for the FIQR 
function, symptoms and overall impact subscales 
(Sensitivity analysis)
None
PPS
MMRM analysis of 
change from 
baselinea
Change from baseline to Week 8 for the FIQR 
function, symptoms and overall impact subscales
(Sensitivity Analysis)
mBOCFc
FAS
ANCOVA analysis 
of change from 
baseline
Change from baseline to EOT for the FIQR function, 
symptoms and overall subscales
LOCF
FAS
ANCOVA analysis 
of change from 
baseline
Overall subject improvement assessed by PGIC at 
Week 2, Week 4 and Week 8 
mBOCFc
FAS
Proportional odds 
model
Overall subject improvement assessed by PGIC at 
Week 2 and Week 4 
(Sensitivity analysis)
LOCF
FAS
Proportional odds 
model
Overall subject improvement assessed by PGIC at EOT
LOCF
FAS
Proportional odds 
model
aMMRM analysis uses data from baseline and change from baseline data at Week 2, Week 4 and Week 8 time 
points.
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bDiscontinuation-reason based multiple imputation (MI) will use a “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 MI for subjects with missing data for other reasons.
cmBOCF is defined as imputation by baseline observation carried forward for subjects who discontinue due to 
lack of efficacy or AEs, and imputation by LOCF for subjects with missing data at the specific analysis time 
point for other reasons.
The following secondary binary response endpoints (responder, non-responder; as defined in 
Section 6.1.2) will be analyzed using the Fisher’s exact test for ASP0819 versus placebo:
Percentage of subjects achieving ≥ 30% (or ≥ 50%) reduction from baseline to Week 8 in 
●
mean daily average pain score assessed by NRS where all subjects with missing Week 8 
data are classified as non-responders, 
Percentage of subjects achieving ≥ 30% (or ≥ 50%) reduction from baseline to Week 8 in 
●
mean daily average pain score assessed by NRS where mBOCF is used to impute a 
responder status for subjects with missing Week 8 data, and
Percentage of subjects achieving ≥ 30% (or ≥ 50%) reduction from baseline to EOT in 
●
mean daily average pain score assessed by NRS.
Summary statistics will show the number and percentage of subjects who show response for 
each treatment group, 2-sided 90% CI for the percentage within each treatment group 
(ASP0819, placebo) calculated using the exact unconditional approach, difference in 
percentages, 2-sided 90% CI for ASP0819 versus placebo calculated using the exact 
unconditional approach, and 1-sided p-value.  In addition, the above responder analysis will 
be repeated in the PPS as a sensitivity analysis of the percentage of subjects achieving ≥30% 
(or ≥ 50%) reduction from baseline to Week 8 in mean daily average pain score assessed by 
NRS where all subjects with missing Week 8 data are classified as non-responders.
The following secondary endpoints will be analyzed using the MMRM analysis as described 
in Section 7.4.1.1 for the primary efficacy analysis (however with only analysis time-points 
Week 2, Week 4 and Week 8 included):
Change from baseline to Week 2, Week 4 and Week 8 for the FIQR function, symptoms 
●
and overall impact subscales (where no explicit imputation is performed).
For each endpoint, standard summaries of the MMRM analysis results will be provided, as 
described in Section 7.4.1.1   This will include an overlay plot.  In addition, the MMRM 
analysis will be repeated in the PPS and also in the FAS under the assumption that data is 
MNAR using decision-reason based multiple imputation as sensitivity analyses of the change 
from baseline to Week 8 for the FIQR function, symptoms and overall impact subscales.
The following secondary endpoints will be analyzed using ANCOVA, as described in 
Section 7.4.1.2 for the second sensitivity analysis of the primary endpoint:
Change from baseline to Week 8 in FIQR function, symptoms and overall impact 
●
subscale scores where mBOCF is used for imputation of missing data at Week 8.  
Modified baseline observation carried forward is defined as imputation by BOCF for 
subjects who discontinue due to lack of efficacy or AEs, and imputation by LOCF for 
subjects with missing data at Week 8 for other reasons.


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Change from baseline to EOT in FIQR function, symptoms, and overall impact subscale 
●
scores.
For each endpoint, standard summaries of the ANCOVA results, as described in 
Section 7.4.1.2, will be provided.
The following secondary endpoints will be analyzed using a proportional odds model for 
ordinal data including treatment group as a factor:
Overall subject improvement assessed by PGIC at Week 2, Week 4 and Week 8 where 
●
mBOCF will be used for subjects with missing data, 
Overall subject improvement assessed by PGIC at Week 2 and Week 4 where LOCF will 
●
be used for subjects with missing data, and
Overall subject improvement assessed by PGIC at EOT.
●
At each time point, the proportion of subjects in each treatment group achieving each level of 
response (1 = “Very Much Improved”, 2 = “Much improved”, 3 = “Minimally Improved”, 
4 = “No Change”, 5 = “Minimally Worse”, 6 = “Much Worse”, 7 = “Very Much Worse”), 
will be presented, together with the odds ratio, associated 90% CI based on profile likelihood 
and 2-sided p-value based on likelihood ratio test for ASP0819 vs placebo.  The cumulative 
logit link will be used to specify the proportional odds model in SAS.
7.4.3
Analysis of Exploratory Endpoints 
Analysis of exploratory efficacy endpoints during the treatment period will be performed on 
the FAS and are described in Table 17   As stated previously, no formal hypothesis testing of 
comparison between treatment groups will be performed for the efficacy data during the 
follow-up period i.e., descriptive statistics will be used to summarize the continuous efficacy 
variables and frequencies and percentages will be used to summarize the categorical efficacy 
data.
Table 17
Summary of the Analyses for the Exploratory Efficacy Variables
Variable
Imputation
Analysis Set
Analysis Type
Treatment period
Change from baseline to Week 1, Week 2, Week 3, 
Week 4, Week 5, Week 6 and Week 7 in mean daily 
average pain score assessed by NRS
None
FAS
MMRM analysis of 
change from 
baselinea
Change from baseline to EOT in mean daily average 
pain score assessed by NRS
LOCF
FAS
ANCOVA analysis 
of change from 
baseline
Percentage of subjects achieving different levels of 
reduction from baseline to Week 8 in mean daily 
average pain score assessed by NRS where all 
subjects with missing Week 8 data are classified as 
non-responders
BOCF
FAS
Descriptive statistics 
only (tabular and 
graphical)
Table continued on next page


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Variable
Imputation
Analysis 
Set
Analysis Type
Percentage of subjects achieving different 
levels of reduction from baseline to Week 8 in 
mean daily average pain score assessed by 
NRS where mBOCF (see Table 5) is used to 
impute a responder status for subjects with 
missing Week 8 data
mBOCFc
FAS
Descriptive statistics 
only (tabular and 
graphical)
Percentage of subjects achieving different 
levels of reduction from baseline to EOT in 
mean daily average pain score assessed by 
NRS
LOCF
FAS
Descriptive statistics 
only (tabular and 
graphical)
Change from baseline to Week 2, Week 4 and 
Week 8 for the FIQR total score
None
FAS
MMRM analysis of 
change from baselineb
Change from baseline to Week 8 for the FIQR 
total score 
mBOCFc
FAS
ANCOVA analysis of 
change from baseline
Change from baseline to EOT for the FIQR 
total score
LOCF
FAS
ANCOVA analysis of 
change from baseline
Change from baseline to Week 2, Week 4 and 
Week 8 for PGIS
None
FAS
MMRM analysis of 
change from baselineb
Change from baseline to Week 8 for the PGIS 
mBOCFc
FAS
ANCOVA analysis of 
change from baseline
Change from baseline to EOT for PGIS
LOCF
FAS
ANCOVA analysis of 
change from baseline
Percentage of subjects achieving a ≥ 30% 
reduction from baseline in FIQR total score at 
Week 8 and at EOT
mBOCFc
(Week 8),
LOCF (EOT)
FAS
Fisher’s exact test
Percentage of subjects achieving a PGIC of 
“very much improved” or “much improved” at 
Week 8 and at EOT
mBOCFc
(Week 8),
LOCF (EOT)
FAS
Fisher’s exact test
Percentage of subjects achieving a composite 
pain response, defined as achieving ≥ 30% 
reduction from baseline in mean daily average 
pain score and PGIC of “very much improved” 
or “much improved” at Week 8 and at EOT
mBOCFc
(Week 8),
LOCF (EOT)
FAS
Fisher’s exact test
Percentage of subjects achieving a composite 
syndrome response, defined as achieving 
≥30% reduction from baseline in mean daily 
average pain score and PGIC of “very much 
improved” or “much improved” and ≥ 30 % 
reduction from baseline in FIQR total score, at 
Week 8 and EOT
mBOCFc
(Week 8),
LOCF (EOT)
FAS
Fisher’s exact test
Change from baseline to Week 1, Week 2, 
Week 3, Week 4, Week 5, Week 6, Week 7 and 
Week 8 in mean daily average FMSD
None
FAS
MMRM analysis of 
change from baselinea
Change from baseline to EOT in mean daily 
average FMSD
LOCF
FAS
ANCOVA analysis of 
change from baseline
Change from baseline to Week 8 and EOT in 
the HADS* depression subscale
None (Week 8),
LOCF (EOT)
FAS
ANCOVA analysis of 
change from baseline
Table continued on next page


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Variable
Imputation
Analysis Set
Analysis Type
Change from baseline to Week 8 and EOT in 
the EQ-VAS scale of the EQ-5D-5L
None (Week 8),
LOCF (EOT)
FAS
Descriptive statistics 
only
Shift from baseline to Week 8 and EOT for 
each of the 5 dimensions of the EQ-5D-5L
None (Week 8),
LOCF (EOT)
FAS
Descriptive statistics 
only
Proportion of days with rescue medication use 
at Week 1, Week 2, Week 3, Week 4, Week 5, 
Week 6, Week 7, Week 8, EOT and Overall 
double-blind treatment period
None
FAS
Negative binomial 
regression
Incidence of subjects using rescue medication 
during Week 1, Week 2, Week 3, Week 4, 
Week 5, Week 6, Week 7, Week 8, EOT and 
Overall double-blind treatment period
None
FAS
Fisher’s exact test
Average daily dosage of rescue medication 
during Week 1, Week 2, Week 3, Week 4, 
Week 5, Week 6, Week 7, Week 8, EOT and 
Overall double-blind treatment period
None
FAS
ANOVA
Change from baseline to Week 2, Week 4 and 
Week 8 for the Irritable Bowel Syndrome 
Symptom Summary Score and abdominal pain, 
stomach pain, abdominal cramps, abdominal 
pressure, and bloating individual items within 
past 24 hours and within past 7 days as 
assessed by the mIBS-D Daily Symptom Diary
None
FAS
MMRM analysis of 
change from baselineb
Change from baseline to EOT for the Irritable 
Bowel Syndrome Symptom Summary Score 
and abdominal pain, stomach pain, abdominal 
cramps, abdominal pressure, and bloating 
individual items within the past 24 hours and 
within past 7 days as assessed by the mIBS-D 
Daily Symptom Diary
LOCF
FAS
ANCOVA analysis of 
change from baseline
Change from baseline to Week 8 and EOT in 
the NPSI total score and NPSI burning pain, 
pressing pain, paroxysmal pain, evoked pain, 
and paresthesia/dysesthesia subscales 
None (Week 8),
LOCF (EOT)
FAS
ANCOVA analysis of 
change from baseline
Follow-up period
Change from baseline and EOT to Week 10 in 
mean daily average pain score
None (Baseline),
LOCF (EOT)
FAS
Descriptive statistics 
only
Change from baseline and EOT to Week 10 in 
FIQR function, symptoms and overall impact 
subscale scores and total score
None (Baseline),
LOCF (EOT)
FAS
Descriptive statistics 
only
Overall subject improvement assessed by PGIC 
at Week 10
None
FAS
Descriptive statistics 
only
Change from baseline and EOT to Week 10 in 
PGIS
None (Baseline),
LOCF (EOT)
FAS
Descriptive statistics 
only
Percentage of subjects achieving a ≥ 30% (or ≥ 
50%) reduction from baseline to Week 10 in 
mean daily average pain score assessed by 
NRS
None
FAS
Descriptive statistics 
only
Table continued on next page


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Variable
Imputation
Analysis 
Set
Analysis Type
Change from baseline to Week 10 in EQ-VAS 
scale of the EQ-5D-5L
None
FAS
Descriptive statistics 
only
Shift from baseline to Week 10 for each of the 
5 dimensions of the EQ-5D-5L
None
FAS
Descriptive statistics 
only
Proportion of days with rescue medication use 
at Week 10 and Overall follow-up period
None
FAS
Descriptive statistics 
only
Incidence of subjects using rescue medication 
at Week 10 and Overall follow-up period
None
FAS
Descriptive statistics 
only
Average daily dosage of rescue medication at 
Week 10 and Overall follow-up period
None
FAS
Descriptive statistics 
only
aMMRM analysis uses data from baseline and change from baseline data at Week 1, Week 2, Week 3, Week 4, 
Week 5, Week 6, Week 7 and Week 8 time points.
bMMRM analysis uses data from baseline and change from baseline data at Week 2, Week 4 and Week 8 time 
points.
cmBOCF is defined as imputation by baseline observation carried forward for subjects who discontinue due to 
lack of efficacy or AEs, and imputation by LOCF for subjects with missing data at Week 8 for other reasons.
*Only for subjects with data captured using the corrected version of the HADS questionnaire.
Treatment period
The MMRM analysis and associated summaries and plots for the primary efficacy analysis as 
described in Section 7.4.1.1 will be used to interpret the exploratory efficacy analyses of 
change from baseline to Week 1, Week 2, Week 3, Week 4, Week 5, Week 6 and Week 7 in 
mean daily average pain score assessed by NRS.
Similarly, the following exploratory endpoints will also be analyzed using the MMRM 
analysis as described in Section 7.4.1.1 for the primary efficacy analysis:
Change from baseline to Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7 
●
and Week 8 in mean daily average FMSD,
Change from baseline to Week 2, Week 4 and Week 8 for the FIQR total score (only 
●
data from Weeks 2, 4 and 8 will be included in the model),
Change from baseline to Week 2, Week 4 and Week 8 for PGIS (only data from Weeks 
●
2, 4 and 8 will be included in the model), and
Change from baseline to Week 2, Week 4 and Week 8 for the Irritable Bowel Syndrome 
●
Symptom Summary Score and abdominal pain, stomach pain, abdominal cramps, 
abdominal pressure, and bloating individual items within past 24 hours and within past 7 
days as assessed by the mIBS-D Daily Symptom Diary (only data from Weeks 2, 4 and 8 
will be included in the model).
For each endpoint, standard summaries of the MMRM analysis results will be provided, as 
described in Section 7.4.1.1
The following exploratory endpoints will be analyzed using ANCOVA as described in 
Section 7.4.1.2 for the second sensitivity analysis of the primary endpoint:
Change from baseline to EOT in mean daily average pain score assessed by NRS,
●


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Change from baseline to Week 8 for the FIQR total score where mBOCF is used for 
●
imputation of missing data at Week 8,
Change from baseline to EOT for the FIQR total score,
●
Change from baseline to Week 8 for the PGIS where mBOCF is used for imputation of 
●
missing data at Week 8,
Change from baseline to EOT for PGIS,
●
Change from baseline to EOT in mean daily average FMSD,
●
Change from baseline to Week 8 (note that no imputation will be performed hence the 
●
ANCOVA will only include subjects with data at both baseline and Week 8) and EOT in 
the HADS depression subscale,
Change from baseline to EOT for the Irritable Bowel Syndrome Symptom Summary 
●
Score and abdominal pain, stomach pain, abdominal cramps, abdominal pressure, and 
bloating individual items within past 24 hours and within past 7 days as assessed by the 
mIBS-D Daily Symptom Diary,
Change from baseline to Week 8 (note that no imputation will be performed hence the 
●
ANCOVA will only include subjects with data at both baseline and Week 8) and EOT in 
the NPSI total score and NPSI burning pain, pressing pain, paroxysmal pain, evoked 
pain, and paresthesia/dysesthesia subscales.
Where appropriate for the above endpoints, mBOCF is defined as imputation by BOCF for 
subjects who discontinue due to lack of efficacy or AEs, and imputation by LOCF for 
subjects with missing data at Week 8 for other reasons.  For each endpoint, standard 
summaries of the ANCOVA results, as described in Section 7.4.1.2, will be provided.
The following exploratory binary response endpoints will be analyzed using Fisher’s exact 
test as described in Section 7.4.2 for the analysis of the secondary binary response endpoints:
Percentage of subjects achieving a ≥ 30% reduction from baseline in FIQR total score at 
●
Week 8 (where mBOCF is used for imputation of missing data at Week 8) and at EOT,
Percentage of subjects achieving a PGIC of “very much improved” or “much improved” 
●
at Week 8 (where mBOCF is used for imputation of missing data at Week 8) and at 
EOT,
Percentage of subjects achieving a composite pain response, defined as achieving ≥ 30% 
●
reduction from baseline in mean daily average pain score and PGIC of “very much 
improved” or “much improved” at Week 8 (where mBOCF is used for imputation of 
missing data at Week 8) and at EOT,
Percentage of subjects achieving a composite syndrome response, defined as achieving 
●
≥30% reduction from baseline in mean daily average pain score and PGIC of “very 
much improved” or “much improved” and ≥ 30 % reduction from baseline in FIQR total 
score, at Week 8 (where mBOCF is used for imputation of missing data at Week 8) and 
EOT, and
Incidence of subjects using rescue medication during Week 1, Week 2, Week 3, Week 4, 
●
Week 5, Week 6, Week 7, Week 8, EOT and Overall double-blind treatment period.


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Refer to Table 5 Section 6.1.3 for the definition of mBOCF for responder variables.
The following exploratory endpoints will be analyzed using a negative binomial regression 
model with terms for treatment group and center (pooled site):
Proportion of days with rescue medication use at Week 1, Week 2, Week 3, Week 4, 
●
Week 5, Week 6, Week 7, Week 8, EOT and Overall double-blind treatment period.
Each analysis time-point will be analyzed separately.  The response variable in each model 
will be the number of days with rescue medication during each analysis time-point, i.e.,
Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, EOT (the last 7 days 
on treatment) and Overall double-blind treatment period.  The logarithm of the follow-up 
time within each analysis time-point (apart from the double-blind treatment period this will 
usually be 7 days, except if the subjects discontinued during that week) will be used as an 
offset variable in the model and there will be no imputation of missing data.
The estimated treatment effect (i.e., the rate ratio of ASP0819 versus placebo), corresponding 
90% confidence interval (CI), and 1-sided p-value for the rate ratio will be presented.  In 
addition, the proportion of days of rescue medication use will be summarized using n, mean, 
SD, minimum, maximum and median for all analysis time-points (Baseline, Week 1, Week 2, 
Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, EOT and Overall double-blind 
treatment period).
The following exploratory endpoints will be analyzed using ANOVA model including log10
average daily dosage of rescue medication during the double-blind treatment period as 
response (subjects with 0 will have a value of 5 imputed prior to log-transforming) and 
treatment group and center (pooled site) as fixed effects:
Average daily dosage of rescue medication during the overall double-blind treatment 
●
period.
The analysis will be performed for theoverall double-blind treatment period and there will be 
no imputation of missing data (note subjects with 0 average daily dosage of rescue 
medication will have a value of 5 imputed prior to log10-transformation).  The ANOVA will
present geometric LS mean (10LS Mean) and 2-sided 90% CI (10 Lower Confidence Limit of LS Mean , 
10Upper Confidence Limit of LS Mean) for each treatment group (ASP0819, placebo).  The ratio of
geometric LS mean of the ASP0819 15mg group divided by the geometric LS mean of the 
placebo group with corresponding 2-sided 90% CI will be derived. The ratio of the geometric 
LS mean estimates will be used to obtain 1-sided p-values for ASP0819 versus placebo.  At 
Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8 and at EOT 
descriptive summaries of the average daily dose of rescue medication will be produced with 
the addition of the 1st and 3rd quartiles. 
For the following exploratory binary response endpoints, descriptive summaries will be 
produced and there will be no formal hypothesis testing of comparison between treatment 
groups:


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Percentage of subjects achieving different levels of reduction from baseline to Week 8 in 
●
mean daily average pain score assessed by NRS where all subjects with missing Week 8 
data are classified as non-responders,
Percentage of subjects achieving different levels of reduction from baseline to Week 8 in 
●
mean daily average pain score assessed by NRS where mBOCF (see Table 5) is used to 
impute a responder status for subjects with missing Week 8 data, and
Percentage of subjects achieving different levels of reduction from baseline to EOT in 
●
mean daily average pain score assessed by NRS.
For each of the above endpoints, the number and percentage of subjects achieving levels of 
reduction in mean daily average pain score assessed by NRS from baseline to Week 8 at 
> 0%, ≥ 10%, ≥ 20%, ≥ 30%, ≥ 40%, ≥ 50%, ≥ 60%, ≥ 70%, ≥ 80%, ≥ 90% and 100% will 
be summarized by treatment group.  In addition to the above summary, an overlay plot will 
be presented for each binary response endpoint for different levels of reduction (range is 
0 to 100% by 10% i.e, >0%, ≥10% to ≥90% by 10%, and =100%) in each treatment group.  
Refer to Section 6.1.2 for ≥ 30% and ≥ 50% responder definitions and Section 6.1.3 for >0%, 
≥ 10%, ≥ 20%, ≥ 40%, ≥ 60%, ≥ 70%, ≥ 80%, ≥ 90% and =100% responder definitions. In 
the plot, the x-axis will display the percentage of improvement i.e., percentage reduction 
versus baseline in mean daily average pain score and y-axis will be percentage of subjects 
improved 
Descriptive statistics will be used to summarize the change from baseline to Week 8 and 
EOT in the EQ-VAS scale of the EQ-5D-5L.  For the EQ-VAS the baseline value, post-
baseline value at each specified time point (Baseline, Week 8 and EOT) and change from 
baseline to each specified post-baseline time point will be summarized using n, mean, SD, 
Q1, Q3, minimum, maximum and median by treatment group.  For each of the 5 dimensions
of the EQ-5D-5L: mobility, self-care, usual activities, pain/discomfort and anxiety/depression, 
number and percentage of subjects will be summarized for each level by baseline value, post-
baseline value at each specified time-point by treatment group.  Shift tables from baseline to 
Week 8, from baseline to EOT and baseline to Week 10 by treatment group will also be 
produced.
Follow-up period
For the follow-up period, data will be summarized with descriptive statistics (number of 
subjects, mean, SD, minimum, median and maximum) for continuous endpoints (absolute 
values at Week 10 analysis timepoint as well as change from baseline to Week 10 and change 
from EOT to Week 10), and frequency and percentage for categorical endpoints (at the 
Week 10 analysis time point as well as shift from baseline to Week 10 and shift from EOT to 
Week 10).
7.4.4
Analysis of Other Variables 
Not applicable.


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7.5
Analysis of Safety
All analysis of safety will be presented by treatment group for SAF, unless specified 
otherwise.  No hypothesis testing will be performed comparing treatment groups for any 
safety parameters.
7.5.1
Adverse Events
Summaries and listings of serious adverse events (SAEs) and serious TEAEs include SAEs 
upgraded by the sponsor based on review of the Sponsor’s list of Always Serious terms if any 
upgrade was done.
Duration of AE will be included in all listings and is calculated as described in Section 6.2.1
The coding dictionary for this study will be MedDRA version 20.0.  It will be used to 
summarize AEs by SOC and PT.  Standardised MedDRA query (SMQs) will also be used to 
identify AEs of interest as described in Section 7.5.2  
7.5.1.1
Adverse Events Prior to First Dose
The number and percentage of subjects with AEs prior to first dose, as classified by SOC and 
PT will be summarized for each treatment group.
7.5.1.2
Treatment Emergent Adverse Events
An overview table will include the following details:
Number of TEAEs,
●
Number and percentage of subjects with TEAEs,
●
Number of drug related TEAEs,
●
Number and percentage of subjects with drug related TEAEs,
●
Number of serious TEAEs,
●
Number and percentage of subjects with serious TEAEs,
●
Number of serious drug related TEAEs,
●
Number and percentage of subjects with serious drug related TEAEs,
●
Number of TEAEs leading to permanent discontinuation of study drug,
●
Number and percentage of subjects with TEAEs leading to permanent discontinuation of 
●
study drug, 
Number of deaths,
●
Number of drug abuse related TEAEs, and
●
Number of drug withdrawal related TEAEs.
●
The above summary will be repeated for TEAEs (treatment period) and TEAEs (follow-up 
period).


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7.5.1.3 Treatment Emergent Adverse Events by SOC and/or PT
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized for each treatment group. Summaries will be provided for:
TEAEs
●
TEAEs (treatment period) and TEAEs (follow-up period),
●
Drug related TEAEs, 
●
Serious TEAEs (including number of events), 
●
Drug related serious TEAEs (including number of events), 
●
TEAEs leading to permanent discontinuation of study drug, 
●
Drug related TEAEs leading to permanent discontinuation of study drug,
●
TEAEs leading to death (including number of events) 
●
Drug related TEAEs leading to death (including number of events),
●
TEAEs excluding serious adverse events that equal to or exceed a threshold of 5% in any 
●
treatment group. 
The number and percentage of subjects with TEAEs, as classified by PT only, will be 
summarized for each treatment group in decreasing order of frequency within the ASP0819 
treatment group. 
The number and percentage of subjects with TEAEs (including number of events), as 
classified by SOC and PT will also be summarized by severity to study drug.  In the subject 
count, if a subject has multiple TEAEs with the same SOC or PT, but with differing severity, 
then the subject will be counted only once with the worst severity. If any of the severity 
values are missing then the subject will be counted only once with worst severity, i.e. severe.  
In the adverse event count, the adverse events will be presented in each category they were 
classified to.
Drug related TEAEs will be presented in a similar way by severity only.  When assessing 
severity for drug-related TEAEs as reported by the investigator, only drug-related TEAEs 
will be used in the analysis and the worst grade for severity will be chosen as described 
above.
7.5.2
Adverse Events of Interest
The number and percent of subjects who have a TEAE within the Drug abuse, dependence 
and withdrawal SMQ (MedDRA 20.0) will be summarized by treatment group. 
Drug abuse related TEAEs
The number and percent of subjects who have a TEAE within the Drug abuse and 
dependence SMQ (MedDRA 20.0) during the treatment period and follow-up period, as 
classified by SOC and PT will be summarized by treatment group.
In addition, the number and percent of subjects who have Drug abuse related TEAEs during 
the treatment period and follow-up period, as defined in Section 10.1  Appendix 1, as 
classified by PT and lowest level term will be summarized by treatment group.  


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Drug withdrawal related TEAEs
The number and percent of subjects who have a TEAE within the Drug withdrawal SMQ 
(MedDRA 20.0) during the treatment period and follow-up period, as classified by SOC and 
PT will be summarized treatment group.
In addition, the number and percent of subjects who have withdrawal related TEAEs during 
the treatment period and follow-up period, as defined in Section 10.2  Appendix 2, as 
classified by SOC and PT will be summarized by treatment group.
7.5.3
Clinical Laboratory Evaluation
The baseline visit is the last measurement taken prior to first dose of study drug.
Quantitative clinical laboratory variables, i.e. hematology & coagulation, and biochemistry 
will be summarized using mean, SD, minimum, maximum and median for each treatment 
group at each visit.  Additionally, a within-subject change will be calculated as the post-
baseline measurement minus the baseline measurement and summarized in the same way.  
Each laboratory result will be classified as low (L), normal (N), or high (H) at each visit 
according to the laboratory supplied reference ranges. 
The number and percentage of subjects below and above the reference range will be 
summarized for each treatment group at each visit.  For hematology and biochemistry, two 
types of shift tables will be presented for each treatment group: 
Shift tables of reference range changes from baseline to post-baseline value at each 
●
specified time point (low, normal, high), and
Summary shifts of reference range changes from baseline to post-baseline value at each 
●
specified time point (shift from normal or high to low, shift from normal or low to high, 
categorized increase [shift from low to normal, low to high or from normal to high], 
categorized no change [value stays in the same reference range], categorized decrease 
[shift from high to normal, high to low or from normal to low]).
The following list of parameters will be summarized using descriptive statistics and for the 
shift table.
Lab panel
Analysis Time point
Parameter
Hematology and 
Coagulation
Baseline
Treatment period
Week 2,
Week 4,
Week 8,
Follow-up
Week 10
Hemoglobin
Hematocrit
Erythrocytes (Red blood cell [RBC])
Leukocytes (White blood cell [WBC])  
Differential WBC
Platelets
PT and INR
MCV
MCH
Reticulocytes
Table continued on next page


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Lab panel
Analysis Time point
Parameter
Biochemistry
Baseline
Treatment period
Week 2,
Week 4,
Week 8,
Follow-up
Week 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
All laboratory measurements, including the derived outcomes (change from baseline and 
flagging of abnormal value with high and low) will be presented in the listing.  Urinalysis 
will be listed only.
7.5.3.1 Liver Enzymes and Total Bilirubin 
The following potentially clinically significant (PCS) criteria for liver tests – defined as 
Alkaline Phosphatase (ALP), Alanine Transaminase (ALT), total bilirubin (TBL), Aspartate 
Transaminase (AST), International Normalized Ratio (INR) and their combination are 
defined.  
Table 18
Potentially Clinically Significant Criteria for Liver Enzymes and Total 
Bilirubin
Parameter
Criteria
ALT
> 3xULN
> 5xULN
> 10xULN
> 20xULN
AST
> 3xULN
> 5xULN
> 10xULN
> 20xULN
ALT or AST
> 3xULN
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Parameter
Criteria
TBL
> 2xULN
INR
> 1.5 (Ratio)
ALP
> 1.5xULN
ALT and/or AST AND TBL(*)
(ALT and/or AST > 3xULN) and TBL > 2xULN
ALT and/or AST 
AND TBL and/or INR(*)
(ALT and/or AST > 3xULN) and (TBL > 2xULN and/or INR > 1.5)
(*) Combination of values measured from the samples collected on the same day.
The number and percentage of subjects with PCS values in liver enzyme and total bilirubin 
tests using the subject’s highest value during the double-blind treatment period will be 
presented by treatment group. Another summary will be created using the subject’s highest 
value during the follow-up period.
In addition to the above summaries the following data will be presented graphically by 
treatment group:
Scatter plot of maximum values for ALT or AST and TBL during the double-blind 
●
treatment period and follow-up period with ALT or AST values on x-axis and TBL 
values on y-axis [Senior, 2014], and
Individual display of liver enzymes and TBL for selected subjects experiencing 
●
potentially clinically significant criteria of ALT > 3xULN or AST > 3xULN or 
TBL > 2xULN during double-blind treatment period or follow-up period.
7.5.3.2
Potentially Clinically Significant Laboratory Criteria
Potentially clinically significant laboratory criteria for other laboratory variables are provided 
in Section 10.3  Appendix 3.  The number and percentage of subjects with PCS values using 
the subject’s highest and/or lowest value (depending on the direction of interest) during the 
double-blind treatment period will be presented by treatment group. Another summary will 
be created using the subject’s highest and/or lowest value (depending on the direction of 
interest) during the follow-up period.
7.5.4
Vital Signs
The baseline visit is the last measurement taken prior to the first dose of study drug.
Vital signs (SBP, DPB and pulse rate) will be summarized using mean, SD, minimum, 
maximum and median by treatment group and visit.  Additionally, a within-subject change 
will be calculated per visit as the post-baseline measurement minus the baseline measurement 
and summarized by treatment group and visit. Table 19 describes PCS criteria for vital signs. 
The number and percentage of subjects with PCS values in vital signs using the subject’s 
worst value during double-blind treatment period will be presented by each treatment group. 
Another summary will be created using the subject’s worst value during the follow-up period.


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Table 19
Potentially Clinically Significant Criteria for Vital Signs
Vital Sign Parameter
Criteria
Worst Value
SBP

<90 mmHg

Decrease of ≥20 mmHg from baseline

>180 mmHg 

Increase of ≥20 mmHg from baseline
Lowest
Lowest
Highest
Highest
DBP

<40 mmHg

Decrease of ≥20 mmHg from baseline

>100 mmHg

Increase of ≥20 mmHg from baseline
Lowest
Lowest
Highest
Highest
Pulse rate

<50 bpm

Decrease of ≥20 bpm from baseline

<50 bpm and decrease of ≥20 bpm from baseline (*)

>100 bpm

Increase of ≥20 bpm from baseline

>100 bpm and increase of ≥20 bpm from baseline (*)
Lowest
Lowest
Lowest
Highest
Highest
Highest
(*) Combination of values from the same time point.
7.5.5
Electrocardiograms
The baseline visit is the last measurement taken prior to the first dose of study drug.
The number and percentage of subjects with normal, not clinically significant abnormal, and 
clinically significant abnormal results as assessed by investigator for the 12-lead ECG will be 
tabulated by treatment group at each treatment visit and time point (Baseline, Week 8, EOT 
and Week 10). 
Number and percent of subjects with 12-lead ECG abnormalities as well as number and 
percent of subjects whose 12-lead ECG reading changed from normal at baseline to abnormal 
will be tabulated by treatment group at each treatment visit and time point (Baseline, Week 8, 
EOT and Week 10)
A shift table of the finding at baseline (‘normal’, ‘abnormal - not clinically significant’ and 
‘abnormal - clinically significant’) to the worst finding during the double-blind treatment 
period and follow-up period will be presented by treatment group.
7.5.6
Physical Examination Findings
Physical examination findings will be listed by treatment group.
7.5.7
Columbia Suicide Severity Rating Scale
Number and percentage of subjects in each of the categories of C-SSRS described in 
Section 6.2.5 will be summarized at each analysis time point (Baseline, Week 2, Week 4, 
Week 8, EOT and Week 10) by treatment group.  For each analysis time point, if a subject 
answers “yes” to more than one question within a category, the worst finding will be used.
For the overall during the double-blind treatment period and the overall during the follow-up 
period, a subject’s worst finding during that period will be used.


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All C-SSRS assessments will be listed only for subjects with at least one event of suicidality 
(suicidal ideation and/or suicidal behavior).
7.5.8
Pregnancies
A detailed listing of all pregnancies will be provided.
7.6
Analysis of PK
A listing of sample times and concentrations will be provided.
7.7
Analysis of PD
Not applicable.
7.8
Subgroups of Interest 
7.8.1
Subgroup Analysis for Primary Endpoint
In order to evaluate homogeneity of treatment effect across subject groups, subgroup 
analyses of the primary efficacy variable (change from baseline in mean daily average pain 
score as assessed by NRS) will be performed.  Separate analyses will be performed for each 
distinct level of a subgroup.
For each subgroup, the primary efficacy endpoint will be summarized descriptively using n, 
mean, SD, minimum, maximum and median by treatment group.  For subgroups where there 
are more than 20 subjects across both treatment groups for each distinct level, an analysis of 
the primary efficacy endpoint will be performed using the MMRM model as described in 
Section 7.4.1.1   Since the study is not designed to detect a treatment effect within each 
subgroup category p-values will be excluded from the summaries of these analyses.
The following subgroups will be assessed: 
Sex,
●
Age group,
●
Category of baseline mean daily average pain score as assessed by NRS, 
●
Central pain etiology as assessed by CMSI total score,
●
Peripheral pain etiology as assessed by NPSI total score and relevant subscales,
●
mIBS-D within past 24 hours at baseline: Symptom summary score, abdominal pain, 
●
stomach pain, abdominal cramps, abdominal pressure and bloating, and
Depression as assessed by M.I.N.I: Current/prior diagnosis versus no current/prior 
●
diagnosis.
Table 20 describes the subgroups defined on the basis of the categorized variables that will 
be used to summarize the primary efficacy endpoint.


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Table 20
Grouping variables for Subgroup Analysis for Primary Endpoint
Subgroup
Subgroup Category
Sex
Female
Male
Age group
<45 years
≥45 to < 65 years
≥ 65 years
BMI
< 30 kg / m2
≥ 30 kg / m2
Baseline mean daily average pain score as 
assessed by NRS
≥4 to < 7 (Moderate)
≥ 7 (Severe)
Central pain etiology as defined by CMSI
More centrally driven FM pain
Non-specific FM pain
More peripherally driven FM pain
Peripheral pain etiology as defined by NPSI: 
NPSI total score and relevant subscales
Low
High
mIBS-D within past 24 hours at baseline:

Abdominal pain 

Stomach pain

Abdominal cramps

Abdominal pressure

Bloating

Symptom summary score
Low
Mid
High
Depression as assessed by M.I.N.I: 
Current/Prior versus No current/Prior
Current/Prior (History of MDD = ‘Yes’)
No current/Prior (History of MDD = ‘No’)
BMI: Body mass index; CMSI: Complex Medical Symptoms Inventory; FM: Fibromyalgia; mIBS-D: Modified 
irritable bowel syndrome - diarrhea predominant; M.I.N.I.: Mini-International Neuropsychiatric Interview;
NPSI: Neuropathic Pain Symptom Inventory; NRS: Numerical rating scale.
There is no pre-defined cut-point which can be used to categorize subjects into those that 
have more centrally driven FM pain versus those who may have more peripherally driven FM 
pain as assessed by baseline CMSI total score.  Similarly, there are no cut-points which can 
be used to split the subjects into those with lower scores on total and/or subscales of the NPSI 
at baseline versus those with higher scores.  This also applies to the mIBS-D symptom 
summary score and individual items.
During blinded data review, for each endpoint scatterplots versus change from baseline to 
Week 8 in mean daily average pain score assessed by NRS were used to assess the most 
appropriate cut-point. For CMSI total score and mIBS-D symptom summary score and 
individual items a decision was made to split subjects into three subgroups using tertiles of 
the measurements at baseline as the cut-point.  For NPSI subscales and NPSI total score a 
decision was made to split subjects into two subgroups using the median of the measurements 
at baseline as the cut-point. 


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7.8.2
Subgroup Analysis for Exploratory Endpoint FMSD
To further assess the impact on changes in sleep the FMSD question “How rested were you 
when you woke up” at baseline will be used to categorize subjects into two subgroups using 
the median as a cut-point.
For each subgroup, the exploratory endpoint of change from baseline to Week 8 for the two 
FMSD questions “How restless was your sleep?” and “How rested were you when you woke 
up?”, will be summarized using n, mean, SD, minimum, maximum and median by treatment 
group.
7.9
Other Analyses
No additional analyses are planned.
7.10
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 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.
7.11
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
7.11.1
Missing Data
As a general principle, no imputation of missing data for other variables will be done.  
Exceptions are the onset date of AE, start and stop dates of non-medication therapy, start and 
stop dates of previous and concomitant medication, onset date of FM symptoms, date of FM 
diagnosis and first/last dose date of double-blind study drug.  In the listings of AEs, non-
medication therapy, previous and concomitant medication and onset date of FM symptoms, 
diagnosis of FM, the first dose/last dose date of double-blind study drug will present the actual 
partial dates; imputed dates will not be shown.
For one of the sensitivity analyses for the primary efficacy endpoint and one of the sensitivity 
analysis for the FIQR secondary endpoint, multiple imputation will be used to impute missing 
data, using a discontinuation reason-based approach as described in Section 7.4.1.2   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 6.1 and Section 7.4
Imputation of Adverse Event Onset Date
For AEs, a missing or incomplete onset date will be imputed according to the following 
conventions:


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If an onset date is missing or only the year is known, the imputed onset date will be the latest 
of the following non-missing dates:
First dose date of double-blind study drug 
●
Randomization date + 1 day
●
If only the month and year is known for onset date, set the surrogate onset date to the first 
day of that month and then apply the following rules:
1.
If the month and year of the onset date is prior to the month and year of the first dose of 
double-blind study drug, then the surrogate onset date will be the imputed onset date.
2.
If the month and year of the onset date is on or after the month and year of the first dose 
of double-blind study drug, then the imputed onset date will be the latest of the 
following non-missing dates:
First dose date of double-blind study drug 
●
Randomization date + 1 day
●
Surrogate onset date
●
If the imputed onset date is after a complete adverse event end date, the imputed onset date 
will be the same as the complete adverse event end date.
Imputation of Adverse Event End Date
For AEs, a missing or incomplete end date will be imputed according to the following 
conventions:
If only the day is missing for end date, set the surrogate end date to the last day of the month.
If the day and the month are missing for end date, set the surrogate end date month to 
December and set the day to the last day of the month (31).
If the year or the entire end date is missing, end date will not be imputed.
If an AE end date has been imputed, then apply the following rule:
1.
If this imputed date falls after the end of participation in the study, then the surrogate end 
date will be set to the date of end of participation.
If the AE is ongoing (outcome is “NOT RECOVERED/NOT RESOLVED” or 
“RECOVERING/RESOLVING”) then the end date will remain missing.
Imputation of Start and Stop Dates of Non-Medication Therapy and Previous and
Concomitant Medication Dates
For Non-Medication Therapy and Previous and Concomitant Medications, a missing or 
incomplete start and stop dates will be imputed according to the following conventions:
If start date is missing or partial:
if month is missing, use January
●
if day is missing, use the first day of the month under consideration
●
if year is missing, use year of the informed consent date
●


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if entire date is missing, use informed consent date
●
If stop date is missing or partial and medication or therapy is not ongoing:
if month is missing, use December
●
if day is missing, use the last day of the month under consideration
●
if year or the entire date is missing, set to December 31st, 2099
●
If the imputed start date is after the stop date, then the imputed start date will be one day prior 
to the stop date.
If the medication or therapy is ongoing, the stop date will remain missing.
Missing Onset Date of FM Symptoms and Date of FM diagnosis
An incomplete onset date of FM Symptoms or date of FM diagnosis will be imputed 
according to the following conventions:
Missing day, but month and year are present: the day will be imputed as the 15 th day of 
●
the month.
Missing day and month, but year is present: the day and month will be imputed as 
●
30 June of the year.
Missing year, but day and month are present: No imputations will occur, and the subject 
●
will be excluded from all summaries related to time since FM symptoms and diagnosis. 
Missing day, month and year: No imputations will occur, and the subject will be 
●
excluded from all summaries related to time since FM symptoms and diagnosis.
If any such imputed date falls after the informed consent date, then the onset date will be 
●
taken as equal to the informed consent date.
Imputation of Study Drug Start Date Double-Blind Treatment Period
For subjects who are randomized to double-blind study drug, the first dose date of double-
blind study drug will be imputed if both of the following criteria are met:
There is a missing or partial date for the first dose of double-blind study drug AND 
●
The number of capsules dispensed does not equal the number of capsules returned 
●
(including missing values).
If the first dose date of double-blind study drug is missing or partial, the first dose date of 
double-blind study drug is defined as the non-missing dispense date at randomization.
Imputation of Study Drug End Date Double-Blind Treatment Period
For subjects who are randomized to double-blind study drug, the last dose date of double-
blind study drug will be imputed if both of the following criteria are met:
There is a missing or partial date for the last dose of double-blind study drug AND 
●
The number of capsules dispensed does not equal the number of capsules returned 
●
(including missing values).
If only the day is missing for the last dose date of double-blind study drug, the last day of the 
month under consideration will be used.


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If the month and/or year are missing for the last dose date of double-blind study drug, then 
the latest of the following non-missing dates will be used:
1.
last dispense date + 1 day OR
2.
the date of the last vital sign measurement during the double-blind treatment period OR
3.
the date of the first dose of double-blind study drug in the double-blind treatment period 
+ 1 day
7.11.2
Outliers
All values will be included in the analyses.
7.11.3
Values below limit of quantification (BLOQ)
For quantitative laboratory variables, values recorded as “<X” or “<=X” or “>Y” or “>=Y” 
will be imputed by “X” and “Y” respectively for descriptive statistics.  This will be 
documented in a footnote to all summary tables and all output where such a replacement was 
performed.
7.11.4
Visit Windows for Efficacy Variables
7.11.4.1 Duplicate Values
For daily average pain scores assessed by NRS and FMSD scores any data captured in the 
e-diary up to 2am in the morning of the following day will be assigned to the previous day in 
the derivation of Study Day (Section 7.1).
For all efficacy variables (either recorded in the e-diary or the tablet device), if more than one 
value is measured/recorded on the same Study Day, then the first of the values will be used.  
This should be applied before implementing the visit windows as described in 
Section 7.11.4.3
7.11.4.2 Post Dosing Efficacy Observations
For efficacy variables, observations will not contribute to the efficacy analyses during the 
treatment period if the subject’s last dose of double-blind study drug is as follows:
Any diary days or non-diary days which are > 4 days after the last dose of double-blind study 
drug will not be included in the analysis related to on-treatment time points and the EOT time 
point.  This should be applied before implementing the visit windows in Section 7.11.4.3
7.11.4.3 Visit Windows
Subjects do not always adhere strictly to the visit timing in the protocol.  Therefore, the 
designation of time points will be based on Study Day and Follow-Up Day (as defined in 
Section 7.1) rather than the nominal visit recorded in the eCRF. 
To assign a measurement to a Week t during the double-blind treatment period, the first step 
consists of selecting all measurements falling within the double-blind treatment period as 
defined above.  To further determine the Week t measurement, mutually exclusive relative 
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These day windows are defined to provide derived time points that correspond to the post 
baseline time points specified in the protocol.
Table 21 provides day windows for daily average pain scores assessed by NRS and rescue 
medication data.  Table 22 provides day windows for the FMSD questionnaire data.  
Table 23 provides day windows for FIQR, PGIS, PGIC and mIBS-D questionnaire data.  
Table 24 provides day windows for HADS, EQ-5D-5L and NPSI questionnaire data.
Table 21
Day Windows: NRS questionnaire and rescue medication
Analysis Time point
Visit Window (Day)
Baseline
Study days -7 to -1
Week 1
Study days 2 to 7
Week 2
Study days 8 to 14
Week 3
Study days 15 to 21
Week 4
Study days 22 to 28
Week 5
Study days 29 to 35
Week 6
Study days 36 to 42
Week 7
Study days 43 to 49
Week 8
Study days 50 to 56
EOT
Study day 2 to 56, where post-baseline data from the last 7 calendar days on 
or prior to the last NRS score will be used.  If there is no post-baseline data 
available EOT will be imputed using the baseline measurement.
Double-blind treatment perioda
Study days 2 to 56
Week 10
Follow-up days 7 to 13
Follow-up perioda
Follow-up days 5 to 28
aOnly applicable to rescue medication.
Table 22
Day Windows: FMSD questionnaire
Analysis Time point
Visit Window (Day)
Baseline
Study days -6 to 1
Week 1
Study days 3 to 8
Week 2
Study days 9 to 15
Week 3
Study days 16 to 22
Week 4
Study days 23 to 29
Week 5
Study days 30 to 36
Week 6
Study days 37 to 43
Week 7
Study days 44 to 50
Week 8
Study days 51 to 57
EOT
Study day 3 to 57, where post-baseline data from the last 7 calendar days on 
or prior to the last FMSD scores will be used.  If there is no post-baseline 
data available EOT will be imputed using the baseline measurement.
Week 10
Follow up days 8 to 14


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Table 23
Day Windows: FIQR, PGIS, PGIC and mIBS-D questionnaires 
Analysis Time point
Target Day
Visit Window (Day)
Week 2
Study day 15
Study days 2 to 22
Week 4
Study day 29
Study days 23 to 43
Week 8
Study day 57
Study day 44 to 71
EOTa
Not applicable
Study day 2 to Follow-up day 4
Week 10b
Follow-up day 14
Follow-up day 5 to 28
Apart from PGIC, baseline is defined as the last assessment on or prior to the first dose day (Day 1) of double-
blind study drug.
a EOT value is the last available non-missing post-baseline measurement within the visit window.  If there is no 
post-baseline data available EOT will be imputed using the baseline measurement.
b mIBS-D is not collected at Week 10 
Table 24
Day Windows: HADS, EQ-5D-5L and NPSI questionnaires 
Analysis Time point
Target Day
Visit Window (Day)
Week 8
Study day 57
Study day 44 to 71
EOTa
Not applicable
Study day 2 to Follow-up day 4
Week 10
Follow-up day 14
Follow-up days 5 to 28
Baseline is defined as the last assessment on or prior to the first dose day (Day 1) of double-blind study drug.
a EOT value is the last available non-missing post-baseline measurement within the visit window. If there is no 
post-baseline data available EOT will be imputed using the baseline measurement.
For efficacy variables recorded in the e-diary (NRS questionnaire, rescue medication and 
FMSD questionnaire data), the following rule will apply:
Measurements recorded on all valid diary days which fall within the Day Range for a 
●
specified visit as defined in Table 21 (NRS questionnaire and rescue medication) and 
Table 22 (FMSD questionnaire) will be used to calculate the average.
For efficacy variables recorded in the tablet device, the following rule will apply:
If a subject has more than one time point with a measurement included within a window, 
●
the assessment closest to the target day will be used. In case of ties between observations 
located on different sides of the scheduled day, the later assessment will be used. In case 
of ties located on the same side of the scheduled day (i.e. more than one value for the 
same day), the first value will be used. 
7.11.5
Visit Windows for Safety Variables
7.11.5.1 Duplicate Values
For safety laboratory data and vital signs, if more than one value is reported on the same day, 
then the mean of the values will be used.  This needs to be done before creating the analysis 
time points.


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7.11.5.2 Post Dosing Safety Observations
For safety variables, observations will not contribute to the safety analyses during the 
treatment period if the subject’s last dose of double-blind study drug is as follows:
Any days which are > 4 days after the last dose of double-blind study drug will not be 
included in the analysis related to on-treatment time points and the EOT time point.  This 
needs to be done before creating the analysis time points.
7.11.5.3 Visit Windows
Table 25 provides day windows for safety laboratory variables, vital sign variables and 
C-SSRS.  Table 26 provides day windows for the categorical ECG assessment.
Table 25
Day Windows: Laboratory, Vital Sign Variables and C-SSRS
Analysis Time point
Target Day
Visit Window (Day)
Week 2
Study day 15
Study days 2 to 22
Week 4
Study day 29
Study days 23 to 43
Week 8
Study day 57
Study days 44 to 71
EOTa
Not applicable
Study day 2 to Follow-up day 4
Double-blind treatment periodb
Not applicable
Study day 2 to Follow-up day 4
Week 10
Follow up day 14
Follow-up days 5 to 28
Follow-up periodb
Not applicable
Follow-up day 5 onwards
Baseline is defined as the last assessment on or prior to the first dose day (Day 1) of double-blind study drug.
a EOT value is the last available non-missing post-baseline measurement within the visit window.
bOnly applicable to potentially clinically significant laboratory parameters, potentially clinically significant vital 
signs and C-SSRS. 
Table 26
Day windows: Categorical ECG assessment
Analysis Time point
Target Day
Visit Window (Day)
Week 8
Study day 57
Study days 44 to 71
EOTa
Not applicable
Study day 2 to Follow-up day 4
Double-blind treatment period
Not applicable
Study day 2 to Follow-up day 4
Week 10
Follow-up day 14
Follow-up days 5 to 28
Follow-up period
Not applicable
Follow-up day 5 onwards
Baseline is defined as the last assessment on or prior to the first dose day (Day 1) of double-blind study drug.
a EOT value is the last available non-missing post-baseline measurement within the visit window.
For safety variables, the following rules will apply:
1.
For laboratory and vital sign variables, if a subject has more than one visit with a 
measurement included within a window, the assessment closest to the target day will be 
used.  In case of ties between observations located on different sides of the scheduled 
day, the later assessment will be used. In case of ties located on the same side of the 
target day (i.e., more than one value for the same day), the mean of the values will be 
used. 


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2.
For the categorical ECG assessment, if a subject has more than one result with a 
measurement included within a window, the assessment closest to the target day will be 
used.  In case of ties between observations located on different sides of the target day, 
the later assessment will be used in the analyses.  In case of ties located on the same side 
of the scheduled day (i.e. more than one value for the same day), the worst-case 
parameter value (where ‘abnormal - clinically significant’ is considered worse than 
‘abnormal - not clinically significant’, which in turn are both considered worse than 
‘normal’) will be used.
3.
For the C-SSRS, if a subject answers “yes” to more than one question within a window, 
the worst-case response (within a category) will be used irrespective of whether this is 
closest to the target day.
7.11.6
Pooling Sites Algorithm
Approximately 178 subjects will be enrolled in approximately 35 sites.  When “center” is 
included as a factor in a statistical model, sites that have less than 10 FAS subjects in total 
will be identified and then combined for statistical analysis purpose according to the 
following algorithm:
Step 1. Divide the sites into 2 groups with Group 1 including all sites that have at least 
10 FAS subjects in total and Group 2 including all remaining sites.  Sort each group 
in ascending order by total sample size and site number. 
Step 2. Starting at the top of the Group 2 list (i.e., the first site with the smallest total sample 
size), combine the minimum number of sites required to achieve a “study site” that 
has at least 10 FAS subjects in total.  Continue forming “center” in this manner until 
all Group 2 sites have been grouped or it is no longer possible to form a “center” with 
at least 10 FAS subjects in total.  
Step 3. If there is a site (or several sites) left after step 2, combined the site(s) with the last 
pooled site that is created.  For the situation where no previous pooled site is created, 
combine the site(s) with the first site on the sorted Group 1 list. 
Pooled sites will be assigned names PoolSite01, PoolSite02, etc. 
For all sites that have been combined into pooled sites, the assigned pooled site will be used 
instead of the original site identification in all statistical models that include “center” as a 
factor.  However, the original site identification will be used in all summaries of subject 
disposition or discontinuation by site and in all data listings.


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8
DOCUMENT REVISION HISTORY 


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Version
Date
Changes
Comment/rationale for change
1.0
10-Mar-2017
NA
Document finalized
2.0
10-Apr-2018
Page 1: Changed “Subjects” to 
“Patients” in study title.
Typographical error. 
2.0
10-Apr-2018
Section 5.2.1 Table 2:
Updated criteria to criterion where 
appropriate.
Additional text included for FIQR 
inclusion criteria: ‘Inclusion 
criterion #11 is No and/or FIQR pain 
item score < 4 at Screening.’
Percent overall compliance is <70% 
for a subject, calculated over day 1 to 
Week 8/EOT. Subjects with missing 
compliance will be reviewed on a 
case by case basis.
Additional text included for HADS 
exclusion criteria: Exclusion 
Criterion #9 is Yes and/or HADS 
total score > 14 (using HADS 
corrected questionnaire) at 
Screening or Visit 3 (Randomization). 
Subjects who completed the 
incorrect version of this 
questionnaire will be reviewed on a 
case by case basis.
Typographical errors.
Criterion numbering updated and 
additional text included for clarification 
to match classification specification
2.0
10-Apr-2018
Section 6.1:
Additional sentence added: ‘For 
FIQR, PGIS, EQ-5D-5L, mIBS-D and 
HADS baseline is defined as the last 
assessment on or prior to the first dose 
day (Day 1) of double-blind study 
drug.
Clarification of derivation of baseline 
for questionnaires captured on the 
tablet at site. 
2.0
10-Apr-2018
Section 6.1.3 Table 5: 
‘Baseline’ removed from the 
description of ‘Handling of missing 
data’ column for the ‘Percentage of 
subjects achieving a PGIC of “Very 
Much Improved” or “Much 
Improved” at Week 8 and EOT’ rows
Typographical error


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Version
Date
Changes
Comment/rationale for change
2.0
10-Apr-2018
Section 6.1.3:
Additional text added to FMSD 
section: ‘Change from baseline is 
defined in Section 7.1.  For FMSD 
Item 1, Item 2, Item 3, Item 4 and 
Item 7 a negative change indicates a 
reduction/improvement from baseline 
(i.e., a favorable outcome); whereas 
FMSD Item 5, Item 6 and Item 8 a 
positive change indicates an 
improvement in sleep symptoms 
compared to baseline.’
Clarification that direction of change 
differs for different FMSD Items.
2.0
10-Apr-2018
Section 6.1.3:
Additional text added to HADS 
depression subscale ‘Change from 
baseline to Week 8 and to EOT for the 
HADS depression subscale will only 
be calculated for subjects who have 
baseline data captured using the 
corrected version of the questionnaire. 
For subjects who have baseline HADS 
data captured using the original 
version of the questionnaire that was 
used at the start of the study change 
from baseline will not be derived. 
Data captured using the original 
version of the questionnaire will be 
listed only and will not be presented 
in any tables.’
Clarification that change from baseline 
for the HADS depression subscale total 
score will only be calculated for 
subjects with baseline data captured 
using the corrected version of this 
questionnaire.
2.0
10-Apr-2018
Section 6.1.3 Table 7:
Additional row added for the 
derivation of the HADS depression 
subscale total score using the 
corrected version of the HADS 
questionnaire. 
Additional column added to 
distinguish the derivations required 
for the original and corrected HADS 
questionnaire.
Post-baseline analysis visits removed 
from the original HADS 
questionnaire.
Section updated to include the 
corrected version of the HADS 
questionnaire and derivation of the 
HADS depression subscale total score. 
Analysis timepoints for the original 
version of the HADS questionnaire 
updated to include baseline only. 
2.0
10-Apr-2018
Section 6.1.3:
Additional text has been to the 
following sentence: ‘Change from 
baseline is defined in Section 7.1 and 
only applies to the EQ-VAS.’
Clarification that change from baseline 
only applies to the EQ-VAS.
2.0 
10-Apr-2018
Section 6.1.3 Table 9:
Total Number of days replaced with 
‘Minimum of (upper bound of the 
time window, last assessment day 
from e-dairy data) – lower bound of 
the time window + 1’
Additional text included to define the 
denominator for each week (Total 
number of days) for subjects who 
discontinue early or who come in early 
for their last visit (but within the 
designated window in the protocol.)


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Date
Changes
Comment/rationale for change
2.0
10-Apr-2018
Section 6.4.7:
Additional sentences added to the end 
of this section:
‘The CMSI total score at baseline will 
be calculated and ranges from 0 to 39 
for males and 0 to 41 for females. 
Baseline is defined as the last 
assessment on or prior to the first dose 
day (Day 1) of double-blind study 
drug.’
Extra clarification regarding derivation 
of CMSI total score and definition of 
baseline.
2.0
10-Apr-2018
Section 7.1:
Additional sentences added to the end 
of the following paragraph: 
‘Summaries based on FAS and PPS 
(e.g. disposition, baseline and efficacy 
data) will be presented by planned 
treatment group, unless specifically 
stated otherwise.  Safety analysis and 
other summaries based on SAF will be 
presented by actual treatment 
received.  For summaries which 
present both absolute values over 
time and change from baseline 
values over time the number of 
subjects used to calculate the 
descriptive statistics will be those 
who have non-missing data at each 
analysis visit and at baseline. For 
endpoints which include mBOCF, 
LOCF or mLOCF imputation the 
descriptive statistics will be 
calculated after the imputation has 
been performed.’
Unless otherwise specified, statistical 
comparisons will be made using one-
sided tests at the α=0.05 significance 
level and two-sided 90% confidence 
intervals (CIs) will be presented when 
applicable.  When two-sided p-
values are presented statistical 
comparisons will be made using an 
α=0.1 significance level.
Extra clarification regarding the 
number of subjects which will be 
presented in summary tables.
Significance level added for 2-sided 
p-values.


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Date
Changes
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2.0
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Section 7.2.4:
Additional paragraph added:
All previous medications for taken for 
any pain prior to the baseline diary 
run-in; all previous medications taken 
for any pain during baseline diary run-
in; all concomitant medications taken 
for any pain during the double blind 
treatment period and all concomitant 
medications taken for any pain during 
the follow-up period will also be 
summarized by preferred WHO name 
by treatment group and ‘Total’ over 
all treatment groups.
Description of extra summaries of 
previous medications and concomitant 
medications for any pain added.
2.0
10-Apr-2018
Section 7.2.3.2, Table 13:
Footnote added: *Only for subjects 
with data captured using the corrected 
version of the HADS questionnaire.
Clarification that HADS depression 
subscale total score will only be 
calculated for subjects with data 
captured using the corrected version of 
this questionnaire.
2.0
10-Apr-2018
Section 7.2.3.3, Table 14:
Additional group added to each of 
CMSI total score and NPSI total score 
and subscales. Footnote regarding 
definition of cut-points for CMSI total 
score, NPSI total score and subscales 
and mIBS-D summary score and 
individual items updated.
Decision made to split CMSI total 
score into three groups; NPSI total 
score and subscales into two groups; 
mIBS-D summary score and individual 
items into three groups based on 
assessment of scatterplots during blind 
data review. 
2.0
10-Apr-2018
Section 7.4.2:
In the section describing the 
proportional odds analysis of overall 
subject improvement assessed by 
PGIC the text has been updated to:
At each time point, the proportion of 
subjects in each treatment group 
achieving each level of response (1 = 
“Very Much Improved”, 2 = “Much 
improved”, 3 = “Minimally 
Improved”, 4 = “No Change”, 5 = 
“Minimally Worse”, 6 = “Much 
Worse”, 7 = “Very Much Worse”), 
will be presented, together with the 
odds ratio, associated 90% CI based 
on profile likelihood and 2-sided p-
value based on likelihood ratio test
for ASP8062 vs placebo. The 
cumulative logit link will be used to 
specify the proportional odds model in 
SAS.
p-value updated to 2-sided rather than 
1-sided. Additional detail provided 
regarding methods used for calculation 
of CI and p-value.


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Version
Date
Changes
Comment/rationale for change
2.0
10-Apr-2018
Section 7.4.1.1:
In the description of the MMRM 
model the text ‘baseline mean daily 
average pain score-by-treatment 
interaction’ has been replaced by 
‘baseline mean daily average score-
by-time interaction’ and subject as a 
random effect has been removed from 
the model
Typographical error ‘treatment’ 
replaced with ‘time’. Subject as a 
random effect has been removed from 
model due to issues with convergence.
2.0
10-Apr-2018
Section 7.4.3, Table 17:
Footnote added: *Only for subjects 
with data captured using the corrected 
version of the HADS questionnaire.
Clarification that HADS depression 
subscale total score will only be 
calculated for subjects with data 
captured using the corrected version of 
this questionnaire.
2.0
10-Apr-2018
Section 7.4.3, Table 17:
Additional rows for shifts from 
baseline to Week 8 and to EOT for the 
Treatment Period and from baseline to 
Week 10 for the Follow-up Period for 
each of the 5 dimensions of the EQ-
5D-5L have been added. 
As EQ-5D-5L dimensions are 
categorical have replaced summary 
tables of change from baseline with 
shift tables
2.0
10-Apr-2018
Section 7.4.3 Table 17:
NPSI total score added to the list of 
exploratory analyses: ‘Change from 
baseline to Week 8 and EOT in the 
NPSI total score and NPSI burning 
pain, pressing pain, paroxysmal pain, 
evoked pain, and 
paresthesia/dysesthesia subscales’
Typographical error
2.0
10-Apr-2018
Section 7.4.3:
NPSI total score added to list of 
exploratory analyses: 

Change from baseline to 
Week 8 (note that no 
imputation will be performed 
hence the ANCOVA will 
only include subjects with 
data at both baseline and 
Week 8) and EOT in the 
NPSI total score and NPSI 
burning pain, pressing pain, 
paroxysmal pain, evoked 
pain, and 
paresthesia/dysesthesia 
subscales.
Typographical error


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Version
Date
Changes
Comment/rationale for change
2.0
10-Apr-2018
Section 7.4.3:
ANOVA analysis of average daily 
dose of rescue medication updated to 
specify that this will be performed for 
the overall double-blind treatment 
period only. In addition, the response 
variable will be log10 transformed 
and values of 0 imputed as 5 prior to 
analysis.
Normality assumptions reviewed 
during blind data review and judged 
invalid for ANOVA at Week 1, 
Week 2, Week 3, Week 4, Week 5, 
Week 6, Week 7, Week 8 and EOT. 
Upon log10 transformation normality 
assumptions deemed acceptable for 
average daily dose of rescue medicine 
during the double-blind treatment 
period.
2.0
10-Apr-2018
Section 7.4.3:
Additional text added to clarify that 
descriptive summaries of change from 
baseline apply to EQ-VAS only. 
Additional text included to describe 
the shift tables that will be produced 
for the EQ-5D-5L 5 dimensions.
As EQ-5D-5L dimensions are 
categorical have replaced summary 
tables of change from baseline with 
shift tables. Clarification provided that 
change from baseline summaries apply 
to EQ-VAS only.
2.0
10-Apr-2018
Section 7.5.1.3:
Text updated so that AEs with missing 
severity will be imputed with worst 
severity, i.e severe rather than treated 
as missing.
Updated to comply with latest version 
of Astellas standards
2.0
10-Apr-2018
Section 7.5.3:
Bullet point describing summary 
shifts of laboratory parameters so that 
‘low to high’ is included as a 
categorized increase and ‘high to low’ 
is included as a categorized decrease.
Study team feedback provided that
these extra conditions should be 
included in these definitions.
2.0
10-Apr-2018
Section 7.5.4 Table 19:
Criteria for SBP absolute worst lowest 
value changed from <100 mmHg to 
<90 mmHg
Criteria for SBP absolute worst 
highest value changed from >160 
mmHg to >180 mmHg
Updates to absolute worst lowest and 
highest criteria definition for SBP per 
study team feedback. 
2.0
10-Apr-2018
Section 7.8.1:
Text updated to describe updates to 
the cut-points being used to split the 
CMSI total score, NPSI total score 
and subscales and mIBS-D summary 
score and individual items into 
subgroups. 
Decision made to split CMSI total 
score into three groups; NPSI total
score and subscales into two groups; 
mIBS-D summary score and individual 
items into three groups based on 
assessment of scatterplots during blind 
data review.


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Changes
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2.0
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Section 7.11.4.3: 
Tables 21 and 22
Imputation of EOT updated to specify 
that baseline is carried forward when 
there are no measurements post 
baseline.
Tables 23 and 24
Extra footnote providing the definition 
of baseline and imputation of EOT 
when there are no post-baseline 
measurements added.
Extra clarification regarding imputation 
at EOT timepoint provided for NRS, 
FMSD, FIQR, PGIS, PGIC mIBS-D, 
HADS, EQ-5D-5L and NPSI 
questionnaires.
Definition of baseline provided for 
FIQR, PGIS, mIBS-D, HADS, EQ-5D-
5L and NPSI questionnaires.
2.0
10-Apr-2018
Section 7.11.5.3:
Extra footnote providing definition of 
baseline added to Tables 25 and 26.
Extra clarification regarding definition 
of baseline for laboratory parameters, 
vital signs variables, C-SSRS 
questionnaire and ECG assessments. 
2.0
10-Apr-2018
Appendix 10.1:
MedDRA version updated to 20.0. 
List of Lower Level Terms updated to 
reflect update to MedDRA v2.0. 
Lower Level Codes added to table.
Table updated to reflect change to 
MedDRA v20.0
2.0
10-Apr-2018
Appendix 10.2:
MedDRA version updated to 20.0. 
List of Lower Level Terms updated to 
reflect update to MedDRA v2.0. 
Lower Level Codes added to table.
Table updated to reflect change to 
MedDRA v20.0
2.0
10-Apr-2018
Section 6.1, 7.2 and 7.4: “FIQR 
physical function” was changed to 
“FIQR function” wherever it was 
mentioned.
Typographical error.


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9
REFERENCES
Carpenter JR, Roger JH & Kenward MG. 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.
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics).
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics).
O’Kelly M & Ratitch B. Clinical Trials with Missing Data: A Guide for Practitioners. Statistics in 
Practice (2014):189 – 190.
Senior JR. Evolution of the Food and Drug Administration Approach to Liver Safety Assessment for 
New Drugs: Current Status and Challenges. Drug Safety (2014) 37 (Suppl 1):S9–S17.


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10
APPENDICES


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10.1
Appendix 1: Drug Abuse Related Adverse Events
Abuse related adverse events of interest (MedDRA 20.0) that are explicitly referenced in the 
2010 draft guidance
System 
Organ Class
Higher Level 
GT
Higher 
Level Term
Preferred 
term
Lowest Level Term
Lower Level Code
Psychiatric 
disorders
Mood 
disorders and 
disturbances 
NEC
Emotional 
and mood 
disturbances 
NEC
Euphoric 
Mood
Euphoria
10015533
Euphoric
10015534
Euphoric mood
10015535
Exaggerated well-
being
10015584
Feeling high
10016333
Felt high
10016382
High
10020044
High feeling
10020063
Hyperthimic
10020847
Hyperthimic state
10020849
Laughter
10024042
Mood elevated
10027949
Mood altered
Affect alteration
10054199
Affect altered
10001439
Altered mood
10001850
Bad mood
10004064
Mood alteration 
NOS
10027937
Mood altered
10027940
Mood change
10027941
Affect 
alterations
Inappropriate 
affect
Elation 
inappropriate
10014339
Exhilaration 
inappropriate
10015672
Exhiliration 
inappropriate
10015673
Inappropriate affect
10021588
Inappropriate crying
10021589
Inappropriate elation
10021592
Inappropriate 
exhilaration
10021593
Inappropriate 
laughter
10021595
Inappropriate mood 
elevation
10021596
Mood elevation 
inappropriate
10027950
Table continued on next page


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System 
Organ Class
Higher Level 
GT
Higher 
Level Term
Preferred 
term
Lowest Level Term
Lower Level Code
Psychiatric 
disorders
Disturbances 
in thinking 
and 
perception
Perception 
disturbances
Hallucination
Drug-induced 
hallucinosis
10013761
Hallucinating
10019062
Hallucination
10019063
Hallucination NOS
10019066
Hallucinations
10019077
Hallucinations 
aggravated
10019078
Kinesthetic 
hallucination
10023450
Organic hallucinosis 
syndrome
10031079
Pseudohallucination
10066297
Sensory 
hallucinations
10040028
Stump hallucination
10042263
Hallucination, 
auditory
Auditory 
hallucinations
10003785
Hallucination 
auditory
10019064
Hallucination, 
auditory
10019070
Verbal 
hallucinations
10069415
Hallucination, 
visual
Hallucination visual
10019068
Hallucination with 
color
10055527
Hallucination with 
colour
10019069
Hallucination, visual
10019075
Visual 
hallucinations
10047570
Table continued on next page


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System 
Organ Class
Higher Level 
GT
Higher 
Level Term
Preferred 
term
Lowest Level Term
Lower Level Code
General 
disorders and 
administration 
site conditions
General 
system 
disorders 
NEC
Feelings and 
sensations 
NEC
Feeling drunk
Drunk-like effect
10013767
Drunkenness feeling 
of
10013769
Feeling drunk
10016330
Feeling 
abnormal
Cotton wool in head
10011221
Feeling abnormal
10016322
Feeling bad
10016324
Feeling dazed
10050462
Feeling floating
10016331
Feeling lifeless
10016340
Feeling miserable
10016342
Feeling stoned
10070679
Feeling strange
10016366
Feeling weightless
10016372
Feels awful
10016375
Feels bad
10016376
Feels poorly
10016377
Felt like a zombie
10016384
Floating feeling
10016782
Foggy feeling head
10016876
Funny episode
10017552
Fuzzy
10017565
Fuzzy head
10017566
Muzzy head
10028405
Neck strange feeling 
of
10028844
Soft feeling
10041286
Spaced out
10041374
Thick head
10043428
Unstable feeling 
10046253
Weird feeling
10047904
The AE term of sedation is mentioned in the 2010 Draft Guidance but is not included in this table.


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10.2
Appendix 2: Drug Withdrawal Related Adverse Events
Drug Withdrawal – Related Adverse Events Occurring Following Drug Discontinuation 
(Preferred Terms; MedDRA 20.0)
System Organ 
Class
Higher Level GT
Higher Level 
Term
Preferred Term
Preferred Term 
Code
Psychiatric 
disorders
Anxiety disorders 
and symptoms
Anxiety symptoms
Agitation
10001497
Nervous system 
disorders
Neurological 
disorders NEC
Neurological signs 
and symptoms NEC
10001497
Psychiatric 
disorders
Depressed mood 
disorders and 
disturbances
Mood alterations 
with depressive 
symptoms
Anhedonia
10002511
Psychiatric 
disorders
Anxiety disorders 
and symptoms
Anxiety symptoms
Anxiety
10002855
Musculoskeletal 
and connective 
tissue disorders
Muscle disorders
Muscle related 
signs and symptoms 
NEC
Chills
10008531
Musculoskeletal 
and connective 
tissue disorders
Muscle disorders
Feelings and 
sensations NEC
10008531
Psychiatric 
disorders
Depressed mood 
disorders and 
disturbances
Mood alterations 
with depressive 
symptoms
Depressed mood
10012374
Psychiatric 
disorders
Depressed mood 
disorders and 
disturbances
Depressive 
disorders
Depression
10012378
Gastrointestinal 
disorders
Gastrointestinal 
motility and 
defaecation 
conditions
Diarrhoea (excl 
infective)
Diarrhoea
10012735
Psychiatric 
disorders
Mood disorders and 
disturbances
Emotional and 
mood disturbances 
NEC
Dysphoria
10013954
Nervous system 
disorders
Sleep disturbances 
(incl subtypes)
Sleep disturbances 
NEC
Dyssomnia
10061827
Psychiatric 
disorders
Sleep disorders and 
disturbances 
Dyssomnias
10061827
Psychiatric 
disorders
Depressed mood 
disorders and 
disturbances
Depressive 
disorders
Persistent 
depressive disorder
10077804
Psychiatric 
disorders
Depressed mood 
disorders and 
disturbances
Mood alterations 
with depressive 
symptoms
Feeling of despair
10016344
Nervous system 
disorders
Headaches
Headaches NEC
Headache
10019211
Table continued on next page


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System Organ 
Class
Higher Level GT
Higher Level 
Term
Preferred Term
Preferred Term 
Code
Skin and 
subcutaneous tissue 
disorders 
Skin appendage 
conditions
Apocrine and 
eccrine gland 
disorders
Hyperhidrosis
10020642
General disorders 
and administration 
site conditions
General system 
disorders NEC
General signs and 
symptoms NEC
10020642
Psychiatric 
disorders
Sleep disorders and 
disturbances 
Disturbances in 
initiating and 
maintaining sleep
Insomnia
10022437
Nervous system 
disorders
Sleep disturbances
Disturbances in 
initiating and 
maintaining sleep
10022437
Psychiatric 
disorders
Depressed mood 
disorders and 
disturbances
Mood alterations 
with depressive 
symptoms
Morose
10027977
Gastrointestinal 
disorders
Gastrointestinal 
signs and symptoms
Nausea and 
vomiting symptoms
Nausea
10028813
Psychiatric 
disorders
Depressed mood 
disorders and 
disturbances
Mood alterations 
with depressive 
symptoms
Negative thoughts
10058672
Psychiatric 
disorders
Anxiety disorders 
and symptoms
Anxiety symptoms
Nervousness
10029216
Psychiatric 
disorders
Anxiety disorders 
and symptoms
Obsessive-
compulsive 
disorders and 
symptoms
Obsessive thoughts
10029897
General disorders 
and administration 
site conditions
General system 
disorders NEC
Pain and discomfort 
NEC
Pain
10033371
Nervous system 
disorders
Sleep disturbances 
(incl subtypes)
Sleep disturbances 
NEC
Poor quality sleep
10062519
Psychiatric 
disorders
Sleep disorders and 
disturbances 
Dyssomnias
10062519
Cardiac disorders
Cardiac disorder 
signs and symptoms
Cardiac signs and 
symptoms NEC
Syncope
10042772
Vascular disorders
Decreased and 
nonspecific blood 
pressure disorders 
and shock
Circulatory collapse 
and shock
10042772
Nervous system 
disorders
Neurological 
disorders NEC
Disturbances in 
consciousness NEC
10042772
Psychiatric 
disorders
Sleep disorders and 
disturbances 
Disturbances in 
initiating and 
maintaining sleep
Terminal insomnia 
(lower level term of 
interest:  early 
morning 
awakening)
10068932
Nervous system 
disorders
Sleep disturbances
Disturbances in 
initiating and 
maintaining sleep
10068932
Table continued on next page


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System Organ 
Class
Higher Level GT
Higher Level 
Term
Preferred Term
Preferred Term 
Code
Nervous system 
disorders
Movement disorders 
(incl parkinsonism)
Tremor (excl 
congenital)
Tremor
10044565
Gastrointestinal 
disorders
Gastrointestinal 
signs and symptoms
Nausea and 
vomiting symptoms
Vomiting
10047700


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10.3
Appendix 3: Potentially Clinically Significant Laboratory Criteria
Potentially Clinically Significant Laboratory Criteria
Laboratory 
Parameter
Low PCS criteria 
(Classical unit)
High PCS 
criteria 
(Classical unit)
Conv. 
factor
Low PCS 
criteria 
(SI unit)
High PCS 
criteria 
(SI unit)
Hematology and Coagulation
Hemoglobin
< 7.0 g/dL
> 20.0 g/dL
10
< 70 g/L
> 200 g/L
Hematocrit
< 20.0 %
> 60.0 %
0.01
< 0.200 v/v 
(Fraction)
> 0.600 v/v 
(Fraction)
Leukocytes 
(White Blood Cell 
Count)
< 2.00 x103/µL
> 30.00 x103/µL
1
< 2.00 x109 /L
> 30.00 x109 /L
Platelets
< 40 x103/µL
> 1000 x103/µL
1
< 40 x109 /L
> 1000 x109 /L
International 
Normalized Ratio 
(INR)
No lower limit
> 2 (Ratio)
1
No lower limit
> 2.00 (Ratio)
Other Biochemistry*
Sodium
< 120 mEq/L
> 160 mEq/L
1
< 120 mmol/L
> 160 mmol/L
Potassium
< 2.8 mEq/L
> 6.2 mEq/L
1
< 2.8 mmol/L
> 6.2 mmol/L
Calcium
< 6.0 mg/dL
> 13.0 mg/dL
0.25
< 1.50 mmol/L
> 3.25 mmol/L
Chloride
< 80 mEq/L
> 120 mEq/L
1
< 80 mmol/L
> 120 mmol/L
Magnesium
< 0.98 mg/dL
> 4.74 mg/dL
0.4114
< 0.400 mmol/L
> 1.950 mmol/L
Glucose
< 40 mg/dL
> 450 mg/dL
0.0555
< 2.22 mmol/L
> 24.98 mmol/L
Creatinine
No lower limit
> 5.00 mg/dL
88.4
No lower limit
> 442.0 µmol/L
Uric Acid
No lower limit
> 13.0 mg/dL
59.48
No lower limit
> 773 µmol/L
Blood Urea 
Nitrogen (BUN)
No lower limit
> 80 mg/dL
0.357
No lower limit
> 28.6 mmol/L
Source: Tietz. Textbook of Clinical Chemistry and Molecular Diagnostics, 4th Edition. Elsevier Saunders, 2006, 
section VII, chapter 56, pages 2317-2318.
Conv.: Conversion; PCS: Potentially Clinically Significant; SI: International System of Units.
* PCS criteria for Liver Enzymes and Total Bilirubin are provided in Table 18, Section 7.5.3.1


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10.4
Appendix 4: Key contributors and Approvers
List of Key Contributors and Approvers
Key Contributors
The following contributed to or reviewed this Statistical Analysis Plan as relevant to their 
indicated discipline or role.
Primary author (s)
Contributors and Reviewers
Data Science
Medical Science
Data Science 
PPD
PPD
PPD
PPD
PPD


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Author and Approver Signatories 
Authored by:
Date (DD Mmm YYYY)
PPD