Clinical trial NCT03092726
Conditions: Fibromyalgia
Keywords: ASP8062 Fibromyalgia
Sponsor: Astellas Pharma Global Development, Inc.
Start date: 2017-05-08; Completion date: 2018-03-06
Enrollment: 183 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to assess analgesic efficacy of ASP8062 relative to placebo as well as the safety and tolerability. This study also assessed the treatment differences in physical function as well the improvements in overall subject status (e.g., fibromyalgia symptoms, global functioning) of ASP8062 relative to placebo.

Detailed description:

Arms: arm 1: Participants received 30 mg of ASP8062 orally once daily for 8 weeks. arm 2: Participants received matching placebo orally once daily for 8 weeks.
Interventions: intervention 1: ASP8062 intervention 2: Placebo
Intervention descriptions: intervention 1: ASP8062 30 mg was administered orally as a single daily dose, taken preferably in the morning with or without food. intervention 2: Placebo was administered orally as a single daily dose, taken preferably in the morning with or without food.

Protocol documents:
Prot_000.pdf: 
A Phase 2a, Randomized, Double-Blind Placebo-
controlled, Parallel-group Study to Assess the Analgesic 
Efficacy and Safety of ASP8062 in Subjects with 
Fibromyalgia
ISN/Protocol 8062-CL-0101
ClinicalTrials.gov Identifier: NCT03092726
Date of Protocol v1.2: 14 Aug 2017
Sponsor: Astellas Pharma Global Development
1 Astellas Way
Northbrook, IL 60062


A Phase 2a, Randomized, Double-Blind Placebo-
controlled, Parallel-group Study to Assess the Analgesic 
Efficacy and Safety of ASP8062 in Subjects with 
Fibromyalgia
ISN/Protocol 8062-CL-0101
ClinicalTrials.gov Identifier: NCT03092726
Date of Protocol v1.2: 14 Aug 2017
Sponsor: Astellas Pharma Global Development
1 Astellas Way
Northbrook, IL 60062


Sponsor: APGD
ISN/Protocol 8062-CL-0101
- CONFIDENTIAL -
14 Aug 2017
Astellas
Page 1 of 112
Version 1.2 Incorporating Nonsubstantial Amendment 2
A Phase 2a, Randomized, Double-Blind Placebo-controlled, 
Parallel-group Study to Assess the Analgesic Efficacy and Safety 
of ASP8062 in Subjects with Fibromyalgia
ISN/Protocol 8062-CL-0101
Version 1.2
Incorporating Non-Substantial Amendment 2 [See Attachment 1]
14 August 2017
IND 125639
Sponsor:
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062
Protocol History: 
Version 1.0 [19Dec2016]
Version 1.1 [30Mar2017] Incorporating Non-Substantial Amendment 1
-------------------------------------------------------------------------------------------------------------------------
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. 


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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
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································26
1
INTRODUCTION·················································································31
1.1
Background ····················································································31
1.2
Nonclinical and Clinical Data ·······························································32
1.3
Summary of Key Safety Information for Study Drugs ···································35
1.4
Risk Benefit Assessment ·····································································35
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ··································36
2.1
Study Objective(s) ············································································36
2.1.1
Primary Objectives······································································36
2.1.2
Secondary Objectives ···································································36
2.1.3
·································································36
2.2
Study Design and Dose Rationale···························································36
2.2.1
Study Design·············································································36
2.2.2
Dose Rationale···········································································39
2.3
Endpoints·······················································································39
2.3.1
Primary Endpoints·······································································39
2.3.2
Secondary Endpoints····································································40
2.3.3
··································································40
3
STUDY POPULATION··········································································42
3.1
Selection of Study Population ·······························································42
3.2
Inclusion Criteria··············································································42
3.3
Exclusion Criteria ·············································································44
4
TREATMENT(S)··················································································47
4.1
Identification of Investigational Product(s) ················································47
4.1.1
Study Drug ···············································································47
4.1.2
Comparative Drug·······································································47
4.1.3
Rescue Medication ······································································47


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4.2
Packaging and Labeling ······································································47
4.3
Study Drug Handling ·········································································47
4.4
Blinding ························································································48
4.4.1
Blinding Method·········································································48
4.4.2
Confirmation of the Indistinguishability of the Study Drugs ······················48
4.4.3
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking ··················································································48
4.4.4
Breaking the Treatment Code for Emergency ·······································49
4.4.5
Breaking the Treatment Code by the Sponsor ·······································49
4.5
Assignment and Allocation ··································································49
5
TREATMENTS AND EVALUATION························································50
5.1
Dosing and Administration of Study Drug(s) and Other Medication(s)················50
5.1.1
Dose/Dose Regimen and Administration Period ····································50
5.1.2
Increase or Reduction in Dose of the Study Drug(s)································50
5.1.3
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy) ··················································································50
5.1.4
Treatment Compliance··································································52
5.1.5
Restrictions During the Study··························································53
5.2
Demographics and Baseline Characteristics ···············································53
5.2.1
Demographics············································································53
5.2.2
Medical History··········································································53
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease··············53
5.2.4
Mini-International Neuropsychiatric Interview······································54
5.2.5
Hospital Anxiety and Depression Scale (depression subscale only) ··············54
5.3
Efficacy and Pharmacokinetics Assessments··············································55
5.3.1
Efficacy Assessments ···································································55
5.3.2
Pharmacokinetics Assessments························································57
5.4
Safety Assessment ············································································58
5.4.1
Vital Signs················································································58
5.4.2
Adverse Events ··········································································58
5.4.3
Laboratory Assessments································································58
5.4.4
Physical Examination···································································60
5.4.5
Electrocardiogram·······································································61
5.4.6
Colombia Suicide Severity Rating Scale ·············································61
5.4.7
Safety Narrative Plan ···································································61


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5.5
Adverse Events and Other Safety Aspects ·················································61
5.5.1
Definition of Adverse Events ··························································61
5.5.2
Definition of Serious Adverse Events·················································62
5.5.3
Special Situations········································································62
5.5.4
Criteria for Causal Relationship to the Study Drug ·································63
5.5.5
Criteria for Defining the Severity of an Adverse Event ····························63
5.5.6
Reporting of Serious Adverse Events·················································63
5.5.7
Follow-up of Adverse Events··························································65
5.5.8
Monitoring of Common Serious Adverse Events ···································65
5.5.9
Adverse Events of Special Interest ····················································65
5.5.10
Procedure in Case of Pregnancy·······················································65
5.5.11
Emergency Procedures and Management of Overdose ·····························66
5.5.12
Supply of New Information Affecting the Conduct of the Study··················66
5.6
Test Drug Concentration ·····································································66
5.7
Other Measurements, Assessments or Methods ···········································67
5.7.1
Blood Sample for Future Pharmacogenomics Analysis (Retrospective 
Pharmacogenomics Analysis) (Optional)·············································67
5.7.2
Subject Training Materials ·····························································67
5.8
Total Amount of Blood·······································································67
6
DISCONTINUATION············································································67
6.1
Discontinuation of Individual Subject(s)···················································67
6.2
Discontinuation of the Site···································································68
6.3
Discontinuation of the Study·································································68
7
STATISTICAL METHODOLOGY ···························································69
7.1
Sample Size····················································································69
7.2
Analysis Sets···················································································69
7.2.1
Full Analysis Set ········································································69
7.2.2
Per Protocol Set··········································································70
7.2.3
Safety Analysis Set······································································70
7.3
Demographics and Baseline Characteristics ···············································70
7.3.1
Subject Disposition······································································70
7.3.2
Previous and Concomitant Medications ··············································70
7.3.3
Medical History··········································································70
7.4
Analysis of Efficacy ··········································································71


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7.4.1
Analysis of Primary Endpoint ·························································71
7.4.2
Analysis of Secondary Endpoints ·····················································72
7.4.3
····················································73
7.5
Analysis of Safety·············································································75
7.5.1
Adverse Events ··········································································75
7.5.2
Laboratory Assessments································································75
7.5.3
Vital Signs················································································75
7.5.4
Electrocardiograms······································································76
7.5.5
Columbia Suicide Severity Rating Scale ·············································76
7.5.6
Analysis of Pharmacokinetics··························································76
7.6
Protocol Deviations ···········································································76
7.7
Interim Analysis (and Early Discontinuation of the Clinical Study)····················76
7.8
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········76
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················77
8.1
Procedure for Clinical Study Quality Control ·············································77
8.1.1
Data Collection ··········································································77
8.1.2
ePRO······················································································77
8.1.3
Specification of Source Documents···················································78
8.1.4
Clinical Study Monitoring······························································78
8.1.5
Direct Access to Source Data/Documents············································78
8.1.6
Data Management ·······································································79
8.1.7
Protocol Deviations ·····································································79
8.1.8
End of Trial in All Participating Countries···········································79
8.2
Ethics and Protection of Subject Confidentiality··········································80
8.2.1
Institutional Review Board/Competent Authorities ·································80
8.2.2
Ethical Conduct of the Study···························································80
8.2.3
Informed Consent of Subjects ·························································80
8.2.4
Subject Confidentiality and Privacy···················································81
8.3
Administrative Matters ·······································································82
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ·····82
8.3.2
Documents and Records Related to the Clinical Study ·····························82
8.3.3
Protocol Amendment and/or Revision················································83
8.3.4
Signatory Investigator for Clinical Study Report····································83
9
QUALITY ASSURANCE········································································84


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10
STUDY ORGANIZATION······································································84
10.1
Data Monitoring Committee·································································84
10.2
Interim Analysis [and Early Discontinuation of the Study]). ····························84
10.3
Other Study Organization ····································································84
11
REFERENCES ····················································································85
12
APPENDICES ·····················································································88
12.1
List of Excluded Concomitant Medications - Excluded Medications with 
Efficacy or Potential Efficacy in Fibromyalgia Pain······································88
12.2
List of Allowed Anti-depressants and Sleep Aids·········································92
12.3
Liver Safety Monitoring and Assessment ··················································93
12.4
Common Serious Adverse Events···························································96
12.5
Retrospective Pharmacogenomics Sub-Study ·············································97
12.6
Questionnaires·················································································99
12.7
Adverse Events of Interest Related to Abuse ············································ 100
12.8
Drug Withdrawal – Related Adverse Events Occurring Following Drug 
Discontinuation (Preferred Terms; MedDRA 18.0)····································· 104
13
ATTACHMENT 1:  NON-SUBSTANTIAL AMENDMENT 2························· 107
14
COORDINATING INVESTIGATOR’S SIGNATURE·································· 111
15
SPONSOR’S SIGNATURES·································································· 112


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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].


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2. COORDINATING INVESTIGATOR’S SIGNATURE 
The Coordinating Investigator’s signature can be found in [Section 14 Coordinating 
Investigator’s Signature]; located at the end of this document.


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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 ASP8062 in Subjects with 
Fibromyalgia
ISN/Protocol 8062-CL-0101 
Version 1.2 / Incorporating Nonsubstantial Amendment 2
14 August 2017
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
APGD
Astellas Pharma Global Development, Inc.
AST
Aspartate aminotransferase (GOT)
BMI
Body mass index
BOCF
Baseline observation carried forward
Cmax
Maximum concentration
CMSI
Complex Medical Symptoms Inventory
CRF
Case report form
CRO
Contract research organization
CSF
Cerebrospinal fluid
C-SSRS
Columbia-Suicide Severity Rating Scale
ECG
Electrocardiogram
eCRF
Electronic case report form
EOS
End of study
EOT
End of treatment
ePRO
Electronic patient reported outcome
FAS
Full analysis set
FIQ
Fibromyalgia Impact Questionnaire
FIQR
Fibromyalgia Impact Questionnaire Revised
GCP
Good clinical practice
GMP
Good manufacturing practices
HADS
Hospital Anxiety and Depression Scale
HBsAg
Hepatitis B surface antigen
IB
Investigator’s brochure
ICF
Informed consent form
ICH 
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IDMC
Independent Data Monitoring Committee
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
LOCF
Last observation carried forward
mBOCF
Modified Baseline Observation Carried Forward
M.I.N.I.
Mini-International Neuropsychiatric Interview


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Abbreviations
Description of abbreviations
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed model repeated measures
NRS
Numerical rating scale
NSAID
Nonsteroidal anti-inflammatory drug
PGIC
Patient global impression of change
PGIS
Patient global impression of severity
PGx
Pharmacogenomics
PKAS
Pharmacokinetic analysis set
PPS
Per protocol set
PRO
Patient reported outcome
 
PSG
Polysomnography
QD
Quaque die (once daily)
SAE
Serious adverse event
SAF
Safety analysis set
SOP
Standard operating procedure
SS
Symptom severity
SUSAR
Suspected unexpected serious adverse reactions
SWS
Slow Wave Sleep
t ½
Terminal elimination half-life
TBL
Total bilirubin
TEAE
Treatment emergent adverse event 
tmax
Time of maximum concentration 
ULN
Upper limit of normal
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 NRS 
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: 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 is now considered non-standard.
Endpoint 
Variable that pertains to the efficacy or safety evaluations of a trial.
Enroll
To register or enter a subject into a clinical trial. NOTE: Once a subject has 
signed the informed consent, 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 electronic patient-reported outcome (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, 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 consent 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 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:
14 August 2017, Version 1.2
Sponsor:  
Astellas Pharma Global Development Inc (APGD)
Protocol Number:
8062-CL-0101
Name of Study Drug:
ASP8062
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 ASP8062 in Subjects with Fibromyalgia
Planned Study Period: 
From 2Q2017 to 3-4Q2018 
Study Objective(s):
The objectives of the study, conducted in subjects with fibromyalgia, are the following:
Primary Objectives

Assess analgesic efficacy of ASP8062 relative to placebo. 

Assess the safety and tolerability of ASP8062 relative to placebo.
Secondary Objectives 

Assess treatment differences in physical function of ASP8062 relative to placebo.

Assess the improvements in overall subject status (e.g., fibromyalgia symptoms, global 
functioning) of ASP8062 relative to placebo. 
 
 
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 / Randomized:  
Approximately 356 subjects are planned to be screened for 178 randomized subjects (89/arm) (50% 
screen fail rate).




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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. 
Subjects will take study drug
once per day (QD). Subjects randomized to ASP8062 will receive 30 mg (1 tablet of 25 mg and 1 
tablet of 5 mg). In order to maintain the study blind, ASP8062 and placebo treated subjects will 
receive matching tablets. 
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. Subjects are encouraged to abstain from alcohol. Rescue medication is allowed 
during the follow-up period. Subjects will continue to enter their daily average pain score (NRS), 
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., 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:
Postmenopausal (defined as at least 1 year without any menses) prior to Screening, or, 
Documented as surgically sterile (e.g., hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy).
Or, if of childbearing potential, 
Agree not to try to become pregnant during the study and for 28 days after the final 
study drug administration,
Have a negative blood pregnancy test at Screening and negative urine test on Day 1,
And 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.
7.
Male subject must not donate sperm starting at Screening and throughout the study period, and for 
90 days after the final study drug administration.


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8.
A sexually active male subject with female partner(s) who are of childbearing potential is eligible 
if:
Agree to use a male condom starting at screening and continue throughout study treatment 
and for 90 days after the final study drug administration. If the male subject has not had a 
vasectomy or is not sterile as defined below their female partner(s) is utilizing 1 form of 
highly effective birth control* starting at screening and continue throughout study 
treatment, and for 90 days after the male subject receives their final study drug 
administration.
9.
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 90 days after 
the final study drug administration.
10. 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:
i.
Pain on right and left sides of the body.
ii.
Pain above and below the waist.
iii.
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.
i.
Digital palpation should be performed with an approximate force of 4 kg. 
11. 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. 
12. Subject has a pain score ≥ 4 on the revised fibromyalgia impact questionnaire (FIQR) pain item at 
Screening.
13. 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.
14. 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.
15. 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). 
16. 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. And subject agrees to maintain usual level of activity for the duration 
of the study.
17. Subject is capable of completing study assessments and procedures, in the opinion of the 
Investigator.
18. 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 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.
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 ASP8062.
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 (for example, rheumatoid arthritis, ankylosing 
spondylitis, psoriatic arthritis, gout), autoimmune disease (for example, 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 judged by the Investigator at Screening and at the time of 
Visit 3 (Randomization).


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11. Subject has clinically significant abnormalities in clinical chemistry, hematology, or urinalysis, or 
a serum creatinine > 1.5x 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 > 180 mmHg or < 90 mmHg, and/or a sitting 
diastolic blood pressure > 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 device) neurologic, dermatologic, 
psychiatric, renal and/or other major disease (exclusive of fibromyalgia), as judged 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. 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, 
including over-the-counter (OTC) products and grapefruit and/or grapefruit juice. [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.


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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.
Investigational Product(s):
ASP8062 5 and 25 mg tablets
Dose(s):  
30 mg QD (1 x 25 mg tablet and 1 x 5 mg tablet).
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 ASP8062 tablets.
Dose(s):
2 placebo to match ASP8062 tablets.
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 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 case report form 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 case report form.
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:
Nonsteroidal anti-inflammatory drugs (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), for example: gabapentinoids, antidepressants (except for selective serotonin 
reuptake inhibitors), ketamine, 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.
●
CYP3A4 inhibitors (including most protease inhibitors, most antifungals, calcium channel 
blockers, cimetidine, select antibiotics, grapefruit and/or grapefruit juice).
●
CYP3A4 inducers (including phenytoin, carbamazepine, and St. John’s wort).
●
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, 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.
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, 
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 to 10 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, massage therapy.
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.








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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-Indd
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
X
Medical/Surgical History
X
Xc
Medication History and Concomitant 
Medication
X
FM Diagnosis (ACR 1990 & 2010)  
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
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x)
Fibromyalgia Impact Questionnaire Revised (FIQR) will be completed by the subject at screening, randomization and at week 2, 4, 8/EOT and week 10/follow up visits. At 
screening, subject only completes the item for pain of the FIQR.
y)
z)
Columbia Suicide Severity Rating Scale (C-SSRS). Questionnaire will be facilitated by the Principal Investigator/Site staff, as appropriately trained, at screening, 
randomization,  weeks 2, 4, 8/EOT, and week 10/follow up 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 will be collected from the time of signing the informed consent through 4 weeks post-last dose.
dd) 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.


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1
INTRODUCTION
Protocol 8062-CL-0101 is a proof-of-concept study to examine the effects of ASP8062 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, 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 (US: pregabalin, duloxetine, 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, clinical studies support the hypothesis that 
increased glutamate or decreased GABA within the posterior insula may be related to 
apparent central sensitization in FM pathophysiology [Foerster et al., 2012; Harris et al., 
2009; Harris et al., 2008].
Background on Pharmacological Concept
γ-aminobutyric acid (GABA), the most abundant inhibitory neurotransmitter, activates 
2 types of receptors: ionotropic GABA type A (GABAA) receptors [Olsen & Sieghart, 2008] 
and metabotropic GABAB receptors [Bowery et al, 2002]. Based on evidence from GABAB
receptor agonists (baclofen and sodium oxybate [SXB]), stimulation of GABAB receptors 
may constitute a putative new target in treating disorders such as fibromyalgia [Russell et al, 
2011]. A double-blind, placebo-controlled randomized fibromyalgia clinical trial with the 


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GABAB receptor agonist SXB provides promise that optimal activation of GABAB receptors 
might result in clinically significant improvements in efficacy for patients with fibromyalgia
compared to currently available treatments [Spaeth et al, 2012; Russell et al, 2011; Russell et 
al, 2009]. However, the muscle relaxant, bradycardia-inducing and sedative properties of 
baclofen and SXB limit their potential widespread therapeutic utility [Dario & Tomei, 2004; 
Chin et al, 1998]. One possible alternative approach is the use of positive allosteric modulator
(PAM) [Ong & Kerr, 2005]. They positively modulate the effect of the agonist by binding to 
an allosteric site without directly stimulating the receptor and are, therefore, expected to exert 
agonist-like activity with lower incidence of undesirable side effects [May et al, 2004].
Animal studies have established the antinociceptive action of GABAB receptor agonists, 
probably by effects on both spinal cord and brain [Bowery et al, 2002]. Altered spinal GABA 
levels may contribute to the induction phase of chronic pain [Eaton et al, 1999]; and lowering 
GABA levels within the insula is reported to enhance pain in an animal model [Jasmin et al, 
2003].
In a clinical study, patients with fibromyalgia had significantly decreased GABA levels in the 
right anterior insula versus the levels seen in healthy volunteers [Foerster et al, 2012]. 
Diminished inhibitory neurotransmission resulting from lower concentrations of GABA 
within the brain may play a role in the pathophysiology of fibromyalgia, suggesting the 
activation of GABA transmission can be a possible therapeutic approach against fibromyalgia. 
These concepts are supported by clinical efficacy of SXB on pain, fatigue, sleep disturbance 
and functionality in fibromyalgia patients [Russell et al, 2011].
Rationale for Clinical Trial with ASP8062
ASP8062 is an orally available small-molecule with GABAB receptor-PAM activity 
discovered by Astellas Pharma Inc. In the reserpine-induced myalgia model, a rat model of 
fibromyalgia [Nagakura et al, 2009], ASP8062 significantly recovered the decrease in muscle 
pressure threshold via the potentiation of GABAB receptor function. Based on nonclinical 
studies, ASP8062 may effectively ameliorate fibromyalgia while minimizing side effects 
seen with GABAB agonists. Double-blind, placebo-controlled randomized fibromyalgia
clinical trials with the GABAB receptor agonist SXB provides promise that optimal activation 
of GABAB receptors might result in clinically significant improvements in efficacy for 
patients with fibromyalgia compared to currently available treatments [Spaeth et al, 2012; 
Russell et al, 2011; Russell et al, 2009].
1.2
Nonclinical and Clinical Data
ASP8062 is an orally available, new molecular entity discovered by Astellas Pharma Inc. 
ASP8062 is a GABAB receptor positive allosteric modulatory (PAM) with activity in the 
CNS. Three Phase I clinical trials have been completed to date prior to initiation of the 8062-
CL-0101 study: the single ascending dose (SAD) study (8062-CL-0001), the multiple 
ascending dose (MAD) study (8062-CL-0002) and the single dose polysomnography study 
(8062-CL-0003). The 3 studies included healthy male and female subjects.


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Clinical Pharmacokinetics
In general, the pharmacokinetic properties of ASP8062 administered at doses of 1-30 mg 
once daily QD for 14 days were similar to single doses of ASP8062. Tmax values were in the 
same range as single doses (1.5 to 3 hours) and were not dose dependent, suggesting 
absorption is consistent following single or multiple dosing. Accumulation following 
multiple doses was predictable and was approximately 2 to 3-fold for AUC. Steady-state 
conditions were observed for all dose levels following approximately 9 days of dosing. The 
terminal half-life was moderately long with on average t1/2 approximately 65 hours. This is
consistent with single dose t1/2 values suggesting no evidence of time variant 
pharmacokinetics (e.g., auto-induction or auto-inhibition). Based on statistical testing of the 
power model slope, AUC24 and Cmax were dose proportional across a 1-30 mg QD dose at 
steady-state. Following 14-days of 30 mg QD dosing the predefined mean AUC24
(2339 ng*hr/mL) exposure limit was approached with one subject having exceeded this 
AUC24 value. No individual subjects exceeded the mean Cmax limit of 247 ng/mL after a 
single dose of 70 mg or multiple doses of 30 mg QD. Given the comparable PK profiles and 
predictable accumulation, a 70 mg single dose would provide comparable exposures to a 
30 mg QD dose at steady-state. 
Continuous CSF (cerebrospinal fluid) sampling over 24-hours following a 10 mg or 30 mg 
ASP8062 single dose showed approximately 1% penetration into the CSF based on AUC 
comparisons of CSF and plasma. Since ASP8062 is 2% unbound to plasma protein, and only 
unbound ASP8062 will enter the CSF, these data suggest most unbound drug enters the CSF 
following a single dose. Finally, no significant effect of a high-fat meal was seen on either 
AUC or Cmax at 10 mg supporting dosing with or without food in future studies.
Clinical Safety
Ninety-four unique subjects have received single or multiple doses of ASP8062 in the 3 Phase 
1 studies (e.g., single ascending dose with food-effect cohort, multiple ascending dose with 
single dose CSF cohort, single dose polysomnography study) completed prior to the 8062-CL-
0101 study. Twenty-four subjects were exposed to placebo alone. Overall, ASP8062 was well 
tolerated in all subjects. There were no deaths, no SAEs reported or discontinuations due to 
TEAEs. All AEs were transient and mild or moderate in severity. The most common possibly 
drug-related TEAEs observed in subjects during phase 1 studies were headache, dizziness and 
lightheadedness. These TEAEs occurred more often following multiple doses of 10 mg (4 
AEs) and 30 mg (7 AEs) suggestive of dose dependency. No ASP8062-related findings 
suggestive of hepatic, cardiovascular, or hematopoietic safety issues in AEs, changes in 
laboratory parameters, or vital changes were observed. No effect on QTc or exposure/QTc 
relationship was observed. No withdrawal effects were seen based on review of AEs, 
cognition assessments, and Clinical Institute Withdrawal Assessment for benzodiazepines 
(CIWA-B) after dosing was completed. There was no impact to mood or subjective effects 
(including abuse liability) or a potential effect on (causing/triggering) suicidal ideation or 
behavior based on review of AEs, Bond-Lader, Addiction Research Center Inventory (ARCI)
or Columbia-Suicide Severity Rating Scale (C-SSRS). A single subject did report a buzzed 


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feeling during most days of ASP8062 administration, however the report was only made 
during the follow-up outpatient visit. Safety and tolerability data from phase 1 studies in 
healthy male and female subjects show that ASP8062 is well-tolerated. 
Clinical PSG Data
Changes in slow-wave (stage N3) or rapid eye movement (REM) sleep as well as increases in 
EEG delta band power have previously been seen following GABAB agonist dosing in 
preclinical rodent studies, and similarly in clinical studies of healthy volunteers and 
narcolepsy patients. Since ASP8062 is a positive allosteric modulator for the GABAB
receptor, activity on these endpoints in the clinic would provide evidence that ASP8062 can 
lead to modulation of GABAB receptors in the human brain. The 8062-CL-0003 
polysomnography (PSG) study was a 4 period crossover designed trial with single doses of
35 mg ASP8062, 70 mg ASP8062, 40 mg paroxetine or placebo administered on day 1 of 
each period to 20 healthy male or female volunteers. Following each nightly dose of study 
drug polysomnographic and sleep electroencephalogram (EEG) measures were taken over the 
subsequent 8 hrs of sleep. A minimum 14 day washout period occurred between periods. The 
primary objective of the polysomnography study was to evaluate the effects of a single dose 
of ASP8062 on stage N3 (slow-wave sleep) and REM sleep in healthy subjects. Preliminary 
results showed a dose dependent significant increase in duration of the primary endpoint, N3,
over the whole night of sleep (Figure 1) following both the 35 mg (p=0.072) and 70 mg 
(p=0.006) single dose. These data are further supported by a significant (p<0.1) increase in 
N3 duration (35 mg and 70 mg) and % N3 (70 mg) over the first third of the night when the 
majority of slow-wave sleep occurs. Secondary measures, usually associated with slow-wave 
sleep changes: time spent in stage N1 and number of awakenings showed significant or 
directional trends which are consistent with clinical findings with the GABAB agonist sodium 
oxybate. Interestingly, contrary to preclinical findings, no significant effect of ASP8062 on 
REM sleep, the other primary endpoint, was present at either dose over the whole night of 
recording. Finally, Paroxetine 40 mg was included as an active control in the study given its 
known effects on REM reduction. A significant (p<0.001) reduction on total minutes REM 
sleep was seen following single dose 40 mg paroxetine both in whole night, and over various 
thirds of the night showing assay sensitivity.


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Figure 1
Mean (+SD) of slow wave sleep (stage N3) duration (minutes) over the 
whole night of PSG recordings
Please refer to the IB for detailed information from nonclinical and clinical studies.
1.3
Summary of Key Safety Information for Study Drugs
Given the early stage of development, there are currently no expected adverse events (AEs) 
for ASP8062.
ASP8062 may be associated with Treatment Emergent Adverse Events (TEAEs) based on the 
nonclinical studies. The following were key non-clinical observations: headache, dizziness 
and lightheadedness. (Refer to the IB for detailed information).
1.4
Risk Benefit Assessment
No clinical efficacy studies have been conducted to date with ASP8062 in the treatment of 
pain associated with fibromyalgia: therefore, the actual benefit of ASP8062 in the treatment 
of pain associated with fibromyalgia is unknown. There are no known risks identified with 
this mechanism of action, as ASP8062 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 ASP8062 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. The potential risks 
are reversible, therefore, no additional safety monitoring is required. 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. Please see section 2.2.2
Dose Rationale for safety margins relative to non-clinical toxicology.


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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 ASP8062 relative to placebo. 

Assess the safety and tolerability of ASP8062 relative to placebo.
2.1.2
Secondary Objectives 

Assess treatment differences in physical function of ASP8062 relative to placebo.

Assess the improvements in overall subject status (e.g., fibromyalgia symptoms, global 
functioning) of ASP8062 relative to placebo. 
2.1.3
 
 
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 ASP8062 in subjects with fibromyalgia. 
The study will be conducted in the US in up to approximately 35 sites. Approximately 356
subjects are planned to be screened for 178 randomized subjects (89/arm) (50% 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.


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
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 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 18).  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.
Subjects who meet the eligibility 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]) 
 
 in the e-diary. They will receive instructions regarding its 
use and begin entering daily scores.
 
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 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, electrocardiogram (ECG), pregnancy test, HADS, C-SSRS, 
 


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PGIS, 
 FIQR, 
 and 
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. A single 
pharmacokinetic sample will be taken on day 1 in the clinic at approximately 1-4 hour(s) 
after dosing and once at each visit during weeks 2, 4 and 8/EOT. PK samples at weeks 2, 4, 
and 8/OT should be evenly split between the following 3 sampling windows: before dosing, 
1-4 hours post dose and >4 hours post dose. Time of the last dose and time of sample 
collection will be captured in the eCRF during these visits.
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 
ASP8062 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 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. Subjects are 
encouraged to abstain from alcohol.
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. 
 
 Subjects will take study drug once per day (QD). Subjects randomized to 
ASP8062 will receive 30 mg (1 tablet of 25 mg and 1 tablet of 5 mg). In order to maintain the 
study blind, placebo treated subjects will receive matching tablets. 
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. Subjects are encouraged to abstain from alcohol. 
Rescue medication is allowed during the follow-up period. Subjects will continue to enter 
their daily average pain score (NRS), 
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).


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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 ASP8062 will be assessed at a dose of 30 mg QD over a period of 
8 weeks.
The dose for the 8062-CL-0101 study is 30 mg QD. This dose is based on collective Phase 1 
experiences with regard to safety, tolerability, PK, biomarker response, and modeling and 
simulation. Importantly, the modeled steady state AUC24 for 30 mg QD (2017 ng*hr/mL) is 
similar to the 70 mg single dose AUC24, the highest dose tested in the polysomnography 
study (8062-CL-0003). ASP8062 exposures following the 70 mg single dose resulted in 
statistically significant increases in Slow Wave Sleep (SWS) (N3) compared to placebo; 
suggesting ASP8062 can enter the brain and lead to modulation of the GABAB receptor at 
these exposures. In addition, the modeled Ctrough (mean 55 ng/mL) following a 30 mg QD 
dose is well above the exposures in a rat vagotomy FM model (EC80 = 0.488 ng/mL).
Regarding safety and tolerability of ASP8062, modeling and simulation of anticipated human 
Cmax (100 ng/mL) and AUC24 (2017 ng.hr/mL) mean exposures following a 30 mg QD dose 
fall below the previously defined human mean exposure limits, 247 ng/mL and 
2339 ng*hr/mL respectively. These limits were approached in the highest SAD cohort 
(70 mg) and MAD cohort (30 mg QD) and were not associated with any safety or tolerability 
concerns. 
The 4 and 13-wk dog toxicology studies both identified the 3 mg/kg dose as a NOAEL. 
LOEALs (10 mg/kg) in these studies were both defined by vomiting and salivation in the 
dogs, the most sensitive toxicological species. These findings were reversible during the 4-
week recovery period and are monitorable in the clinical studies. There is approximately a 
2-3-fold and 4-fold safety margin to the LOAELs AUC24 and Cmax exposures respectively, 
compared to the observed mean AUC24 from a 30 mg QD dose in the MAD study. AUC24
and Cmax safety margins to the 13-week toxicology NOAELs are 1- and 2-fold respectively.
Thus, a dose of 30 mg QD should provide exposures which have shown pharmacological 
activity at the GABAB receptor on PSG endpoints but still be 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.


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Safety and Tolerability Endpoints
●
Treatment-emergent adverse events (AEs)/serious adverse events (SAEs) from 
Screening until EOS.
●
Safety laboratory tests at Weeks 2, 4, 8 and 10
●
Vital signs 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 Patient Global Impression of Change (PGIC) 
at Weeks 2, 4, 8, and EOT. 
2.3.3
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 Informed Consent and privacy 
language as per national regulations (e.g., HIPAA Authorization for U.S. 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:
●Postmenopausal (defined as at least 1 year without any menses) prior to 
Screening, or, 
●Documented surgically sterile (e.g., hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy).
●
Or, if of childbearing potential, 
●Agree not to try to become pregnant during the study and for 28 days after the 
final study drug administration,
●Have a negative blood pregnancy test at Screening and negative urine test on 
Day 1,
●And 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
7.
Male subject must not donate sperm starting at Screening and throughout the study 
period, and for 90 days after the final study drug administration.
8.
A sexually active male subject with female partner(s) who are of childbearing potential 
is eligible if:
●Agree to use a male condom starting at screening and continue throughout study 
treatment and for 90 days after the final study drug administration. If the male 


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subject has not had a vasectomy or is not sterile as defined below their female 
partner(s) is utilizing 1 form of highly effective birth control* starting at screening 
and continue throughout study treatment, and for 90 days after the male subject
receives their final study drug administration.
9.
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 90 days after the final study drug administration. 
10. 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:
i.
Pain on right and left sides of the body.
ii.
Pain above and below the waist.
iii.
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.
ii.
Digital palpation should be performed with an approximate force of 4 kg. 
11. 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. 
12. Subject has a pain score ≥ 4 on the revised fibromyalgia impact questionnaire (FIQR) 
pain item at Screening.
13. 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.
14. 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.
15. 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). 
16. 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. And subject agrees to maintain 
usual level of activity for the duration of the study.


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17. Subject is capable of completing study assessments and procedures, in the opinion of the 
Investigator.
18. Subject agrees not to participate in another interventional study from Screening through 
the EOS visit.
* 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 ASP8062.
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 (for example, rheumatoid arthritis, 
ankylosing spondylitis, psoriatic arthritis, gout), autoimmune disease (for example, 
systemic lupus erythematosus), or other widespread rheumatic disease other than 
fibromyalgia.


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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 judged 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 > 1.5x 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 > 180 mmHg or < 90 mmHg, and/or a 
sitting diastolic blood pressure > 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.


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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 device) neurologic, dermatologic, psychiatric, renal and/or other major 
disease (exclusive of fibromyalgia), as judged 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 including over-the-counter (OTC) products and grapefruit and/or grapefruit 
juice [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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4
TREATMENT(S)
4.1
Identification of Investigational Product(s)
4.1.1
Study Drug
The test drug ASP8062 will be supplied as 5 mg round, reddish yellow film-coated tablets 
and 25 mg oval, reddish yellow film-coated tablets. For storage conditions, see label text.
4.1.2
Comparative Drug
Matching placebo tablets 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 FM. Rescue medication use will be captured in the e-diary. NSAIDs will be 
allowed, as needed for non-fibromyalgia pain; see section 5.1.3 Concomitant Medications.
Doses:
The maximum amount of acetaminophen is up to 1000 mg per dose, 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 Astellas  or Sponsor’s designee in accordance with Astellas 
or Sponsor’s designee Standard Operating Procedures (SOPs), Good Manufacturing Practice 
(GMP) guidelines, ICH 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.


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●
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 
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 ASP8062 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).
The randomization list will be provided to Global Pharmacovigilance of Astellas, who will 
break the codes for all suspected unexpected serious adverse reaction cases for reporting 
purposes only. They are also capable of breaking the code in emergency situations. The 
randomization list is also provided to BioAnalysis Scientist for the purposes of PK analysis 
prior to unblinding.  The PK analysis results will not be shared prior to unblinding at 
database lock. 
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).


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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 
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 Interactive Response Technology (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 ASP8062 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.


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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 ASP8062 group will receive ASP8062 30 mg (1 tablet of 25 mg 
and 1 tablet of 5 mg) QD for the duration of 8 weeks. Subject randomized to the placebo 
group will receive placebo to match ASP8062 (2 tablets) 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.
Subjects should be reminded not to drive and/or operate machinery within 4 hours of dosing, 
this applies only to the 1st dose of study drug. 
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. 
A single pharmacokinetic sample will be taken on day 1 in the clinic at approximately 
1-4 hour(s) after dosing and once at each visit during weeks 2, 4 and 8/EOT. PK samples at 
weeks 2, 4, and 8/OT should be evenly split between the following 3 sampling windows: 
before dosing, 1-4 hours post dose and >4 hours post dose. Time of the last dose and time of 
sample collection will be captured in the eCRF during these visits. 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 electronic case report form (eCRF). 
5.1.2
Increase or Reduction in Dose of the Study Drug(s)
The dose of 30 mg QD of ASP8062 was tested in the Phase 1 multiple dose study 
(30 mg QD). This 30 mg QD dose was well tolerated and no maximum tolerated dose was 
determined. Stopping criteria are presented in Section 6.1. Study 8062-CL-0101 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 case report form as prior 
fibromyalgia medications or other prior medication, respectively. Subjects taking prohibited 
medications who are willing to discontinue these medications, as clinically indicated and


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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 case report form 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 case 
report form.
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 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), for example: gabapentinoids, antidepressants (except for serotonin 
reuptake inhibitors), ketamine, 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.
●
CYP3A4 inhibitors (including most protease inhibitors, most antifungals, calcium 
channel blockers, cimetidine, select antibiotics, grapefruit and/or grapefruit juice).
●
CYP3A4 inducers (including phenytoin, carbamazepine, and St. John’s wort).
●
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, 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.


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Please 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). 
●
Please 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. 
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. 


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5.1.5
Restrictions During the Study
Subjects are encouraged to abstain from alcohol. Subjects are requested not to eat grapefruit 
and/or drink grapefruit juice (see exclusion criteria 22). 
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, long QT syndrome, depression and bipolar 
disorder 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, date 
of onset of fibromyalgia symptoms, 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.
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 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. 


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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 DSM-V and 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, 
1997; Lecrubier et al, 1997; Sheehan et al, 1998; Amorim et al, 1998].
The M.I.N.I. 7.0 will be completed at Screening on paper by trained site personnel, in 
accordance with the structured interview requirements.
5.2.5
Hospital Anxiety and Depression Scale (depression subscale only)
The 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.


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5.3
Efficacy and Pharmacokinetics Assessments
5.3.1
Efficacy Assessments
The subjects will use a handheld device, e-diary, to report daily average pain NRS scores, 
 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, 
 will be reported on a tablet device [see also 
Appendix 12.6]. 
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.
5.3.1.1 Daily Average Pain Numerical Rating Scale
The Daily Average Pain Numerical Rating Scale (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 
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.
 
 
 
 
 
 
 
 


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5.3.1.3 Fibromyalgia Impact Questionnaire Revised
The 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 numerical rating scale, 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. 
5.3.1.4 Patient Global Impression of Change  and Patient Global Impression of 
Severity
The Patient Global Impression of Change (PGIC) and Patient Global Impression of Severity 
(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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5.3.2
Pharmacokinetics Assessments
A single pharmacokinetic sample will be taken on day 1 in the clinic at approximately 
1-4 hour(s) after dosing and once at each visit during weeks 2, 4 and 8/EOT. PK samples at 
weeks 2, 4, and 8/OT should be evenly split between the following 3 sampling windows: 
before dosing, 1-4 hours post dose and >4 hours post dose. Time of the last dose and time of 


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sample collection will be captured in the eCRF during these visits, 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 ASP8062 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.
ASP8062 penetrates the CNS in humans; therefore, a prospective assessment of suicidality 
will be performed using the C-SSRS.
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 
adverse event 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 Tests value [(LFT), 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.
Clinical significance of out-of-range laboratory findings is to be determined and documented 
by the investigator/sub-investigator who is a qualified physician.


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Panel
Visits
Parameters to be analyzed
Hematology
and
Coagulation
Screening, Randomization, 
Weeks 2, 4, 8/EOT and 10
Hemoglobin,
Hematocrit,
Erythrocytes (red blood cell),
Leukocytes (white blood cell),
Differential white blood cell
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,
Lactate dehydrogenase (LDH),
Aspartate transaminase (AST),
Alanine transaminase (ALT),
Gamma glutamyl transpeptidase (GGT),
Total bilirubin (direct and indirect),
Total protein,
Albumin,
Total cholesterol,
Triglycerides,
Uric Acid,
Blood Urea Nitrogen (BUN),
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,
Blood,
Urobilinogen,
Bilirubin,
Ketones,
Potassium
Table continued on next page


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Panel
Visits
Parameters to be analyzed
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 
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 adverse event.


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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 Columbia Suicide Severity Rating Scale (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, 
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.
5.4.7
Safety Narrative Plan 
The subject narratives will be detailing potential signals of abuse, for more details please 
refer to Appendix 12.7 and 12.8
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 30 days 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 adverse events 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 


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eCRF or electronic data source. If the AE meets the definition of serious, these SAEs are to 
be collected via the 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 outside what is stated in the protocol 
X
Overdose* of the medicinal product(s) (see 
Section 5.5.11 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. 
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 adverse event

Mild: 
No disruption of normal daily activities

Moderate: Affect normal daily activities

Severe: 
Inability to perform daily activities
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. 


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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:
 
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), 

Causal relationship to the study drug, and
The Sponsor or Sponsor's designee will submit expedited safety reports (e.g., IND Safety 
Reports, Council for International Organizations of Medical Sciences-I) to the regulatory 
agencies (e.g., FDA, EMA) per current local regulations, and will inform the investigators of 
such regulatory reports as required. Investigators must submit safety reports as required by 
their Institutional Review Board (IRB) within timelines set by regional regulations (e.g., EU, 
(e)CTD, FDA) where required. Documentation of the submission to and receipt by the IRB 
of expedited safety reports should be retained by the site.
The Sponsor will notify all investigators responsible for ongoing clinical studies with the 
study drug of all SUSARs which require submission per local IRB requirements.
The investigators should provide written documentation of IRB notification for each report to 
the Sponsor.


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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
Adverse Events of Special Interest
Any AEs/SAEs that are considered abuse of the study drug will be collected and followed.
To complete subject narratives, additional information around AEs of special interest will be 
collected. AEs of special interest related to potential abuse are listed in [Appendix 12.7
Adverse Events of Interest Related to Abuse].
5.5.10
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 90 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 below.
●
"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.
5.5.11
Emergency Procedures and Management of Overdose
No information on overdose with ASP8062 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 as applicable.
5.5.12
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 ASP8062 
and any metabolites (if applicable). A single pharmacokinetic sample will be taken on day 1 
in the clinic at approximately 1-4 hour(s) after dosing and once at each visit during weeks 2, 
4 and 8/EOT. PK samples at weeks 2, 4, and 8/OT should be evenly split between the 
following 3 sampling windows: before dosing, 1-4 hours post dose and >4 hours post 
dose. Time of the last dose and time of sample collection will be captured in the eCRF during 
these visits, 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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Details on sample collection, processing, labeling, storage, and shipment procedures are 
provided in the laboratory manual. Analysis will be performed using a validated liquid
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 ASP8062. The samples will be destroyed maximally 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)
A 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.
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.


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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 TBL > 2 x ULN, testing
should be repeated within 48 to 72 hours of notification of the test results. 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
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.
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.


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7
STATISTICAL METHODOLOGY
The statistical analysis will be coordinated by the responsible biostatistician of 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
 
 
 
 
 
 
 
 
 
7.2
Analysis Sets
Detailed criteria for analysis sets will be laid out in Classification Specifications and 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.
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. 


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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 pharmacokinetic analysis set (PKAS) will consist of the subset of SAF for which at least 
1 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 with inform 
consent. 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 (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. 


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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% confidence interval 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 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-time 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 ASP8062 vs 
placebo with 2-sided 90% confidence intervals. A one-sided 5% significance level will be used 
for the comparison involving ASP8062 vs placebo. 
The hypothesis for comparisons is given as follows:
H0: The change from baseline to Week 8 in the mean daily average pain NRS for 
ASP8062 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 
ASP8062 group is less than the placebo group.


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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 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: 
gender, age category, category of baseline pain score, with or without depression, and central 
or peripheral nerve component (subgroups by CMSI, 
). 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) 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 
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 imputation of ‘No Change’ for subjects who discontinue due to lack of efficacy or AEs, 


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and imputation by LOCF for subjects with missing data at Week 8 for other reasons. An 
additional analysis at Weeks 2 and 4 will use LOCF. 
7.4.3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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. Treatment Emergent Adverse Event (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.


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7.5.4
Electrocardiograms
The shift table of the finding at baseline (normal, not clinically significant normal, clinically 
significant normal) to the worst finding during treatment period and follow-up period will be 
presented by treatment group. 
7.5.5
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.
7.5.6
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 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).
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 and concomitant medication and last dose date of double blind study 
drug. 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 


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imputed date of study drug will be used to calculate duration of 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 
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
ePRO
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 World Health Organization (WHO) Drug Dictionary, 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. 

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 Investigator’s Brochure, 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 consent forms 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 European Union (EU) Data Protection Directive, and Sponsor 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 Investigator's Brochure 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)
●
Investigator’s Brochure (and amendments, where applicable)
●
eCRFs 
●
Study drug with all necessary documentation
●
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)
●
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 NDA or discontinuation of the IND). The Sponsor will notify the 
site/investigator if the NDA/MAA/J-NDA is approved or if the IND/IMPD/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 case report forms (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, case report forms, and source documents. Direct access to these documents will 
be required by the auditors.
10
STUDY ORGANIZATION
10.1
Data Monitoring Committee
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.
10.2
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 Interim Analysis Plan (IAP).
10.3
Other Study Organization
Not applicable.


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11
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γ-aminobutyric acid in fibromyalgia. Arthritis Rheum. 2012;64:579-83.
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Kim SH, Kim DH, Oh DH, Clauw DJ. Characteristic electron microscopic findings in the skin of 
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Kleinman et al. Assessment of sleep in patients with fibromyalgia: qualitative development of the 
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Kratz, A. et al. Development and Initial Validation of a Brief Self-Report Measure of Cognitive 
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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: 
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receptors. Curr Pharm Des. 2004;10:2003-13.
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intermediate conductance calcium-activated potassium channels in the rat sensory nervous 
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Nagakura Y, Oe T, Aoki T, Matsuoka N. Biogenic amine depletion causes chronic muscular pain and 
tactile allodynia accompanied by depression: a putative animal model of fibromyalgia. Pain. 
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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 
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double-blind, placebo-controlled, multicenter clinical trial. Arthritis Rheum. 2009;60:299-309
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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 CYP3A Inhibitors and Inducers
Strong CYP3A inhibitors (> 5-fold increase in AUC)
indinavir /RIT
tipranavir/RIT
Ritonavir
cobicistat (GS-9350)
Indinavir
Nelfinavir
Saquinavir
elvitegravir / RIT
saquinavir / RIT
lopinavir / RIT
Boceprevir
Telaprevir
danoprevir / RIT
Ketoconazole
Itraconazole
Voriconazole
Posaconazole
Telithromycin
Troleandomycin
Clarithromycin
Conivaptan
Nefazodone
Mibefradil
grapefruit juice DS
Idelasib
LCL161
Weak/moderate CYP3A inhibitors 
(>2-fold increase in AUC)
atazanavir / RIT
Darunavir
darunavir / RIT
Atazanavir
Amprenavir
Cyclosporine
Ledipasvir
Table continued on next page


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Fluconazole
Ciprofloxacin
Erythromycin
Imatinib
Crizotinib
Verapamil
Diltiazem
Dronedarone
Aprepitant
Casopitant
Netupitant
Cimetidine
Tofisopam
grapefruit juice
schisandra sphenanthera 
Lomitapide
ACT-178882
FK1706
Potent CYP3A inducers (> 80% )
Rifampin
Rifabutin
Mitotane
Enzalutamide
Phenytoin
Carbamazepine
Avasimibe
St John's Wort


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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 Reputake 
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 (AT) 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 International Normalized Ratio (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 


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Sponsor should be contacted and informed of all subjects for whom severe hepatic liver 
function abnormalities possibly attributable to study drug are observed.
To further assess abnormal hepatic laboratory findings, the investigator is expected to:
●
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: 
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:
●
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 to50% mortality 


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(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 
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 serious adverse events 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.
PGx 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 PGx 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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12.7
Adverse Events of Interest Related to Abuse
Screening Terms with Respect to Narratives
Euphoria-related Terms
Preferred term
Lowest level term
Euphoric mood
Feeling high
Elevated mood
Feeling abnormal
Feeling drunk
Feeling of relaxation
Thinking abnormal
Hallucination, mixed
Inappropriate affect
Dizziness and giddiness
Dissociative/Psychotic Terms
Preferred term
Lowest level term
Psychosis acute
Psychosis
Aggression
Confusion and disorientation
Terms Indicative of Impaired Attention, Cognition, Mood, and Psychomotor Events
Preferred term
Lowest level term
Somnolence
Psychomotor hyperactivity/decreased activity
Hyperactivity/hypoactivity
Mood disorders and disturbances
Mental impairment disorders
Drug tolerance, habituation, drug withdrawal 
syndrome, substance-related disorders
Inappropriate Affect
Preferred term
Lowest level term
Inappropriate affect
Elation inappropriate
Exhilaration inappropriate
Inappropriate mood elevation
Product tampering
Medication tampering


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Complete Abuse ScreeningTerms
System Organ Class
Higher Level 
GT
Higher 
Level Term
Preferred 
term
Lower Level Term
Psychiatric disorders
Mood 
disorders and 
disturbances 
NEC
Emotional 
and mood 
disturbances 
NEC
Euphoric 
Mood
Euphoria
Euphoric
Euphoric mood
Exaggerated well-
being
Feeling high
Felt high
High
High feeling
Laughter
Mood altered
Affect alteration
Affect altered
Altered mood
Bad mood
Mood alteration 
NOS
Mood altered
Mood change
Elevated 
mood
Elevated mood
Mood elevated
Affect 
alterations
Inappropriate 
affect
Elation 
inappropriate
Exhilaration 
inappropriate
Exhiliration 
inappropriate
Feeling happy 
inappropriately
Inappropriate affect
Inappropriate crying
Inappropriate 
elation
Inappropriate 
exhilaration
Inappropriate 
laughter
Inappropriate mood 
elevation
Mood elevation 
inappropriate


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System Organ Class
Higher Level 
GT
Higher 
Level Term
Preferred 
term
Lower Level Term
Disturbances 
in thinking 
and 
perception
Perception 
disturbances
Hallucination
Drug-induced 
hallucinosis
Hallucinating
Hallucination
Hallucination NOS
Hallucinations
Hallucinations 
aggravated
Kinesthetic 
hallucination
Organic 
hallucinosis 
syndrome
Pseudohallucination
Sensory 
hallucinations
Stump hallucination
Hallucination, 
auditory
Auditory 
hallucinations
Hallucination 
auditory
Hallucination, 
auditory
Verbal 
hallucinations
Hallucination, 
visual
Hallucination visual
Hallucination with 
color
Hallucination with 
colour
Hallucination, 
visual
Visual 
hallucinations
General disorders and 
administration site 
conditions
General 
system 
disorders 
NEC
Feelings and 
sensations 
NEC
Feeling drunk
Drunk-like effect
Drunkenness 
feeling of
Feeling drunk
Feeling 
abnormal
Cotton wool in head
Feeling abnormal
Feeling bad
Feeling dazed
Feeling floating


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System Organ Class
Higher Level 
GT
Higher 
Level Term
Preferred 
term
Lower Level Term
Feeling lifeless
Feeling miserable
Feeling stoned
Feeling strange
Feeling weightless
Feels awful
Feels bad
Feels poorly
Felt like a zombie
Floating feeling
Foggy feeling head
Funny episode
Fuzzy
Fuzzy head
Muzzy head
Neck strange 
feeling of
Soft feeling
Spaced out
Thick head
Unstable feeling 
Weird feeling


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12.8
Drug Withdrawal – Related Adverse Events Occurring Following 
Drug Discontinuation (Preferred Terms; MedDRA 18.0)
Higher Level GT
Higher Level Term
Preferred Term
Psychiatric disorders
Anxiety disorders 
and symptoms
Anxiety symptoms
Agitation
Nervous system 
disorders
Neurological 
disorders NEC
Neurological signs 
and symptoms NEC
Psychiatric disorders
Depressed mood 
disorders and 
disturbances
Mood alterations 
with depressive 
symptoms
Anhedonia
Psychiatric disorders
Anxiety disorders 
and symptoms
Anxiety symptoms
Anxiety
Musculoskeletal and 
connective tissue 
disorders
Muscle disorders
Muscle related signs 
and symptoms NEC
Chills
Musculoskeletal and 
connective tissue 
disorders
Muscle disorders
Feelings and 
sensations NEC
Psychiatric disorders
Depressed mood 
disorders and 
disturbances
Mood alterations 
with depressive 
symptoms
Depressed mood
Psychiatric disorders
Depressed mood 
disorders and 
disturbances
Depressive disorders
Depression
Gastrointestinal 
disorders
Gastrointestinal 
motility and 
defaecation 
conditions
Diarrhoea (excl 
infective)
Diarrhoea
Psychiatric disorders
Mood disorders and 
disturbances
Emotional and mood 
disturbances NEC
Dysphoria
Nervous system 
disorders
Sleep disturbances 
(incl subtypes)
Sleep disturbances 
NEC
Dyssomnia
Psychiatric disorders
Sleep disorders and 
disturbances 
Dyssomnias
Psychiatric disorders
Depressed mood 
disorders and 
disturbances
Depressive disorders
Dysthymic disorder
Psychiatric disorders
Depressed mood 
disorders and 
disturbances
Mood alterations 
with depressive 
symptoms
Feeling of despair
Nervous system 
disorders
Headaches
Headaches NEC
Headache


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Higher Level GT
Higher Level Term
Preferred Term
Skin and 
subcutaneous tissue 
disorders 
Skin appendage 
conditions
Apocrine and eccrine 
gland disorders
Hyperhidrosis
General disorders 
and administration 
site conditions
General system 
disorders NEC
General signs and 
symptoms NEC
Psychiatric disorders
Sleep disorders and 
disturbances 
Disturbances in 
initiating and 
maintaining sleep
Insomnia
Nervous system 
disorders
Sleep disturbances
Disturbances in 
initiating and 
maintaining sleep
Psychiatric disorders
Depressed mood 
disorders and 
disturbances
Mood alterations 
with depressive 
symptoms
Morose
Gastrointestinal 
disorders
Gastrointestinal signs 
and symptoms
Nausea and vomiting 
symptoms
Nausea
Psychiatric disorders
Depressed mood 
disorders and 
disturbances
Mood alterations 
with depressive 
symptoms
Negative thoughts
Psychiatric disorders
Anxiety disorders 
and symptoms
Anxiety symptoms
Nervousness
Psychiatric disorders
Anxiety disorders 
and symptoms
Obsessive-
compulsive disorders 
and symptoms
Obsessive thoughts
General disorders 
and administration 
site conditions
General system 
disorders NEC
Pain and discomfort 
NEC
Pain
Nervous system 
disorders
Sleep disturbances 
(incl subtypes)
Sleep disturbances 
NEC
Poor quality sleep
Psychiatric disorders
Sleep disorders and 
disturbances 
Dyssomnias
Cardiac disorders
Cardiac disorder 
signs and symptoms
Cardiac signs and 
symptoms NEC
Syncope
Vascular disorders
Decreased and 
nonspecific blood 
pressure disorders 
and shock
Circulatory collapse 
and shock
Nervous system 
disorders
Neurological 
disorders NEC
Disturbances in 
consciousness NEC


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Higher Level GT
Higher Level Term
Preferred Term
Psychiatric disorders
Sleep disorders and 
disturbances 
Disturbances in 
initiating and 
maintaining sleep
Terminal insomnia 
(lower level term of 
interest:  early 
morning awakening)
Nervous system 
disorders
Sleep disturbances
Disturbances in 
initiating and 
maintaining sleep
Nervous system 
disorders
Movement disorders 
(incl parkinsonism)
Tremor (excl 
congenital)
Tremor
Gastrointestinal 
disorders
Gastrointestinal signs 
and symptoms
Nausea and vomiting 
symptoms
Vomiting


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13
ATTACHMENT 1:  NON-SUBSTANTIAL AMENDMENT 2
I.  The purpose of this amendment is:
Non-Substantial Changes
1.
Update Analysis of Primary Endpoint
DESCRIPTION OF CHANGE:
Replace “baseline pain-by-treatment” with “baseline pain-by-time in Section 7.4.1.1 Primary 
Analysis. 
RATIONALE:
Correction to incorrectly specified analysis model.
2.
Clarify the Baseline Diary Run-In
DESCRIPTION OF CHANGE:
Add a footnote to Table 1 (Schedule of Assessments) to clarify that the baseline diary run-in 
may be extended up to 2 days, but screening should not exceed 42 days.
RATIONALE:
This information is included in Section 2.2.1 of the protocol and is added to Table 1 to 
provide clarity to the site.
3.
Remove Requirement for Special Situation Worksheet for Overdoses
DESCRIPTION OF CHANGE:
Remove the footnote under the table in Section 5.5.3 Special Situations that states in the 
event of an intentional overdose, the Special Situation worksheet must be completed.
RATIONALE:
Sites are to report all instances of overdose via Special Situation reporting whether it is 
intentional or accidental.
4.
Clarify Imputation Method for PGIC 
DESCRIPTION OF CHANGE:
In Section 7.4.2 Analysis of Secondary Endpoints, add language to clarify the primary 
analysis for PGIC in subjects with missing data.
RATIONALE:
Clarification of imputation method for PGIC, since the baseline assessment for PGIC is not 
appropriate.




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II.  Amendment Summary of Changes:
IV Synopsis, Statistical Methods (Efficacy) and 7 Statistical Methodology
7.4.1.1 Primary Analysis
WAS:
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.
IS AMENDED TO:
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-treatmenttime
interaction and subject as a random effect.
V Flow Chart and Schedule of Assessments
Table 1. Schedule of Assessments
ADDED:
dd 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.
5 Treatment and Evaluation
5.5.3 Special Situations
DELETED
**In the event of an intentional overdose, the Special Situation worksheet must be filled out.
7 Statistical Methodology
7.4.2 Analysis of Secondary Endpoints
WAS:
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.
IS AMENDED TO:
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, 






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[GPF v5.0]
15
SPONSOR’S SIGNATURES


 
S-1 
ELECTRONIC SIGNATURE PAGE 
Document Type :  
Document Control Number :  
Amendment Number :  
International Study Number :  
Departmental Study Number :  
Actual Version Number :  
Document Version :  
Nonclinical Initial SD Approved Date (UTC) :  
Date (UTC) 
Signed by 
Sign Off Meaning 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
*UTC: Coordinated Universal Time 
08/16/2017 13:50:29
Clinical Study Protocol
Study Physician Approval
Study Statistician Approval
Reissue v1.2, 14Aug2017
08/14/2017 20:21:17
Study Manager Approval
N/A
08/14/2017 18:36:05
N/A
MGC1700838
8062-CL-0101
2.0
N/A

SAP_001.pdf: 
A Phase 2a, Randomized, Double-Blind Placebo-controlled, 
Parallel-group Study to Assess the Analgesic Efficacy and Safety 
of ASP8062 in Subjects with Fibromyalgia
ISN/Protocol 8062-CL-0101
ClinicalTrials.gov Identifier: NCT03092726
Date of Statistical Analysis Plan v2.0: 19 Apr 2018
Sponsor: Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062


A Phase 2a, Randomized, Double-Blind Placebo-controlled, 
Parallel-group Study to Assess the Analgesic Efficacy and Safety 
of ASP8062 in Subjects with Fibromyalgia
ISN/Protocol 8062-CL-0101
ClinicalTrials.gov Identifier: NCT03092726
Date of Statistical Analysis Plan v2.0: 19 Apr 2018
Sponsor: Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062


Sponsor: Astellas Pharma Global Development, Inc. (APGD)
SAP Final Version 2.0
ISN/Protocol 8062-CL-0101
19-Apr-2018
Astellas
Page 1 of 96
STATISTICAL ANALYSIS PLAN
Final Version 2.0, dated 19-Apr-2018 
A Phase 2a, Randomized, Double-Blind Placebo-controlled, Parallel-group Study to 
Assess the Analgesic Efficacy and Safety of ASP8062 in Subjects with Fibromyalgia
ISN: 8062-CL-0101
IND number: 125639
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.


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SAP Final Version 2.0
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19-Apr-2018
Astellas
Page 2 of 96
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······················································15
3.1
Study Objective(s) ············································································15
3.1.1
Primary Objectives······································································15
3.1.2
Secondary Objectives ···································································15
3.1.3
·································································15
3.2
Study Design···················································································15
3.3
Randomization·················································································16
4
SAMPLE SIZE·····················································································16
5
ANALYSIS SETS ·················································································17
5.1
Full Analysis Set (FAS) ······································································17
5.2
Per Protocol Set (PPS)········································································17
5.2.1
Reasons for Exclusion From PPS ·····················································17
5.3
Safety Analysis Set (SAF) ···································································20
5.4
Pharmacokinetics Analysis Set (PKAS)····················································20
6
ANALYSIS VARIABLES ·······································································20
6.1
Efficacy Endpoints············································································20
6.1.1
Primary Efficacy Endpoint(s)··························································20
6.1.2
Secondary Efficacy Endpoints·························································21
6.1.3
·······················································24
6.2
Safety Variables ···············································································35
6.2.1
Adverse Events ··········································································36
6.2.2
Clinical Laboratory Variables··························································37
6.2.3
Vital Signs················································································37
6.2.4
Electrocardiograms······································································37
6.2.5
Columbia Suicide Severity Rating Scale ·············································37
6.3
Pharmacokinetic Variables···································································38
6.4
Other Variables················································································39
6.4.1
Exposure··················································································39
6.4.2
Percent Overall Compliance ···························································39


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Page 3 of 96
6.4.3
Previous and Concomitant Medication ···············································39
6.4.4
Time Since Onset of Fibromyalgia Symptoms and Time Since Diagnosis·······40
6.4.5
Mini-International Neuropsychiatric Interview······································40
6.4.6
Widespread Pain Index and Symptom Severity Scale score ·······················40
6.4.7
Complex Medical Symptoms Inventory··············································41
7
STATISTICAL METHODOLOGY ···························································41
7.1
General Considerations·······································································41
7.2
Study Population ··············································································43
7.2.1
Disposition of Subjects ·································································43
7.2.2
Protocol Deviations ·····································································44
7.2.3
Demographic and Other Baseline Characteristics ···································44
7.2.4
Previous and Concomitant Medications ··············································49
7.2.5
Previous and Concomitant Non-Medication Therapy·······························50
7.3
Study Drugs····················································································51
7.3.1
Exposure··················································································51
7.3.2
Treatment Compliance··································································51
7.4
Analysis of Efficacy ··········································································52
7.4.1
Analysis of Primary Endpoint(s) ······················································52
7.4.2
Analysis of Secondary Endpoints ·····················································55
7.4.3
····················································58
7.4.4
Analysis of Other Variables····························································64
7.5
Analysis of Safety·············································································64
7.5.1
Adverse Events ··········································································64
7.5.2
Adverse Events of Interest ·····························································65
7.5.3
Clinical Laboratory Evaluation ························································66
7.5.4
Vital Signs················································································68
7.5.5
Electrocardiograms······································································70
7.5.6
Physical Examination Findings························································70
7.5.7
Columbia Suicide Severity Rating Scale ·············································70
7.5.8
Pregnancies···············································································70
7.6
Analysis of Pharmacokinetics ·······························································70
7.7
Analysis of Pharmacodynamics ·····························································71
7.8
Subgroups of Interest ·········································································71
7.8.1
Subgroup Analysis for Primary Endpoint ············································71


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7.8.2
·······························72
7.9
Other Analyses ················································································72
7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)····················73
7.11
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········73
7.11.1
Missing Data ·············································································73
7.11.2
Outliers ···················································································76
7.11.3
Values Below Limit of Quantification (BLOQ) ·····································76
7.11.4
Visit Windows for Efficacy Variables ················································76
7.11.5
Visit Windows for Safety Variables···················································78
7.11.6
Pooling Sites Algorithm ································································80
8
DOCUMENT REVISION HISTORY ·························································80
9
REFERENCES ····················································································87
10
APPENDICES ·····················································································88
10.1
Appendix 1: Drug Abuse Related Adverse Events········································88
10.2
Appendix 2: Drug Withdrawal Related Adverse Events ·································91
10.3
Appendix 3: Potentially Clinically Significant Laboratory Criteria·····················93
10.4
Appendix 4: Key Contributors and Approvers ············································94


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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
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-VAS
EQ Visual Analog Scale
FAS
Full Analysis Set
FIQR
Fibromyalgia Impact Questionnaire Revised
FM
Fibromyalgia
FU
Follow-up
GD-US
Global Development - United States
H
High
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




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Abbreviations
Description of abbreviations
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) 
 
 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
X
Medical/Surgical History
X
Xc
Medication History and 
Concomitant Medication
X
FM Diagnosis (ACR 1990 & 2010)  
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
Table continued on next page




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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 randomization. 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.
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)
Resting blood pressure and pulse rate values will be the average of the supine triplicates from the orthostatic measures for those days when orthostatic blood pressure is assessed. 
Pulse rate will be measured in triplicate after the subject has rested for at least 7 minutes in the supine position, each measurement approximately 1 minute apart (-3, -2, and -1 
minutes before standing). Afterwards, the subject will be instructed to stand up within 10 seconds and remain free standing with no support on wall or furniture. Standing blood 
pressure and pulse rate will be measured after the subject has been in the free standing position at 3 minutes (every attempt should be made to take the measurement as close as 
possible to 3 minutes). Orthostatic vital signs will be captured on day 1 pre-dose and approximately 2 hours post dose and at week 8/EOT. Resting vital sign measurements 
should be collected at all other visits (except visit 2). All vital sign measurements 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. Sample is to be collected prior to randomization, and at week 8/EOT, and week 10/ follow-up visits.
m) Sample to be collected one time, preferably prior to first dose on day 1; however, can be collected at any time during the course of the study. Separate pharmacogenomics 
informed consent will need to be obtained from subject prior to collecting.
n)
A single pharmacokinetic sample will be taken on day 1 in the clinic at approximately 1-4 hour(s) after dosing and once at each visit during weeks 2, 4 and 8/EOT. PK samples 
at weeks 2, 4, and 8/OT should be evenly split between the following 3 sampling windows: before dosing, 1-4 hours post dose and >4 hours post dose. Time of the last dose and 
time of sample collection will be captured in the eCRF during these visits. 
o)
Mini-International Neuropsychiatric Interview (MINI) will be completed by site personnel at screening.
p)
Hospital Anxiety and Depression Scale (HADS). Questionnaire will be completed by the subject at screening, randomization and the week 8/EOT visits.
q)
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. 
r)
s)
Patient Global Impression of Change (PGIC). Questionnaire will be completed by the subject at week 2, 4 and 8/EOT follow-up visits.
t)
Patient Global Impression of Severity (PGI-S). Questionnaire will be completed by the subject at randomization and week 2, 4 and 8/EOT follow-up visits.
u)
.
v)
Footnotes continued on next page




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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 ASP8062 relative to placebo. 
●
Assess the safety and tolerability of ASP8062 relative to placebo.
3.1.2
Secondary Objectives 
●
Assess treatment differences in physical function of ASP8062 relative to placebo.
●
Assess the improvements in overall subject status (e.g., fibromyalgia symptoms, global 
functioning) of ASP8062 relative to placebo. 
3.1.3
 
 
3.2
Study Design
This is a Phase 2a, randomized, double-blind, placebo-controlled parallel group study to 
assess analgesic efficacy and safety of ASP8062 in subjects with fibromyalgia.
The study will be conducted in the United States (US) in up to 35 sites.  Approximately 
356 subjects are planned to be screened for 178 randomized subjects (89/arm; 50% screen 
fail rate).  Subjects will be randomized in a 1:1 ratio to one of two treatment groups: 
ASP8062 30 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 ASP8062 group will receive ASP8062 30 mg [1 tablet of 25 mg and 
1 tablet of 5 mg] once daily; subjects randomized to the placebo group will receive placebo 
[2 tablets] to match ASP8062 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 


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anti-inflammatory drugs (NSAIDs) may be used (with the exception of celecoxib) as needed 
for non-fibromyalgia pain (e.g., headache).  Subjects are encouraged to abstain from alcohol.
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 
ASP8062 30 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
 
 
 
 


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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 # 13: 
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 # 14: 
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 # 10: 
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 # 10 is No and/or pain in 
<11 tender point sites
2.2
Inclusion Criterion # 11: 
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 #11 is No and/or
WPI >=7 and SS scale score <5 or 
WPI 3-6 and SS scale <9 or 
WPI<3
2.3
Inclusion Criterion # 12:
Subject has a pain score ≥ 4 on the revised 
fibromyalgia impact questionnaire revised (FIQR) 
pain item at Screening.
Inclusion criterion #12 is No and/or FIQR 
pain item score <4 at Screening.
Table continued on next page


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Number
Source
Criterion/Criteria
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 (MDD) 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).
HADS Depression subscale score > 14 at 
Screening or Visit 3 (Randomization), or 
Exclusion Criterion #9 is Yes.
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.
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 Study Day 1 to 
Week 8/EOT. Subjects with missing 
compliance will be reviewed on a case-by-
case basis.
Table continued on next page


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Number
Source
Criterion/Criteria
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 
received 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 ASP8062 will be summarized in the ASP8062 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, 
 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], 
 
 
nd Hospital Anxiety and Depression 
Scale [HADS]) depression subscale will be reported on a tablet device that is available at the 
site. For FIQR, PGIS, 
, 
and HADS, baseline is defined as the 
last assessment on or prior to the first dose day (Day 1) of double-blind study drug.
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).


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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 26  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.
o
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. 
o
Subjects who do not have Week 8 data will be classified as non-responders. 
o
Subjects who do not have baseline data will be classified as non-responders. 
●
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 
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o
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. 
o
Subjects who do not have EOT data will be classified as non-responders.
o
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). 


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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:
3)
Brush or comb your hair
4)
Walk continuously for 20 mins
5)
Prepare a homemade meal
6)
Vacuum, scrub or sweep floors
7)
Lift and carry a full bag of 
groceries
8)
Climb one flight of stairs
9)
Change bed sheets
10) Sit in a chair for 45 mins
11) 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.
Overall impact subscale score:
12) Fibromyalgia prevented me from 
accomplishing goals for the week
13) 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:
14) Your level of pain
15) Your level of energy
16) Your level of stiffness
17) The quality of your sleep
18) Your level of depression
19) Your level of memory problems
20) Your level of anxiety
21) Your level of tenderness to touch
22) Your level of balance problems
23) 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.


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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.
6.1.3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 










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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, unless it worsens in severity after Day 1 (up to day 30 after last 
dose).
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 
relationship. 
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).


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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 
Day 1 2-hours post dose, Weeks 2, 4, Week 8/EOT and Week 10.  Orthostatic SBP, DBP and 
pulse rate are assessed on Day 1 pre-dose, Day 1 2-hours post dose, Week 8/EOT (triplicate 
supine measurements approximately 1 minute apart [-3, -2, -1 minutes before standing] 
followed by a single standing measurement approximately 3 minutes after standing).  Single 
resting measurements of SBP, DBP and pulse rate are measured on at Screening, Weeks 2, 4 
and Week 10.
Orthostatic vital signs (SBP, DBP, pulse rate) will be derived for each subject as follows:
Table 13
Derivation of Orthostatic Vital Signs
Analysis Time point
Item
Derivation
Baseline,
Treatment period
Day 1 2-hours post dose,
Week 8/EOT
Average supine result
Average of the non-missing supine triplicates taken 
approximately 1 minute apart (-3, -2, and -1 minutes 
before standing). 
Orthostatic result
Standing result – Average supine result. 
If the result for standing or average supine is not 
available, then the result will be set to missing.
6.2.4
Electrocardiograms
The 12-lead electrocardiograms (ECG) scheduled assessments will be made at Baseline, 
Week 8/EOT 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:


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Table 14
Derivation of Columbia Suicide Severity Rating Scale (C-SSRS) Scores
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 answer “yes” to more than one suicidal 
ideation question within a visit window as an 
analysis time point (Section 7.11.5.3  Table 30) the 
worst-case response (i.e. the highest) will be used in 
any summaries. 
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 answer “yes” to more than one suicidal 
behavior question within a visit window (Section 
7.11.5.3  Table 30), 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 at Weeks 2, 4 and 8 /EOT.  PK samples at weeks 2, 4, and 
8/EOT should be evenly split between the following 3 sampling windows: before dosing, 
1-4 hours post dose and >4 hours post dose.  Time of the last dose and time of sample 
collection will be captured in the electronic Case Report Form (eCRF) during these visits, as 
well as the date and time of the last meal in relation to that dose will be captured in the eCRF.
Analysis of ASP8062 and any metabolites (if applicable) will be performed using a validated 
method at a bioanalytical laboratory specified by the Sponsor. 


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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 2 tablets once per day, one tablet of 25 mg and 1 tablet of 
5 mg. 
Percent tablet-count compliance is defined as the number of tablets taken divided by the total 
number of tablets that should have been taken: 
Total number of tablets actually received during 8 weeks of treatment period
Total number of tablets planned to receive during 8 weeks of treatment periodx100
Where, 
●
Total number of tablets actually received during 8 weeks of treatment period = total 
number of tablets dispensed during 8 weeks of treatment period – total number of 
tablets returned during 8 weeks of treatment period.
●
Total number of tablets planned to receive during 8 weeks of treatment period = 2 x 
duration of exposure. Duration of exposure will be calculated as described in 
Section 6.4.1
Double-blind study drug compliance for the entire double-blind treatment period will be 
calculated for subjects whose total number of tablets 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.


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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. 
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.


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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
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%. 


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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.
 
 
 
 
 
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). 


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For daily average pain scores assessed by NRS 
 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.
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 
 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. 
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);


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●
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 
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.


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7.2.3.1 Demographics
Demographic characteristics will be summarized by descriptive statistics for the following 
variables listed in Table 15   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 15
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
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 16   This will be done for all randomized subjects, the 
SAF, FAS and PPS by treatment group and ‘Total’ over all treatment groups.


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Table 16
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
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
Table continued on next page


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Characteristic
Summarized as
Categories
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
CMSI: Complex Medical Symptom Inventory, 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, 
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 17   This will be done for all randomized 
subjects, the SAF, FAS and PPS by treatment group and ‘Total’ over all treatment groups.
Table 17
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
WPI
Continuous
-------
SS scale score
Continuous
-------
Tender point count
Continuous
-------
PGIS
Categorical
●
No symptoms
●
Very mild
●
Mild
●
Moderate
●
Severe
●
Very severe
Table continued on next page




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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 baseline diary run-in,
●
All previous medications taken for FM pain (FM pain only or FM pain and Other type of 
pain) prior to 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.
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,


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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,
●
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 


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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:
o
1 to 7 days,
o
8 to 14 days, 
o
15 to 28 days, 
o
29 to 48 days,
o
49 to 64 days,
o
≥ 65 days
●
Number and percentage of subjects in the following cumulative extent of exposure time 
categories:
o
≥ 1 day,
o
≥ 8 days;
o
≥ 15 days,
o
≥ 29 days,
o
≥ 49 days
o
≥ 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.


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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:
o
< 50%,
o
≥ 50% to < 80%,
o
≥ 80% to < 100%,
o
= 100%,
o
> 100% to < 120%,
o
≥ 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 18 describes the primary analysis and sensitivity analyses that will be performed for 
the primary efficacy endpoint.
Table 18
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.


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7.4.1.1 Primary Analysis of Primary Endpoint
The hypothesis for comparison of mean change from baseline between ASP8062 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 ASP8062 30 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 ASP8062 30 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.
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 e-diary only, i.e. mean daily average pain score 
assessed by NRS 
 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 (ASP8062, placebo),
●
The difference in LS means for ASP8062 versus placebo, SE for the difference and 
2-sided 90% CI for the difference at each analysis time-point,
●
One-sided p-value for ASP8062 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. 


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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 
that only baseline values are used in the imputation of missing values for subjects in the 
ASP8062 30 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 (ASP8062, placebo),
●
The difference in LS means for ASP8062 versus placebo, SE for the difference and 
2-sided 90% CI for the difference at Week 8,
●
One-sided p-value for ASP8062 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. 


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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 (ASP8062, placebo).  For
comparisons between ASP8062 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 ASP8062 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.
7.4.1.3 Subgroup analysis
The subgroup analysis of the primary efficacy endpoint is described in Section 7.8.1
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 19
Table 19
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
Table continued on next page


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Variable
Imputation
Analysis 
Set
Analysis Type
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.
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 ASP8062 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 
(ASP8062, placebo) calculated using the exact unconditional approach, difference in 


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percentages, 2-sided 90% CI for ASP8062 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.
●
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 ASP8062 vs placebo. The cumulative 
logit link will be used to specify the proportional odds model in SAS.








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7.4.4
Analysis of Other Variables 
Not applicable.
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. Standardized 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 drug related serious TEAEs,
●
Number and percentage of subjects with drug related serious 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, 


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●
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).
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 ASP8062 
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. 


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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: Drug 
Abuse Related Adverse Events, as classified by PT and lowest level term will be summarized 
by treatment group.  
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: Drug 
Withdrawal Related Adverse Events, 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.


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Table 21
Laboratory Parameters for Descriptive Statistics and 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
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 (GTT)
Total bilirubin (direct and indirect)
Total protein
Albumin
Total cholesterol
Triglycerides
Uric Acid
Blood Urea Nitrogen (BUN)
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.  


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Table 22
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
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: Potentially Clinically Significant Laboratory Criteria  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.


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Supine (average)/resting vital signs (SBP, DPB and pulse rate) will be summarized using 
mean, SD, minimum, maximum and median by treatment group and visit (Baseline, Day 1 
2-hours post-dose, Week 2, Week 4, Week 8/EOT, Week 10).  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. Section 7.11.5.3 describes the 
derivation of visit windows for vital signs.
Standing vital signs (SBP, DPB and pulse rate) will be summarized using mean, SD, 
minimum, maximum and median by treatment group and visit (Baseline, Day 1 2-hours 
post-dose, Week 8 / EOT).  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 23 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. The summary will include all vital signs at 
both scheduled and unscheduled visits. It will include resting and orthostatic (supine 
[average] and standing) vital signs. For criteria comparing with baseline, vital signs at 
standing will be compared with vital signs at standing and vital signs at supine 
(average)/resting will be compared with vital signs at supine (average)/resting. 
Another summary will be created using the subject’s worst value (resting vital signs only) 
during the follow-up period. 
Table 23
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.
Table 24 describes orthostatic outlier criteria for vital signs. The number and percentage of 
patients with orthostatic outlier values in vital signs will be presented by each treatment 
group at each post-baseline time point. For the overall during the double-blind treatment 
period, a subject’s largest drop during that period will be used. The summary will also 
include results for the number and percentage of subjects where orthostatic challenge test 
lead to clinically significant results or symptoms. 


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Table 24
Orthostatic Outlier Criteria for Vital Signs 
Analysis Time Point
Vital Sign Parameter
Criteria
Treatment period
Day 1 2-hours post-dose,
Week 8 / EOT,
Double-blind treatment 
period
Orthostatic SBP
≥ 20 mmHg decrease from average supine value
Orthostatic DBP
≥10 mmHg decrease from average supine value
Orthostatic Challenge 
Test
≥20 mmHg decrease from average supine value for 
orthostatic SBP
OR
≥10 mmHg decrease from average supine value for 
orthostatic DBP
Orthostatic Pulse rate
≥20 bpm increase from average supine value
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.
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 Pharmacokinetics
PK assessments will only be performed in subjects treated with ASP8062. Summary tables of 
PK concentration will be provided for Day 1 (1-4 hours post-dose) and by sampling 


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timepoint (pre-dose, 1-4 hours post dose and >4 hours post dose) across Weeks 2, 4 and 
8/EOT combined (see table below). Descriptive statistics will include n [number of samples], 
mean, standard deviation, minimum, median, maximum, coefficient of variation and 
geometric mean. 
PK Summary Table Schema
Week 1
Weeks 2, 4, 8/EOT
1-4 hours post dose
Pre-dose
1-4 hours post dose
>4 hours post dose 
A listing of sample times and concentrations will be provided.
7.7
Analysis of Pharmacodynamics
Not applicable.
7.8
Subgroups of Interest 
7.8.1
 
 
 
 
 
 
 
 
 
 
 
 




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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:
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.


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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
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
●
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.


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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 15th 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 tablets dispensed does not equal the number of tablets 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 tablets dispensed does not equal the number of tablets 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.
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:
11.
last dispense date + 1 day OR
12.
the date of the last vital sign measurement during the double-blind treatment period 
OR
13.
3.the date of the first dose of double-blind study drug in the double-blind treatment 
period + 1 day


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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.
ASP8062 plasma concentrations that are below the limit of quantification (BLOQ) will be set 
to 0 for calculating descriptive statistics.
7.11.4
Visit Windows for Efficacy Variables
7.11.4.1 Duplicate Values
For daily average pain scores assessed by NRS 
 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 
day windows are used. 
These day windows are defined to provide derived time points that correspond to the post 
baseline time points specified in the protocol.
Table 26 provides day windows for daily average pain scores assessed by NRS and rescue 
medication data. 
  Table 28






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7.11.5.3 Visit Windows
Table 30 provides day windows for safety laboratory variables, vital sign variables and 
C-SSRS.  Table 31 provides day windows for the categorical ECG assessment. 
Table 30
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 10c
Follow up day 14
Follow-up days 5 to 28
Follow-up periodd
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. Vital signs
will also include Day 1 2 hours post-dose.
bOnly applicable to potentially clinically significant laboratory parameters, potentially clinically significant vital 
signs, orthostatic outlier vital signs and C-SSRS. Vital signs will also include Day 1 2 hours post-dose.
cOrthostatic vital signs are not captured at Week 10.
dOnly applicable to potentially clinically significant laboratory parameters, potentially clinically significant vital 
signs and C-SSRS. 
Table 31
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 
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 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. 
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 


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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’).
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.
8
DOCUMENT REVISION HISTORY 
Version
Date
Changes
Comment/rationale for change
1.00
05-APR-2017
NA
Document finalized
2.0
19-Apr-2018
Section 5.2.1 Table 2:
Updated criteria to 
criterion where 
appropriate.
Additional text included 
for FIQR inclusion 
criteria: ‘Inclusion 
criterion #12 is No 
and/or FIQR pain item 
Typographical errors.
Additional text included for clarification to 
match classification specification




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Version
Date
Changes
Comment/rationale for change
2.0 
19-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.)
2.0
19-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
19-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 
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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Version
Date
Changes
Comment/rationale for change
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.
2.0
19-Apr-2018
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.








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Version
Date
Changes
Comment/rationale for change
updated to 20.0. List of 
Lower Level Terms 
updated to reflect update 
to MedDRA v2.0. 
Lower Level Codes 
added to table.
2.0
19-Apr-2018
Section 6.1, 7.2 and 7.4: 
“FIQR physical 
function” was changed 
to “FIQR function” 
wherever it was 
mentioned.
Typographical error.
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
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
Exhilaration 
inappropriate
10015673
Feeling happy 
inappropriately
10016332
Inappropriate affect
10021588
Inappropriate crying
10021589
Inappropriate elation
10021592
Inappropriate 
exhilaration
10021593
Inappropriate 
laughter
10021595
Inappropriate mood 
elevation
10021596 
Mood elevation 
inappropriate
10027950


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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
General 
disorders and 
administratio
n 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


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System 
Organ Class
Higher Level 
GT
Higher 
Level Term
Preferred 
term
Lowest Level Term
Lower Level Code
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
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 
Sleep disorders and 
Disturbances in 
Insomnia
10022437


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System Organ 
Class
Higher Level GT
Higher Level 
Term
Preferred Term
Preferred Term 
Code
disorders
disturbances 
initiating and 
maintaining sleep
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
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 22, 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)
 M.S., 
Contributors and Reviewers
 PhD, Director, 
MD PhD,
 PhD,