Clinical trial NCT04448561
Conditions: Opioid Use Disorder
Keywords: Opioid Use Disorder pharmacokinetic ASP8062 morphine
Sponsor: Astellas Pharma Global Development, Inc.
Start date: 2020-06-30; Completion date: 2020-09-11
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of this study was to assess the safety and tolerability of multiple doses of ASP8062 or placebo alone and in combination with a single dose of morphine.

This study also assessed the potential for pharmacokinetic interaction between ASP8062 and morphine.

Detailed description:
Participants were screened for up to 28 days prior to first investigational product administration. Eligible participants were admitted to the clinical unit on day -1 and were residential for a single period of 17 days/16 nights.

Participants were discharged from the clinical unit on day 16 on the condition that all required assessments had been performed and that there were no medical reasons for a longer stay in the clinical unit.

Arms: arm 1: Participants received ASP8062 tablet, orally once daily on days 1 through 10. On day 10, participants also received morphine tablet as single oral dose immediately after the ASP8062 dose. arm 2: Participants received ASP8062 matching placebo tablet, orally once daily on days 1 through 10. On day 10, participants also received morphine tablet as single oral dose immediately after the ASP8062 matching placebo dose.
Interventions: intervention 1: ASP8082 intervention 2: morphine intervention 3: Placebo
Intervention descriptions: intervention 1: oral intervention 2: oral intervention 3: oral

Protocol documents:
Prot_SAP_000.pdf: 
Sponsor: APGD
ISN/Protocol 8062-CL-2002
- CONFIDENTIAL -
Clinical Study Protocol
30 Jul 2020
Astellas
Page 1 of 105
Version 1.1 Incorporating Nonsubstantial Amendment 1
A Phase 1 Randomized, Placebo-controlled Study to Assess 
the Safety, Tolerability and Pharmacokinetics of Multiple Doses 
of ASP8062 with a Single Dose of Morphine 
in Recreational Opioid Using Participants
ISN/Protocol 8062-CL-2002
Version 1.1
Incorporating Nonsubstantial Amendment 1 [See Section 12]
30 Jul 2020
IND 146215
IND Grantor: CDER
Sponsor:
Astellas Pharma Global Development Inc.
1 Astellas Way
Northbrook, IL 60062, US
Protocol History:
Version 1.0 Original [23 Apr 2020]
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
SIGNATURES································································································ 8
CONTACT DETAILS OF SPONSOR’S KEY PERSONNEL ·····································10
1
PROTOCOL SUMMARY·······································································11
1.1
Synopsis························································································11
1.2
Study Schema··················································································13
1.3
Schedule of Assessments·····································································14
2
INTRODUCTION·················································································20
2.1
Study Rationale················································································20
2.2
Background ····················································································20
2.3
Risk/Benefit Assessment·····································································22
2.3.1
Risk Assessment·········································································22
2.3.2
Benefit Assessment ·····································································22
2.3.3
Overall Risk-Benefit Conclusion······················································23
3
OBJECTIVES, ENDPOINTS AND ESTIMANDS ·········································23
4
STUDY DESIGN AND DOSE RATIONALE················································24
4.1
Overall Study Design ·········································································24
4.2
Scientific Rationale for Study Design ······················································24
4.3
Dose Rationale ················································································24
4.4
End of Study Definition ······································································25
5
STUDY POPULATION··········································································25
5.1
Inclusion Criteria··············································································25
5.2
Exclusion Criteria ·············································································26
5.3
Lifestyle Considerations······································································28
5.3.1
Exercise···················································································28
5.3.2
Dietary and Fluid Restrictions ·························································28
5.3.3
Smoking Restrictions ···································································29
5.4
Screen Failures ················································································29
5.4.1
Rescreening ··············································································29
6
INVESTIGATIONAL PRODUCT(S) ·························································30
6.1
Investigational Product(s) Administered ···················································30
6.2
Preparation/Handling/Storage/Accountability·············································30


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6.2.1
Packaging and Labeling ································································30
6.2.2
Handling, Storage and Accountability ················································31
6.3
Randomization and Blinding ································································31
6.3.1
Blinding Method·········································································31
6.3.2
Confirmation of the Indistinguishability of the Investigational Product··········31
6.3.3
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking ··················································································31
6.3.4
Breaking the Treatment Code for Emergency ·······································31
6.3.5
Breaking the Treatment Code by the Sponsor ·······································32
6.3.6
Assignment and Allocation·····························································32
6.3.6.1
Participant Number································································32
6.3.6.2
Randomization ·····································································32
6.4
Investigational Product Compliance ························································33
6.5
Dose Modification ············································································33
6.6
Continued Access to Investigational Product After the End of the Study··············33
6.7
Treatment of Overdose ·······································································33
6.8
Concomitant Therapy·········································································33
7
STUDY PROCEDURES AND ASSESSMENTS ············································34
7.1
Efficacy Assessments·········································································34
7.2
Safety Assessments ···········································································34
7.2.1
Laboratory Assessments································································34
7.2.2
Vital Signs················································································35
7.2.3
Continuous Pulse Oximetry and Spot Blood Oxygen Saturation··················35
7.2.4
Electrocardiogram·······································································35
7.2.4.1
12-lead Electrocardiogram························································35
7.2.5
Physical Examination···································································36
7.2.6
Columbia-Suicide Severity Rating Scale ·············································36
7.2.7
49-item Short Form of Addiction Research Center Inventory Scale ··············36
7.2.8
Continuous and Spot End Tidal Carbon Dioxide····································36
7.2.9
Order of Assessments···································································37
7.3
Adverse Events and Other Safety Aspects ·················································37
7.3.1
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information·····························································38
7.3.2
Method of Detecting Adverse Events and Serious Adverse Events···············38


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7.3.3
Follow-up of Adverse Events and Serious Adverse Events························38
7.3.4
Regulatory Reporting Requirements for Serious Adverse Events·················39
7.3.5
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events ··········································39
7.3.6
Adverse Events of Special Interest ····················································39
7.3.7
Special Situations········································································39
7.4
Pharmacokinetics··············································································40
7.4.1
Analysis of ASP8062 and Metabolites in Plasma ···································40
7.4.2
Analysis of Morphine and Metabolites in Plasma···································40
7.5
Pharmacodynamics ···········································································41
7.6
Pharmacogenomics ···········································································41
7.7
Biomarkers·····················································································41
7.8
Immunogenicity Assessments ·······························································41
7.9
Clinical Outcome Assessment·······························································41
7.10
Total Amount of Blood·······································································42
8
PARTICIPANT DISCONTINUATION ······················································42
8.1
Discontinuation of Individual Participant(s) from Study Treatment····················42
8.2
Discontinuation of Individual Participant(s) from Study·································43
8.3
Lost to Follow-up ·············································································43
8.4
Discontinuation of the Study·································································43
9
STATISTICAL CONSIDERATIONS·························································44
9.1
Statistical Hypotheses ········································································44
9.2
Sample Size Determination ··································································44
9.3
Populations for Analyses·····································································44
9.4
Statistical Analyses ···········································································44
9.4.1
General Considerations ·································································44
9.4.2
Analysis of Efficacy·····································································45
9.4.3
Analysis of Safety ·······································································45
9.4.3.1
Adverse Events·····································································45
9.4.3.2
Laboratory Assessments ··························································46
9.4.3.3
Vital Signs··········································································46
9.4.3.4
Continuous Pulse Oximetry and Spot Blood Oxygen Saturation ············46
9.4.3.5
Electrocardiogram ·································································47


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9.4.3.6
Columbia-Suicide Severity Rating Scale ·······································47
9.4.3.7
49-item Short Form of Addiction Research Center Inventory Scale ········47
9.4.3.8
Continuous and Spot End Tidal Carbon Dioxide ······························48
9.4.4
Analysis of Pharmacokinetics··························································48
9.4.4.1
Pharmacokinetic Concentrations·················································48
9.4.4.2
Estimation of Pharmacokinetic Parameters·····································49
9.4.4.3
Statistical Analysis of Pharmacokinetic Parameters···························49
9.4.5
Other Analyses···········································································49
9.5
Interim Analysis···············································································49
9.6
Additional Conventions ······································································50
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS ·············································································51
10.1
Appendix 1: Ethical, Regulatory and Study Oversight Considerations·················51
10.1.1
Regulatory and Ethical Considerations ···············································51
10.1.2
Financial Disclosure ····································································51
10.1.3
Informed Consent of Participants······················································51
10.1.3.1
Informed Consent Process························································51
10.1.3.2
Supply of New and Important Information Influencing the 
Participant’s Consent and Revision of the Written Information ·············52
10.1.4
Data Protection ··········································································52
10.1.5
Committee(s) Structure ·································································53
10.1.6
Dissemination of Clinical Study Data·················································53
10.1.7
Data Quality Assurance·································································53
10.1.8
Source Documents ······································································54
10.1.9
Study and Site Start and Closure ······················································54
10.1.10
Arrangement for Use of Information and Publication of the Study ···············55
10.1.11
Quality Assurance·······································································55
10.2
Appendix 2: Contraception Requirements ·················································57
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting ······················································59
10.3.1
Definition of Adverse Events ··························································59
10.3.2
Abnormal Laboratory Findings························································60
10.3.2.1
Potential Cases of Drug-induced Liver Injury··································60
10.3.3
Definition of Serious Adverse Events·················································60
10.3.4
Assessment of Causality································································61


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10.3.5
Assessment of Severity ·································································63
10.3.6
Recording and Follow-up of AEs and/or SAEs······································63
10.3.7
Reporting Procedures for Serious Adverse Events··································63
10.3.8
Reporting Procedures for Special Situations·········································65
10.3.8.1
Contraceptive Guidance and Collection of Pregnancy Information ·········65
10.3.8.2
Medication Error, Overdose and “Off-label Use” ·····························66
10.3.8.3
Misuse/Abuse ······································································66
10.3.8.4
Occupational Exposure ···························································66
10.3.8.5
Suspected Drug-drug Interaction ················································66
10.3.9
Supply of New Information Affecting the Conduct of the Study··················66
10.3.10
Urgent Safety Measures ································································67
10.3.11
Reporting Urgent Safety Measures····················································67
10.4
Appendix 4: Liver Safety Monitoring and Assessment···································68
10.5
Appendix 5: List of Excluded Concomitant Medications ································71
10.6
Appendix 6: Clinical Laboratory Assessments ············································72
10.7
Appendix 7: Pharmacogenomic Analysis with Banked Sample·························74
10.8
Appendix 8: Columbia-Suicide Severity Rating Scale ···································76
10.8.1
Baseline/Screening Version····························································76
10.8.2
Since Last Visit··········································································80
10.9
Appendix 9: 49-item Short Form of Addiction Research Center Inventory Scale ····85
10.10
Appendix 10: Adverse Events of Interest Related to Potential Substance Abuse 
and Following Drug Withdrawal····························································89
10.11
List of Abbreviations and Definition of Key Study Terms·······························95
11
REFERENCES ····················································································98
12
NONSUBSTANTIAL AMENDMENT 1···················································· 101
13
SPONSOR’S SIGNATURES·································································· 105


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List of In-text Tables
Table 1
Schedule of Assessments·····································································14
Table 2
Sample Collection Schedule ·································································17
Table 3
Study Objectives and Endpoints·····························································23
Table 4
Investigational Product(s)····································································30
Table 5
Established Limits for End Tidal Carbon Dioxide ········································37
Table 6
Blood Volume ·················································································42
Table 7
Criteria for Respiratory Rate·································································46
Table 8
Criteria for Assessing Spot Blood Oxygen Saturation····································47
Table 9
Criteria for 12-lead Electrocardiogram ·····················································47
Table 10
Criteria for Assessing Spot End Tidal Carbon Dioxide ··································48
Table 11
Quality Tolerance Limits·····································································56
Table 12
Moderate and Severe Liver Abnormalities·················································68
List of In-text Figures
Figure 1
Study Schema··················································································13


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SIGNATURES
1.  SPONSOR’S SIGNATURES
Required signatures (e.g., protocol authors and contributors, etc.) are located in [Section 13
Sponsor’s Signatures].


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2.  INVESTIGATOR’S SIGNATURE
A Phase 1 Randomized, Placebo-controlled Study to Assess the Safety, Tolerability and 
Pharmacokinetics of Multiple Doses of ASP8062 with a Single Dose of Morphine in 
Recreational Opioid Using Participants
ISN/Protocol 8062-CL-2002
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I have read all pages of this 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 of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
Good Clinical Practice (GCP) guidelines and applicable local regulations.  I will also 
ensure that subinvestigator(s) and other relevant members of my personnel 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:
Date (DD-MMM-YYYY)
Printed Name:
Address of 
trial site:


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CONTACT DETAILS OF SPONSOR’S KEY PERSONNEL
24-hour Contact for 
Serious Adverse Events
See [Section 10.3.7
Appendix 3 Reporting 
Procedures for Serious 
Adverse Events]
Please fax or email the serious adverse events/special 
situations worksheet to:
Astellas Pharma Global Development Inc.
US Pharmacovigilance
North America fax number: +1-888-396-3750
North America alternate fax number: +1-847-317-1241
Email: safety-us@astellas.com
Medical Monitor
Development Medical Science, Medical Specialties
Astellas Pharma Global Development Inc.
1 Astellas Way
Northbrook, IL 60062, US
PPD
PPD


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1
PROTOCOL SUMMARY
1.1
Synopsis
Title of Study:
A Phase 1 Randomized, Placebo-controlled Study to Assess the Safety, Tolerability and 
Pharmacokinetics of Multiple Doses of ASP8062 with a Single Dose of Morphine in Recreational 
Opioid Using Participants
Planned Study Period/Duration:
2Q2020 to 4Q2020
Planned Total Number of Study Sites and Location(s):
One study site in the US
Study Objectives, Endpoints and Estimands:
Objectives and Endpoints
Objectives
Endpoints
Primary
●
To assess the safety and tolerability of 
multiple doses of ASP8062 or placebo alone 
and in combination with a single dose of 
morphine
●
Nature, frequency and severity of AEs
●
Clinical laboratory tests (hematology, 
biochemistry and urinalysis)
●
Vital signs (blood pressure, pulse and 
respiratory rate)
●
12-lead ECG
●
C-SSRS
●
SpO2
●
End tidal CO2
Secondary
●
To assess the potential for pharmacokinetic 
interaction between ASP8062 and morphine
●
Plasma ASP8062: AUC24 and Cmax
●
Plasma morphine and its metabolites (M3G and 
M6G): AUCinf, AUClast and Cmax
Exploratory
●
To assess additional safety and tolerability of 
multiple doses of ASP8062 or placebo alone 
and in combination with a single dose of 
morphine
●
Oral temperature
●
ARCI-49
●
To assess the general pharmacokinetic 
parameters of ASP8062, its metabolites, 
morphine and its metabolites
●
Plasma ASP8062: CL/F, t½, tmax, tlag, Vz/F, 
Ctrough and PTR
●
Plasma ASP8062 metabolites (AS3486189, 
AS3486191 and AS3486192): Cmax, AUC24, t½, 
tmax, tlag, Vz/F, Ctrough and PTR
●
Plasma morphine and its metabolites (M3G and 
M6G): AUCinf(%extrap), CL/F (morphine), t½, 
tmax, tlag and Vz/F
●
To assess the potential for pharmacokinetic 
interaction between ASP8062 and morphine 
via metabolites
●
Plasma ASP8062 metabolites (AS3486189, 
AS3486191 and AS3486192): AUC24 and Cmax
AE: adverse event; ARCI-49: 49-item short form of Addiction Research Center Inventory scale; CO2: carbon 
dioxide; C-SSRS: Columbia-suicide severity rating scale; ECG: electrocardiogram; 
M3G: morphine-3β-D-glucuronide; M6G: morphine-6β-D-glucuronide; SpO2: blood oxygen saturation


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Estimands:
Not applicable.
Study Population:
This study will enroll male and female participants (18 to 60 years of age, inclusive) who have at 
least 10 lifetime uses of a recreational opioid drug with at least 1 opioid use in the last 90 days.
Number of Participants:
Approximately 24 male and female participants to complete at least 18 participants.  An attempt 
will be made to enroll 1 female participant for every 3 male participants.
Study Design Overview:
This will be a randomized, participant- and investigator-blinded, placebo-controlled, single 
sequence study comprising of male and female recreational opioid-using participants.
Participants will be screened for up to 28 days prior to first investigational product administration.  
Eligible participants will be admitted to the clinical unit on day -1 and will be residential for a 
single period of 17 days/16 nights.  After randomization, participants will receive multiple oral 
doses of ASP8062 or placebo (2:1 ratio) on days 1 through 10.  On day 10, all participants will also 
receive a single oral dose of morphine immediately after the ASP8062 or placebo dose followed by 
a 144-hour in-house blood sampling period.  Scheduled safety and tolerability assessments will be 
conducted as indicated in the Schedule of Assessments [Table 1].  Participants are to remain 
awake, seated or semirecumbent and avoid lying on either the left or right side for at least 4 hours 
postdose on days 9 and 10.  Participants will be discharged from the clinical unit on day 16 on the 
condition that all required assessments have been performed and that there are no medical reasons 
for a longer stay in the clinical unit.
The study will be completed with an end-of-study visit (ESV).  The ESV will take place 5 to 9 days 
after the day 16 pharmacokinetic sample is collected or at early discontinuation/termination from 
the study.
Treatment Groups and Duration:
Arm/IP Name
ASP8062
Placebo ASP8062
Morphine sulfate
Use
Test product
Placebo for ASP8062
Test product
Dose
25 mg (1 × 25 mg tablet)
NA (1 × tablet)
45 mg (3 × 15 mg 
immediate-release tablets)
Frequency
Once daily
Once daily
Single dose
Route
Oral
Oral
Oral
Duration
10 days
10 days
1 day
IP: investigational product; NA: not applicable
The anticipated duration of the study for each participant, including screening and follow-up, is 
approximately 53 days.




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1.3
Schedule of Assessments
Table 1
Schedule of Assessments
Study Phase
Screening Period1
Investigational Period
Follow-up 
Period/ET
Day(s)
-28 to -2
-1
1
2 to 8
9
10
11
12 to 15
162,3
ESV4
Residential Period
X
X
X
X
X
X
X
X
Informed Consent
X
Inclusion and Exclusion Criteria
X
X
Randomization5
X
(X)
Demographics
X
Medical History
X
X
Drug Use History/TLFB6
X
X
Body Weight and Height7
X
X
X
X
Clinical Laboratory Tests8
X
X
X
X
X
X
X
X
X
X
Drugs of Abuse/Alcohol Tests
X
X
Pregnancy Test (Female Participants 
Only)9
X
X
X
FSH Test (Postmenopausal Female 
Participants Only)
X
Vital Signs10
X
X
X
X
X
X
X
X
X
X
Continuous Pulse Oximetry11
X
X
12-lead ECG12
X
X
X
X
X
X
X
Physical Examination13
X
X
(X)
(X)
X
Spot SpO214
X
X
X
C-SSRS15
X
X
X
X
X
ARCI-49
X
X
X
X
Continuous and Spot End Tidal CO216
X
X
Table continued on next page


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Study Phase
Screening Period1
Investigational Period
Follow-up 
Period/ET
Day(s)
-28 to -2
-1
1
2 to 8
9
10
11
12 to 15
162,3
ESV4
Blood sampling for Biomarker 
Analysis17
X
(X)
Blood Sampling for PGx Analysis17
X
(X)
Dosing ASP8062 or Placebo18
X
X
X
X
Dosing Morphine19
X
Blood Sampling for ASP8062 and its 
Metabolites (AS3486189, AS3486191 
and AS3486192) Pharmacokinetics
X
X
X
X
X
X
Blood Sampling for Morphine and its 
Metabolites (M3G and M6G) 
Pharmacokinetics
X
X
X
Adverse Event Assessment
X
X
X
X
X
X
X
X
X
X
Previous/Concomitant Medications
X
X
X
X
X
X
X
X
X
X
ARCI-49: 49-item short form of Addiction Research Center Inventory scale; CO2: carbon dioxide; C-SSRS: Columbia-suicide severity rating scale; ECG: electrocardiogram; 
ESV: end-of-study visit; ET: early termination; FSH: follicle-stimulating hormone; M3G: morphine-3β-D-glucuronide; M6G: morphine-6β-D-glucuronide; PGx: pharmacogenomic; 
SpO2: blood oxygen saturation; TLFB: timeline follow-back
1.
Screening period is days -28 to -1.  Eligibility will be confirmed at screening and on day -1.  Participants who do not meet eligibility criteria on day -1 are considered screen 
failures.
2.
Scheduled sampling up to day 16 (144 hours postdose of morphine).
3.
Participants will be discharged from the clinical unit on day 16 on the condition that all required assessments have been performed and that there are no medical reasons for a 
longer stay in the clinical unit.  If a participant discontinues early from the study, discharge/ESV procedures will be performed upon discontinuation.
4.
The ESV will take place 5 to 9 days after the day 16 pharmacokinetic sample is collected or at early discontinuation/termination from the study.
5.
Randomization can occur on day -1 or predose on day 1 provided that eligibility is confirmed prior to randomization.
6.
TLFB will be collected for 2 weeks prior to screening or on day -1 (prior to any assessments).
7.
Height to be collected at screening only.
8.
Clinical laboratory tests include blood collection for serology (at screening only), hematology and biochemistry and urine collection for urinalysis.
9.
Serum pregnancy test at screening and urine pregnancy test on day -1 and at the ESV.
10. Vital signs include measurements of blood pressure, pulse, respiratory rate and oral temperature.  Measurements will be taken after the participant has been resting in the supine 
position for at least 5 minutes.  Measurements will be taken in duplicate at screening and on day -1 and at all other time points as single measurements.
Footnotes continued on next page


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11. Continuous pulse oximetry will begin predose on days 9 and 10 until at least 8 hours postdose..
12. 12-lead ECGs will be taken after the participant has been resting in the supine position for at least 5 minutes. 12-lead ECGs will be taken in triplicate.
13. Symptom-directed physical examinations may be performed on days 9 and 16.  Full physical examinations will be performed at screening, day -1 and ESV.
14. Single SpO2 measurements will be taken at designated time points.
15. The version of the C-SSRS to be performed at screening is the “Baseline/Screening” and the version of the C-SSRS to be performed on days -1, 9 and 16 and at the ESV is the 
“Since Last Visit”.
16. Continuous and spot end tidal CO2 to be collected starting predose on days 9 and 10 until 8 hours postdose.  Time points will be recorded predose and 1, 2, 4 and 8 hours postdose.
The cannula may be removed while participants dose or eat.
17. The blood sample for biomarker and PGx analysis (biobanking) can be collected on day -1 or predose on day 1.
18. On days 1, 9 and 10, ASP8062 or placebo will be administered orally under fasting conditions (i.e., no food or beverage will be allowed from at least 10 hours predose through at 
least 4 hours postdose) with approximately 240 mL water.  Water intake will be prohibited from at least 1 hour predose through at least 1 hour postdose, except for the 
approximately 240 mL water to swallow the investigational product.  On all other dosing days, ASP8062 or placebo will be administered orally under standardized fed conditions 
(i.e., meals will be served up to 1 hour predose or at least 2 hours postdose) with approximately 240 mL water.  Water intake will be allowed ad libitum.
19. On day 10, morphine will be administered as a single oral dose under existing fasting conditions with approximately 240 mL water, immediately after the ASP8062 or placebo 
dose.  Water intake will be prohibited from at least 1 hour predose through at least 1 hour postdose, except for the approximately 240 mL water to swallow the investigational 
product.


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Table 2
Sample Collection Schedule
Day
Time Point
Pharmacokinetics
ASP8062/metabolites
Pharmacokinetics
Morphine/metabolites
Vital Signs
Clinical 
Laboratory 
Tests
12-lead ECG
ARCI-49
Spot End 
Tidal CO2
Spot SpO2
Days -28 to -2
Screening
X
X
X
-1
X
X
X
1
Predose
X
X
X
X
X
2 hours
2
Predose
2 hours
3
Predose
X
X
2 hours
4
Predose
2 hours
5
Predose
2 hours
6
Predose
X
X
2 hours
7
Predose
2 hours
8
Predose
2 hours
Table continued on next page


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Day
Time Point
Pharmacokinetics
ASP8062/metabolites
Pharmacokinetics
Morphine/metabolites
Vital Signs
Clinical 
Laboratory 
Tests
12-lead ECG
ARCI-49
Spot End 
Tidal CO2
Spot SpO2
9
Predose
X
X
X
X
X
X
X
0.25 hour
X
0.5 hour
X
1 hour
X
X
X
X
1.5 hours
X
2 hours
X
X
X
X
X
X
X
2.5 hours
X
3 hours
X
4 hours
X
X
X
X
X
X
6 hours
X
8 hours
X
X
X
X
X
12 hours
X
X
X
X
X
16 hours
X
10
Predose
X
X
X
X
X
X
X
X
0.25 hour
X
X
0.5 hour
X
X
1 hour
X
X
X
X
X
1.5 hours
X
X
2 hours
X
X
X
X
X
X
X
X
2.5 hours
X
3 hours
X
X
4 hours
X
X
X
X
X
X
X
Table continued on next page


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Day
Time Point
Pharmacokinetics
ASP8062/metabolites
Pharmacokinetics
Morphine/metabolites
Vital Signs
Clinical 
Laboratory 
Tests
12-lead ECG
ARCI-49
Spot End 
Tidal CO2
Spot SpO2
10
6 hours
X
8 hours
X
X
X
X
X
X
12 hours
X
X
X
X
X
X
16 hours
X
X
11
24 hours postdose 
day 10
X
X
X
X
X
36 hours postdose 
day 10
X
X
12
48 hours postdose 
day 10
X
X
X
X
60 hours postdose 
day 10
X
13
72 hours postdose 
day 10
X
X
X
14
96 hours postdose 
day 10
X
X
X
15
120 hours postdose 
day 10
X
X
X
16
144 hours postdose 
day 10
X
X
X
X
ESV
5 to 9 days after the 
day 16 
pharmacokinetic 
sample/ED/ET
X
X
X
X
ARCI-49: 49-item short form of Addiction Research Center Inventory scale; CO2: carbon dioxide; ECG: electrocardiogram; ED: early discontinuation; ESV: end-of-study visit; 
ET: early termination; SpO2: blood oxygen saturation


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2
INTRODUCTION
2.1
Study Rationale
An in vitro cytochrome P450 (CYP) identification study suggested that ASP8062 is mainly 
metabolized by CYP3A4, while morphine shows no inhibitory effect on CYP3A in an in vitro 
study [Haaz et al, 1998].  Morphine is metabolized by multiple UDP-glucuronosyltransferases 
[De Gregori et al, 2012; Sato et al, 2012; Court et al, 2003; Projean et al, 2003].  Therefore, 
the pharmacokinetic drug-drug interaction (DDI) potential of ASP8062 with opioids is 
considered to be low.  Potential interaction such as opioid effects on respiratory depression is 
theoretically possible because both ASP8062 and opioids are centrally active [Pattinson, 
2008].
For future studies in opioid use disorder (OUD) patients, ASP8062 will be coadministered with 
opioids, including standard medication-assisted treatments such as buprenorphine/naloxone.  
Among opioid receptors, the µ-receptor is considered to play a role in the decrease in the 
respiratory response to hypoxia, resulting in a decreased stimulus to breathe and the 
development of apnea [Schiller & Mechanic, 2019].  ASP8062 has not been observed to 
directly interact with opioid receptor [study 8062-PH-9005] and the preclinical DDI study 
[study 8062-PH-9055] between ASP8062 and morphine, a full agonist for opioid µ-receptor, 
failed to find any pharmacodynamic (i.e., respiratory depression) interaction including general 
condition.  This clinical DDI/safety study will provide relevant safety (particularly for 
respiratory depression), tolerability and pharmacokinetic data in order to assess the potential 
risk of ASP8062 coadministered with morphine, a full agonist for opioid µ-receptor to support 
future studies in this patient population.  The study was designed particularly to investigate if 
ASP8062 has any additive effect on top of morphine by instituting the sensitive measure of end 
tidal carbon dioxide (CO2), using a single morphine dose slightly above the highest approved 
individual morphine dose, but presumably still allowing room to detect potential additive 
effects of ASP8062.
2.2
Background
ASP8062 is a novel compound with positive allosteric modulator (PAM) activity on the 
gamma-aminobutyric acid type B (GABAB) receptor that is intended for oral administration 
and is currently being developed for the treatment of OUD and alcohol use disorder.  
ASP8062 is a crystal, which is practically insoluble in water and slightly soluble in ethanol.
An estimated 2.1 million Americans had an OUD in 2017 [Substance Abuse and Mental 
Health Services Administration, 2018].  Overdose deaths due to opioid use have skyrocketed 
to over 47600 in 2017 [Scholl et al, 2018].  National Institute on Drug Abuse (NIDA) data 
show that use of opioids can lead to neonatal abstinence syndrome [NIDA, 2019a] as well as 
the spread of infectious diseases like human immunodeficiency virus (HIV) and hepatitis 
[NIDA, 2019b].  Medication assisted treatment with buprenorphine (with or without 
naloxone), methadone or naltrexone is the current standard of care, and has resulted in 
decreases in opioid use, overdose deaths, criminal activity and infectious disease transmission 
[Mattick et al, 2014; Schwartz et al, 2013; Mattick et al, 2009].  However, buprenorphine can 


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induce withdrawal on first administration, has an overdose potential, induces withdrawal 
symptoms and a loss of tolerance on cessation, is also subject to abuse and diversion and can 
cause respiratory suppression.  Buprenorphine’s ceiling effect may limit its effectiveness in 
patients with ongoing opioid use [Bart, 2012].
The Diagnostic and Statistical Manual of Mental Disorders, edition 5 (DSM-5) defines 
substance use disorders as a constellation of recurrent pathological cognitive, behavioral and 
physiological symptoms arising from the ongoing use of a substance.  The DSM-5 has 
combined the Diagnostic and Statistical Manual of Mental Disorders, edition 4 categories of 
substance abuse and substance dependence under the single heading of substance use 
disorders, which is classified by severity based on the number of symptom criteria (out of a 
total of 11) that are met: mild (2 to 3 criteria), moderate (4 to 5 criteria) and severe (more 
than 6 criteria) [Hasin et al, 2013].  Different drugs produce different effects on the user, but 
important shared features include a dysregulation of brain reward pathways and an overactive 
brain stress system, which together reinforce use of the substance to achieve a pleasurable 
high, even if pursuing this high incurs great cost or negative consequences for the user.
Gamma-aminobutyric acid (GABA), the most abundant inhibitory neurotransmitter, activates 
2 types of receptors: ionotropic GABA type A receptors [Olsen & Sieghart, 2008] and 
metabotropic GABAB receptors [Bowery et al, 2002].  Studies with GABAergic drugs and 
drugs of abuse have indicated that the GABAB receptor mediates suppression of 
self-administration/craving across several drug modalities.  Drugs triggering abuse act by 
enhancing dopamine release in the ventral tegmental, striatal, and prefrontal cortical areas of 
the brain.  The effects of GABAergic compounds on decreasing drug self-administration and 
drug-seeking behavior act by either directly or indirectly decreasing dopamine release in the 
aforementioned brain areas [Filip et al, 2015].
GABAB agonists or PAMs have been found to attenuate opioid-, alcohol-, cocaine- and 
nicotine-seeking behavior [Augier et al, 2017; Vlachou et al, 2011; Franklin et al, 2009; Filip 
& Frankowska, 2007; Paterson et al, 2004; Di Ciano & Everitt, 2003b; Di Ciano & Everitt, 
2003a] and also attenuate the drugs of abuse-evoked changes during intracranial 
self-stimulation [Vlachou et al, 2011; Paterson et al, 2008; Slattery et al, 2005].  However, 
activation of GABAB receptors by orthosteric agonists such as baclofen induces side effects 
such as sedation, somnolence, excessive weakness, vertigo and cognitive impairment.  The 
sedative properties of baclofen limits its potential widespread therapeutic utility [Dario & 
Tomei, 2004].  Accordingly, activation of GABAB receptors by PAMs is one of the 
prioritized medication treatment approaches for NIDA in response to the opioid crisis 
[Rasmussen et al, 2019].
For information on the nonclinical and clinical data of ASP8062, please refer to the 
[Investigator’s Brochure].


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2.3
Risk/Benefit Assessment
2.3.1
Risk Assessment
ASP8062 has a potential to decrease use of illicit opioid drugs and improve the quality of life 
in patients with OUD.  In the present study however where only a single daily 25 mg oral 
dose of ASP8062 will be administered for 10 consecutive days, there is no likelihood of a 
therapeutic effect.  Given the safety profile of ASP8062 when administered to healthy 
participants, there appears to be relatively minimal risk to participants taking a daily 25 mg 
oral dose.  The clinical unit has appropriately trained staff and required equipment available 
to treat participants presenting with both opioid withdrawal and morphine associated adverse 
events (AEs) including respiratory depression.
The risks of morphine immediate-release tablets are well known.  Risks are mitigated in that 
only a single dose of morphine will be administered on day 10 following 10 consecutive 
daily administrations of ASP8062 [Morphine Sulfate Package Insert].  Risks are also 
minimized because the participants are confined at a clinical unit that has administered a 
range of opioids, including morphine.  Side effects of opioids in general include respiratory 
depression, central nervous system depression and drowsiness, euphoria, feelings of 
relaxation, dependence, reduction of gastrointestinal motility, hepatitis with or without 
jaundice, allergic reactions, impairment in the ability to drive, orthostatic hypotension, 
elevation of cerebrospinal fluid pressure and intracholendochal pressure.
There is no expected benefit to the participants from the administration of morphine.
This will be the first study where a multiple daily oral dose of ASP8062 is administered in 
participants that will also be given morphine after the participants have reached near 
steady-state peak to trough exposures of ASP8062.  Risks are minimized by confining 
participants in an experienced clinical unit testing the effects of approved medications or new 
chemical entities when combined with morphine.  This study is also being conducted after the 
initiation of the phase 1b study examining a single dose of ASP8062 (60 mg) in participants 
also administered buprenorphine-naloxone at doses/exposures consistent with OUD standard 
of care.  Continuous pulse oximetry and capnography for at least 8 hours will be employed on 
day 10 when ASP8062 is given with morphine so that the potential for respiratory depression 
will be noted immediately, and appropriate medical treatment may be given.  Participants will 
also be monitored by experienced staff for signs of opioid withdrawal.  Vital signs will be 
monitored daily from days 9 to 16 and electrocardiograms (ECGs) will be monitored on 
day 10 to detect potential cardiovascular symptoms several hours postdose.  AEs will be 
assessed daily throughout the study.  Potential hepatic toxicity will be monitored with clinical 
laboratory testing on at least a daily basis from days 10 to 16 of the investigational period.
2.3.2
Benefit Assessment
There is not expected to be a benefit from multiple consecutive daily oral doses of ASP8062 
for 10 days in addition to a single oral dose of 45 mg morphine immediate-release tablets.


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2.3.3
Overall Risk-Benefit Conclusion
Participants in this study will not benefit from administration of ASP8062.  In contrast, 
participants might experience AEs related to ASP8062 or procedural complications 
(e.g., blood draws, slight skin irritation from the adhesive on the ECG electrodes).
Overall, the risk associated with the participation of recreational opioid using participants in 
this study is considered acceptable.
3
OBJECTIVES, ENDPOINTS AND ESTIMANDS
Table 3
Study Objectives and Endpoints
Objectives
Endpoints
Primary
●
To assess the safety and tolerability of multiple 
doses of ASP8062 or placebo alone and in 
combination with a single dose of morphine
●
Nature, frequency and severity of AEs
●
Clinical laboratory tests (hematology, 
biochemistry and urinalysis)
●
Vital signs (blood pressure, pulse and respiratory 
rate)
●
12-lead ECG
●
C-SSRS
●
SpO2
●
End tidal CO2
Secondary
●
To assess the potential for pharmacokinetic
interaction between ASP8062 and morphine
●
Plasma ASP8062: AUC24 and Cmax
●
Plasma morphine and its metabolites (M3G and 
M6G): AUCinf, AUClast and Cmax
Exploratory
●
To assess additional safety and tolerability of 
multiple doses of ASP8062 or placebo alone 
and in combination with a single dose of 
morphine
●
Oral temperature
●
ARCI-49
●
To assess the general pharmacokinetic 
parameters of ASP8062, its metabolites, 
morphine and its metabolites
●
Plasma ASP8062: CL/F, t½, tmax, tlag, Vz/F, Ctrough
and PTR
●
Plasma ASP8062 metabolites (AS3486189, 
AS3486191 and AS3486192): Cmax, AUC24, t½, 
tmax, tlag, Vz/F, Ctrough and PTR
●
Plasma morphine and its metabolites (M3G and 
M6G): AUCinf(%extrap), CL/F (morphine), t½, 
tmax, tlag and Vz/F
●
To assess the potential for pharmacokinetic 
interaction between ASP8062 and morphine via 
metabolites
●
Plasma ASP8062 metabolites (AS3486189, 
AS3486191 and AS3486192): AUC24 and Cmax
AE: adverse event; ARCI-49: 49-item short form of Addiction Research Center Inventory scale; CO2: carbon 
dioxide; C-SSRS: Columbia-suicide severity rating scale; ECG: electrocardiogram; 
M3G: morphine-3β-D-glucuronide; M6G: morphine-6β-D-glucuronide; SpO2: blood oxygen saturation
Estimands
Not applicable.


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4
STUDY DESIGN AND DOSE RATIONALE
4.1
Overall Study Design
This will be a randomized, participant- and investigator-blinded, placebo-controlled, single 
sequence study comprising of male and female recreational opioid-using participants.  
Approximately 24 male and female participants will be randomly assigned to complete at 
least 18 participants.  An attempt will be made to enroll 1 female participant for every 3 male 
participants.  The study will be conducted at 1 study site in the US.
Participants will be screened for up to 28 days prior to first investigational product (IP) 
administration.  Eligible participants will be admitted to the clinical unit on day -1 and will be 
residential for a single period of 17 days/16 nights.  After randomization, participants will 
receive multiple oral doses of ASP8062 or placebo (2:1 ratio) on days 1 through 10.  On 
day 10, all participants will also receive a single oral dose of morphine immediately after the 
ASP8062 or placebo dose followed by a 144-hour in-house blood sampling period.  
Scheduled safety and tolerability assessments will be conducted as indicated in the Schedule 
of Assessments [Table 1].  Participants are to remain awake, seated or semirecumbent and 
avoid lying on either the left or right side for at least 4 hours postdose on days 9 and 10.  
Participants will be discharged from the clinical unit on day 16 on the condition that all 
required assessments have been performed and that there are no medical reasons for a longer 
stay in the clinical unit.
The study will be completed with an end-of-study visit (ESV).  The ESV will take place 5 to 
9 days after the day 16 pharmacokinetic sample is collected or at early 
discontinuation/termination from the study.
4.2
Scientific Rationale for Study Design
A randomized, participant- and investigator-blinded, placebo-controlled, single sequence 
study was chosen to assess the safety and tolerability of multiple doses of ASP8062 alone 
and ASP8062 in combination with a single dose of morphine sulfate, a full µ-opioid receptor 
agonist.  Participants will be randomized to treatment to reduce selection bias.  Participants 
and the investigator will both be blinded to treatment to reduce bias in the measurement of 
the primary safety endpoints.  Given the long pharmacokinetic t½ of ASP8062 (approximately 
60 hours), a single sequence study was chosen.
4.3
Dose Rationale
The primary objective of this study is to assess the safety and tolerability of multiple doses of 
ASP8062 alone and ASP8062 in combination with a single dose of morphine sulfate, a full 
µ-opioid receptor agonist.  In the 8062-CL-0005 study, the AUCs of 30 mg ASP8062 with 
tablet B formulation (provided as a 30 mg tablet) were approximately 10% higher than 30 mg 
ASP8062 with tablet A formulation (provided as a 25 mg tablet plus a 5 mg tablet) with the 
90% CI within the standard bioequivalence limits (80.00, 125.00); Cmax was approximately 
60% higher.  With this finding, multiple doses of 25 mg ASP8062 with tablet B formulation 
will be proposed for future clinical studies for OUD.  The predicted exposures after multiple 


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doses of 25 mg ASP8062 are 1828 h•ng/mL for AUC24 and 143 ng/mL for Cmax.  These 
exposures will be comparable to exposures in the previous clinical studies and will not 
exceed mean exposure limit set in previous phase 1 studies (247 ng/mL for Cmax and 
2339 h•ng/mL for AUC24); which means exposures achieved in this study are expected to be 
pharmacologically active (as seen in 8062-CL-0003) and also safe and tolerated based on 
data from previous clinical studies in a total of 137 healthy participants and 95 fibromyalgia 
patients.
The single dose of 45 mg morphine sulfate is 1.5 times higher than the approved highest 
individual dose per package insert [Morphine Sulfate Package Insert].  This dose is 
equivalent to 30 mg oxycodone, which is 2 times higher than the recommended highest 
individual dose and considered to be sufficient to show a sign of µ-receptor agonism.  Cmax
after a single dose of 45 mg morphine sulfate immediate-release tablet is expected to be close 
to the reported maximum serum morphine concentration after intramuscular administration of 
morphine chloride (0.15 mg/kg body weight) in which most participants showed depression 
of the ventilatory response, characterized by the slopes of the carbon dioxide tension 
ventilation curves [Møller et al, 1982].
4.4
End of Study Definition
The end of the study is defined as the last visit or scheduled procedure shown in Schedule of 
Assessments [Table 1] for the last participant in the study.
5
STUDY POPULATION
All screening assessments must be completed and reviewed to confirm the potential 
participant meets all eligibility criteria.  Prospective approval of protocol deviations to 
eligibility criteria (also known as protocol waivers or exemptions) is not permitted.
The study population will consist of male and female participants (18 to 60 years of age, 
inclusive) who have at least 10 lifetime uses of a recreational opioid drug with at least 
1 opioid use in the last 90 days.
5.1
Inclusion Criteria
Participant is eligible for participation in the study if all of the following apply:
1.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved written 
informed consent and privacy language as per national regulations (e.g., Health 
Insurance Portability and Accountability Act authorization for US sites) must be 
obtained from the participant prior to any study-related procedures (including withdrawal 
of prohibited medication, if applicable).
2.
Participant is a male or female participant between 18 to 60 years of age, inclusive at 
screening.
3.
Participant is a recreational opioid user who has used opioids for nontherapeutic 
(recreational) purposes on at least 10 occasions within their lifetime, with at least 
1 opioid use in the last 90 days.


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4.
Participant has a body mass index (BMI) range of 18 to 36 kg/m2, inclusive and weighs 
at least 50 kg at screening.
5.
Female participant is not pregnant (see [Section 10.2 Appendix 2 Contraception 
Requirements]) and at least 1 of the following conditions apply:
a.
Not a woman of childbearing potential (WOCBP) (see [Section 10.2 Appendix 2 
Contraception Requirements])
b.
WOCBP who agrees to follow the contraceptive guidance (see [Section 10.2
Appendix 2 Contraception Requirements]) from the time of informed consent 
through at least 28 days after final IP administration.
6.
Female participant must agree not to breastfeed starting at screening and throughout the 
study period and for 28 days after final IP administration.
7.
Female participant must not donate ova starting at first dose of IP and throughout the 
study period and for 28 days after final IP administration.
8.
Male participant with female partner(s) of childbearing potential (including breastfeeding 
partner[s]) must agree to use contraception (see [Section 10.2 Appendix 2 Contraception 
Requirements]), throughout the treatment period and for 90 days after final IP 
administration.
9.
Male participant must not donate sperm during the treatment period and for 90 days after 
final IP administration.
10. Male participant with a pregnant partner(s) must agree to remain abstinent or use a 
condom with spermicide for the duration of the pregnancy throughout the study period 
and for 90 days after final IP administration.
11. Participant agrees to not participate in another interventional study while participating in 
the present study.
12. Participant must be willing to abstain from smoking (including use of tobacco-containing 
products and nicotine or nicotine-containing products [e.g., electronic vapes]) from at 
least 1 hour predose through at least 8 hours postdose on days 9 and 10.
5.2
Exclusion Criteria
Participant will be excluded from participation in the study if any of the following apply:
1.
Participant has received any investigational therapy within 28 days or 5 half-lives, 
whichever is longer, prior to screening.
2.
Participant has any condition which, in an investigator’s opinion, makes the participant 
unsuitable for study participation.
3.
Female participant who has been pregnant within 6 months prior to screening or 
breastfeeding within 3 months prior to screening.
4.
Participant has a known or suspected hypersensitivity to ASP8062 or morphine and/or 
other opioids, or any components of the formulations used.
5.
Participant has had previous exposure with ASP8062.
6.
Participant has any of the liver function tests (alkaline phosphatase [ALP], alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyl transferase 


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and total bilirubin [TBL]) ≥1.5 × upper limit of normal (ULN) on day -1.  In such a 
case, the assessment may be repeated once.
7.
Participant has any clinically significant history of allergic conditions (including drug 
allergies, asthma or anaphylactic reactions, but excluding untreated, asymptomatic, 
seasonal allergies) prior to first IP administration as judged by an investigator.
8.
Participant has any history or evidence of any clinically significant cardiovascular, 
gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, 
pulmonary, neurologic, dermatologic, renal and/or other major disease or malignancy, as 
judged by an investigator, with exception of history of cholecystectomy.
9.
Participant has a history of moderate or severe use disorder for any substance other than 
caffeine or tobacco (based on the DSM-5 criteria).
10. Participant has a history or presence of any clinically significant psychiatric disorders 
such as, bipolar 1, schizophrenia, schizoaffective disorder or major depressive disorders, 
as judged by an investigator.
11. Participant has had recent suicidal ideation within the last 12 months or participant who 
is at significant risk to commit suicide, as judged by an investigator, using the 
Baseline/Screening Columbia-suicide severity rating scale (C-SSRS) at screening and the 
Since Last Visit C-SSRS on day -1.
12. Participant has/had febrile illness or symptomatic, viral, bacterial (including upper 
respiratory infection) or fungal (noncutaneous) infection within 1 week prior to day -1.
13. Participant has any clinically significant abnormality following an investigator’s review 
of the physical examination, ECG and protocol-defined clinical laboratory tests at 
screening or on day -1.
14. Participant has a mean pulse < 50 or > 90 bpm; mean systolic blood pressure 
> 150 mmHg; mean diastolic blood pressure > 95 mmHg (measurements taken in 
duplicate after participant has been resting in the supine position for at least 5 minutes) 
on day -1.  If the mean blood pressure exceeds the limits above, 1 additional duplicate 
may be taken.
15. Participant has a mean corrected QT interval using Fridericia’s formula (QTcF) of 
> 450 msec (for male participants) and > 470 msec (for female participants) on day -1.  If 
the mean QTcF exceeds the limits above, 1 additional triplicate ECG may be taken.
16. Participant has a positive test for amphetamines, barbiturates, benzodiazepines, cocaine, 
phencyclidine, alcohol and/or opiates on day -1.  Positive tetrahydrocannabinol is not 
exclusionary and a cannabis intoxication evaluation will be performed.  Participant may 
be reconsidered at an investigator’s discretion.
17. Participant has used any prescribed or nonprescribed drugs (including vitamins and 
natural and herbal remedies, e.g., St. John’s Wort) in the 2 weeks prior to first IP 
administration, except for occasional use of acetaminophen (up to 2 g/day), topical 
dermatological products, including corticosteroid products, hormonal contraceptives and 
hormone replacement therapy (HRT).
18. Criterion Removed.


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19. Participant has used any inducer of CYP3A4-related metabolism (e.g., barbiturates, 
rifampin, apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, St. John’s 
wort, bosentan, efavirenz, etravirine, phenobarbital, primidone, armodafinil, modafinil, 
and rufinamide) in the 3 months prior to day -1.
20. Participant has had significant blood loss, donated approximately 500 mL of whole blood 
(excluding plasma donation) within 56 days prior to screening or donated plasma within 
7 days prior to day -1.
21. Participant has a positive serology test for hepatitis B surface antigen, hepatitis C virus 
antibodies or antibodies to HIV type 1 and/or type 2 at screening.
22. Participant has loss of ability to freely provide consent through imprisonment or 
involuntary incarceration for treatment of either a psychiatric or physical (e.g., infectious 
disease) illness.
23. Participant is an employee of Astellas, the study-related contract research organizations 
(CROs) or the clinical unit.
5.3
Lifestyle Considerations
5.3.1
Exercise
Participants will refrain from strenuous exercise from 48 hours prior to admission to the 
clinical unit up to and including the ESV.
Participants are encouraged to walk and stretch during the confinement period to avoid AEs 
associated with the sedentary environment.
5.3.2
Dietary and Fluid Restrictions
To avoid false positive results of the drugs of abuse test, no food or drinks containing poppy 
seeds (e.g., specialty breads and muffins) will be allowed from 48 hours prior to admission to 
the clinical unit up to and including the ESV.
Participants will not be allowed to consume food and drinks which may interact with 
circulatory, gastrointestinal, liver or renal function from at least 24 hours for alcohol or 
xanthine-containing products (including caffeine) and 72 hours for grapefruit/Seville orange 
or grapefruit/Seville orange-containing products prior to admission to the clinical unit up to 
and including the ESV.
Participants will be served normal balanced caloric drinks and meals at consistent times 
during their stay in the clinical unit.  Total daily caloric intake will preferably not exceed 
normal daily limits (approximately 2800 kcal/male and female participants).  Dietary and 
fluid restrictions apply to dosing conditions as specified in [Section 6.1 Investigational 
Product(s)].  The menu and nutritional information will be documented in the clinical study 
file.
Standardized lunch and dinner will be served at fixed time points on day 1.  On other days, 
the participants will receive standard meals.


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5.3.3
Smoking Restrictions
Participants will not be allowed to smoke (including using tobacco-containing products and 
nicotine or nicotine-containing products [e.g., electronic vapes]) from at least 1 hour predose 
through at least 8 hours postdose on days 9 and 10 during measurements for continuous pulse 
oximetry and end tidal CO2.
5.4
Screen Failures
A screen failure is defined as a potential participant who signed the informed consent form 
(ICF), but did not meet one or more criteria required for participation in the study and was 
not randomized.
For screen failures, the demographic data, date of signing the ICF, inclusion and exclusion 
criteria, AEs up to the time of screen failure and reason for screen failure will be collected in 
the electronic data source.
5.4.1
Rescreening
Results of screening assessments that do not meet the parameters required by eligibility 
criteria (e.g., clinical laboratory tests, vital signs, physical examination, ECG, etc.) may be 
repeated once within the 28-day screening period without the need to register the participant 
as a screen failure. If the participant meets exclusion criteria that cannot resolve during the 
screening period, or more than 28 days elapse from the date of signing the ICF, the 
participant must be documented as a screen failure. In order to re-screen after prior screen 
failure, a new ICF must be signed and the participant entered into screening with a new 
participant identification number. Rescreening is only allowed once for an individual 
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6
INVESTIGATIONAL PRODUCT(S)
6.1
Investigational Product(s) Administered
Table 4
Investigational Product(s)
IP Name
ASP8062
Placebo ASP8062
Morphine sulfate
Use
Test product
Placebo for ASP8062
Test product
Dosage Form
Tablet
Tablet
Immediate-release tablet
Physical 
Description
Round, light 
yellowish-red film 
coated tablet
Round, light yellowish-red 
film coated tablet
White, biconvex tablet scored 
on 1 side and product 
identification “54” over “733” 
debossed on the other side
Unit Dose 
Strength
25 mg (1 × 25 mg 
tablet)
NA (1 × tablet)
45 mg (3 × 15 mg 
immediate-release tablets)
Frequency
Once daily
Once daily
Single dose
Duration
10 days
10 days
1 day
Packaging and 
Labeling
1 × aluminum/alumin
um blister strips 
(2 × 7 configuration 
per strip in carton
1 × aluminum/aluminum 
blister strips (2 × 7 
configuration per strip in 
carton
100 tablets (10 × 10) unit-dose 
tablets, packaged in carton
Route
Oral
Oral
Oral
Administration
On days 1, 9 and 10, ASP8062 or placebo will be 
administered orally under fasting conditions (i.e., no 
food or beverage will be allowed from at least 
10 hours predose through at least 4 hours postdose) 
with approximately 240 mL water.  Water intake 
will be prohibited from at least 1 hour predose 
through at least 1 hour postdose, except for the 
approximately 240 mL water to swallow the IP.  On 
all other dosing days, ASP8062 or placebo will be 
administered orally under standardized fed 
conditions (i.e., meals will be served up to 1 hour 
predose or at least 2 hours postdose) with 
approximately 240 mL water.  Water will be 
allowed ad libitum.
On day 10, morphine will be 
administered orally under the 
existing fasting conditions 
with approximately
240 mL water, immediately 
after the ASP8062 or placebo 
dose.  Water intake will be 
prohibited from at least 1 hour 
predose through at least 1 hour 
postdose, except for the 
approximately 240 mL water 
to swallow the IP.
IMP or Non-IMP
IMP
IMP
IMP
Sourcing
Provided centrally by 
sponsor
Provided centrally by 
sponsor
Provided locally by 
investigator site
IMP: Investigational Medicinal Product; IP: investigational product
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Packaging and Labeling
All IP used in this study will be prepared, packaged and labeled under the responsibility of 
qualified personnel at Astellas Pharma Global Development Inc. (APGD) or sponsor’s 
designee in accordance with APGD or sponsor’s designee standard operating procedures 
(SOPs), current Good Manufacturing Practice (GMP) guidelines, International Council for 


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Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good 
Clinical Practice (GCP) guidelines and applicable local laws/regulations.
Each carton will bear a label conforming to regulatory guidelines, GMP and local laws and 
regulations that identifies the contents as investigational drug.
6.2.2
Handling, Storage and Accountability
●
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all IP received and any discrepancies are reported and 
resolved before use of the IP.
●
Only participants enrolled in the study may receive IP and only authorized study site 
personnel may supply or administer IP.  Only IP with appropriate expiry/retest dating 
may be dispensed.
●
All IP must be stored in a secure, environmentally controlled and monitored (manual or 
automated) area in accordance with the labeled storage conditions and access must be 
limited to the investigator and authorized study site personnel.
●
The investigator, institution or the head of the medical institution (where applicable) is 
responsible for accountability, reconciliation and record maintenance (i.e., receipt, 
reconciliation and final disposition records).
●
After final reconciliation is confirmed, further guidance and instruction of used and 
unused IP will be provided.
6.3
Randomization and Blinding
6.3.1
Blinding Method
The study will be conducted as participant- and investigator-blinded.
In order to maintain the blind, the participants will receive the same number of tablets.  The 
pharmacist will provide the investigator or designee with blinded IP to participants.
6.3.2
Confirmation of the Indistinguishability of the Investigational Product
The appearance of both the dosage form and packaging of ASP8062 are identical to those of 
its placebo.
6.3.3
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking
The randomization list will be stored with the clinical unit pharmacist in a locked storage
facility.  The individual emergency code envelopes (ECEs) will be stored with medical staff 
for medical emergency use.
6.3.4
Breaking the Treatment Code for Emergency
For every randomized participant, an individual ECE will be stored in a secure location with 
access by designated personnel, in the event of a medical emergency requiring knowledge of 
the treatment assigned to the participant.  A code break can only be requested by the 
investigator or subinvestigators designated to have access to perform blind-breaking.  In case 
of a medical emergency, the investigator (or his/her designated backup) has the sole 


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responsibility for determining if unblinding of the participant’s treatment assignment is 
warranted.  Participant safety must always be the first consideration in making such 
determination.  If the investigator decides that unblinding is warranted, the investigator 
should make every effort to contact the sponsor prior to unblinding a participant’s treatment 
assignment unless this could delay emergency treatment for the participant.
The investigator must have a designated backup to support emergency unblinding 
requirements.
Prior to randomization, participants should be provided with information that includes the 
study site emergency contact number and backup contact number in case of a medical 
emergency.  Any unblinding by the investigational personnel must be reported immediately 
to the sponsor and include an explanation of why the IP was unblinded.  Personnel who will 
be unblinded will not convey information regarding treatment assignments in the study, 
whether informally or formally, to any other person, unless required for medical reasons.  
The time and date of opening, any of these ECEs must be documented in the study file and 
the medical monitor should be contacted to discuss the case, if possible, before unblinding.  If 
unblinding is associated with a serious adverse event (SAE), the investigator is to follow the 
instructions in [Section 10.3.7 Appendix 3 Reporting Procedures for Serious Adverse 
Events].
All unopened ECEs will be destroyed at the end of the study.  Opened ECEs will remain at 
the study site with the participant’s study records.
6.3.5
Breaking the Treatment Code by the Sponsor
The sponsor may break the treatment code for participants 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 personnel who are responsible to break the codes for all SUSAR cases 
for reporting purposes.
6.3.6
Assignment and Allocation
6.3.6.1 Participant Number
Participants will be assigned a participant number at study entry (i.e., signing of informed 
consent).  The participant numbers will be sequential and rising.
The participant number will comprise of a 5-digit clinical unit number and 5-digit screening 
number.
6.3.6.2 Randomization
Prior to dosing, participants will be assigned a randomization number in accordance with the 
randomization code generated by the sponsor’s Data Science department or designee.  
Participants will be randomized in a 2:1 ratio to ASP8062 or placebo.
Once a randomization number has been allocated to a participant, it will not be assigned to 
another participant.  If a participant withdraws prematurely from the study and is replaced 


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under the direction of the sponsor, then a replacement randomization number will be 
assigned.  A replacement randomization code will be generated such that replacement 
participants are assigned to the same treatment as the discontinued participant.
6.4
Investigational Product Compliance
Dosing will take place in the clinical unit.  The administration of IP will be supervised to 
ensure treatment compliance.  After IP administration, a check of the participant’s mouth and 
hands will be performed.  The exact day and time of IP administration will be documented.
6.5
Dose Modification
Dose modifications are not allowed.
6.6
Continued Access to Investigational Product After the End of the 
Study
Not applicable.
6.7
Treatment of Overdose
In the event of suspected ASP8062 overdose, the participant should receive supportive care 
and monitoring.  The medical monitor/expert should be contacted as applicable.
In the event of suspected morphine overdose, refer to the approved package insert, summary 
of product characteristics or local product information supplied by the manufacturer for the 
IP.  The medical monitor/expert should be contacted as applicable.
Refer to [Section 10.3.8 Appendix 3 Reporting Procedures for Special Situations] for 
reporting requirements for suspected overdose or other medication error.
6.8
Concomitant Therapy
All medicinal products, including prescribed and nonprescribed drugs used prior to IP 
administration will be considered previous medication.
Specific restrictions on previous medications are provided in [Section 5.2 Exclusion Criteria].
All medication taken within 4 weeks prior to admission to the clinical unit will be 
documented.
All medicinal products other than the IP(s), including prescribed or nonprescribed drugs 
(including vitamins and natural and herbal remedies, e.g., St. John’s Wort), used from first IP 
administration until the ESV will be considered concomitant medication.
Participants will only be allowed to use the following concomitant medication, if needed, 
from first IP administration until the ESV:
●
Acetaminophen (up to 2 g/day)
●
Topical dermatological products, including corticosteroid products
●
Hormonal contraceptives
●
HRT


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If a participant’s health condition necessitates the use of any medication other than the 
permitted medications during the study, an investigator and medical monitor, or designee(s), 
will discuss the case and determine if the participant should be withdrawn from the study 
and/or excluded from analysis sets, depending on if, and how, the medication(s) used 
influence(s) the study outcome.  The nonpermitted concomitant medication will be recorded 
as a protocol deviation.
All concomitant treatments (medication and nonmedication therapy) will be documented.
7
STUDY PROCEDURES AND ASSESSMENTS
●
Study procedures and their timing are summarized in the Schedule of Assessments 
[Table 1].  Adherence to the study design requirements, including those specified in the 
Schedule of Assessments [Table 1], is essential and required for study conduct.  
Prospective protocol waivers or exemptions are not allowed.
●
Any change, divergence or departure from the study design or procedures identified in 
the protocol is considered a protocol deviation.  All deviations from the protocol are to 
be recorded.
●
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment.
●
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
●
Procedures conducted as part of the participant’s routine clinical management 
(e.g., imaging, blood count) and obtained before signing of the ICF may be utilized for 
screening or baseline purposes provided the procedures met the protocol-specified 
criteria and were performed within the time frame defined in the Schedule of 
Assessments [Table 1].
●
Analyte results that could unblind the study will not be reported to investigative sites or 
other blinded personnel until the study has been unblinded.
7.1
Efficacy Assessments
Not applicable.
7.2
Safety Assessments
7.2.1
Laboratory Assessments
Clinical laboratory tests will be performed at a local laboratory (apart from drugs of abuse 
and alcohol tests performed at the clinical unit).
Blood samples will be collected via a peripherally placed intravenous cannula or by direct 
venipuncture in a suitable vein.


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Blood samples for serology, hematology and biochemistry and urine samples for urinalysis 
will be collected as indicated in the Schedule of Assessments [Table 1] and Sample 
Collection Schedule [Table 2].  The clinical laboratory tests to be performed in the study are 
listed in [Section 10.6 Appendix 6 Clinical Laboratory Assessments].
Drugs of abuse and alcohol tests will be performed according to the clinical site’s preferred 
method as indicated in the Schedule of Assessments [Table 1].
Pregnancy tests (female participants only) will be performed according to the clinical site’s 
preferred method as indicated in the Schedule of Assessments [Table 1].
A blood sample will be collected for follicle-stimulating hormone (FSH) tests 
(postmenopausal female participants only) as indicated in the Schedule of Assessments 
[Table 1].
If any of the clinical laboratory tests results are outside the normal range at any scheduled 
time point during the study, an investigator may decide to repeat the test(s) on new samples.  
The clinical relevance of the abnormal results will be documented.  Clinically relevant 
changes will be recorded as AEs (see [Section 7.3 Adverse Events and Other Safety 
Aspects]).
7.2.2
Vital Signs
Blood pressure (systolic and diastolic blood pressure), pulse, respiratory rate and oral 
temperature will be taken as indicated in the Schedule of Assessments [Table 1] and Sample 
Collection Schedule [Table 2].  Measurements will be taken after the participant has been 
resting in the supine position for at least 5 minutes.  Measurements will be taken in duplicate 
with approximately 2-minute intervals at screening and on day -1 and at all other time points 
as single measurements.
7.2.3
Continuous Pulse Oximetry and Spot Blood Oxygen Saturation
Continuous pulse oximetry will be taken as indicated in the Schedule of Assessments 
[Table 1].  Continuous pulse oximetry will be measured using a pulse oximeter placed on the 
participant’s fingertip. The alarm value will be < 90% for the continuous pulse oximetry, 
which may indicate opioid-induced respiratory depression.
Spot blood oxygen saturation (SpO2) levels will be measured as indicated in the Schedule of 
Assessments [Table 1] and Sample Collection Schedule [Table 2].  SpO2 will be measured 
using a pulse oximeter placed on the participant’s fingertip.
7.2.4
Electrocardiogram
7.2.4.1 12-lead Electrocardiogram
12-lead ECGs will be taken as indicated in the Schedule of Assessments [Table 1] and 
Sample Collection Schedule [Table 2].  12-lead ECGs will be taken after the participant has 
been resting in the supine position for at least 5 minutes.  12-lead ECGs will be taken in 
triplicate with approximately 1-minute intervals and all 3 ECGs will be completed within 
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The investigator will use the system at the phase 1 unit to review, sign and date the ECG after 
recording to ensure participant safety.  The time of the ECG, the interval measurements, as 
well as an overall conclusion, will be documented.  This overall conclusion will be recorded 
as normal, abnormal not clinically significant, or abnormal clinically significant.  If the 
overall conclusion is abnormal, the applicable abnormality code as provided by the sponsor 
must be recorded.  Considering their relatively rare occurrence in healthy participants, an 
ECG judged as abnormal clinically significant by an investigator for phase 1 studies must be 
further evaluated by another investigator, and if confirmed will be recorded as an AE.
Per time point, the ECG printouts will be reviewed in a timely manner by the investigator.  
Paper ECGs will be stored with the participant source.  The time of the ECG, the interval 
measurements and the overall conclusion will be transcribed into the electronic CRF.
7.2.5
Physical Examination
Physical examination will be performed as indicated in the Schedule of Assessments 
[Table 1] and whenever there is a medical indication.
The investigator should examine the body systems as described in the clinical site’s SOP for 
physical examination.  New or worsening clinically significant physical examination findings 
after IP administration will be recorded as AEs if they meet the criteria in [Section 7.3
Adverse Events and Other Safety Aspects].
7.2.6
Columbia-Suicide Severity Rating Scale
The C-SSRS [Posner et al, 2009] is a feasible, low-burden rating scale that assesses the full 
spectrum of suicidality: suicidal ideation, intensity of ideation, suicidal behaviors and actual 
attempts.  Ratings will be performed as indicated in the Schedule of Assessments [Table 1] 
using the C-SSRS [Section 10.8 Appendix 8 Columbia-Suicide Severity Rating Scale].
7.2.7
49-item Short Form of Addiction Research Center Inventory Scale
The 49-item short form of Addiction Research Center Inventory scale (ARCI-49) [Haertzen 
et al, 1963] is a standardized questionnaire for assessing subjective effects of psychoactive 
drugs and in discriminating some similarities and differences of naturally occurring and 
experimentally induced behavioral abnormalities.  Participants will self-report using 
“sentence completion” and other association techniques.  Only part 1 (i.e., 49-items) will be 
used.  Ratings will be performed as indicated in the Schedule of Assessments [Table 1] and 
Sample Collection Schedule [Table 2] using the ARCI-49 [Section 10.9 Appendix 9 49-item 
Short Form of Addiction Research Center Inventory Scale].
7.2.8
Continuous and Spot End Tidal Carbon Dioxide
Continuous monitoring of end tidal CO2 will be taken as indicated in the Schedule of 
Assessments [Table 1].  End tidal CO2 measurements will be obtained by a health care 
professional directly monitoring a portable bedside capnography device.  Time points for 
recorded measurements will be performed as indicated in the Schedule of Assessments 
[Table 1] and Sample Collection Schedule [Table 2]. The alarm values for the capnography 
continuous values, which may indicate potential respiratory depression, are high end tidal


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CO2, low respiratory rate and no breath alarms. Alarms during continuous end tidal CO2
suggesting pulmonary issues other than opioid-induced respiratory depression include low 
end tidal CO2 and high respiratory rate [see Table 5].
Table 5
Established Limits for End Tidal Carbon Dioxide
Parameter
Established Limit
End Tidal CO2 High
50 mmHg
End Tidal CO2 Low
25 mmHg
Respiratory Rate High
24 bpm
Respiratory Rate Low
6 bpm
No Breath Alarm
20 seconds
CO2: carbon dioxide
7.2.9
Order of Assessments
All predose procedures, e.g., 12-lead ECG, vital signs and blood or urine sampling for 
clinical laboratory tests, will be performed within 60 minutes prior to dosing.  All other 
measurements for 12-lead ECG and vital signs, will be performed within 15 minutes of the 
nominal time point.  Pharmacokinetic sampling will be collected within 5 minutes from the 
nominal time point.
When time points for procedures overlap, blood sampling for pharmacokinetics will be 
collected at the nominal time point.  Blood sampling for clinical laboratory tests, 12-lead 
ECG, vital signs (including SpO2, if applicable), ARCI-49 and end tidal CO2 are to be 
collected before or after the nominal blood sampling for pharmacokinetics.
7.3
Adverse Events and Other Safety Aspects
The definitions of an AE or SAE can be found in [Section 10.3.1 Appendix 3 Definition of 
Adverse Events and Section 10.3.3 Appendix 3 Definition of Serious Adverse Events], 
respectively.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant’s legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study IP, or that caused the 
participant to discontinue the IP and/or study [Section 10.3 Appendix 3 Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-up and Reporting].
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in [Section 10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up and Reporting].


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7.3.1
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information
All SAEs will be collected from the signing of the ICF until the follow-up visit at the time 
points specified in the Schedule of Assessments [Table 1] and reported on the electronic data 
source.
All AEs will be collected from the signing of the ICF until the follow-up visit at the time 
points specified in the Schedule of Assessments [Table 1] and reported on the electronic data 
source.
If the severity of an AE/SAE changes, the event should be relisted on the electronic data 
source with the new severity and new onset date.
If the severity decreases, the AE/SAE should be relisted on the electronic data source with 
the new severity and new onset date.  The exception is ongoing predose events that continue 
postdose and improve postdose.  Such events should not be relisted.
If the severity of an SAE reduces, the details of the AE should be provided on the SAE 
worksheet for the medical assessor to be able to assess the course of the event.
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in [Section 10.3 Appendix 3: Adverse 
Events: Definitions and Procedures for Recording, Evaluating, Follow-up and Reporting].  
The investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available.
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation.  However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study IP or study participation, the investigator must promptly 
notify the sponsor.
7.3.2
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences.
7.3.3
Follow-up of Adverse Events and Serious Adverse Events
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts.  All SAEs and AEs of special interest (as defined in 
[Section 7.3.6 Adverse Events of Special Interest]) will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as 
defined in [Section 8.3 Lost to Follow-up]).  Further information on follow-up procedures is 
provided in [Section 10.3 Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting].


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If after the protocol-defined AE collection period (see [Section 7.3.1 Time Period and 
Frequency for Collecting Adverse Event and Serious Adverse Event Information]), an AE
progresses to an SAE, or the investigator learns of any (S)AE (serious adverse event or 
adverse event) including death, where he/she considers there is reasonable possibility it is 
related to the IP or study participation, the investigator must promptly notify the sponsor.
7.3.4
Regulatory Reporting Requirements for Serious Adverse Events
●
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study IP under clinical investigation are met.
●
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study IP under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC and investigators.
●
Investigator safety reports must be prepared for SUSAR according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
●
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements.
7.3.5
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events
Not applicable.
7.3.6
Adverse Events of Special Interest
AEs of special interest are AEs the sponsor may wish to carefully monitor.  These AEs may
be serious or nonserious and should be reported on the electronic data source and the SAE 
worksheet.  These AEs are not considered SAEs unless they meet the definition of an SAE.
AEs related to potential substance abuse and suicide (serious or nonserious) are considered to 
be of scientific and medical concern specific to ASP8062, for which ongoing monitoring and 
reporting is required.
Additional information around AEs of special interest will be collected to complete 
participant narratives.  AEs of special interest related to potential substance abuse are listed in 
[Section 10.10 Appendix 10 Adverse Events of Interest Related to Potential Substance Abuse 
and Following Drug Withdrawal].
AEs of special interest with respect to morphine include respiratory depression, constipation, 
nausea, vomiting, sedation, somnolence, lightheadedness, dizziness, and sweating.
7.3.7
Special Situations
Certain special situations observed in association with the IP, such as incorrect administration 
(e.g., wrong dose of IP or background therapy) are reported as protocol deviations and/or 


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may require special reporting, as described below.  These special situations are not 
considered AEs, but do require to be communicated to Astellas as per the timelines defined 
below.
If a special situation is associated with, or results in, an AE, the AE is to be assessed 
separately from the special situation and captured as an AE in the electronic data source.  If
the AE meets the definition of an SAE, the SAE is to be reported as described in 
[Section 10.3.7 Appendix 3 Reporting Procedures for Serious Adverse Events] and the details 
of the associated special situation are to be included in the clinical description on the special 
situation worksheet or pregnancy reporting form.
The special situations are:
●
Pregnancy
●
Lactation
●
Medication error, overdose and “off-label use”
●
Misuse/abuse
●
Occupational exposure
●
Suspected DDI
Instructions and procedures for reporting special situations are provided in [Section 10.3.8
Appendix 3 Reporting Procedures for Special Situations].
7.4
Pharmacokinetics
7.4.1
Analysis of ASP8062 and Metabolites in Plasma
Blood samples for the determination of ASP8062 and its metabolites (AS3486189, 
AS3486191 and AS3486192) in plasma will be collected as indicated in the Schedule of 
Assessments [Table 1] and Sample Collection Schedule [Table 2] for the evaluation of 
pharmacokinetics.  If needed, other metabolites may also be measured.
Blood will be drawn in plastic tubes containing K2-EDTA.  The actual date and time of each 
blood sample collection will be documented.  Plasma will be prepared according to 
procedures further specified in the laboratory manual.  Samples will be shipped to the 
designated CRO and analyzed using a validated method.
When deemed appropriate at a later date, plasma samples remaining after the 
pharmacokinetic analysis may be used for exploratory metabolite profiling or exploratory 
biomarker analysis after the study.  These tests will be described in a separate report and will 
not be incorporated in the integrated clinical study report (CSR).
7.4.2
Analysis of Morphine and Metabolites in Plasma
Blood samples for the determination of morphine and its metabolites 
(morphine-3β-D-glucuronide [M3G] and morphine-6β-D-glucuronide [M6G]) in plasma will 
be collected as indicated in the Schedule of Assessments [Table 1] and Sample Collection 
Schedule [Table 2] for the evaluation of pharmacokinetics.  Plasma will be prepared 


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according to procedures further specified in the laboratory manual.  Samples will be shipped 
to the designated CRO and analyzed using a validated method.
When deemed appropriate at a later date, plasma samples remaining after the 
pharmacokinetic analysis may be used for exploratory metabolite profiling or exploratory 
biomarker analysis after the study.  These tests will be described in a separate report and will 
not be incorporated in the integrated CSR.
7.5
Pharmacodynamics
Not applicable.
7.6
Pharmacogenomics
Pharmacogenomic (PGx) research may be conducted in the future to analyze or determine 
genes of relevance to clinical response, pharmacokinetics, toxicity/safety.  A 4 mL sample of 
whole blood for possible banked PGx analysis will be collected as indicated in the Schedule 
of Assessments [Table 1].  Samples will be shipped to a sponsor-designated sample banking 
CRO.
Details on sample collection, labeling, storage and shipment procedures will be provided in a
separate laboratory manual.
See [Section 10.7 Appendix 7: Pharmacogenomic Analysis with Banked Sample] for further 
details on the banking procedures.
7.7
Biomarkers
Knowledge of polymorphisms of genes GABAB receptors and/or opioid receptors may help 
understand/explain observed differences in efficacy/safety of ASP8062.  A 2 mL whole blood 
sample for the analysis of these biomarker (genes) will be collected as indicated in the 
Schedule of Assessments [Table 1].
For detailed sample collection, sample labeling and sample shipment procedures refer to the 
laboratory manual.  All samples will be transferred to the central laboratory and then shipped 
to the analytical laboratory where they will be analyzed using appropriate validated methods.
7.8
Immunogenicity Assessments
Not applicable.
7.9
Clinical Outcome Assessment
Not applicable.


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7.10
Total Amount of Blood
The approximate total blood volume taken per participant will be as follows:
Table 6
Blood Volume
Sample Type
Number of Samples
Sample Volume (mL)
Total Volume (mL)
Clinical Laboratory Tests
16
9
(+ 8.5)†‡
152.5
ASP8062 and its Metabolites 
(Including AS3486189, 
AS3486191 and AS3486192) 
Pharmacokinetics
35
2.0
70.0
Morphine and its Metabolites 
(M3G and M6G) 
Pharmacokinetics
14
1.0
14.0
Biomarker Analysis
1
2.0
2.0
PGx Analysis
1
4.0
4.0
Total
242.5
M3G: morphine-3β-D-glucuronide; M6G: morphine-6β-D-glucuronide; PGx: pharmacogenomic
† Includes pregnancy test (female participants only) and follicle-stimulating hormone test (postmenopausal 
female participants only) at screening.
‡ Includes serology test at screening.
Additional blood may be drawn for safety reasons.  The maximum amount of blood drawn 
during the study will not exceed 500 mL.
8
PARTICIPANT DISCONTINUATION
Refer to [Section 10.1.9 Appendix 1 Study and Site Start and Closure] regarding 
discontinuation of study sites or of the study as a whole.
8.1
Discontinuation of Individual Participant(s) from Study Treatment
A discontinuation from treatment is defined as a participant who enrolled in the study and for 
whom study treatment is permanently discontinued for any reason.
The participant 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 participant from study treatment or to terminate a 
participant’s involvement in the study at any time if the participant’s clinical condition 
warrants it.
The reason for discontinuation from study treatment must be documented in the participant’s 
medical records.
A participant must discontinue study treatment for any of the following reasons:
●
Participant requests to stop treatment
●
Any clinical AE, laboratory abnormality or intercurrent illness, in the opinion of the 
investigator, indicates continued treatment is not in the best interest of the participant


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●
Female participant becomes pregnant
●
If participant experiences symptomatic decrease in SpO2 requiring medical intervention 
prior to day 10 (predose)
8.2
Discontinuation of Individual Participant(s) from Study
All participants who discontinue study treatment will remain in the study and must continue 
to be followed for protocol-specific follow-up procedures as outlined in the Schedule of 
Assessments [Table 1].  The only exception to this is when the participant specifically 
withdraws consent for any further contact with him/her or persons previously authorized by 
the participant to provide this information.
8.3
Lost to Follow-up
Every reasonable effort is to be made to contact any participant lost to follow-up during the 
course of the study to complete study-related assessments, record outstanding data and 
retrieve IP.  These contact attempts should be documented in the participant’s medical record.
8.4
Discontinuation of the Study
The sponsor will terminate this study if 1 of the following criteria are met.  The sponsor will 
unblind the affected participant(s) to an investigator/delegate before a final decision is made.
1.
If after coadministration of morphine and ASP8062 or placebo on day 10, 
≥5 ASP8062-treated participants experience ASP8062-related AEs of severe intensity 
that are considered by an investigator to be of clinical concern
2.
If after coadministration of morphine and ASP8062 or placebo on day 10, 
≥3 ASP8062-treated participants experience an ASP8062-related SAE and there is no 
plausible alternate explanation for these events
3.
If after coadministration of morphine and ASP8062 or placebo on day 10, 
≥5 ASP8062-treated participants show at least 1 of the following findings in 
2 consecutive measurements within 24 hours postdose:
●
ALT or AST ≥3 × ULN and ALT or AST is > 3 × day 9 (day prior to ASP8062 or 
placebo ASP8062 and morphine coadministration) values
●
ALT or AST ≥2 × ULN and ALT or AST ≥5 × day 9 (day prior to ASP8062 or 
placebo and morphine coadministration) values
●
TBL ≥2 × ULN and participant does not have Gilbert Syndrome
4.
If after coadministration of ASP8062 or placebo and morphine on day 10, 
≥3 ASP8062-treated participants have QTcF interval > 500 msec in 2 consecutive 
measurements within 24 hours postdose
5.
If after coadministration of ASP8062 or placebo and morphine on day 10:
●
≥4 ASP8062-treated participants experience ASP8062-related symptomatic 
decrease in SpO2 requiring more than 2 liters of supplemental oxygen via nasal 
cannula or,
●
≥1 ASP8062-treated participant experiences ASP8062-related symptomatic decrease 
in SpO2 requiring intubation, for medically significant respiratory depression.


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9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
Not applicable.
9.2
Sample Size Determination
Approximately 24 participants will be enrolled to complete at least 18 participants.  
Participants who discontinue early from the study may be replaced at the discretion of the 
sponsor.  No formal sample size calculation is performed as this is not a statistically powered 
study.  The number of participants is based on the precedent set by other studies of similar 
nature.  The number of participants planned is considered sufficient to achieve the study 
objectives.
Based on data from Study 8062-CL-0005, the intrasubject coefficient of variation (CV) for 
pharmacokinetic parameters AUCinf and Cmax of ASP8062 are estimated to be between 10% 
and 24%. Based on the literature, the intrasubject CV for pharmacokinetic parameter Cmax of 
morphine is estimated to be 27% [Center for Drug Evaluation and Research, 2008].
Assuming the underlying variability is similar to 27% and the true underlying ratio is 100%, 
the 90% CI will lie within (76, 131) with > 80% probability.
9.3
Populations for Analyses
For each treatment group, the number and percentage of participants will be characterized for 
all randomized participants and by each population.
The following populations are defined:
Population
Description
Randomized
All participants who are randomized.  Participants will be analyzed according to the 
study treatment to which they are randomized.
SAF
All participants randomly assigned to study IP and who take at least 1 dose of study IP.  
Participants will be analyzed according to the IP they actually received.
The SAF will be used for all summaries and analysis of the safety data.
PKAS
All participants who receive at least 1 dose of IP for which concentration data are 
available to facilitate derivation of at least 1 primary pharmacokinetic parameter.  
Inclusion of participants in the PKAS with missing data or major protocol deviations 
will be considered by the pharmacokineticist on a case-by-case basis.
The PKAS will be used for all summaries and analyses of the pharmacokinetic data.
IP: investigational product; PKAS: pharmacokinetic analysis set; SAF: safety analysis set
9.4
Statistical Analyses
9.4.1
General Considerations
In general, data will be summarized with descriptive statistics for continuous endpoints, and 
frequency and percentage for categorical endpoints, unless otherwise specified.  Percentages 
by categories will be based on the number of participants with no missing data (i.e., will add 
up to 100%).


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Baseline will be defined as the last nonmissing observation prior to first administration of IP, 
unless otherwise specified.
Demographics and baseline characteristics (age, sex, race, ethnicity, body weight, height and 
BMI) will be summarized by treatment group and overall for all randomized participants.
The number and percentage of participants who completed and discontinued treatment and 
reasons for treatment discontinuation will be presented for all randomized participants and 
for participants in the safety analysis set (SAF) by treatment group (ASP8062 alone, placebo 
alone, morphine in combination with ASP8062, morphine in combination with placebo) and 
overall.  Similar tables for screening disposition, investigational period disposition and 
follow-up disposition will also be presented for all randomized participants by treatment 
group (ASP8062 alone, placebo alone, morphine in combination with ASP8062, morphine in 
combination with placebo) and overall.  All disposition details and dates of first and last 
evaluations for each participant will be listed.
Previous and concomitant treatment (medication and nonmedication therapy) and medical 
history will be listed.  The number and percentage of participants exposed to IP will be 
summarized by treatment group (ASP8062 alone, placebo alone, morphine in combination 
with ASP8062, morphine in combination with placebo) and visit.  All IP exposure data will 
be listed.
9.4.2
Analysis of Efficacy
Not applicable.
9.4.3
Analysis of Safety
For analysis of safety, the treatment groups are (ASP8062 alone, placebo alone, morphine in 
combination with ASP8062, morphine in combination with placebo).
9.4.3.1 Adverse Events
AEs will be coded using MedDRA.  An AE with onset at any time from first dosing until last 
scheduled procedure will be classified as a treatment-emergent adverse event (TEAE) for 
inclusion in the summary tabulations.  An IP-related TEAE is defined as any TEAE with a 
causal relationship assessed as “yes” by the investigator, or records where the relationship is 
missing.
An overview and separate summaries of the number and percentage of participants with 
TEAEs, IP-related TEAEs, TEAEs leading to withdrawal of treatment, IP-related TEAEs 
leading to withdrawal of treatment and TEAEs excluding SAEs that equal or exceed a 
threshold of 5% in any treatment group will be presented by SOC, preferred term and 
treatment group.  Also included in the overview are the number and percentage of 
participants with serious TEAEs, IP-related serious TEAEs, TEAEs leading to death and 
IP-related TEAEs leading to death.
The number and percentage of participants who have a TEAE within the drug abuse 
dependence Standardized MedDRA Queries (SMQ) (MedDRA v22.0) as classified by SOC 


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and preferred term, will be summarized by treatment group.  In addition, the number and 
percentage of participants who have drug abuse-related TEAEs as classified by preferred 
term and lowest level term will be summarized by treatment group [Section 10.10
Appendix 10 Adverse Events of Interest Related to Potential Substance Abuse and Following 
Drug Withdrawal].
The number and percentage of participants who have a TEAE with the drug withdrawal SMQ 
(MedDRA v22.0) as classified by SOC and preferred term will be summarized by treatment 
group.  In addition, the number and percentages of participants who have withdrawal-related 
TEAEs as classified by SOC and preferred term will be summarized by treatment group 
[Section 10.10 Appendix 10 Adverse Events of Interest Related to Potential Substance Abuse 
and Following Drug Withdrawal].
AE data will be listed.
9.4.3.2 Laboratory Assessments
For quantitative clinical laboratory measurements (hematology and biochemistry), descriptive 
statistics will be used to summarize results and change from baseline by treatment group and 
time point.
The number and percentage of participants with potentially clinically significant values in 
liver enzymes and TBL will be tabulated.
Laboratory data will be listed.
9.4.3.3 Vital Signs
Descriptive statistics will be used to summarize vital sign results (blood pressure, pulse and 
respiratory rate) and changes from baseline for participants in the SAF by treatment group 
and time point.
The number and percentage of participants with respiratory rate values as per [Table 7] at any 
time point will be summarized by treatment group.  The lowest and highest respiratory rate, 
respectively, will be used in the analysis.
Table 7
Criteria for Respiratory Rate
Vital Sign
Criteria
Respiratory Rate (breaths/minute)
< 6, < 8, < 10
> 24, > 28, > 32, > 36
The number and percentage of participants who reach an alarm value for the continuous 
respiratory rate, and the number of times an alarm value was reached will be listed and 
summarized by treatment.
Vital signs data will be listed.
9.4.3.4 Continuous Pulse Oximetry and Spot Blood Oxygen Saturation
The spot SpO2 levels and change from baseline (day 1) will be listed and summarized by 
treatment group and time point.  The number and percentage of participants with SpO2 levels 


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as per [Table 8] at any time point will be summarized by treatment group.  The lowest SpO2
level across the time points will be used in the analysis.
Table 8
Criteria for Assessing Spot Blood Oxygen Saturation
Parameter
Criteria
SpO2 level (%)
< 90, < 92, < 94, < 96
SpO2: blood oxygen saturation
The number and percentage of participants who reach an alarm value of continuous pulse 
oximetry, and the number of times an alarm value was reached will be listed and summarized 
by treatment.
9.4.3.5 Electrocardiogram
9.4.3.5.1
12-lead Electrocardiogram
The number and percentage of participants with 12-lead ECG criteria as per [Table 9] will be 
provided by treatment group, at each time point and overall by visit.
The average of the triplicate ECG measurements will be used for the analysis.
Table 9
Criteria for 12-lead Electrocardiogram
Parameter
Criteria
Absolute QTcF Interval (msec)
> 450, > 480, > 500
PR (msec)
> 200
QRS (msec)
> 110
Heart Rate (bpm)
> 100
QTcF Interval Increases from Baseline (msec)
> 30, > 60
QTcF: corrected QT interval using Fridericia’s formula
12-lead ECG data and interpretations will be listed.
9.4.3.6 Columbia-Suicide Severity Rating Scale
The listings will include only C-SSRS assessments that show at least 1 event of suicidality 
(suicidal ideation and/or suicidal behavior).
9.4.3.7 49-item Short Form of Addiction Research Center Inventory Scale
From the completed ARCI-49 questionnaire, scores for the amphetamine, benzedrine, 
pentobarbital-chlorpromazine-alcohol, morphine-benzedrine and lysergic-acid-diethylamide 
groups will be calculated.  The calculated subscale score and change from baseline will be 
listed and summarized by treatment group and time point.
The algorithm for scoring the ARCI-49 [Martin et al, 1971] is presented in [Section 10.9
Appendix 9 49-item Short Form of Addiction Research Center Inventory Scale, 
Questionnaire Scoring].  One point will be given for each response that agrees with the 
scoring direction.  Specifically, 1 point will be given for each “true” response (i.e., item has 
associated scoring coefficient +1), and 1 point will be given for each “false” response in the 


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reverse-scored items (i.e., item has associated scoring coefficient -1).  Each subscale score 
will be derived as the linear combination (sum) of mathematically-signed points among the 
relevant items, i.e., matched true/false responses.  Some items belong to more than 
1 subscale.
No missing data will be imputed.
9.4.3.8 Continuous and Spot End Tidal Carbon Dioxide
The spot end tidal CO2 levels and change from baseline (day 9) will be listed and summarized 
by treatment group and time point.  The number and percentage of participants with end tidal 
CO2 levels as per [Table 10] at any time point will be summarized by treatment group.  The 
lowest and the highest end tidal CO2 level, respectively, will be used in the analysis.
Table 10
Criteria for Assessing Spot End Tidal Carbon Dioxide
Parameter
Criteria
End Tidal CO2 (mmHg)
< 20, < 25, < 30, < 35
> 35, > 40, > 45, > 50
CO2: carbon dioxide
The number and percentage of participants who reach an alarm value of continuous end tidal 
CO2, and the number of times an alarm value was reached will be listed and summarized by 
treatment.
9.4.4
Analysis of Pharmacokinetics
Descriptive statistics will include n, mean, SD, minimum, median, maximum, CV, geometric 
mean and geometric CV.  For the pharmacokinetic parameters tmax and tlag, only n, median, 
minimum and maximum will be calculated.
9.4.4.1 Pharmacokinetic Concentrations
Descriptive statistics will be presented for plasma concentrations of morphine and its 
metabolites (M3G and M6G) in combination with placebo and in combination with ASP8062 
by scheduled sample time.  Standard graphics including mean plasma concentration-time 
profiles, overlay (spaghetti) plots and individual participant plasma concentration-time 
profiles for morphine and its metabolites (M3G and M6G) in combination with placebo and 
in combination with ASP8062 will be produced.
Descriptive statistics will be presented for plasma concentrations of ASP8062 and its 
metabolites (including AS3486189, AS3486191 and AS3486192) alone and ASP8062 in 
combination with morphine by scheduled sample time. Standard graphics including mean 
plasma concentration-time profiles, overlay (spaghetti) plots and individual participant 
plasma concentration-time profiles for ASP8062 and its metabolites (including AS3486189, 
AS3486191 and AS3486192) alone and ASP8062 in combination with morphine will be
produced.


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9.4.4.2 Estimation of Pharmacokinetic Parameters
Noncompartmental analysis will be used for the calculation of plasma pharmacokinetic 
parameters using Phoenix version 6.3 or higher (Certara LP, 100 Overlook Center, Suite 101, 
Princeton, NJ 08540, US).
Plasma pharmacokinetic parameters of morphine and its metabolites (M3G and M6G) in 
combination with placebo and in combination with ASP8062 will be listed and summarized 
using descriptive statistics.
Plasma pharmacokinetic parameters of ASP8062 and its metabolites (including AS3486189, 
AS3486191 and AS3486192) alone and ASP8062 in combination with morphine will be 
listed and summarized using descriptive statistics.
9.4.4.3 Statistical Analysis of Pharmacokinetic Parameters
To assess the effect of morphine on the pharmacokinetics of ASP8062 and its metabolites 
(AS3486189, AS3486191 and AS3486192), an analysis of variance (ANOVA) model with 
treatment (ASP8062 in combination with morphine and ASP8062 alone) as a fixed effect and 
participants as a random effect will be fitted on natural logarithmic-transformed AUC24 and 
Cmax.  Within the ANOVA, the least squares (LS) mean differences between ASP8062 in 
combination with morphine and ASP8062 alone, along with 90% CIs for the differences will 
be estimated.  The LS means for AUC24 and Cmax will be back-transformed to produce the 
geometric LS means and presented with the number of participants for each treatment.  The 
geometric LS mean ratios and their corresponding 90% CIs for each pharmacokinetic 
parameter will be presented by back-transforming and expressed as percentages.
To assess the effect of ASP8062 on the pharmacokinetics of morphine and its metabolites 
(M3G and M6G), similar analysis will be done with treatment (morphine in combination with 
ASP8062 and morphine in combination with placebo) as a fixed effect and participant as a 
random effect.
If all participants did not complete treatment, then the above analyses will be repeated using 
an ANOVA with fixed effects for treatment and participant; this analysis will only include 
participants with complete data in all treatments.
9.4.5
Other Analyses
Select polymorphisms of genes GABAB receptor and/or opioid receptors will be summarized 
and listed.  In addition, polymorphisms of genes may be summarized graphically or 
descriptively as they relate to clinical measures, as applicable.  All analyses described in this 
section are based on availability of data.
9.5
Interim Analysis
Not applicable.


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9.6
Additional Conventions
As a general principle, no imputation of missing data will be done.  Exceptions are the start 
and stop dates of AEs and concomitant medications if they are missing on day of first IP 
administration.  The imputed dates will be used to assess if the AEs or concomitant 
medications are treatment-emergent or concomitant, respectively.  Listings of the AEs and 
concomitant medications will present the actual partial dates; imputed dates will not be 
shown.


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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Ethical, Regulatory and Study Oversight Considerations
10.1.1
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:
●
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines
●
Applicable ICH GCP Guidelines
●
Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:
●
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC
●
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
●
Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations
10.1.2
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3
Informed Consent of Participants
10.1.3.1 Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study.
Participants must be informed that their participation is voluntary.  Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 


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local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.  
The authorized person obtaining the informed consent must also sign the ICF.
Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study.
A copy of the ICF(s) must be provided to the participant.
10.1.3.2 Supply of New and Important Information Influencing the Participant’s 
Consent and Revision of the Written Information
The investigator or his/her representative will immediately inform the participant verbally 
whenever new information becomes available that may be relevant to the participant’s 
consent or may influence the participant’s willingness to continue participating in the study 
(e.g., report of serious adverse drug reaction).  The communication must be documented in 
the participant’s medical records and whether the participant is willing to remain in the study 
or not must be confirmed and documented.
The investigator must update the participant’s ICF and submit it for approval to the IRB/IEC.  
The investigator or his/her representative must obtain written informed consent from the 
participant on all updated ICFs throughout their participation in the study.  The investigator 
or his/her designee must reconsent participants with the updated ICF even if relevant 
information was provided verbally.  The investigator or his/her representative who obtained 
the written informed consent and the participant should sign and date the ICF.  A copy of the 
signed ICF will be given to the participant and the original will be placed in the participant’s
medical record.  An entry must be made in the participant’s records documenting the 
reconsent process.
10.1.4
Data Protection
Individual participant medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited unless the participant provides 
written consent or approval.  Additional medical information may be given only after 
approval of the participant to the investigator or to other appropriate medical personnel 
responsible for the participant’s well-being.
The sponsor shall not disclose any confidential information on participants obtained during 
the performance of their duties in the 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 a participant’s privacy due to direct access to source 
documents, or from other sources, they may not disclose the content to third parties.
The sponsor affirms the participant’s right to protection against invasion of privacy.  Only a 
participant identification number will identify participant data retrieved by the sponsor.  


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However, the sponsor requires the investigator to permit the sponsor, sponsor’s 
representative(s), the IRB/IEC 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 
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 the sponsor shall serve as the controller of 
such data, as defined by the EU Data Protection Directive (DPD), and investigator and/or 
third party shall act only under the instructions of the sponsor in regard to personal data.  If 
the sponsor is not based in the EEA, the sponsor must appoint a third party to act as its local 
data protection representative or arrange for a co-controller established in the EU for data 
protection purposes in order to comply with the DPD.
10.1.5
Committee(s) Structure
Not applicable.
10.1.6
Dissemination of Clinical Study Data
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final CSR that 
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 the coordinating 
investigator(s) or the principal investigator(s) will be selected from the participating 
investigators by the sponsor prior to database lock.
10.1.7
Data Quality Assurance
●
All participant data relating to the study will be recorded on the electronic data source 
unless transmitted to the sponsor or designee electronically in an external data file 
(e.g., central laboratory data).  The investigator is responsible for verifying that data 
entries on the electronic data source are accurate and correct by physically or 
electronically signing the electronic data source.
●
Guidance on completion of case report forms (CRFs) will be provided in a separate 
electronic CRF Completion Guideline.
●
The investigator must permit study-related monitoring, audits, IRB/IEC review and 
regulatory agency inspections and provide direct access to source data documents.
●
Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote or on-site monitoring) 
are provided in the Monitoring Plan.


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●
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
●
The sponsor assumes accountability for actions delegated to other individuals 
(e.g., CROs).
●
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator according to ICH or applicable local regulatory 
requirements, whichever is longer, after study completion.  No records may be destroyed 
during the retention period without the written approval of the sponsor.  No records may 
be transferred to another location or party without written notification to the sponsor.
10.1.8
Source Documents
1.
Source data must be available at the study site to document the existence of the 
participants 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 participant.
2.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
3.
The investigator is responsible for ensuring the source data are attributable, legible, 
contemporaneous, original, accurate and complete whether the data are handwritten on 
paper or entered electronically.  If source data are created (first entered), modified, 
maintained, achieved, retrieved or transmitted electronically via computerized systems 
(and/or other kind of electronic devices) as part of regulated study activities, such 
systems must be compliant with all applicable laws and regulations governing use of 
electronic records and/or electronic signatures.  Such systems may include, but are not 
limited to, electronic medical/health records, protocol-related assessments, AE tracking, 
electronic clinical outcome assessment and/or drug accountability.
4.
Paper records from electronic systems used in place of electronic format must be 
certified copies.  A certified copy must be an exact copy and must have all the same 
attributes and information as the original.  Certified copies must include signature and 
date of the individual completing the certification.  Certified copies must be a complete 
and chronological set of study records (including notes, attachments and audit trail 
information, if applicable).  All printed records must be kept in the participant file and be 
available for archiving.
5.
Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete and verifiable 
from source documents; that the safety and rights of participants are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements.
10.1.9
Study and Site Start and Closure
The study start date is the date the first participant signs the ICF for the study.
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor.  Study sites will be closed upon 


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study completion.  A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but 
are not limited to:
For study termination:
●
Discontinuation of further study test product development
For site termination:
●
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines
●
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator
●
Total number of participants included earlier than expected
If the study is prematurely terminated or suspended, the sponsor or designee shall promptly 
inform the investigators, the IECs/IRBs, the regulatory authorities and any CRO(s) used in 
the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements.  The investigator shall promptly inform the participant and should 
assure appropriate participant therapy and/or follow-up.
10.1.10 Arrangement for Use of Information and Publication of the Study
Information concerning the test product, 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 study in connection with the development of the product 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 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 study agreement.
10.1.11 Quality Assurance
The sponsor is implementing and maintaining quality assurance (QA) and quality control 
(QC) 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 QA and QC systems and written SOPs of 
the CRO will be applied.


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The sponsor or sponsor’s designee may arrange to audit the study at any or all study sites and 
facilities.  The audit may include on-site review of regulatory documents, CRFs and source 
documents.  Direct access to these documents will be required by the auditors.
To support quality around participant safety and reliability of study results, quality tolerance 
limits (QTLs) are defined and monitored.  QTLs represent the acceptable variation of study 
data, taking into consideration the current state of medical and statistical knowledge about the 
variables to be analyzed, as well as the statistical design of the study.  It is a level, point or 
value associated with a parameter that should trigger an evaluation if a deviation is detected 
to determine if there is a possible systematic issue (i.e., a trend has occurred).  The QTLs 
defined for this study are provided below.
Table 11
Quality Tolerance Limits
QTL #: Name and Parameter
Definition
Parameter Justification
QTL 1: Safety assessment 
compliance
Number of safety assessments not 
collected or collected outside the 
allowed collection window
A high number of safety 
assessments missed or collected 
outside of the window can 
negatively impact the data 
integrity for the primary endpoint
QTL: quality tolerance limit
QTL Management Activities:
●
For control of risks associated with “QTL 1: Safety assessment compliance,” refer to the 
Schedule of Assessments [Table 1] and Sample Collection Schedule [Table 2].
Additional information regarding the QTL limit and limit justification, as well as associated 
activities can be found in STL-3458 QTL Monitoring Plan.


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10.2
Appendix 2: Contraception Requirements
WOCBP who are eligible for participation in the study, including those who choose complete 
abstinence, must have pregnancy tests as specified in the Schedule of Assessments [Table 1].  
Pregnancy test results must confirm that the participant is not pregnant.
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND METHODS OF 
CONTRACEPTION DEFINITIONS
A female is considered fertile (i.e., WOCBP) following menarche and until becoming 
postmenopausal unless permanently sterile.
Females in the following categories are not considered WOCBP
●
Premenopausal with one of the following (i.e., permanently sterile):
o
Documented hysterectomy
o
Documented bilateral salpingectomy
o
Documented bilateral oophorectomy
●
Postmenopausal
A postmenopausal state is defined as at least 12 months after last menstrual bleeding without 
an alternative medical cause.
In case the last menstrual bleeding cannot be clearly determined, confirmation with more 
than 1 FSH measurement of at least > 40 IU/L (or higher per local institutional guidelines) is 
required.
Females on HRT and whose menopausal status is in doubt will be required to use 1 of the 
nonestrogen hormonal highly effective contraception methods if they wish to continue their 
HRT during the study.  Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status by repeated FSH measurements before study enrollment.  Female 
participants must be on a stable dose of HRT for 2 months prior to day -1.
Documentation of any of these categories can come from the study site personnel’s review of 
the female participant’s medical records, medical examination or medical history interview.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF 
CHILDBEARING POTENTIAL
Female participants of childbearing potential are eligible for participation in the study if they 
agree to use 1 of the highly effective methods of contraception listed below from the time of 
signing the ICF and until the end of relevant systemic exposure, defined as 28 days after the 
final IP administration.a
Highly effective methods of contraception (failure rate of < 1% per year when used 
consistently and correctly)b:
●
A condom and spermicide
●
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation for at least 30 days prior to first dose of IP


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o
Oral
o
Intravaginal
o
Transdermal
●
Progestogen-only hormonal contraception associated with inhibition of ovulation for at 
least 30 days prior to first dose of IP
o
Oral
o
Injectable
o
Implantable
●
Other combined (estrogen- and progesterone-containing) methods for at least 30 days 
prior to first dose of IP
o
Vaginal ring
o
Injectable
o
Implantable
o
Intrauterine hormone-releasing system or intrauterine device
●
Bilateral tubal occlusion or ligation
●
Vasectomized partner
A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP.
●
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the test 
product.  The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.  It is not 
necessary to use any other method of contraception when complete abstinence is elected.
a Local laws and regulations may require use of alternative and/or additional contraception methods.
b Typical use failure rates may differ from those when used consistently and correctly.  Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical 
studies.
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) 
OF CHILDBEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible for participation 
in the study if they agree to the following during treatment and until the end of relevant 
systemic exposure defined as 90 days after final drug administration.a
●
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator
●
Use a condom and spermicide
●
Female partners of male participants who have not undergone a vasectomy or a bilateral 
orchiectomy should consider use of effective methods of contraception
●
If sexual abstinence is practiced, sexual abstinence should be practiced from 30 days 
prior to screening and participant should agree to continue practicing sexual abstinence 
during study participation
a Local laws and regulations may require use of alternative and/or additional contraception methods.


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10.3
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting
10.3.1
Definition of Adverse Events
AE Definition:
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study IP, whether or not considered related to the study 
IP.
“Adverse event” means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.
NOTE: 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 study IP.  This includes events related to the comparator and events related to the 
(study) procedures.
Events Meeting the AE Definition
●
Any abnormal laboratory test results (hematology, clinical chemistry or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease)
●
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition
●
New conditions detected or diagnosed after study IP administration even though it may 
have been present before the start of the study
Events NOT Meeting the AE Definition
●
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition
●
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition
●
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads 
to the procedure is the AE
●
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital)
●
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen


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10.3.2
Abnormal Laboratory Findings
Any abnormal laboratory test result (e.g., hematology, biochemistry or urinalysis) or other 
safety assessment (e.g., vital signs, physical examination or ECGs), including those that 
worsen from baseline, that is considered to be clinically significant in the medical and 
scientific judgment of the investigator and not related to underlying disease, is to be reported 
as an (S)AE.
Any clinically significant abnormal laboratory finding or other abnormal safety assessment,
which is associated with the underlying disease, does not require reporting as an (S)AE, 
unless judged by the investigator to be more severe than expected for the participant’s 
condition.
Repeating an abnormal laboratory test or other safety assessment, in the absence of any of the 
above criteria, does not constitute an AE. Any abnormal test result that is determined to be 
an error does not require reporting as an AE.
10.3.2.1 Potential Cases of Drug-induced Liver Injury
Refer to [Section 10.4 Appendix 4: Liver Safety Monitoring and Assessment] for detailed 
instructions on drug-induced liver injury. Abnormal values in AST and/or ALT concurrent 
or with abnormal elevations in TBL that meet the criteria outlined in [Section 10.4
Appendix 4: Liver Safety Monitoring and Assessment], in the absence of other causes of liver 
injury, are considered potential cases of drug-induced liver injury (potential Hy’s Law cases) 
and are always to be considered important medical events and reported per [Section 10.3.7
Appendix 3 Reporting Procedures for Serious Adverse Events].
10.3.3
Definition of Serious Adverse Events
An SAE is defined as any untoward medical occurrence that, at any dose:
●
Results in death
●
Is life-threatening
o
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
●
Requires inpatient hospitalization or prolongation of existing hospitalization
o
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
o
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.


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●
Results in persistent or significant disability/incapacity
o
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
o
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle), which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
●
Is a congenital anomaly/birth defect
●
Other situations:
o
Medical or scientific judgment should be exercised in deciding whether SAE 
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 participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition.  These events should 
usually be considered serious.
o
Examples of such events include invasive or malignant cancers, 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.
If an event is not an AE per definition in [Section 10.3.1 Appendix 3 Definition of Adverse 
Events], then it cannot be an SAE even if serious conditions are met (e.g., hospitalization for 
signs/symptoms of the disease under study, death due to progression of disease).
10.3.4
Assessment of Causality
●
The investigator is obligated to assess the relationship between study IP and each 
occurrence of each AE/SAE.
●
A “reasonable possibility” of a relationship conveys that there are facts, evidence and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
●
The investigator will use clinical judgment to determine the relationship.
●
Alternative causes, such as underlying disease(s), concomitant therapy and other risk 
factors, as well as the temporal relationship of the event to study IP administration will 
be considered and investigated.
●
The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment.
●
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
●
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor.  However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the sponsor.
●
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.


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●
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Following a review of the relevant data, the causal relationship between the IP and each 
(S)AE will be assessed by answering “yes” or “no” to the question “Do you consider that 
there is a reasonable possibility that the event may have been caused by the IP?”
When making an assessment of causality, the following factors are to be considered when 
deciding if there is evidence and/or arguments to suggest there is a “reasonable possibility” 
that an (S)AE may have been caused by the IP (rather than a relationship cannot be ruled out) 
or if there is evidence to reasonably deny a causal relationship:
●
Has the participant been administered IP?
●
Plausibility (i.e., could the event have been caused by the suspect IP?  Consider biologic 
and/or pharmacologic mechanism, half-life, literature evidence, drug class, preclinical 
and study data, etc.)
●
Dechallenge/dose reduction/rechallenge:
o
Dechallenge: did the (S)AE resolve or improve after only stopping the dose of the 
suspect drug without any treatment?
o
Dose reduction: did the (S)AE resolve or improve after reducing the dose of the 
suspect drug?
o
Rechallenge: did the (S)AE reoccur if the suspected drug was reintroduced after 
having been stopped?
●
Laboratory or other test results: a specific laboratory investigation supports the 
assessment of the relationship between the (S)AE and the IP (e.g., based on values pre-, 
during and post-treatment)
●
Available alternative explanations independent of IP exposure; such as other 
concomitant drugs, past medical history, concurrent or underlying disease, risk factors 
including medical and family history, season, location, etc., and strength of the 
alternative explanation
●
Temporal relationship between exposure to the IP and (S)AE onset and/or resolution. 
Did the (S)AE occur in a reasonable temporal relationship to the administration of the 
IP?
●
Finally, judging which are more likely based on all the above contents, factors of 
reasonable possibility or confounding factors, comprehensive judgment of plausible will 
be provided.
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor.  While it is very important that the 
investigator always assesses causality for every event before the initial transmission of the 
SAE data to the sponsor, the initial report should be submitted without delay (i.e., within 
24 hours of awareness).  With limited or insufficient information about the event to make an 
informed medical judgment and in absence of any indication or evidence to establish a causal 
relationship, a causality assessment of “no” is to be considered.  In such instance, the 
investigator is expected to obtain additional information regarding the event as soon as 


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possible and to re-evaluate the causality upon receipt of additional information.  The 
medically qualified investigator may revise his/her assessment of causality in light of new 
information regarding the SAE and shall send an SAE follow-up report and update the 
electronic data source with the new information and updated causality assessment.
10.3.5
Assessment of Severity
The investigator will use the following definitions to rate the severity of each AE:
●
Mild: 
No disruption of normal daily activities
●
Moderate: Affect normal daily activities
●
Severe: 
Inability to perform daily activities
10.3.6
Recording and Follow-up of AEs and/or SAEs
AE and SAE Recording
●
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event.
●
The investigator will then record all relevant AE/SAE information in the electronic data 
source.
●
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor in lieu of completion of the electronic data source.
●
There may be instances when copies of medical records for certain cases are requested 
by the sponsor.  In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the sponsor.
●
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Follow-up of AEs and SAEs
●
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor 
to elucidate the nature and/or causality of the AE or SAE as fully as possible.  This may 
include additional laboratory tests or investigations, histopathological examinations or 
consultation with other health care professionals.
●
New or updated information will be recorded in the originally completed electronic data 
source.
●
The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information.
10.3.7
Reporting Procedures for Serious Adverse Events
The investigator must complete and submit an SAE worksheet containing all information that 
is required by local and/or regional regulations to the sponsor by fax or email immediately 
(within 24 hours of awareness).


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The SAE worksheet must be signed by a medically qualified investigator (as identified on 
delegation of authority log).  Signature confirms accuracy and completeness of the SAE data, 
as well as the investigator causality assessment including the explanation for the causality 
assessment.
If the SAE is associated with emergency unblinding by the investigator as outlined in 
[Section 6.3.4 Breaking the Treatment Code for Emergency], this is to be recorded on the 
SAE worksheet.  On the SAE worksheet, the investigator is to include when unblinding took 
place in association with the SAE.
For contact details, see [Contact Details of Sponsor’s Key Personnel].  Fax or email the 
SAE/special situations/product defect worksheet to:
Astellas Pharma Global Development Inc.
US Pharmacovigilance
North America fax number: +1-888-396-3750
North America alternate fax number: +1-847-317-1241
Email: safety-us@astellas.com
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
sponsor’s medical monitor/study physician or their designee [Contact Details of Sponsor’s 
Key Personnel].
Follow-up information for the event should be sent promptly (as soon as available but no 
longer than 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 electronic data source.
The following minimum information is required:
●
International study number/study number
●
Participant number, sex and age
●
Date of report
●
Description of the SAE (event and seriousness criteria)
●
Causal relationship to the IP (including reason)
●
Drug provided (if any)
The sponsor or sponsor’s designee will medically evaluate the SAE and determine if the 
report meets the requirements for expedited reporting based on seriousness, causality and 
expectedness of the events (e.g., SUSAR reporting) according to current local/regional 
regulatory requirements.  The sponsor or sponsor’s designee will submit expedited safety 
reports to competent authorities and concerned ethics committee per current local regulations 
and will inform the investigators of such regulatory reports as required.  Investigators must 
submit safety reports as required by their IRB/IEC within timelines set by regional 
regulations (e.g., EMA, FDA) where required.  Documentation of the submission to and 
receipt by the IRB/IEC of expedited safety reports should be retained by the study site.  In the 
US, FDA expedited IND reporting guidelines will be followed.


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The sponsor will notify all investigators responsible for ongoing clinical studies with the test 
product of all SUSARs, which require submission per local requirements IRB/IEC.
The heads of the study sites/investigators should provide written documentation of IRB/IEC 
notification for each report to the sponsor.
The investigator may contact the sponsor’s medical monitor/study physician for any other 
problem related to the rights, safety or well-being of the participant.
10.3.8
Reporting Procedures for Special Situations
10.3.8.1 Contraceptive Guidance and Collection of Pregnancy Information
If a female participant 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 10.3.7 Appendix 3 Reporting Procedures for Serious 
Adverse Events] using the SAE worksheet as a special situation and in the electronic data 
source.
The investigator will attempt to collect pregnancy information on any female partner of a 
male participant who becomes pregnant during the study dosing period or within 90 days 
from the discontinuation of dosing and report the information to the sponsor according to the 
timelines in [Section 10.3.7 Appendix 3 Reporting Procedures for Serious Adverse Events] 
using the special situation worksheet or pregnancy form.
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.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
termination (including elective termination) of a pregnancy is to be reported for a female 
participant as an AE in the electronic data source or SAE per [Section 10.3.7 Appendix 3 
Reporting Procedures for Serious Adverse Events].  Participant pregnancy outcomes listed 
below are to be reported as SAEs:
●
Spontaneous abortion/miscarriage, abortion and missed abortion
●
Death of a newborn or infant within 1 month after birth is to be reported as an SAE 
regardless of its relationship with the IP
●
If an infant dies more than 1 month after the birth, it is to be reported if a relationship 
between the death and intrauterine exposure to the IP is judged as “possible” by the 
investigator
●
Congenital anomaly (including anomaly in miscarried fetus)
●
Benign hydatidiform mole
●
Blighted ovum
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 or other 
means as appropriate.  (S)AEs experienced by the newborn/infant should be reported via the 


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pregnancy reporting form.  Generally, follow-up will be no longer than 6 to 8 weeks 
following the estimated delivery date.
10.3.8.2 Medication Error, Overdose and “Off-label Use”
If a medication error (defined as an unintended failure in the treatment process that leads to, 
or has the potential to lead to, harm to the participant), overdose or “off-label use” (i.e., use 
outside of the target disease defined in the protocol) is suspected, refer to [Section 6.7
Treatment of Overdose].  Any associated (S)AEs are to be reported in the electronic data 
source.  If the AE meets the definition of an SAE, the SAE is also to be reported as described 
in [Section 10.3.7 Appendix 3 Reporting Procedures for Serious Adverse Events] together 
with the details of the medication error, overdose and/or “off-label use.”
10.3.8.3 Misuse/Abuse
Definition of misuse: situations where the IP is/are intentionally and inappropriately used not 
in accordance with the intended use as defined in the protocol.
Definition of abuse: persistent or sporadic, intentional excessive use of medicinal products 
which is accompanied by harmful physical or psychological effects.
If misuse or abuse of the IP is suspected, the investigator must forward the special situation 
worksheet to the sponsor by fax or email immediately (within 24 hours of awareness).  Any 
associated (S)AEs are to be reported in the electronic data source.  If the AE meets the 
definition of an SAE, the SAE is also to be reported as described in [Section 10.3.7
Appendix 3 Reporting Procedures for Serious Adverse Events] together with details of the 
misuse or abuse of the IP.
10.3.8.4 Occupational Exposure
If occupational exposure (e.g., inadvertent exposure to the IP of study site personnel while 
preparing it for administration to the participant) to the IP occurs, the investigator must 
forward the special situation worksheet to the sponsor by fax or email immediately (within 
24 hours of awareness).  Any associated (S)AEs occurring to the individual associated with 
or resulting from the special situation are to be reported on the special situations worksheet.
10.3.8.5 Suspected Drug-drug Interaction
If a DDI associated with the IP is suspected, the investigator must forward the special 
situation worksheet to the sponsor by fax or email immediately (within 24 hours of 
awareness).  Any associated (S)AEs are to be reported in the electronic data source.  If the 
AE meets the definition of an SAE, the SAE is also to be reported as described in 
[Section 10.3.7 Appendix 3 Reporting Procedures for Serious Adverse Events] together with 
details of the suspected DDI.
10.3.9
Supply of New Information Affecting the Conduct of the Study
When new information becomes available that is necessary for conducting the study properly, 
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regulatory authorities.  Investigators should inform the IRB/IEC of such information when 
needed.
The investigator will also inform the participants, who will be required to sign an updated 
ICF in order to continue in the study.
10.3.10 Urgent Safety Measures
An urgent safety measure (USM) is an intervention that is not defined by the protocol and 
can be put in place with immediate effect without needing to gain prior approval by the 
sponsor, relevant competent authorities, IRB/IEC, where applicable, in order to protect 
participants from any immediate hazard to their health and/or safety.  Either the investigator 
or the sponsor can initiate a USM.  The cause of a USM can be safety-, product- or 
procedure-related.
10.3.11 Reporting Urgent Safety Measures
In the event of a potential USM, the investigator must contact the study physician (within 
24 hours of awareness).  Full details of the potential USM are to be recorded in the 
participant’s medical records.  The sponsor may request additional information related to the 
event to support their evaluation.
If the event is confirmed to be a USM, the sponsor will take appropriate action to ensure the 
safety and welfare of the participants.  These actions may include but are not limited to a 
change in study procedures or study treatment, halting further enrollment in the study or 
stopping the study in its entirety.  The sponsor or sponsor’s designee will notify the relevant 
competent authorities and concerned ethics committee within the timelines required per 
current local regulations and will inform the investigators, as required.  When required, 
investigators must notify their IRB/IEC within timelines set by regional regulations.


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10.4
Appendix 4: Liver Safety Monitoring and Assessment
The purpose of this appendix is to provide guidance for the monitoring of drug-induced liver 
injury during the course of the study.  It should be noted that this section does not specify the 
end-of-study analyses of liver enzymes.  Any participant enrolled in a 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 ALP, ALT, 
AST 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 and 
study team.  Participants 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 is as 
shown below.
Table 12
Moderate and Severe Liver Abnormalities
ALT or AST
TBL
Moderate
> 3 × ULN
or
> 2 × ULN
Severe
> 3 × ULN
and†
> 2 × ULN
ALT: alanine aminotransferase; AST: aspartate aminotransferase; TBL: total bilirubin; ULN: upper limit of 
normal
†Samples taken simultaneously or within a maximum of 24 hours.
In addition, the participant 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† TBL > 2 × ULN or international normalized ratio (INR) 
> 1.5 (if INR testing is applicable/evaluated)
●
ALT or AST > 5 × ULN and† (TBL > 2 × ULN in participants with liver metastases)
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%)
†Samples taken simultaneously or within a maximum of 24 hours.
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 clinical laboratory tests.  The study site personnel are to complete 


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the liver abnormality case report form (LA-CRF).  Participants with confirmed abnormal 
liver function testing should be followed as described below.
Confirmed moderately abnormal liver function tests should be repeated 2 to 3 times weekly, 
and then weekly or less if abnormalities stabilize or the IP has been discontinued and the 
participant 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 an SAE.  
The sponsor should be contacted and informed of all participants for whom severe hepatic 
liver function abnormalities possibly attributable to IP 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 are to be recorded as “AEs” within the electronic data source.  
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 participants 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 are to be entered in the electronic data source.  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 participant’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 clinical laboratory tests, including INR and direct bilirubin
●
Consider gastroenterology or hepatology consultations.
●
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document.
Study Treatment Discontinuation
In the absence of an explanation for increased liver function tests, such as viral hepatitis, 
pre-existing or acute liver disease, or exposure to other agents associated with liver injury, 
the participant may be discontinued from study treatment.  The investigator may determine 
that it is not in the participant’s best interest to continue study treatment.  Discontinuation of 
study treatment should be considered if:
●
ALT or AST > 8 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks


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●
ALT or AST > 3 × ULN and† TBL > 2 × ULN or INR > 1.5) (if INR testing is 
applicable/evaluated)
●
ALT or AST > 5 × ULN and† (TBL > 2 × ULN in participants with liver metastases)
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%)
† Samples taken simultaneously or within a maximum of 24 hours.
In addition, if close monitoring for a participant with moderate or severe hepatic laboratory 
tests is not possible, study treatment should be discontinued.
Hy’s Law definition: Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10% to 50% 
mortality (or transplant).
The 2 “requirements” for Hy’s Law are:
1.
Evidence that a drug can cause hepatocellular-type injury, generally shown by an 
increase in AT elevations > 3 × ULN (“2 × ULN elevations are too common in treated 
and untreated participants to be discriminating”).
2.
Cases of increased TBL (at least 2 × ULN) with concurrent AT elevations at least 
3 × ULN and no evidence of intra- or extra-hepatic bilirubin obstruction (elevated ALP) 
or Gilbert’s syndrome [Temple, 2006].
FDA Guidance for Industry titled, “Drug-induced Liver Injury: Premarketing Clinical 
Evaluation” issued by the FDA on July 2009:
1.
The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold 
or greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) control 
drug or placebo.
2.
Among participants showing such AT elevations, often with ATs much greater than 
3 × ULN, one or more also show elevation of serum TBL to > 2 × ULN, without initial 
findings of cholestasis (elevated serum ALP).
3.
No other reason can be found to explain the combination of increased AT and TBL, such 
as viral hepatitis A, B, or C; pre-existing or acute liver disease; or another drug capable 
of causing the observed injury.


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10.5
Appendix 5: List of Excluded Concomitant Medications
Not applicable.


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10.6
Appendix 6: Clinical Laboratory Assessments
Serology
Visit
Matrix
Parameters to be Analyzed
See Schedule of 
Assessments [Table 1]
Serum
HAV antibodies (IgM)
HBc antibodies
HBsAg
HCV antibodies
Antibodies to HIV types 1 and 2
Hematology
Visit
Matrix
Parameters to be Analyzed
See Schedule of 
Assessments [Table 1]
Blood
Hemoglobin
Hematocrit
Erythrocytes
Leukocytes
Differential leukocytes
Neutrophils
Platelets
Biochemistry
Visit
Matrix
Parameters to be Analyzed
See Schedule of 
Assessments [Table 1]
Serum
Sodium
Potassium
Calcium
Chloride
Magnesium
Inorganic phosphorus
Glucose
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
Gamma-glutamyl transferase
Total bilirubin
Total cholesterol
Triglycerides
Blood urea nitrogen
Creatinine
Creatine kinase
Lactate dehydrogenase
Total protein
Uric acid
Albumin
Amylase
Lipase
FSH (postmenopausal female participants only)
Carbon dioxide


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Urinalysis
Visit
Parameters to be Analyzed
See Schedule of 
Assessments [Table 1]
Dipstick
Protein
Glucose
pH
Blood
Leukocytes
Urobilinogen
Bilirubin
Ketones
Nitrite
Microscopy 
(optional)
Casts
Crystals
Epithelial cells
Leucocytes
Erythrocytes
Bacteria
Drugs of Abuse and Alcohol Tests
Visit
Matrix
Parameters to be Analyzed
See Schedule of 
Assessments [Table 1]
Urine
Amphetamines
Barbiturates
Benzodiazepines
Cannabinoids
Cocaine
Methadone
Opiates
Phencyclidine
Urine
Alcohol
Pregnancy Test
Visit
Matrix
Parameters to be Analyzed
See Schedule of 
Assessments [Table 1]
Serum/urine
Human chorionic gonadotropin (female participants only)
FSH: follicle-stimulating hormone; HAV: hepatitis A virus; HBc: hepatitis B core; HBsAg: hepatitis B surface 
antigen; HCV: hepatitis C virus; HIV: human immunodeficiency virus; IgM: immunoglobulin M


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10.7
Appendix 7: Pharmacogenomic Analysis with Banked Sample
INTRODUCTION
PGx research aims to provide information regarding how naturally occurring differences in a 
participant’s gene and/or expression of genes based on genetic variation may impact what 
treatment options are best suited for the participant.  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, 
toxicity or disease may be better understood.  As many diseases may be influenced by one or 
more genetic variations, PGx research may identify which genes are involved in determining 
the way a participant 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/or toxicity/safety and/or disease.
By analyzing genetic variations, it may be possible to predict an individual participant’s 
response to treatment in terms of efficacy and/or toxicity and/or disease.
PARTICIPANT PARTICIPATION
Participants who have consented to participate in this study will participate in the PGx 
substudy.  Participants must provide written consent prior to providing any blood samples
that may be used at a later time for PGx analysis.
SAMPLE COLLECTION AND STORAGE
Participants who consent to participate in this substudy will provide 4 mL sample of whole 
blood per Astellas’ instructions.  Each sample will be identified by the unique participant 
number. Samples will be shipped to a designated banking CRO as directed by Astellas.
PGx ANALYSIS
Details on the potential PGx analysis cannot be established yet.  Astellas may initiate the 
PGx analysis if evidence suggests that genetic variants may be influencing the drug’s 
pharmacokinetics, efficacy and/or safety and/or disease.
DISPOSAL OF PGx SAMPLES/DATA
All PGx samples collected will be stored for a period of up to 15 years following study 
database lock.  If there is no requirement for analysis, the whole blood sample will be 
destroyed after the planned storage period.  The participant has the right to withdraw consent 
at any time.  When a participant’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 unless otherwise specified by local regulation.


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INFORMATION DISCLOSURE TO THE PARTICIPANTS
Exploratory PGx analysis may be conducted following the conclusion of the study, if 
applicable.  The results of the PGx analysis will not be provided to any investigators or 
participants, 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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10.9
Appendix 9: 49-item Short Form of Addiction Research Center 
Inventory Scale
This document is a template from which the study-specific version will be created.
TRUE FALSE
1.
My speech is slurred.
□
□
2.
I am not as active as usual.
□
□
3.
I have a feeling of just dragging along rather than coasting.
□
□
4.
I feel sluggish.
□
□
5.
My head feels heavy.
□
□
6.
I feel like avoiding people although I usually do not feel this way.
□
□
7.
I feel dizzy.
□
□
8.
It seems harder than usual to move around.
□
□
9.
I am moody.
□
□
10.
People might say I am a little dull today.
□
□
11.
I feel drowsy.
□
□
12.
I am full of energy.
□
□
13.
Today I say things in the easiest possible way.
□
□
14.
Things around me seem more pleasing than usual.
□
□
15.
I have a pleasant feeling in my stomach.
□
□
16.
I feel I will lose the contentment that I have now.
□
□
17.
I feel in complete harmony with the world and those about me.
□
□
18.
I can completely appreciate what others are saying when I am in this 
mood.
□
□
19.
I would be happy all the time if I felt as I feel now.
□
□
20.
I feel so good that I know other people can tell it.
□
□
21.
I feel as if something pleasant has just happened to me.
□
□
22.
I would be happy all the time if I felt as I do now.
□
□
23.
I feel more clear-headed than dreamy.
□
□
24.
I feel as if I would be more popular with people today.
□
□
25.
I feel a very pleasant emptiness.
□
□
26.
My thoughts come more easily than usual.
□
□


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TRUE FALSE
27.
I feel less discouraged than usual.
□
□
28.
I am in the mood to talk about the feelings I have.
□
□
29.
I feel more excited than dreamy.
□
□
30.
Answering these questions was very easy today.
□
□
31.
My memory seems sharper to me than usual.
□
□
32.
I feel as if I could write for hours.
□
□
33.
I feel very patient.
□
□
34.
Some parts of my body are tingling.
□
□
35.
I have a weird feeling.
□
□
36.
My movements seem faster than usual.
□
□
37.
I have better control over myself than usual.
□
□
38.
My movements seem slower than usual.
□
□
39.
I find it hard to keep my mind on a task or job.
□
□
40.
I don’t feel like reading anything right now.
□
□
41.
It seems I am spending longer than I should on each of these questions.
□
□
42.
My hand feels clumsy.
□
□
43.
I notice my hand shakes when I write.
□
□
44.
I have a disturbance in my stomach.
□
□
45.
I have an increasing awareness of bodily sensations.
□
□
46.
I feel anxious and upset.
□
□
47.
I have unusual weakness of my muscles.
□
□
48.
A thrill has gone through me one or more times since I started this test.
□
□
49.
My movements are free, relaxed and pleasurable.
□
□


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Questionnaire Scoring
#
Question
GROUP
PCA
B
LSD
MB
AMP
1.
My speech is slurred.
1
2.
I am not as active as usual.
1
3.
I have a feeling of just dragging along rather than 
coasting.
1
4.
I feel sluggish.
1
5.
My head feels heavy.
1
6.
I feel like avoiding people although I usually do not 
feel this way.
1
7.
I feel dizzy.
1
8.
It seems harder than usual to move around.
1
9.
I am moody.
1
10.
People might say I am a little dull today.
1
-1
11.
I feel drowsy.
1
-1
12.
I am full of energy.
-1
13.
Today I say things in the easiest possible way.
1
14.
Things around me seem more pleasing than usual.
1
15.
I have a pleasant feeling in my stomach.
1
16.
I feel I will lose the contentment that I have now.
1
17.
I feel in complete harmony with the world and those 
about me.
1
18.
I can completely appreciate what others are saying 
when I am in this mood.
1
19.
I would be happy all the time if I felt as I feel now.
1
20.
I feel so good that I know other people can tell it.
1
21.
I feel as if something pleasant has just happened to me.
1
22.
I would be happy all the time if I felt as I do now.
-1
1
23.
I feel more clear-headed than dreamy.
-1
1
1
24.
I feel as if I would be more popular with people today.
1
1


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#
Question
GROUP
PCA
B
LSD
MB
AMP
25.
I feel a very pleasant emptiness.
1
1
26.
My thoughts come more easily than usual.
1
1
1
27.
I feel less discouraged than usual.
1
1
28.
I am in the mood to talk about the feelings I have.
1
1
29.
I feel more excited than dreamy.
-1
1
30.
Answering these questions was very easy today.
1
1
31.
My memory seems sharper to me than usual.
1
1
32.
I feel as if I could write for hours.
1
1
33.
I feel very patient.
-1
1
34.
Some parts of my body are tingling.
1
1
1
35.
I have a weird feeling.
1
1
36.
My movements seem faster than usual.
1
37.
I have better control over myself than usual.
1
38.
My movements seem slower than usual.
-1
39.
I find it hard to keep my mind on a task or job.
-1
40.
I don’t feel like reading anything right now.
-1
41.
It seems I am spending longer than I should on each of 
these questions.
1
42.
My hand feels clumsy.
1
43.
I notice my hand shakes when I write.
1
44.
I have a disturbance in my stomach.
1
45.
I have an increasing awareness of bodily sensations.
1
46.
I feel anxious and upset.
1
47.
I have unusual weakness of my muscles.
1
48.
A thrill has gone through me one or more times since I 
started this test.
-1
1
49.
My movements are free, relaxed and pleasurable.
-1
AMP: amphetamine; B: benzedrine; LSD: lysergic-acid-diethylamide; MB: morphine-benzedrine; 
PCA: pentobarbital-chlorpromazine-alcohol


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10.10 Appendix 10: Adverse Events of Interest Related to Potential 
Substance Abuse and Following Drug Withdrawal
a. Includes Adverse Events of Interest Related to Potential Substance Abuse
Preferred Term
Lowest Level Term
Euphoria-related Terms
Euphoric mood
Feeling high
Euphoria
Euphoric
Euphoric mood
Elevated mood
Mood elevated
Feeling abnormal
Feeling drunk
Feeling of relaxation
Thinking abnormal
Hallucination, mixed
Dizziness
Dizziness and giddiness
Dissociative/Psychotic Terms
Psychosis
Aggression
Confusion
Disorientation
Terms Indicative of Impaired Attention, Cognition, Mood and Psychomotor Events
Somnolence
Somnolence
Psychomotor hyperactivity/decreased activity
Hyperactivity/hypoactivity
Mood disorders
Mental impairment
Drug tolerance, habituation, drug withdrawal 
syndrome, substance-related disorders
Inappropriate Affect
Inappropriate affect
Elation inappropriate
Exhilaration inappropriate
Inappropriate mood elevation
Product tampering
Medication tampering


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b. Related Adverse Events Occurring Following Drug Withdrawal
MedDRA v22.0
SOC
Higher Level Group 
Term
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
Feeling 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 (excluding 
infective)
Diarrhoea
Psychiatric disorders
Mood disorders and 
disturbances
Emotional and mood 
disturbance NEC
Dysphoria
Nervous system disorders
Sleep disturbances 
(including 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
Skin and subcutaneous 
tissue disorders
Skin appendage conditions
Apocrine and eccrine glad 
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
Table continued on next page


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MedDRA v22.0
SOC
Higher Level Group 
Term
Higher Level Term
Preferred Term
General disorders and 
administration site 
conditions
General system disorders 
NEC
Pain and discomfort NEC
Pain
Nervous system disorders
Sleep disturbances 
(including subtypes)
Sleep disturbances NEC
Poor quality sleep
Psychiatric disorders
Sleep disorders and 
disturbances
Dyssomnias
Cardia disorders
Cardiac disorder signs and 
symptoms
Cardia 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
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 
(including parkinsonism)
Tremor (excluding 
congenital)
Tremor
Gastrointestinal disorders
Gastrointestinal signs and 
symptoms
Nausea and vomiting 
symptoms
Vomiting
NEC: not elsewhere classified


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c. Analysis Search Strategy for Adverse Events of Interest Related to Potential Substance 
Abuse
MedDRA v22.0
SOC
Higher Level 
Group Term
Higher Level Term
Preferred Term
Lowest Level Term
Nervous system 
disorder
Neurological 
disorder NEC
Neurological signs 
and symptoms
Dizziness
Dizziness and giddiness
Psychiatric 
disorders
Psychosis
Psychosis
Psychosis
Deleria
Confusion and 
Disorientation
Disorientation
Confusion
Personality disorder
Behavior and 
socializing 
disturbance
Aggression
Cognitive and 
attention disorders 
and disturbances
Cognitive and 
attention disorders 
and disturbances 
NEC
Mental 
impairment
Mental impairment
Sleep disorders and 
disturbances
Dyssomnias
Somnolence
Somnolence
Changes in physical 
activity 
Increased physical 
activity level
Psychomotor 
hyperactivity 
Hyperactivity
Decreased physical 
activity level
Decreased 
activity 
Hypoactivity 
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
Hyperthimic
Laughter
Mood altered
Mood elevated
Affect alteration
Affect altered
Altered mood
Bad mood
Mood alteration NOS
Mood altered
Mood change
Mood disorders NEC
Affective disorder
Mood disorder
Table continued on next page


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MedDRA v22.0
SOC
Higher Level 
GT
Higher Level 
Term
Preferred Term
Lowest Level Term
Affect alterations
Inappropriate 
affect
Elation inappropriate
Exhilaration inappropriate
Exhiliration inappropriate
Inappropriate crying
Inappropriate elation
Inappropriate exhilaration
Inappropriate laughter
Inappropriate mood elevation
Mood elevation inappropriate
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 color
Hallucination, visual
Visual hallucinations
Hallucination
Hallucinations, 
mixed
Auditory and visual 
hallucination
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
Feeling lifeless
Feeling miserable
Table continued on next page


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MedDRA v22.0
SOC
Higher Level 
GT
Higher Level 
Term
Preferred Term
Lowest Level Term
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
NEC: not elsewhere classified; NOS: not otherwise specified term
The adverse event term of sedation is mentioned in the 2010 Draft Guidance but is not included in this table.


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10.11 List of Abbreviations and Definition of Key Study Terms
List of Abbreviations
Abbreviations
Description of abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANOVA
analysis of variance
APGD
Astellas Pharma Global Development Inc.
ARCI-49
49-item short form of Addiction Research Center Inventory scale
AST
aspartate aminotransferase
AT
aminotransferase
AUC
area under the concentration-time curve
AUC24
area under the concentration-time curve from the time of dosing to 24 hours
AUCinf
area under the concentration-time curve from the time of dosing extrapolated to 
time infinity
AUCinf(%extrap)
area under the concentration-time curve from the time of dosing extrapolated to 
time infinity as a percentage of total area under the concentration-time curve
AUClast
area under the concentration-time curve from the time of dosing to the last 
measurable concentration
BMI
body mass index
CL/F
apparent clearance
Cmax
maximum concentration
CO2
carbon dioxide
CRF
case report form
CRO
contract research organization
C-SSRS
Columbia-suicide severity rating scale
CSR
clinical study report
Ctrough
concentration immediately prior to dosing at multiple dosing
CV
coefficient of variation
CYP
cytochrome P450
DDI
drug-drug interaction
DPD
Data Protection Directive
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, edition 5
ECE
emergency code envelope
ECG
electrocardiogram
EEA
European Economic Area
ESV
end-of-study visit
FSH
follicle-stimulating hormone
GABA
gamma-aminobutyric acid
GABAB
gamma-aminobutyric acid type B
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HIV
human immunodeficiency virus


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Abbreviations
Description of abbreviations
HRT
hormone replacement therapy
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
INR
international normalized ratio
IP
investigational product
IRB
Institutional Review Board
ISN
international study number
LA-CRF
liver abnormality case report form
LS
least squares
M3G
morphine-3β-D-glucuronide
M6G
morphine-6β-D-glucuronide
NIDA
National Institute on Drug Abuse
OUD
opioid use disorder
PAM
positive allosteric modulator
PGx
pharmacogenomic
PTR
peak trough ratio
QA
quality assurance
QC
quality control
QTcF
corrected QT interval using Fridericia’s formula
QTL
quality tolerance limit
(S)AE
serious adverse event or adverse event
SAE
serious adverse event
SAF
safety analysis set
SMQ
Standardized MedDRA Queries
SOP
standard operating procedure
SpO2
blood oxygen saturation
SUSAR
suspected unexpected serious adverse reactions
t½
terminal elimination half-life
TBL
total bilirubin
TEAE
treatment-emergent adverse event
tlag
time prior to the time corresponding to the first measurable (nonzero) 
concentration
tmax
time of maximum concentration 
ULN
upper limit of normal
USM
urgent safety measure
Vz/F
apparent volume of distribution during terminal phase after oral/extravascular 
administration
WOCBP
woman of childbearing potential


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Definition of Key Study Terms
Terms
Definition of Terms
Baseline
Assessments of participants as they enter a study before they receive any 
treatment.
Endpoint
Variable that pertains to the efficacy or safety evaluations of a study.
Note: not all endpoints are themselves assessments since certain endpoints 
might apply to populations or emerge from analysis of results.  That is, 
endpoints might be facts about assessments (e.g., prolongation of survival).
Enroll
To register or enter a participant into a study.  Note: once a participant has 
received the IP or placebo, the protocol applies to the participant. 
Investigational 
period
Period of time where major interests of protocol objectives are observed and 
where the test product or comparative drug (sometimes without 
randomization) is given to a participant and continues until the last 
assessment after completing administration of the test product or 
comparative drug.
Investigational 
product
The drug, device, therapy or process under investigation in a study that is 
believed to have an effect on outcomes of interest in a study 
(e.g., health-related quality of life, efficacy, safety and pharmacoeconomics).
Randomization
The process of assigning participants to treatment or control groups using an 
element of chance to determine assignments in order to reduce bias.
Note: unequal randomization is used to allocate participants into groups at a 
differential rate; for example, 3 participants may be assigned to a treatment 
group for every 1 assigned to the control group.
Screen failure
Potential participant who signed the ICF, but did not meet one or more 
criteria required for participation in the study and was not randomized.
Screening
A process of active consideration of potential participants for randomization 
in a study.
Screening period
Period of time before entering the investigational period, usually from the 
time when a participant signs the consent form until just before the test 
product or comparative drug (sometimes without randomization) is given to 
a participant.
Study period
Period of time from the first study site initiation date to the last study site 
completing the study.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.


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NONSUBSTANTIAL AMENDMENT 1
I.  The purpose of this amendment is:
Nonsubstantial Changes
1.
Update screening language 
DESCRIPTION OF CHANGE:
Edit the rescreening language
RATIONALE:
To allow for the repeat of screening assessments within the screening window or to allow a 
subject to rescreen once for the study. Due to the nature of the participant population and 
the study design, subject safety and data integrity will not be impacted.
2.
Clarify inclusion and exclusion criteria
DESCRIPTION OF CHANGE:
Move exclusion criterion 18 to the inclusion criteria and clarify the CYP450 enzymes that 
are excluded for exclusion criterion 19.
RATIONALE:
Previous exclusion 18 should be answered affirmatively in order for the subject to be 
eligible for participation; as a result, this exclusion should be listed as an inclusion. 
Exclusion 19 excluded all inducers of metabolism; however, after consideration, it is only 
necessary to exclude inducers of CYP3A4. 
3.
Clarify procedure for continuous end tidal CO2
DESCRIPTION OF CHANGE:
Add clarification that subjects may remove cannula to dose or eat.
RATIONALE:
The timepoints overlap for the collection of end tidal CO2 and it would not be possible for 
the subject to dose or eat with the cannula in place.
4.
Lower the respiratory rate alarm for continuous end tidal CO2 alarms
DESCRIPTION OF CHANGE:
The alarm for respiratory rate low was 10 bpm and is now 6 bpm. 


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RATIONALE:
Generally, respiratory rates between 6 and 10 are not clinically relevant. A low respiratory 
rate alarm of 6 will allow a more accurate clinical determination of a true signal. 
5.
Edit Spot CO2 respiratory rate values
DESCRIPTION OF CHANGE:
The spot values are lowered to start at > 24, and continue with increments of 4 bpm: >28, 
>32, and >36.
RATIONALE:
This change is made to align with the protocol, Table 7,  alarm values.  
II.  Amendment summary of changes:
5.2 Exclusion Criteria #18 
WAS:
18. Participant must be willing to abstain from smoking (including use of tobacco-
containing products and nicotine or nicotine-containing products [e.g., electronic 
vapes]) from at least 1 hour predose through at least 8 hours postdose on days 9 and 10.
IS AMENDED TO:
18. Criterion Removed
5.1 Inclusion Criteria #12
ADDED:
12. Participant must be willing to abstain from smoking (including use of tobacco-
containing products and nicotine or nicotine-containing products [e.g., electronic 
vapes]) from at least 1 hour predose through at least 8 hours postdose on days 9 
and 10.
5.2 Exclusion Criteria #19
WAS:
19. Participant has used any inducer of metabolism (e.g., barbiturates, and rifampin) in the 
3 months prior to day -1.


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IS AMENDED TO:
19. Participant has used any inducer of CYP3A4-related metabolism (e.g., barbiturates, 
rifampin, apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, St. 
John’s wort, bosentan, efavirenz, etravirine, phenobarbital, primidone, 
armodafinil, modafinil, and rufinamide) in the 3 months prior to day 1.
5.4.1 Rescreening 
WAS:
Rescreening is allowed only in situations in which a participant underwent the screening 
procedures and due to logistical circumstances, the allocated time window for these tests 
has expired and the participant is documented as a screen failure.  In order to rescreen, a 
new ICF must be signed and a new participant screening number assigned.  Rescreening is 
only allowed once for an individual participant.
IS AMENDED TO:
Rescreening is allowed only in situations in which a participant underwent the screening 
procedures and due to logistical circumstances, the allocated time window for these tests 
has expired and the participant is documented as a screen failure.  In order to rescreen, a 
new ICF must be signed and a new participant screening number assigned.  Rescreening is 
only allowed once for an individual participant.
Results of screening assessments that do not meet the parameters required by 
eligibility criteria (e.g., clinical laboratory tests, vital signs, physical examination, 
ECG, etc.) may be repeated once within the 28-day screening period without the need 
to register the participant as a screen failure. If the participant meets exclusion 
criteria that cannot resolve during the screening period, or more than 28 days elapse 
from the date of signing the ICF, the participant must be documented as a screen 
failure. In order to re-screen after prior screen failure, a new ICF must be signed and 
the participant entered into screening with a new participant identification number. 
Rescreening is only allowed once for an individual participant.
7.2.8 Continuous and Spot End Tidal Carbon Dioxide, Table 5, Established Limits for End 
Tidal Carbon Dioxide 
WAS:  
Respiratory Rate Low              10 bpm
IS AMENDED TO:
Respiratory Rate Low             10  6 bpm


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9.4.3.3 Vital Signs, Table 7, Criteria for Respiratory Rate 
WAS:  
Respiratory Rates (breaths/minute) < 6, < 8, < 10, > 26, > 30, > 34, > 38
IS AMENDED TO:
Respiratory Rates (breaths/minute) < 6, < 8, < 10, > 24, > 28, > 32, > 36  > 26, > 30, > 34, > 38
9.4.3.4 Continuous Pulse Oximetry and Spot Blood Oxygen Saturation 
WAS:
The spot SpO2 levels and change from baseline (day 9) will be listed and summarized by 
treatment group and time point.
IS AMENDED TO:
The spot SpO2 levels and change from baseline (day 9) (day 1) will be listed and 
summarized by treatment group and time point.
III.  Nonsubstantial amendment rationale:
Rationale for Nonsubstantial Designation
All revisions made to the protocol are administrative in nature and do not impact the safety 
or scientific value of the clinical study.


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SPONSOR’S SIGNATURES
Astellas Signatories
(Electronic signatures are attached at the end of the document.)
Development Medical Science, 
Medical Specialties
Data Science, Medical and 
Development
Global Protocol Format v9.0
PPD
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