Conditions: Opioid Use Disorder
Keywords: Suboxone® Opioid Use Disorder buprenorphine/naloxone ASP8062 pharmacokinetic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 23
Healthy volunteers: no

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

This study also assessed the potential for pharmacokinetic interaction between ASP8062 and buprenorphine/naloxone.

Detailed description:
Participants were screened for up to 28 days prior to first investigational product (IP) administration. Eligible participants were admitted to the clinical unit on day -1 and were residential for a single period of 27 days/26 nights.

Participants were discharged from the clinical unit after completion of down-titration on the condition that all required assessments were performed and that there were no medical reasons for a longer stay in the clinical unit; which was the end-of-study visit (ESV). Prior to discharge, participants were provided with local buprenorphine and methadone providers for their reference.

Arms:
arm 1: Participants received multiple sublingual doses of buprenorphine/naloxone on days 1 through 26. In the Investigational Period participants were on a stable daily dose of buprenorphine/naloxone on days 5 through 18. After randomization on day 12, participants received a single oral dose of ASP8062 concomitantly with buprenorphine/naloxone. The stable dose of buprenorphine/naloxone was down titrated from days 19 through 26. arm 2: Participants received multiple sublingual doses of buprenorphine/naloxone on days 1 through 26. In the Investigational Period participants were on a stable daily dose of buprenorphine/naloxone on days 5 through 18. After randomization on day 12, participants received a single oral dose of placebo concomitantly with buprenorphine/naloxone. The stable dose of buprenorphine/naloxone was down titrated from days 19 through 26.

Interventions: intervention 1: ASP8062 intervention 2: Placebo ASP8062 intervention 3: buprenorphine/naloxone
Intervention descriptions: intervention 1: Oral intervention 2: Oral intervention 3: Sublingual

Protocol document:
Prot_SAP_000.pdf: 
Sponsor: APGD
ISN/Protocol 8062-CL-2003
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Version 1.2 Incorporating Nonsubstantial Amendment 2
A Phase 1b Randomized, Placebo-controlled Study to Assess the 
Effect of a Single Dose of ASP8062 on the Multiple Dose Safety, 
Tolerability and Pharmacokinetics of Buprenorphine/Naloxone in 
Subjects with Opioid Use Disorder
ISN/Protocol 8062-CL-2003
Version 1.2
Incorporating Nonsubstantial Amendment 2 [See Section 13]
29 Jul 2020
IND 146215
Sponsor:
Astellas Pharma Global Development Inc.
1 Astellas Way
Northbrook, IL 60062, US
Protocol History:
Version 1.0 Original [05 Mar 2020]
Version 1.1 Incorporating Nonsubstantial Amendment 01 [08 Jun 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 subject; 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.
NCT04447287


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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··················································································19
1.3
Schedule of Assessments·····································································20
1.3.1
Sample Collection Schedule ···························································24
2
INTRODUCTION·················································································28
2.1
Background ····················································································28
2.1.1
Substance-use Disorders································································28
2.1.2
Background on Pharmacological Concept············································28
2.1.3
Nonclinical and Clinical Data··························································29
2.1.3.1
Clinical Pharmacokinetics/Pharmacodynamics ································30
2.1.3.2
Clinical Safety······································································31
2.1.4
Summary of Key Safety Information for Investigational Product(s)··············32
2.2
Study Rationale················································································32
2.3
Risk Benefit Assessment ·····································································32
3
STUDY OBJECTIVE(S) AND ENDPOINT(S)··············································34
4
STUDY DESIGN AND DOSE RATIONALE················································34
4.1
Study Design···················································································34
4.2
Dose Rationale ················································································35
4.3
End of Study Definition ······································································36
5
STUDY POPULATION··········································································36
5.1
Inclusion Criteria··············································································36
5.2
Exclusion Criteria ·············································································37
5.3
Restrictions During the Study ·······························································39
5.3.1
Exercise···················································································39
5.3.2
Dietary and Fluid Restrictions ·························································39
5.3.3
Smoking Restrictions ···································································39
5.4
Screen Failures ················································································39
5.4.1
Rescreening ··············································································40


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6
INVESTIGATIONAL PRODUCT(S) ·························································40
6.1
Investigational Product(s) Administered ···················································40
6.2
Preparation/Handling/Storage/Accountability·············································41
6.2.1
Packaging and Labeling ································································41
6.2.2
Handling, Storage and Accountability ················································42
6.3
Randomization and Blinding ································································42
6.3.1
Blinding Method·········································································42
6.3.2
Confirmation of the Indistinguishability of the Investigational Product··········42
6.3.3
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking ··················································································42
6.3.4
Breaking the Treatment Code for Emergency ·······································42
6.3.5
Breaking the Treatment Code by the Sponsor ·······································43
6.3.6
Assignment and Allocation·····························································43
6.3.6.1
Subject Number····································································43
6.3.6.2
Randomization ·····································································43
6.4
Investigational Product Compliance ························································44
6.5
Previous and Concomitant Treatment (Medication and Nonmedication Therapy)····44
6.5.1
Previous Treatment (Medication and Nonmedication Therapy)···················44
6.5.2
Concomitant Treatment (Medication and Nonmedication Therapy)··············44
6.5.3
Rescue Medications·····································································45
6.6
Dose Modification ············································································45
6.7
Criteria for Continuation of Treatment ·····················································45
7
STUDY PROCEDURES AND ASSESSMENTS ············································46
7.1
Efficacy Assessments·········································································46
7.1.1
Opioid Craving Visual Analogue Scale···············································46
7.2
Safety Assessments ···········································································46
7.2.1
Adverse Events ··········································································46
7.2.2
Laboratory Assessments································································46
7.2.3
Vital Signs················································································47
7.2.4
Physical Examination···································································47
7.2.5
Electrocardiogram·······································································47
7.2.5.1
12-lead Electrocardiogram························································47
7.2.6
Continuous Pulse Oximetry and Spot Blood Oxygen Saturation··················47
7.2.7
Columbia-Suicide Severity Rating Scale ·············································48


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7.2.8
Continuous End Tidal Carbon Dioxide and Spot End Tidal Carbon Dioxide····48
7.2.9
Clinical Opiate Withdrawal Scale ·····················································48
7.2.10
Order of Assessments···································································48
7.3
Adverse Events and Other Safety Aspects ·················································48
7.3.1
Time Period for Collecting Adverse Event and Serious Adverse Event 
Information···············································································48
7.3.2
Method of Detecting Adverse Events and Serious Adverse Events···············49
7.3.3
Follow-up of Adverse Events··························································49
7.3.4
Reporting of Serious Adverse Events·················································49
7.3.5
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events ··········································49
7.3.6
Adverse Events of Special Interest ····················································49
7.3.7
Special Situations········································································50
7.3.8
Supply of New Information Affecting the Conduct of the Study··················50
7.3.9
Urgent Safety Measures ································································50
7.3.10
Reporting Urgent Safety Measures····················································51
7.4
Pharmacokinetics··············································································51
7.4.1
Analysis of ASP8062, Buprenorphine/Naloxone and Metabolite 
(Norbuprenorphine) in Plasma·························································51
7.5
Pharmacodynamics ···········································································51
7.6
Electronic Clinical Outcome Assessment ··················································51
7.7
Other Assessments ············································································51
7.7.1
Sample for the Analysis of Genes Related to Efficacy/Safety ·····················51
7.7.2
Sample for Banked Pharmacogenomic Sample Analysis···························52
7.8
Total Amount of Blood·······································································52
8
DISCONTINUATION············································································52
8.1
Discontinuation of Individual Subject(s) From Study Treatment ·······················52
8.2
Discontinuation of Individual Subject(s) From Study ····································53
8.2.1
Lost to Follow-up········································································53
8.3
Discontinuation of the Study Site ···························································53
8.4
Discontinuation of the Study·································································53
9
STATISTICAL METHODOLOGY ···························································54
9.1
Sample Size····················································································54
9.2
Analysis Sets···················································································55


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9.2.1
Full Analysis Set ········································································55
9.2.2
Safety Analysis Set······································································55
9.2.3
Pharmacokinetic Analysis Set ·························································55
9.3
Demographics and Baseline Characteristics ···············································55
9.3.1
Demographics············································································55
9.3.2
Subject Disposition······································································55
9.3.3
Previous and Concomitant Treatment (Medication and Nonmedication 
Therapy) ··················································································56
9.3.4
Medical History··········································································56
9.3.5
Investigational Product Exposure ·····················································56
9.4
Analysis of Efficacy ··········································································56
9.4.1
Opioid Craving Visual Analogue Scale···············································56
9.5
Analysis of Safety·············································································56
9.5.1
Adverse Events ··········································································56
9.5.2
Laboratory Assessments································································57
9.5.3
Vital Signs················································································57
9.5.4
Electrocardiogram·······································································57
9.5.4.1
12-lead Electrocardiogram························································57
9.5.5
Columbia-Suicide Severity Rating Scale ·············································58
9.5.6
Blood Oxygen Saturation·······························································58
9.5.7
End Tidal Carbon Dioxide ·····························································58
9.6
Analysis of Pharmacokinetics ·······························································58
9.6.1
Plasma Concentrations··································································58
9.6.2
Estimation of Pharmacokinetic Parameters ··········································58
9.6.3
Statistical Analysis of Pharmacokinetic Parameters ································59
9.7
Analysis of Pharmacodynamics ·····························································59
9.8
Other Analyses ················································································59
9.9
Major Protocol Deviations ···································································59
9.10
Interim Analysis (and Early Discontinuation of the Study)······························59
9.11
Additional Conventions ······································································59
10
OPERATIONAL CONSIDERATIONS·······················································60
10.1
Data Collection················································································60
10.2
Demographics and Baseline Characteristics ···············································60
10.2.1
Demographics············································································60


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10.2.2
Medical History··········································································60
10.2.3
Diagnosis of the Target Disease, Severity and Duration of Disease ··············60
10.3
Major Protocol Deviations ···································································60
10.4
Study Organization············································································61
10.4.1
Data Safety Monitoring Board·························································61
10.4.2
Other Study Organization ······························································61
11
REFERENCES ····················································································62
12
APPENDICES ·····················································································65
12.1
Ethical, Regulatory and Study Oversight Considerations ································65
12.1.1
Ethical Conduct of the Study···························································65
12.1.2
Institutional Review Board/Independent Ethics Committee/Competent 
Authorities················································································65
12.1.3
Protocol Amendment and/or Revision················································65
12.1.4
Financial Disclosure ····································································66
12.1.5
Informed Consent of Subjects ·························································66
12.1.5.1
Subject Information and Consent················································66
12.1.5.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ·····························66
12.1.6
Source Documents ······································································67
12.1.7
Record Retention ········································································67
12.1.8
Subject Confidentiality and Privacy···················································67
12.1.9
Arrangement for Use of Information and Publication of the Study ···············68
12.1.10
Signatory Investigator for Clinical Study Report····································68
12.2
Procedure for Study Quality Control ·······················································69
12.2.1
Study Monitoring········································································69
12.2.2
Direct Access to Source Data/Documents············································69
12.2.3
Data Management ·······································································69
12.2.4
Quality Assurance·······································································69
12.3
Contraception Requirements·································································71
12.4
Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up and Reporting ··············································································73
12.4.1
Definition of Adverse Events ··························································73
12.4.1.1
Abnormal Laboratory Findings ··················································73
12.4.1.2
Potential Cases of Drug-induced Liver Injury··································73
12.4.2
Definition of Serious Adverse Events·················································73


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12.4.3
Criteria for Causal Relationship to Investigational Product························74
12.4.4
Criteria for Defining the Severity of an Adverse Event ····························75
12.4.5
Reporting Procedures for Serious Adverse Events··································75
12.4.6
Reporting Procedures for Special Situations·········································77
12.4.6.1
Pregnancy···········································································77
12.4.6.2
Medication Error, Overdose and “Off-label Use” ·····························77
12.4.6.3
Misuse/Abuse ······································································78
12.4.6.4
Occupational Exposure ···························································78
12.5
Liver Safety Monitoring and Assessment ··················································79
12.6
List of Excluded Concomitant Medications················································82
12.7
Laboratory Assessments······································································83
12.8
Pharmacogenomic Analysis with Banked Sample ········································85
12.9
Opioid Craving Visual Analogue Scale ····················································87
12.10
Columbia-Suicide Severity Rating Scale···················································88
12.10.1
Baseline/Screening Version····························································88
12.10.2
Since Last Visit··········································································92
12.11
Clinical Opiate Withdrawal Scale···························································97
12.12
Adverse Events of Interest Related to Potential Substance Abuse and Following 
Drug Withdrawal··············································································98
12.13
List of Abbreviations and Definition of Key Study Terms····························· 104
13
ATTACHMENT 1:  NONSUBSTANTIAL AMENDMENT 2·························· 108
14
SPONSOR’S SIGNATURES·································································· 111


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SIGNATURES
1.  SPONSOR’S SIGNATURES
Required signatures (e.g., protocol authors and contributors, etc.) are located in [Section 14
Sponsor Signature].


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2.  INVESTIGATOR’S SIGNATURE
A Phase 1b Randomized, Placebo-controlled Study to Assess the Effect of a Single Dose 
of ASP8062 on the Multiple Dose Safety, Tolerability and Pharmacokinetics of 
Buprenorphine/Naloxone in Subjects with Opioid Use Disorder
ISN/Protocol 8062-CL-2003
Version 1.2 Incorporating Nonsubstantial Amendment 2
29 Jul 2020
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:








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Inclusion/Exclusion Criteria:
Inclusion Criteria:
Subject is eligible for participation in the study if all of the following apply:
1.
Institutional Review Board/Independent Ethics Committee-approved written informed consent 
and privacy language as per national regulations (e.g., Health Insurance Portability and 
Accountability Act authorization for US study sites) must be obtained from the subject prior to 
any study-related procedures (including withdrawal of prohibited medication, if applicable).
2.
Subject is a male or female subject between 18 to 60 years of age, inclusive at screening.
3.
Subject has a body mass index range of 18 to 36 kg/m2, inclusive and weighs at least 50 kg at 
screening.
4.
Subject has a diagnosis of moderate or severe OUD according to the DSM-5 at screening.
5.
Subject tests positive for opioids at screening and/or on day -1 or subject shows signs of 
opioid withdrawal on day -1.
6.
Subject is willing to take buprenorphine/naloxone and is not taking buprenorphine or 
buprenorphine/naloxone at screening.
7.
Female subject is not pregnant (see [Appendix 12.3 Contraception Requirements]) and at least 
1 of the following conditions apply:
a.
Not a woman of childbearing potential (WOCBP) (see [Appendix 12.3 Contraception 
Requirements])
b.
WOCBP who agrees to follow the contraceptive guidance (see [Appendix 12.3
Contraception Requirements]) from the time of informed consent through at least 
30 days after final IP administration.
8.
Female subject must agree not to breastfeed starting at screening and throughout the study 
period and for 30 days after final IP administration.
9.
Female subject must not donate ova starting at first dose of IP and throughout the study period 
and for 30 days after final IP administration.
10. Male subject with female partner(s) of childbearing potential (including breastfeeding partner) 
must agree to use contraception (see [Appendix 12.3 Contraception Requirements]) 
throughout the study period and for 90 days after final IP administration.
11. Male subject must not donate sperm during the treatment period and for 90 days after final IP 
administration.
12. Male subject with pregnant partner(s) must agree to remain abstinent or use a condom and 
spermicide for the duration of the pregnancy throughout the study period and for 90 days after 
final IP administration.
13. Subject agrees not to participate in another interventional study while participating in the 
present study.
14. 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 11 and 12.
Exclusion Criteria:
Subject will be excluded from participation in the study if any of the following apply:
1.
Subject has received any investigational therapy within 28 days or 5 half-lives, whichever is 
longer, prior to screening.
2.
Subject has any condition which, in an investigator’s opinion, makes the subject unsuitable for 
study participation.
3.
Female subject who has been pregnant within 6 months prior to screening or breastfeeding 
within 3 months prior to screening.
4.
Subject has a known or suspected hypersensitivity to ASP8062, buprenorphine, naloxone or 
any components of the formulations used.


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5.
Subject has had previous exposure with ASP8062.
6.
Subject has any of the liver function tests (alkaline phosphatase, alanine aminotransferase 
[ALT], aspartate aminotransferase [AST], gamma-glutamyl transferase and total bilirubin 
[TBL]) > 2 × upper limit of normal (ULN) on day -1.  In such a case, the assessment may be 
repeated once.
7.
Subject 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.
Subject 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 the investigator, with exception of history of cholecystectomy.
9.
Subject has current or recent diagnosis (within the last 12 months) of moderate or severe 
alcohol, sedative, hypnotic, anxiolytic, cocaine or any other substance use disorder (except for 
opioids, caffeine, tobacco or nicotine) according to the DSM-5 at screening.
10. Subject 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. Subject tests positive for alcohol, benzodiazepine or methadone on day -1.  Subject tests 
positive for buprenorphine on day -1.
12. Subject has had recent suicidal ideation within the last 12 months or subject who is at 
significant risk to commit suicide, as judged by the investigator, using the Columbia-Suicide 
Severity Rating Scale (C-SSRS) at screening or since the last visit on day -1.
13. Subject has/had febrile illness or symptomatic, viral, bacterial (including upper respiratory 
infection) or fungal (noncutaneous) infection within 1 week prior to day -1.
14. Subject has any clinically significant abnormality following the investigator’s review of the 
physical examination, electrocardiogram (ECG) and protocol-defined clinical laboratory tests 
at screening or on day -1.
15. Subject has a mean pulse < 45 or > 110 beats per minute (unless out of range [> 110 beats per 
minute] pulse is deemed to be secondary to opioid withdrawal, as judged by the investigator); 
mean systolic blood pressure > 150 mmHg; mean diastolic blood pressure > 95 mmHg (unless 
out of range blood pressure is deemed to be secondary to opioid withdrawal, as judged by the 
investigator) (measurements taken in duplicate after subject has been resting in the supine 
position for at least 5 minutes; pulse will be measured automatically) on day -1.  If the mean 
blood pressure exceeds the limits above, 1 additional duplicate may be taken.
16. Subject has a mean corrected QT interval using Fridericia’s formula (QTcF) of > 450 msec 
(for male subjects) and > 470 msec (for female subjects) on day -1.  If the mean QTcF exceeds 
the limits above, 1 additional duplicate ECG may be taken.
17. Subject has used any prescribed drugs, vitamins and natural or herbal remedies (including, 
St. John’s Wort) in the 2 weeks prior to first IP administration, except for rescue medications, 
milk of magnesia, acetaminophen, topical dermatological products, including corticosteroid 
products, hormonal contraceptives and hormone replacement therapy (HRT).
18. Subject has used any inducer of CYP2C8, 2C9 or 3A4-related metabolism (e.g., barbiturates, 
rifampin, aprepitant, ritonavir, apalutamide, carbamazepine, enzalutamide, mitotane, 
phenytoin, rifampin, St. John’s wort, bosentan, efavirenz, etravirine, phenobarbital, primidone, 
armodafinil, modafinil, and rufinamide) in the 3 months prior to day -1.
19. Subject has had significant blood loss or 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.


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20. Subject has a positive serology test for antibodies to human immunodeficiency virus type 1 
and/or type 2, acute hepatitis B virus infection or acute hepatitis C virus infection, excluding 
asymptomatic hepatitis C virus infection at screening.
21. Subject 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.
22. Criterion removed.
23. Subject is an employee of Astellas, the study-related contract research organizations or the 
clinical unit.
Investigational Product(s):
Name/Use:
ASP8062 (test product)
Placebo ASP8062 (placebo)
Suboxone® (buprenorphine/naloxone) (test product)
Dose(s):
ASP8062: single dose of 60 mg ASP8062 (2 × 30 mg tablets)
Placebo ASP8062: single dose of placebo ASP8062 (2 × tablets)
There will be no modification for the single planned ASP8062 dose of 60 mg.
Buprenorphine/naloxone: multiple doses of buprenorphine/naloxone (sublingual film)
On day 1, subjects will receive a 4/1 mg buprenorphine/naloxone dose in the morning and a 
4/1 mg buprenorphine/naloxone dose in the afternoon.  On day 2, subjects will receive an 
8/2 mg buprenorphine/naloxone dose in the morning and a 4/1 mg buprenorphine/naloxone dose in 
the afternoon.  On day 3, subjects will receive a 12/3 mg buprenorphine/naloxone dose in the 
morning.  On day 4, subjects will receive a 16/4 mg buprenorphine/naloxone dose in the morning.  
Titration may be extended based on subject tolerability; however, subjects must be on a stable dose 
of 16/4 mg buprenorphine/naloxone by day 5.  Subjects not on a stable dose of 16/4 mg 
buprenorphine/naloxone by day 5 will be discontinued from the study.  Subjects will be on a stable, 
total daily dose of 16/4 mg buprenorphine/naloxone on days 5 through 18.  The stable dose of 
buprenorphine/naloxone (16/4 mg) will be down-titrated from days 19 through 26, according to the 
table below.
Schedule of Down-titration of Buprenorphine/Naloxone Dose
Day(s)
Subjects with Stabilized Buprenorphine/Naloxone Dose of 16/4 mg
18
16/4 mg
19
8/2 mg
20
8/2 mg
21
8/2 mg
22
4/1 mg
23
4/1 mg
24
4/1 mg
25
2/0.5 mg
26
2/0.5 mg
27
(Discharge/ESV)
ESV: end-of-study visit
Mode(s) of Administration:
On all dosing days (excluding days 11 and 12), buprenorphine/naloxone will be administered 
sublingually under standardized fed conditions (i.e., meals will be served up to 1 hour predose or at 
least 2 hours postdose).  Water will be allowed ad libitum.  On days 11 and 12, 
buprenorphine/naloxone will be administered sublingually under fasting conditions (i.e., no food or 


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beverage will be allowed from at least 10 hours predose through at least 4 hours postdose).  Water 
intake will be prohibited from at least 1 hour predose through at least 2 hours postdose.
On day 12, ASP8062 or placebo ASP8062 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 2 hours postdose except for the approximately 240 mL water to swallow 
the IP.
Concomitant Treatment (Medication and Nonmedication Therapy) Restrictions or 
Requirements:
All medicinal products other than the IPs, 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.
Subjects will only be allowed to use the following concomitant medication(s), if needed, from first 
IP administration until the ESV:
●
Rescue medications:
○Hydroxyzine pamoate: 50 mg (1 or 2 × tablets) every 6 hours, as needed
○Mylanta/Maalox: 10 to 20 mL, per product instruction, as needed
○Loperamide: 2 mg, per product instruction, as needed
○Methocarbamol: 750 mg (1 or 2 × tablets) every 6 hours, as needed
○Ibuprofen: 200 mg (2 × tablets) every 6 hours, as needed
○Promethazine: 25 mg oral or intramuscular, every 6 hours, as needed
○Clonidine: 0.1 mg, every 12 hours, as needed
●
Milk of magnesia (except for days 11 and 12)
●
Acetaminophen (up to 2 g/day)
●
Topical dermatological products, including corticosteroid products
●
Hormonal contraceptives
●
HRT
If a subject’s health condition necessitates the use of any medication other than the permitted 
medications during the study, the investigator and medical monitor, or designee(s), will discuss the 
case and determine if the subject 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.
Duration of Treatment:
Single dose of 60 mg ASP8062 or placebo ASP8062 on day 12 with concomitant administration of 
buprenorphine/naloxone (16/4 mg).
Multiple doses of buprenorphine/naloxone for up to 26 days.


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Formal Stopping Rules:
Discontinuation of Individual Subject(s) From Study Treatment:
A subject must discontinue study treatment for any of the following reasons:
●
Subject requests to stop treatment
●
Any clinical adverse events (AEs), laboratory abnormality or intercurrent illness, in the 
opinion of the investigator, indicates continued treatment is not in the best interest of the 
subject
●
Participation in another interventional study while participating in the present study
●
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
●
Female subject becomes pregnant
Discontinuation of the Study:
The sponsor will terminate this study if 1 of the following criteria are met.  The sponsor will 
unblind the affected subject(s) to an investigator/delegate, before a final decision is made.
1.
If after concomitant administration of buprenorphine/naloxone and ASP8062 or placebo 
ASP8062 on day 12, ≥5 ASP8062-treated subjects experience ASP8062-related AEs of 
severe intensity that are considered by an investigator to be of clinical concern
2.
If after concomitant administration of buprenorphine/naloxone and ASP8062 or placebo 
ASP8062 on day 12, ≥3 ASP8062-treated subjects experience an ASP8062-related serious 
adverse event and there is no plausible alternate explanation for these events
3.
If after concomitant administration of buprenorphine/naloxone and ASP8062 or placebo 
ASP8062 on day 12, ≥5 ASP8062-treated subjects 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 11 (day prior to concomitant 
administration of buprenorphine/naloxone and ASP8062 or placebo ASP8062) values
●ALT or AST ≥2 × ULN and ALT or AST ≥5 × day 11 (day prior to concomitant 
administration of buprenorphine/naloxone and ASP8062 or placebo ASP8062) values
●TBL ≥2 × ULN and subject does not have Gilbert Syndrome
4.
If after concomitant administration of buprenorphine/naloxone and ASP8062 or placebo 
ASP8062 on day 12, ≥3 ASP8062-treated subjects have QTcF interval > 500 msec in 
2 consecutive measurements within 24 hours postdose
5.
If after concomitant administration of buprenorphine/naloxone and ASP8062 or placebo 
ASP8062 on day 12:
●≥4 ASP8062-treated subjects experience ASP8062-related symptomatic decrease in 
blood oxygen saturation (SpO2) requiring more than 2 liters of supplemental oxygen via 
nasal cannula or,
●≥1 ASP8062-treated subjects experience ASP8062-related symptomatic decrease in 
SpO2 requiring intubation, for medically significant respiratory depression




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1.2
Study Schema
Figure 1
Flow Chart
Screening Period
Run-in Period
Investigational Period
Days -28 to -2
Informed consent
Screening procedures
Day -1
Admission to clinical unit
Days 1 to 11
Buprenorphine/naloxone 
stabilization
Day 12
Randomization to a single dose of 
ASP8062 or placebo ASP8062 
administration concomitantly with 
buprenorphine/naloxone
Days 13 to 18
ASP8062 pharmacokinetic 
washout
Down-titration Period
Days 19 to 26
Discharge
Day 27
ESV
ESV: end-of-study visit


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1.3
Schedule of Assessments
Table 1
Schedule of Assessments
Study Phase
Screening 
Period1
Run-in Period
Investigational Period
Down-titration 
Period
Discharge/
ET2
Buprenorphine/Naloxone alone
ASP8062/
Buprenorphine/
Naloxone
Buprenorphine/Naloxone 
alone
Buprenorphine/
Naloxone alone
Day(s)
-28 to -2
-1
1
2 to 10
11
12
13
14 to 17
18
19 to 263
27
ESV2
Residential Period
X
X
X
X
X
X
X
X
X
Informed Consent
X
Inclusion and Exclusion Criteria
X
X
Randomization
X
Demographics
X
Medical History
X
X
Drug Use History/TLFB4
X
X
Body Weight and Height5
X
X
X
Clinical Laboratory Tests6
X
X
X
X
X
X
X
X
X
Drugs of Abuse/Alcohol Tests
X
X
Pregnancy Test (Female Subjects Only)7
X
X
X
FSH Test (Postmenopausal Female 
Subjects Only)
X
Vital Signs8
X
X
X
X
X
X
X
X
X
X
X
Continuous Pulse Oximetry9
X
X
12-lead ECG10
X
X
X
X
X
Physical Examination
X
X
X
C-SSRS11
X
X
X
Spot SpO212
X
X
X
X
Continuous and Spot End Tidal CO213
X
X
COWS
X
X
Opioid Craving VAS Training14
X
Table continued on next page


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Study Phase
Screening 
Period1
Run-in Period
Investigational Period
Down-titration 
Period
Discharge/
ET2
Buprenorphine/Naloxone alone
ASP8062/
Buprenorphine/
Naloxone
Buprenorphine/Naloxone 
alone
Buprenorphine/
Naloxone alone
Day(s)
-28 to -2
-1
1
2 to 10
11
12
13
14 to 17
18
19 to 263
27
ESV2
Opioid Craving VAS15
X
X
X
ASP8062 or Placebo ASP8062 
Administration16
X
Buprenorphine/naloxone 
Administration17
X
X
X
X
X
X
X
X
Buprenorphine/naloxone down-titration 
period
X
Blood Sampling for ASP8062 
Pharmacokinetics18
X
X
X
X
X
Blood Sampling for 
Buprenorphine/naloxone and Metabolite 
(Norbuprenorphine) Pharmacokinetics19
X
X
X
X
Blood Sample for Biomarker20
X
(X)
Blood Sample for PGx Analysis20
X
(X)
Adverse Event Assessment
X
X
X
X
X
X
X
X
X
X
X
Previous/Concomitant Treatment 
(Medication and Nonmedication 
Therapy)
X
X
X
X
X
X
X
X
X
X
X
COWS: clinical opiate withdrawal scale; C-SSRS: Columbia-Suicide Severity Rating Scale; CO2: carbon dioxide; ECG: electrocardiogram; ESV: end-of-study visit; ET: early 
termination; FSH: follicle-stimulating hormone; PGx: pharmacogenomics; SpO2: blood oxygen saturation; TLFB: timeline follow-back; VAS: visual analogue scale
1.
Screening period is days -28 to -1.  Eligibility will be confirmed at screening and on day -1.  Subjects who do not meet eligibility criteria on day -1 are considered screen failures.
2.
Subjects will be discharged from the clinical unit after completion of down-titration 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; which is the ESV.  Upon early termination or if a subject discontinues early from the study, discharge/ESV procedures will 
be performed upon early termination/discontinuation.
3.
The stable dose of buprenorphine/naloxone (16/4 mg) will be down-titrated from days 19 through 26.
4.
TLFB will be collected for 2 weeks prior to screening or on day -1 (prior to any assessments).
Footnotes continued on next page


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5.
Height to be collected at screening only.
6.
Clinical laboratory tests include blood collection for serology tests (at screening only), hematology and biochemistry and urine collection for urinalysis.
Blood samples will be collected at screening, on day -1 and predose on day 1.  Blood samples will be collected predose on day 11, at the following postdose time point on day 11: 
2 hours, predose on day 12 and at the following postdose time point on day 12: 2 hours.  Blood samples will also be collected once daily on days 13 through 18 and day 26.
Urine samples will be collected at screening, on day -1 and predose on day 1.  Urine samples will be collected predose on day 11, at the following postdose time point on day 11: 
2 hours, predose on day 12 and at the following postdose time point on day 12: 2 hours.
7.
Blood pregnancy test at screening and urine pregnancy test on days -1 and 26.
8.
Vital signs include measurements of blood pressure, pulse, respiratory rate and oral temperature.  Measurements will be taken after the subject 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.  Oral temperature will be 
taken as a single measurement at all time points.  Measurements will be taken at screening, on day -1 and predose on days 1, 4 and 8.  Measurements will be taken predose on 
day 11, at the following postdose time points on day 11: 1, 2, 4, 8 and 12 hour(s), predose on day 12 and at the following postdose time points on day 12: 1, 2, 4, 8 and 12 hour(s).  
Measurements will also be taken once daily on days 13 through 18.  During the down-titration period, vital signs will be taken once daily at approximately the same time each day 
through the ESV.
9.
Continuous pulse oximetry will begin predose on days 11 and 12 until at least 8 hours postdose.
10.
12-lead ECGs will be taken after the subject has been resting in the supine position for at least 5 minutes.  12-lead ECGs will be taken in duplicate.  12-lead ECGs will be taken at 
screening, on day -1, predose on day 11 and at the following postdose time points on day 11: 2, 4 and 12 hours, predose on day 12 and at the following postdose time points on 
day 12: 2, 4 and 12 hours and at the ESV.
11.
The version of the C-SSRS to be used at screening is the “Baseline/Screening” version and the version to be used on day -1 and at the ESV is the “Since Last Visit”.
12.
Spot SpO2 measurements will be taken on day -1, predose on day 11, at the following postdose time points on day 11: 1, 2, 4, 8 and 12 hour(s), predose on day 12, at the following 
postdose time points on day 12: 1, 2, 4, 8 and 12 hour(s) and at the ESV.
13.
Continuous end tidal CO2 to be collected starting predose on days 11 and 12 until 8 hours postdose. Timepoints will be recorded predose and 1, 2, 4 and 8 hours postdose. The 
cannula may be removed while subjects dose or eat.
14.
Opioid craving VAS training will occur on day -1.  Additional trainings may occur, as needed.
15.
The opioid craving VAS will be performed on day -1.  The opioid craving VAS will be performed predose on days 11, at the following postdose time point on day 11: 2 hours, 
predose on day 12 and at the following postdose time point on day 12: 2 hours.
16.
On day 12, ASP8062 or placebo ASP8062 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 2 hours postdose except for the
approximately 240 mL water to swallow the investigational product.  ASP8062 or placebo ASP8062 will be administered with the approximately 240 mL of water and the
buprenorphine/naloxone will be administered immediately after the subject has consumed the ASP8062 or placebo with the approximately 240 mL of water.
17.
On all dosing days (excluding days 11 and 12), buprenorphine/naloxone will be administered sublingually under standardized fed conditions (i.e., meals will be served up to 
1 hour predose or at least 2 hours postdose).  Water will be allowed ad libitum.  On days 11 and12, buprenorphine/naloxone will be administered sublingually under fasting 
conditions (i.e., no food or beverage will be allowed from at least 10 hours predose through at least 4 hours postdose).  On days 11 and 12, water intake will be prohibited from at 
least 1 hour predose through at least 2 hours postdose, except for the approximately 240 mL water provided to administer the IP.  On day 11, the subject will consume 
approximately 240 mL of water and then place the buprenorphine/naloxone sublingually to match the dosing condition on day 12.  On day 12, buprenorphine/naloxone will be 
administered concomitantly with ASP8062 or placebo ASP8062.


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Footnotes continued on next page
18.
Blood samples for ASP8062 pharmacokinetics will be collected predose on day 12 and at the following postdose time points on day 12: 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 
24, 36, 48, 60, 72, 96, 120, 144, 168, 216 and 264 hour(s).
19.
Blood samples for buprenorphine and its metabolite (norbuprenorphine) and naloxone pharmacokinetics will be collected predose on day 11 and at the following postdose time 
points on day 11: 0.25, 0.5, 1, 1.5, 2, 3, 4, 8, 12 and 16 hour(s).  Blood samples for buprenorphine and its metabolite (norbuprenorphine) and naloxone pharmacokinetics will be 
collected predose on day 12 and at the following postdose time points on day 12: 0.25, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 16, 24, 168, 216 and 264 hour(s).
20.
The blood sample for biomarker and PGx analysis (biobanking) can be collected on day -1 or predose on day 1.


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1.3.1
Sample Collection Schedule
Table 2 Sample Collection Schedule
Day
Time 
Point
Pharmacokinetics
ASP8062
Pharmacokinetics 
and Metabolite 
Profiling
Buprenorphine/
naloxone
Clinical
Laboratory Tests
Vital 
Signs
Continuous 
Pulse 
Oximetry
12-lead 
ECG
Physical 
Examination C-SSRS SpO2
End 
Tidal 
CO2
COWS
Opioid 
Craving 
VAS
Blood
Urine
Day -28 to -2
Screening
X
X
X
X
X
X
-1
X
X
X
X
X
X
X
X
X
1
Predose
X
X
X
X
2
3
4
Predose
X
5
6
7
8
Predose
X
9
10
11
Predose
X
X
X
X
X
X
X
X
X
0.25 hours
X
0.50 hours
X
1 hour
X
X
X
X
1.5 hours
X
2 hours
X
X
X
X
X
X
X
X
3 hours
X
4 hours
X
X
X
X
X
8 hours
X
X
X
X
12 hours
X
X
X
X
16 hours
X
Table continued on next page


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Day
Time 
Point
Pharmacokinetics
ASP8062
Pharmacokinetics 
and Metabolite 
Profiling
Buprenorphine/
naloxone
Clinical
Laboratory Tests
Vital 
Signs
Continuous 
Pulse 
Oximetry
12-lead 
ECG
Physical 
Examination C-SSRS SpO2
End 
Tidal 
CO2
COWS
Opioid 
Craving 
VAS
Blood
Urine
12
Predose
X
X
X
X
X
X
X
X
X
X
0.25 hours
X
X
0.50 hours
X
X
1 hour
X
X
X
X
X
1.50 hours
X
X
2 hours
X
X
X
X
X
X
X
X
X
2.50 hours
X
3 hours
X
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
X
13
24 hours 
postdose 
day 12
X
X
X
X
36 hours 
postdose 
day 12
X
14
48 hours 
postdose 
day 12
X
X
X
60 hours 
postdose 
day 12
X
15
72 hours 
postdose 
day 12
X
X
X
Table continued on next page


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Day
Time 
Point
Pharmacokinetics
ASP8062
Pharmacokinetics 
and Metabolite 
Profiling
Buprenorphine/
naloxone
Clinical
Laboratory Tests
Vital 
Signs
Continuous 
Pulse 
Oximetry
12-lead 
ECG
Physical 
Examination C-SSRS SpO2
End 
Tidal 
CO2
COWS
Opioid 
Craving 
VAS
Blood
Urine
16
96 hours 
postdose 
day 12
X
X
X
17
120 hours 
postdose 
day 12
X
X
X
18
144 hours 
postdose 
day 12
X
X
X
19
168 hours 
postdose 
day 12
X
X
X
20
192 hours 
postdose 
day 12
X
21
216 hours 
postdose 
day 12
X
X
X
22
240 hours 
postdose 
day 12
X
23
264 hours 
postdose 
day 12
X
X
X
24
X
25
X
26
X
X
X
Table continued on next page


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Day
Time 
Point
Pharmacokinetics
ASP8062
Pharmacokinetics 
and Metabolite 
Profiling
Buprenorphine/
naloxone
Clinical
Laboratory Tests
Vital 
Signs
Continuous 
Pulse 
Oximetry
12-lead 
ECG
Physical 
Examination C-SSRS SpO2
End 
Tidal 
CO2
COWS
Opioid 
Craving 
VAS
Blood
Urine
27 (ESV)
After 
completion 
of down-
titration 
period
X
X
X
X
X
COWS: clinical opiate withdrawal scale; C-SSRS: Columbia-Suicide Severity Rating Scale; CO2: carbon dioxide; ECG: electrocardiogram; ESV: end-of-study visit; SpO2: blood 
oxygen saturation; VAS: visual analogue scale


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2
INTRODUCTION
2.1
Background
ASP8062 is a novel compound with positive allosteric modulator (PAM) activity on the 
γ-aminobutyric acid type B (GABAB) receptor that is intended for oral administration and is 
currently being developed for the treatment of opioid use disorder (OUD) and alcohol use 
disorder (AUD).  ASP8062 is a crystal, which is practically insoluble in water and slightly 
soluble in ethanol (EtOH).  
2.1.1
Substance-use Disorders
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 
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 DSM-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.
2.1.2
Background on Pharmacological Concept
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 
craving/self-administration 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 


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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].
2.1.3
Nonclinical and Clinical Data
ASP8062 is an orally available, new molecular entity discovered by Astellas Pharma Inc.  
ASP8062 is a GABAB receptor PAM with activity in the central nervous system (CNS).
ASP8062 (1, 3 and 10 mg/kg orally) decreased self-administration of EtOH in male and 
female rats (Study 8062-PH-9054).  Intragastric administration of ASP8062 (0.3, 1 and 
3 mg/kg) to rhesus monkeys decreased self-administrations with morphine 
(Study 8062-PH-9052).  In a rat conditioned place preference (CPP) study, ASP8062 (1, 3 
and 10 mg/kg orally) decreased cocaine-induced elevation of CPP score in a dose-related 
manner (Study 8062-PH-9051).  Intragastric administration of ASP8062 (0.1, 0.3 and 
1 mg/kg) to rhesus monkeys significantly decreased the mean number of self-administrations 
with cocaine in 1 of the 3 animals (Study 8062-PH-9053).  Overall, the findings in rats and 
rhesus monkeys indicate ASP8062 has potential suppressing effects on substance use 
disorders such as alcohol, morphine and cocaine in humans.
ASP8062 did not affect the retention time in the rotarod test in rats up to 30 mg/kg 
(Study 8062-PH-9035).  ASP8062 at doses of 10, 30 and 100 mg/kg orally had no synergistic 
effect on motor coordination when combined with EtOH at doses of 0.5, 1 and 2 g/kg orally, 
but may have antagonistic effects in a mouse accelerating rotarod performance test 
(Study 8062-PH-9038).  γ-hydroxybutyrate (GHB) at doses of 0.1, 0.2 and 0.4 g/kg orally 
had an additive effect with EtOH.  These results suggest that ASP8062 has no stronger 
additive interaction with EtOH compared to GHB (Study 8062-PH-9039).
The 4-week toxicity studies in rats and dogs and 13-week toxicity study in rats showed 
mainly monitorable, mild and reversible changes driven by exaggerated pharmacology.  
ASP8062 showed no effects on motor coordination using an accelerating rotarod test in rats 
at doses up to 30 mg/kg orally.  ASP8062 at doses of 10, 30 and 100 mg/kg orally had no 
synergistic effect on motor coordination when combined with EtOH at doses of 0.5, 1 and 
2 g/kg orally in a mouse accelerating rotarod performance test.  ASP8062 at 3 and 10 mg/kg 
did not potentiate respiratory suppression induced by morphine in cynomolgus monkeys.  


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Potential ASP8062-related toxicities, based on nonclinical studies, are described in 
[Section 2.3 Risk Benefit Assessment].
Six clinical studies (5 phase 1 studies and 1 phase 2a study) of ASP8062 have been 
completed prior to initiation of this study.  The phase 1 studies include the single ascending 
dose study (8062-CL-0001, including food effect), the multiple ascending dose study 
(8062-CL-0002, including cerebrospinal fluid distribution), the single dose polysomnography 
study (8062-CL-0003), the sequential single and multiple dose study in Japanese subjects 
(8062-CL-0004) and the single dose crossover study comparing ASP8062 new tablet 
(tablet B formulation) and reference tablet (tablet A formulation, which was used previously 
in 5 phase 1 studies and 1 phase 2a study) (8062-CL-0005, including food effect).  In 
addition, 20 healthy subjects were exposed to single oral doses of ASP8062 (60 mg) together 
with a single dose of alcohol (EtOH dose: 0.6 g/kg for females and 0.7 g/kg for males) in 
Study 8062-CL-2001 (report in progress).  All these studies were in healthy male and/or 
female subjects.  The phase 2a study includes an efficacy and safety study (8062-CL-0101).  
This study was in male and female fibromyalgia (FM) patients.  The reference tablet (used in 
phase 1 and phase 2a FM studies) is referred to as “tablet A formulation” and the new tablet 
(used in OUD/AUD studies) is referred to as “tablet B formulation”.  Clinical data has been 
summarized in [Section 2.1.3.1 Clinical Pharmacokinetics/Pharmacodynamics] and 
[Section 2.1.3.2 Clinical Safety].
Detailed information from nonclinical and clinical studies can be found in the [Investigator’s 
Brochure].
2.1.3.1 Clinical Pharmacokinetics/Pharmacodynamics
In general, pharmacokinetic properties of ASP8062 1 to 30 mg administered once daily for 
14 days were similar to ASP8062 0.3 to 70 mg administered as single doses.  Median tmax
values after multiple doses on day 14 (2 to 3 hours) were in the same range as single doses 
(1 to 4 hours).  Accumulation following multiple doses was predictable and was 
approximately 2 to 3-fold for AUC.  Steady-state conditions were observed for all dose levels 
by day 14.  There was no dose dependency, nor was there evidence for either auto-induction 
or auto-inhibition.  AUC for the tablet B formulation (tablets to be used in the current study)
was approximately 8% to 13% higher than the tablet A formulation and Cmax was 
approximately 60% higher.
Suboxone® sublingual film contains buprenorphine, a partial-opioid agonist, and naloxone, 
an opioid antagonist.  Buprenorphine is metabolized and eliminated in urine and feces.  
Norbuprenorphine is the major metabolite which has been found to bind opioid receptors in 
vitro.  Naloxone undergoes metabolism as well.  Naloxone has no clinically significant effect 
when administered by the sublingual route, although blood levels of drug were measurable.  
When Suboxone® sublingual film is administered sublingually or buccally, buprenorphine 
has a mean elimination half-life ranging from 24 to 42 hours and naloxone has a mean 
elimination half-life ranging from 2 to 12 hours [Suboxone Package Insert].


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There was a significant and likely dose-related increase in slow-wave sleep (SWS) over the 
whole night for single doses of 35 mg and 70 mg ASP8062 compared to placebo.  This 
increase in SWS was mainly observed during the first third of the night where SWS was most 
prevalent.  However, there was no consistent or dose-related effect of ASP8062 compared to 
placebo on rapid eye movement sleep.  With regards to pharmacodynamics, growth hormone 
release was generally greater in the ASP8062 treatment groups and appeared to be 
dose-related.
An in vitro cytochrome P450 (CYP) study suggested ASP8062 is mainly metabolized by 
CYP3A4.  Neither naloxone nor buprenorphine are listed as an inhibitor or inducer of 
CYP3A4 in the regulatory guidance.  Buprenorphine is metabolized by multiple CYPs 
(CYP3A4; major, CYP2C8 and 2C9; minor) and multiple UDP-glucuronosyltransferases 
(UGTs) [Rouguieg et al, 2010; Picard et al, 2005].  Naloxone is metabolized by multiple 
UGTs [Di Marco et al, 2005; Cheng et al, 1999].  An in vitro CYP study suggested ASP8062 
is mainly metabolized by CYP3A4 (IND 125639 study 8062-ME-9001).  The half-maximal 
inhibitory concentration values of ASP8062 were 9.25 μmol/L for CYP2C9 and > 10 μmol/L 
for all other CYP isoforms tested (IND 125639 study 8062-ME-0003).  In addition, ASP8062 
did not show more than dose proportional pharmacokinetics or time variant pharmacokinetics 
in humans.  These data suggest that there is no significant inhibitory effect of ASP8062 for
CYPs under the proposed clinical dose/exposure.  Assessments based on the relevant data of 
ASP8062, literature and regulatory guidance (the FDA’s 2020 Final Guidance for Industry on 
in vitro Cytochrome P450- and transporter- mediated drug-drug interaction (DDI) studies, the 
2018 MHLW Guideline on drug interactions for drug development and appropriate provision 
of information and the 2012 EMA Guideline on the investigation of drug interactions) 
indicate no remarkable concerns of a pharmacokinetic DDI between ASP8062 and opioids 
(e.g., morphine and buprenorphine) and naloxone.
2.1.3.2 Clinical Safety
A total of 117 healthy subjects were exposed to single oral doses of ASP8062 (fasted 0.3, 1, 
3, 10, 30, 35 or 70 mg, or fed 10 or 30 mg), including 26 subjects who also received multiple 
doses (3, 10 or 30 mg) over 14 days (Study 8062-CL-0004).  Thirty-six additional healthy 
subjects were exposed to multiple doses of ASP8062 (1, 3, 10 or 30 mg) over 14 days.  
Ninety-five FM patients were exposed to multiple doses of 30 mg ASP8062 over 8 weeks.  
Overall, ASP8062 was well tolerated in healthy subjects at single doses up to 70 mg and 
multiple doses (once daily) for 14 days up to 30 mg.  In addition, 20 healthy subjects were 
exposed to single oral doses of ASP8062 (60 mg) together with a single dose of alcohol 
(EtOH dose: 0.6 g/kg for females and 0.7 g/kg for males) in Study 8062-CL-2001 (report in 
progress).  There were no deaths or serious treatment-emergent adverse events (TEAEs) 
reported in any study.  All adverse events (AEs) were transient and mild or moderate in 
severity.  Dizziness and headache, within the SOC nervous system disorders, were the only 
TEAEs occurring in all 6 phase 1 studies (most of these events were considered by the 
investigator to be related to study drug).  Safety findings were generally similar for the 30 mg 
ASP8062 tablet A formulation and the 30 mg ASP8062 tablet B formulation.  In FM patients 
administered ASP8062 30 mg once daily for 8 weeks, dizziness was the most commonly 


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reported TEAE (28 [29.5%] patients), almost 13 times the incidence of patients administered 
placebo (2 [2.3%] patients).  Dizziness resulted in discontinuation of 8 (8.4%) FM patients 
treated with 30 mg ASP8062.  Potential ASP8062-related safety considerations, based on 
clinical studies, are described in [Section 2.3 Risk Benefit Assessment].
Detailed information from clinical studies can be found in the [Investigator’s Brochure].
Clinical safety information of buprenorphine/naloxone can be found in [Section 2.3 Risk 
Benefit Assessment].
2.1.4
Summary of Key Safety Information for Investigational Product(s)
Based on available safety information with ASP8062, there are currently no expected serious 
adverse reactions for ASP8062.
Detailed reference safety information (RSI) for ASP8062 can be found in the [Investigator’s 
Brochure].
Detailed safety information of buprenorphine/naloxone can be found in the [Suboxone 
Package Insert].
2.2
Study Rationale
While the pharmacokinetic DDI potential of ASP8062 with opioids is considered to be low 
[Section 2.1.3.1 Clinical Pharmacokinetics/Pharmacodynamics], potential interaction such as 
opioid effects on respiratory depression is theoretically possible because both ASP8062 and 
opioids are centrally active [Pattinson, 2008].  In addition, for future studies in OUD patients, 
ASP8062 will be co-administered with opioids, including standard medication-assisted 
treatments such as buprenorphine/naloxone.  This DDI/safety study will provide relevant 
safety, tolerability and pharmacokinetic data in order to assess potential risk of ASP8062 
co-administered with buprenorphine/naloxone for future studies in this patient population.
2.3
Risk Benefit 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 60 mg oral dose of 
ASP8062 will be administered, there is no likelihood of a therapeutic effect.  Given the safety 
profile of ASP8062 when administered to healthy subjects there appears to be relatively 
minimal risk to subjects taking a single 60 mg oral dose.
The risks of buprenorphine-naloxone from a number of formulations are well known and 
comfortably administered on an outpatient basis.  Once subjects show minimal withdrawal 
symptoms they will be started on an upward titration of buprenorphine/naloxone sublingual 
film from an initial dose of 4 mg/1 mg (buprenorphine-naloxone) to a daily dose of 
16 mg/4 mg by at least day 5.  Risks of buprenorphine-induced TEAEs are minimized by 
virtue of the fact the final daily dose that subjects are stabilized on is below the maximal dose 
of 24 mg/6 mg described in [Suboxone Package Insert].  Risks are also minimized because 
the subjects are confined at a research unit that has given a range of opioids, including 
buprenorphine/naloxone.  Side effects of opioids in general include respiratory depression, 


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CNS depression, dependence, hepatitis with or without jaundice, allergic reactions, 
impairment in the ability to drive, orthostatic hypotension, elevation of cerebrospinal fluid 
pressure and intracholendochal pressure.  These AEs are minimized due to the relatively 
weak partial agonist effects of buprenorphine at μ-opioid receptors and the combination with 
the non-selective opioid antagonist naloxone (which especially reduces the likelihood of 
respiratory depression based on the naloxone terminal half-life.  The most common AE 
(> 1%) associated with sublingual administration of buprenorphine-naloxone film was oral 
hypoesthesia.  Other AEs included constipation, glossodynia, oral mucosal erythema, nausea, 
vomiting, palpitations, hyperhidrosis and blurred vision.  Buprenorphine/naloxone will be 
down-titrated from days 19 through 26 in a manner known to be safe and well-tolerated.  The 
site has appropriately trained staff and required equipment available to treat subjects 
presenting with both opioid withdrawal and buprenorphine/naloxone associated AEs.
There is no expected benefit to the subjects from the administration of buprenorphine/naloxone 
other than the potential that subjects may gain insight that this may be a useful treatment for 
them.  All subjects will be provided with referrals for treatment of OUD before planned 
discharge.
This will be the first study where a single oral dose of ASP8062 is administered in subjects 
stabilized on a buprenorphine/naloxone sublingual film.  Risks are minimized by confining 
subjects in an experienced research unit testing the effects of approved medications or new 
chemical entities when combined with buprenorphine formulations or other opioids.  
Continuous pulse oximetry for at least 8 hours will be employed on day 12 when ASP8062 is 
given with buprenorphine/naloxone so that the low potential for respiratory depression will 
be noted immediately, and appropriate medical treatment may be given.  Patients will also be 
monitored by experienced staff for signs of opioid withdrawal.  Vital signs will be monitored 
on a daily basis and electrocardiograms (ECGs) will be monitored on day 12 to detect 
potential cardiovascular symptoms.  AEs will be assessed on a daily basis for early detection 
of untoward effects with the combination of treatments administered on day 12.  Potential 
hepatic toxicity will be monitored with clinical laboratory testing on a daily basis through 
day 14 to 17 of the investigational period.  Prior to discharge, subjects will be provided with 
local buprenorphine and methadone providers for their reference.
There is not expected to be a benefit from a single oral dose of ASP8062 provided on top of 
stabilized treatment with buprenorphine-naloxone.




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begin once a clinical opiate withdrawal scale (COWS) ≥5 is achieved.  Titration may be 
extended based on subject tolerability; however, subjects must be on a stable dose of 
16/4 mg buprenorphine/naloxone by day 5.  Subjects will be on a stable, total daily dose of 
16/4 mg buprenorphine/naloxone on days 5 through 18.  After randomization on day 12, 
subjects will receive a single oral dose of 60 mg ASP8062 or placebo ASP8062 (2:1 ratio) 
concomitantly with buprenorphine/naloxone and undergo repeat intensive safety assessment 
on day 12 with continued safety and pharmacokinetic assessments up to day 23 (264 hours 
postdose of ASP8062 or placebo ASP8062).  The stable dose of buprenorphine/naloxone 
(16/4 mg) will be down-titrated from days 19 through 26.  Subjects 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 11 and 12.
Subjects will be discharged from the clinical unit after completion of down-titration 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; which is the end-of-study visit (ESV).  Prior to 
discharge, subjects will be provided with local buprenorphine and methadone providers for 
their reference.
4.2
Dose Rationale
The primary objective of this study is to assess the safety and tolerability of multiple doses of 
buprenorphine/naloxone alone and buprenorphine/naloxone in combination with a single 
dose of ASP8062.  ASP8062 is primarily metabolized by CYP3A4.  Buprenorphine and 
naloxone are not CYP3A4 inhibitors or inducers at clinically relevant dose/exposure and 
therefore, not expected to affect ASP8062 pharmacokinetic profiles.  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 the 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 trials for OUD.  For this study, a single dose of 60 mg ASP8062 with tablet B 
formulation is expected to achieve comparable exposures after multiple doses of 25 mg 
ASP8062 and exposures in the previous clinical studies.  Based on the preliminary 
pharmacokinetic data in the 8062-CL-2001 study, Cmax and AUC24 after single dose of 60 mg 
were 218 ng/mL and 1820 ng•hr/mL, which did not exceed mean exposure limit set in 
previous phase 1 studies (247 ng/mL for Cmax and 2339 ng•hr.mL for AUC24).  The 
exposures achieved in this study is also expected to be pharmacologically active (as seen in 
study 8062-CL-0003) and safe and tolerated based on data from previous clinical studies in 
total of 137 healthy subjects and 95 fibromyalgia patients as reviewed in [Section 2.1.3.1
Clinical Pharmacokinetics/Pharmacodynamics and Section 2.1.3.2 Clinical Safety].
The buprenorphine/naloxone dosage and administration is per the Suboxone® label 
[Suboxone Package Insert].  For down-titration of buprenorphine/naloxone, [Ling et al, 2009] 
has reported no difference between 7-day and 28-day taper group in terms of providing urine 


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samples free of illicit opioids.  In the light of safety, 9-day down-titration was selected for 
this study.
4.3
End of Study Definition
The study start is defined as the date the first subject signs informed consent.  End of the 
study is defined as the last visit or scheduled procedure shown in Schedule of Assessments 
[Table 1] for the last subject in the study.
5
STUDY POPULATION
The study population will consist of male and female subjects (18 to 60 years of age, 
inclusive) with moderate or severe OUD according to the DSM-5, who are willing to take 
buprenorphine/naloxone.
All screening assessments must be completed and reviewed to confirm the potential subject 
meets all eligibility criteria.  Prospective approval of protocol deviations to eligibility criteria 
(also known as protocol waivers or exemptions) is not permitted.
5.1
Inclusion Criteria
Subject 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 study sites) must be 
obtained from the subject prior to any study-related procedures (including withdrawal of 
prohibited medication, if applicable).
2.
Subject is a male or female subject between 18 to 60 years of age, inclusive at screening.
3.
Subject has a body mass index (BMI) range of 18 to 36 kg/m2, inclusive and weighs at 
least 50 kg at screening.
4.
Subject has a diagnosis of moderate or severe OUD according to the DSM-5 at 
screening.
5.
Subject tests positive for opioids at screening and/or on day -1 or subject shows signs of 
opioid withdrawal on day -1.
6.
Subject is willing to take buprenorphine/naloxone and is not taking buprenorphine or 
buprenorphine/naloxone at screening.
7.
Female subject is not pregnant (see [Appendix 12.3 Contraception Requirements]) and at 
least 1 of the following conditions apply:
a. Not a woman of childbearing potential (WOCBP) (see [Appendix 12.3
Contraception Requirements])
b. WOCBP who agrees to follow the contraceptive guidance (see [Appendix 12.3
Contraception Requirements]) from the time of informed consent through at least 
30 days after final IP administration.
8.
Female subject must agree not to breastfeed starting at screening and throughout the 
study period and for 30 days after final IP administration.


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9.
Female subject must not donate ova starting at first dose of IP and throughout the study 
period and for 30 days after final IP administration.
10. Male subject with female partner(s) of childbearing potential (including breastfeeding 
partner) must agree to use contraception (see [Appendix 12.3 Contraception 
Requirements]) throughout the study period and for 90 days after final IP administration.
11. Male subject must not donate sperm during the treatment period and for 90 days after 
final IP administration.
12. Male subject with pregnant partner(s) must agree to remain abstinent or use a condom 
and spermicide for the duration of the pregnancy throughout the study period and for 
90 days after final IP administration.
13. Subject agrees not to participate in another interventional study while participating in the 
present study.
14. 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 11 and 12.
5.2
Exclusion Criteria
Subject will be excluded from participation in the study if any of the following apply:
1.
Subject has received any investigational therapy within 28 days or 5 half-lives, 
whichever is longer, prior to screening.
2.
Subject has any condition which, in an investigator’s opinion, makes the subject 
unsuitable for study participation.
3.
Female subject who has been pregnant within 6 months prior to screening or 
breastfeeding within 3 months prior to screening.
4.
Subject has a known or suspected hypersensitivity to ASP8062, buprenorphine, naloxone 
or any components of the formulations used.
5.
Subject has had previous exposure with ASP8062.
6.
Subject has any of the liver function tests (alkaline phosphatase [ALP], alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyl transferase 
and total bilirubin [TBL]) > 2 × upper limit of normal (ULN) on day -1.  In such a case, 
the assessment may be repeated once.
7.
Subject 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.
Subject 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 the investigator, with exception of history of cholecystectomy.
9.
Subject has current or recent diagnosis (within the last 12 months) of moderate or severe 
alcohol, sedative, hypnotic, anxiolytic, cocaine or any other substance use disorder
(except for opioids, caffeine, tobacco or nicotine) according to the DSM-5 at screening.


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10. Subject 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. Subject tests positive for alcohol, benzodiazepine or methadone on day -1.  Subject tests 
positive for buprenorphine on day -1.
12. Subject has had recent suicidal ideation within the last 12 months or subject who is at 
significant risk to commit suicide, as judged by the investigator, using the Columbia-Suicide 
Severity Rating Scale (C-SSRS) at screening or since the last visit on day -1.
13. Subject has/had febrile illness or symptomatic, viral, bacterial (including upper 
respiratory infection) or fungal (noncutaneous) infection within 1 week prior to day -1.
14. Subject has any clinically significant abnormality following the investigator’s review of 
the physical examination, ECG and protocol-defined clinical laboratory tests at screening 
or on day -1.
15. Subject has a mean pulse < 45 or > 110 beats per minute (unless out of range 
[> 110 beats per minute] pulse is deemed to be secondary to opioid withdrawal, as 
judged by the investigator); mean systolic blood pressure (SBP) > 150 mmHg; mean 
diastolic blood pressure (DBP) > 95 mmHg (unless out of range blood pressure is 
deemed to be secondary to opioid withdrawal, as judged by the investigator) 
(measurements taken in duplicate after subject has been resting in the supine position for 
at least 5 minutes; pulse will be measured automatically) on day -1.  If the mean blood 
pressure exceeds the limits above, 1 additional duplicate may be taken.
16. Subject has a mean corrected QT interval using Fridericia’s formula (QTcF) of 
> 450 msec (for male subjects) and > 470 msec (for female subjects) on day -1.  If the 
mean QTcF exceeds the limits above, 1 additional duplicate ECG may be taken.
17. Subject has used any prescribed drugs, vitamins and natural or herbal remedies 
(including, St. John’s Wort) in the 2 weeks prior to first IP administration, except for 
rescue medications, milk of magnesia, acetaminophen, topical dermatological products, 
including corticosteroid products, hormonal contraceptives and hormone replacement 
therapy (HRT).
18. Subject has used any inducer of CYP2C8, 2C9 or 3A4-related metabolism (e.g., 
barbiturates, rifampin, aprepitant, ritonavir, apalutamide, carbamazepine, enzalutamide, 
mitotane, phenytoin, rifampin, St. John’s wort, bosentan, efavirenz, etravirine, 
phenobarbital, primidone, armodafinil, modafinil, and rufinamide) in the 3 months prior 
to day -1.
19. Subject has had significant blood loss or 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.
20. Subject has a positive serology test for antibodies to HIV type 1 and/or type 2, acute 
hepatitis B virus infection or acute hepatitis C virus infection, excluding asymptomatic 
hepatitis C virus infection at screening.
21. Subject 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.


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22. Criterion removed.
23. Subject is an employee of Astellas, the study-related contract research organizations 
(CROs) or the clinical unit.
5.3
Restrictions During the Study
5.3.1
Exercise
Subjects will refrain from strenuous exercise from 48 hours prior to admission to the clinical 
unit up to and including the ESV.
Subjects are encouraged to walk and stretch while in the clinical unit 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.
Subjects 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 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.
Subjects 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 subjects).  Dietary and fluid 
restrictions apply to administration 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 subjects will receive standard meals.
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 1hour predose 
through at least 8 hours postdose on days 11 and 12 during measurements for continuous 
pulse oximetry and end tidal CO2.
5.4
Screen Failures
A screen failure is defined as a potential subject who signed the informed consent form 
(ICF), but did not meet 1 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 case report form (eCRF).


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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 
participant.
6
INVESTIGATIONAL PRODUCT(S)
6.1
Investigational Product(s) Administered
Table 4
Investigational Product(s)
Name
ASP8062
Placebo ASP8062
Suboxone® (buprenorphine 
hydrochloride/naloxone 
hydrochloride)
Use
Test Product
Placebo
Test Product
Dosage 
Formulation
Tablet
Tablet
Film
Physical 
Description
Round, reddish-yellow 
film-coated tablet
Round, reddish-yellow 
film-coated tablet
Orange rectangular sublingual 
film
Dose Strength
Single dose of 60 mg 
ASP8062 (2 × 30 mg 
tablets)
Single dose of placebo 
ASP8062 (2 × tablets)
See [Section 6.6 Dose 
Modification]
Packaging and 
Labeling
1 × aluminum/aluminum 
blister strips (2 × 7 
configuration per strip in 
carton
1 × aluminum/aluminum 
blister strips (2 × 7 
configuration per strip in 
carton
2 mg/0.5 mg sublingual film
(30 films per box)
8 mg/2 mg sublingual film 
(30 films per box)
4 mg/1 mg sublingual film in foil 
pouch (30 films per box)
12 mg/3 mg sublingual film in 
foil pouch (30 films per box)
Route of 
Administration
Oral
Oral
Sublingual
Table continued on next page


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Name
ASP8062
Placebo ASP8062
Suboxone® (buprenorphine 
hydrochloride/naloxone 
hydrochloride)
Administration 
Instruction
On day 12, ASP8062 
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 2 hours 
postdose except for the
approximately 240 mL 
water to swallow the 
investigational product.
On day 12, placebo 
ASP8062 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 2 hours 
postdose except for the 
approximately 240 mL 
water to swallow the 
investigational product.
On all dosing days (excluding 
days 11 and 12), 
buprenorphine/naloxone will be 
administered sublingually under 
standardized fed conditions (i.e., 
meals will be served up to 1 hour 
predose or at least 2 hours 
postdose).  Water will be 
allowed ad libitum.  On days 11 
and 12, buprenorphine/naloxone 
will be administered sublingually 
under fasting conditions (i.e., no 
food or beverage will be allowed 
from at least 10 hours predose 
through at least 4 hours 
postdose).  On day 11, the 
subject will consume 
approximately 240 mL of water 
and then place the 
buprenorphine/naloxone 
sublingually to match the dosing 
conditions on day 12.
IMP or 
Non-IMP
IMP
IMP
Non-IMP
Sourcing
Provided centrally by 
sponsor
Provided centrally by 
sponsor
Provided locally by investigator 
site
IMP: Investigational medicinal product
Refer to the pharmacy manual for detailed information regarding preparation, handling and 
storage of the IP.
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), Good Manufacturing Practice (GMP) guidelines, International Council for 
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.
Refer to the pharmacy manual for detailed information regarding packaging and labeling of
the IP.


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6.2.2
Handling, Storage and Accountability
1.
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.
2.
Only subjects 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.
3.
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.
4.
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).
5.
Further guidance and instruction on final disposition of used and unused IP is provided 
in the pharmacy manual.
Refer to the pharmacy manual for detailed information regarding handling, storage and 
accountability of the IP.
6.3
Randomization and Blinding
6.3.1
Blinding Method
The study will be conducted as subject- and investigator-blinded.
In order to maintain the blind, the subjects will receive the same number of tablets.  The 
pharmacist will provide the investigator or designee with blinded IP to subjects.
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 subject, 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 subject.  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 has the sole responsibility for determining if unblinding of the 
subject’s treatment assignment is warranted.  Subject safety must always be the first 
consideration in making such determination.  If the investigator decides that unblinding is 


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warranted, the investigator should make every effort to contact the sponsor prior to 
unblinding a subject’s treatment assignment unless this could delay emergency treatment for 
the subject.
The investigator must have a designated backup to support emergency unblinding 
requirements.
Prior to randomization, subjects 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 
[Appendix 12.4.5 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 subject’s study records.
6.3.5
Breaking the Treatment Code by the Sponsor
The sponsor may break the treatment code for subjects who experience a suspected 
unexpected serious adverse reaction (SUSAR), in order to determine if the individual case or 
a group of cases requires expedited regulatory reporting.  Individual emergency codes will be 
provided to the limited 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 Subject Number
Subjects will be assigned a subject number at study entry (i.e., signing of informed consent).  
The subject numbers will be sequential and rising.
The subject number will comprise of a 5-digit clinical unit number and 5-digit screening 
number.
6.3.6.2 Randomization
Prior to dosing on day 12, subjects will be assigned a randomization number in accordance 
with the randomization code generated by the sponsor’s Data Science department or 
designee.  Subjects will be randomized in a 2:1 ratio to ASP8062 or matching placebo.
Once a randomization number has been allocated to a subject, it will not be assigned to 
another subject.  If a subject withdraws prematurely from the study and is replaced under the 
direction of the sponsor, then a replacement randomization number will be assigned.  A 
replacement randomization code will be generated such that replacement subjects are 
assigned to the same cohort and treatment as the discontinued subject.


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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 subject’s mouth and 
hands will be performed. The exact day and time of IP administration will be documented.
6.5
Previous and Concomitant Treatment (Medication and 
Nonmedication Therapy)
6.5.1
Previous Treatment (Medication and Nonmedication Therapy)
All medicinal products, including prescribed or nonprescribed drugs, used prior to first IP 
administration will be considered previous medication.
The subjects must abstain from use of any prescribed drugs, vitamins and natural or herbal 
remedies (including St. John’s Wort) in the 2 weeks prior to first IP administration, except for:
●
Rescue medications [Section 6.5.3 Rescue Drugs]
●
Milk of magnesia
●
Acetaminophen
●
Topical dermatological products, including corticosteroid products
●
Hormonal contraceptives
●
HRT
At screening, subjects will be questioned regarding the medicinal products that they have 
been using over the past 3 months.  All medication used within 4 weeks prior to admission to 
the clinical unit will be documented.
6.5.2
Concomitant Treatment (Medication and Nonmedication Therapy)
All medicinal products other than the IPs, 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.
Subjects will only be allowed to use the following concomitant medication(s), if needed, 
from first IP administration until the ESV:
●
Rescue medications [Section 6.5.3 Rescue Drugs]
●
Milk of magnesia (except for days 11 and 12)
●
Acetaminophen (up to 2 g/day)
●
Topical dermatological products, including corticosteroid products
●
Hormonal contraceptives
●
HRT
If a subject’s health condition necessitates the use of any medication other than the permitted 
medications during the study, the investigator and medical monitor, or designee(s), will 
discuss the case and determine if the subject 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 (see [Section 10.3 Major Protocol Deviations], protocol deviation 4).


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All concomitant treatments (medication and nonmedication therapy) will be documented.
6.5.3
Rescue Medications
Buprenorphine/Naloxone
●
Hydroxyzine pamoate: 50 mg (1 or 2 × tablets) every 6 hours, as needed
●
Mylanta/Maalox: 10 to 20 mL, per product instruction, as needed
●
Loperamide: 2 mg, per product instruction, as needed
●
Methocarbamol: 750 mg (1 or 2 × tablets) every 6 hours, as needed
●
Ibuprofen: 200 mg (2 × tablets) every 6 hours, as needed
●
Promethazine: 25 mg oral or intramuscular, every 6 hours, as needed
●
Clonidine: 0.1 mg, every 12 hours, as needed
6.6
Dose Modification
There will be no modification for the single planned ASP8062 dose of 60 mg.
On day 1, subjects will receive a 4/1 mg buprenorphine/naloxone dose in the morning and a 
4/1 mg buprenorphine/naloxone dose in the afternoon.  On day 2, subjects will receive an 
8/2 mg buprenorphine/naloxone dose in the morning and a 4/1 mg buprenorphine/naloxone 
dose in the afternoon.  On day 3, subjects will receive a 12/3 mg buprenorphine/naloxone 
dose in the morning.  On day 4, subjects will receive a 16/4 mg buprenorphine/naloxone dose 
in the morning.  Titration may be extended based on subject tolerability; however, subjects 
must be on a stable dose of 16/4 mg buprenorphine/naloxone by day 5.  Subjects not on a 
stable dose of 16/4 mg buprenorphine/naloxone by day 5 will be discontinued from the study.  
Subjects will be on a stable, total daily dose of 16/4 mg buprenorphine/naloxone on days 5
through 18.  The stable dose of buprenorphine/naloxone (16/4 mg) will be down-titrated from 
days 19 through 26, according to [Table 5].
Table 5
Schedule of Down-titration of Buprenorphine/Naloxone Dose
Day(s)
Subjects with Stabilized Buprenorphine/Naloxone Dose of 16/4 mg
18
16/4 mg
19
8/2 mg
20
8/2 mg
21
8/2 mg
22
4/1 mg
23
4/1 mg
24
4/1 mg
25
2/0.5 mg
26
2/0.5 mg
27
(Discharge/ESV)
ESV: end-of-study visit
6.7
Criteria for Continuation of Treatment
Not applicable.


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7
STUDY PROCEDURES AND ASSESSMENTS
7.1
Efficacy Assessments
7.1.1
Opioid Craving Visual Analogue Scale
The opioid craving visual analogue scale (VAS) will be used to measure subjects’ opioid 
craving.  Ratings will be performed as indicated in the Schedule of Assessments [Table 1] 
using the opioid craving VAS [Appendix 12.9 Opioid Craving Visual Analogue Scale].
All subjects will undergo a scripted training and practice regimen.  Additional training 
sessions will be done as needed and will be documented in source document.
7.2
Safety Assessments
7.2.1
Adverse Events
See [Section 7.3 Adverse Events and Other Safety Aspects] for information regarding AE 
collection and data handling.
7.2.2
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.
Blood samples for serology, hematology and biochemistry and urine samples for urinalysis 
will be collected as indicated in the Schedule of Assessments [Table 1].  The clinical 
laboratory tests to be performed in the study are listed in [Appendix 12.7 Laboratory 
Assessments].
Drugs of abuse and alcohol tests will be performed according to the clinical site’s preferred 
method.  Drugs of abuse and alcohol tests will be performed as indicated in the Schedule of 
Assessments [Table 1].
Pregnancy tests (female subjects only) will be performed according to the clinical site’s 
preferred method.  Pregnancy tests will be performed as indicated in the Schedule of 
Assessments [Table 1].
A blood sample will be collected for follicle-stimulating hormone (FSH) tests 
(postmenopausal female subjects 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, the 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]).


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7.2.3
Vital Signs
Blood pressure (SBP and DBP), pulse, respiratory rate and oral temperature measurements 
will be taken as indicated in the Schedule of Assessments [Table 1].  Measurements will be 
taken after the subject 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.  At all other time points, single measurements will be taken.  Oral temperature 
will be taken as a single measurement at all time points.
7.2.4
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].
7.2.5
Electrocardiogram
7.2.5.1 12-lead Electrocardiogram
12-lead ECGs will be taken as indicated in the Schedule of Assessments [Table 1].  12-lead 
ECGs will be taken after the subject has been resting in the supine position for at least 
5 minutes.  12-lead ECGs will be taken in duplicate with approximately 1-minute intervals 
and both ECGs will be completed within 5 minutes.
The investigator will use the system at the phase 1 unit to review, sign and date the ECG after 
recording to ensure subject 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 subjects, an ECG judged as 
abnormal clinically significant by a local physician for phase 1 studies must be further 
evaluated by another physician, and if confirmed will be recorded as an AE.
Per time point, the ECGs printouts will be reviewed in a timely manner by the investigator.  
Paper ECGs will be stored with the subject source.  The time of the ECG, the interval 
measurements and the overall conclusion will be transcribed into the eCRF.
7.2.6
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 
subject’s fingertip.
Blood oxygen saturation (SpO2) levels will be measured as indicated in the Schedule of 
Assessments [Table 1]. SpO2 will be measured using a pulse oximeter placed on the 
subject’s fingertip.


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7.2.7
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 [Appendix 12.10 Columbia-Suicide Severity Rating Scale].
7.2.8
Continuous End Tidal Carbon Dioxide and Spot End Tidal Carbon Dioxide
Continuous monitoring of end tidal carbon dioxide (CO2) will be taken as indicated in the 
Schedule of Assessments [Table 1].  End tidal CO2 measurements will be obtained per 
subject utilizing a portable bedside capnography device.  Timepoints for recorded 
measurements will be performed as indicated in the Schedule of Assessments [Table 1].
7.2.9
Clinical Opiate Withdrawal Scale
The COWS [Wessen & Ling, 2003] will be used to assess subjects’ symptoms for opiate 
withdrawal over a period of time.  Ratings will be performed as indicated in the Schedule of 
Assessments [Table 1] using the COWS [Appendix 12.11 Clinical Opiate Withdrawal Scale].
7.2.10
Order of Assessments
All predose procedures, e.g., 12-lead ECG, vital signs, opioid craving VAS, spot pulse 
oximetry, spot end tidal CO2, 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.  Opioid craving 
VAS will be performed within 10 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, they should be performed in the following order: 12-lead ECG, vital 
signs (including SpO2, if applicable), blood sampling for pharmacokinetics collected
(including blood for clinical laboratory tests, if applicable) at the nominal time point and
opioid craving VAS.
7.3
Adverse Events and Other Safety Aspects
The definitions of an AE or SAE can be found in [Appendix 12.4 Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-up and Reporting].
The investigator and medically qualified designee(s) are responsible for detecting, 
documenting and recording events that met the definition of an AE or SAE.
7.3.1
Time Period for Collecting Adverse Event and Serious Adverse Event 
Information
In order to identify any events that may be associated with study procedures and could lead to 
a change in the conduct of the study, Astellas collects AEs even if the subject has not 
received IP.  AE collection begins after the signing of the ICF and will be collected until 
12 days for ASP8062 and 1 day for Suboxone® after the final IP administration or when the 
subject is determined to be a screen failure.


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7.3.2
Method of Detecting Adverse Events and Serious Adverse Events
The methods of recording, evaluating and assessing seriousness, causality and severity of 
AEs and SAEs are described in [Appendix 12.4 Adverse Events: Definitions and Procedures 
for Recording, Evaluating, Follow-up and Reporting].  Care will be taken not to introduce 
bias when detecting AEs and/or SAEs.  Open-ended and nonleading verbal questioning of the 
subject is the preferred method to inquire about AE occurrences.
An AE with a change in severity is recorded as a new AE.
7.3.3
Follow-up of Adverse Events
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized by the investigator.
If after the protocol-defined AE collection period (see [Section 7.3.1 Time Period for 
Collecting Adverse Event and Serious Adverse Event Information]), an AE progresses to an
SAE, or the investigator learns of any serious adverse event or adverse event ([S]AE) 
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
Reporting of 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 subjects and the safety of a study 
intervention under clinical investigation are met.
In the case of an SAE, the investigator must contact the sponsor by fax or email immediately 
(within 24 hours of awareness).
Procedures for reporting SAEs to the sponsor are described in [Appendix 12.4.5 Reporting 
Procedures for Serious Adverse Events].
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 related to potential substance abuse and suicide (serious or nonserious) are considered to 
be of scientific and medical concern specific to ASP8062 and Suboxone®, for which ongoing 
monitoring and reporting is required.
Additional information around AEs of special interest will be collected to complete subject 
narratives.  AEs of special interest related to potential substance abuse are listed in 
[Appendix 12.12 Adverse Events of Interest Related to Potential Substance Abuse].
One of the most clinically salient AEs of special interest for Suboxone® is respiratory 
depression.  Respiratory depression following administration of only Suboxone® is very rare 
but is more common when administered with known CNS depressants such as 


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benzodiazepines.  For this reason, continuous monitoring of blood oxygen saturation will be 
performed on day 12 when ASP8062 is administered with Suboxone®.  In addition to this 
monitoring, clinically significant decreases in blood oxygen saturation requiring medical 
information will lead to stopping the study [Section 8.4 Discontinuation of the Study].
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 collected in the eCRF, as protocol 
deviation per [Section 10.3 Major Protocol Deviations] or 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 eCRF.  If the AE meets the 
definition of an SAE, the SAE is to be reported as described in [Appendix 12.4.5 Reporting 
Procedures for Serious Adverse Events] and the details of the associated special situation are 
to be included in the clinical description on the SAE worksheet.
The special situations are:
●
Pregnancy
●
Medication error, overdose and “off-label use”
●
Misuse/abuse
●
Occupational exposure
Instructions and procedures for reporting special situations are provided in [Appendix 12.4.6
Reporting Procedures for Special Situations].
7.3.8
Supply of New Information Affecting the Conduct of the Study
When new information becomes available that is necessary for conducting the study properly, 
the sponsor will inform all investigators involved in the study as well as the appropriate 
regulatory authorities.  Investigators should inform the IRB/IEC of such information when 
needed.
The investigator will also inform the subjects, who will be required to sign an updated ICF in 
order to continue participation in the study.
7.3.9
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 and IRB/IEC, where applicable, in order to protect 
subjects 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.


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7.3.10
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 subject’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 subjects.  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.
7.4
Pharmacokinetics
7.4.1
Analysis of ASP8062, Buprenorphine/Naloxone and Metabolite 
(Norbuprenorphine) in Plasma
Blood samples for the analysis of ASP8062 and buprenorphine/naloxone in plasma will be 
collected as indicated in the Schedule of Assessments [Table 1] for the evaluation of 
pharmacokinetics.
The actual date and time of each blood sample collection will be documented.  Blood sample 
collection, handling and storage will be described in the laboratory manual.  Analysis will be
performed using a validated assay method at a bioanalytical laboratory specified by the 
sponsor.
When deemed appropriate, plasma samples remaining after the pharmacokinetic analysis may 
be used for exploratory metabolic 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).
7.5
Pharmacodynamics
Not applicable.
7.6
Electronic Clinical Outcome Assessment
Not applicable.
7.7
Other Assessments
7.7.1
Sample for the Analysis of Genes Related to Efficacy/Safety
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].


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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.
7.7.2
Sample for Banked Pharmacogenomic Sample Analysis
Pharmacogenomic (PGx) research may be conducted in the future to analyze or determine 
genes of relevance to clinical response, pharmacokinetics and 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 
banking CRO.
Details on sample collection, labeling, storage and shipment procedures will be provided in a 
separate laboratory manual.
See [Appendix 12.8 Pharmacogenomic Analysis with Banked Sample] for further details on 
the banking procedures.
7.8
Total Amount of Blood
The approximate total blood volume taken per subject will be as follows:
Table 6
Blood Volume
Sample Type
Number of Samples
Sample Volume (mL)
Total Volume (mL)
Clinical Laboratory Tests
14
9.0
(+ 8.5)†
134.5
ASP8062 Pharmacokinetics
24
1.0
24.0
Buprenorphine/Naloxone 
Pharmacokinetics
26
3.0
78.0
Biomarker
1
2.0
2.0
Pharmacogenomics
1
4.0
4.0
Total
242.5
†
Additional blood collection for screening.
Additional blood may be drawn for safety reasons.  The maximum amount of blood drawn 
during the study will not exceed 500 mL.
8
DISCONTINUATION
8.1
Discontinuation of Individual Subject(s) From Study Treatment
A discontinuation from treatment is defined as a subject who enrolled in the study and for 
whom study treatment is permanently discontinued for any reason.
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice.  The 
investigator is also free to discontinue the subject from study treatment or to terminate a 
subject’s involvement in the study at any time if the subject’s clinical condition warrants it.
The reason for discontinuation from study treatment must be documented in the subject’s 
medical records.


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A subject must discontinue study treatment for any of the following reasons:
●
Subject requests to stop treatment
●
Any clinical AEs, laboratory abnormality or intercurrent illness, in the opinion of the 
investigator, indicates continued treatment is not in the best interest of the subject
●
Participation in another interventional study while participating in the present study
●
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
●
Female subject becomes pregnant
8.2
Discontinuation of Individual Subject(s) From Study
All subjects who discontinue study treatment will remain in the study and must continue to 
be followed for protocol-specific follow-up procedures as outlined in Schedule of 
Assessments [Table 1].  The only exception to this is when the subject specifically withdraws 
consent for any further contact with him/her or persons previously authorized by the subject 
to provide this information.  Subjects not on a stable dose of 16/4 mg 
buprenorphine/naloxone by day 5 will be discontinued from the study.
8.2.1
Lost to Follow-up
Every reasonable effort is to be made to contact any subject lost to follow-up during the 
course of the study to complete study-related assessments and record outstanding data.
8.3
Discontinuation of the Study Site
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the sponsor.
8.4
Discontinuation of the Study
The sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination.  Advance notice is not required if the study is stopped due to safety concerns. If 
the sponsor terminates the study for safety reasons, the sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination.
The sponsor will terminate this study if 1 of the following criteria are met.  The sponsor will 
unblind the affected subject(s) to an investigator/delegate, before a final decision is made.
1.
If after concomitant administration of buprenorphine/naloxone and ASP8062 or placebo 
ASP8062 on day 12, ≥5 ASP8062-treated subjects experience ASP8062-related AEs of 
severe intensity that are considered by an investigator to be of clinical concern
2.
If after concomitant administration of buprenorphine/naloxone and ASP8062 or placebo 
ASP8062 on day 12, ≥3 ASP8062-treated subjects experience an ASP8062-related SAE 
and there is no plausible alternate explanation for these events


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3.
If after concomitant administration of buprenorphine/naloxone and ASP8062 or placebo 
ASP8062 on day 12, ≥5 ASP8062-treated subjects 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 11 (day prior to concomitant 
administration of buprenorphine/naloxone and ASP8062 or placebo ASP8062) 
values
●
ALT or AST ≥2 × ULN and ALT or AST ≥5 × day 11 (day prior to concomitant 
administration of buprenorphine/naloxone and ASP8062 or placebo ASP8062) 
values
●
TBL ≥2 × ULN and subject does not have Gilbert Syndrome
4.
If after concomitant administration of buprenorphine/naloxone and ASP8062 or placebo 
ASP8062 on day 12, ≥3 ASP8062-treated subjects have QTcF interval >500 msec in 
2 consecutive measurements within 24 hours postdose
5.
If after concomitant administration of buprenorphine/naloxone and ASP8062 or placebo 
ASP8062 on day 12:
●
≥4 ASP8062-treated subjects experience ASP8062-related symptomatic decrease in 
SpO2 requiring more than 2 liters of supplemental oxygen via nasal cannula or,
●
≥1 ASP8062-treated subjects experience ASP8062-related symptomatic decrease in 
SpO2 requiring intubation, for medically significant respiratory depression
9
STATISTICAL METHODOLOGY
In general, all 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 subjects with no missing data (i.e., 
will add up to 100%).
Baseline will be defined as the last nonmissing observation on or prior to first administration 
of IP, unless otherwise specified.
9.1
Sample Size
Approximately 30 subjects will be enrolled to complete at least 18 subjects (i.e., 12 subjects 
on ASP8062 and 6 subjects on placebo ASP8062). Approximagely 8 female subjects will be 
enrolled so that at least 25% of the enrolled subjects are female. Subjects 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 subjects 
is based on the precedent set by other studies in similar nature.  The number of subjects 
planned is considered sufficient to achieve the study objectives.
Based on the literature, the intrasubject coefficient of variation (CV) for pharmacokinetic 
parameters AUCinf and Cmax of buprenorphine and naloxone are estimated to be 26%.
Assuming the underlying variability is similar to 26% and the true underlying ratio is 100%, 
the 90% CI will lie within (77.0 129.0) with > 80% probability.


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9.2
Analysis Sets
For each treatment group, the number and percentage of subjects will be characterized for all 
randomized subjects and by each analysis set.
9.2.1
Full Analysis Set
The full analysis set (FAS) will consist of all subjects who are randomized, received at least 
1 dose of IP and all of the opioid craving VAS measurement.  The FAS will be used set for 
the efficacy analysis.
9.2.2
Safety Analysis Set
The safety analysis set (SAF) consists of all subjects who receive at least 1 dose of IP.
The SAF will be used for all summaries and analysis of the safety data.
9.2.3
Pharmacokinetic Analysis Set
The pharmacokinetic analysis set (PKAS) consists of all subjects 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 subjects 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.
9.3
Demographics and Baseline Characteristics
9.3.1
Demographics
Demographics and baseline characteristics (age, sex, race, ethnicity, body weight, height and 
BMI) will be provided separately for all subjects in the SAF and by treatment 
(buprenorphine/naloxone in combination with ASP8062 [B/N + ASP] and 
buprenorphine/naloxone in combination with placebo [B/N + Pbo]) for all randomized 
subjects.
9.3.2
Subject Disposition
The number and percentage of subjects with screening disposition and reasons for screening 
disposition will be presented for all subjects with informed consent.  Similar tables will be 
provided for subjects with run in disposition and reasons for run in disposition will be 
presented for all subjects in the SAF.  The number and percentage of subjects who completed 
and discontinued treatment and reasons for treatment discontinuation will be provided for all 
subjects in the SAF and by treatment (B/N + ASP and B/N + Pbo) for all randomized 
subjects.  Similar summaries will be created for investigational period and down-titration 
period disposition presented by treatment (B/N + ASP and B/N + Pbo) for all randomized 
subjects.  All disposition details and dates of first and last evaluations for each subject will be 
listed.


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9.3.3
Previous and Concomitant Treatment (Medication and Nonmedication 
Therapy)
All previous and concomitant treatment (medication and nonmedication therapy) will be 
listed.
9.3.4
Medical History
Medical history for each subject will be listed.
9.3.5
Investigational Product Exposure
The exposure tables will be presented for each IP (buprenorphine, naloxone and ASP8062).  
The number and percentage of subjects exposed to buprenorphine and naloxone, total daily 
dose will be summarized by treatment group (buprenorphine/naloxone alone [B/N alone], 
B/N + ASP and B/N + Pbo).  The buprenorphine/naloxone in combination with ASP8062 
(active and placebo) treatment groups will be summarized by period (Investigational period 
[day 12 to 18] and Down-titration period [day 19 to 26]).  The number and percentage of 
subjects exposed to ASP8062 will be summarized by treatment group (B/N + ASP and 
B/N + Pbo).
All IP exposure data will be listed.
9.4
Analysis of Efficacy
9.4.1
Opioid Craving Visual Analogue Scale
To characterize preliminary efficacy, descriptive statistics will be provided for the opioid 
craving VAS results and change from baseline by treatment group (B/N + ASP and 
B/N + Pbo) and time points.
Opioid craving VAS data will be displayed in listings.
9.5
Analysis of Safety
For analysis of safety, the treatment groups are B/N alone, B/N + ASP and B/N + Pbo.
9.5.1
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 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 subjects 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 subjects with serious TEAEs, 
IP-related serious TEAEs, TEAEs leading to death and IP-related TEAEs leading to death.


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The number and percentage of subjects who have a TEAE within the drug abuse dependence 
SMQ (MedDRA v23.0) as classified by SOC and preferred term will be summarized by 
treatment group.  In addition, the number and percent of subjects who have drug abuse 
related TEAEs as classified by preferred term and lowest level term will be summarized by 
treatment group.
The number and percent of subjects who have a TEAE with the drug withdrawal SMQ 
(MedDRA v23.0) as classified by SOC and preferred term will be summarized by treatment 
group.  In addition, the number and percentages of subjects who have withdrawal related 
TEAEs as classified by SOC and preferred term will be summarized by treatment group.
For all the mentioned above summaries, the buprenorphine/naloxone in combination with 
ASP8062 (active or placebo) treatment groups will be split into periods (Investigational 
period [day 12 to 18] and Down-titration period [day 19 to 26]).
AE data will be listed.
9.5.2
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 subjects with potentially clinically significant values in liver 
enzymes and TBL will be tabulated.
Laboratory data will be listed.
9.5.3
Vital Signs
Descriptive statistics will be used to summarize vital sign (blood pressure, pulse and 
respiratory rate) results and changes from baseline for subjects in the SAF by treatment group 
and time point.
Vital signs data will be listed.
The number and percent of subjects with a respiratory rate < 6 breaths per minute (bpm), 
< 8 bpm and < 10 bpm and the number and percent of subjects with a respiratory rate 
> 24 bpm, > 28 bpm, > 32 bpm and > 36 bpm at any time point will be summarized by 
treatment group.  The lowest and highest respiratory rate, respectively, will be used in the 
analysis.
9.5.4
Electrocardiogram
9.5.4.1 12-lead Electrocardiogram
12-lead ECG data and interpretations will be listed.
The number and percentage of subjects with absolute QTcF interval > 450 msec, > 480 msec, 
> 500 msec, PR > 200 msec, QRS > 110 msec and heart rate > 100 bpm will be provided by 
treatment group, at each time point and overall by visit.  Similar summary information will be 
provided for QTcF interval increases from baseline of > 30 msec and > 60 msec.


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9.5.5
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).
9.5.6
Blood Oxygen Saturation
The spot SpO2 levels and change from baseline will be listed and summarized by treatment 
group and time point.  The number and percent of subjects with SpO2 levels < 90%, < 92%, 
< 94% and < 96% at any time point will be summarized by treatment group.  The lowest 
SpO2 level across the time points will be used in the analysis. 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.
9.5.7
End Tidal Carbon Dioxide
The spot end tidal CO2 levels, respiratory rate and change from baseline (day 11 predose) 
will be listed and summarized by treatment group and time point.  The number and percent of 
subjects with an end tidal CO2 level < 20 mm Hg, < 25 mm Hg, < 30 mm Hg and 
< 35 mm Hg and the number and percent of subjects with an end tidal CO2 > 35 mm Hg, 
> 40 mm Hg, > 45 mm Hg and > 50 mm Hg 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. 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.
9.6
Analysis of Pharmacokinetics
Descriptive statistics will include n, mean, SD, CV, geometric mean, and geometric CV, 
minimum, median, maximum.  For the pharmacokinetic parameters tmax and tlag, only n, 
median, minimum and maximum will be calculated.
9.6.1
Plasma Concentrations
Descriptive statistics will be presented for plasma concentrations of buprenorphine and its 
metabolite (norbuprenorphine) and naloxone by treatment group (B/N + ASP and B/N alone) 
and scheduled sample time.  Standard graphics including mean plasma concentration-time 
profiles, overlay (spaghetti) plots and individual subject plasma concentration-time profiles 
for buprenorphine and its metabolite (norbuprenorphine) and naloxone by treatment group 
will be produced.  Plasma concentrations of ASP8062 will be listed and summarized using 
descriptive statistics by scheduled sample time.
9.6.2
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).


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Plasma pharmacokinetic parameters of buprenorphine, its metabolite (norbuprenorphine) and 
naloxone for B/N + ASP and B/N alone will be listed and summarized using descriptive 
statistics.
Plasma pharmacokinetic parameters of ASP8062 in combination with 
buprenorphine/naloxone will be listed and summarized using descriptive statistics.
9.6.3
Statistical Analysis of Pharmacokinetic Parameters 
To assess the effect of ASP8062 on the pharmacokinetics of buprenorphine and its metabolite 
(norbuprenorphine) and naloxone, an analysis of variance (ANOVA) model with treatment 
(B/N + ASP and B/N alone) as a fixed effect and subject as a random effect will be fitted on 
natural logarithm-transformed AUC24 and Cmax.  Within the ANOVA, the least square (LS) 
mean differences between buprenorphine/naloxone in combination with ASP8062 and 
buprenorphine/naloxone 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 subjects 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.
If all subjects did not complete treatment, then the above analyses will be repeated using an 
ANOVA with fixed effects for treatment and subject; this analysis will only include subjects 
with complete data in all treatments.
9.7
Analysis of Pharmacodynamics
Not applicable.
9.8
Other Analyses
 
 
9.9
Major Protocol Deviations
Major protocol deviations as defined in [Section 10.3 Major Protocol Deviations] will listed.
9.10
Interim Analysis (and Early Discontinuation of the Study)
Not applicable.
9.11
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.
CCI


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Listings of the AEs and concomitant medications will present the actual partial dates; 
imputed dates will not be shown.
10
OPERATIONAL CONSIDERATIONS
10.1
Data Collection
All procedures conducted under the protocol must be documented.
The investigator or designee is responsible for eCRF completion and will ensure that all data 
and queries are accurate, complete and are verifiable with the source.  The source should be 
appropriately maintained by the clinical unit.
Electronic data sources and any supporting documents should be available for 
review/retrieval by the sponsor/designee at any time.
10.2
Demographics and Baseline Characteristics
10.2.1
Demographics
Demographics and baseline characteristics will be collected as indicated in the Schedule of 
Assessments [Table 1].  This will include age, sex, race, ethnicity, body weight, height and 
BMI.
10.2.2
Medical History
A complete medical history including substance use will be collected as indicated in the 
Schedule of Assessments [Table 1].
10.2.3
Diagnosis of the Target Disease, Severity and Duration of Disease
Information of subject opiate use will be collected at the screening visit to determine if the 
subject has moderate or severe OUD.  Information will also be collected to evaluate when 
subject OUD started.  Refer to [Section 5.1 Inclusion Criteria].
10.3
Major Protocol Deviations
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change.  All deviations from the protocol are to be 
recorded.  A protocol waiver is a documented prospective approval of a request from an 
investigator to deviate from the protocol.  Protocol waivers are strictly prohibited.
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol and must protect the rights, safety and 
well-being of subjects.  The investigator should not implement any deviation from, or 
changes of, the protocol, unless it is necessary to eliminate an immediate hazard to subjects.
A major protocol deviation is 1 that may potentially impact the completeness, accuracy or 
reliability of data contributing to the primary endpoint or affect the rights, safety or 
well-being of a subject.  Major protocol deviations will have additional reporting 
requirements.


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When a major deviation from the protocol is identified for an individual subject, the 
investigator or designee must ensure the sponsor is notified.  The sponsor will follow up with 
the investigator, as applicable, to assess the deviation and the possible impact to the safety 
and/or pharmacokinetic parameters of the subject to determine subject continuation in the 
study.
The major protocol deviation criteria that will be summarized at the end of the study are as 
follows:
PD1 - Entered into the study even though the subject did not satisfy entry criteria
PD2 - Developed withdrawal criteria during the study and was not withdrawn
PD3 - Received wrong treatment or incorrect dose
PD4 - Received excluded concomitant treatment
The investigator will also assure that deviations meeting IRB/IEC and appropriate regulatory 
authorities’ criteria are documented and communicated appropriately.  All documentation and 
communications to the IRB/IEC and appropriate regulatory authorities will be provided to the 
sponsor and maintained within the Trial Master File.
10.4
Study Organization
10.4.1
Data Safety Monitoring Board  
A Data Safety Monitoring Board (DSMB) will be implemented for this study to monitor 
interim safety data. The DSMB consists of an Astellas medical doctor, a biostatistician and 
clinical pharmacology representative who are independent from the study team, who are not 
involved with day-to-day operations with the study, and do not communicate with site staff 
regarding the study. Additional details, including the responsibilities of the DSMB, are 
outlined in the DSMB charter.
10.4.2
Other Study Organization
Not applicable.


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11
REFERENCES
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allosteric modulator ADX71441 attenuates alcohol self-administration and relapse to alcohol 
seeking in rats. Neuropsychopharmacology. 2017;42:1789-99.
Bart G. Maintenance medication for opiate addiction: the foundation of recovery. J Addict Dis. 
2012;31:207-25.
Bowery NG, Bettler B, Froestl W, Gallagher JP, Marshall F, Raiteri M, et al. International Union of 
Pharmacology. XXXIII. Mammalian γ-aminobutyric acidB receptors: structure and function.
Pharmacol Rev. 2002;54:247-64.
Cheng Z, Radominska-Pandya A, Tephly TR. Studies on the substrate specificity of human intestinal 
UDP-glucuronosyltransferases 1A8 and 1A10. Drug Metab Dispos. 1999;27:1165-70.
Dario A, Tomei G. A benefit-risk assessment of baclofen in severe spinal spasticity. Drug Saf. 
2004;27:799-818.
Di Ciano P, Everitt BJ. The GABA(B) receptor agonist baclofen attenuates cocaine- and 
heroin-seeking behavior by rats. Neuropsychopharmacology. 2003a;28:510-8.
Di Ciano P, Everitt BJ. Differential control over drug-seeking behavior by drug-associated 
conditioned reinforcers and discriminative stimuli predictive of drug availability. Behav 
Neurosci. 2003b;117:952-60.
Di Marco A, D’Antoni M, Attaccalite S, Carotenuto P, Laufer R. Determination of drug 
glucuronidation and UDP-glucuronosyltransferase selectivity using a 96-well radiometric 
assay. Drug Metab Dispos. 2005;33:812-9.
Filip M, Frankowska M. Effects of GABA(B) receptor agents on cocaine priming, discrete contextual 
cue and food induced relapses. Eur J Pharmacol. 2007;571:166-73.
Filip M, Frankowska, M, Sadakierska-Chudy A, Suder A, Szumiec L, Mierzejewski P, et al. GABAB 
receptors as a therapeutic strategy in substance use disorders: Focus on positive allosteric 
modulators. Neuropharmacology. 2015;88:36-47.
Franklin TR, Harper D, Kampman K, Kildea-McCrea S, Jens W, Lynch KG, et al. The GABAB 
agonist baclofen reduces cigarette consumption in a preliminary double-blind 
placebo-controlled smoking reduction study. Drug Alcohol Depend. 2009;103:30-6.
Hasin DS, O’Brien CP, Auriacombe M, et al. DSM-5 criteria for substance use disorders: 
recommendations and rationale. Am J Psychiatry. 2013;170:834-51.
Investigator’s Brochure ASP8062, Astellas.
Ling W, Hillhouse M, Domier C, Doraimani G, Hunter J, Thomas C, et al. Buprenorphine tapering 
schedule and illicit opioid use. Addict. 2009;104:256-65.
Mattick RP, Breen C, Kimber J, Davoli M. Buprenorphine maintenance versus placebo or methadone 
maintenance for opioid dependence. Cochrane Database Syst Rev. 2014;(2):CD002207.


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Mattick RP, Breen C, Kimber J, Davoli M. Methadone maintenance therapy versus no opioid 
replacement therapy for opioid dependence. Cochrane Database Syst Rev. 2009;(3):CD002209.
NIDA: National Institute on Drug Abuse; National Institutes of Health; U.S. Department of Health 
and Human Services. Dramatic Increases in Maternal Opioid Use and Neonatal Abstinence 
Syndrome [Internet]. Rockville, MD: National Institutes of Health; 2019a [updated 2019 Jan; 
cited 2019 Aug 07]. Available from: https://www.drugabuse.gov/related-topics/trends-
statistics/infographics/dramatic-increases-in-maternal-opioid-use-neonatal-abstinence-
syndrome
NIDA: National Institute on Drug Abuse; National Institutes of Health; U.S. Department of Health 
and Human Services. Drug Use and Viral Infections (HIV, Hepatitis) [Internet]. Rockville, 
MD: National Institutes of Health; 2019b [updated 2019 Jul; cited 2019 Aug 07]. Available 
from: https://www.drugabuse.gov/publications/drugfacts/drug-use-viral-infections-hiv-hepatitis
Paterson NE, Froestl W, Markou A. The GABAB receptor agonists baclofen and CGP44532 
decreased nicotine self-administration in the rat. Psychopharmacology (Berl). 2004;172:179-86.
Paterson NE, Vlachou S, Guery S, Kaupmann K, Froestl W, Markou A. Positive modulation of 
GABA(B) receptors decreased nicotine self-administration and counteracted nicotine-induced 
enhancement of brain reward function in rats. J Pharmacol Exp Ther. 2008;326:306-14.
Pattinson KTS. Opioids and the control of respiration. Fr. J. Anaesth. 2008;100:747-58.
Picard N, Cresteil T, Djebli N, Marquet P. In vitro metabolism of buprenorphine: evidence for new 
metabolic pathways. Drug Metab Dispos. 2005;33:689-95.
Posner K, Brent D, Lucas C, Gould M, Stanley B, Brown G, et al. Columbia Suicide-Severity Rating 
Scale: Baseline/Screening Version and Since Last Visit. New York, NY: The Research 
Foundation for Mental Hygiene: 2009.
Olsen RW, Sieghart W. International Union of Pharmacology. LXX. Subtypes of γ-aminobutyric 
acidA receptors: classification on the basis of subunit composition, pharmacology, and 
function. Update. Pharmacol Rev. 2008;60:243-60.
Rasmussen, K, White DA, Acri JB. NIDA’s medication development priorities in response to the 
Opioid Crisis: ten most wanted. . Neuropsychopharmacology. 2019;44:657-659.
Rouguieg K, Picard N, Sauvage F-L, Gaulier J-M, Marquet P. Contribution of the different 
UDP-glucuronosyltransferase (UGT) isoforms to buprenorphine and norbuprenorphine 
metabolism and relationship with main UGT polymorphisms in a bank of human liver 
microsomes. Drug Metab Dispos. 2010;38:40-5.
Scholl L, Seth P, Kariisa M, Wilson N, Baldwin G. Drug and Opioid-Involved Overdose 
Deaths - United States, 2013–2017. MMWR Morb Mortal Wkly Rep 2018;67:1419–27.
Schwartz RP, Gryczynski J, O’Grady KE, Sharfstein JM, Warren G, Olsen Y, et al. Opioid agonist 
treatments and heroin overdose deaths in Baltimore, Maryland, 1995-2009. Am J Public 
Health. 2013;103:917-22.


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Slattery DA, Markou A, Froestl W, Cryan JF. The GABAB receptor-positive modulator GS39783 and 
the GABAB receptor agonist baclofen attenuate the reward-facilitating effects of cocaine: 
intracranial self-stimulation studies in the rat. Neuropsychopharmacology. 2005;30:2065-75.
Suboxone® (highlights of prescribing information). Reckitt Benckiser Pharmaceuticals Inc.; Aug 2010.
Substance Abuse and Mental Health Services Administration. Key substance use and mental health 
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Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. 2018 
[accessed 2019 Aug 07]. Available from: https://www.samhsa.gov/data/sites/default/files/cbhsq-
reports/NSDUHFFR2017/NSDUHFFR2017.pdf
Vlachou S, Guery S, Froestl W, Banerjee D, Benedict J, Finn MG, et al. Repeated administration of 
the GABAB receptor positive modulator BHF177 decreased nicotine self-administration, and 
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2003;35(2):253-9.


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12
APPENDICES
12.1
Ethical, Regulatory and Study Oversight Considerations
12.1.1
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing study conduct and the ethical principles that have their 
origin in the Declaration of Helsinki.
12.1.2
Institutional Review Board/Independent Ethics Committee/Competent 
Authorities
GCP requires that the protocol, any protocol amendments, investigator’s brochure, ICF and 
all other forms of subject information related to the study (e.g., advertisements used to recruit 
subjects) and any other necessary documents be reviewed by an IRB/IEC.  The IRB/IEC will 
review the ethical, scientific and medical appropriateness of the study before it is conducted.  
IRB/IEC approval of the protocol, ICF and subject information and/or advertising, as 
relevant, will be obtained prior to initiation of any study-specific procedures.
Any substantial amendments to the protocol will require competent authority and IRB/IEC 
approval before implementation, except for changes necessary to eliminate an immediate 
hazard to subjects.
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 study site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, EU Regulation No. 536/2014 for 
studies (if applicable), and all other applicable local regulations
12.1.3
Protocol Amendment and/or Revision
Any changes to the study that arise after approval of the protocol must be documented as
protocol amendments: substantial amendments and/or nonsubstantial amendments. 
Depending on the nature of the amendment, either IRB/IEC or competent authority approval 
or notification may be required. The changes will become effective only after the approval of 
the sponsor, investigator, IRB/IEC and appropriate regulatory authorities.
Amendments to this protocol must be signed by the sponsor and investigator. Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented. 
Modifications to the protocol that are administrative in nature do not require IRB/IEC 
approval, but will be submitted to the IRB/IEC for their information, if required by local 
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If there are changes to the ICF, written verification of IRB/IEC approval must be forwarded 
to the sponsor. An approved copy of the new ICF must also be forwarded to the sponsor.
12.1.4
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.
12.1.5
Informed Consent of Subjects
12.1.5.1 Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the subject 
and answer all questions regarding this study.  Prior to any study-related screening 
procedures being performed on the subject, the ICF will be reviewed, signed and dated by the 
subject, the person who administered the ICF and any other signatories according to local 
requirements.  A copy of the signed ICF will be given to the subject and the original will be 
placed in the subject’s medical record.  An entry must also be made in the subject’s dated 
source documents to confirm that the ICF was signed prior to any study-related procedures 
and that the subject received a signed copy of the ICF.
The signed ICFs will be retained by the investigator and made available (for review only) to 
the study monitor, auditor and appropriate regulatory authorities and other applicable 
individuals upon request.
12.1.5.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information
1.
The investigator or his/her representative will immediately inform the subject verbally 
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue participating in the study 
(e.g., report of serious adverse drug reaction).  The communication must be documented 
in the subject’s medical records and whether the subject is willing to remain in the study 
or not must be confirmed and documented.
2.
The investigator must update the subject’s ICF and submit it for approval to the 
IRB/IEC.  The investigator or his/her representative must obtain written informed 
consent from the subject on all updated ICFs throughout their participation in the study.  
The investigator or his/her designee must reconsent subjects with the updated ICF even if 
relevant information was provided verbally.  The investigator or his/her representative 
who obtained the written informed consent and the subject should sign and date the ICF.  
A copy of the signed ICF will be given to the subject and the original will be placed in 
the subject’s medical record.  An entry must be made in the subject’s records 
documenting the reconsent process.


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12.1.6
Source Documents
Source data must be available at the study site to document the existence of the subjects and 
to substantiate the integrity of study data collected.  Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject.
The 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 
(eCOA) and/or drug accountability.
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 subject file and be available for archiving.
12.1.7
Record Retention
The investigator will archive all study data (e.g., subject identification code list, source data, 
CRFs and investigator’s file) and relevant correspondence.  These documents are to be kept 
on file for the appropriate term determined by local regulation (for US study sites, 2 years 
after approval of the NDA or discontinuation of the IND).  The investigator agrees to obtain 
the sponsor’s agreement prior to disposal, moving or transferring of any study-related 
records.  The sponsor will archive and retain all documents pertaining to the study according 
to local regulations.
Data generated by the methods described in the protocol will be recorded in the subject’s 
medical records and/or study progress notes.
12.1.8
Subject Confidentiality and Privacy
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited unless the subject provides written 
consent or approval.  Additional medical information may be given only after approval of the 
subject to the investigator or to other appropriate medical personnel responsible for the 
subject’s well-being.
The sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the study without justifiable reasons.


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Even though any individuals involved in the study, including the study monitors and auditors, 
may get to know matters related to a subject’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 subject’s right to protection against invasion of privacy.  Only a 
subject identification number will identify subject data retrieved by the sponsor.  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.
12.1.9
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 drug and 
therefore may disclose it as required to other clinical investigators or to regulatory agencies.  
In order to allow for the use of the information derived from this 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.
12.1.10 Signatory Investigator for Clinical Study Report
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 hard-lock.


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12.2
Procedure for Study Quality Control
12.2.1
Study Monitoring
The sponsor or delegated CRO is responsible for monitoring the study to ensure that the 
rights, safety and well-being of subjects are protected, the study is properly conducted in 
adherence to the current protocol and GCP and the study data reported by the 
investigator/subinvestigator are accurate, complete and verifiable with the source.  The 
sponsor is responsible for assigning the study monitor(s) to this study for proper monitoring.  
They will monitor the study in accordance with planned monitoring procedures.
12.2.2
Direct Access to Source Data/Documents
The investigator and the study site must accept monitoring and auditing by the sponsor or 
delegated CRO, as well as inspections from the IRB/IEC and appropriate regulatory 
authorities.  In these instances, they must provide all study-related records including source 
documents when they are requested by the sponsor monitors and auditors, the CRO, the 
IRB/IEC or appropriate regulatory authorities.  The confidentiality of the subject’s identity 
shall be well protected consistent with local and national regulations when the source 
documents are subject to direct access.
12.2.3
Data Management
Data management will be coordinated by the Data Science department or designee of the 
sponsor in accordance with the SOPs for data management.  All study-specific processes and 
definitions will be documented by data management.  Coding of medical terms and 
medications will be performed using MedDRA and the WHO Drug Dictionary, respectively.  
Data management is accountable for eCOA.
12.2.4
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.
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, case report forms 
and source documents.  Direct access to these documents will be required by the auditors.
To support quality around subject 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.


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Table 7
Quality Tolerance Limit
QTL #: Name and Parameter
Definition
Parameter Justification
QTL1:  Subject study treatment 
discontinuation
Number of subjects that 
discontinue during run-in period
A high number of subjects that 
discontinue during the run-in 
period will impact the number of 
evaluable subjects for the primary 
endpoint
QTL: quality tolerance limit
QTL Management Activities:
●
For control of risks associated with QTL1: Subject study treatment discontinuation, refer 
to [Section 4.1 Study Design and Section 4.2 Dose Rationale] where the 
buprenorphine/naloxone dose titration and ASP8062 dose rationale is described, in 
addition, [Section 9.1 Sample Size] discusses the planned enrollment of 30 subjects to 
achieve 18 evaluable subjects.


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12.3
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 subject 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 1 of the following (i.e., permanently sterile):
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
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.  Females 
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 subject’s medical records, medical examination or medical history interview.
CONTRACEPTION GUIDANCE FOR FEMALE SUBJECTS OF CHILDBEARING 
POTENTIAL
Female subjects 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 30 days after the 
final IP administration.a
Highly effective methods of contraception (failure rate of < 1% per year when used 
consistently and correctly)b:
●
Use 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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○
Oral
○
Intravaginal
○
Transdermal
●
Progestogen-only hormonal contraception associated with inhibition of ovulation for at 
least 30 days prior to first dose of IP
○
Oral
○
Injectable
○
Implantable
●
Other combined (estrogen- and progesterone-containing) methods for at least 30 days 
prior to first dose of IP
○
Vaginal ring
○
Injectable
○
Implantable
○
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 subject.  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 subjects participating in clinical studies.
CONTRACEPTION GUIDANCE FOR MALE SUBJECTS WITH PARTNER(S) OF 
CHILDBEARING POTENTIAL.
Male subjects 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 subjects 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 subject 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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12.4
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting
12.4.1
Definition of Adverse Events
An AE is any untoward medical occurrence in a subject administered an IP and which does 
not necessarily have to have a causal relationship with this treatment. 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 IP whether 
or not considered related to the IP.
12.4.1.1 Abnormal Laboratory Findings
Any abnormal laboratory test result (e.g., hematology, biochemistry or urinalysis) or other 
safety assessment (e.g., vital signs, physical examination, ECGs or radiographic scans), 
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 subject’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.
12.4.1.2 Potential Cases of Drug-induced Liver Injury
Refer to [Appendix 12.5 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 [Appendix 12.5 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 [Appendix 12.4.5 Reporting 
Procedures for Serious Adverse Events].
12.4.2
Definition of Serious Adverse Events
An AE is considered “serious” if, in the view of either the investigator or sponsor, the event:
●
Results in death
●
Is life-threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the subject at immediate risk of death; it 
does not include an AE that, had it occurred in a more severe form, might have caused 
death)
●
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions
●
Results in congenital anomaly or birth defect


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●
Requires inpatient hospitalization (except for planned procedures as allowed per study) 
or leads to prolongation of hospitalization (except if prolongation of planned 
hospitalization is not caused by an AE)
●
Other medically important events (defined in paragraph below)
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization, but may jeopardize the 
subject or may require intervention to prevent 1 of the other outcomes listed in the definition 
above. These events, including those that may result in disability/incapacity, usually are 
considered serious. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse.
12.4.3
Criteria for Causal Relationship to Investigational Product
A medically qualified investigator is obligated to assess the relationship between IP and each 
occurrence of each (S)AE.  This investigator will use medical judgment as well as the RSI 
[Section 2.1.4 Summary of Key Safety Information for Investigational Product(s)] to 
determine the relationship.  The causality assessment is 1 of the criteria used when 
determining regulatory reporting requirements.
The investigator is requested to provide an explanation for the causality assessment for each 
(S)AE and must document in the medical notes that he/she has reviewed the (S)AE and has 
provided an assessment of causality.
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 subject been administered IP?
●
Plausibility (i.e., could the event have been caused by the suspect drug?  Consider 
biologic and/or pharmacologic mechanism, half-life, literature evidence, drug class, 
preclinical and study data, etc.)
●
Dechallenge/dose reduction/rechallenge:
○
Dechallenge: did the (S)AE resolve or improve after only stopping the dose of the 
suspect drug without any treatment?
○
Dose reduction: did the (S)AE resolve or improve after reducing the dose of the 
suspect drug?
○
Rechallenge: did the (S)AE reoccur if the suspected drug was reintroduced after 
having been stopped?


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●
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
●
Finally, judging which are more likely based on all the above contents, factors of 
reasonable possibility or confounding factors, comprehensive judgment of plausible 
temporal relationship between exposure to the IP and (S)AE onset and/or resolution will 
be provided.  Did the (S)AE occur in a reasonable temporal relationship to the 
administration of the IP?
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 assesses causality for every event before the initial transmission of the 
SAE data to the sponsor.  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 
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 eCRF
with the new information and updated causality assessment.
12.4.4
Criteria for Defining the Severity of an Adverse Event
The investigator will use the following definitions to rate the severity of each AE:
●
Mild: No disruption of normal daily activities
●
Moderate: Affect normal daily activities
●
Severe: Inability to perform daily activities
12.4.5
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).
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.


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For contact details, see [Contact Details of Sponsor’s Key Personnel].  Fax or email the 
SAE/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
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 eCRF.
The following minimum information is required:
●
International study number/study number
●
Subject 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.
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 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 subject.


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12.4.6
Reporting Procedures for Special Situations
12.4.6.1 Pregnancy
If a female subject becomes pregnant during the study dosing period or within 30 days from 
the discontinuation of dosing, the investigator is to report the information to the sponsor 
according to the timelines in [Appendix 12.4.5 Reporting Procedures for Serious Adverse 
Events] using the SAE worksheet as a special situation and in the eCRF.
The investigator will attempt to collect pregnancy information on any female partner of a 
male subject who becomes pregnant during the study dosing period or within 90 days from 
the discontinuation of dosing and report the information to sponsor according to the timelines 
in [Appendix 12.4.5 Reporting Procedures for Serious Adverse Events] using the SAE 
worksheet as a special situation.
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 
subject as an AE in the eCRF or SAE per [Appendix 12.4.5 Reporting Procedures for Serious 
Adverse Events].  For (S)AEs experienced by a female partner of a male subject, (S)AEs are 
to be reported via the SAE worksheet.
Additional information regarding the outcome of a pregnancy when also categorized as an 
SAE is mentioned below:
●
“Spontaneous abortion” includes 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)
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 
pregnancy reporting form.  Generally, follow up will be no longer than 6 to 8 weeks 
following the estimated delivery date.
12.4.6.2 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 subject), overdose or “off-label use” (i.e., use 
outside of what is stated in the protocol) is suspected, refer to [Section 10.3 Major Protocol 
Deviations].  Any associated (S)AEs are to be reported in the eCRF.  If the AE meets the 
definition of an SAE, the SAE is also to be reported as described in [Appendix 12.4.5


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Reporting Procedures for Serious Adverse Events] together with the details of the medication 
error, overdose and/or “off-label use.”
In the event of suspected ASP8062 overdose, the subject should receive supportive care and 
monitoring.  The medical monitor/expert should be contacted as applicable.
In the event of suspected buprenorphine/naloxone overdose, refer to the approved package 
insert supplied by the manufacturer for IP.  The medical monitor/expert should be contacted 
as applicable.
12.4.6.3 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 eCRF.  If the AE meets the definition of an SAE, 
the SAE is also to be reported as described in [Appendix 12.4.5 Reporting Procedures for 
Serious Adverse Events] together with details of the misuse or abuse of the IP.
12.4.6.4 Occupational Exposure
If occupational exposure (e.g., inadvertent exposure to the IP of study site personnel while 
preparing it for administration to the subject) to the IP occurs, the investigator must forward 
the special situations 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.


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12.5
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 subject 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.  Subjects should be asked if they have any symptoms suggestive of hepatobiliary 
dysfunction.
Definition of Liver Abnormalities
Confirmed abnormalities will be characterized as moderate and severe where ULN is as 
shown below.
Table 8
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 maximum 24 hours.
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following:
●
ALT or AST > 8 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks.
●
ALT or AST > 3 × ULN and† TBL > 2 × ULN or international normalized ratio (INR) 
> 1.5 (if INR testing is applicable/evaluated)
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%)
† 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 
the liver abnormality case report form (LA-CRF).  Subjects with confirmed abnormal liver 
function testing should be followed as described below.


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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 
subject is asymptomatic.
Severe hepatic liver function abnormalities as defined above, in the absence of another 
etiology, may be considered an important medical event and may be reported as a SAE.  The 
sponsor should be contacted and informed of all subjects for whom severe hepatic liver 
function abnormalities possibly attributable to 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 eCRF.  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 subjects 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 eCRF.  Information on alcohol, other 
substance use and diet should be entered on the LA-CRF or an appropriate document.
●
Obtain a history of exposure to environmental chemical agents.
●
Based on the subject’s history, other testing may be appropriate including:
○
Acute viral hepatitis (A, B, C, D, E or other infectious agents)
○
Ultrasound or other imaging to assess biliary tract disease
○
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, 
preexisting or acute liver disease, or exposure to other agents associated with liver injury, the 
subject may be discontinued from study treatment.  The investigator may determine that it is 
not in the subject’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
●
ALT or AST > 3 × ULN and† TBL > 2 × ULN or INR > 1.5) (if INR testing is 
applicable/evaluated)
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%)
† Samples taken simultaneously or within a maximum of 24 hours.


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In addition, if close monitoring for a subject 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 subjects to be discriminating”).
2.
Cases of increased total bilirubin (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 subjects showing such AT elevations, often with ATs much greater than 
3 × ULN, 1 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; preexisting or acute liver disease; or another drug capable of 
causing the observed injury.
References
Temple R. Hy’s Law: Predicting Serious Hepatotoxicity. Pharmacoepidemiol Drug Saf. 
2006;15:241-3.


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12.6
List of Excluded Concomitant Medications
Not applicable.


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12.7
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
FSH (postmenopausal female subjects 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
Buprenorphine
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 subjects 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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12.8
Pharmacogenomic Analysis with Banked Sample
INTRODUCTION
PGx research aims to provide information regarding how naturally occurring differences in a 
subject’s gene and/or expression of genes based on genetic variation may impact what 
treatment options are best suited for the subject.  Through investigation of PGx by 
technologies such as genotyping, gene sequencing, statistical genetics and Genome-Wide 
Association studies, the relationship between gene profiles and a drug’s kinetics, efficacy or 
toxicity may be better understood.  As many diseases may be influenced by 1 or more genetic 
variations, PGx research may identify which genes are involved in determining the way a 
subject may or may not respond to a drug.
OBJECTIVES
The PGx research that may be conducted in the future with acquired blood samples is 
exploratory.  The objective of this research will be to analyze or determine genes of 
relevance to clinical response, pharmacokinetics and/or toxicity/safety.
By analyzing genetic variations, it may be possible to predict an individual subject’s response 
to treatment in terms of efficacy and/or toxicity.
SUBJECT PARTICIPATION
Subjects who have consented to participate in this study will participate in the PGx substudy.  
Subjects 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
Subjects 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 subject 
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.
DISPOSAL OF PGx SAMPLES/DATA
All PGx samples collected will be stored for a period of up to 15 years following study 
database hard-lock.  If there is no requirement for analysis, the whole blood sample will be 
destroyed after the planned storage period.  The subject has the right to withdraw consent at 
any time.  When a subject’s withdraw notification is received, the PGx sample will be 
destroyed.  The results of any PGx analysis conducted on a sample prior to its withdrawal 
will be retained at Astellas indefinitely unless otherwise specified by local regulation.


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INFORMATION DISCLOSURE TO THE SUBJECTS
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 
subjects, nor can the results be requested at a later date. Any information that is obtained 
from the PGx analysis will be the property of Astellas.


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12.9
Opioid Craving Visual Analogue Scale
This document is a template from which the study-specific version will be created.
No craving
_________________________________
[100 mm scale]
Strongest craving ever




















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12.11 Clinical Opiate Withdrawal Scale
This document is a template from which the study-specific version will be created.
For each item, circle the number that best describes the patient’s signs or symptoms.  Rate on 
just the apparent relationship to opiate withdrawal.  For example, if heart rate is increased 
because the patient was jogging just prior to assessment, the increase pulse rate would not 
add to the score.
Patient’s Name: ______________________
Date and Time ____ / ____ / ____ :__________
Reason for this assessment: ________________________________________________________________
Resting Pulse Rate:                   ______beats/minute
Measured after patient is sitting or lying for one minute
0 pulse rate 80 or below
1 pulse rate 81 – 100
2 pulse rate 101 – 120
4 pulse rate greater than 120
GI Upset: over last ½ hour
0 no GI symptoms
1 stomach cramps
2 nausea or loose stool
3 vomiting or diarrhea
5 multiple episodes of diarrhea or vomiting
Sweating: over past ½ hour not accounted for by room 
temperature or patient activity
0 no report of chills or flushing
1 subjective report of chills or flushing
2 flushed or observed moistness on face
3 beads of sweat on brow or face
4 sweat streaming off face
Tremor observation of outstretched hands
0 no tremor
1 tremor can be felt, but not observed
2 slight tremor observable
4 gross tremor or muscle twitching
Restlessness Observation during assessment
0 able to sit still
1 reports difficulty sitting still, but is able to do so
3 frequently shifting or extraneous movements of legs/arms
5 unable to sit still for more than a few seconds
Yawning Observation during assessment
0 no yawning
1 yawning once or twice during assessment
2 yawning three or more times during assessment
4 yawning several times/minute
Pupil size
0 pupils pinned or normal size for roomlight
1 pupils possible larger than normal for roomlight
2 pupils moderately dilated
5 pupils so dilated that only the rim of the iris is visible
Anxiety or Irritability
0 none
1 patient reports increasing irritability or 
anxiousness
2 patient obviously irritable or anxious
4 patient so irritable or anxious that participation in 
the assessment is difficult
Bone or Joint aches If patient was having pain previously, 
only the additional components attributed to opiates 
withdrawal is scored
0 not present
1 mild diffuse discomfort
2 patient reports severe diffuse aching of joints/muscle
4 patient is rubbing joints or muscles and is unable to sit still 
because of discomfort
Gooseflesh skin
0 skin is smooth
3 piloerrection of skin can be felt or hairs standing 
up on arms
5 prominent piloerrection
Runny nose or tearing Not accounted for by cold symptoms 
or allergies
0 not present
1 nasal stuffiness or unusually moist eyes
2 nose running or tearing
4 nose constantly running or tears streaming down cheeks
Total Score _______
The total score is the sum of all 11 items
Initials of person
completing assessment:     ___________
Score: 5 – 12 = mild; 13 – 24 = moderate; 25 – 36 = moderately severe; more than 36 = severe withdrawal


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12.12 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
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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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 v23.0
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 v23.0
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 colour
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 v23.0
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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12.13 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.
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
AUClast
area under the concentration-time curve from the time of dosing to the last 
measurable concentration
AUD
alcohol use disorder
BMI
body mass index
bpm
breaths per minute
B/N alone
buprenorphine/naloxone alone
B/N + ASP
buprenorphine/naloxone in combination with ASP8062
B/N + Pbo
buprenorphine/naloxone in combination with placebo
CL/F
apparent clearance
Cmax
maximum concentration
CNS
central nervous system
CO2
carbon dioxide
COWS
clinical opiate withdrawal scale
CPP
conditioned place preference
CRO
contract research organization
CSR
clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale
Ctrough
concentration immediately prior to dosing at multiple dosing
CV
coefficient of variation
CYP
cytochrome P450
DBP
diastolic blood pressure
DDI
drug-drug interaction
DPD
Data Protection Directive
DSM-4
Diagnostic and Statistical Manual of Mental Disorders, edition 4
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, edition 5
ECE
emergency code envelopes
ECG
electrocardiogram
eCOA
electronic clinical outcome assessment
eCRF
electronic case report form


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Abbreviations
Description of abbreviations
EEA
European Economic Area
ESV
end-of-study visit
EtOH
ethanol
FAS
full analysis set
FM
fibromyalgia
FSH
follicle-stimulating hormone
GABA
gamma-aminobutyric acid
GABAB
gamma-aminobutyric acid type B
GCP
Good Clinical Practice
GHB
γ-hydroxybutyrate
GMP
Good Manufacturing Practice
HIV
human immunodeficiency virus
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
LA-CRF
liver abnormality case report form
LS
least square(s)
NIDA
National Institute on Drug Abuse
OUD
opioid use disorder
PAM
positive allosteric modulator
PGx
pharmacodynamics
PKAS
pharmacokinetic analysis set
PTR
peak trough ratio
QA
quality assurance
QC
quality control
QTcF
corrected QT interval using Fridercia’s formula
QTL
quality tolerance limit
RSI
reference safety information
(S)AE
serious adverse event or adverse event
SAE
serious adverse event
SAF
safety analysis set
SBP
systolic blood pressure
SOP
standard operating procedure
SpO2
blood oxygen saturation
SUSAR
suspected unexpected serious adverse reaction
SWS
slow-wave sleep
t½
terminal elimination half-life


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Abbreviations
Description of abbreviations
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
UGT
UDP-glucuronosyltransferases
ULN
upper limit of normal
USM
urgent safety measure
VAS
visual analogue scale
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 subjects as they enter a study before they receive any IP.
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 subject into a study.  Note: once a subject has received 
the IP or placebo, the protocol applies to the subject.
Intervention
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).
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 subject and continues until the last assessment 
after completing administration of the test product or comparative drug.
Randomization
The process of assigning subjects 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 subjects into groups at a 
differential rate; for example, 3 subjects may be assigned to a treatment 
group for every 1 assigned to the control group.
Screen failure
Potential subject who signed the informed consent form, but did not meet 
1 or more criteria required for participation in the study and was not 
randomized.
Screening
A process of active consideration of potential subjects for randomization in a 
study.
Screening period
Period of time before entering the investigational period, usually from the 
time when a subject signs the consent form until just before the test product 
or comparative drug (sometimes without randomization) is given to a 
subject.
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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13
ATTACHMENT 1: NONSUBSTANTIAL AMENDMENT 2
I.  The purpose of this amendment is:
Nonsubstantial Changes
1.
Update to the rescreening 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 23 to the inclusion criteria and clarify the CYP450 enzymes that 
are excluded for exclusion criterion 18.
RATIONALE:
Previous exclusion 23 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 18 excluded all inducers of metabolism; however, after consideration, it is only 
necessary to exclude inducers of CYP2C8, 2C9, and 3A4.
3.
Clarify procedure for continuous end tidal CO2
DESCRIPTION OF CHANGE:
Add clarification that subjects may remove canula 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 canula in place.


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II.  Amendment summary of changes:
1.1 Synopsis, Inclusion Criteria & 5.1 Inclusion Criteria
ADDED: 
14. 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 11 
and 12.
1.1 Synopsis, Exclusion Criteria & 5.2 Exclusion Criteria 
WAS:
18. Subject has used any inducer of metabolism (e.g., barbiturates and rifampin) in the 
3 months prior to day -1.
IS AMENDED TO:
18. Subject has used any inducer of metabolism (e.g., barbiturates and rifampin) in the 
3 months prior to day 1. has used any inducer of CYP2C8, 2C9 or 3A4-related 
metabolism (e.g., barbiturates, rifampin, aprepitant, ritonavir, apalutamide, 
carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort, 
bosentan, efavirenz, etravirine, phenobarbital, primidone, armodafinil, 
modafinil, and rufinamide) in the 3 months prior to day -1.
1.1 Synopsis, Exclusion Criteria & 5.2 Exclusion Criteria 
DELETED: 
22. 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 11 and 
12.
1.3 Schedule of Assessments Table 1 footnote 13
WAS:
13.Continuous end tidal CO2 to be collected starting predose on days 11 and 12 until 8 
hours postdose.  Timepoints will be recorded predose and 1, 2, 4 and 8 hours postdose.
IS AMENDED TO:
13.Continuous end tidal CO2 to be collected starting predose on days 11 and 12 until 8 hours 
postdose. Timepoints will be recorded predose and 1, 2, 4 and 8 hours postdose. The 
cannula may be removed while subjects dose or eat.


Sponsor: APGD
ISN/Protocol 8062-CL-2003
- CONFIDENTIAL -
29 Jul 2020
Astellas
Page 110 of 111
Version 1.2 Incorporating Nonsubstantial Amendment 2
5.4.1 Rescreening 
WAS:
Rescreening is allowed only in situations in which a subject underwent the screening 
procedures and due to logistical circumstances, the allocated time window for these tests 
has expired and the subject is documented as a screen failure.  In order to rescreen, a new 
ICF must be signed and a new subject screening number assigned. Rescreening is only 
allowed once for an individual subject.
IS AMENDED TO:
Rescreening is allowed only in situations in which a subject underwent the screening 
procedures and due to logistical circumstances, the allocated time window for these tests 
has expired and the subject is documented as a screen failure.  In order to rescreen, a new 
ICF must be signed and a new subject screening number assigned.  Rescreening is only 
allowed once for an individual subject.
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.
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.


Sponsor: APGD
ISN/Protocol 8062-CL-2003
- CONFIDENTIAL -
29 Jul 2020
Astellas
Page 111 of 111
Version 1.2 Incorporating Nonsubstantial Amendment 2
14
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
PPD
PPD