Clinical trial NCT05704543
Conditions: Opioid Use Disorder
Keywords: medicine for opioid use disorder (MOUD)
Sponsor: Indivior Inc.
Start date: 2023-03-01; Completion date: 2023-11-01
Enrollment: 132 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Extended-release buprenorphine (SUBLOCADE®) injection is currently approved for subcutaneous administration in the abdomen for treatment of opioid use disorder (OUD). Having alternative injection sites is desirable to provide additional flexibility to patients, particularly for those who may prefer less visible or more convenient injection locations.

The primary objective of this study is to assess the relative bioavailability of extended-release buprenorphine when administered at alternative injection locations (test treatments), in comparison to the abdomen (reference treatment).

Detailed description:

Arms: arm 1: Participants will receive a single, subcutaneous injection of 300 mg extended-release buprenorphine in the abdomen on Day 1. arm 2: Participants will receive a single, subcutaneous injection of 300 mg extended-release buprenorphine in the back of the upper arm on Day 1. arm 3: Participants will receive a single, subcutaneous injection of 300 mg extended-release buprenorphine in the buttocks on Day 1. arm 4: Participants will receive a single, subcutaneous injection of 300 mg extended-release buprenorphine in the thigh on Day 1.
Interventions: intervention 1: Buprenorphine Extended-Release Injection
Intervention descriptions: intervention 1: Administered as a subcutaneous injection.

Protocol documents:
SAP_002.pdf: 
STATISTICAL ANALYSIS PLAN: INDV-6000-405
Addendum
Protocol Title:  A Single-Dose Study to Evaluate the Relative 
Bioavailability, Safety, and Tolerability of SUBLOCADE at 
Alternative Injection Locations in Adults 
Final Version: 19 Mar 2024
NCT: NCT05704543


Statistical Analysis Plan Addendum 
Protocol ID: INDV-6000-405 
Date: 19MAR2024 
Description: 
After database lock, it was noted that the appendix of the SAP the following definition was used to 
derive medications prior to SUBLOCADE injection. 
End Date of Non-
Study Medication 
Start Date of Non-Study Medication 
Missing 
< Start date of 
SUBOXONE 
≥ Start date of SUBOXONE 
and ≤ end date of 
SUBOXONE 
Missing (includes 
flagged as “Ongoing”) 
Prior 
Concomitant 
(Run-In) 
Prior 
Concomitant (Run-
In) 
Concomitant (Run-In) 
< Start date of 
SUBOXONE  
Prior 
Prior 
Data Error 
≥ Start date of 
SUBOXONE and ≤ 
end date of 
SUBOXONE 
Prior 
Concomitant 
(Run-In) 
Prior 
Concomitant (Run-
In) 
Concomitant (Run-In) 
However, in the last row of this table, it implies that prior medications and Run-In concomitant 
medications do not include a medication started before injection and ended after last dose of 
SUBOXONE. The first column last row should not include the clause “and ≤ end date of SUBOXONE”.   
In addition, medications should be considered run-in concomitant as long as its start date is between 
start of SUBOXONE and SUBLOCADE injection date (if injection took place). Therefore, the last column 
should be split into two situations, with and without injection. 
After modification, the definition should read the following: 
End Date of 
Non-Study 
Medication 
Start Date of Non-Study Medication 
Missing 
< Start date of 
SUBOXONE 
≥ Start date of 
SUBOXONE if no 
injection 
≥ Start date of 
SUBOXONE and ≤ 
SUBLOCADE 
injection date if there 
is SUBLOCADE 
injection 
Missing 
(includes 
flagged as 
“Ongoing”) 
Prior 
Concomitant 
(Run-In) 
Prior 
Concomitant 
(Run-In) 
Concomitant (Run-
In) 
Concomitant (Run-In) 
< Start date of 
SUBOXONE  
Prior 
Prior 
Data Error 
Data Error 


≥ Start date of 
SUBOXONE 
Prior 
Concomitant 
(Run-In) 
Prior 
Concomitant 
(Run-In) 
Concomitant (Run-
In) 
Concomitant (Run-In) 
 
Implications:  
Run-In concomitant medications flag and consequently, Table 14.1.5.2 will be updated.  

Prot_000.pdf: 
CLINICAL STUDY PROTOCOL: INDV-6000-405 
Protocol Title: A Single-Dose Study to Evaluate the 
Relative Bioavailability, Safety, and Tolerability of 
SUBLOCADE at Alternative Injection Locations in Adults 
Protocol Number: INDV-6000-405
Original Protocol Date: 18 Nov 2022
NCT: NCT05704543


SUBLOCADE® (buprenorphine extended-release) injection  
Clinical Study Protocol: INDV-6000-405 
Indivior Inc. 
18 Nov. 2022 
 
CONFIDENTIAL 
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TITLE PAGE 
PROTOCOL TITLE: A Single-Dose Study to Evaluate the Relative Bioavailability, Safety, and 
Tolerability of SUBLOCADE at Alternative Injection Locations in Adults 
Protocol Number: INDV-6000-405 
Investigational New Drug (IND) Number: 107,607 
Product:  SUBLOCADE® (buprenorphine extended-release) injection  
Brief Title: SUBLOCADE Alternative Injection Locations 
Study Phase: IV 
Sponsor Name: Indivior Inc. 
Legal Registered Address: 
Indivior Inc. 
10710 Midlothian Turnpike, Suite 125 
North Chesterfield, VA 23235 USA 
 
Approval Date: 18 Nov. 2022  
Sponsor Signatories: 


SUBLOCADE® (buprenorphine extended-release) injection 
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MEDICAL MONITOR NAME AND CONTACT INFORMATION


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18 Nov. 2022
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CONFIDENTIALITY AND INVESTIGATOR STATEMENT
Protocol Number: INDV-6000-405
Protocol Title: A Single-Dose Study to Evaluate the Relative Bioavailability, Safety, and 
Tolerability of SUBLOCADE at Alternative Injection Locations in Adults
The information contained in this protocol and all other information relevant to this study drug 
is the confidential and proprietary information of Indivior, and except as may be required by 
local laws or regulation, may not be disclosed to others without prior written permission of 
Indivior. 
I have read the protocol, including all appendices, and I agree that it contains all of the 
necessary information for me and my staff to conduct this study as described. My staff and/or I 
will conduct this study as outlined herein, in accordance with the regulations stated in the 
International Council on Harmonisation E6 / Good Clinical Practice (ICH/GCP) guidelines and will 
make a reasonable effort to complete the study within the time designated. 
I agree to ensure all associates, colleagues, and employees delegated to assist with the conduct 
of the study are trained on this study protocol and amendments, and other study-related 
materials, and are qualified to perform their delegated tasks. I will provide all study personnel 
copies of the protocol and any amendments, and grant access to all information provided by 
Indivior or specified designees. I will discuss the material with them to ensure that they are fully 
informed about SUBOXONE and SUBLOCADE and appropriate information throughout the 
study. Mechanisms are in place to ensure that site staff receives the appropriate information 
throughout the study.
_______________________________________
_______________________________
Signed 
Date: DD MMM YYYY
Printed Name and Credentials:
Title:
Site Number:
Site Name: 
Telephone:
Address:


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Indivior Inc.
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TABLE OF CONTENTS
TITLE PAGE......................................................................................................................................1
MEDICAL MONITOR NAME AND CONTACT INFORMATION ...........................................................2
CONFIDENTIALITY AND INVESTIGATOR STATEMENT .....................................................................3
TABLE OF CONTENTS ......................................................................................................................4
TABLE OF TABLES............................................................................................................................7
TABLE OF FIGURES..........................................................................................................................7
ABBREVIATIONS..............................................................................................................................8
PROTOCOL SUMMARY..................................................................................................................11
1.1 Synopsis............................................................................................................................11
1.2 Schema .............................................................................................................................14
1.3 Schedules of Events..........................................................................................................15
2
INTRODUCTION ......................................................................................................................19
2.1 Study Rationale.................................................................................................................19
2.2 Background.......................................................................................................................19
2.3 Benefit/Risk Assessment ..................................................................................................19
2.3.1
Risk Assessment......................................................................................................19
2.3.2
Benefit Assessment.................................................................................................20
2.3.3
Overall Benefit Risk Conclusion ..............................................................................20
3
OBJECTIVES AND ENDPOINTS.................................................................................................21
4
STUDY DESIGN........................................................................................................................22
4.1 Overall Design...................................................................................................................22
4.2 Scientific Rationale for Study Design................................................................................23
4.3 Justification for Dose ........................................................................................................23
4.4 End of Study Definition.....................................................................................................23
4.5 Protocol Deviations ..........................................................................................................24
5
STUDY POPULATION...............................................................................................................24
5.1 Inclusion Criteria...............................................................................................................24
5.2 Exclusion Criteria ..............................................................................................................24
5.3 Randomisation Criteria.....................................................................................................25
5.4 Lifestyle Considerations....................................................................................................25
5.4.1
Concomitant Medications ......................................................................................25


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5.4.2
Activity....................................................................................................................26
5.4.3
Other Restrictions...................................................................................................26
5.5 Screen Failures..................................................................................................................26
5.6 Criteria for Temporarily Delaying Administration of Study Intervention .........................26
5.7 Run-in Failure....................................................................................................................26
5.8 Early Discontinuation........................................................................................................27
6
STUDY DRUG AND CONCOMITANT THERAPY.........................................................................27
6.1 Study Drugs Administered................................................................................................28
6.2 Preparation, Handling, Storage, and Accountability.........................................................29
6.2.1
Drug Preparation ....................................................................................................29
6.2.2
Drug Administration ...............................................................................................29
6.2.3
Reporting Product Complaints................................................................................30
6.3 Assignment to Study Intervention....................................................................................30
6.4 Blinding.............................................................................................................................30
6.5 Study Drug Compliance ....................................................................................................30
6.6 Dose Modification ............................................................................................................31
6.6.1
Retreatment Criteria...............................................................................................31
6.7 Treatment Access to Study Drug After the End of the Study ...........................................31
6.8 Treatment of Study Drug Overdose..................................................................................31
6.9 Prior and Concomitant Therapy .......................................................................................31
6.9.1
Prohibited Concomitant Therapies.........................................................................32
6.9.2
Restricted Concomitant Therapies .........................................................................32
6.9.3
Permitted Concomitant Therapies and Rescue Medication...................................33
7
DISCONTINUATION OF STUDY DRUG, PARTICIPANT DISCONTINUATION/WITHDRAWAL AND 
STOPPING CRITERIA......................................................................................................................33
7.1 Discontinuation of Study Drug and Study Stopping Criteria.............................................33
7.2 Participant Discontinuation/Withdrawal From the Study................................................33
7.3 Lost to Follow Up..............................................................................................................34
8
STUDY ASSESSMENTS AND PROCEDURES ..............................................................................35
8.1 Administrative and General Procedures...........................................................................35
8.2 Efficacy Assessments ........................................................................................................35
8.3 Safety Assessments ..........................................................................................................35
8.3.1
Physical Examinations.............................................................................................35
8.3.2
Local Injection Site Tolerability...............................................................................36
8.3.3
Vital Signs................................................................................................................36


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8.3.4
Clinical Safety Laboratory Tests..............................................................................36
8.3.5
Electrocardiograms.................................................................................................37
8.3.6
Pregnancy Testing...................................................................................................37
8.4 Adverse Events, Serious Adverse Events, and Other Safety Reporting ............................37
8.4.1
Time Period and Frequency for Collecting AE and SAE Information.......................41
8.4.2
Method of Detecting AEs and SAEs ........................................................................41
8.4.3
Reporting and Follow-up of AEs and SAEs..............................................................41
8.4.4
Regulatory Reporting Requirements for SAEs ........................................................43
8.4.5
Pregnancy ...............................................................................................................43
8.5 Pharmacokinetics .............................................................................................................44
8.6 Pharmacodynamics...........................................................................................................44
8.7 Genetics............................................................................................................................44
8.8 Biomarkers........................................................................................................................44
8.9 Health Economics .............................................................................................................44
9
STATISTICAL CONSIDERATIONS ..............................................................................................45
9.1 Statistical Hypotheses.......................................................................................................45
9.1.1
Multiplicity Adjustment ..........................................................................................45
9.2 Analyses Sets ....................................................................................................................45
9.3 Statistical Analyses ...........................................................................................................46
9.3.1
General Considerations ..........................................................................................46
9.3.2
Primary Analysis......................................................................................................46
9.3.3
Secondary Endpoint Analysis..................................................................................47
9.3.4
Exploratory Endpoint Analyses...............................................................................47
9.3.5
Other Safety Analyses.............................................................................................48
9.4 Interim Analysis ................................................................................................................48
9.5 Sample Size Determination ..............................................................................................48
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS..............................50
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ......................50
10.1.1
Regulatory and Ethical Considerations...................................................................50
10.1.2
Financial Disclosure ................................................................................................50
10.1.3
Informed Consent Process......................................................................................51
10.1.4
Data Protection.......................................................................................................51
10.1.5
Committees Structure ............................................................................................52


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10.1.6
Data Quality Assurance...........................................................................................52
10.1.7
Source Documents..................................................................................................53
10.1.8
Study and Site Start and Closure ............................................................................54
10.1.9
Publication Policy....................................................................................................55
10.2
Appendix 2: Clinical Laboratory Tests ........................................................................56
10.3
Appendix 3: Guidance on Highly Effective Contraception..........................................58
10.4
Appendix 4: Country-specific Requirements..............................................................59
10.5
Appendix 5: Prohibited Concomitant Therapies ........................................................60
10.6
Appendix 6: Schedule of Assessments – Day -3 to Day 3 ...........................................61
11 REFERENCES............................................................................................................................64
TABLE OF TABLES
Table 1
Objectives and Endpoints...........................................................................................11
Table 2
Schedule of Events – Screening to Day 3....................................................................15
Table 3
Schedule of Events – Outpatient Day 4 to End of Study.............................................18
Table 4
Objectives and Endpoints...........................................................................................21
Table 5
Study Drugs Administered – Label .............................................................................28
Table 6
Populations for Analysis .............................................................................................45
Table 7
Primary PK Parameters of BUP following SUBLOCADE injection................................46
Table 8
Additional PK Parameters of BUP Following SUBLOCADE Injection...........................47
Table 9
PK Parameters of Norbuprenorphine Following SUBLOCADE Injection.....................48
Table 10
Protocol-required Safety Laboratory Tests ................................................................56
Table 11
Schedule of Events – Detailed Inpatient Day -3 to Day 3 With Assessment Windows
61
TABLE OF FIGURES
Figure 1
Study Schema.............................................................................................................14


SUBLOCADE® (buprenorphine extended-release) injection 
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ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUC
area under the curve (see also Table 7, Table 8, and Table 9)
BLQ
below the lower limit of quantification
BMI
body mass index
BUN
blood urea nitrogen
BUP
buprenorphine
CFR
Code of Federal Regulations
CI
confidence interval
Cmax
maximum plasma concentration
Ctrough
trough plasma concentration measured on Day 29
CPK
creatine phosphokinase
CRF
case report form
CRO
Contract Research Organisation
CSR
clinical study report
CYP
cytochrome P450
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
ECG
electrocardiogram
eCRF
electronic case report form
EOS
End of Study
EOT
End of Treatment
ET
Early Termination
FDA
Food and Drug Administration


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GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
GMP
Good Manufacturing Practice
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
INR
international normalised ratio
IRB
Institutional Review Board
IV
intravenous
IVRS/IXRS 
Interactive Voice Response System
LDH
lactate dehydrogenase
MCH
mean corpuscular haemoglobin
MCHC
mean corpuscular haemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary For Regulatory Activities 
MOUD
medicine for opioid use disorder
OUD
opioid use disorder
PK
pharmacokinetic(s)
PT
prothrombin time
PTT
activated partial thromboplastin time
QD
once daily
QTcF
heart rate-corrected QT interval (Fridericia’s)
RBC
red blood cell (count)
SAE
serious adverse event


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SAP
statistical analysis plan
SC
subcutaneous(ly)
SD
standard deviation
SoE
Schedule(s) of Events
SOP
Standard Operating Procedure
SUSAR
suspected unexpected serious adverse reaction 
TEAE
treatment-emergent adverse event
TM
transmucosal
Tmax
time to maximum plasma concentration
UDS
urine drug screen
ULN
upper limit of normal
US
United States
VAS
visual analogue scale
WBC
white blood cell (count)
WHO
World Health Organization


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PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: A Single-Dose Study to Evaluate the Relative Bioavailability, Safety, and 
Tolerability of SUBLOCADE at Alternative Injection Locations in Adults 
Short Title: SUBLOCADE Alternative Injection Locations 
Rationale: SUBLOCADE® (extended-release BUP injection) for SC use (CIII) is currently approved 
for SC administration in 4 different quadrants of the abdomen. Injection locations are rotated 
to minimise irritation.  
Having 1 or more alternate injection sites is desirable in this patient population who may be 
taking SUBLOCADE for extended durations, based upon clinical response.  
Data cited from literature suggests that the proposed alternative injection locations for SC 
administration are viable options for delivering similar PK properties: back of upper arm, 
buttocks, and thigh. 
Objectives and Endpoints 
Table 1 
Objectives and Endpoints 
Objective 
Corresponding Endpoint 
Primary 
 
 To assess the relative bioavailability of 
BUP when administered at alternative 
injection locations (test treatments), in 
comparison to the abdomen (reference 
treatment) following a single SC injection 
of SUBLOCADE in participants with OUD 
 AUC0-28days and Cmax for BUP  
Secondary 
 
 To evaluate the safety and tolerability of 
SUBLOCADE when administered at 
alternative injection locations, in 
comparison to the abdomen  
 Proportion of participants with TEAEs  
 Proportion of participants with TEAEs 
identified as injection site reactions 
 Proportion of participants with 
treatment-emergent SAEs 
 Injection site grading at 10 minutes and 
2 hours post SUBLOCADE dosing 
 Injection Site Pain VAS at 1, 5, 10, 15, and 
30 minutes post SUBLOCADE dosing 
AUC=area under the curve; BUP=buprenorphine; Cmax=maximum plasma concentration; 
OUD=opioid use disorder; SAE=serious adverse event; SC=subcutaneous; TEAE=treatment-
emergent adverse event; VAS=visual analogue scale 
 


SUBLOCADE® (buprenorphine extended-release) injection  
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Overall Design Synopsis 
This is a multicentre, randomised, open-label, single-dose, parallel-group study in participants 
with moderate or severe OUD (based on criteria from the DSM-5 or documented history of 
moderate to severe OUD and receiving/stabilised on MOUD).  
Brief Summary: The purpose of this study is to measure the relative bioavailability of BUP when 
administered at alternative injection locations in comparison to the abdomen following a single 
SC injection of SUBLOCADE in participants with OUD.  
Participants will provide written informed consent before any protocol-related procedures 
commence. The study includes both a Residential (Inpatient) Period and a Non-Residential 
(Outpatient) Period. 
Following Screening, all eligible participants must be stabilised on 12 mg SUBOXONE® 
(BUP/naloxone) sublingual film QD for a minimum of 7 days before the SUBLOCADE injection. 
Dose induction/stabilisation onto SUBOXONE may be completed as outpatient or inpatient, as 
necessary, according to the prescribing information for a maximum of 14 days before 
SUBLOCADE injection.  
All participants will be admitted to the residential facility by the evening of Day -3.  
The period from the first dose of SUBOXONE administered as part of this study through Day -1 
will be referred to as the Run-in Period.  
Following the Run-in Period, on Day 1, eligible participants will be randomised to a treatment 
arm.  
Each treatment arm will receive a single, SC injection of 300 mg SUBLOCADE at a different 
injection location ie, abdomen (reference) or 1 of the alternative injection locations (test) ie, 
back of upper arm, buttocks, and thigh.  
Safety measurements and blood samples for PK assessments during the Residential Period will 
be collected at scheduled time points until the participants are discharged from the residential 
facility on Day 3. 
Participants will return to the clinical facility as outpatients for safety and PK assessments to be 
conducted according to the SoE until EOT. 
Any participant with ongoing AEs at the EOT or ET visit will also be followed up by phone 
2 weeks later for the EOS visit to assess any ongoing AEs and concomitant medications 
associated with those ongoing AEs only. 
It is important that participants do not use any BUP-containing products, either therapeutically 
or illicitly during the course of the study. Such use would compromise the PK assessment of 
BUP and its metabolite, norbuprenorphine. 
Number of Participants: 
No formal statistical power analysis was performed to determine the sample size of this study. 
Based on historical experience from previous similar clinical trials, approximately 
80 participants will be randomised in total, ideally to achieve 15 PK evaluable participants per 
each of the 4 treatment arms (injection locations): abdomen (reference), back of upper arm, 
buttocks, and thigh. 


SUBLOCADE® (buprenorphine extended-release) injection  
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Note: Screened means participants’ agreement to participate in a clinical study following 
completion of the informed consent process. Potential participants who are screened for the 
purpose of determining eligibility for the study, but do not participate in the study, are not 
considered enroled, unless otherwise specified by the protocol. A participant will be considered 
enroled if the informed consent is not withdrawn prior to receiving the first dose of SUBOXONE 
film during run-in.   
Study Duration: 
The total duration of the study for each participant, including Screening, Run-in, Treatment, and 
Follow up, will be up to approximately 86 days, divided as follows: 
 Screening: Up to 30 days 
 Run-in Period: Up to 14 days 
 Treatment Period: 28 days 
 Follow-up Period: up to 14 days 
 


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1.2
Schema
Figure 1
Study Schema


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1.3
Schedules of Events
See Section 10.6 for a detailed SoE for inpatient Day -3 to Day 3 with assessment windows.
Table 2
Schedule of Events – Screening to Day 3
Inpatient/ 
Outpatient
Inpatient (See Section 10.6 for Details)
Evaluation
Screening
SUBOXONE 
Dosinga
Clinic 
Admissiona
SUBLOCADE 
Injection
Day
-14 to -4
-3
-2
-1
1
2
3
Informed Consentb
X
Inclusion/Exclusion 
Criteria 
X
Demographics 
X
Medical/Psychiatric 
History
X
Drug Use History
X
Height/Weight/BMIc
X
12-Lead ECGd
X
X
Vital Signse
X
X
X
X
X
Physical Examinationf
X
Adverse Event 
Assessment
<------------------------------------------------------X---------------------------------------------------->
Concomitant 
Medicationsg
<------------------------------------------------------X---------------------------------------------------->
Haematology  
X
Serum Chemistry
X
HIV-1/HIV-2, Hep B, and 
Hep C Antibody 
Testingh
X
Liver Function Testingi
X
X
PTT/PT/INR
X
Urinalysis
X
Urine Pregnancy Testj
X
X
Urine Drug Screen (UDS)k
X
SUBOXONE 
Administration
X
Xl
X
X


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Inpatient/ 
Outpatient
Inpatient (See Section 10.6 for Details)
Evaluation
Screening
SUBOXONE 
Dosinga
Clinic 
Admissiona
SUBLOCADE 
Injection
Day
-14 to -4
-3
-2
-1
1
2
3
Randomisation Criteria 
Reviewed
X
Randomisation
X
PK Samplingm
X
X
X
X
X
SUBLOCADE 
Administration
X
Injection Site Evaluationn
X
Injection Site Gradingo
X
Injection Site Pain VASp
X
Discharge from 
Residential Facility
X
Psychosocial/Behavioural 
Counsellingq
<---------------------------------------------X--------------------------------------------->
BMI=body mass index; ECG=electrocardiogram; Hep=Hepatitis; HIV=human immunodeficiency virus; ICF=informed 
consent form; INR=international normalised ratio; PK=pharmacokinetic; PT=prothrombin time; QD=once daily; 
VAS=visual analogue scale; PTT=partial thromboplastin time
a.
All participants must be administered 12 mg SUBOXONE QD as part of the study (after signing ICF) at least 
7 days before SUBLOCADE injection. Participants may be administered SUBOXONE as part of the study 
(inpatient or outpatient) for a maximum of 14 days, with all participants completing the last 3 days as 
inpatients.
b.
Informed consent form will be signed before screening procedures are initiated. Screening assessments must 
be completed within 30 days of SUBOXONE dosing for this study.
c.
Body mass index will be calculated within the database using weight and height. 
d.
12-lead ECGs will be collected after the participant has been in a supine position for ≥5 minutes and 
performed prior vital signs and to clinical laboratory tests (haematology, serum chemistry, and urinalysis).
e.
Vital signs include temperature, systolic and diastolic blood pressure, pulse rate, and respiratory rate after the 
participant has been in a supine or sitting position for ≥3 minutes. On Day 1, vital signs will be taken 
≤60 minutes prior to SUBLOCADE administration and 1 and 8 hours post dose. Vital signs will also be taken on 
Day 2 at 24 hours and Day 3, 48 hours (see Section 10.6 [appendix] for assessment windows).
f.
Complete physical examination to include an assessment of general appearance, skin and extremities, head 
and neck, lymph nodes, eyes, ears, nose, throat, thyroid, neurological system, lungs, cardiovascular system, 
and abdomen (liver and spleen). The examination will not include a breast, pelvic or rectal exam, unless 
clinically indicated. Clinically significant abnormal changes from Screening will be recorded as AEs.
g.
Includes a review of any previous (taken within 30 days of providing written informed consent) and ongoing 
medications (including over-the-counter) and herbal supplements.
h.
HIV-1/HIV-2, Hep B and Hep C antibody testing to be performed only in the absence of a positive 
(documented) medical history for these conditions. If there is a positive result for HIV-2/HIV-2 or Hep C, an 
additional blood draw will be collected at the following site visit for confirmatory testing. 


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i.
A subset of serum chemistry to be performed including alkaline phosphatase, alanine aminotransferase, 
aspartate aminotransferase, bilirubin, albumin, total protein, gamma glutamyl transferase, and lactate 
dehydrogenase only. 
j.
Required for female participants of childbearing potential only.
k.
Qualitative test to be performed at Screening including the following: opioids (including fentanyl, oxycodone, 
opiates/morphine, and methadone), cocaine, amphetamines, cannabinoids, barbiturates, benzodiazepines, 
methamphetamine, phencyclidine.
l.
12 mg SUBOXONE QD should be administered at approximately at the same time each day. Therefore, on 
Day -3, the SUBOXONE administration may occur prior to clinic admission.
m.
A 6-mL blood sample will be collected for PK analysis (see Section 10.6 [appendix] for assessment windows)
n.
Injection site will be evaluated for signs of attempted removal. Any injection site reactions or infections will be 
recorded as AEs.
o.
Injection site grading will be performed within 10 minutes after injection and again at 2 hours post injection 
(see Section 10.6 [appendix] for assessment windows).
p.
Injection site pain will be assessed by the participant using a 100 mm VAS scale. The Injection Site Pain VAS 
scores will be obtained (after the completion of the injection) at 1, 5, 10, 15 and 30 minutes (see Section 10.6 
[appendix] for assessment windows).
q.
Psychosocial/behavioural counselling should be performed per standard of care as part of the 
SUBOXONE/SUBLOCADE treatment plan and should be documented into the source records.


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Table 3
Schedule of Events – Outpatient Day 4 to End of Study
Outpatient Period/Follow-Up
Day
4
6
8
11
15
18 
22
25
29 (EOT/ET)
EOSa
Visit Window
NA
NA
NA
±1
±1
±1
±1
±1
±1
±2
AE Assessment
<----------------------------------------------------X------------------------------------------------>
X
Concomitant Medicationsb
<----------------------------------------------------X------------------------------------------------>
PK Samplingc
X
X
X
X
X
X
X
X
X
Vital Signsd
X
Urine Drug Screene
X
Liver Function Testf
X
Injection Site Evaluation
X
X
X
Psychosocial/Behavioural Counselling
X
X
X
X
X
X
X
X
X
Post-study Treatment Optionsg
X
X
X
AE=adverse event; EOS=end of study; EOT=end of treatment; ET=early termination; PK=pharmacokinetic
a.
Any participant with ongoing AEs at the EOT or ET visit will also be followed up by phone 2 weeks later for the EOS visit to assess any ongoing AEs and 
concomitant medications associated with those ongoing AEs only. 
b.
Includes a review of ongoing medications (including over-the-counter) and herbal supplements.
c.
A 6-mL blood sample will be collected for PK analysis, as close to the time of SUBLOCADE injection performed on Day 1 as possible. 
d.
Vital signs include temperature, systolic and diastolic blood pressure, pulse rate, and respiratory rate after the participant has been in a sitting or supine 
position for ≥3 minutes. 
e.
Qualitative test to be performed including the following: opioids (including fentanyl, oxycodone, opiates/morphine, methadone), cocaine, amphetamines, 
cannabinoids, barbiturates, benzodiazepines, methamphetamine, phencyclidine.
f.
Blood sample to be collected for a subset of serum chemistry including alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, 
bilirubin, albumin, total protein, gamma glutamyl transferase, and lactate dehydrogenase only.
g.
Alternative treatment options should be discussed with the participant for initiation after EOT, including the possibility of joining another Indivior study 
(eg, INDV-6000-406, Long-Term Outcomes). 


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2
INTRODUCTION
SUBLOCADE® (extended-release BUP injection) for SC use (CIII) contains BUP, a partial mu-
opioid receptor agonist, and is indicated for the treatment of moderate to severe OUD. 
2.1
Study Rationale
SUBLOCADE is currently approved for SC administration in 4 different quadrants of the 
abdomen. Injection locations are rotated to minimise irritation. 
Having 1 or more alternate injection sites is desirable in this patient population who may be 
taking SUBLOCADE for extended durations, based upon clinical response. 
Data cited from literature suggests that the proposed alternative injection locations for SC 
administration are viable options for delivering similar PK properties: back of upper arm, 
buttocks, and thigh.
2.2
Background
A detailed description of the chemistry, pharmacology, efficacy, and safety of SUBLOCADE is 
provided in the prescribing information.
The study will be carried out in accordance with the protocol and with local legal and regulatory 
requirements, ICH/GCP, and all applicable participant privacy requirements.
2.3
Benefit/Risk Assessment
BUP is a partial agonist at the mu-opioid receptor. As such, it produces a submaximal 
pharmacological response compared with that of a full agonist at these receptors and provides 
a greater margin of safety with respect to respiratory depression. SUBLOCADE has been shown 
to be an efficacious and safe treatment for moderate to severe OUD. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of SUBLOCADE may be found in the prescribing information.
2.3.1
Risk Assessment
The safety profile of BUP is well established, and the AEs expected with BUP are well 
characterised (see applicable product prescribing information). Commonly reported AEs include 
drug withdrawal syndrome, constipation, headache, nausea, and vomiting. BUP has been 
approved for multiple indications and routes of administration (eg, TM, intramuscular, IV, 
transdermal, rectal, and subdermal) in multiple countries and by various manufacturers. BUP 
has also been approved as a weekly and monthly SC injection for the treatment of OUD. 
The systemic safety profile for SUBLOCADE, given by a health care provider in clinical studies, is 
consistent with the known safety profile of TM BUP with the expected exception of injection 
site reactions. 


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A single injection of SUBLOCADE 300 mg provides BUP Cmax and average plasma concentration  
corresponding to 12 mg/day of TM BUP and BUP plasma concentrations well below those 
measured for SUBLOCADE 300 mg at steady-state in the Phase III programme. 
2.3.2
Benefit Assessment
SUBLOCADE is an approved product for treatment of OUD. Clear efficacy was demonstrated in 
the pivotal and additional supporting studies of the SUBLOCADE clinical development 
programme (detailed information provided in the applicable product prescribing information). 
The results of the primary and key secondary efficacy analyses from the Phase III double-blind 
study are compelling and are supported by results from other secondary endpoints.  
In addition, a sustained-release formulation of BUP using the ATRIGEL Delivery System offers a 
number of potential benefits relative to shorter acting formulations, including improved 
participant compliance and reduced diversion and misuse, as well as a reduced risk of 
accidental exposure to participants, their families, and the community. All participants in this 
study will receive SUBLOCADE (active treatment) and counselling.
In this study, participants will be initiated on TM BUP and will receive a single injection of 
SUBLOCADE 300 mg. Successful treatment outcomes are associated with retention and 
engagement in a treatment programme. It is important for participants to have access to 
continuing care at the conclusion of the study.
2.3.3
Overall Benefit Risk Conclusion
Taking into account the additional monitoring visits and other measures designed to minimise 
risk to participants in this study, the potential risks identified in association with SUBLOCADE 
are justified by the anticipated benefits that may be afforded to participants with OUD.


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3
OBJECTIVES AND ENDPOINTS
Table 4
Objectives and Endpoints
Objective
Corresponding Endpoint
Primary

To assess the relative bioavailability of BUP 
when administered at alternative injection 
locations (test treatments), in comparison 
to the abdomen (reference treatment) 
following a single SC injection of 
SUBLOCADE in participants with OUD 

AUC0-28days and Cmax for BUP 
Secondary

To evaluate the safety and tolerability of 
SUBLOCADE when administered at 
alternative injection locations, in 
comparison to the abdomen 

Proportion of participants with TEAEs 

Proportion of participants with TEAEs 
identified as injection site reactions

Proportion of participants with 
treatment-emergent SAEs

Injection site grading at 10 minutes and 
2 hours post SUBLOCADE dosing

Injection Site Pain VAS at 1, 5, 10, 15, 
and 30 minutes post SUBLOCADE dosing
Exploratory

To assess other BUP PK parameters 

To assess the relative bioavailability of 
norbuprenorphine

To assess other norbuprenorphine PK 
parameters

AUClast, Tmax, and Ctrough for BUP

AUC0-28days, AUClast, and Cmax for 
norbuprenorphine

Tmax and Ctrough for norbuprenorphine
AUC=area under the curve; BUP=buprenorphine; Cmax=maximum plasma concentration; 
Ctrough=trough plasma concentration measured on Day 29; OUD=opioid use disorder; 
SAE=serious adverse event; SC=subcutaneous; TEAE=treatment-emergent adverse event; 
Tmax=time to maximum plasma concentration; VAS=visual analogue scale
The primary clinical question of interest is the following: Is the bioavailability of BUP when 
SUBLOCADE is administered in the back of upper arm, buttocks, and thigh similar to that when 
administered in the currently approved location, the abdomen?


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The estimand for the primary endpoints is described by the following attributes:

Estimand strategy: While on treatment strategy.

Population: PK evaluable population (see Table 6).

Endpoints: AUC0-28 days  and Cmax  of BUP.

Treatment condition: Administration of SUBLOCADE to 1 of the randomised injection 
site locations. 

Remaining intercurrent events: There are no other intercurrent events anticipated at 
this time.

Population-level summary: The ratio of geometric means and corresponding 90% CI for 
each alternative injection site vs the reference site (abdomen).
4
STUDY DESIGN
4.1
Overall Design
This is a multicentre, randomised, open-label, single-dose, parallel-group study in participants 
with moderate or severe OUD (based on criteria from the DSM-5 or documented history of 
moderate to severe OUD and receiving/stabilised on MOUD). 
Participants will provide written informed consent before any protocol-related procedures 
commence within 30 days of the first SUBOXONE dose administered as part of this study (ie, 
after signing the ICF; see Section 10.1 [appendix] for details). The study includes both a 
Residential (Inpatient) Period and a Non-Residential (Outpatient) Period.
Following Screening, all eligible participants must be stabilised on 12 mg SUBOXONE 
(BUP/naloxone) sublingual film QD for a minimum of 7 days before the SUBLOCADE injection. 
Dose induction/stabilisation onto SUBOXONE may be completed as outpatient or inpatient, as 
necessary, according to the prescribing information for a maximum of 14 days before 
SUBLOCADE injection. 
All participants will be admitted to the residential facility by the evening of Day -3. 
The period from the first dose of SUBOXONE administered as part of this study through Day -1 
will be referred to as the Run-in Period. 
Following the Run-in Period, on Day 1, eligible participants will be randomised to a treatment 
arm. 
Each treatment arm will receive a single, SC injection of 300 mg SUBLOCADE at a different 
injection location ie, abdomen (reference) or one of the alternative injection locations (test) ie, 
back of upper arm, buttocks, and thigh. 
Safety measurements and blood samples for PK assessments during the Residential Period will 
be collected at scheduled time points until the participants are discharged from the residential 
facility on Day 3.


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Participants will return to the clinical facility as outpatients for safety and PK assessments to be 
conducted according to the SoE until EOT. Alternative treatment options should be discussed 
with the participant for initiation after EOT, including the possibility of joining another Indivior 
study (eg, INDV-6000-406).
Any participant with ongoing AEs at the EOT or ET visit will also be followed up by phone 
2 weeks later for the EOS visit to assess any ongoing AEs and concomitant medications 
associated with those ongoing AEs only.
It is important that participants do not use any BUP-containing products, either therapeutically 
or illicitly. Such use would compromise the PK assessment of BUP and its metabolite, 
norbuprenorphine.
Approximately 80 participants in the United States will be randomised in total, ideally to 
achieve 15 completed participants per each of the 4 treatment arms (injection locations): 
abdomen (reference), back of upper arm, buttocks, and thigh. The total duration of the study 
for each participant, including Screening (up to 30 days), Run-in (up to 14 days), Treatment 
(28 days), and possible Follow up (2 weeks), will be up to approximately 86 days.
Participants who prematurely discontinue from the study will not be replaced.
4.2
Scientific Rationale for Study Design
While having 1 or more alternate injection location is desirable in this patient population, it 
needs to be demonstrated that there is similar bioavailability of BUP when SUBLOCADE is 
injected in different locations. In addition, it needs to be assessed whether the injections are 
safe and tolerable (eg, with respect to injection site pain) at the different injection locations. 
The primary and secondary objectives and endpoints are aligned with these requirements.
It is anticipated that measuring the PK profile at the times outlined in Section 10.6 (appendix) 
will provide adequate data to compare the bioavailability of BUP after SUBLOCADE injection 
between the alternate injection locations and the abdomen (reference location). Likewise, the 
collection of TEAEs and injection location information (grading and VAS) will provide a safety 
and tolerability profile that can be compared between alternate injection locations vs the 
abdomen.
All of these assessments have been used in previous studies by Indivior, including in those that 
provided adequate and well-controlled data to support the marketing application.
4.3
Justification for Dose
The dose selected for this study reflects the prescribing information for the first SUBLOCADE 
injection and is the highest dose strength approved.
4.4
End of Study Definition
The end of the study is defined as the date on which the last participant completes the last 
assessment to collect final data for the primary outcome measures, secondary outcome 
measures, and adverse events (that is, the last participant’s last visit).


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A participant is considered to have completed the study if the participant has completed the 
last scheduled procedure shown in the SoE (Section 1.3).
4.5
Protocol Deviations
A protocol deviation is any noncompliance with the clinical study protocol or ICH/GCP 
requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study-site staff. It is the responsibility of the investigator and study-site staff 
to use continuous vigilance to identify and report deviations to Indivior or specified designee, 
and to the IRB/IEC per local requirements. 
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1.
Signed the ICF and have the ability to comply with the requirements and restrictions 
listed therein.
2.
Sex: male or female.
3.
Between the ages of 18 and 65 years inclusive, at the time of signing the ICF.
4.
Currently meets DSM-5 criteria for moderate or severe OUD, or documented history of 
moderate to severe OUD and receiving/stabilised on MOUD.
5.
Body mass index: ≥18.0 to ≤33.0 kg/m2.
6.
New to treatment and seeking MOUD, or currently prescribed TM BUP for OUD at the 
dose of 12 mg daily or can dose adjust to 12 mg daily . 
7.
Agree not to take any BUP-containing products, other than those administered for the 
current study, throughout the duration of the study.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1.
Has current diagnosis, other than OUD, requiring chronic opioid treatment.
2.
Has concurrent primary substance use disorder, as defined by DSM-5 criteria, other than 
opioid, tobacco, cannabis, or mild to moderate alcohol use disorders.
3.
Has target areas unsuitable for SC injections or evaluation of injections site (eg, nodules, 
scarring, lesions, excessive pigment) in the areas designated for possible injection in the 
study.
4.
Has had significant traumatic injury or major surgical procedure (as defined by the 
investigator) within 30 days prior to the first dose of SUBLOCADE or still recovering from 
prior such injury or surgery.
5.
Known personal and/or family history of congenital QT prolongation, or taking Class IA 
antiarrhythmic medications (eg, quinidine, procainamide, disopyramide) or Class III 


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antiarrhythmic medications (eg, sotalol, amiodarone) or other mediations that prolong 
the QT interval. Known family history of sudden unexplained death.
6.
Currently taking (within the 30 days prior to signing the ICF) prescription or over-the-
counter medications that are clinically relevant CYP 3A4 or CYP 2C8 inducers or 
inhibitors (eg, rifampin, azole antifungals [eg, ketoconazole], macrolide antibiotics [eg, 
erythromycin]). See Section 10.5 (appendix) for a list containing examples of excluded 
medications.
7.
Has history of suicidal ideation within 30 days prior to informed consent or history of a 
suicide attempt in the 6 months prior to informed consent.
8.
Has any active medical condition, or psychiatric illness, or social/legal situation 
(including court order requiring treatment for OUD), or organ disease, or concurrent 
medication/treatment that may compromise participant safety, interfere with study 
endpoints, or limit compliance with study requirements, or compromise the ability of 
the participant to provide written informed consent. 
9.
Moderate or severe hepatic impairment (Child-Pugh B or C).
10.
Has known allergy or hypersensitivity to BUP or any component of the ATRIGEL Delivery 
System. 
11.
Concurrent or has had prior treatment with any BUP long-acting injectable product (eg, 
SUBLOCADE) in the past 3 years prior to consent; or treatment with depot naltrexone 
within the 3 months prior to consent. 
12.
Treatment with another investigational agent within 30 days prior to Screening or 
enrolment in another clinical study (except for an observational study).
13.
Concurrent treatment with medications contraindicated for use with BUP as per local 
prescribing information.
14.
Is a member of site staff, has a financial interest in Indivior, or is an immediate family 
member of anyone directly involved in the study (ie, site staff or Indivior employee).
5.3
Randomisation Criteria
1. Females of reproductive potential must have a negative urine pregnancy test on Day -3. 
2. Dose-stabilised on 12 mg QD of SUBOXONE sublingual film for a minimum of 7 days (last 
dose on the morning of Day -1).
5.4
Lifestyle Considerations
5.4.1
Concomitant Medications
Eligible participants that are new to treatment with BUP will be advised to abstain from short 
acting opioids (such as morphine sulfate, oxycodone, hydromorphone, oxymorphone, or 
codeine) for at least 6 hours and long -acting opioids (such as methadone or levorphanol) for at 
least 24 hours before SUBOXONE induction. Participants will be informed that under reporting 
their last use of opioids and undergoing induction with remaining exposure to opioids places 
them at high risk for rapid and intense onset of withdrawal symptoms. Risk is increased with 


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high doses of potent opioids, such as fentanyl; an on-site dipstick UDS at Screening to identify 
current opioids of abuse will support this discussion between investigator and trial participant. 
Eligible participants will be advised to abstain from alcohol throughout the study, as central 
nervous system depressants increase the risk of respiratory depression, profound sedation, 
coma, and death in patients taking BUP.
5.4.2
Activity
Participants should avoid strenuous exercise from Day -1 until Day 3 after SUBLOCADE dosing.
5.4.3
Other Restrictions
Participants may be restricted for smoking and use of nicotine-containing products during their 
time in the inpatient research clinic, per local site restrictions.
Participants will be asked to refrain from donating blood for the duration of their study 
participation.
5.5
Screen Failures
See Table 6 for the definition of an enroled participant.
A screen failure occurs when a participant who has consented to participate in the clinical study 
is not subsequently given study drug. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details (eg, 
reason for screen failure, such as not eligible, withdrew consent, AE), eligibility criteria, and any 
SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened with documented approval from the medical monitor. Rescreened participants 
should be assigned a new participant number. 
5.6
Criteria for Temporarily Delaying Administration of Study Intervention
Participants may be administered SUBOXONE as part of this study for more than 14 days before 
the SUBLOCADE injection only with documented approval from the medical monitor.
Delays of enrolment are not permitted, screening assessments must be completed within 
30 days prior to the first dose of study drug. 
5.7
Run-in Failure
A participant will be considered a run-in failure if the participant doses with SUBOXONE as part 
of this study and is not administered with SUBLOCADE. 


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5.8
Early Discontinuation 
A participant will be considered an early discontinuer if the participant received study drug and 
did not complete all visits. Reasons for not completing all visits will be captured in the 
participant source documents and the eCRF. 
The definition of a study completer is provided in Section 4.4. 
6
STUDY DRUG AND CONCOMITANT THERAPY
Study interventions (ie, study drugs and concomitant medications) are all pre-specified, 
investigational and non-investigational medicinal products, medical devices, and other 
interventions (eg, surgical and behavioural) intended to be administered to the study 
participants during the study conduct.
Study drug is a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorisation but used 
or assembled (formulated or packaged) in a way different from the authorised form, or when 
used for an unauthorised indication, or when used to gain further information about the 
authorised form. Medicinal products with a marketing authorisation are study drugs when they 
are to be used as the test substance, reference substance, or comparator in a clinical study, 
provided the requirement(s) in the definition is/are met.
Concomitant medication is a medicinal product that is not classified as study drug, but may be 
taken by participants during the study, eg, concomitant or rescue/escape medication used for 
preventative, diagnostic, or therapeutic reasons or medication given to ensure that adequate 
medical care is provided for the participant during a study.


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6.1
Study Drugs Administered
The following table presents study drugs to be administered in this protocol.
Table 5
Study Drugs Administered – Label
Drug Name
SUBLOCADE® (BUP)
SUBOXONE® (BUP/naloxone) 
Study Drug 
Description
Single SC injection, 300 mg
Sublingual film 12 mg once daily 
for a minimum of 7 days prior to 
SUBLOCADE injection
Type 
Drug 
Drug
Dose Formulation
Extended-release injection
Sublingual film
Unit Dose 
Strengths
300 mg/1.5 mL provided in a 
prefilled syringe
2, 4, and 12 mg
Dosage Levels
300 mg
12 mg once daily for a minimum of 
7 days prior to SUBLOCADE 
injection
Duration of 
Administration
Single dose
Minimum of 7 days prior to 
SUBLOCADE injection
Route of 
Administration
SC injection
Sublingual
Use
Experimental
Experimental
Study Drug and 
Concomitant 
Medication
Study drug
Study drug
Sourcing
Packaging and 
Labelling
BUP=buprenorphine; SC=subcutaneous


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6.2
Preparation, Handling, Storage, and Accountability
6.2.1
Drug Preparation
SUBLOCADE and SUBOXONE will be prepared according to the Instructions for Use in the 
applicable product labelling information. 
6.2.2
Drug Administration
Time of dose for SUBLOCADE is defined as the time the SC injection is complete. The time of 
dose and any dosing observations (eg, partial doses or other issues with the injection) will be 
recorded in the source documentation; in addition, time of dose will be recorded in the eCRF. 
Time of dose for SUBOXONE is defined as the time the TM BUP is placed into the oral cavity. 
Participants should be administered 12 mg SUBOXONE QD at approximately the same time 
each day. 
All unused study drug will either be destroyed by the investigator, as per local SOPs, or returned 
to the clinical study drug distributor, as agreed with the sponsor. The study drug must be 
handled strictly in accordance with the protocol, Pharmacy Manual, Safety Data Sheet, and the 
local prescribing information; it must be stored in a locked, limited access area under 
appropriate environmental conditions. 


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All study drug dispensation will be performed by a pharmacist or designee, checked by a study-
site staff member and documented on a drug dispensation form. Unused study drug must be 
available for verification by the site monitor during on-site monitoring visits.
6.2.3
Reporting Product Complaints
The investigator and study-site staff are responsible for prompt recognition and reporting of 
product quality complaints to Indivior. 
A product complaint is any concern pertaining to the manufacturing or quality control of the 
study drug and includes, but is not limited to, short counts/empty pouches, leaking syringes, 
broken needles, labelling defects, missing inserts, packaging defects, or difficult to open 
packaging, study drug that is thought to be ineffective, or has an appearance, taste, or odour 
that is outside of what is expected. 
See the pharmacy manual for further details. 
6.3
Assignment to Study Intervention
The investigator is responsible for maintaining a master list (ie, a participant identification list) 
of all consented participants and will document all participants that did not meet study 
eligibility criteria (ie, screen failures), including reason(s) for ineligibility (ie, a participant 
screening and enrolment log).
All participants will receive the same study drugs, however, will be centrally assigned to a 
randomised injection location using an IWRS. Before the study is initiated, the directions for the 
IWRS will be provided to each site. 
6.4
Blinding
This is an open-label study; however, the randomisation number will be assigned via the IWRS, 
using central, blocked, stratified randomisation schedules. The randomisation factor will be 
SUBLOCADE injection location. The site will contact the IWRS prior to the start of study drug 
administration for each participant. The site will record the injection location assignment on the 
applicable CRF, if required. 
6.5
Study Drug Compliance
All participants are dosed with SUBLOCADE at the site, so they will receive study drug directly 
from the investigator or designee, under medical supervision. The dose of study drug and study 
participant identification will be confirmed at the time of dosing by a member of the study-site 
staff other than the person administering the study intervention. 
The site personnel administering the dose will examine the injection site at each visit for 
evidence of tampering. 
Any doses of SUBOXONE administered at the site, dispensed to the participant, and taken by 
the participant outside of the clinic should be recorded. For reconciliation and study drug 
compliance, participants will be asked to return any study drug not taken as well as all empty 


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packaging for all study drug taken. The investigator may ask the participant to return for dose 
adjustment as many times as necessary during induction and stabilisation.
6.6
Dose Modification
During the Run-in Period, SUBOXONE doses will be adjusted over time to achieve the target 
12 mg dose once daily. 
Modification of the SUBLOCADE dose is not permitted.
6.6.1
Retreatment Criteria
Not applicable
6.7
Treatment Access to Study Drug After the End of the Study
SUBLOCADE is an approved MOUD. Alternative treatment options should be discussed with the 
participant for initiation after EOT, including the possibility of joining another Indivior study (eg, 
INDV-6000-406, Long-Term Outcomes).
6.8
Treatment of Study Drug Overdose
For this study, any dose of TM BUP greater than 24 mg daily, or more than 1 injection of 
SUBLOCADE during this study will be considered an overdose.
The antidote to study drug is Naloxone and may be used in case of symptomatic overdose with 
respiratory depression.
In the event of a study drug overdose, the investigator/treating physician should do the 
following:
1. Evaluate the participant to determine, in consultation with the medical monitor, if possible, 
whether study drug should be interrupted or the injection depot should be removed.
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities as medically 
appropriate and at least until the next scheduled follow up.
3. Obtain a plasma sample for PK analysis if requested by the medical monitor (requirement 
and time frame from last dose will be determined on a case-by-case basis).
4. Document the quantity of the excess dose as well as the duration of the overdose.
Any instance of study drug overdose must be communicated within 24 hours and fully 
documented (see Section 8.4). Details of any signs or symptoms and their management should 
be recorded, including details of any antidote(s) administered.
6.9
Prior and Concomitant Therapy
Any prior prescription or nonprescription drugs (including vitamins and dietary or herbal 
supplements) taken within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 
half-lives (whichever is longer) before the start of dosing with SUBOXONE for this study should 
be recorded in the source documents and in the eCRF.


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The investigator may prescribe concomitant medications or treatments deemed necessary to 
the participant, with the exception of those medications defined in Section 6.9.1 and 
Section 6.9.2. 
Concomitant medication uses will be collected from Screening through the completion of the 
EOT visit at the time points listed in Section 1.3. Any concomitant medications (including herbal 
preparations) taken during the study will be recorded in the source documents and in the eCRF. 
Any changes in concomitant therapy during the study will be documented, including cessation 
of therapy, initiation of therapy, and dose changes.
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
6.9.1
Prohibited Concomitant Therapies
Participants should be instructed to inform the investigator or site staff of any medications, 
including over-the-counter products taken. 
Participants are not permitted to take any more than 12 mg of SUBOXONE during the 7 days of 
dose stabilisation, nor supplemental TM BUP after the SUBLOCADE injection.
Prescription use of additional BUP (after Day 1), methadone, or naltrexone for OUD is 
prohibited. The use of all prescription opioids should be avoided in this study. In the event that 
a participant is prescribed opioids for any reason, use should be captured as a concomitant 
medication and the investigator should notify and discuss with the medical monitor if the 
participant should remain in the study. 
Other concomitant therapies (inhibitors/inducers of cytochrome P450 3A4 or 2C8) subject to 
the restrictions indicated in Section 10.5 (appendix) may be used only following approval by the 
sponsor unless a medical need necessitates their use.
6.9.2
Restricted Concomitant Therapies
Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other central 
nervous system depressants, including alcohol, increases the risk of respiratory depression, 
profound sedation, coma, and death. However, a 2017 FDA Drug Safety Communication noted 
that although concomitant use of BUP or methadone with benzodiazepines increases the risk of 
an adverse reaction, including overdose death, opioid agonist treatment should not be denied 
to patients solely on the basis of their taking benzodiazepines, because untreated OUD can 
pose a greater risk of morbidity and mortality. The FDA advises that careful medication 
management by health care professionals can reduce risk (see 
https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-
urges-caution-about-withholding-opioid-addiction-medications for more information).
The SUBOXONE and SUBLOCADE prescribing information should be referenced regarding use of 
the below concomitant therapies. 

Benzodiazepines and other central nervous system depressants

Antiretrovirals: non-nucleoside reverse transcriptase inhibitors

Antiretrovirals: protease inhibitors


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
Serotonergic drugs

Monoamine oxidase inhibitors

Muscle relaxants

Diuretics

Anticholinergic drugs
Contact the Indivior medical monitor if you have any questions or concerns if any enroled 
participants initiating chronic treatment with any of these restricted medications.
6.9.3
Permitted Concomitant Therapies and Rescue Medication
The investigator may prescribe concomitant medications or treatments deemed necessary to 
the participant, except those medications defined in Section 6.9.1 and Section 6.9.2 of this 
protocol. 
If the participant experiences withdrawal symptoms at any time, he/she may be treated 
symptomatically. Below are the concomitant therapies listed in SAMHSA TIP 63 2020:

Nausea: ondansetron or metoclopramide

Diarrhoea: loperamide

Anxiety, irritability, sweating: clonidine

Insomnia: diphenhydramine, trazodone

Pain: nonsteroidal anti-inflammatory drugs
Investigators will be asked to identify concomitant medications administered to alleviate 
withdrawal symptoms. 
7
DISCONTINUATION OF STUDY DRUG, PARTICIPANT 
DISCONTINUATION/WITHDRAWAL AND STOPPING CRITERIA
7.1
Discontinuation of Study Drug and Study Stopping Criteria
Not applicable for this single-dose study.
7.2
Participant Discontinuation/Withdrawal From the Study

A participant may withdraw from the study at any time at the participant’s own request for 
any reason (with or without providing any reason).

A participant may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, or compliance reasons. 

At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted, as shown in the SoE (Section 1.3). See SoE for data to be collected at the time 
of study discontinuation and follow-up and for any further evaluations that need to be 
completed.

The participant will be permanently discontinued both from the study drug and from the 
study at that time.


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
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

If a participant withdraws from the study, the participant may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
records.
7.3
Lost to Follow Up
In cases of a missed visit, the investigator or designee must attempt to contact the participant 
and reschedule as soon as possible. The investigator or designee must counsel the participant 
on the importance of maintaining the assigned visit schedule and ascertain whether or not the 
participant wishes to and/or should continue in the study.
An enroled participant who has received study drug will be considered lost to follow-up if he or 
she repeatedly fails to return for scheduled visits and is unable to be contacted by the study 
site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.

Before a participant is deemed lost to follow up, the investigator or designee should make 
every effort to regain contact with the participant (where possible, 2 contact attempts (eg, 
telephone calls and/or emails). A certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record. 

Should the participant continue to be unreachable, the participant will be considered to 
have withdrawn from the study. 

For the purpose of documenting date of discontinuation for a participant confirmed to be 
lost to follow-up, the date of discontinuation should be the date of last contact with the 
participant. 

In the case where a certified letter is sent but not confirmed as received by the participant, 
the date of discontinuation is the date the certified letter was sent.

In the case where a certified letter is sent and has been confirmed as received by the 
participant, the date of discontinuation is the date of the confirmed participant receipt.

In the event that neither of these above cases applies (which should be explained in the 
source documents), the date of discontinuation is the date of the participant's last study 
visit.


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8
STUDY ASSESSMENTS AND PROCEDURES
8.1
Administrative and General Procedures
A signed written ICF must be obtained from the participant before any study assessments or 
procedures may be performed. At Screening, if an assessment or procedure has already been 
performed as part of routine standard of care and was completed within the protocol-specified 
screening window, the assessment or procedure does not need to be repeated, unless clinically 
indicated and must be clearly documented in the source that the assessment or procedure was 
performed as part of standard of care. All assessments and procedures may be performed more 
frequently, if clinically indicated.
Any relevant medical and psychiatric history will be obtained during the Screening Period. This 
will include information regarding the participant’s history of medical and psychiatric 
conditions, diagnoses, procedures, treatments, medications, demographics (including sex, race, 
age, and ethnicity).
A detailed history of drug use and drugs of abuse (illicit and prescribed) will capture the drug 
class, compounds, routes, dose, and frequency of use for lifetime and for the past 30 days. 
Eligible participants must have documented history of moderate or severe OUD as defined by 
DSM-5 criteria and must be seeking medication for treatment of OUD. Any updates to medical 
or psychiatric history information made available during the study will be captured.
8.2
Efficacy Assessments
Efficacy is not evaluated in this study.
8.3
Safety Assessments
Safety will be measured using the following assessments:

TEAEs including the following: 
o
TEAEs identified as injection site reactions
o
SAEs
o
TEAEs leading to treatment discontinuation

Injection site grading 

Injection Site Pain VAS
Planned time points for all safety assessments are provided in the SoE.
8.3.1
Physical Examinations
A complete physical examination will be conducted by the investigator or a medically qualified 
sub-investigator according to the SoE (Section 1.3). This examination will include an assessment 
of general appearance, skin and extremities, head and neck, lymph nodes, eyes, ears, nose, 
throat, thyroid, neurological system, lungs, cardiovascular system, and abdomen (liver and 
spleen). 
If any clinically significant change from Screening is noted, it will be reported as an AE and 
followed up to resolution or until reaching a stable end point.


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Investigators should pay special attention to clinical signs related to previous serious illnesses.
8.3.2
Local Injection Site Tolerability
8.3.2.1 Injection Site Grading
Local injection site grading will be performed by the investigator or a trained and certified 
health care professional, according to the SoE in Section 1.3 and Section 10.6 (appendix). 
Injection sites will be assessed for pain, tenderness, erythema/redness, induration, or swelling. 
Local injection site tolerability will be assigned a severity grade, including none (grade 0), mild 
(grade 1), moderate (grade 2), severe (grade 3), or potentially life-threatening (grade 4) utilising 
the Injection Site Grading Scale.  
8.3.2.2 Injection Site Evaluation
The SUBLOCADE injection site will be evaluated according to the SoE in Section 1.31.3 and 
Section 10.6 (appendix). Any signs of attempted depot removal must be discussed with the 
medical monitor to determine if the participant should remain in the study. Any injection site 
reactions or infections will be recorded as AEs.
8.3.2.3 Injection Site Pain VAS 
Injection site pain will be assessed by the participant at each injection visit on paper with a 
100 mm VAS scale, where 0 represents no pain and 10 represents maximum pain according to 
the SoE in Section 1.3 and Section 10.6 (appendix). The timing of the Injection Site Pain VAS 
should be measured from the end of the injection. In addition to rating pain levels by marking 
on the line the point they feel best represents their perception of their current state, the 
participant will also answer the following question with either a Yes or No: Are you currently 
experiencing any burning or stinging at the injection site?
8.3.3
Vital Signs
Vital signs will be measured in a sitting or supine position after 3 minutes rest according to the 
SoE in Section 1.3 and Section 10.6 (appendix). These assessments will include temperature, 
systolic, and diastolic blood pressure, and pulse and respiratory rate. 
8.3.4
Clinical Safety Laboratory Tests
See Section 10.2 (appendix) for the list of clinical laboratory tests to be performed and to the 
SoE (Section 1.3) for the timing and frequency.
The investigator must review the laboratory results, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory results must be 
retained with the source documents. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor.


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If clinically significant values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the aetiology should be identified and the sponsor notified.
All protocol-required laboratory tests, as defined in Section 10.2 (appendix), must be conducted 
in accordance with the laboratory manual and the SoE.
If laboratory values from non–protocol-specified laboratory tests performed at the institution’s 
local laboratory require a change in participant management or are considered clinically 
significant by the investigator (eg, SAE or AE or dose modification), then the results must be 
recorded.
8.3.5
Electrocardiograms
12-Lead ECGs will be performed as indicated in the SoE, Section 1.3. All ECGs will be performed 
after the participant has been in the supine position for a minimum of 5 minutes. Recordings 
will be taken using an ECG machine that automatically calculates the heart rate as well as 
measures PR, QRS, QT, and QTcF intervals.
Additional 12-lead ECGs may be performed at the discretion of the investigator or medically 
qualified sub-investigator. The findings of the ECGs will be marked by the investigator (or 
designee physician) as normal, abnormal - not clinically significant or abnormal - clinically 
significant. All ECGs that are considered abnormal and clinically significant should be evaluated 
for a change from baseline that must be captured as an AE.
8.3.6
Pregnancy Testing
During the study, pregnancy urine testing will be performed per the SoE, Section 1.3 to confirm 
that the participant is not pregnant before dosing. For further details regarding pregnancy 
reporting, refer to Section 8.4.5.
8.4
Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of AEs and SAEs are provided below, as are criteria for assessment of AE/SAE 
intensity and causality. 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE. Any clinically significant symptoms 
will be reported as AEs. All AEs and corresponding treatment will be recorded in the eCRFs and 
a summary of all safety data will be presented in the final CSR. Any ongoing AEs will be 
appropriately followed up until resolution or 14 days after EOT/ET (defined as the EOS visit). 
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study drug, whether or not considered related to the 
study drug.

NOTE: An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study drug.


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Events Meeting the AE Definition

Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline (signing of the ICF), considered clinically significant in the medical 
and scientific judgement of the investigator (ie, not related to progression of underlying 
disease, or more severe than expected for the participant’s condition).

Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study drug administration even though it may 
have been present before signing the ICF.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction or that 
resulted in additional intervention (eg, concomitant medication, surgery).

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or a 
concomitant medication. Overdose should be reported as an AE unless serious criteria are 
met, including an intentional overdose taken with possible suicidal/self-harming intent. 
Such overdoses should be reported in 24 hours regardless of sequelae.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported 
as AE or SAE if they fulfil the definition of an AE or SAE. 
Events Not Meeting the AE Definition

Any abnormal laboratory findings or other abnormal safety assessments that are associated 
with the underlying disease, unless judged by the investigator to be more severe than 
expected for the participant’s condition.

Any abnormal laboratory findings or other abnormal safety findings that are not considered 
to be clinically significant by the investigator.

The disease/disorder being studied or expected progression, signs or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital, hospitalisation for elective surgery, hospitalisation for 
observation in the absence of an AE).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present at or 
detected after signing the ICF that do not worsen.
Definition of SAE
An SAE is defined as any untoward medical occurrence that:
a. Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.


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c.
Requires inpatient hospitalisation or prolongation of existing hospitalisation

In general, hospitalisation signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalisation are AEs. If a 
complication prolongs hospitalisation or fulfils any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalisation” occurred or was necessary, the 
AE should be considered serious.

Hospitalisation for elective treatment of a pre-existing condition that did not worsen 
from baseline (signing of the ICF) is not considered an AE.
d. Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e. Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgement should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.
o
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation, or development of study drug 
dependency or study drug abuse.
Any instance of overdose (whether or not it involved study drug) must be communicated within 
24 hours and fully documented. Details of any signs or symptoms and their management should 
be recorded, including details of any antidote(s) administered.
An SAE must be reported for participants with ALT or AST ≥3 × ULN and bilirubin ≥2 × ULN 
(>35% direct).
Definition of SUSAR
A SUSAR is an SAE related to the study drug administered in any dose and that, in its nature or 
severity, is inconsistent with the applicable product labelling information. Indivior Global Safety 
(or designated representative) will determine if an SAE meets the definition of a SUSAR and 
distribute SUSAR reports according to country-specific regulatory requirements and Indivior 
policy. An investigator who receives a safety report describing an SAE or other specific safety 
information (eg, summary or line listing of SAEs, Dear Investigator Letter) will file it with the 


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applicable product labelling information and will notify the IRB/EC, if required according to local 
requirements.  
Assessment of Intensity
The investigator will assess intensity for each AE and SAE reported during the study and assign 
it to 1 of the following categories: 

Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily 
living.

Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention.  The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the research participant.

Severe: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
Assessment of Causality

The investigator is obligated to assess the relationship between study drug and each 
occurrence of each AE/SAE. The investigator will use clinical judgement to determine the 
relationship.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study drug administration will 
be considered and investigated.

For causality assessment, the investigator will also consult the IB and/or product 
information, for marketed products.

The investigator must review and provide an assessment of causality for each AE/SAE and 
document this in the medical notes. There may be situations in which an SAE has occurred 
and the investigator has minimal information to include in the initial report to Indivior 
Pharmacovigilance. However, it is very important that the investigator always make an 
assessment of causality for every event before the initial transmission of the SAE data to 
Indivior Pharmacovigilance.

The investigator may change opinion of causality in light of follow-up information and send 
an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Clinical Laboratory Changes
Changes in laboratory values, vital signs, or other safety parameters (eg, neurological and 
clinical symptom assessments) as noted in the protocol are a subset of AEs and are reportable 
only if the laboratory test result is considered to be clinically significant by the investigator or 
medically qualified designee. Generally, these findings would be associated with accompanying 
symptoms, and/or require additional diagnostic testing or intervention (medical, surgical), 


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and/or require additional significant treatment, and/or require temporal or permanent 
discontinuation of study drug.. 
Screening laboratory assessments, even if determined to be clinically significant by the 
investigator, are not AEs.
8.4.1
Time Period and Frequency for Collecting AE and SAE Information
All AEs and SAEs will be collected from the signing of the ICF until the follow-up visit at the time 
points specified in the SoE (Section 1.3).
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours from first becoming aware of the event, as indicated 
in Section 8.4.3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and the investigator considers the event to 
be reasonably related to the study drug or study participation, the investigator must promptly 
notify the sponsor.
Additional PK samples may be collected for participants who experience an SAE. Samples 
should be collected as soon as the investigator is made aware of the SAE and additional blood 
samples may be collected, after a period of time, to confirm resolution of the SAE.
8.4.2
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences.
8.4.3
Reporting and Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilisation, the event 
is otherwise explained or the participant is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is provided in Section 8.4.3.2.
Once the investigator determines that an event meets the protocol definition of an SAE, the 
SAE will be reported to Indivior (or designated representative) by the investigator (or designee) 
within 24 hours from first being aware of the event using the form provided by Indivior or 
designated representative. Any follow-up information on a previously reported SAE will also be 
reported to Indivior within 24 hours.
Where additional information is needed or expected, the investigator will not wait to receive all 
information before reporting the event to Indivior. The investigator must provide an 
assessment of causality at the time of the initial report as described in Section 8.4. 


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8.4.3.1 Reporting of SAEs
SAE Reporting to Indivior 

The primary mechanism for reporting an SAE, or an update to an existing SAE, to Indivior 
Pharmacovigilance will be by completing a paper SAE Reporting Form and submitting via 
email or Facsimile transmission:
Indivior
10710 Midlothian Turnpike, Suite 125
North Chesterfield, VA 23235

In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE Reporting Form sent by overnight mail or courier 
service.

Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE data collection tool within the designated reporting time frames.
8.4.3.2 Recording and Follow-up of AE and/or SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Indivior in lieu of completion of the SAE Reporting Form.

There may be instances when copies of medical records for certain cases are requested by 
Indivior Pharmacovigilance. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to Indivior Pharmacovigilance.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Indivior 
Pharmacovigilance to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognised follow-up 
period, the investigator will provide Indivior Pharmacovigilance with a copy of any 
postmortem findings including histopathology. 


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
New or updated information will be recorded in the originally submitted documents.

The investigator will submit any updated SAE data to the sponsor within 24 hours of receipt 
of the information.
8.4.4
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study drug under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study drug under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/IEC, and investigators.

Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
8.4.5
Pregnancy
Female participants who become pregnant

If a female participant suspects that she is pregnant (eg, missed period, self-administered 
pregnancy test) during treatment or within 3 months of the last dose of SUBOXONE (for 
participants who receive only SUBOXONE) and until 12 months following the dose of 
SUBLOCADE (approximately 6 to 8 terminal half-lives) after the discontinuation of study 
drug, treatment will be stopped immediately, where applicable. The participant will be 
instructed to return to the clinical unit as soon as possible (preferably within 48 hours) or at 
the next visit to undergo a serum pregnancy test. 

In the case where a participant’s routine pregnancy test as required per protocol is positive 
for pregnancy, treatment will be stopped immediately. If the participant has a positive urine 
pregnancy test, a confirmatory serum pregnancy test should be performed. The investigator 
should fully inform the female participant of the serious risk to the fetus as well as discuss 
the desirability of continuing the pregnancy.

Pregnancy of a study participant without associated unexpected or adverse sequelae is not 
a reportable AE but must be reported to Indivior Global Safety (or designated 
representative) using the Safety Information Collection Form within 24 hours of the 
Investigator or designee first being aware of the pregnancy (contact details for reporting via 
email or fax are the same as for SAEs).

Abnormal pregnancy outcomes (eg, fetal death, stillbirth, congenital anomalies, ectopic 
pregnancy, abortion [except pregnancy in habitual aborter, prophylaxis of abortion], pre-
eclampsia, eclampsia) are considered SAEs and will be reported as such.


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
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the sponsor. Generally, follow up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of pregnancy 
will be reported, regardless of fetal status (presence or absence of anomalies) or indication 
for procedure.

Any poststudy pregnancy-related SAE considered reasonably related to the study drug by 
the investigator will be reported to the sponsor as described in Section 8.4.4. While the 
investigator is not obligated to actively seek this information in former participant, he or 
she may learn of an SAE through spontaneous reporting.
8.5
Pharmacokinetics

Blood samples of approximately 6 mL will be collected for measurement of plasma 
concentrations of BUP and norbuprenorphine at times points specified in the SoE. 

Additional samples may be collected for participants who experience an SAE. Samples 
should be collected as soon as the investigator is made aware of the SAE and additional 
blood samples may be collected, after a period of time, to confirm resolution of the SAE. 

Instructions for the collection and handling of samples will be provided by the sponsor. The 
actual date and time (24-hour clock time) of each sample will be recorded. Briefly, blood 
will be collected in a pre-labelled 6-mL K2EDTA vacutainer tube by individual venipuncture. 
Blood samples will be centrifuged and the plasma will be transferred into 2 aliquots of 
approximately 1.5 mL each in pre-labelled polypropylene tubes. Plasma samples will be 
stored at -20°C until analysis. 

The plasma concentration of BUP and norbuprenorphine will be quantified using a 
previously validated liquid chromatography tandem mass spectroscopy method.
8.6
Pharmacodynamics
Not applicable
8.7
Genetics
Genetics are not evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.9
Health Economics
Health economics parameters are not evaluated in this study.


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9
STATISTICAL CONSIDERATIONS
The statistical analysis plan will be finalised prior to database lock and it will include a more 
technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints.
9.1
Statistical Hypotheses
No formal statistical hypotheses will be tested in this study. Relative bioavailability of BUP when 
administered to alternative injection sites (back of upper arm, buttocks, and thigh) compared to 
that when administered to the abdomen will be informally evaluated.
9.1.1
Multiplicity Adjustment
Not applicable for this study.
9.2
Analyses Sets
For purposes of analysis, the following populations are defined:
Table 6
Populations for Analysis
Population
Description
Screened
All participants who sign the ICF.
Enroled
All screened participants who received the first dose of SUBOXONE 
film during run-in.
Randomised
All enroled participants who are randomised to one of the 4 treatment 
arms (injection locations). 
PK Analysis Set
All randomised participants who receive SUBLOCADE injection and 
provide at least 1 PK sample post randomisation. The participants 
will be analysed corresponding to the injection location used.
PK Evaluable 
Analysis Set
All randomised participants who receive SUBLOCADE injection and 
provide an adequate number of post randomisation PK samples to 
derive key PK parameters for SUBLOCADE (ie, Cmax, and AUC0-
28days). The participants will be analysed corresponding to the 
injection location used.
Safety Analysis Set
All enroled participants who received SUBLOCADE injection. The 
participants will be analysed corresponding to the injection 
location used.  
Run-In Safety 
Analysis Set
All enroled participants who receive at least 1 dose of SUBOXONE film 
during run-in. 


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9.3
Statistical Analyses
9.3.1
General Considerations
Continuous variables will be summarised using descriptive statistics such as mean, SD, median, 
interquartile range, minimum, and maximum. Categorical variables will be reported as 
frequency counts (including number missing) and the percentage of participants in 
corresponding categories. 
BUP and norbuprenorphine plasma concentrations following SUBLOCADE injection will be 
summarised at each scheduled time point by injection location using the PK Analysis set. BUP 
and norbuprenorphine plasma concentrations during run-in with SUBOXONE film will also be 
summarised at each scheduled time point using the Enroled participant set for participants who 
have at least 1 PK sample post SUBOXONE dose. Concentrations that are below the lower limit 
of quantification (BLQ) will be treated as zero for the summary statistics. Mean BUP and 
norbuprenorphine plasma concentration-time curves will be presented for the Run-in Period 
with SUBOXONE film for overall and for SUBLOCADE phase stratified by injection locations. 
Details for handling missing and aberrant plasma concentrations for deriving BUP and 
norbuprenorphine PK parameters will be detailed in the SAP.
9.3.2
Primary Analysis
9.3.2.1 Definition of Endpoints
The primary PK parameters of BUP following SUBLOCADE injection will be derived as shown in 
Table 7 using the PK evaluable set. Calculations will be done by noncompartmental analysis 
using WinNonlin Phoenix version 6.3 or higher.
Table 7
Primary PK Parameters of BUP following SUBLOCADE injection
AUC0-28days
Area under the concentration-time curve from study Day 1 to Day 29 
of BUP, calculated by the linear trapezoidal method
Cmax
Maximum observed plasma concentration of BUP
9.3.2.2 Main Analytical Approach
Natural log-transformed AUC0-28days and Cmax from SUBLOCADE Phase for BUP will be analysed 
using an ANOVA model with injection site location as the independent variable. The 90% CI will 
be estimated for the ratio of population geometric means (test/reference) corresponding to 
exponentiated differences in least square means. 
The comparisons of interest are the 3 alternative injection sites (test) versus abdomen 
(reference, namely:  back of upper arm vs abdomen, buttocks vs abdomen, and thigh vs 
abdomen.)


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9.3.3
Secondary Endpoint Analysis
All secondary endpoints summaries will be based on the Safety Population.
The following secondary endpoints will be derived as the proportion of participants reporting at 
least one of the specified events, and summarised using frequency counts and percentages:

Proportion of participants with TEAEs 

Proportion of participants with TEAEs identified as injection site reactions

Proportion of participants with treatment-emergent SAEs
TEAEs identified as injection site reactions will be summarised using customised MedDRA 
queries. Details of the customised MedDRA queries will be provided in the SAP.
Each component of the Injection site grading (induration, swelling, pain, tenderness and 
erythema) at 10 minutes and 2 hours post SUBLOCADE dosing will be summarised using 
frequency counts and percentages of participants reporting the specific level of severity.
Injection Site Pain VAS at 1, 5, 10, 15, and 30 minutes post SUBLOCADE dosing will be 
summarised using descriptive statistics. 
All summaries will be by the injection site anatomical location and overall.  No hypotheses 
testing will be performed to compare the injection site locations.
9.3.4
Exploratory Endpoint Analyses
The following PK parameters for SUBLOCADE will be derived as shown in Table 8 for BUP and 
Table 9 for norbuprenorphine using the PK Evaluable Analysis Set. Calculations will be done by 
noncompartmental analysis using WinNonlin Phoenix. The plasma terminal half-life and AUC 
extrapolated to infinity (AUC0-inf) are not calculated as the duration of the PK evaluation is 
shorter than the half-life reported for SUBLOCADE (43-60 days).
Table 8
Additional PK Parameters of BUP Following SUBLOCADE Injection
AUClast
Area under the concentration-time curve from time 0 to the last 
quantifiable BUP concentration, calculated by the linear trapezoidal 
method 
Tmax
Time to attain the maximum observed BUP plasma concentration 
Ctrough
Trough BUP plasma concentration measured on Day 29


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Table 9
PK Parameters of Norbuprenorphine Following SUBLOCADE Injection
AUC0-28days
Area under the concentration-time curve from Study Day 1 to Day 29 
of norbuprenorphine, calculated by the linear trapezoidal method 
AUClast
Area under the concentration-time curve from time 0 to the last 
quantifiable concentration of norbuprenorphine, calculated by the 
linear trapezoidal method 
Cmax
Maximum observed norbuprenorphine plasma concentration 
Tmax
Time to attain the maximum observed norbuprenorphine plasma 
concentration 
Ctrough
Trough norbuprenorphine plasma concentration measured on 
Day 29
AUClast for both analytes, and AUC0-28days and Cmax for norbuprenorphine will be analysed using 
the same statistical ANOVA model as described in Section 9.3.2.
9.3.5
Other Safety Analyses
TEAEs are defined as AEs with a start time that is equal to or later than the initiation of the drug 
treatment or any AE already present that worsens in either severity or frequency following drug 
exposure. Specifically, TEAEs following exposure to SUBOXONE treatment will be associated 
with the Run-in Period and those following SUBLOCADE treatment will be associated with the 
Post-randomisation Period.
TEAEs will be summarised separately for the Post-randomisation Period and the Run-in Period 
using safety analysis set and run-in safety analysis set, respectively. The summaries will be by 
injection site and overall for the Post-randomisation Period, and overall only for the Run-in 
Period. Complete details of the safety analyses will be provided in the SAP.
Adverse events will be coded using MedDRA and grouped by system organ class. Incidence and 
incidence proportion of TEAE (number and percentage of participants reporting the TEAE at 
least once during the Post-randomisation Period and the Run-in Period, as applicable) will be 
summarised by system organ class and preferred term. Separate summaries will be provided 
for all TEAEs, TEAEs identified as injection site reactions, serious TEAEs, drug related TEAEs, and 
TEAEs leading to discontinuation of study treatment. 
9.4
Interim Analysis 
No interim analysis is planned.
9.5
Sample Size Determination
No formal statistical power analysis was performed to determine the sample size of this study. 
Based on historical experience from previous similar clinical trials, approximately 
80 randomised participants was considered adequate to achieve at least 15 PK evaluable 


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participants per injection site location to assess the relative bioavailability of SUBLOCADE 
300 mg at each of the alternate injection site locations compared to the abdomen (the 
reference injection location).


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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1 Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) international ethical guidelines
o
Applicable ICH GCP guidelines
o
Applicable laws and regulations

The protocol, protocol amendments, ICF, investigator’s brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before use in the study. If required by local 
regulations, the protocol should be re-approved by the IRB/IEC annually. The IRB/IEC must 
be constituted and operate in accordance with the principles and requirements of ICH/GCP. 

Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.

Protocols and any substantial amendments to the protocol may require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard 
to study participants.

The investigator will be responsible for the following, as applicable:
o
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
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures
o
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for 
clinical studies, European Medical Device Regulation 2017/745 for clinical device 
research, and all other applicable local regulations
10.1.2 Financial Disclosure
Investigators and sub-investigators 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.


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10.1.3 Informed Consent Process

The investigator or the investigator’s representative will explain the nature of the study to 
the participant and answer all questions regarding the study. Potential participants must be 
informed that their participation is voluntary. They will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, and privacy and data protection requirements, where applicable, and the 
IRB/IEC or study centre.

Written informed consent must be obtained prior to any study-related procedures. 

The authorised person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study, if required by the IRB/IEC.

A copy of the ICF(s) must be provided to the participant.

Any changes to the ICF must be reviewed and approved by Indivior before submission to the 
IRB/IEC.

In the event that new safety information emerges that represents a significant change in 
the risk/benefit assessment, the ICF will be updated accordingly and submitted to the 
IRB/IEC for approval. 
Participants who are rescreened are required to sign a new ICF.
10.1.4 Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.

Participants must be informed that their personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent. 

Participants must be informed that their study records may be examined by Clinical Quality 
Assurance auditors or other authorised personnel appointed by the sponsor, by the IRB/IEC, 
and by inspectors from regulatory authorities.

All participant bodily fluids and/or other materials collected shall be used solely in 
accordance with the study protocol and the ICF signed by the participant, unless the 
participant agrees to additional procedures in writing with the sponsor.

The investigator must maintain all study-related records (except for those required by local 
regulation to be maintained elsewhere) in a safe and secure location throughout the 
conduct and following the closure of the study. The records must be accessible upon 
request (eg, for an IRB/IEC, Indivior, or regulatory inspection) along with the facility, study 
personnel, and supporting systems/hardware. All documents pertaining to the study, 
including all versions of the approved study protocol, copy of the ICF and other documents 
as required per local laws and regulations (eg, Health Insurance Portability and 
Accountability Act documents), completed CRFs, source records (participant records, 


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participant diaries, hospital records, laboratory records, drug accountability records, etc), 
and other study-related materials will be retained in the permanent archives of the study 
site.
Where permitted by local laws and regulations, records may be maintained in a format 
other than hard copy (eg, electronically in an electronic medical records system). The 
investigator must ensure that all reproductions are an accurate legible copy of the original 
and that they meet necessary accessibility and retrieval standards. The investigator must 
also ensure that a quality control process is in place for making reproductions and that the 
process has an acceptable backup of any reproductions.
The minimum retention time for retaining study records will be in accordance with the 
strictest standard applicable for the study site as determined by local laws, regulations, or 
institutional requirements. At a minimum, records will be maintained as dictated by 
ICH/GCP guidelines, as well as in accordance with the site’s SOP requirements. If the 
investigator withdraws from the study (eg, relocation, retirement) all study-related records 
should be transferred, in a written agreement with Indivior, to a mutually agreed upon 
designee within Indivior-specified time frame.

The contract between sponsor and study sites specifies responsibilities of the parties 
related data protection, including handling of data security breaches and respective 
communication and cooperation of the parties.

Information technology systems used to collect, process, and store study-related data are 
secured by technical and organisational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorised disclosure or access.
10.1.5 Committees Structure
Not applicable
10.1.5.1  Dissemination of Clinical Study Data
This study will be registered on ClinicalTrials.gov. Release of applicable clinical study results will 
proceed in compliance with local regulations in accordance with the principles of Good 
Publication Practice.
A CSR will be prepared following completion of the study. An investigator signatory may be 
identified for the approval of the report if required by applicable regulatory requirements.
10.1.6 Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRFs 
unless transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.

Guidance on completion of CRFs will be provided in the data entry guidelines.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.


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
Investigator Site Audits include, but are not limited to, review of drug supply, presence of 
required documents, the informed consent process, comparison of CRFs with source 
documents, and any other study-specific information/documentation that the auditor 
deems appropriate for review during the audit. The investigator agrees to participate with 
audits conducted at a reasonable time in a reasonable manner. Full consultation with the 
investigator will be made prior to and during such an audit, which will be conducted 
according to Indivior’s or a CRO’s Quality Assurance SOPs. 

In addition, this study is subject to inspections by regulatory authorities. If such a regulatory 
inspection occurs, the investigator agrees to allow the regulatory inspector direct access to 
all relevant study documents. The investigator must contact Indivior immediately if this 
occurs and must fully cooperate with the inspection conducted at a reasonable time in a 
reasonable manner.

Monitoring details describing strategy including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, remote, or on-site monitoring) are provided in the monitoring plan.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (eg, contract 
research organisations).

Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator as dictated by ICH/GCP guidelines, as well as in accordance 
with the site’s SOP requirements and local regulations or institutional policies. No records 
may be destroyed without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor.
10.1.7 Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.

The investigator is responsible for the quality of the data recorded in the CRFs. The data 
recorded should be a complete and accurate account of the participant’s record collected 
during the study.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 

Source documents may be electronic, hard copy, or a combination of both and are defined 
as the results of original observations and activities of a clinical investigation. Source 
documents will include, but are not limited to, progress notes, electronic data, screening 
logs, and recorded data from automated instruments. All source documents pertaining to 


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this study will be maintained by the investigator and made available for direct inspection by 
the authorised study personnel outlined in the ICF. 

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.

The sponsor or designee will perform monitoring to confirm that data entered into the CRF 
by authorised site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
10.1.8 Study and Site Start and Closure
Study/Site Termination
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to the following:
For study termination:

Discontinuation of further study drug development
For site termination:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor’s procedures, or GCP guidelines

Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants 
by the investigator

Total number of participants included earlier than expected
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organisation(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.
Should this be necessary, Indivior, or a specified designee will inform the appropriate regulatory 
authorities of the termination of the study and the reasons for its termination, and the 
investigator will inform the IRB/IEC of the same. In terminating the study, Indivior and the 
investigator will assure that adequate consideration is given to the protection of the 
participants’ interests.


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10.1.9 Publication Policy
The study data will be owned by Indivior. Publication of any and all data will be at the discretion 
of Indivior. The investigator will not disseminate, present, or publish any of the study data 
without the prior written approval from Indivior to do so.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.


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10.2 Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 10 will be performed by the central laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations.
Table 10
Protocol-required Safety Laboratory Tests
Laboratory 
Assessments
Parameters
Haematology
Platelet count 
Red blood cell (RBC) count
RBC indices:
•
Mean corpuscular volume (MCV)
•
Mean corpuscular haemoglobin (MCH)
White blood cell (WBC) count with 
differential:
•
Neutrophils
•
Lymphocytes
•
Monocytes
•
Eosinophils
•
Basophils
Haemoglobin
Haematocrit
Clinical Chemistrya
Blood urea nitrogen (BUN) 
Albumin
Potassium
Creatinine 
Sodium
Calcium
Bicarbonate
Chloride
Glucose (fasting or nonfasting)
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline phosphataseb (ALP)
Creatine phosphokinase (CPK)
Gamma glutamyl transferase 
(GGT)
Lactate dehydrogenase (LDH)
Total and direct bilirubin
Total protein
Routine Urinalysisc
Specific gravity
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick
Microscopic examination (if blood or protein is abnormal)d
Appearance
Colour
Pregnancy Testing
Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential)c


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Urine Drug Screenc
Opioids
Cocaine
Fentanyle
Oxycodone
Opiates/Morphine
Amphetamines
Methadone
Cannabinoids
Barbiturates
Benzodiazepines
Methamphetamine
Phencyclidine
Other Laboratory 
Tests
Serology (HIV-1 and -2 antibodies, hepatitis B surface antigen [HbsAg], 
and hepatitis C virus antibody, PTT, and PT with INR)f
 
NOTES: 
a  All events of ALT ≥3× (ULN) and bilirubin ≥2×ULN (>35% direct bilirubin) must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).
b  If alkaline phosphatase is elevated, consider fractionating.
c  On-site urine testing will be used for this protocol.
d  Microscopic examination of sediment will be performed only if the results of the urinalysis evaluation are 
positive (microscopic examination may include but is not limited to WBC count, RBC count, casts, and 
crystals).
e  Fentanyl may not show up in all opiate assays and should be assessed separately.
f  HIV-1/HIV-2, Hepatitis B and Hepatitis C antibody testing to be performed only in the absence of a positive 
(documented) medical history for these conditions. If there is a positive result for HIV-2/HIV-2 or Hepatitis C, an 
additional blood draw will be collected at the following site visit for confirmatory testing. 
Investigators must document their review of each laboratory safety report.


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10.3 Appendix 3: Guidance on Highly Effective Contraception
Not applicable


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10.4 Appendix 4: Country-specific Requirements
Not applicable


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10.5 Appendix 5: Prohibited Concomitant Therapies
Medications prohibited during the study include, but are not limited to, the following: 
 
Cytochrome 
P450 3A4 
Inhibitors 
Cytochrome 
P450 3A4 
Inducers 
Cytochrome 
P450 2C8 
Inhibitors 
Cytochrome 
P450 2C8 
Inducers 
Amiodarone 
Ketoconazole 
Barbiturates 
Gemfibrozil 
Rifampicin 
Amprenavir 
Metronidazole 
Carbamazepine 
Trimethoprim 
 
Aprepitant 
Mibefradil 
Dexamethasone 
Glitazones 
 
Chloramphenicol Miconazole 
Efavirenz 
Montelukast 
 
Cimetidine 
Mifepristone 
Ethosuximide 
Quercetin 
 
Ciprofloxacin 
Nefazodone 
Glucocorticoids 
 
 
Clarithromycin 
Nelfinavir 
Glutethimide 
 
 
Clotrimazole 
Nicardipine 
Modafinil 
 
 
Cyclosporine 
Norfloxacin 
Nevirapine 
 
 
Delavirdine 
Norfluoxetine 
Oxcarbazepine 
 
 
Diethyl-
dithiocarbamate 
Propofol 
Phenobarbital 
 
 
Diltiazem 
Quinine 
Phenytoin 
 
 
Ethinyl estradiol 
Ritonavir 
Pioglitazone 
 
 
Erythromycin 
Saquinavir 
Primidone 
 
 
Fluconazole 
Sertraline 
Rifabutin 
 
 
Fluoxetine 
Starfruit 
Rifampin 
 
 
Fluvoxamine 
Telithromycin 
Hypericum 
perforatum 
 
 
Gestodene 
Troleandomycin Sulfadimidine 
 
 
Grapefruit juice 
Verapamil 
Sulfinpyrazone 
 
 
Imatinib 
Voriconazole 
Troglitazone 
 
 
Indinavir 
Zafirlukast 
Troleandomycin 
 
 
Itraconazole 
 
 
 
 
Source: http://medicine.iupui.edu/clinpharm/ddis/clinical-table/. Accessed 31 July 2015. 


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10.6 Appendix 6: Schedule of Assessments – Day -3 to Day 3
Table 11
Schedule of Events – Detailed Inpatient Day -3 to Day 3 With Assessment 
Windows
Assessment Window
Assessment
Day -3
Prior to vital signs and clinical laboratory 
assessments
12-lead ECG
After 12-lead ECG
Vital signs
After 12-lead ECG
Liver function assessment
After 12-lead ECG
Urine pregnancy test
Day -2
≤15 minutes prior to SUBOXONE dose
PK sample
0 hour
SUBOXONE dose
Day -1
≤15 minutes prior to SUBOXONE dose
PK sample
0 hour
SUBOXONE dose
+30 minutes (±5 minutes)
PK sample
+1 hour (±5 minutes)
PK sample
+2 hours (±5 minutes)
PK sample
+4 hours (±5 minutes)
PK sample
+6 hours (±15 minutes)
PK sample
+12 hours (±15 minutes)
PK sample
Days 1 to 3
Pre-Dose SUBLOCADE
Prior to SUBLOCADE injection
Randomisation criteria reviewed and 
randomisation
≤60 minutes prior to SUBLOCADE injection
Vital signs
≤30 minutes prior to SUBLOCADE injection
PK sample


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Assessment Window
Assessment
0 hour
300 mg SUBLOCADE administration
+1 minute (±1 minute)
Injection Site Pain VAS
+5 minutes (±2 minutes)
Injection Site Pain VAS
≤10 minutes 
Injection site grading
+10 minutes (±2 minutes)
Injection Site Pain VAS
+15 minutes (±2 minutes)
Injection Site Pain VAS
+30 minutes (±5 minutes)
Injection Site Pain VAS
+1-hour Post-Dose SUBLOCADE
(±5 minutes)
PK sample
(±15 minutes)
Vital signs
(±30 minutes)
Injection site evaluation
+2 hours Post-Dose SUBLOCADE
(±5 minutes)
PK sample
(±30 minutes)
Injection site evaluation
(±30 minutes)
Injection site grading
+4 hours Post-Dose SUBLOCADE
(±5 minutes)
PK sample
+6 hours Post-Dose SUBLOCADE
(±15 minutes)
PK sample
+8 hours Post-Dose SUBLOCADE
(±15 minutes)
Vital signs
(±15 minutes)
PK sample
+12 hours Post-Dose SUBLOCADE
(±15 minutes)
PK sample
+16 hours Post-Dose SUBLOCADE
(±15 minutes)
PK sample
+20 hours Post-Dose SUBLOCADE
(±15 minutes)
PK sample


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Assessment Window
Assessment
+24 hours Post-Dose SUBLOCADE
(±15 minutes)
PK sample
(±60 minutes)
Vital signs
+28 hours Post-Dose SUBLOCADE
(±15 minutes)
PK sample
+32 hours Post-Dose SUBLOCADE
(±15 minutes)
PK sample
+36 hours Post-Dose SUBLOCADE
(±15 minutes)
PK sample
+40 hours Post-Dose SUBLOCADE
(±15 minutes)
PK sample
+44 hours Post-Dose SUBLOCADE
(±15 minutes)
PK sample
+48 hours Post-Dose SUBLOCADE
(±15 minutes)
PK sample
(±60 minutes)
Vital signs
Anytime during Day 3
Liver function assessment
Discharge from Facility
Following conclusion of all assessments
ECG=electrocardiogram; PK=pharmacokinetic; VAS=visual analogue scale


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11 REFERENCES
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors.  Contraceptive 
Technology. 19th ed. New York: Ardent Media; 2007:24-8.
Ogston-Tuck S. Subcutaneous injection technique: an evidence-based approach. Nursing 
standard. 2014 Sep 17;29(3).
Substance Abuse and Mental Health Services Administration. Clinical Guidelines for the Use of 
Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) 
Series. C. f. S. A. Treatment.40. 2004.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN: INDV-6000-405
Protocol Title:  A Single-Dose Study to Evaluate the Relative 
Bioavailability, Safety, and Tolerability of SUBLOCADE at 
Alternative Injection Locations in Adults 
Final Version: 23 Oct 2023
NCT: NCT05704543


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STATISTICAL ANALYSIS PLAN 
Title Page 
Protocol Title: A Single-Dose Study to Evaluate the Relative Bioavailability, Safety, and 
Tolerability of SUBLOCADE at Alternative Injection Locations in Adults 
Protocol Number: INDV-6000-405 
Product: SUBLOCADE® (buprenorphine extended-release) injection 
Short Title: SUBLOCADE Alternative Injection Locations 
Sponsor Name: Indivior Inc. 
Legal Registered Address: Indivior Inc., 10710 Midlothian Turnpike, Suite 125, North 
Chesterfield, VA 23235 USA 
Regulatory Agency Identifier Number(s) 
Registry ID: NCT05704543 
Registry Name: clinicaltrial.gov 
Version: 2.0 
Confidentiality Statement 
The information contained in this document is privileged and confidential. Do not copy, 
circulate or otherwise distribute without written authorization from Indivior Inc. 


Statistical Analysis Plan – Protocol INDV6000-405 
FRM.GMD.3639 v2.0 
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Statistical Analysis Plan Approval 


Statistical Analysis Plan – Protocol INDV6000-405 
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Table of Contents 
LIST OF TABLES ................................................................................................................................. 4 
LIST OF FIGURES ............................................................................................................................... 4 
1 INTRODUCTION ..........................................................................................................................5 
1.1 Version History ..................................................................................................................5 
1.2 Objectives and Endpoints ..................................................................................................5 
1.3 Study Design ......................................................................................................................7 
2 STATISTICAL HYPOTHESES .......................................................................................................... 8 
2.1 Multiplicity Adjustment ..................................................................................................... 8 
3 SAMPLE SIZE DETERMINATION ..................................................................................................8 
4 POPULATIONS FOR ANALYSIS .....................................................................................................9 
5 STATISTICAL ANALYSES ...............................................................................................................9 
5.1 General Considerations ..................................................................................................... 9 
5.1.1 Timing of Analyses ............................................................................................... 10 
5.1.2 Populations for Analyses ..................................................................................... 10 
5.2 Participant Dispositions ................................................................................................... 10 
5.3 Primary Endpoint(s) Analysis ........................................................................................... 11 
5.3.1 Definition of endpoint(s) ..................................................................................... 11 
5.3.2 Main analytical approach .................................................................................... 11 
5.4 Secondary Endpoint(s) Analysis ...................................................................................... 11 
5.5 Tertiary/Exploratory Endpoint(s) Analysis ...................................................................... 12 
5.6 Other Safety Analyses ..................................................................................................... 13 
5.6.1 Extent of Exposure .............................................................................................. 13 
5.6.2 Adverse Events .................................................................................................... 13 
5.6.3 Additional safety assessments ............................................................................ 14 
5.7 Other Analyses ................................................................................................................ 16 
5.7.1 Major Protocol Deviations................................................................................... 16 
5.7.2 Demographic and Baseline Disease Characteristics ............................................ 16 
5.7.3 Medical and Psychiatric History .......................................................................... 16 
5.7.4 Urine Drug Screen Results ................................................................................... 17 
5.7.5 Prior and Concomitant Therapies and Medications ............................................ 17 
5.7.6 Subgroup analyses ............................................................................................... 17 
5.8 Interim Analyses .............................................................................................................. 17 


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6 SUPPORTING DOCUMENTATION ............................................................................................. 17 
6.1 Appendix 1: List of Abbreviations .................................................................................... 17 
6.2 Appendix 2: Changes to Protocol-Planned Analyses ....................................................... 18 
6.3 Appendix 3: Definition and Use of Visit Windows in Reporting ...................................... 18 
6.4 Appendix 4: Endpoint Derivations ................................................................................... 18 
6.4.1 PK Parameters ..................................................................................................... 18 
6.4.2 Handling of BLQ and abberant plasma concentrations ....................................... 18 
6.4.3 Injection site Reactions Customised MedDRA Queries (CMQ) ........................... 19 
6.5 Appendix 5: Methods to Manage Missing Data .............................................................. 20 
6.5.1 Adverse event data ............................................................................................. 20 
6.5.2 Missing Date Information for Concomitant Medications ................................... 21 
6.6 Appendix 6: Methods to Manage Character Values of Clinical Laboratory Parameters22 
6.7 Appendix 7: Data Set Descriptions .................................................................................. 22 
6.8 Appendix 8: Concomitant Medication Definition ............................................................ 23 
7 REFERENCES ............................................................................................................................. 23 
Table 1. SAP Version History Summary ........................................................................................... 5 
Table 2 Objectives, Endpoints and Estimands ................................................................................. 6 
Table 3. Populations for Analysis .................................................................................................... 9 
Table 4. Primary PK parameters ................................................................................................... 11 
Table 5. Additional PK Parameters of BUP Following SUBLOCADE Injection ................................ 12 
Table 6. PK Parameters of Norbuprenorphine Following SUBLOCADE Injection ........................... 13 
Table 7. Laboratory Assessments ................................................................................................... 15 
Table 8. List of Abbreviations ......................................................................................................... 17 
Table 9 CMQ List of Preferred Terms for Injection Site Reactions ................................................. 19 
Table 10 Definition of Prior and Concomitant Medications for Run-In Period .............................. 23 
Table 11 Definition of Concomitant Medications for Post Injection Period .................................. 23 
LIST OF TABLES 
LIST OF FIGURES 
Figure 1. Study schematic ............................................................................................................... 8 


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1 INTRODUCTION 
SUBLOCADE is currently approved for SC administration in 4 different quadrants of the 
abdomen. Injection locations are rotated to minimize irritation. 
Having one or more alternate injection sites is desirable in this patient population who may be 
taking SUBLOCADE for extended durations, based upon clinical response. 
Data cited from literature suggests that the proposed alternative injection locations for SC 
administration are viable options for delivering similar PK properties: back of upper arm, 
buttocks, and thigh. Therefore, this study will assess the relative bioavailability of 
buprenorphine (BUP) when SUBLOCADE is administered to these alternate injection sites 
compared to the currently approved injection location, abdomen in participants with OUD. 
1.1 
Version History 
This Statistical Analysis Plan (SAP) for study INDV-6000-405 is based on the protocol dated 18 
Nov. 2022 and eCRF dated 6 Dec. 2022. SAP approval history is shown in Table 1. 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in Study INDV-6000-405. This document may modify the plans outlined in the 
protocol; however, any major modifications of the primary endpoint definition or its analysis 
will also be reflected in a protocol amendment. 
Table 1. SAP Version History Summary 
SAP Version 
Associated 
Protocol 
Amendment 
Approval Date 
Change 
Rationale 
1.0 
Not Applicable 
23OCT2023 
Not Applicable 
Original version 
2.0 
Not Applicable 
Changed definition of prior 
and concomitant medication
Added Appendix 8 to 
illustrate this definition. 
To be consistent 
with the other 
studies in the 
portfolio. 
1.2 
Objectives and Endpoints 
Objectives, endpoints and estimands are detailed in Table 2. 


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Table 2 Objectives, Endpoints and Estimands 
 
Objective 
Clinical Category 
Statistical 
Category 
Estimand 
Endpoint 
Population 
population-level summary 
Primary Objective: To assess the relative bioavailability of buprenorphine (BUP) when administered at alternative injection locations (test treatments), in 
comparison to the abdomen (reference treatment) following a single SC injection of SUBLOCADE in participants with OUD. 
Pharmacokinetic 
Primary 
AUC0-28 Days of BUP plasma concentration 
PK evaluable 
Geometric mean ratios with 90% 
confidence intervals (CIs) 
Primary 
Cmax of BUP plasma concentration 
PK evaluable 
Geometric mean ratios with 90% CIs 
Secondary Objective: To evaluate the safety and tolerability of SUBLOCADE when administered at alternative injection locations, in comparison to the abdomen 
AEs 
Secondary 
Proportion of participants with treatment-emergent 
adverse events (TEAEs) 
Safety 
Categorical descriptive 
Secondary 
Proportion of participants with TEAEs identified as 
injection site reactions 
Safety 
Categorical descriptive 
Secondary 
Proportion of participants with treatment-emergent 
serious adverse events (SAEs) 
Safety 
Categorical descriptive 
Injection site 
assessments 
Secondary 
Injection site grading at 10 minutes and 2 hours post 
SUBLOCADE dosing 
Safety 
Numeric or categorical descriptive 
Secondary 
Injection Site Pain VAS at 1, 5, 10, 15 and 30 minutes 
post SUBLOCADE dosing 
Safety 
Numeric descriptive 
Exploratory Objectives: 
• 
To assess other PK parameters of BUP when administered at alternative injection locations (test treatments), in comparison to the abdomen (reference 
treatment) following a single SC injection of SUBLOCADE in participants with OUD 
• 
To assess the relative bioavailability of norbuprenorphine and other norbuprenorphine PK parameters following the single SC injection of SUBLOCADE. 
Pharmacokinetic 
Exploratory 
AUClast of BUP plasma concentration 
PK evaluable 
Geometric mean ratios with 90% CIs 
Exploratory 
Tmax of BUP plasma concentration 
PK evaluable 
Medians, ranges, descriptive 
Exploratory 
Ctrough of BUP plasma concentration 
PK evaluable 
Numeric, descriptive 
Exploratory 
AUC0-28 Days of norbuprenophine plasma concentration 
PK evaluable 
Geometric mean ratios with 90% CIs 
Exploratory 
Cmax of norbuprenophine plasma concentrationfrom 
PK evaluable 
Geometric mean ratios with 90% CIs 
Exploratory 
AUClast of norbuprenophine plasma concentration 
PK evaluable 
Geometric mean ratios with 90% CIs 
Exploratory 
Tmax of norbuprenophine plasma concentration 
PK evaluable 
Medians, ranges, descriptive 
Exploratory 
Ctrough of norbuprenophine plasma concentration 
PK evaluable 
Numeric, descriptive 


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1.3 
Study Design 
This is a multi-centre, randomized, open-label, single-dose, parallel-group pharmacokinetic 
study in participants with moderate or severe OUD (based on criteria from the DSM-5). 
Participants will provide written informed consent before any protocol-related procedures 
commence. The study includes both a Residential (Inpatient) Period and a Non-Residential 
(Outpatient) Period. 
Following Screening, all eligible participants must be stabilized on 12 mg SUBOXONE® 
(BUP/naloxone) sublingual film QD for a minimum of 7 days before the SUBLOCADE injection. 
Dose induction/stabilization onto SUBOXONE film may be completed as outpatient or inpatient, 
as necessary, according to the prescribing information. 
All participants will be admitted to the residential facility by the evening of Day -3. 
Following the residential period (Day -3 to Day -1), on Day 1, eligible participants will be 
randomized to receive a single, SC injection of 300 mg SUBLOCADE at a different injection 
location ie, abdomen (reference) or one of the alternative injection locations (test) ie, back of 
upper arm, buttocks, and thigh. 
On Day -2, a blood sample will be collected prior to the SUBOXONE dose. On Day -1, blood 
samples will be collected prior to the SUBOXONE dose, and at 0.5, 1, 2, 4, 6, 12 hours post dose. 
On Day 1, blood samples will be collected prior to injection of SUBLOCADE, and at 1, 2, 4, 6, 8, 
12, 16, 20, 24, 28, 32, 36, 40, 44 and 48 hours post dose. Blood samples will also be collected on 
Days 4, 6, 8, 11, 15, 18, 22, 25 and 29, as close to the time of SUBLOCADE injection performed 
on Day 1 as possible. 
It is important that participants do not use any BUP-containing products, either therapeutically 
or illicitly since their use would compromise the PK assessment of BUP and its metabolite, 
norbuprenorphine. 
Approximately 80 participants in the United States will be randomized in total, ideally to 
achieve 15 completed participants per each of the 4 treatment arms (injection locations): 
Abdomen (reference), back of upper arm, buttocks, and thigh. The total duration of the study 
for each participant, including Screening (up to 30 days), Treatment (up to 11 days in the 
Residential Period and up to 25 days in the Non-residential Period), and Follow up, will be up to 
approximately 66 days. 
The study schematic is illustrated in Figure 1 below. 


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Figure 1. Study schematic 
 
 
2 STATISTICAL HYPOTHESES 
No formal statistical hypotheses will be tested in this study. Relative bioavailability of BUP when 
administered to alternative injection sites (back of upper arm, buttocks, and thigh) compared to 
that when administered to the abdomen will be informally evaluated. 
2.1 
Multiplicity Adjustment 
Not applicable, as there will be no formal hypothesis testing. 
 
3 SAMPLE SIZE DETERMINATION 
No formal statistical power analysis was performed to determine the sample size of this study. 
Based on historical experience from previous similar clinical trials, approximately 80 
randomized participants was considered adequate to achieve at least 15 PK evaluable 
participants per injection site location to assess the relative bioavailability of SUBLOCADE 


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300 mg at each of the alternate injection site locations compared to the the abdomen (the 
reference injection location). 
 
4 POPULATIONS FOR ANALYSIS 
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to releasing the database. Classifications will be 
documented per standard operating procedures. 
The analysis populations are defined as shown in Table 3. below. 
Table 3. Populations for Analysis 
 
Population 
Description 
Screened 
All participants who sign the ICF. 
Enrolled 
All screened participants who receive at least 1 dose of SUBOXONE 
film during run-in. 
Randomised 
All enrolled participants who are randomised to one of the 
4 treatment arms (injection locations). 
PK Evaluable 
Analysis Set 
All randomised participants who receive SUBLOCADE injection and 
provide an adequate number of post randomization PK samples to 
derive key PK parameters for SUBLOCADE (ie, Cmax and AUC0-28 Days). 
The participants will be analysed corresponding to the actual injection 
location used. 
Safety Analysis Set 
All enrolled participants who received SUBLOCADE injection. The 
participants will be analysed corresponding to the actual injection 
location used. 
Run-In Safety 
Analysis Set 
All enrolled participants who receive at least 1 dose of SUBOXONE film 
during run-in, and same as the enrolled population 
 
5 STATISTICAL ANALYSES 
5.1 
General Considerations 
AUC and Cmax values will be summarized using descriptive statistics such as the geometric mean 
and coefficient of variation (CV%). Tmax values will be summarized as the median, minimum, 
and maximum. Other continuous variables will be summarised using descriptive statistics such 
as mean, standard deviations (SD) and/or CV%, median, minimum, and maximum. Categorical 
variables will be reported as frequency counts (including number missing) and the percentage 
of participants in corresponding categories. 


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PK parameters will be derived by noncompartmental analysis with PhoenixTM WinNonlin® 
software (Version 8.3.4 or higher, Certara, LP)1 in conjunction with Certara Integral (Version 
22.10.1 or higher, Certara, USA, Inc.)2 using actual sampling times. SAS® software (SAS Institute, 
Cary, North Carolina)3 will be used for the statistical analyses and the production of TFLs. 
BUP and norbuprenophine plasma concentrations following SUBLOCADE injection will be 
summarised at each scheduled time point by injection location. The PK profile of each analyte 
will be summarized graphically by injection site, using both linear and semi-log plots. 
Additionally, BUP and norbuprenophine plasma concentrations during the run-in period with 
SUBOXONE film will also be be summarised at each scheduled time point, and graphically 
displayed using both linear and semi-log plots. 
Spaghetti plots (each individual participant’s plasma concentration shown on the same plot, 
separate plots for each injection site location) will also be generated for both analytes. These 
plots will include each participant’s plasma concentrations during both the inpatient portion of 
the run-in period and the randomized period. (ie. X-axis will range from Day -2 to Day 29). 
5.1.1 Timing of Analyses 
Final data analysis will be performed after all BUP and norbuprenorphine PK parameters have 
been derived, participants belonging to each analysis population (Table 3. ) documented and 
the database locked. 
5.1.2 Populations for Analyses 
By-timepoint summaries and graphical displays of PK profiles (e.g., buprenorphine plasma 
concentration) following the SUBLOCADE dose will use the Safety Analysis Set. 
PK parameters following the SUBLOCADE dose will be summarized and analysed using the PK 
evaluable set. 
All safety data (eg. TEAEs, injection site grading) following the SUBLOCADE dose will be 
summarized using the Safety Analysis Set. 
By-timepoint summaries and graphical displays of PK profiles (e.g., buprenorphine plasma 
concentration) during the run-in period will use the Enrolled participant set. 
All safety data during the run-in period will be summarized using the Run-In Safety Analysis Set 
(same as the Enrolled participant set). 
5.2 
Participant Dispositions 
The number and percentage of participants who were screened, enrolled (i.e., received at least 
1 dose of SUBOXONE film), randomised and not randomised (including the reason for not 
randomising), will be summarized by study site and overall, using the number of participants in 
the screened population as the denominator. 


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The number and percentage of participants who received SUBLOCADE dose and completed the 
study, and the number and percentage of participants who belong to the PK Evaluable Set and 
the safety analysis set (i.e., received SUBLOCADE dose), as well as participants who 
discontinued early and reason, will be summarized by randomised injection site location and 
overall, using the number of participants in the randomised population as the denominator. If 
actual treatment (injection site location) received is different from the randomised treatment 
for any participant, dispositions will be repeated by the actual injection site location. 
5.3 
Primary Endpoint(s) Analysis 
5.3.1 Definition of endpoint(s) 
The primary PK parameters of BUP following SUBLOCADE injection will be derived as shown in 
Table 4. 
Table 4. Primary PK parameters 
 
Parameter 
Description 
AUC0-28 Days 
Area under the BUP plasma concentration-time curve from time zero 
(Day 1) to 28 days post-dose (Day 29), calculated by the linear 
trapezoidal method. 
Cmax 
Maximum observed plasma concentration of BUP 
5.3.2 Main analytical approach 
Estimand strategy: Principal stratum strategy will be used, such that only subjects with an 
adequate amount of PK data will be included in the analysis. 
Analysis set: PK Evaluable Set 
Analysis methodology: Natural log-transformed BUP AUC0-28 Days and Cmax from SUBLOCADE 
Phase will be analyzed using an analysis of variance (ANOVA) model with injection site location 
as the independent variable. The 90% confidence interval will be estimated for the ratio of 
population geometric means (test/reference) corresponding to exponentiated differences in 
least square means. 
The comparisons of interest are the three alternative injection sites (test) versus abdomen 
(reference; [namely: back of upper arm vs abdomen, buttocks vs abdomen, and thigh vs 
abdomen]) 
Intercurrent events and missing data: Missing values will be retained as missing in the analysis. 
5.4 
Secondary Endpoint(s) Analysis 
All secondary endpoints (i.e., safety endpoints) will be based on the Safety Analysis Set. All 
summaries will be by the actual injection site location and for overall. The difference to 


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abdomen injection location (with 95% confidence interval) will be estimated for injection 
locations of upper arm, buttocks, and thigh. 
The following secondary endpoints will be derived as the proportion of participants reporting at 
least one of the specified events, and summarized using frequency counts and percentages: 
• 
Proportion of participants with TEAEs 
• 
Proportion of participants with TEAEs identified as injection site reactions 
• 
Proportion of participants with treatment-emergent SAEs 
TEAEs identified as injection site reactions will be summarised using customised MedDRA 
queries (CMQ). See Section 6.4 for the complete list of PTs for the CMQ. 
Further details on Safety Analysis are detailed in Section 5.6.2. 
Each component of the Injection site grading (pain, tenderness and erythema/redness, 
induration, swelling) at 10 minutes and 2 hours post SUBLOCADE dosing will be summarized 
using frequency counts and percentages of participants reporting the specific level of severity, 
including none (Grade 0), mild (Grade 1), moderate (Grade 2), severe (Grade 3), or potentially 
life threatening (Grade 4) as continuous score (0 to 4). The assessments will be tabulated 
according to nominal time points, with/without excluding the assessments at time points out of 
the assessment windows (Protocol 10.6 Appendix 6 Table 11). 
Injection Site Pain Visual Analog Scale (VAS) at 1, 5, 10, 15 and 30 minutes post SUBLOCADE 
dosing will be summarized using descriptive statistics. The assessments will be tabulated 
according to nominal time points, with/without excluding the assessments at time points out of 
the assessment windows. 
5.5 
Tertiary/Exploratory Endpoint(s) Analysis 
The following PK parameters for SUBLOCADE will be derived as shown in Table 5. for BUP and 
Table 6. for norbuprenorphine. The plasma terminal half-life and AUC extrapolated to infinity 
(AUC0-inf) are not calculated as the duration of the PK evaluation is shorter than the plasma 
terminal half-life reported for SUBLOCADE (43-60 days). 
Table 5. Additional PK Parameters of BUP Following SUBLOCADE Injection 
 
Parameter 
Description 
AUClast 
Area under the BUP plasma concentration-time curve from time 0 
(Day 1) to the last quantifiable BUP concentration, calculated by the 
linear trapezoidal method 
Tmax 
Time to attain the maximum observed BUP plasma concentration 
Ctrough 
BUP plasma concentration measured on Day 29 


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Table 6. PK Parameters of Norbuprenorphine Following SUBLOCADE Injection 
 
Parameter 
Description 
AUC0-28 Days 
Area under the norbuprenorphine plasma concentration-time curve 
from time zero (Day 1) to 28 days post dose (Day 29), calculated by 
the linear trapezoidal method 
AUClast 
Area under the norbuprenorphine plasma concentration-time curve 
from time 0 (Day 1) to the last quantifiable concentration, calculated 
by the linear trapezoidal method 
Cmax 
Maximum observed norbuprenorphine plasma concentration 
Tmax 
Time to attain the maximum observed norbuprenorphine plasma 
concentration 
Ctrough 
Norbuprenorphine plasma concentration measured on Day 29 
 
AUClast for both analytes, and AUC0-28 Days and Cmax for norbuprenorphine will be analyzed using 
the same statistical model as described in Section 5.3.2. 
5.6 
Other Safety Analyses 
5.6.1 Extent of Exposure 
Regarding the exposure to SUBOXONE in the Run-in Period, the following will be summarized 
for the Run-In safety and Safety Analyses Sets. 
• 
The number of days of SUBOXONE use prior to randomization. The number of days will 
be calculated as the date of the last dose of SUBOXONE minus the date of the first dose 
of SUBOXONE plus 1. 
• 
The total SUBOXONE dose and average daily SUBOXONE dose during the entire run-in 
period, calculated as the total cumulative dose divided by the number of days of use. 
• 
The total SUBOXONE dose and average daily SUBOXONE dose between day -7 and day 
-1. 
 
5.6.2 Adverse Events 
Treament Emergent Adverse Events (TEAEs) are defined as adverse events with a start time 
that is equal to or later than the initiation of the drug treatment or any event already present 
that worsens in either intensity or frequency following drug exposure. 
TEAEs with start date-time after the date of the 1st SUBOXONE dose and before the date of 
SUBLOCADE injection will be reported for the run-in period, using run-in safety and Safety 
Analysis Set. 


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TEAEs with start date-time equal to or after SUBLOCADE injection will be reported for the post- 
injection period, using Safety Analysis Set, by actual injection site and overall. 
TEAEs will be coded to system organ class (SOC) and preferred term (PT) using MedDRA. 
Incidence and incidence proportion of TEAE (number and percentage of participants reporting 
the TEAE at least once during the run-in period or the post-injection period) and TEAEs 
identified as injection site reactions (post-injection period only) will be summarised by SOC and 
PT. Separate summaries will be provided for the two periods for all TEAEs, TEAEs identified as 
injection site reactions (post-injection period only), Serious TEAEs, drug related TEAEs and 
TEAEs leading to discontinuation of study treatment (SUBOXONE or SUBLOCADE). 
TEAEs will also be summarized by maximum severity and relatedness within SOC and PT. If an 
AE is reported more than once by a subject within a SOC and/or PT, the maximum reported 
level of severity/relatedness will be used at each level of summation in the severity/relationship 
summary tables. Missing severity and relatedness will be queried until resolution. If resolution 
is not possible, missing severity will be summarized as “severe” and missing relatedness will be 
summarized as “related.” 
5.6.3 Additional safety assessments 
5.6.3.1 Laboratory Data 
Except for the pregnancy test which is done both at screening and upon admission to the 
clinical site, all laboratory evaluations (Table 7) at screening will be summarized using both the 
Run-In safety and the Safety Analysis Set. Liver function tests will be summarized by time point, 
using Safety Analysis Set. In calculating summary statistics for numeric lab test values, any 
reported value that include qualifiers (ie, <, ≤, >, ≥) will be summarized as the limit of 
quantification. E.g. > 9 will be summarized as 9. 
Pregnancy test results will only be listed. 


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Table 7. Laboratory Assessments 
 
Laboratory 
Assessments 
Parameters 
Haematology 
Platelet count 
Red blood cell (RBC) count 
RBC indices: 
• 
Mean corpuscular volume (MCV) 
• Mean corpuscular haemoglobin (MCH) 
White blood cell (WBC) count with 
• 
Neutrophils 
differential: 
• 
Lymphocytes 
• Monocytes 
• Eosinophils 
• Basophils 
Haemoglobin 
Haematocrit 
Clinical Chemistry 
Blood urea nitrogen (BUN) 
Potassium 
Creatinine 
Sodium 
Calcium 
Bicarbonate 
Chloride 
Glucose (fasting or non-fasting) 
Creatine phosphokinase (CPK) 
Liver Function Test 
Albumin 
Lactate dehydrogenase (LDH) 
Total protein 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Alkaline phosphatase (ALP) 
Gamma glutamyl transferase (GGT) 
Total and direct bilirubin 
Pregnancy Testing 
Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential) 
Urine Drug Screen 
Opioids 
Cocaine 
Fentanyl 
Oxycodone 
Opiates/Morphine 
Amphetamines 
Methadone 
Cannabinoids 
Barbiturates 
Benzodiazepines 
Methamphetamine 
Phencyclidine 


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Other Laboratory 
Tests 
Serology (HIV-1 and -2 antibodies, hepatitis B surface antigen [HbsAg], 
and hepatitis C virus antibody, PTT, and PT with INR) If a central 
laboratory is being utilised and protocol-required additional local 
laboratory assessments are needed, include the last bullet in the Other 
screening tests section of the table ([All study required laboratory…): 
Urinalysis 
(Categorical) 
Specimen Appearance, Bilirubin, Color, Glucose, Ketone, Leucocyte 
Esterase, Nitrite, Occult Blood, Protein, Urobilinogen, Erythrocytes, 
Leukocytes 
Urinalysis 
(Continuous) 
pH, Specific Gravity. 
5.6.3.2 Vital signs 
Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate) will be 
summarized by time point, using the Safety Analysis Set and Run-In Safety Set. 
5.6.3.3 ECG data 
ECG interpretation (normal, abnormal but not clinically significant, abnormal and clinically 
significant) will be summarized by time point. Numeric 12-lead ECG parameters [heart rate, PR 
interval, QRS duration, QT interval, Fridericia’s corrected QT interval (QTcF)] will also be 
summarized. All summaries will be based on the Safety Analysis Set and Run-In Safety Set. 
5.7 
Other Analyses 
5.7.1 Major Protocol Deviations 
Major protocol deviations will be identified and documented prior to database lock and will be 
summarized by category (eg, prohibited medication, out-of-window assessment), per the 
Protocol Deviation Plan for the study, for screened subjects. Deviations that occur in subjects 
who were randomized and not randomized will be summarized separately. All major protocol 
deviations will be listed. 
5.7.2 Demographic and Baseline Disease Characteristics 
Demographic and other baseline characteristics will be summarized separately for the run-in 
safety set, safety set and PK Evaluable Set, if different. Parameters to be summarized will be 
age, sex, race, ethnicity, fertility status, and height/weight/body mass index, drug use history 
and route of administration. 
5.7.3 Medical and Psychiatric History 
Relevant medical history will be coded using MedDRA and will be summarized for the Run-In 
Safety population and safety population (PK population, if different). 


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5.7.4 Urine Drug Screen Results 
The number and percentage of participants with positive UDS will be summarized by time 
point, using the Run-In safety analysis set and Safety Analysis Set. The denominator of the 
percentage is the number of participants with available results for the individual drug. The 
opioids (overall) will include opiates/morphine, methadone, oxycodone, and fentanyl. If any of 
these are “Positive”, then opioids (overall) will be defined as “Positive”. If all non-missing test 
results are negative, then opioids (overall) will be defined as “Negative”. Amphetamine and 
methamphetamine will be combined into one class as amphetamine/methamphetamine, using 
the similar definition for “Positive/Negative” as opioids (overall). 
5.7.5 Prior and Concomitant Therapies and Medications 
Therapies and medications will be collected from screening through EOS and will be coded 
using Anatomical Therapeutic Chemical (ATC) classification codes via the World Health 
Organization Drug Dictionary (WHO-DD). Prior and concomitant medications during run- 
in/post-injection period are defined in Appendix 8: Concomitant Medication Definition. 
Prior and concomitant medications will be summarized using the run-in safety and safety 
populations. Concomitant medications during the run-in and post-injection periods will be 
summarized separately using the run-in safety and safety populations, respectively. The 
summary of incidence (number and percentage of subjects reporting the medication at least 
once) will be sorted alphabetically by therapeutic class (ATC level 3) and standardized 
medication name. 
5.7.6 Subgroup analyses 
In order to understand the study site-to-site variation in injection technique and assessment of 
injection site reactions, injection site grading and injection site pain VAS summary tables will be 
repeated for each study site. 
5.8 
Interim Analyses 
Not applicable. 
 
6 SUPPORTING DOCUMENTATION 
6.1 
Appendix 1: List of Abbreviations 
Table 8. List of Abbreviations 
 
Abbreviation 
Definition 
AE 
adverse event 
ANOVA 
Analysis of variance 
ATC 
Anatomic Therapeutic Chemical 
AUC 
area under the curve 
BLQ 
below the limit of quantitation 
BP 
blood pressure 


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Table 8. List of Abbreviations 
 
Abbreviation 
Definition 
BUP 
buprenophine 
CI 
confidence interval 
Cmax 
maximum observed concentration 
CMQ 
customised MedDRA queries 
CSR 
clinical study report 
ECG 
electrocardiogram 
ICF 
Informed consent form 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
pharmacokinetic(s) 
PT 
preferred term 
QT 
QT 
QTcF 
corrected QT (Fridericia method) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 
6.2 
Appendix 2: Changes to Protocol-Planned Analyses 
Not applicable. 
6.3 
Appendix 3: Definition and Use of Visit Windows in Reporting 
Regardless of any actual blood draw time deviations from the scheduled time, summary 
statistics by time point (for data tabulations and figures) will use the scheduled time point. 
6.4 
Appendix 4: Endpoint Derivations 
6.4.1 PK Parameters 
Plasma PK parameters will be calculated by non-compartmental analysis using WinNonlin 
software for BUP and norbuprenorphine. Actual sampling times will be used in the calculations. 
If quantifiable data are not available through 28 days (Tlast <28 days), the following rules will be 
used to extrapolate AUC0-28 Days from AUClast via linear regression through the terminal log-linear 
segment of the plasma concentration-time curve: 
• At least three quantifiable concentrations will be used in the regression 
• Cmax or data prior to Cmax will not be included in the regression. 
• The adjusted regression coefficient (R2 adj) should be ≥ 0.80. 
6.4.2 Handling of BLQ and abberant plasma concentrations 
Plasma concentrations that are below the lower limit of quantification (BLQ) will be treated as 
zero for the time point summary statistics and linear-scale plots of concentrations and excluded 
from semi-logarithmic-scale plots of concentrations. 


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For deriving BUP and norbuprenorphine PK parameters, all plasma concentrations that are BLQ 
prior to the peak plasma concentration (Cmax) will be set to zero. Post Cmax, BLQ values will be 
handled as follows: 
- 
Embedded BLQ values that are between two measurable concentrations will be set to 
missing 
- 
Measurable concentrations between two BLQ values will be set to missing 
- 
If two or more consecutive BLQ concentrations are followed by quantifiable 
concentrations, these quantified values will be set to missing 
- 
If a BLQ concentration is followed by a quantifiable concentration, and the quantifiable 
concentration is then followed by two or more consecutive BLQ concentrations, the 
quantifiable concentration will be set to missing 
- 
Terminal BLQ values following the last quantifiable time point will be set to missing 
- 
No concentration estimates will be imputed for missing sample values. 
6.4.3 Injection site Reactions Customised MedDRA Queries (CMQ) 
The PTs used to categorize the injection site reactions are shown in Table 9 below. 
Table 9 CMQ List of Preferred Terms for Injection Site Reactions 
Preferred Term 
Preferred Term 
Immediate post-injection reaction 
Injection site ulcer 
Injection related reaction 
Injection site urticaria 
Injection site abscess 
Injection site vesicles 
Injection site cellulitis 
Injection site warmth 
Injection site infection 
Injection site ischaemia 
Injection site pustule 
Injection site coldness 
Injection site abscess sterile 
Injection site discolouration 
Injection site anaesthesia 
Injection site photosensitivity reaction 
Injection site atrophy 
Injection site swelling 
Injection site bruising 
Injection site discomfort 
Injection site cyst 
Injection site calcification 
Injection site dermatitis 
Injection site movement impairment 
Injection site erosion 
Injection site lymphadenopathy 
Injection site erythema 
Injection site nodule 
Injection site extravasation 
Embolia cutis medicamentosa 
Injection site fibrosis 
Injection site scar 
Injection site granuloma 
Injection site discharge 
Injection site haematoma 
Injection site pallor 
Injection site haemorrhage 
Injection site papule 
Injection site hypersensitivity 
Injection site injury 
Injection site hypertrophy 
Injection site scab 
Injection site induration 
Injection site eczema 


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Injection site inflammation 
Injection site streaking 
Injection site irritation 
Injection site dryness 
Injection site mass 
Injection site laceration 
Injection site necrosis 
Injection site macule 
Injection site nerve damage 
Injection site vasculitis 
Injection site oedema 
Injection site exfoliation 
Injection site pain 
Injection site dysaesthesia 
Injection site paraesthesia 
Injection site plaque 
Injection site phlebitis 
Injection site hyperaesthesia 
Injection site pruritus 
Injection site hypoaesthesia 
Injection site rash 
Injection site hypertrichosis 
Injection site reaction 
Injection site thrombosis 
 
 
6.5 
Appendix 5: Methods to Manage Missing Data 
6.5.1 Adverse event data 
Missing AE Severity 
In the unlikely event that resolution is not possible, missing severity will be imputed as “severe” 
in summaries. 
Missing AE Relationship to Study Drug 
In the unlikely event that resolution is not possible, missing relationship will be imputed as 
“related” in summaries. 
Missing Date Information for Adverse Events 
• 
Missing day and month 
o If the year is the same as the year of the date of the first dose of investigational 
product, then the day and month of the date of the first dose of investigational 
product will be assigned to the missing fields. 
o If the year is before the year of the date of the first dose of investigational product, 
then December 31 will be assigned to the missing fields. 
o If the year is after the year of the date of the first dose of investigational product, 
then January 1 will be assigned to the missing fields. 
• 
Missing month only 
o The day will be treated as missing and both month and day will be replaced 
according to the above procedure. 
• 
Missing day only 


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o If the month and year are the same as the month and year of the date of the first 
dose of investigational product, then the day of the first dose of investigational 
product will be assigned to the missing day. 
o If either the year is before the year of the date of the first dose of investigational 
product or if both years are the same but the month is before the month of the date 
of the first dose of investigational product, then the last day of the month will be 
assigned to the missing day. 
o If either the year is after the year of the date of the first dose of investigational 
product or if both years are the same but the month is after the month of the date 
of the first dose of investigational product, then the first day of the month will be 
assigned to the missing day. 
o If the stop date is after the date of the first dose of investigational product, the date 
of the first dose of investigational product will be assigned to the missing start date. 
o If the stop date is before the date of the first dose of investigational product, the 
stop date will be assigned to the missing start date. 
6.5.2 Missing Date Information for Concomitant Medications 
• 
Missing day and month 
o If the year of the incomplete start date is the same as the year of the date of the first 
dose of investigational product, then the day and month of the date of the first dose 
will be assigned to the missing fields. 
o If the year of the incomplete start date is before the year of the date of the first dose 
of investigational product, then December 31 will be assigned to the missing fields. 
o If the year of the incomplete start date is after the year of the date of the first dose 
of investigational product, then January 1 will be assigned to the missing fields. 
• 
Missing month only 
o The day will be treated as missing and both month and day will be replaced 
according to the above procedure. 
• 
Missing day only 
o If the month and year of the incomplete start date are the same as the month and 
year of the date of the first dose of investigational product, then the day of the first 
dose will be assigned to the missing day. 
o If either the year is before the year of the date of the first dose of investigational 
product or if both years are the same but the month is before the month of the date 
of the first dose of investigational product, then the last day of the month will be 
assigned to the missing day. 
o If either the year is after the year of the date of the first dose of investigational 
product or if both years are the same but the month is after the month of the date 
of the first dose of investigational product, then the first day of the month will be 
assigned to the missing day. 


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• 
Incomplete Stop Date 
o For deriving concomitant medication flag, the following rules will be applied to 
impute the missing numerical fields. If the date of the last dose of investigational 
product is missing, impute it as descripted in Section 17.4. If the imputed stop date 
is before the start date (imputed or non-imputed start date), then the imputed stop 
date will be equal to the start date. 
• 
Missing day and month 
o If the year of the incomplete stop date is the same as the year of the date of the last 
dose of investigational product, then the day and month of the date of the last dose 
will be assigned to the missing fields. 
o If the year of the incomplete stop date is before the year of the date of the last dose 
of investigational product, then December 31 will be assigned to the missing fields. 
o If the year of the incomplete stop date is after the year of the date of the last dose 
of investigational product, then January 1 will be assigned to the missing fields. 
• 
Missing month only 
o The day will be treated as missing and both month and day will be replaced 
according to the above procedure. 
• 
Missing day only 
o If the month and year of the incomplete stop date are the same as the month and 
year of the date of the last dose of investigational product, then the day of the last 
dose will be assigned to the missing day. 
o If either the year is before the year of the date of the last dose of investigational 
product or if both years are the same but the month is before the month of the date 
of the last dose of investigational product, then the last day of the month will be 
assigned to the missing day. 
o If either the year is after the year of the date of the last dose of investigational 
product or if both years are the same but the month is after the month of the date 
of the last dose of investigational product, then the first day of the month will be 
assigned to the missing day. 
6.6 
Appendix 6: Methods to Manage Character Values of Clinical Laboratory Parameters 
Reported values of clinical laboratory parameters that include qualifiers (ie, <, ≤, >, ≥) will be 
listed as reported but will be summarized without the qualifier. 
6.7 
Appendix 7: Data Set Descriptions 
Trial data sets will consist of CRF exports and external data files. External files may be used for 
PK parameters, protocol deviations and data from the central laboratory, for example. 


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6.8 
Appendix 8: Concomitant Medication Definition 
The definition of prior and concomitant medications is illustrated below. Two timing flags will 
be derived based on the tables below. 
Table 10 Definition of Prior and Concomitant Medications for Run-In Period 
 
End Date of Non-Study 
Medication 
Start Date of Non-Study Medication 
Missing 
< Start date of 
SUBOXONE 
 Start date of SUBOXONE and ≤ 
end date of SUBOXONE 
Missing (includes flagged as 
“Ongoing”) 
Prior 
Concomitant (Run-In) 
Prior 
Concomitant (Run-In) 
Concomitant (Run-In) 
< Start date of SUBOXONE 
Prior 
Prior 
Data Error 
 Start date of SUBOXONE 
and ≤ end date of 
SUBOXONE 
Prior 
Concomitant (Run-In) 
Prior 
Concomitant (Run-In) 
Concomitant (Run-In) 
 
If a medication’s end date is on or after the date of SUBLOCADE injection, then it will be 
classified as concomitant Post-Injection as shown in Table 11. 
Table 11 Definition of Concomitant Medications for Post Injection Period 
 
End Date of Non-Study 
Medication 
Start Date of Non-Study Medication 
Missing 
< SUBLOCADE injection date 
 SUBLOCADE injection date 
Missing (includes flagged as 
“Ongoing”) 
Concomitant (Post- 
Injection) 
Concomitant (Post-Injection) 
Concomitant (Post-Injection) 
 SUBLOCADE injection 
date 
Concomitant (Post- 
Injection) 
Concomitant (Post-Injection) 
Concomitant (Post-Injection) 
Prior medications will be defined using the first table only. A medication is considered 
concomitant if it is concomitant either during run-in period or during post-injection period. 
 
7 REFERENCES 
1. Phoenix™ WinNonlin® (Version 8.3.4.295 or higher, Certara, LP.) 
2. Certara Integral (Version 22.10.1, Certara, USA, Inc.) 
3. SAS Institute Inc., Cary, NC, 27513, USA