A Randomised, Double-Blind Study Comparing 2 Maintenance Dosing Regimens of Buprenorphine Extended-Release Subcutaneous Injection (RBP-6000) in Treatment-Seeking Adult Participants With Opioid Use Disorder and High-risk Opioid Use
Phase: PHASE4
Conditions: Moderate to Severe Opioid-use Disorder
Sponsor: Indivior Inc.

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16.1.1 CLINICAL RESEARCH PROTOCOL
DRUG:
SUBLOCADE (RBP-6000)
STUDY NUMBER:
INDV-6000-401
PROTOCOL TITLE:
A Randomised, Double-Blind Study Comparing 
2 Maintenance Dosing Regimens of Buprenorphine 
Extended-Release Subcutaneous Injection 
(RBP-6000) in Treatment-Seeking Adult 
Participants with Opioid Use Disorder and High-risk 
Opioid Use  
SHORT PROTOCOL 
TITLE:
Transform Study 
TReating AddictioN in high risk population with 
Sublocade FOR Maintenance
PHASE:
IV 
IND NUMBER:
107,607
SPONSOR:
Indivior Inc.
10710 Midlothian Turnpike, Suite 125
North Chesterfield, VA 23235
USA
AMENDMENT 3 
PROTOCOL DATE:
 07 Apr 2022 (Version 4.0)

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CLINICAL PROTOCOL APPROVAL FORM 
Protocol Title: 
A Randomised, Double-Blind Study Comparing 
2 Maintenance Dosing Regimens of Buprenorphine 
Extended-Release Subcutaneous Injection (RBP-6000) in 
Treatment-Seeking Adult Participants with Opioid Use 
Disorder and High-risk Opioid Use     
Protocol Number: 
INDV-6000-401 
Amendment 3 Date:  
 07 Apr 2022 (Version 4.0) 
 
This clinical study protocol was subject to critical review and has been approved by the 
appropriate protocol review committee of Indivior. The information contained in this 
protocol is consistent with: 
 The current risk-benefit evaluation of the investigational medicinal product. 
 The moral, ethical and scientific principles governing clinical research as set out in 
the principles of International Council on Harmonisation (ICH) E6 (Good Clinical 
Practice) and according to applicable local laws and regulations. 
The Investigator will be supplied with details of any significant or new findings, 
including adverse events, relating to treatment with the investigational medicinal product. 
 
 

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CONFIDENTIALITY AND INVESTIGATOR STATEMENT
Protocol Title:
A Randomised, Double-Blind Study Comparing 
2 Maintenance Dosing Regimens of Buprenorphine 
Extended-Release Subcutaneous Injection (RBP-6000) in 
Treatment-Seeking Adult Participants with Opioid Use 
Disorder and High-risk Opioid Use    
Protocol Number:
INDV-6000-401
Amendment 3 Date: 
07 Apr 2022 (Version 4.0)
The information contained in this protocol and all other information relevant to this 
investigational medicinal product 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, 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 RBP-
6000 and appropriate information throughout the study. Mechanisms are in place to ensure that 
site staff receives the appropriate information throughout the study. 

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STUDY PERSONNEL INFORMATION

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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document History
Document: 
Date
Amendment 3
07 Apr 2022 
Amendment 2 
31 Jan 2022 
Amendment 1
15 Jul 2021 
Original Protocol
26 Jan 2021 
Amendment 3 (07 Apr 2022) 
This amendment is created because it affects the selection, the criteria for selection, 
monitoring, and dismissal of a clinical trial subject.
Rationale for the Amendment:
Section Number and 
Name
Description of Change
Brief Rationale

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STUDY SUMMARY
Protocol Title:
A Randomised, Double-Blind Study Comparing 2 Maintenance Dosing Regimens of 
Buprenorphine Extended-Release Subcutaneous Injection (RBP-6000) in Treatment-Seeking 
Adult Participants with Opioid Use Disorder and High-risk Opioid Use 
Protocol Number: 
INDV-6000-401
Rationale:

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The safety objective of this study is to assess the safety and tolerability of RBP-6000 in 
participants who use opioids via an injection route and/or use high doses of opioids. 
Open-label Induction Sub-study
The primary objective of the sub-study is to compare treatment retention of participants 
following rapid induction or SoC induction onto RBP-6000. 
The secondary objective of the sub-study is to evaluate the safety and tolerability of RBP-6000 
in participants during the Open-label Induction Sub-study.
Study Design:
This randomised, double-blind, parallel group, multicentre study will compare the efficacy, 
safety and tolerability of 100mg and 300mg maintenance doses of RBP-6000 administered 
every 4 weeks to high-risk, treatment-seeking adult participants with moderate to severe OUD 
(as assessed by DSM5) who use opioids via an injection route and/or use high doses of opioids. 
An Open-label Induction Sub-study is nested within this study and will compare treatment 
retention and safety and tolerability of RBP-6000 in participants following rapid induction or 
SoC induction. 
Participants who provide written informed consent will be assessed for eligibility during an up 
to 30-day Screening Period. During Screening, the Investigator will ask the participant to self-
report recent drug use (including the use of a TimeLine Follow Back [TLFB]) to assess 
eligibility for high-risk opioid use. Eligibility will be assessed by the participants’ TLFB only, 
and the Investigator may discuss any positive UDS results with the participant only after the 
completion of the TLFB.
Participants determined to be eligible will be advised to abstain from short-acting opioids (such 
as morphine sulphate, 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 arriving at the site for TM buprenorphine 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. This risk 
is increased with high doses of potent opioids, such as fentanyl, which may take longer to clear 
due to high lipophilicity, redistribution into fat, and prolonged excretion patterns 
(Mariani 2020). An on-site dipstick UDS at Screening to identify current opioids of abuse will 
support discussion between the Investigator and study participant about the optimal period of 
abstinence before starting induction. 

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Eligible participants may complete the induction visit once all inclusion and exclusion criteria 
are confirmed, including applicable laboratory assessments. 
Approval from the sponsor must be obtained for any local laboratory and the laboratory normal 
ranges utilized to determine eligibility for screening. If a local laboratory is utilized for 
eligibility, the laboratory samples will also be sent to the central laboratory for the baseline 
analysis value. 
If eligibility is confirmed at the screening visit, participants may complete the induction visit. 
Participants having same-day screening and induction visits are not required to repeat the UDS, 
pregnancy test, vitals, and ECG for the induction visit.
On induction days, eligible participants will provide a urine sample for a UDS dipstick and 
pregnancy test (female participants of child-bearing potential only). If a female participant has 
a positive pregnancy test, she will be discontinued and will not proceed with subsequent 
assessments. The Investigator will ask him/her to self-report recent drug use (including the use 
of a TLFB). The Investigator may discuss any positive UDS results with the participant only 
after completion of the TLFB. 
Participants who report that they have used long-acting opioids within the previous 24 hours 
will not be permitted to proceed with induction until the 24-hour period has passed. If 
necessary, induction may be rescheduled. The 1st day of the repeat induction should be 
scheduled within 30 days of informed consent. Participants who have used short-acting opioids 
within the previous 6 hours may be permitted to proceed with the induction visit at the 
discretion of the Investigator. All concomitant medications used since Screening will be 
reviewed. 
When the participant has met the TM buprenorphine dosing criteria, he/she will be randomised 
at a 2:1 ratio to RBP-6000 rapid induction or SoC induction. Due to the potential for fentanyl 
use to impact the response to TM buprenorphine induction, randomisation will be stratified 
according to the same-day UDS result for fentanyl (negative or positive). The rapid induction 
arm is designed to initiate RBP-6000 treatment following a single dose of TM buprenorphine, 
while the SoC induction arm inducts the participant onto RBP-6000 using a TM buprenorphine 
containing product for a minimum of 7 days.
If the participant displays any allergic/hypersensitivity reaction to TM buprenorphine, the 
participant will be discontinued from the study. 
Following TM buprenorphine induction using either rapid induction or SoC induction, and 
confirmation that the participant is eligible for dosing with RBP-6000, pre–RBP-6000 
assessments will be conducted; if eligible, 300 mg RBP-6000 may be administered SC and the 
visit will be considered Day 1. 
Following the first injection of RBP-6000 (300 mg), the participants will remain at the site for 
at least 4 hours after the injection and be monitored for safety and tolerability. 
If the participant experiences exacerbated withdrawal symptoms at any time (including 
precipitated withdrawal), he/she may be treated symptomatically per the SAMHSA TIP 63 

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2020 guidelines: 

Nausea: ondansetron or metoclopramide

Diarrhoea: loperamide

Anxiety, irritability, sweating: clonidine

Insomnia: diphenhydramine, trazodone

Pain: Nonsteroidal anti-inflammatory drugs
For participants in the rapid induction arm, following the first injection of 300 mg RBP 6000, 
TM buprenorphine in increments of 2 to 4 mg up to a maximum dose of 12 mg (inclusive of 
pre–RBP-6000 TM buprenorphine) may be administered on Day 1 at the discretion of the 
Investigator to alleviate withdrawal symptoms while on site. Regardless of induction arm, 
participants are not permitted to take home supplemental TM buprenorphine after RBP-6000 is 
administered. 
The second RBP-6000 dose will be administered at Week 2, 1 week (+4 days) after the first 
injection.
Participants will be followed up via telephone the day after the first and second RBP-6000 
injections.
Participants eligible to continue treatment will be randomised at Week 6 prior to Injection 3 in 
a 1:1 ratio to receive maintenance doses of either 300 mg or 100 mg every 4 weeks 
(-2/+4 days) for a total of up to 8 maintenance injections. Randomisation prior to the third 
RBP-6000 dose will be stratified according to opioid use predominantly via injection route at 
Screening (yes or no) and Week 6 UDS result for opioids (negative or positive). 
Participants will return to the site for weekly UDS and collection of self-reported drug use, 
including TLFB, from Weeks 1 to 10. From the fourth injection until the end of the treatment 
period (Weeks 10 to 38), UDS and self-reported drug use, including TLFB, will be obtained at 
every injection visit. In addition, random visits to assess UDS and TLFB (only) will be 
scheduled by the Investigator in between every injection (2 weeks post each injection ±7 days) 
from Injection 4 through Injection 10. All participants will receive counselling, per SoC, from 
Day 1, Week 1, through the end of the treatment period. 
All participants will continue study treatment until they complete the end-of-treatment (EOT) 
Visit (Week 38). Participants who prematurely discontinue RBP-6000 treatment will complete 
the early termination (ET) visit. During the last injection visit (Week 34) through the EOT visit 
(or the ET for those who prematurely discontinue), the Investigator or a medically qualified 
sub-Investigator will discuss available options for continued treatment. Any participant with 
ongoing adverse events (AE) at the EOT or ET visit will also be followed up by phone 2 weeks 
later for the End of Study (EOS) visit to assess any ongoing AEs and concomitant medications 
associated with those ongoing AEs only.
No dose increases or decreases of RBP-6000 are allowed. 
Primary Efficacy Endpoint
The proportion of responders for weekly opioid use, where a responder is defined as a 
participant whose percentage of visits with opioid abstinence (as measured via negative UDS 
and TLFB for the prior week) is greater than or equal to 80% over Weeks 20 to 38 (inclusive).

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Secondary Efficacy Endpoints
The secondary efficacy endpoints are as follows: 

participants’ percentage of days opioids were used out of days assessed (TLFB) over 
Weeks 10 to 38 (inclusive).

proportion of responders for weekly opioid use, where a responder is defined as a 
participant whose percentage of visits with opioid abstinence (as measured via negative 
UDS and TLFB for the prior week) is greater than or equal to 80% over Weeks 10 to 38 
(inclusive)

participants’ percentage of visits with opioid abstinence (defined as negative UDS and 
TLFB for opioid use) over Weeks 10 to 38 (inclusive)

proportion of responders for weekly opioid use, defined as participants’ percentage of 
visits with opioid abstinence being greater than or equal to 80% for the last 5 visits planned 
for UDS and TLFB assessment over Week 30 to Week 38.

proportion of responders for daily opioid use, defined as participants’ percentage of days 
opioids were used out of days assessed (TLFB) being less than or equal to 20% for 
participants’ last 5 visits with observed TLFB post randomisation.

participants’ percentage of visits with opioid abstinence (defined as negative UDS and 
TLFB for opioid use) overall (Week 2 to 38 inclusive)

participants’ percentage of days opioids were used out of days assessed (TLFB) overall 
(Week 2 to 38 inclusive)

for participants who use opioids via the injection route for an average of 5 or more days 
per week in the last 4 weeks prior to Screening, participants’ percentage of days opioids 
were used via the injection route out of days assessed (TLFB) overall (Weeks 10 to 38 
inclusive)

average number of times opioids were used per week (TLFB) by visit

change in participants’ number of times opioids were used per week from Screening or 
randomisation baseline to each visit

proportion of participants abstinent (defined as negative UDS and TLFB for opioid use) by 
visit

average number of days opioids were used per week (TLFB) by visit

treatment retention since randomisation

proportion of randomised participants who complete the last scheduled injection of 
RBP-6000
Exploratory Efficacy Endpoints

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Safety Assessments/Endpoints
Major safety endpoints include the proportion of participants with at least 
1 treatment-emergent AE (TEAE) of the following types at any time during the treatment 
period: any TEAE, drug-related TEAE, treatment-emergent serious AE (SAE), drug-related 
treatment-emergent SAE, or TEAE leading to treatment discontinuation. Additional safety 
endpoints include assessment of laboratory results, vital signs and concomitant medications. 
Participants will be contacted by phone the day following Injections 1 and 2 to ask about AEs 
and concomitant medication use.
Open-label Induction Sub-study Endpoints
The primary endpoint of this sub-study is treatment retention at Injection 2, defined as the 
proportion of participants receiving Injection 2 at the Week 2 visit among those who received 
at least 1 dose of TM buprenorphine for induction and did not demonstrate idiosyncratic 
response to the first dose of TM buprenorphine. 
The secondary endpoints of this sub-study are the following:

time to treatment discontinuation from the first dose of TM buprenorphine used for 
induction during the Open-label Treatment Period (OLTP), defined as the number of days 
from the first dose of TM buprenorphine until the last scheduled visit observed during the 
OLTP. Participants receiving the third RBP-6000 injection (i.e., the first randomised 
injection) will be censored administratively at the end of the OLTP; otherwise participants 
will be viewed as having discontinued treatment at their last scheduled visit observed 
during the OLTP. Participants discontinued due to idiosyncratic response to the first dose 
of TM buprenorphine will not be included.

adverse events up to Injection 2, and between Injections 2 and 3 

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TABLE OF CONTENTS
CONFIDENTIALITY AND INVESTIGATOR STATEMENT ...................................3
STUDY PERSONNEL INFORMATION........................................................................4
PROTOCOL AMENDMENT SUMMARY OF CHANGES.........................................5
STUDY SUMMARY..........................................................................................................6
TABLE OF CONTENTS ................................................................................................14
LIST OF IN-TEXT TABLES .........................................................................................19
LIST OF IN-TEXT FIGURES .......................................................................................19
LIST OF ABBREVIATIONS .........................................................................................20
1
INTRODUCTION AND RATIONALE .................................................................23
1.1
Background ..........................................................................................................23
1.3
Risk-Benefit Assessment......................................................................................27
1.3.1
Risk Assessment .............................................................................................28
1.3.2
Benefit Assessment.........................................................................................29
1.3.3
Overall Risk-Benefit Summary ....................................................................30
2
STUDY OBJECTIVES ............................................................................................31
2.1
Primary.................................................................................................................31
2.2
Secondary..............................................................................................................31
2.4
Safety.....................................................................................................................31
2.5
Sub-Study .............................................................................................................31
3
STUDY ENDPOINTS ..............................................................................................32
3.1
Primary Efficacy Endpoint.................................................................................32
3.2
Secondary Efficacy Endpoints............................................................................32
3.4
Safety Assessments...............................................................................................34
3.5
Open-label Induction Sub-study Endpoints......................................................34
4
STUDY PLAN...........................................................................................................35
4.1
Study Design.........................................................................................................35
4.1.1
Screening and Induction Qualification........................................................35
4.1.2
Induction.........................................................................................................38

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4.1.3
Second Dose of RBP-6000 .............................................................................42
4.1.4
Double-blind Treatment Period....................................................................42
4.2
Study Schematic...................................................................................................43
5
POPULATION..........................................................................................................44
5.1
Number of Participants.......................................................................................44
5.2
Inclusion Criteria.................................................................................................44
5.3
Exclusion Criteria................................................................................................45
5.4
Eligibility Criteria for Open-label Induction Sub-study..................................46
5.5
Participant Screening ..........................................................................................46
5.6
TM Buprenorphine Dosing Criteria ..................................................................47
5.7
RBP-6000 Dosing Criteria...................................................................................47
5.8
Deviation from Inclusion/Exclusion Criteria ....................................................47
5.9
Participant Rescreening ......................................................................................47
6
STUDY CONDUCT..................................................................................................48
6.1
Screening Period ..................................................................................................48
6.1.1
Participant Screening ....................................................................................48
6.1.2
Not Enrolled (Discontinuation Prior to Enrolment)...................................48
6.2
Enrolment.............................................................................................................48
6.3
TM Buprenorphine Induction Period................................................................48
6.4
TM Buprenorphine Early Termination.............................................................49
6.5
Treatment Period.................................................................................................49
6.5.1
Open-label Treatment Period .......................................................................49
6.5.2
Randomisation and Double-Blind Treatment Period.................................49
6.6
Participant Completion .......................................................................................49
6.7
Premature Discontinuation.................................................................................49
6.7.1
Participant Withdrawal from Treatment....................................................49
6.7.2
Participant Withdrawal from the Study......................................................50
6.7.5
Participant Withdrawal of Consent .............................................................51
6.7.6
Participants Lost to Follow-up .....................................................................51
7
STUDY SUSPENSION OR TERMINATION .......................................................53
8
DESCRIPTION OF STUDY PROCEDURES.......................................................54
8.1
Demographics and Medical/Psychiatric History...............................................54
8.2
Substance Use History.........................................................................................54
8.3
Efficacy Assessments ...........................................................................................54
8.3.1
Urine Drug Screening....................................................................................54
8.3.2
TimeLine Follow Back...................................................................................55
8.3.4
Clinical Opiate Withdrawal Scale ................................................................56

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8.7
Safety Assessments...............................................................................................59
8.7.1
Physical Examination ....................................................................................59
8.7.2
Injection site Evaluations ..............................................................................59
8.7.3
Clinical Laboratory Tests..............................................................................59
8.7.4
Vital Signs.......................................................................................................61
8.7.5
12-Lead Electrocardiograms.........................................................................61
8.8
Protocol Deviations..............................................................................................62
9
STUDY DRUG MANAGEMENT...........................................................................63
9.1
Description............................................................................................................63
9.1.1
Formulation....................................................................................................63
9.1.2
Storage ............................................................................................................63
9.2
Packaging and Labelling.....................................................................................64
9.3
Shipment...............................................................................................................64
9.4
Method of Assigning Participants to Treatment Groups.................................64
9.4.1
Randomisation into the Open-label Induction Sub-study..........................64
9.4.2
Randomisation into the DBTP......................................................................65
9.5
Blinding.................................................................................................................65
9.6
Procedure for Breaking the Blind ......................................................................66
9.7
Dose and Administration.....................................................................................66
9.7.1
Transmucosal Buprenorphine......................................................................66
9.7.2
RBP-6000 ........................................................................................................67
9.8
Accountability ......................................................................................................68
9.9
Concomitant Therapies .......................................................................................68
9.10
Prohibited Concomitant Therapies....................................................................69
9.11
Restricted Concomitant Therapies.....................................................................69
9.12
Lifestyle Restrictions ...........................................................................................70
9.13
Permitted Concomitant Therapies.....................................................................70
9.14
Compliance...........................................................................................................71
9.15
Reporting Product Complaints...........................................................................71
9.16
Schedule of Assessments......................................................................................72
10
ADVERSE EVENTS ................................................................................................73
10.1
AE of Special Interest..........................................................................................74
10.2
Assessing and Documenting Adverse Events ....................................................74
10.3
Time Period for Collecting Adverse Events ......................................................75

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10.4
Assessment of Intensity........................................................................................75
10.5
Assessment of Causality ......................................................................................75
10.6
Clinical Laboratory, Vital Signs, and Other Safety Findings..........................76
10.7
RBP-6000 Depot Removal...................................................................................77
11
SERIOUS ADVERSE EVENT................................................................................78
11.1
Definition of Serious Adverse Event ..................................................................78
11.2
Documenting Serious Adverse Events ...............................................................79
11.2.1
Investigator Reporting of Serious Adverse Events.....................................79
11.2.2
Regulatory Reporting Requirements for Serious Adverse Events............80
11.2.3
Overdosing with RBP-6000...........................................................................81
12
PREGNANCY...........................................................................................................82
12.1
Collecting and Reporting Pregnancy Information ...........................................82
12.2
Action to be Taken if Pregnancy Occurs in a Female Participant..................82
13
DATA MANAGEMENT..........................................................................................84
13.1
Data Collection and Management......................................................................84
13.2
Database Quality Assurance...............................................................................84
13.3
Source Documentation.........................................................................................84
14
STATISTICS.............................................................................................................86
14.1
General Procedures .............................................................................................86
14.2
Statistical Hypothesis...........................................................................................86
14.3
Sample Size...........................................................................................................86
14.4
Analysis Populations............................................................................................88
14.4.1
Efficacy Analysis Population ........................................................................88
14.4.2
Safety Analysis Populations ..........................................................................88
14.4.4
Sub-study ........................................................................................................89
14.5
Demographic and Disease Characteristics ........................................................89
14.6
Efficacy Analysis..................................................................................................89
14.6.1
Definition of Baseline.....................................................................................89
14.6.2
Primary and Secondary Estimands..............................................................90
14.6.3
Primary Efficacy Endpoint.........................................................................102
14.6.4
Secondary Efficacy Endpoint Analysis......................................................104
14.6.6
Subgroup Analysis .......................................................................................107
14.6.7
Multiplicity ...................................................................................................108
14.7
Interim Analysis.................................................................................................108
14.8
Handling of Missing Data..................................................................................108
14.9
Other Statistical Considerations.......................................................................108
14.9.3
Sub-study Analysis.......................................................................................110
14.10 Safety Analysis ...................................................................................................110

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14.10.1
Adverse Events.............................................................................................110
14.10.2
Extent of Exposure.......................................................................................111
14.10.3
Other Safety Variables ................................................................................111
15 ETHICS AND RESPONSIBILITIES...................................................................112
15.1
Good Clinical Practice.......................................................................................112
15.2
Data and Safety Monitoring Committee..........................................................112
15.3
Institutional Review Board/Independent Ethics Committee .........................112
15.4
Informed Consent ..............................................................................................112
15.5
Study Files and Record Retention....................................................................113
16 AUDITING AND MONITORING........................................................................114
17
AMENDMENTS.....................................................................................................116
18
STUDY REPORT AND PUBLICATIONS..........................................................117
19
STUDY DISCONTINUATION.............................................................................118
20
CONFIDENTIALITY ............................................................................................119
21
REFERENCES .......................................................................................................120
22
APPENDICES.........................................................................................................123
22.1
Schedule of Events – Screening (within 30 days prior to first induction 
day)......................................................................................................................123
22.2
Schedule of Events – Rapid Induction Day 1 (Injection 1) ............................125
22.3
Schedule of Events – Standard of Care (SoC) Induction...............................128
22.4
Schedule of Events – Week 1 Day 2 to Week 16 – All On-site Visits ............131
22.5
Schedule of Events – Week 18 to 36 – All On-site Visits................................133
22.6
Schedule of Events – Week 38 to Week 40 End of Study and Early 
Termination........................................................................................................135
22.7
Liver Safety.........................................................................................................137
22.8
Morphine Dose Analgesic Equivalence Table .................................................139
22.9
Open-Label Induction Sub-study.....................................................................140
1.
SUB-STUDY INTRODUCTION AND RATIONALE........................................140
2.
SUB-STUDY OBJECTIVES .................................................................................140
3.
SUB-STUDY ENDPOINTS ...................................................................................140
4.
SUB-STUDY PLAN................................................................................................141
5.
SUB-STUDY POPULATION................................................................................141
6.
SUB-STUDY CONDUCT ......................................................................................141
6.1.
Sub-study Screening ..........................................................................................141
6.2.
Sub-study Enrolment.........................................................................................141
7.
DESCRIPTION OF SUB-STUDY PROCEDURES............................................141
8.
SUB-STUDY STATISTICS...................................................................................142
8.1.
General Procedures ...........................................................................................142
8.1.1.
Analysis Conduct .........................................................................................142
8.1.2.
Analysis Conventions...................................................................................142
8.1.3.
Groups for Comparison ..............................................................................142
8.2.
Statistical Hypothesis.........................................................................................142

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8.3.
Sample Size and Power for Sub-study .............................................................142
8.4.
Analysis Populations..........................................................................................144
8.4.1.
Sub-study Enrolled Population...................................................................144
8.4.2.
Sub-study Full Analysis Set ........................................................................144
8.5.
Primary Endpoint Analysis: Treatment Retention at Injection 2 
(received at Week 2 visit) ..................................................................................144
8.6.
Secondary Endpoint Analysis: Time to Treatment Discontinuation 
from the First Dose of TM Buprenorphine Induction....................................144
8.8.
Safety Analysis ...................................................................................................145
8.8.1.
Extent of Exposure.......................................................................................145
8.8.2.
Adverse Events.............................................................................................145
8.9.
Other Analyses ...................................................................................................145
8.10.
Interim Analysis.................................................................................................146
8.11.
Handling of Missing Data..................................................................................147
LIST OF IN-TEXT TABLES
Table 1
List of Laboratory Tests..........................................................................61
Table 2
Schedules of Events..................................................................................73
Table 3
RBP-6000 300/300 mg Responder Rate for the Binary Primary 
Endpoint Comparison Required Under Assumptions of a Lower 
RBP-6000 300/100 mg Responder Rate .................................................88
Table 4
Power Under Various Assumed Responder Rates for RBP-6000 
300/300 mg and RBP 6000 300/100 mg ..................................................89
Table 5
Primary and Secondary Estimands........................................................93
Table 6
Overall TLFB Opioid Use Derivation Based on Daily TLFB Results at 
a Given Visit ...........................................................................................103
Table 7
Opioid Use Derivation Based on UDS and Overall TLFB Opioid Use 
Results at a Given Visit..........................................................................103
LIST OF IN-TEXT FIGURES
Figure 2
Screening Through Induction Qualification Flow Chart.....................37
Figure 3
Rapid Induction Flow Chart...................................................................41

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LIST OF ABBREVIATIONS
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BMI
body mass index
CI
confidence interval
COWS
Clinical Opiate Withdrawal Scale
CRF
case report form
DBTP
Double-Blind Treatment Period
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
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
IA
interim analysis
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IE
intercurrent events
IEC
Independent Ethics Committee
IES
intercurrent events strategy

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INR
international normalised ratio
IRB
Institutional Review Board
IV
intravenous(ly)
IXRS
Interactive Voice/Web Response System
KM
Kaplan-Meier
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
MOUD
medications for opioid use disorder
msec
millisecond
n
number of participants
NI
non-inferiority
 
 
OLTP
Open-label Treatment Period
OUD
opioid use disorder
Ph3DB
Phase III double-blind (study) – RB-US-13-0001
PLGH
poly(DL-lactide-co-glycolide) with a carboxylic acid end group
QTcF
corrected QT – Fridericia’s
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous(ly)
SD
standard deviation
SEP
Sub-study Enrolled Population
SFAS
Sub-study Full Analysis Set
SoC
standard of care
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
TLFB
TimeLine Follow Back

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1 INTRODUCTION AND RATIONALE
1.1 Background
Opioid use disorder (OUD) is a neurobehavioral syndrome characterised by repeated, 
compulsive seeking or use of an opioid despite adverse social, psychological and physical 
consequences (SAMHSA 2004). This chronic, relapsing disease has grown to epidemic 
proportions. The clinical course of OUD typically includes periods of exacerbation and 
remission, but the patient is never disease-free. A combination of counselling/behavioural 
therapy with medications for OUD (MOUD) provides for a whole-patient approach and is 
recommended by treatment guidelines as the current standard of care (SoC) for OUD. 
(Kampman 2015).    
SUBLOCADE® (extended-release buprenorphine) injection (RBP-6000), for 
subcutaneous (SC) use (CIII) is currently indicated for the treatment of moderate to 
severe OUD in patients who have initiated treatment with a transmucosal (TM) 
buprenorphine containing product for a minimum of 7 days to suppress opioid 
withdrawal signs and symptoms (SUBLOCADE prescribing information) in the United 
States of America (USA) and for similar indications in other regions. SUBLOCADE is 
administered once monthly (i.e., every 4 weeks) by SC injection and provides sustained 
plasma levels of buprenorphine, a mu opioid- receptor partial agonist, over the dosing 
interval. SUBLOCADE uses buprenorphine and the ATRIGEL® Delivery System, which 
consists of a biodegradable poly(DL-lactide-co-glycolide) with a carboxylic acid end 
group (PLGH) polymer, dissolved in a biocompatible solvent, N-methyl-2-pyrrolidone. 
SUBLOCADE is injected as a solution, and subsequent precipitation of the polymer 
creates a solid depot containing the buprenorphine. After initial formation of the depot, 
buprenorphine is released via diffusion from, and the biodegradation of, the depot. 
SUBLOCADE should be used as a part of a complete treatment programme that includes 
counselling and psychosocial support.
Approval of SUBLOCADE by the USA Food and Drug Administration (FDA) in 2017 
was based in part on results of a pivotal Phase III double-blind, placebo-controlled study 
(Ph3DB; RB-US-13-0001; NCT02357901). That study evaluated 2 dosing regimens of 
SUBLOCADE: 2 monthly doses of 300 mg followed by 4 monthly doses of 300 mg 
(300/300-mg regimen), and 2 monthly doses of 300 mg followed by 4 monthly doses of 
100 mg (300/100-mg regimen). The primary efficacy endpoint of the pivotal Ph3DB 
study was participants’ percentage abstinence from opioid use (based on urine drug 
screening [UDS] and self-reports) from Week 5 to Week 24. Both the 300/300-mg and 
300/100-mg SUBLOCADE regimens showed higher participants’ percentage abstinence 
compared with the placebo group (300/300 mg: 41%; 300/100 mg: 43%; placebo: 5%; 
P<0.0001). The key secondary endpoint was treatment success, defined as any participant 
with >80% abstinence from opioid use between Week 5 and Week 24. The 

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SUBLOCADE groups had higher proportions of participants who achieved at least 80% 
abstinence compared with the placebo group (300/300 mg: 29%; 300/100 mg: 28%; 
placebo: 2%; P<0.0001).
The recommended dose of SUBLOCADE is 300 mg monthly for the first 2 months 
followed by monthly 100-mg maintenance doses; increasing the monthly maintenance 
dose to 300 mg may be considered for patients who tolerate the 100-mg dose, but do not 
demonstrate a satisfactory clinical response, as evidenced by self-reported opioid use or 
UDS positive for opioid use. This current study is designed to evaluate differences 
between the 100-mg and 300-mg maintenance doses in participants predicted to benefit 
from the higher 300-mg maintenance dose based on their historical pattern of high-risk 
drug use, and to further describe the benefits and risks of the 300-mg and 100-mg 
maintenance doses. “High-risk opioid use” as defined in this protocol includes use of 
opioids for an average of 5 or more days per week in the last 4 weeks either via the 
injection route or at quantities of at least 500 mg intravenous (IV) heroin equivalent, 
which is consistent with the definition of high-risk drug use provided by the European 
Monitoring Centre for Drugs and Drug Addiction (EMCDDA 2014). Because 
quantitation of heroin equivalent is challenging to estimate, self-reported use of any dose 
of highly potent synthetic opioids (fentanyl and analogues excluding transdermal patches) 
was added. 
The study will be carried out in accordance to the protocol and with local legal and 
regulatory requirements, International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH)/Good Clinical Practice (GCP) 
and all applicable participant privacy requirements.
1.2 Study Rationale

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1.3 Risk-Benefit Assessment 
Buprenorphine 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. 
RBP-6000 has been shown to be an efficacious and safe treatment for moderate to severe 
OUD. 

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1.3.1
Risk Assessment 
The safety profile of buprenorphine is well-established, and the adverse events (AE) 
expected with buprenorphine are well characterised (see applicable product labelling 
information). Commonly reported AEs include drug withdrawal syndrome, constipation, 
headache, nausea and vomiting. Buprenorphine has been approved for multiple 
indications and routes of administration (e.g., TM, intramuscular, IV, transdermal, rectal 
and subdermal) in multiple countries and by various manufacturers. Buprenorphine has 
also been approved as a monthly SC injection for the treatment of OUD. 
The systemic safety profile for RBP-6000, given by a healthcare provider in clinical 
studies, is consistent with the known safety profile of TM buprenorphine with the 
expected exception of injection site reactions. In the Ph3DB study, participants receiving 
RBP-6000 300/300 mg (6 doses of 300-mg SC injections), 300/100 mg (300-mg SC 
injections for the first 2 doses followed by 4 doses of 100-mg SC injections), and placebo 
(volume-matched ATRIGEL Delivery System SC injections) experienced the following 
common, non-injection site adverse reactions: constipation, nausea, vomiting, abnormal 
liver enzymes, headache, sedation and somnolence. Most RBP-6000 injection site 
reactions were of mild to moderate severity, with 1 report of severe injection site pruritus. 
None of the injection site reactions were serious. One reaction, an injection site ulcer, led 
to study treatment discontinuation. The findings reported during post-marketing 
surveillance are consistent with those observed during the Ph3DB study, and do not 
indicate any trend of increased safety risk in patients.
In the Ph3DB study, AEs led to premature discontinuation in 4% of the group receiving 
RBP-6000 compared with 2% in the placebo group. 
In the Phase 3 open-label study (RB-US-13-0003, NCT02510014), AEs leading to drug 
dose reductions were reported in 7.3% of participants receiving RBP-6000. Participants 
in this long-term study received up to 12 injections of RBP-6000.
In INDV-6000-403 (which used the more rapid induction that is also explored in this 
current protocol), the most commonly reported treatment-emergent AEs (TEAE) were 
irritability, anxiety, nausea and pain. The majority of participants reported TEAEs within 
48 hours of RBP-6000 administration. Overall, the AE profile and level of sedation 
indicate that it is safe and tolerable to initiate RBP-6000 following a single dose of TM 
buprenorphine. There were no unexpected safety findings.
Like the participants in Study INDV-6000-403, participants in the current study will be 
treatment-seeking but still using opioids, which puts them at high risk for rapid and 
intense onset of withdrawal symptoms if buprenorphine is administered too soon after 
their last use of a full opioid agonist. The risk is increased with high doses of potent 
opioids, such as fentanyl, thus, an on-site dipstick UDS at Screening to identify current 

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opioids of abuse will support this discussion between the Investigator and study 
participant. As supported by the results of Study INDV-6000-403, this risk is also 
mitigated by the requirement for participants to be in withdrawal prior to receiving the 
first dose of TM buprenorphine. A single dose of 4 mg TM buprenorphine should be 
sufficient to identify hypersensitivity to buprenorphine and to minimise the occurrence of 
precipitated withdrawal (as a result of the participant inadequately/incorrectly reporting 
use of long- or short-acting opioids). Also, use of concomitant medications is permitted 
to alleviate any withdrawal symptoms that occur, such as ondansetron for 
nausea/vomiting, clonidine for anxiety/irritability and ibuprofen for pain/body aches, in 
accordance with SAMHSA TIP 63 2020 guidelines. In addition, following the first 
injection of 300 mg RBP-6000, TM buprenorphine in increments of 2 to 4 mg up to a 
maximum dose of 12 mg (inclusive of pre–RBP-6000 TM buprenorphine) may be 
administered on Day 1 at the discretion of the Investigator to alleviate withdrawal 
symptoms while on site. 
1.3.2
Benefit Assessment 
Clear efficacy was demonstrated in the pivotal and additional supporting studies of the 
RBP-6000 clinical development programme (detailed information provided in the 
applicable product labelling information). The results of the primary and key secondary 
efficacy analyses from the Ph3DB study are compelling and are supported by results 
from other secondary endpoints, as outlined briefly in Section 1. 
In addition, a sustained-release formulation of buprenorphine 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 to participants, their families and the community. All 
participants in this study will receive RBP-6000 (active treatment) and counselling.
Specific to this study, it was observed in the Ph3DB study that the subgroup of injecting 
opioid users achieved higher percentage abstinence at Week 24 with the 300/300-mg 
regimen compared with the 300/100-mg regimen and that the difference in the percentage 
of injecting opioid users remaining abstinent for the last 4 weeks of the 24-week 
treatment period was higher with 300/300 mg than with 300/100 mg, as detailed in 
Section 1.2. These observations are consistent with the scientific literature indicating that 
some individuals require higher buprenorphine exposure and higher levels of mu-opioid 
receptor occupancy to maximise abstinence and retention in treatment (Hillhouse 2011, 
Romero-Gonzalez 2017). Thus, participants in the current study (who use opioids via an 
injection route and/or use high doses of opioids) are expected to benefit from the higher 
maintenance dose of 300 mg. As demonstrated from the Ph3DB study data, participants 
who are randomised to the lower maintenance dose of 100 mg will still receive benefit 
from treatment (in terms of control of withdrawal and craving), even if it is not optimal 
with respect to abstinence from opioid use.

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1.3.3
Overall Risk-Benefit Summary 
Taken together, these findings indicate a favourable benefit/risk assessment in the main 
study to evaluate 2 dose regimens for RBP-6000 for use in patients with OUD who use 
opioids via an injection route and/or use high doses of opioids, and in the Open-label 
Induction Sub-study to evaluate rapid induction compared with SoC induction.

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2 STUDY OBJECTIVES
2.1 Primary
The primary objective of this study is to compare the efficacy of 100-mg and 300-mg 
maintenance doses of RBP-6000 administered every 4 weeks in participants who use 
opioids via an injection route and/or use high doses of opioids.
2.2 Secondary
The secondary objective of this study is to assess the effect of 100-mg and 300-mg 
maintenance doses of RBP-6000 administered every 4 weeks on treatment retention and 
parameters of harm reduction (e.g., frequency of opioid use) in participants who use 
opioids via an injection route and/or use high doses of opioids.
2.3 Exploratory
2.4 Safety 
The safety objective of this study is to assess the safety and tolerability of RBP-6000 in 
participants who use opioids via an injection route and/or use high doses of opioids. 
2.5 Sub-Study
Objectives for the Open-label Induction Sub-study are provided in Appendix 22.9.

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3 STUDY ENDPOINTS
3.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is:

proportion of responders for weekly opioid use, where a responder is defined as a 
participant whose percentage of visits with opioid abstinence (as measured via 
negative UDS and TLFB for the prior week) is greater than or equal to 80% over 
Weeks 20 to 38 (inclusive).
3.2 Secondary Efficacy Endpoints

participants’ percentage of days opioids were used out of days assessed (TLFB) over 
Weeks 10 to 38 (inclusive).

proportion of responders for weekly opioid use, where a responder is defined as a 
participant whose percentage of visits with opioid abstinence (as measured via 
negative UDS and TLFB for the prior week) is greater than or equal to 80% over 
Weeks 10 to 38 (inclusive).

participants’ percentage of visits with opioid abstinence (defined as negative UDS 
and Time-Line Follow Back [TLFB] for opioid use) over Weeks 10 to 38 (inclusive).

proportion of responders for weekly opioid use, defined as participants’ percentage of 
visits with opioid abstinence being greater than or equal to 80% for the last 5 visits 
planned for UDS and TLFB assessment over week 30 to week 38.

proportion of responders for daily opioid use, defined as participants’ percentage of 
days opioids were used out of days assessed (TLFB) being less than or equal to 20% 
for participants’ last 5 visits with observed TLFB post randomisation.

participants’ percentage of visits with opioid abstinence (defined as negative UDS 
and TLFB for opioid use) overall (Week 2 to 38 inclusive)

participants’ percentage of days opioids were used out of days assessed (TLFB) 
overall (Week 2 to 38 inclusive)  

for participants who use opioids via the injection route for an average of 5 or more 
days per week in the last 4 weeks prior to Screening, participants’ percentage of days 
opioids were used via the injection route out of days assessed (TLFB) overall 
(Weeks 10 to 38 inclusive)

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
average number of times opioids were used per week (TLFB) by visit

change in participants’ number of times opioids were used per week from Screening 
or randomisation baseline to each visit

proportion of participants abstinent (defined as negative UDS and TLFB for opioid 
use) by visit

average number of days opioids were used per week (TLFB) by visit

treatment retention since randomisation

proportion of randomised participants who complete the last scheduled injection of 
RBP-6000  
3.3 Exploratory Endpoints

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3.4 Safety Assessments
Major safety endpoints include the proportion of participants with at least 1 TEAE of the 
following types at any time during the treatment period: any TEAE, drug-related TEAE, 
treatment-emergent serious AE (SAE), drug-related treatment-emergent SAE, or TEAE 
leading to treatment discontinuation. 
Additional safety endpoint assessments include laboratory results, vital signs and use of 
concomitant medications. Participants will be followed up via telephone the day 
following Injections 1 and 2 to ask about AEs and associated concomitant medication 
use. 
3.5 Open-label Induction Sub-study Endpoints
Endpoints for the Open-label Induction Sub-study are described in Appendix 22.9. 

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4 STUDY PLAN
4.1 Study Design
All participants are expected to take part in both the main study and the Open-label 
Induction Sub-study (i.e., the activities of this nested sub-study are integral to the main 
study; the objectives and analyses of the sub-study are separate from those in the main 
study).  
4.1.1
Screening and Induction Qualification
This randomised, double-blind, parallel-group, multicentre study will compare the 
efficacy, safety and tolerability of 100-mg and 300-mg maintenance doses of RBP-6000 
administered every 4 weeks to treatment-seeking adult participants with moderate to 
severe OUD (as assessed by Diagnostic and Statistical Manual of Mental Disorders, 
5th Edition [DSM-5]) who use opioids via an injection route and/or use high doses of 
opioids. The flow of activities from Screening through induction qualification is provided 
in Figure 2. 

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Figure 2
Screening Through Induction Qualification Flow Chart
Participants who provide written informed consent will be assessed for eligibility during 
an up to 30-day Screening Period. During Screening, the Investigator will ask the 
participant to self-report recent drug use (including the use of a TLFB) to assess 
eligibility for high-risk opioid use. Eligibility will be assessed by the participants’ TLFB 
only, and the Investigator may discuss any positive UDS results with the participant only 
after the completion of the TLFB.
Participants determined to be eligible will be advised to abstain from short-acting opioids 
(such as morphine sulphate, oxycodone, hydromorphone, oxymorphone or codeine) for at 
least 6 hours, and long-acting opioids (such as methadone or levorphanol) for 24 hours 
before arriving at the site for TM buprenorphine induction. Participants will be informed 
that under-reporting their last use of opioids and undergoing induction with remaining 

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exposure to opioids places them at high risk for rapid and intense onset of withdrawal 
symptoms. This risk is increased with high doses of potent opioids, such as fentanyl, 
which may take longer to clear due to high lipophilicity, redistribution into fat, and 
prolonged excretion patterns (Mariani 2020). An on-site dipstick UDS at Screening to 
identify current opioids of abuse will support this discussion between the Investigator and 
study participant about the optimal period of abstinence for starting induction.
Eligible participants may complete the induction visit once all inclusion and exclusion 
criteria are confirmed, including applicable laboratory assessments. 
Approval from the sponsor must be obtained for any local laboratory and the laboratory 
normal ranges utilized to determine eligibility for screening. If a local laboratory is 
utilized for eligibility, the laboratory samples will also be sent to the central laboratory 
for the baseline analysis value. 
If eligibility is confirmed at the screening visit, participants may complete the induction 
visit. Participants having same-day screening and induction visits are not required to 
repeat the UDS, pregnancy test, vitals and ECG for the induction visit.
On induction days, eligible participants will provide a urine sample for a UDS dipstick 
and pregnancy test (female participants of child-bearing potential only). If a female 
participant has a positive pregnancy test, she will be discontinued and will not proceed 
with subsequent assessments. The Investigator will ask him/her to self-report recent drug 
use (including the use of a TLFB assessment). The Investigator may discuss any positive 
UDS results with the participant only after completion of the TLFB:
1. Participants who report that they have used long-acting opioids within the 
previous 24 hours will not be permitted to proceed with induction until the 
24-hour period has passed. If necessary, induction may be rescheduled. The 1st 
day of the repeat induction should be scheduled within  30 days of informed 
consent. 
2. Participants who have used short-acting opioids within the previous 6 hours may 
be permitted to proceed with the induction visit at the discretion of the 
Investigator. 
All concomitant medications used since Screening will be reviewed. 
The COWS will then be completed to assess withdrawal symptoms. 

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Participants must meet both of the following criteria to receive TM buprenorphine:
1. Have a negative pregnancy test (if female and of childbearing potential)
2. Be in withdrawal (COWS score ≥8) 
If a participant’s COWS score is <8, the participant may either be re-scheduled for 
induction within 30 days of informed consent or remain at the site (at the Investigator’s 
discretion), and the COWS may be repeated until the participant has a score ≥8. Only 
when the COWS score is ≥8 and all pre-TM buprenorphine assessments have been 
completed may the participant receive TM buprenorphine to begin induction.
4.1.2
Induction
When the participant has met the TM buprenorphine dosing criteria, he/she will be 
randomised at a 2:1 ratio to 1 of 2 induction arms: RBP-6000 rapid induction or SoC 
induction. Due to the potential for fentanyl use to impact the response to TM 
buprenorphine induction, randomisation will be stratified according to the same-day UDS 
result for fentanyl (negative or positive). 
The following points apply to both induction arms:

After randomisation, the participant will complete the pre-TM buprenorphine 
assessments: 
 
vital signs, 12-lead electrocardiogram (ECG) and a review of AEs. 

If the participant displays any allergic/hypersensitivity reaction to TM buprenorphine, 
the participant will be discontinued from the study. 

Participants experiencing precipitated withdrawal symptoms post-TM buprenorphine 
may be treated symptomatically (see Section 9.13).
4.1.2.1
Rapid Induction
The flow of activities for participants in the rapid induction arm is provided in Figure 3.
After completing the pre-TM buprenorphine assessments, participants will then be 
administered 4 mg of TM buprenorphine. 
After a minimum of 1 hour has elapsed since the 4-mg dose of TM buprenorphine was 
administered, the participant will be re-assessed for withdrawal symptoms (COWS) and 
tolerability (AEs). Participants must meet all of the following criteria to receive 
RBP-6000 using rapid induction:

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1. The participant does not display any allergic/hypersensitivity reaction to TM 
buprenorphine.
2. Based on the Investigator’s judgment, the participant did not experience 
precipitated withdrawal symptoms from the most recent TM buprenorphine 
administration that would prevent RBP-6000 administration. 
3. Based on the Investigator’s judgment, the participant is not sedated (i.e., 
participant cannot be easily aroused by external stimuli).
After receiving TM buprenorphine, if the participant is sedated or has precipitated 
withdrawal symptoms that would prevent RBP-6000 administration, in the opinion of the 
Investigator, the participant may either remain in the clinic to repeat the 4 mg TM 
buprenorphine later that same day or may return to the site and repeat the induction 
within 30 days of informed consent.
If the participant is eligible for dosing with RBP-6000, pre–RBP-6000 assessments will 
be conducted including, but not limited to, vital signs, 
 
will be collected. If the participant is eligible, 
300 mg RBP-6000 may be administered SC and the visit will be considered Day 1. 
Participants will be asked to remain in the clinic for at least 4 hours post-RBP-6000.  A 
COWS assessment will be completed at 1, 2 and 4 hours and an injection site evaluation 
will be completed at 1 and 2 hours post–RBP-6000. 
 
All AEs and concomitant medications should be recorded. If the 
participant experiences withdrawal symptoms post RBP-6000 on Day 1, the participant 
may be treated symptomatically (SAMHSA TIP 63 2020; see Section 9.13 for treatment 
of withdrawal symptoms). Also, following the first injection of 300 mg RBP 6000, TM 
buprenorphine in increments of 2 to 4 mg up to a maximum dose of 12 mg (inclusive of 
pre–RBP-6000 TM buprenorphine) may be administered on Day 1 at the discretion of the 
Investigator to alleviate withdrawal symptoms while on site. 
Prior to the participant leaving the site, the Investigator will be asked to assess the 
following:

Did the participant experience precipitated withdrawal after TM buprenorphine, and 
if so, which AEs were associated with the event? 

Did the participant experience precipitated withdrawal after the RBP-6000 injection 
and if so, which AEs were associated with the event? 

After how many hours would you have let the participant leave the clinic if you had 
not been required to observe them for at least 4 hours post injection?

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The participant will be followed up via telephone the day after the first RBP-6000 
injection.
Figure 3
Rapid Induction Flow Chart
 
 
4.1.2.2
Standard of Care (SoC) Induction 
After completing the pre-TM buprenorphine assessments, participants should then be 
inducted per SoC according to the applicable TM buprenorphine product labelling 

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information, that is, a participant should be dose-adjusted onto TM buprenorphine for a 
minimum of 7 days. 
On the first induction day, participants will be asked to remain in the clinic for at least 
5 hours after the first TM buprenorphine dose, completing COWS assessments at 1, 2, 3 
and 5 hours post TM buprenorphine. All AEs and concomitant medications should be 
recorded. If the participant experiences exacerbated withdrawal symptoms at any time, 
he/she may be treated symptomatically. 
Prior to the participant leaving the site, the Investigator will be asked to assess the 
following:

Did the participant experience precipitated withdrawal after TM buprenorphine, and 
if so, which AEs were associated with the event? 
Any doses of TM buprenorphine administered at the site, dispensed to the participant and 
taken by the participant outside of the clinic should be recorded. For reconciliation, 
participants will be asked to return any doses not taken as well as the empty packaging 
for all doses taken. The Investigator may ask the participant to return for dose adjustment 
as many times as necessary per SoC, recording any AEs and concomitant medications at 
each visit. 
Participants must meet all of the following criteria to receive RBP-6000 using SoC 
induction:
1. The participant has been dose-adjusted onto TM buprenorphine for a minimum of 
7 days and, based on the Investigator’s judgment, appears eligible for dosing with 
RBP-6000.
2. The participant does not display any allergic/hypersensitivity reaction to TM 
buprenorphine.
3. Based on the Investigator’s judgment, the participant did not experience 
precipitated withdrawal from the most recent TM buprenorphine administration 
that would prevent RBP-6000 administration.
4. Based on the Investigator’s judgment, the participant is not sedated (i.e., 
participant cannot be easily aroused by external stimuli).
5. The participant has a negative pregnancy test (if female and of childbearing 
potential).
If a female participant has a positive pregnancy test, she will be discontinued from the 
study and will not proceed with subsequent assessments.

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Participants will return to the site for weekly UDS and collection of self-reported drug 
use, including TLFB, from Weeks 1 to 10. From the fourth injection until the end of the 
treatment period (Weeks 10 to 38), UDS and self-reported drug use (including TLFB) 
will be obtained at every injection visit. In addition, random visits (2 weeks post each 
injection ±7 days) are to be scheduled by the Investigator to complete UDS and TLFB 
only. All participants will receive counselling, per SoC, from the first induction day 
through the end of the treatment period (Week 38/EOT). 
All participants will continue study treatment until they complete the EOT visit 
(Week 38). Participants who prematurely discontinue RBP-6000 treatment will complete 
the early termination (ET) visit. During the last injection visit (Week 34) through the 
EOT visit (or the ET for those who prematurely discontinue), the Investigator or a 
medically qualified sub-Investigator will discuss available treatment options for 
continued treatment. Any participant with ongoing AEs at the EOT or ET visit will also 
be followed up by phone 2 weeks later for the End of Study (EOS) visit to assess any 
ongoing AEs and concomitant medications associated with those ongoing AEs only.
Participants are not permitted to use supplemental TM buprenorphine after they leave the 
site on Day 1. No dose increases or decreases of RBP-6000 are allowed. 
If the participant experiences withdrawal symptoms at any time, he/she may be treated 
symptomatically (SAMHSA TIP 63 2020; see Section 9.13 for treatment of withdrawal 
symptoms).
4.2 Study Schematic
BUP=buprenorphine; min=minimum; SoC=standard of care; TM=transmucosal

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8. Agrees not to use buprenorphine-containing products other than those administered as 
part of study treatment for the duration of the treatment period.
9. A female participant is eligible to participate if she is not pregnant (as confirmed by a 
negative serum or urine human chorionic gonadotrophin test, not lactating and, if of 
childbearing potential, agrees not to become pregnant while on the study and to use 
medically acceptable means of contraception while on the study). The following 
methods of contraception are considered to be medically acceptable: established use 
of oral, injected or implanted hormonal contraception; placement of an intrauterine 
device or intrauterine system; or use of a double-barrier method of contraception 
(condom or occlusive cap with use of a spermicide).
5.3 Exclusion Criteria
A participant will not be eligible for inclusion in this 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 alcohol use disorders.
3. Meets DSM-5 criteria for severe alcohol use disorder.
4. Has had significant traumatic injury or major surgical procedure (as defined by 
the Investigator) within 30 days prior to the first dose of RBP-6000 or still 
recovering from prior such injury or surgery.
5. Has congenital long QT syndrome, history of prolonged QT in the 3 months prior 
to Screening, or history of medications or other factors that are at risk for 
Torsades de Pointes. 
6. Has abdominal area unsuitable for SC injections (e.g., nodules, scarring, lesions, 
excessive pigment).
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 uncontrolled intercurrent illness including, but not limited to, a medical or 
psychiatric illness/social situation that would limit compliance with study 
requirements or compromise the ability of the participant to provide written 
informed consent.

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9. Has any other active medical condition, organ disease or concurrent medication or 
treatment that may either compromise participant safety or interfere with study 
endpoints. 
10. Has total bilirubin ≥1.5 × upper limit of normal (ULN) (with direct bilirubin 
>1.3 mg/dL), ALT ≥3 × ULN, AST ≥3 × ULN, serum creatinine >2 × ULN, or 
international normalised ratio (INR) >1.5 × ULN at Screening.
11. Has known allergy or hypersensitivity to buprenorphine or any component of the 
ATRIGEL Delivery System. 
12. Is undergoing concurrent or has had prior treatment with any long -acting form of 
a buprenorphine-containing product in the past 2 years, or if >2 years has a 
positive UDS for buprenorphine at screening; treatment with oral buprenorphine, 
oral naltrexone or methadone products within 14 days prior to consent; or 
treatment with depot naltrexone within the 3 months prior to consent. 
13. Is undergoing concurrent treatment with another investigational agent or 
enrolment in another clinical study (except for an observational study) or 
treatment with another investigational agent within 30 days prior to Screening.
14. Is undergoing concurrent treatment with medications contraindicated for use with 
buprenorphine as per local prescribing information.
15. Has any pending legal status or pending legal action that could prohibit full 
participation in or compliance with study procedures.
16. Is under court order requiring treatment for OUD.
17. Is a member of site staff and/or has a financial interest in Indivior, or is an 
immediate family member of either the site staff and/or Indivior employee, 
directly involved in the study.
5.4 Eligibility Criteria for Open-label Induction Sub-study 
Inclusion and exclusion criteria for participants in the Open-label Induction Sub-study are 
identical to those in the main study.
5.5 Participant Screening
Participants who provide written informed consent will be assessed for eligibility during 
an up to 30-day Screening Period. 

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Participants determined to be eligible will be advised to abstain from short-acting opioids 
(such as morphine sulphate, 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 arriving at the site for TM buprenorphine induction. It will be explained 
that under-reporting the last use of opioids puts the participant at high risk for rapid and 
intense onset of withdrawal symptoms.
5.6 TM Buprenorphine Dosing Criteria 
Dosing criteria for the induction are provided in Section 4.1.1.
5.7 RBP-6000 Dosing Criteria 
Dosing criteria for the first RBP-6000 injection are provided in Section 4.1.2.1 (rapid 
induction) and Section 4.1.2.2 (SoC induction).
5.8 Deviation from Inclusion/Exclusion Criteria
Waivers from inclusion and exclusion criteria are not allowed because they have the 
potential to jeopardise participant safety, the scientific integrity of the study or regulatory 
acceptability of the data. Indivior does not grant waivers to the protocol-defined inclusion 
and exclusion criteria, and strict adherence to these criteria as outlined in the protocol is 
essential.
5.9 Participant Rescreening
Participants not meeting one or more inclusion/ exclusion criteria will be screen failures. 
Participants who have a change in clinical status may be rescreened with documented 
approval of the Sponsor’s Medical Monitor. 
Eligible participants who were not randomized to an induction arm (Section 4.1.2) within 
the 30-day screening period, may be rescreened for study participation following 
documented approval of the Medical Monitor. 
Eligible participants who were randomized to an induction arm (Section 4.1.2), may not 
be rescreened, regardless of whether they were administered TM buprenorphine. 
If a participant is rescreened, all screening assessments, as described in Appendix 22.1, 
will be repeated, including the re-signing of informed consent. The 30-day screening 
window will begin upon signature of the informed consent. 

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6 STUDY CONDUCT
6.1 Screening Period
The Screening period begins once written informed consent is obtained and ends at 
administration of TM buprenorphine. 
6.1.1
Participant Screening
Participants are considered screened once written informed consent is obtained; a 
participant identification number is then assigned. The participant identification number 
will be used to identify the participant during the Screening process and throughout study 
participation.
The Investigator is responsible for maintaining a master list (i.e., a participant 
identification list) of all consented participants and will document all participants that did 
not meet study eligibility criteria (i.e., screen failures), including reason(s) for 
ineligibility (i.e., a participant Screening and Enrolment Log). This document will be 
reviewed by Indivior or designated representative for accuracy and completeness. 
Ineligible participants, as defined by the protocol-specific inclusion and exclusion 
criteria, should not receive study drugs (TM buprenorphine or RBP-6000) and should be 
documented as screen failures.
6.1.2
Not Enrolled (Discontinuation Prior to Enrolment)
A participant will be considered discontinued prior to enrolment if written informed 
consent is obtained but the participant does not receive TM buprenorphine. Participants 
who discontinue from the study before TM buprenorphine administration will not be 
required to complete an EOT visit. Reasons for discontinuation prior to enrolment (e.g., 
withdrawal of consent, does/not meet specified inclusion or exclusion criteria, or does not 
meet TM buprenorphine dosing criteria) will be recorded in the electronic case report 
form (eCRF).
6.2 Enrolment
A participant will be considered enrolled if he/she receives at least 1 dose of TM 
buprenorphine, as defined in the study procedures.
6.3 TM Buprenorphine Induction Period
The TM Buprenorphine Induction Period begins when the participant receives TM 
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6.4 TM Buprenorphine Early Termination
Participants who discontinue from the study after TM buprenorphine administration and 
before any RBP-6000 administration will be withdrawn from the study. Any participants 
with ongoing AEs will be contacted via telephone 24 to 72 hours after TM buprenorphine 
administration to follow up on those ongoing AEs and associated concomitant 
medications.
6.5 Treatment Period
The treatment period begins when the participant receives TM buprenorphine and ends 
when the Week 38 EOT visit or ET visit has been completed. 
6.5.1
Open-label Treatment Period
The Open-label Treatment Period (OLTP) begins when the first TM buprenorphine dose 
is given and ends immediately prior to a participant receiving double-blind RBP-6000 
Injection 3. Note that pre-dose assessments for Injection 3 are considered part of the 
OLTP. 
6.5.2
Randomisation and Double-Blind Treatment Period
The randomised Double-blind Treatment Period (DBTP) begins when the participant 
receives randomised treatment at Week 6 (Injection 3) and ends when the Week 38 EOT 
visit or ET visit has been completed. 
6.6 Participant Completion
A completed participant for the main study is one who has completed the study through 
the EOT visit (Week 38). 
A completed participant for the Open-label Induction Sub-study is one who has been 
enrolled and has completed Injection 3, otherwise he/she is considered prematurely 
discontinued. Note that participants who prematurely discontinue from the Open-label 
Induction Sub-study will also prematurely discontinue from the main study.
6.7 Premature Discontinuation
6.7.1
Participant Withdrawal from Treatment 

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6.7.2
Participant Withdrawal from the Study 
If the participant has permanently discontinued study treatment and is no longer being 
followed for study assessments and procedures (including follow-up procedures), he/she 
will be considered withdrawn from the study. The primary reason for withdrawing from 
the study must be entered into the eCRF (e.g., participant is lost to follow-up, Indivior 
terminates the study, or Investigator discretion). 
Participants who discontinue from the study before TM buprenorphine administration 
will not be required to have any follow up. 
Participants who discontinue from the study after TM buprenorphine administration, and 
before RBP-6000 administration and have ongoing AEs, will be contacted via telephone 
24 to 72 hours after TM buprenorphine administration to assess those ongoing AEs and 
associated concomitant medications. 
All participants who receive RBP-6000 (including those who wish to discontinue early), 
will be encouraged to attend the ET visit 4 weeks after the last RBP-6000 administration. 
If the participant has any ongoing AEs, he/she will be contacted via telephone 2 weeks 
later to assess those ongoing AEs and associated concomitant medications.
6.7.3
Liver Chemistry Stopping Criteria 

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6.7.4
QTc Stopping Criteria 
6.7.5
Participant Withdrawal of Consent 
If a participant withdraws consent, he/she will not receive any additional doses of study 
treatment. However, the participant may be offered additional tests as needed to monitor 
safety (e.g., EOT safety assessments or procedures). 
6.7.6
Participants Lost to Follow-up 
In cases of a missed visit, the Investigator or designee must attempt to contact the 
participant and re-schedule 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. 

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In the event a participant is lost to follow-up, the Investigator or designee must make a 
reasonable effort to contact the participant. Two documented attempts (e.g., phone, email, 
etc.) to contact the participant followed by a certified mailed letter is considered 
reasonable. 
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 of the participant’s last study visit. 

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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7 STUDY SUSPENSION OR TERMINATION
Indivior reserves the right to temporarily suspend and/or permanently discontinue the 
study at any time and for any reason, including safety or ethical concerns or severe 
non-compliance. If such action is taken, Indivior will discuss the rationale for the 
decision with the Investigator. In cases where a study is suspended or terminated for 
safety reasons, Indivior will promptly inform Investigators and the Regulatory 
Authorities of this action and the reason(s) for the suspension or termination. 
If required by applicable regulations, the Investigator must inform the Institutional 
Review Board/Independent Ethics Committee (IRB/IEC) promptly and provide the 
reason(s) for the suspension or termination. If the study is prematurely discontinued, all 
study data and study drug remaining on site must be returned to Indivior or its designated 
representative.

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UDS (dipstick) may be performed as determined by the Investigator or a medically 
qualified sub-Investigator as per standard-of-care and/or if abuse is suspected. 
Additional information related to the collection and handling of urine specimens is 
located in the laboratory manual. 
8.3.2
TimeLine Follow Back
The TLFB Interview is a reliable and validated method administered by an interviewer to 
assess recent drug use in adults (Fals-Stewart 2000). The interview instrument asks 
participants to retrospectively estimate their daily drug use for each of the past 7 days 
prior to the visit. The TLFB captures only which days drugs were used (“used” or “did 
not use”) by specific opioid drug, or by drug class for other substances (see below). 
Therefore, additional self-report questions for opioids capturing the main route of use 
(and more specifically, if an injectable route was used) and the number of times used 
each day will also be added to those answered “used”. 
The interview will take approximately 10 to 30 minutes to complete. 
Drugs to be assessed in this study include opioids, oxycodone, fentanyl, morphine, 
methadone, buprenorphine, cocaine, cannabinoids, barbiturates, benzodiazepines, 
amphetamines/methamphetamine and phencyclidine. The TLFB is administered and 
scored electronically. 

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8.3.4
Clinical Opiate Withdrawal Scale
The COWS is an 11-item, validated instrument used to assess symptoms of opiate 
withdrawal (Tompkins 2009, Wesson 2003). The score is the sum of the response to each 
of the 11 items and ranges from 0 to 48. A score of 5 to 12 is considered mild, 13 to 24 is 
moderate, 25 to 36 is moderately severe, and a score >36 is considered severe 
withdrawal. 
Where feasible, each participant should be assessed by the same qualified and trained 
individual throughout the course of the study. The COWS is administered and scored 
electronically.
On all injection days, the COWS will be completed prior to RBP-6000 injection; the 
COWS will also be completed post injection on Day 1 (i.e., after the first injection of 
RBP-6000).

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8.7 Safety Assessments
Definitions and procedures for reporting AEs and SAEs are provided in Section 10 and 
Section 11, respectively.
8.7.1
Physical Examination
A complete physical examination will be conducted by the Investigator or a medically 
qualified sub-Investigator as noted on the Schedules of Events displayed in Table 2. 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). The examination will not include 
a breast, pelvic or rectal exam, unless clinically indicated. 
Weight (kg) will be assessed as shown in the Schedules of Events displayed in Table 2. 
Height (cm) will be recorded at Screening only.
8.7.2
Injection site Evaluations 
The RBP-6000 injection site will be evaluated for signs of attempted depot removal. Any 
removals will be reported as an AE of special interest as directed in Section 10.1. If there 
is any evidence of attempted depot removal present, the Investigator must discuss with 
the medical monitor about whether the participant should remain in the study. Any 
injection-site reactions or infections will be recorded as AEs. Injection-site evaluations 
will be performed according to the schedule of assessments, per Table 2.
8.7.3
Clinical Laboratory Tests
Clinical laboratory tests will be performed in a licensed clinical laboratory. Urine 
pregnancy tests may be performed using a dipstick test. Participants are to be in a 
sitting/supine position during blood collection. The following clinical laboratory tests 
(Table 1) will be performed according to the Schedules of Events displayed in Table 2.

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Table 1
List of Laboratory Tests
Haematology:
Haematocrit
Haemoglobin 
Mean corpuscular haemoglobin 
Mean corpuscular haemoglobin 
concentration 
Mean corpuscular volume 
Platelet count
Red blood cell (RBC) count
White blood cell (WBC) count with 
5-part differential
Urinalysis:
Appearance
Bilirubin
Colour
Glucose
Ketones
Leucocyte esterase
Microscopic examination of 
sedimenta
Nitrite
Occult blood
pH
Protein
Specific gravity
Urobilinogen
Other:b
HIV-1 and -2 antibodies
Hep C and Hep B antibodies
Serum Chemistryc:
Albumin
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT)
Amylase
Aspartate aminotransferase (AST)
Blood urea nitrogen
Calcium
Calculated creatinine clearance
Carbon dioxide
Chloride
Creatinine
Creatine kinase
(subtypes may be performed if 
required for clinical 
management) 
Gamma-glutamyl transferase
Glucose (non-fasting)
Lactate dehydrogenase
Lipase
Potassium
Sodium
Total bilirubin
Direct bilirubin (if total is high)
Total protein
Coagulation:
PTT
PT with INR
Pregnancy:
Urine pregnancy (only for 
females not 
postmenopausal or 
surgically sterile for at 
least 1 year)
Serum Pregnancy
Urine Drug Screen 
(UDS):
Opioids
Oxycodone 
Fentanyl 
Morphine
Methadone 
Cocaine
Amphetamines
Methamphetamine
Ecstasy
Cannabinoids
Barbiturates
Benzodiazepines
Phencyclidine
Buprenorphine (results 
collected in CRF from 
on-site dipstick at 
screening and first 
induction day only)
Hep=hepatitis; HIV=human immunodeficiency virus; INR=international normalised ratio; 
PT=prothrombin time; PTT=partial thromboplastin time
a
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).
b
The HIV-1/HIV-2, Hep B and Hep C antibody testing to be performed at Screening only in the 
absence of a positive (documented) medical history for these conditions and at EOT/ET only if 
negative at Screening.
c
The tests listed in serum chemistry are a minimum required list. Additional tests may be performed 
if included in the laboratory panel. 

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8.7.3.1
Sample Collection, Storage, and Shipping
Details for the collection, preparation, storage and shipment of laboratory specimens is 
outlined in the laboratory manual(s).
8.7.3.2
Laboratory Result Review
The Investigator or a medically qualified sub-Investigator will review the laboratory 
results and clearly identify those that are “abnormal, not clinically significant” as well as 
those that are “abnormal, clinically significant”. Any abnormal clinically significant 
laboratory value will be reported as an AE in the eCRF. The Investigator or a medically 
qualified sub-Investigator will sign and date laboratory reports as evidence of review.
8.7.4
Vital Signs
Evaluation of vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate 
and body temperature) will occur after the participant has been sitting for ≥3 minutes. 
Any clinically significant vital sign measurement (as determined by the Investigator or a 
medically qualified sub-Investigator) will be recorded as an AE and re-assessed at 
medically appropriate intervals until the value returns to an acceptable range, a specific 
diagnosis is established, or the condition is otherwise explained.
On injection days, the vital signs will be completed prior to RBP-6000 injection.
8.7.5
12-Lead Electrocardiograms
Electrocardiograms should be collected on the same model ECG machine for each 
participant, where feasible. All ECGs will be performed after the participant has been in a 
supine position for ≥5 minutes and before collecting any blood samples at that visit. 
Recordings will be taken using an ECG machine that automatically calculates the heart 
rate and measures QT and QTc intervals and can perform an arrhythmia analysis. The 
ECGs will be read locally. 
On injection days, the 12-lead ECG will be completed ≤60 minutes prior to RBP-6000 
injection.
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 medically qualified sub-Investigator as normal, abnormal – not clinically 
significant, or abnormal – clinically significant. All ECGs that are considered abnormal –
 clinically significant should be evaluated for a change from baseline and must be 
captured as an AE.

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8.8 Protocol Deviations
A protocol deviation is any noncompliance with the clinical study protocol or ICH/GCP 
requirements. The noncompliance may be on the part of the participant, the Investigator, 
or the study site staff. As a result of deviations, corrective actions are to be developed by 
the site and implemented promptly and in accordance with ICH E6. 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 the IRB/IEC. All deviations must be 
addressed in the study source documents. Protocol deviations must be sent to the local 
IRB/IEC as required. The Investigator and study site staff are responsible for knowing 
and adhering to the IRB/IEC’s requirements.

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9 STUDY DRUG MANAGEMENT
The term “study drug” is used throughout the protocol to describe the TM buprenorphine 
and/or RBP-6000 received by the participant as per the protocol design. Study drug may 
therefore refer to TM buprenorphine and/or RBP-6000. 
The term “study treatment” refers to the participants receiving the study drugs per 
protocol in combination with counselling.
Transmucosal buprenorphine will be administered per the applicable product labelling 
information at the timepoints defined in this protocol. The site will source commercially 
available TM buprenorphine for the study; RBP-6000 will be provided by the Sponsor. 
For this reason, only RBP-6000 is covered in the following section.
9.1 Description
9.1.1
Formulation 
RBP-6000 is a colourless to amber sterile solution for SC injection designed to deliver 
buprenorphine at a dose of 100 mg or 300 mg at a controlled rate over a 1-month 
(4-week) period. The active ingredient in RBP-6000 is buprenorphine (free base), a 
mu-opioid receptor partial agonist and a kappa-opioid receptor antagonist. Buprenorphine 
is dissolved in the ATRIGEL Delivery System at 18% by weight and is a biodegradable 
50:50 poly(DL-lactide-co-glycolide) polymer and a biocompatible solvent, 
N-methyl-2-pyrrolidone. Refer to the applicable product label for additional information 
on the physical and chemical properties of the drug substance and for a list of excipients.
Adequate precautions must be taken to avoid direct contact with the study drug. 
Occupational hazards and recommended handling procedures are provided in the Safety 
Data Sheet. 
9.1.2
Storage
RBP-6000 must be stored in the refrigerator at 2° to 8°C (35.6° to 46.4°F) in a secure 
location with limited access.
Once outside the refrigerator, RBP-6000 may be stored in its unopened original 
packaging at room temperature, 15°C to 30°C (59°F to 86°F), for up to 7 days prior to 
administration. Discard RBP-6000 if left at room temperature for longer than 7 days.
A product unit removed from refrigeration that has been exposed to room temperature 
(no more than 30°C) for no more than 24 hours while still in the original unopened 

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packaging, can be returned to refrigerated storage 1 time only and upon subsequent 
removal may still be held at up to 25°C for 7 days prior to use.
Other study drugs (e.g., TM buprenorphine) should be stored according to the label.
Temperature excursions outside of the defined ranges should be reported to the Sponsor, 
the product should be immediately quarantined and used only if/after Sponsor approval 
has been obtained (see Pharmacy Manual). 
The study drugs must be handled strictly in accordance with the protocol, applicable 
product labelling information, Pharmacy Manual, and applicable local laws and 
regulations.
9.2 Packaging and Labelling
The RBP-6000 clinical study labels will be developed in accordance with Good 
Manufacturing Practice and local regulatory requirements. Detailed information 
regarding the commercial packaging of RBP-6000 is outlined in the applicable product 
labelling information. 
RBP-6000 will be supplied by the Sponsor as a single, pre-filled syringe, the inner 
packaging (pouch) must remain with the outer product carton until the time of 
administration.
9.3 Shipment
RBP-6000 will be shipped under monitored refrigerated temperatures between 2ºC to 8ºC 
(35.6°F to 46.4°F). 
9.4 Method of Assigning Participants to Treatment Groups
When a participant signs the ICF, she/he will be assigned a unique participant number via 
Interactive Voice/Web Response System (IXRS) in numerical sequence, which will be 
used for the duration of the study. The participant number will be recorded in the source 
documentation. 
9.4.1
Randomisation into the Open-label Induction Sub-study
The sub-study randomisation will be implemented using an IXRS.
Qualified participants who meet all of the inclusion criteria, none of the exclusion 
criteria, and all of the TM buprenorphine dosing criteria will be randomised. Eligible 
participants will be randomised following the first induction day UDS, at a 2:1 ratio to 
receive either rapid induction or SoC induction. The induction randomisation number will 

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be assigned via the IXRS, using central, blocked, stratified randomisation schedules. The 
randomisation factor is first induction day UDS positive for fentanyl (yes or no).
Participants who are randomised but do not receive TM buprenorphine will not be 
replaced.
9.4.2
Randomisation into the DBTP 
After receiving two 300-mg RBP-6000 doses given 1 week apart during the OLTP, 
eligible participants will be randomised on Week 6 immediately prior to their third 
injection (i.e., 4 weeks after their second 300-mg dose of RBP-6000), at a 1:1 ratio to 
receive either 300 mg RBP-6000 or 100 mg RBP-6000 for 8 SC injections, 1 injection 
every 4 weeks. The double-blind period randomisation number will be assigned via an 
IXRS, using central, blocked, stratified randomisation schedules. The 2 randomisation 
factors are:1) opioid use predominantly via injection route at Screening (yes or no) and 2) 
Week 6 UDS result for opioids (negative or positive).
9.5 Blinding
Participants, Investigators and site personnel not involved in performing injections of 
RBP-6000 will be blinded to study medication during the DBTP (Injections 3 to 10). The 
blinding of the study will be maintained through several mechanisms.

An IXRS system will be used, which will track the randomisation for each study 
participant and will also assign the treatment that the participant will receive. The 
IXRS will be responsible for subsequent assignment of all RBP-6000 doses.

Each study site will have an unblinded study drug manager and an unblinded drug 
administrator who will have no other responsibilities in the clinical trial. These roles 
can be fulfilled by the same or multiple individuals. The person who administers the 
treatment must be a healthcare provider, who is familiar with giving injections.

At each injection visit in the DBTP (Injections 3 to 10), a unblinded staff member 
will contact IXRS to obtain the treatment assignment. 

The unblinded staff member will then obtain and prepare the RBP-6000 for 
administration. Because of volume and size differences between RBP-6000 
containing 100 mg or 300 mg buprenorphine, study participants and site personnel 
must be shielded from seeing the syringe prior to and during the injection. The 
unblinded staff member will apply a large blank label around the barrel of the syringe 
several times, to mask the volume and size of the injection. RBP-6000 preparation 
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
Once RBP-6000 has been prepared, the unblinded study drug administrator will 
administer RBP-6000 to the participant as described in the applicable product 
labelling information. RBP-6000 administered will be tracked via IXRS and drug 
accountability logs will be maintained for each participant, which the unblinded study 
drug manager will complete.
The Open-label Induction Sub-study will be open label.
9.6 Procedure for Breaking the Blind
The Investigator should not request the treatment assignment code unless knowledge of 
the participant’s treatment is required for the participant’s clinical care and safety. In the 
unlikely event that knowledge of the treatment assignment is necessary in order to treat a 
participant, the Investigator is encouraged to contact the medical monitor by telephone to 
discuss his/her rationale for unblinding. To prevent delays to the Investigator or medical 
personnel responding to a potentially emergent situation, unblinding of study medication 
will be done through the IXRS by the Investigator, and the medical monitor must be 
notified within 24 hours. Documentation of the breaking of the blind (intentional or 
unintentional) should be recorded in the participant’s medical record with the date and 
time the blind was broken, and the names of the personnel involved. The assigned 
treatment should not be communicated to any members of the study team or site staff 
unless necessary to provide treatment for the participant. If any unblinding occurs, the 
medical monitor should be notified.
9.7 Dose and Administration
Eligible participants will be advised to abstain from short-acting opioids (such as 
morphine sulphate, 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 arriving at the site on the morning of the first induction day. Eligible participants 
will be informed that under-reporting of the last use of opioids and undergoing induction 
with remaining exposure to opioids places them at higher risk for rapid and intense onset 
of withdrawal symptoms. Risk is increased with high doses of potent opioids, such as 
fentanyl, which may take longer to clear due to high lipophilicity, redistribution into fat, 
and prolonged excretion patterns (Mariani 2020). An on-site dipstick UDS at Screening 
to identify current opioids of abuse will support this discussion between the Investigator 
and study participant about the optimal period of abstinence for starting induction.
9.7.1
Transmucosal Buprenorphine
Participants are required to be in withdrawal (COWS ≥8) prior to administration of TM 
buprenorphine. The TM buprenorphine will be administered as per local prescribing 
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Participants experiencing exacerbated withdrawal symptoms post-TM buprenorphine will 
be treated symptomatically per the SAMHSA TIP 63 2020 guidelines (see Section 9.13 
for treatment of withdrawal symptoms) and will be asked to remain in the clinic. 
For participants in the rapid induction arm, if the participant does not meet RBP-6000 
dosing criteria (see Section 4.1.2.1) after a minimum of 1 hour after receiving 4 mg TM 
buprenorphine, a second dose of 4 mg TM buprenorphine may be administered later that 
same day at the discretion of the Investigator to reattempt induction while the participant 
is still in the clinic. Alternatively, the participant may return to the site and repeat the 
induction process within 30 days of informed consent.  
If a participant in the rapid induction arm experiences exacerbated withdrawal symptoms 
post RBP-6000 on Day 1, TM buprenorphine in increments of 2 to 4 mg up to a 
maximum dose of 12 mg (inclusive of pre–RBP-6000 TM buprenorphine) may be 
administered on Day 1 at the discretion of the Investigator to alleviate withdrawal 
symptoms while on site.
For participants in the SoC induction arm, TM buprenorphine may be administered and 
dispensed as per applicable product labelling information. Any doses of TM 
buprenorphine administered at the site, dispensed to the participant and taken by the 
participant outside of the clinic should be recorded. For reconciliation, participants will 
be asked to return any doses not taken as well as the empty packaging for all doses taken. 
The Investigator may ask the participant to return for dose adjustment as many times as 
necessary per SoC.
No participants are permitted to take home supplemental TM buprenorphine post the 
RBP-6000 injection on Day 1.
Time of dose is defined as the time the TM buprenorphine is placed into the oral cavity.
9.7.2
RBP-6000
RBP-6000 will be supplied by the Sponsor as a single, pre-filled syringe, the entire 
contents of which should be administered during a single SC injection by a healthcare 
provider as delegated by the Investigator. 
To remain eligible to receive RBP-6000, participants must not display any of the 
following on assessment after the administration of TM buprenorphine: any 
allergic/hypersensitivity reaction to TM buprenorphine, precipitated withdrawal 
symptoms that would prevent RBP-6000 administration or sedation from the most recent 
TM buprenorphine received prior to RBP-6000 dosing, in the opinion of the Investigator.

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RBP-6000 should be administered as per the Instructions for Use in the applicable 
product labelling information. After receiving two 300-mg RBP-6000 doses given 1 week 
(+4 days) apart (OLTP), eligible participants will be randomised immediately prior to 
their third injection, 4 weeks after their second 300-mg dose of RBP-6000, at a 1:1 ratio 
to receive either 300 mg RBP-6000 or 100 mg RBP-6000 for 8 SC injections, 1 injection 
every 4 weeks (-2/+4 days).
Time of dose for RBP-6000 is defined as the time the SC injection is complete. The time 
of dose and any dosing observations (e.g., 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. 
The Investigator will not supply RBP-6000 injection to any person except study 
personnel for SC injection of participants in this study. 
RBP-6000 will be dispensed under the supervision of the Investigator, a suitably 
qualified member of the study team, or by a pharmacist after confirmation that the 
participant meets all eligibility and dosing criteria. The Investigator or designee agrees to 
neither administer RBP-6000 from, nor store it at any location other than the study site 
agreed upon with the Sponsor. Site personnel must maintain accountability records per 
the Pharmacy Manual. 
9.8 Accountability
The Investigator is responsible for ensuring that all study drug received at the site is 
inventoried, accounted for and documented in accurate accountability records which will 
be provided to Indivior. All unused study drug will either be destroyed by the 
Investigator, as per local standard operating procedures (SOP) 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. 
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.
9.9 Concomitant Therapies
Concomitant medications will be collected from Screening through the completion of the 
EOT visit. Any concomitant medications (including herbal preparations) taken during the 

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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.
9.10
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 supplemental TM buprenorphine after they leave the site on 
Day 1.
Prescription use of additional buprenorphine (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. 
9.11
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 buprenorphine 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 healthcare 
professionals can reduce risk (see www.fda.gov/downloads 
/Drugs/DrugSafety/UCM576377.pdf for more information).
The RBP-6000 prescribing information should be referenced regarding use of the below 
concomitant therapies. 

benzodiazepines and other central nervous system depressants

cytochrome P450 3A4 inhibitors

cytochrome P450 3A4 inducers

antiretrovirals: non-nucleoside reverse transcriptase inhibitors

antiretrovirals: protease inhibitors

serotonergic drugs

monoamine oxidase inhibitors

muscle relaxants

diuretics

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
anticholinergic drugs
Contact the Indivior medical monitor if you have any questions or concerns if any 
enrolled participants initiating chronic treatment with any of these restricted medications.
9.12
Lifestyle Restrictions
Eligible participants will be advised to abstain from short-acting opioids (such as 
morphine sulphate, 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 arriving at the site on the morning of RBP-6000 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 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 buprenorphine.
9.13
Permitted Concomitant Therapies
The Investigator may prescribe concomitant medications or treatments deemed necessary 
to the participant, except those medications defined in Section 9.10 and Section 9.11 of 
this protocol. 
If the participant experiences withdrawal symptoms at any time (including withdrawal 
after RBP-6000), he/she may be treated symptomatically (SAMHSA TIP 63 2020):

Nausea: ondansetron or metoclopramide

Diarrhoea: loperamide

Anxiety, irritability, sweating: clonidine

Insomnia: diphenhydramine, trazodone

Pain: nonsteroidal anti-inflammatory drugs
Participants who experience opioid withdrawal after RBP-6000 administration may be 
treated with non-opioid medications as described above. 
For rapid induction participants, if precipitated withdrawal occurs post TM 
buprenorphine that would prevent RBP-6000 administration, an additional 4 mg TM 
buprenorphine may be re-administered later that same day at the discretion of the 
Investigator. Alternatively, the Investigator may permit the participant to return to the 

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facility on another day within 30 days of informed consent. Returning participants will 
repeat all Day 1 scheduled assessments.  In addition for rapid induction participants, 
adjunctive use of TM buprenorphine in increments of 2 to 4 mg up to a maximum of 
12 mg may be administered on Day 1 (i.e., 12 mg total TM buprenorphine on Day 1, 
inclusive of pre–RBP-6000 TM buprenorphine) at the discretion of the Investigator to 
alleviate withdrawal symptoms after the first injection of RBP-6000.
Investigators will be asked to identify concomitant medications administered to alleviate 
withdrawal symptoms. 
Participants will not be discontinued from treatment due to non-prescribed opioid use 
(including TM buprenorphine), but use should be captured on the TLFB. 
9.14
Compliance
All study treatments will be administered at the site, documented in the source and 
recorded in the eCRF. 
RBP-6000 injection compliance will be assessed by inspecting the injection site for 
evidence of attempted removal of the depot by the participant, documented in the source. 
Likewise, surgical removal by a physician will be documented in the source and recorded 
in the eCRF. See Section 10.7 for details on reporting depot removal.
Use of prohibited concomitant medications will be evaluated per the concomitant 
medication assessment outlined in the Schedules of Events accessed via Table 2, 
documented in the source and recorded in the eCRF.
9.15
Reporting Product Complaints 
The Investigator and study site staff are responsible for prompt recognition and reporting 
of product quality complaints to Indivior. A product quality complaint is any concern 
pertaining to the manufacturing or quality control of the study drug and includes, but is 
not limited to, e.g., 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 or odour that is outside of 
what is expected. 
All product quality complaints should be reported to Indivior 
 
in a timely manner and the following information provided: 

site number 

site contact/reported by 

kit number(s) 

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
participant number (if already assigned to a participant) 

description of issue 

picture, if available (photographs should be taken only if safe to do so/within site 
policy or practice to take photograph) 
If the product has not yet been opened (i.e., product does not pose any hazard), retain the 
product and packaging in a quarantined space until further instruction is provided by 
Indivior. If the product is potentially hazardous, dispose per site process and document in 
the source.
9.16
Schedule of Assessments
Schedules of assessments are included in the appendices as detailed in Table 2.
Table 2
Schedules of Events
Appendix
Time Period
22.1
Schedule of Events – Screening (within 30 days prior to first induction day)
22.2
Schedule of Events – Rapid Induction Day 1 (Injection 1)
22.3
Schedule of Events – Standard of Care (SoC) Induction 
22.4
Schedule of Events – Week 1 Day 2 to Week 16 – All On-site Visits
22.5
Schedule of Events – Week 18 to 36 – All On-site Visits
22.6
Schedule of Events – Week 38 to Week 40 End of Study and Early Termination

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10  ADVERSE EVENTS
The Investigator or designee is responsible for identifying, documenting and reporting 
events that meet the definition of an AE. 
An AE is any untoward medical occurrence in a participant associated with the use of a 
study drug regardless of the presence of a causal relationship to the study drug. An AE 
can be any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with a study drug, 
whether or not considered related to the study drug. 
Events meeting the definition of an AE include: 

New condition detected after study drug administration even though the AE may have 
been present prior to receiving study drug. 

Exacerbation of a pre-existing condition (including intensification of a condition 
and/or an increase in frequency). 

Any abnormal laboratory test results or other safety assessments felt to be clinically 
significant in the opinion of the Investigator (including those that worsen from 
baseline). 

Symptoms and/or the clinical sequelae of a suspected interaction. 

Signs, symptoms or the clinical sequelae resulting from special interest conditions 
(see Section 10.1). Overdose per se will not be reported as an AE/SAE unless this is 
an intentional overdose taken with possible suicidal/self-harming intent. This should 
be reported regardless of sequelae. 

Symptoms and/or clinical sequelae resulting from lack of efficacy will be reported if 
they fulfil the definition of an AE. 

Symptoms and/or clinical sequelae that resulted in intervention. 
Events that do not meet the definition of an AE include: 

The disease/disorder being studied, or expected progression, signs, or symptoms of 
the disease being studied, unless more severe than expected for the participant’s 
condition. 

Medical or surgical procedures; the condition that leads to the procedure is an AE. 

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
Situations where an untoward medical occurrence did not occur (e.g., 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 
or detected at the start of the study that do not worsen.
10.1
AE of Special Interest
In this study an AE of special interest is: 

RBP-6000 depot removal (see Section 10.7)
This AE of special interest should be reported to Indivior, by the Investigator (or 
designee) within 24 hours from first being aware of the event, using the same reporting 
process as for SAEs, See Section 11.2.
For the first induction day/Day 1, Investigators also will be asked to identify any AEs that 
were associated with precipitated withdrawal, if based on their clinical judgment, 
precipitated withdrawal occurs. 
10.2
Assessing and Documenting Adverse Events
The Investigator is ultimately responsible for assessing and reporting all AEs as outlined 
in the protocol. The assessment and reporting of AEs may be delegated to a medically 
qualified sub-Investigator, trained on this study protocol, who is listed on the delegation 
of authority log. All AEs regardless of treatment group or suspected causal relationship to 
the study drug will be reported as described in this protocol. 
Adverse events should be volunteered by the participant or solicited from the participant 
using a standard statement, obtained from examination of the participant at a site visit, or 
from observations of clinically significant laboratory values or special examination 
abnormal values. If an event assessed by one of the study scales requires intervention, or 
if in the opinion of the Investigator, it is clinically significant, then it will be reported as 
an AE. 
All AEs are to be assessed and recorded in a timely manner and followed to resolution or 
until the Investigator determines that there is not an anticipated resolution. Each AE is to 
be documented with reference to intensity (severity), date of occurrence, duration, 
treatment and outcome. Furthermore, each AE is to be classified as being serious or 
non-serious. In addition, the Investigator must assess whether the AE is study 
drug-related or not, whether the AE is an opioid withdrawal symptom and whether a 
concomitant medication was given. This should be documented in the eCRF.

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10.3
Time Period for Collecting Adverse Events
Adverse events will be collected from the time of signed informed consent until 
completion of the EOT/ET visit. Thereafter, participants will be contacted by telephone 
to assess AEs that were ongoing at the EOT/ET visit and concomitant medications 
associated with those ongoing AEs. Participants do not need to return to the site unless 
deemed medically necessary by the Investigator.
Participants with ongoing SAEs at the EOS telephone contact that, in the opinion of the 
Investigator, are associated with the study drug, will be followed and reported as 
described in Section 11. Participants with ongoing AEs at EOS telephone contact  will 
not be followed up further.
10.4
Assessment of Intensity
The term “severe” is used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe); the event itself, however, may be of relatively minor medical 
significance (such as a severe headache). This is not the same as “serious,” which is 
based on participant/event outcome or action criteria usually associated with events that 
pose a threat to a participant’s life or functioning. Seriousness (not severity) serves as a 
guide for defining regulatory reporting obligations.
Intensity 
Definition 
Mild 
Causes transient or mild discomfort; no limitation of usual activities; no medical 
intervention required 
Moderate 
Causes mild to moderate limitation in activity; some limitation of usual activities; no 
or minimal medical intervention or therapy is required
Severe 
Causes marked limitation in activity; some assistance is usually required; medical 
intervention or therapy is required; hospitalisation is probable
Adverse events with changes in severity should be documented as separate events.
10.5
Assessment of Causality
The Investigator or a medically qualified sub-Investigator, trained on this study protocol, 
listed on the delegation of authority log is responsible for determining the AE 
relationship to the study drug. 
The following categories will be used to define the relationship of an AE to the 
administration of the study drug: 

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Not Related:
Data are available to identify a clear alternative cause for the AE other 
than the study drug. 
 Related: 
The cause of the AE is related to the study drug and cannot be reasonably 
explained by other factors (e.g., the participant’s clinical state, 
concomitant therapy, and/or other interventions). 
 A “reasonable possibility” is meant to convey that there are facts/evidence or arguments 
to suggest a causal relationship, rather than that a relationship cannot be ruled out. The 
Investigator will use clinical judgment to determine the relationship. Alternative causes, 
such as natural history of the underlying diseases, concomitant therapy, other risk factors 
and the temporal relationship of the event to the study drug will be considered and 
investigated. The Investigator will also consult the applicable product labelling 
information in the determination of his/her assessment. For each AE/SAE, the 
Investigator must document in the medical notes that he/she has reviewed the AE/SAE 
and has provided an assessment of causality. 
There may be situations when an SAE or AE of special interest has occurred and the 
Investigator has minimal information to include in the initial report to Indivior or 
designated representative. However, it is imperative that the Investigator always make an 
assessment of causality for every event prior to the initial transmission of the SAE or AE 
of special interest data to Indivior or designated representative. The Investigator may 
change his/her opinion of causality in light of follow-up information and amend the SAE 
or AE of special interest data collection tool accordingly. The causality assessment is one 
of the criteria used when determining regulatory reporting requirements.
10.6
Clinical Laboratory, Vital Signs, and Other Safety Findings
Changes in laboratory values, vital signs or other safety parameters (e.g., neurological 
and clinical symptom assessments) as noted in the protocol are a sub-set of AEs and are 
reportable only if the lab test result is associated with accompanying symptoms, and/ or 
requires additional diagnostic testing or intervention (medical, surgical), and/or requires 
additional significant treatment, and/or requires temporal or permanent discontinuation of 
study drug, or a change to dosing other than as permitted by protocol, or if considered to 
be clinically significant by Investigator or medically qualified designee. 
Guidance for the procedures to follow for elevated liver function tests are provided in 
Appendix 22.7. 
All ECG findings that are considered abnormal and clinically significant should be 
evaluated for a change from baseline and must be captured as AEs.

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10.7
RBP-6000 Depot Removal
If clinically indicated, the RBP-6000 depot may be surgically removed within 14 days of 
injection. Any occurrence of depot removal will be captured in the database as an AE of 
special interest. In addition, the AE that resulted in the depot removal needs to be 
reported; this is not an AE of special interest. Additional details about the depot removal 
(e.g., the reason for the removal, whether the depot was removed by the participant or the 
Investigator, and whether this was voluntary or involuntary [i.e., whether the participant 
agreed to the removal]) also need to be reported. Depot removal should be reported using 
the same timing as for SAEs (see Section 11.2.1).

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11 SERIOUS ADVERSE EVENT
11.1
Definition of Serious Adverse Event
The Investigator or designee is responsible for identifying, documenting and reporting 
events that meet the definition of an SAE.
An SAE is any event that meets any of the following criteria:

Death

Life-threatening

Inpatient hospitalisation or prolongation of existing hospitalisation

Persistent or significant disability/incapacity

Congenital anomaly/birth defect in the offspring of a participant who received 
RBP-6000

Other: Important medical events that may not result in death, be life-threatening, or 
require hospitalisation, may be considered an SAE when, based upon appropriate 
medical judgment, they may jeopardise the participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such events are:
○
intensive treatment in an emergency room or at home for allergic bronchospasm
○
blood dyscrasias or convulsions that do not result in inpatient hospitalisation
○
development of drug dependency or drug abuse

Laboratory values of ALT or AST >3×ULN and bilirubin >2×ULN are defined as 
SAEs (important medical event), and should be reported to Indivior (or designated 
representative), by the Investigator (or designee) within 24 hours from first being 
aware of the event, using the same reporting process as for SAEs, See Section 11.2.1. 
Potential Hy’s Law cases should be managed as described in 22.7.
An AE is considered “life threatening” if the participant was at immediate risk of death 
from the event as it occurred; i.e., it does not include a reaction that if it had occurred in a 
more serious form might have caused death. For example, study drug-induced hepatitis 
that resolved without evidence of hepatic failure would not be considered life threatening 
even though study drug-induced hepatitis can be fatal. 

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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 10.5 of the protocol. 
In the event of an SAE, the Investigator or designee will notify Indivior Global Safety by 
completing the appropriate form(s) in the eCRF. Follow-up information will also be 
reported in the eCRF.
In the event that the electronic data capture system is not available, a paper Safety 
Information Collection Form should be completed and submitted to Indivior Global 
Safety via email or fax:
When the electronic data capture system is again available, the information recorded on 
the paper Safety Information Collection Form should be entered into the eCRF.
11.2.2
Regulatory Reporting Requirements for Serious Adverse Events 
Prompt receipt of notifications of SAEs to Indivior Global Safety (or designated 
representative) from Investigators is essential in ensuring that legal obligations and 
ethical responsibilities regarding the safety of participants are met. 
Indivior has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study drug. Indivior Global Safety (or 
designated representative) will comply with country-specific regulatory requirements 
pertaining to safety reporting to Regulatory Authorities, IRBs/ECs and Investigators. 
A suspected unexpected serious adverse reaction (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 (e.g., summary or line listing of SAEs, Dear Investigator Letter) will 
file it with the applicable product labelling information and will notify the IRB/EC, if 
required according to local requirements. 

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11.2.3
Overdosing with RBP-6000
Any instance of overdosing with RBP-6000 (e.g., participant received an additional dose 
of RBP-6000 before the appropriate dosing interval) must be communicated to the 
medical monitor within 24 hours. Details of any AEs associated with overdose or use of 
any concomitant medications used in managing those AEs should be recorded.

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12 PREGNANCY 
12.1
Collecting and Reporting Pregnancy Information 
Information on all pregnancies will be collected from receipt of study drug until 3 months 
following the last dose of TM buprenorphine (for participants who receive only TM 
buprenorphine) and until 12 months following the last dose of RBP-6000 (approximately 
6 to 8 terminal half-lives).  All confirmed pregnancies that occur within this study will be 
followed until resolution (i.e., termination [voluntary or spontaneous] or birth). 
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). 
The pregnancy must be followed up to determine outcome (including premature 
termination) and status of mother and infant. 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 foetal status (presence or absence of anomalies) 
or indication for procedure. 
Any pregnancy complication or elective termination for medical reasons must be reported 
as an AE or SAE. Any SAE occurring in association with a pregnancy, brought to the 
Investigator’s attention after the participant has completed the study and considered by 
the Investigator as possibly related to the study treatment, must be promptly reported to 
Indivior or designated representative. While the Investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of a pregnancy 
through spontaneous reporting. 
12.2
Action to be Taken if Pregnancy Occurs in a Female Participant 
If a female participant suspects that she is pregnant (e.g., missed period, self-administered 
pregnancy test) during treatment or within 12 months after the discontinuation of RBP-
6000, treatment will immediately be withheld, where applicable. 
If the participant is still participating in the study and suspects she is pregnant or has a 
positive urine pregnancy test at a visit, she will undergo a confirmatory serum pregnancy 
test at or before the next scheduled visit (prior to RBP-6000 injection). She will not 
receive any further treatment unless the pregnancy tests are confirmed negative. 

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If the result of the serum pregnancy test confirms the participant is pregnant, she will be 
discontinued from the study and will undergo all final study visit procedures (with the 
exception of any additional pregnancy testing); however, pregnant participants who have 
already received their final (10th) RBP-6000 injection may continue to complete the 
study. 
The Investigator should fully inform the female participant of potential risks to the foetus. 

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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. 
See also, Section 15.5, Study Files and Record Retention.

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14 STATISTICS
Statistical analyses for the Open-label Induction Sub-study are detailed in Appendix 22.9.
14.1
General Procedures
This section describes sample size determination, analysis populations and planned 
analyses for efficacy and safety measures. 
A statistical analysis plan (SAP) will be prepared after the protocol is approved and will 
be signed off before database lock occurs. The SAP will provide further details regarding 
analyses. Additional unplanned analyses may be required after all planned analyses have 
been completed. Any deviations from the analyses described below will be outlined in the 
SAP. Any unplanned analyses will be clearly identified in the clinical study report. 
Continuous variables will be summarised using descriptive statistics such as mean, 
standard deviations (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. Individual participant data 
will be presented by participant in data listings. Data listings will include all data 
collected from the initial Screening Visit to the EOS for all participants enrolled.
Buprenorphine plasma concentrations will be summarised at each scheduled time point.  
For summary purposes, buprenorphine plasma concentration values below the limit of 
quantification will be set to zero. 
14.2
Statistical Hypothesis
For the primary efficacy objective, the primary endpoint is the proportion of responders 
for weekly opioid use, where a responder is defined as a participant whose percentage of 
visits with opioid abstinence (as measured via negative UDS and TLFB for the prior 
week) is greater than or equal to 80% over Weeks 20 to 38. 
For the primary endpoint, the null  and alternative hypotheses are
H0: proportion of responders 300mg = proportion of responders 100mg  
HA: proportion of responders 300mg > proportion of responders 100mg.
14.3
Sample Size

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14.4
Analysis Populations
14.4.1
Efficacy Analysis Population
The Full Analysis Set (FAS) will serve as the primary population for the analysis of 
efficacy data in this study. The FAS population consists of all randomised participants 
who received at least 1 maintenance RBP-6000 injection post-randomisation. Participants 
will be included in the treatment group (RBP-6000 300/300 mg or RBP-6000 
300/100 mg) to which they are randomised for the efficacy analysis. 
14.4.2
Safety Analysis Populations
14.4.2.1
RBP-6000 Open-label Safety Population
The RBP-6000 Open-label Safety Population will be used for the safety analysis for the 
OLTP (during which every participant receives two 300-mg RBP-6000 injections). This 
population consists of all participants who received at least 1 post-enrolment open-label 
RBP-6000 injection. 

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14.4.2.2
RBP-6000 Double-blind Safety Population
The RBP-6000 Double-blind Safety Population will be used for the safety analysis for the 
randomised DBTP (i.e., the post-randomisation period). This population consists of all 
participants who received at least 1 maintenance RBP-6000 injection post-randomisation. 
For the DBTP, the participants will be analysed corresponding to the study treatment they 
actually received. For most participants, this will be the treatment group to which they are 
randomised. Any participant who receives incorrect study treatment for the entire DBTP 
will be included in the treatment group corresponding to the study treatment actually 
received.
14.4.4
Sub-study 
For details on analysis populations for participants in the Open-label Induction 
Sub-study, see Appendix 22.9.
14.5
Demographic and Disease Characteristics
Demographic and disease characteristics at Screening, (e.g., sex, race, age, weight, 
height, tobacco use, alcohol use, caffeine use, prior medications, history of drug use, 
route of opioid use, overdose history, medical and psychiatric history, and MOUD) will 
be summarised for FAS population, TM Buprenorphine Safety Population, and 
RBP-6000 Safety Population by treatment group using descriptive statistics. Qualitative 
variables, (e.g., sex, race) will be summarised using frequencies; quantitative variables 
(e.g., age, weight, height) will be summarised (e.g., using mean, SD, median, minimum 
and maximum).
14.6
Efficacy Analysis
14.6.1
Definition of Baseline
For change from baseline efficacy analyses, 3 baselines are defined. For each endpoint, 
the applicable baseline(s) will be specified in the protocol or SAP.  

Screening – the value collected at the Screening Visit.

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
Pre–Open-label Injection baseline – the last value prior to the first RBP-6000 
injection in the OLTP.

Pre–Double-blind Injection baseline – the last value prior to the first RBP-6000 
injection in the DBTP.
14.6.2
Primary and Secondary Estimands
The primary and secondary estimands are presented in Table 5.
The primary estimand aligns with the primary objective of the study. The primary 
endpoint,

Proportion of responders for weekly opioid use, where a responder is defined as a 
participant whose percentage of visits with opioid abstinence (as measured via 
negative UDS and TLFB for the prior week) is greater than or equal to 80% over 
Weeks 20 to 38 (inclusive)
aligns with endpoint recommendations in the FDA Guidance for Industry Opioid Use 
Disorder: Developing Depot Buprenorphine Products for Treatment (FDA 2019).

The endpoint measures a decrease in the use of opioids.

The endpoint is defined using an initial timepoint of Week 20. This 20-week interval 
incorporates a grace period as noted in the guidance (i.e., the 6-week OLTP) which 
allows participants time for engagement in treatment, plus 14 weeks post-
randomisation to allow for sufficient separation between the treatment groups with 
respect to plasma concentrations of buprenorphine.

For proportion of responders for weekly opioid use, missing visits following 
treatment discontinuation and skipped visits missing opioid use assessment are 
considered positive for opioid use and are reflected in the composite strategy for 
intercurrent events (IE). 

The primary endpoint is a responder definition, as per the guidance. 
The population will be the FAS, consisting of all randomised participants who receive at 
least 1 RBP-6000 injection post-randomisation. This population will represent the 
complete randomised population with the exception of participants who are randomised 
but do not receive randomised treatment (which is typically a rare occurrence).
The intercurrent events strategy (IES) is a composite strategy to address the IE of 
discontinuation from the treatment/study and skipped injection/visit. Under the strategy, 

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missing UDS + TLFB assessments at a visit (i.e., both are missing) due to these IEs are 
imputed as positive for opioid use. In addition to aligning with the FDA guidance, this 
composite strategy is considered appropriate in that participants who discontinue from 
the study or miss an injection or a visit can reasonably be assumed to have returned to 
using opioids for that timeframe (i.e., missing visits imputed as positive for opioid use). 
Therefore, in accordance with the composite strategy, the IE is incorporated into the 
endpoint via this imputation. 
The population-level summary statistic is the ratio or difference of the treatment group 
proportions. The estimates of the ratios will be unadjusted and will account for the 
stratified randomisation employed in the study. In addition, a supportive risk-adjusted 
estimation will be provided to adjust for baseline factors potentially impacting treatment 
response.
The primary sensitivity estimand has the same attributes as the primary estimand, except 
that the composite strategy for addressing IEs will utilise a multiple imputation method to 
impute monotone missing data due to discontinuation from the study. This estimand will 
allow evaluation of the primary estimand IES.

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Table 5
Primary and Secondary Estimands
Estimand Attributes
Statistical 
Category
Variable/
Endpoint
Population
IES
PLS
(Analysis)
Primary Objective:  To compare the efficacy of 100-mg and 300-mg maintenance doses of RBP-6000 administered every 4 weeks in participants who use 
opioids via an injection route and/or use high doses of opioids
Primary 
Efficacy 
Endpoint
Proportion of 
responders for 
weekly opioid use, 
where a responder is 
defined as a 
participant whose 
percentage of visits 
with opioid 
abstinence (as 
measured via 
negative UDS and 
TLFB for the prior 
week) is greater than 
or equal to 80% over 
Weeks 20 to 38 
(inclusive)
Study population: OUD 
treatment-seeking patients 
who use opioids via an 
injection route and/or use 
high doses of illicit 
opioids.
Analysis population: FAS
Composite strategy:
Visits with missing opioid assessments, 
i.e., missing both UDS and TLFB due to 
discontinuation from the study (monotone 
missing) or due to skipped visit 
(intermittent missing), will be imputed as 
“positive” for opioid use (i.e., worst-case 
outcome)
Cochran-Mantel-Haenszel test stratified for RF to 
provide the unadjusted treatment group 
comparison
Ratio/difference of the responder proportions (300 
mg vs. 100 mg) will be estimated using non-
parametric ANCOVA accounting for 
randomisation stratification to provide the 95% CI 
for unadjusted estimation 
Non-parametric ANCOVA to account for 
randomisation stratification and to adjust for 
factors at Screening or randomisation baseline 
potentially related to the primary endpoint (age, 
gender, alcohol and tobacco use, years of 
[injection route] opioid use, and concomitant non-
opioid drug use [e.g., cocaine]) to provide the 
95% CI for risk-adjusted estimation 

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Table 5
Primary and Secondary Estimands
Statistical 
Category
Estimand Attributes
Variable/
Endpoint
Population
IES
PLS
(Analysis)
Primary 
Efficacy 
Endpoint  
Sensitivity 
As primary 
As primary 
Composite strategy:
The monotone missing opioid usage 
assessment will be imputed using logistic 
regression method separately within each 
treatment group, under a missing at 
random assumption. The imputation 
model will include the RF and baseline 
factors used for the non-parametric 
ANCOVA. Fifty imputation data sets will 
be generated to draw statistical inference. 
Intermittent missing assessments will be 
imputed using Markov chain Monte Carlo 
method to produce monotone missingness 
or using the worst-case outcome of the 
observed result immediately before and 
after the missing value.
As primary for each imputed dataset

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Table 5
Primary and Secondary Estimands
Statistical 
Category
Estimand Attributes
Variable/
Endpoint
Population
IES
PLS
(Analysis)
Secondary 
Efficacy 
Endpoint 1
Participants’ 
percentage of days 
opioids were used 
out of days assessed 
(TLFB) over Weeks 
10 to Week 38 
(inclusive)
As primary 
While-on-treatment strategy
Missing daily TLFB (monotone or 
intermittent) will not be imputed. For the 
participant who has an injection of 
randomised treatment but without any 
TLFB assessed post-randomisation 
(typically a rare occurrence), participant’s 
percentage of days opioids were used will 
be derived based on his/her last observed 
TLFB prior to the randomisation, i.e., the 
TLFB for 7-day opioid use at the 
randomisation visit or the last observed 
TLFB after the first injection of RBP-6000 
if the TLFB is also missing at the 
randomisation visit.
Wilcoxon rank-sum test stratified for RF to 
provide the unadjusted treatment group 
comparison
Ratio/difference of the treatment group means 
(300 mg vs. 100 mg) will be estimated using non-
parametric ANCOVA accounting for 
randomisation stratification to provide the 95% CI 
for unadjusted estimation 
Non-parametric ANCOVA to account for 
randomisation stratification and to adjust for 
factors at Screening or randomisation baseline 
potentially related to the endpoint (age, gender, 
alcohol and tobacco use, years of [injection route] 
opioid use, and concomitant non-opioid drug use 
[e.g., cocaine]) to provide the 95% CI for risk-
adjusted estimation 

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Table 5
Primary and Secondary Estimands
Statistical 
Category
Estimand Attributes
Variable/
Endpoint
Population
IES
PLS
(Analysis)
Secondary 
Efficacy 
Endpoint 2
Proportion of 
responders for 
weekly opioid use, 
where a responder is 
defined as a 
participant whose 
percentage of visits 
with opioid 
abstinence (as 
measured via 
negative UDS and 
TLFB for the prior 
week) is greater than 
or equal to 80% over 
Weeks 10 to 38 
(inclusive)
As primary
As primary
As primary

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Table 5
Primary and Secondary Estimands
Statistical 
Category
Estimand Attributes
Variable/
Endpoint
Population
IES
PLS
(Analysis)
Secondary Objective:  To compare the efficacy of 100-mg and 300-mg maintenance doses of RBP-6000 administered every 4 weeks on treatment outcomes 
(e.g., treatment retention and harm reduction) in participants who use opioids via an injection route and/or use high doses of opioids
Secondary 3
Percentage of visits 
with opioid 
abstinence (defined 
as negative UDS 
and TLFB for the 
prior week) over 
Weeks 10 to 
Week 38 
(inclusive)
As primary 
As primary 
As secondary 1
Secondary 4
Proportion of 
responders for 
weekly opioid use, 
defined as -
participants’ 
percentage of visits 
with opioid 
abstinence being 
greater than or 
equal to 80% (for 
the last 5 visits 
planned for UDS 
and TLFB 
As primary
Composite strategy: impute missing 
visits as positive
The proportion of responders will be compared 
between treatment groups using the unadjusted 
non-parametric ANCOVA approach accounting 
for randomisation stratification described in 
Section 14.6.3.2. The ratio/difference between 
treatment groups will be estimated with 95% CI.

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Table 5
Primary and Secondary Estimands
Statistical 
Category
Estimand Attributes
Variable/
Endpoint
Population
IES
PLS
(Analysis)
assessment over 
Week 30 to 38)

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Table 5
Primary and Secondary Estimands
Statistical 
Category
Estimand Attributes
Variable/
Endpoint
Population
IES
PLS
(Analysis)
Secondary 5
Proportion of 
responders for 
daily opioid use, 
defined as 
participants’ 
percentage of days 
opioids were used 
out of days 
assessed (TLFB) 
being less than or 
equal to 20% for 
participants’ last 5 
visits with 
observed TLFB 
post randomisation.
As primary 
While-on-treatment
Missing data will not be imputed
As secondary 4
Secondary 6
Participants’ 
percentage of visits 
with opioid 
abstinence (defined 
as negative UDS 
and TLFB for 
opioid use) overall 
(Week 2 to 38 
inclusive)
As primary
As primary 
As primary

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Table 5
Primary and Secondary Estimands
Statistical 
Category
Estimand Attributes
Variable/
Endpoint
Population
IES
PLS
(Analysis)
Secondary 7
Participants’ 
percentage of days 
opioids were used 
out of days 
assessed (TLFB) 
overall (Week 2 to 
38 inclusive)
As primary 
As secondary 1
As secondary 1
Secondary 8
Participants’ 
percentage of days 
opioids were used 
via the injection 
route out of days 
assessed (TLFB) 
overall (Week 10 
to 38 inclusive)
Analysis population: 
The participants who 
use opioids via the 
injection route for an 
average of ≥5 days per 
week in the last 4 weeks 
prior to Screening sub-
population of the FAS
As secondary 1
As secondary 1
Secondary 9
Average number of 
times opioids were 
used per week 
(TLFB) by visit 
As primary 
While-on-treatment strategy
Missing daily TLFB (monotone or 
intermittent) will not be imputed.
The average number of times opioids were used 
per week (TLFB) for each treatment group will 
be summarised by visit from Screening to 
Week 38 for overall and within individual 
randomisation stratum; the difference between 
treatment groups will be estimated with a 
95% CI for each visit.

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Table 5
Primary and Secondary Estimands
Statistical 
Category
Estimand Attributes
Variable/
Endpoint
Population
IES
PLS
(Analysis)
Secondary 
10
Change in 
participants’ 
number of times 
opioids were used 
per week from 
Screening or 
randomisation 
baseline to each 
visit 
As primary
While-on-treatment strategy
Only the participants with complete 
7 daily TLFB information for a given 
visit will be analysed for that visit.
As an alternative approach to handle 
missing data, a supplemental analysis 
will include participants with complete 
or partial daily TLFB information at the 
visit. The participants with partial daily 
TLFB information at a given visit will be 
imputed as number of times used opioid 
divided by the number of days with 
observed TLFB information times 7 for 
that visit.
The mean change value or percentage change 
value from Screening or randomisation baseline 
for each treatment group will be summarised by 
visit from Screening or randomisation baseline 
to Week 38 for overall and within individual 
randomisation stratum; the difference between 
treatment groups will be estimated with a 
95% CI for each visit.
Secondary 
11
Proportion of 
participants 
abstinent (defined 
as negative UDS 
and TLFB for 
opioid use) by 
visit.
As primary
While-on-treatment strategy
Visit with missing opioid use 
assessments will not be imputed.
Proportion of participants abstinent will be 
estimated with 95% CI by visit for individual 
treatment groups from Screening to Week 38. 
The difference between the treatment groups 
will be estimated with 95% CI by visit 
Secondary 
Average number of 
As primary
While-on-treatment strategy
The average number of days opioids were used 

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Table 5
Primary and Secondary Estimands
Statistical 
Category
Estimand Attributes
Variable/
Endpoint
Population
IES
PLS
(Analysis)
12
days opioids were 
used per week 
(TLFB) by visit
Missing daily TLFB (monotone or 
intermittent) will not be imputed.
per week (TLFB) for each treatment group will 
be summarised by visit from Screening to 
Week 38 for overall and within individual 
randomisation stratum; the difference between 
treatment groups will be estimated with a 
95% CI for each visit. 
Secondary 
13
Treatment retention 
since 
randomisation
As primary 
Not applicable:
Intercurrent events are not relevant for 
this endpoint
Kaplan-Meier method to describe the survival 
curves.
Secondary 
14
Proportion of 
randomised 
participants who 
complete the last 
scheduled injection 
of RBP-6000
As primary 
Not applicable:
Intercurrent events are not relevant for 
this endpoint
Difference between treatment groups in the 
proportion
Non-parametric ANCOVA accounting for 
randomisation stratification to provide 
unadjusted estimation of the difference between 
treatment groups with 95% CI
ANCOVA=analysis of covariance; CI=confidence interval; DBTP=Double-Blind Treatment Period; FAS=Full Analysis Set; IES=intercurrent event(s) 
strategy; OUD = opioid use disorder; PLS=population-level summary; RF=randomisation factors; TLFB=TimeLine Follow Back; UDS=urine drug screen 
The 2 RFs are:1) opioid use predominantly via injection route at Screening (yes or no) and 2) Week 6 UDS result (negative or positive for opioids).

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14.6.3
Primary Efficacy Endpoint 
14.6.3.1
Derivation of Opioid Use Combining UDS and TLFB for a Visit
For the primary endpoint (proportion of responders for weekly opioid use over Weeks 20 
to 38), overall opioid use based on the 7 daily TLFB for the prior week at a visit will be 
derived according to Table 6, and opioid use at a visit combining UDS and overall TLFB 
opioid use will be derived according to Table 7. 
Table 6
Overall TLFB Opioid Use Derivation Based on Daily TLFB Results at 
a Given Visit
Daily TLFB Opioids
All Days = Missing All Non-missing Days = Did Not Use Any Day = Used
Overall TLFB Opioids
Missing
Negative
Positive
TLFB=TimeLine Follow Back
Table 7
Opioid Use Derivation Based on UDS and Overall TLFB Opioid Use 
Results at a Given Visit
Overall TLFB Opioids
Missing
Negative
Positive
Missing
Missing
Negative
Positive
Negative
Negative
Negative
Positive
UDS Opioids
Positive
Positive
Positive
Positive
TLFB=TimeLine Follow Back; UDS=urine drug screen
14.6.3.2
Analysis
The primary objective will be evaluated for the FAS by comparing the RBP-6000 
300/300-mg and the RBP-6000 300/100-mg groups on the primary endpoint:

proportion of responders for weekly opioid use, where a responder is defined as a 
participant whose percentage of visits with opioid abstinence (defined as negative 
UDS and TLFB for opioid use) is greater than or equal to 80% over Weeks 20 to 38 

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(inclusive, based on 6 scheduled UDS and TLFB assessments and 4 planned random 
unscheduled UDS and TLFB assessments). 
The percentage of visits with opioid abstinence for an individual participant will be 
derived as his/her number of visits with negative assessments divided by 10 (the number 
of the planned visits for opioid use assessments over Weeks 20 to 38), according to the 
composite IES. This is in fact to impute missing visits as positive. A participant with 8 or 
more opioid negative visits over Week 20 to 38 (i.e., greater than or equal to 80%) will be 
classified as a responder, otherwise as a non-responder.
A Cochran-Mantel-Haenszel (CMH) test stratified for randomisation factor will be 
performed to compare the 2 treatment groups on the primary endpoint. 
The primary endpoint will be summarised using descriptive statistics. The ratio or 
difference of the responder proportions for 300 mg vs 100 mg will be presented within 
individual stratum and overall.
Supplementary analysis using the non-parametric randomisation-based covariance 
analyses (Koch 1998, Zink 2012) will be performed to account for the randomisation 
strata. The unadjusted ratio or difference of the responder proportions and 95% CI will be 
estimated.
Supplementary analysis using the non-parametric randomisation-based covariance 
analyses will also be performed to account for the randomisation strata and to adjust for 
risk factors at Screening and randomisation baseline potentially related to the primary 
endpoint (such as age, gender, alcohol and tobacco use, years of [injection route] opioid 
use, and concomitant non-opioid drug use [e.g., cocaine]). The risk-adjusted ratio or 
difference of the responder proportions and 95% CI will be estimated.
For the primary endpoint sensitivity estimand, the monotone missing opioid use 
assessment will be imputed using the logistic regression method separately within each 
treatment group, under a missing at random assumption. The imputation model will 
account for the randomisation stratification and adjust for the risk factors noted above. 
Intermittent missing assessments will be imputed using Markov chain Monte Carlo 
method to produce monotone missingness or using the worst-case outcome of the 
observed result immediately before and after the missing value. Fifty imputation data sets 
will be generated to draw statistical inference.

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14.6.4
Secondary Efficacy Endpoint Analysis
Participants’ percentage of days opioids were used out of days assessed (TLFB) over 
Weeks 10 to Week 38 (inclusive) will be based on the 7 daily TLFB for the prior week 
collected at the 9 scheduled and 6 random unscheduled visits. The overall opioid use 
percentage for an individual participant will be derived as his/her number of days of 
opioid use divided by the number of days with observed TLFB information, according to 
the while-on-treatment IES. Missing daily TLFB (monotone or intermittent) will not be 
imputed. For the participant who has an injection of randomised treatment but without 
any TLFB assessed post-randomisation (typically a rare occurrence), participant’s 
percentage of days opioids were used will be derived based on his/her last observed 
TLFB assessment prior to the randomisation, i.e., the TLFB for the 7-day opioid use at 
the randomisation visit or the last observed TLFB after the first injection of RBP-6000 if 
the TLFB is also missing at the randomisation visit. A Wilcoxon ranksum (Van Elteren) 
test (van Elteren 1960) stratified for randomisation factor will be performed to compare 
the 2 treatment groups. The endpoint will be summarised using descriptive statistics. The 
cumulative distribution function by treatment group within individual stratum and overall 
will be graphically explored. The ratio or difference of the treatment group means for 300 
mg vs 100 mg will be presented within individual stratum and overall. Supplementary 
analysis using the non-parametric randomisation based covariance analyses (Koch 1998, 
Zink 2012) will be performed to account for the randomisation strata. The unadjusted 
ratio or difference of the treatment group means and 95% CI will be estimated. 
Supplementary analysis using the non-parametric randomisation based covariance 
analyses will also be performed to account for the randomisation strata and to adjust for 
risk factors at Screening and randomisation baseline potentially related to the endpoint 
(such as age, gender, alcohol and tobacco use, years of [injection route] opioid use, and 
concomitant nonopioid drug use [e.g., cocaine]). The risk adjusted ratio or difference of 
the treatment group means and 95% CI will be estimated.
Proportion of responders for weekly opioid use, where a responder is defined as a 
participant whose percentage of visits with opioid abstinence (as measured via negative 
UDS and TLFB for the prior week) is greater than or equal to 80% over Weeks 10 to 38 
(inclusive), will be analysed in the same manner as the primary endpoint. The opioid 
abstinence percentage for an individual participant will be derived as his/her number of 

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visits with negative assessments divided by 15. A participant with 12 or more opioid 
negative visits over Week 10 to 38 (i.e., greater than or equal to 80%) will be classified as 
a responder, otherwise as a non-responder.
Participants’ percentage of visits with opioid abstinence (defined as negative UDS and 
TLFB for opioid use) over Weeks 10 to 38 (inclusive, based on 9 scheduled UDS and 
TLFB assessments and 6 planned random unscheduled UDS and TLFB assessments). 
will use the composite IES to impute missing visits as positive. A Wilcoxon rank-sum 
(Van Elteren) test (van Elteren 1960) stratified for randomisation factor will be 
performed to compare the 2 treatment groups. The cumulative distribution function by 
treatment group within individual stratum and overall will be graphically explored and 
will compare various cut points for classifying a responder. The difference and ratio of 
responder rates for the 2 treatment groups will be described under the various cut points.
The responders for weekly opioid use will be based on participants’ percentage of visits 
with opioid abstinence being greater than or equal to 80% for the last 5 visits planned for 
UDS and TLFB assessment over Week 30 to Week 38, using the composite IES to 
impute missing visits as positive. The opioid abstinence percentage for an individual 
participant will be derived as his/her number of visits with negative assessments divided 
by 5. A participant with 4 or more opioid negative visits over Week 30 to 38 (i.e., greater 
than or equal to 80%) will be classified as a responder, otherwise as a non-responder. 
The responders for the daily opioid use will be based on the 7 daily TLFBs for the prior 
week collected at the last 5 observed visits post randomisation. The opioid use percentage 
for an individual participant will be derived as his/her number of days opioids were used 
divided by the number of days with observed TLFB information at those 5 visits post 
randomisation, according to the while-on-treatment IES with no imputation for missing 
data. For participants who have less than 5 visits with observed TLFB post 
randomisation, all available daily TLFB will be used to derive the opioid use percentage. 
A participant with 20% or less opioid use percentage will be classified as a responder, 
otherwise as a non-responder. The participant without observed daily TLFB will also be 
classified as non-responder.
The proportion of responders (for weekly and daily opioid use) will be compared 
between treatment groups using the unadjusted non-parametric ANCOVA approach 
accounting for randomisation stratification described in Section 14.6.3. The difference 
between treatment groups will be estimated with 95% CI.
The participants’ percentage of visits with opioid abstinence (defined as negative UDS 
and TLFB for opioids use) overall (Week 2 to 38 inclusive) will be analysed in the same 
manner as the primary endpoint. In addition, this endpoint will be graphically presented 
using the cumulative distribution function.

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The 2 secondary endpoints (participants’ percentage of days opioids were used out of 
days assessed [TLFB] overall [Week 2 to 38 inclusive] and participants’ percentage of 
days opioids were used via the injection route out of days assessed [TLFB] overall 
[Week 10 to 38 inclusive]) will be analysed in the same manner as secondary endpoint 2, 
except the analysis population for “used opioids via the injection route” will be those 
participants who use opioids via the injection route for an average of 5 or more days per 
week in the last 4 weeks prior to Screening sub-population of the FAS.
The average number of times opioids were used per week (TLFB) for a given visit within 
a treatment group will be based on the 7 daily TLFBs for the prior week collected at that 
visit, and calculated as the number of times opioids were used divided by the number of 
days with observed TLFB information for all participants within the group for that visit, 
then times 7. The endpoint will utilise a while-on-treatment IES with no imputation for 
missing data. The average value for each treatment group will be summarised by visit 
from Screening to Week 38 for overall and within individual randomisation stratum; the 
difference between treatment groups will be estimated with a 95% CI for each visit.
The change in participants’ number of times opioids were used per week from Screening 
or randomisation baseline to each visit will be based on the 7 daily TLFB for the prior 
week collected at that visit. A “while-on-treatment” strategy will be used to address IEs, 
in that only the participants with complete 7 daily TLFB information for a given visit will 
be analysed for that visit. The mean change value or percentage change value from 
Screening or randomisation baseline for each treatment group will be summarised by visit 
from Screening or randomisation baseline to Week 38 for overall and within individual 
randomisation stratum; the difference between treatment groups will be estimated with a 
95% CI for each visit. As an alternative approach to handle missing data, a supplemental 
analysis will include participants with complete or partial daily TLFB information at the 
visit. The participants with partial daily TLFB information at a given visit will be 
imputed as the number of times opioid were used divided by the number of days with 
observed TLFB information times 7 for that visit.
The proportion of participants abstinent (defined as negative UDS and TLFB for opioid 
use) for a given visit within a treatment group will be calculated as the number of 
participants abstinent (derived according to Table 6 and Table 7) divided by the number 
of participants with observed opioid use assessment for that visit. The average number of 
days opioids were used per week (TLFB) for a given visit within a treatment group will 
be calculated as number of days opioid were used divided by the number of days with 
observed TLFB information for all participants within the group for that visit, then times 
7.  Both endpoints will utilise a while-on-treatment IES with no imputation for missing 
data. The proportion or the average value for each treatment group will be summarised by 
visit from Screening to Week 38 for overall and within individual randomisation stratum; 
the difference between treatment groups will be estimated with a 95% CI for each visit. 

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The treatment retention since randomisation will be derived as the number of days from 
randomisation until the date of discontinuation. Participants who complete the study will 
be censored administratively at the EOT visit. The endpoint will be presented by 
treatment group for overall and within individual randomisation stratum using a 
Kaplan-Meier curve. Intercurrent events and missing data are not applicable for this 
endpoint.
The proportion of participants who complete the last scheduled injection of RBP-6000 at 
Week 34 will be compared between treatment groups using the unadjusted 
non-parametric ANCOVA approach accounting for randomisation stratification described 
in Section 14.6.3. The difference between treatment groups will be estimated with 95% 
CI. Intercurrent events and missing data are not applicable for this endpoint.
14.6.5
Exploratory Efficacy Endpoints Analysis 
14.6.6
Subgroup Analysis
For the primary and secondary efficacy endpoints, the treatment difference between the 
RBP-6000 300/300-mg and the RBP-6000 300/100-mg groups and the corresponding 
95% CI will be presented by the following subgroups:

Race (Black or African American vs. non-Black or African American)

Route of use (injection vs. non-injection) 
Any additional subgroup analyses will be described in the SAP.

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14.6.7
Multiplicity
There will be no multiplicity procedure applied across primary, secondary, and 
exploratory endpoints. Where statistical testing is performed, significance will be 
assessed at a nominal 2-sided 5% alpha-level.
14.7
Interim Analysis
No interim analyses are planned for the main study. For interim analyses in the 
Open-label Induction Sub-study, see Appendix 22.9.
14.8
Handling of Missing Data
The missing value handling approach for the primary efficacy endpoint is described in 
Sections 14.6.2 and 14.6.3, for the secondary efficacy endpoints in Sections 14.6.2 and 
14.6.4, for the exploratory efficacy endpoints in Section 14.6.5
 
. Details for the missing data handling 
approach(es) for the other analyses will be described in the SAP. 
No imputation of missing values will be performed for the safety analysis.
14.9
Other Statistical Considerations

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14.9.3
 Sub-study Analysis
For details on the statistical plan for the Open-label Induction Sub-study, see 
Appendix 22.9.
14.10 Safety Analysis
Safety data will be analysed using descriptive statistics for continuous endpoints and 
frequency counts with percentages for categorical endpoints. For RBP-6000 Open-label 
and Double-blind Safety Populations, safety data will be assessed by treatment group and 
overall for the OLTP and for the DBTP. The TM Buprenorphine Safety Population will 
also be used for summarising safety measures for the induction period. Complete details 
of the safety analyses will be provided in the SAP.
14.10.1
Adverse Events
Adverse events will be coded using MedDRA and grouped by system organ class. Events 
will be summarised with frequency and percentage, by system organ class and preferred 
term, by treatment group and overall for the DBTP and for the OLTP. Separate 
summaries will be provided for all TEAEs, drug-related TEAEs, serious TEAEs, TEAEs 
leading to discontinuation of study treatment, TEAEs associated with opioid withdrawal 
per the Investigator assessment, and TEAEs of special interest. TEAEs identified as 
injection site reactions and hepatic disorders using customised MedDRA queries will also 
be summarised. Details of the customised MedDRA queries will be provided in the SAP.
The incidence of deaths will also be reported and the primary causes of death summarised 
for the DBTP and the OLTP.
For details on TEAE assessment in the Open-label Induction Sub-study, see 
Appendix 22.9.

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14.10.2
Extent of Exposure
The number of participants administered RBP-6000 will be summarised according to the 
duration of treatment. The total number of RBP-6000 injections will be presented as a 
continuous summary and a categorical summary. The cumulative dose/injections of 
RBP-6000 will also be summarised by dose level (100 mg or 300 mg). The number of 
participants who had early surgical removal of the RBP-6000 depot will be summarised. 
The TM buprenorphine dose during the induction period will also be summarised.
14.10.3
Other Safety Variables 
The results of scheduled assessments of laboratory tests (haematology, chemistry and 
urinalysis), body weight, vital signs, 12-lead ECG, and concomitant medications will be 
summarised by treatment group and overall for the DBTP and for the OLTP. Further 
details will be provided in the SAP.

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15 ETHICS AND RESPONSIBILITIES
15.1
Good Clinical Practice
Prior to site activation, Indivior or designated representative will obtain 
approval/favourable opinion from the relevant regulatory agency(ies) to conduct the 
study in accordance with ICH GCP and any applicable country-specific regulatory 
requirements. 
The study will be carried out in accordance to the protocol and with local legal and 
regulatory requirements, ICH GCP and all applicable participant privacy requirements.
15.2
Data and Safety Monitoring Committee
There will be no data and safety monitoring committee for this study.
15.3
Institutional Review Board/Independent Ethics Committee
The protocol, ICF(s) and any other written information and/or materials to be provided to 
participants will be reviewed by an independent and appropriately constituted IRB/IEC. 
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. 
Study drug can only be released to the Investigator after documentation that all ethical 
and legal requirements for starting the study has been received by Indivior or designated 
representative.
15.4
Informed Consent
The Investigator or a person designated by the Investigator (if allowed by local 
regulations) is to obtain written informed consent (including electronic consent) from 
each participant prior to entering the study. All written informed consent documents are 
required to have been reviewed and received a favourable opinion/approval from an 
IRB/IEC prior to presenting them to a potential participant. 
Any changes to the ICF must be reviewed by Indivior before submission to the IRB/IEC. 
The written informed consent process will include the review of oral and written 
information regarding the purpose, methods, anticipated duration and risks involved in 
study participation. The Investigator is to ensure that each participant is given the 
opportunity to ask questions and allowed time to consider the information provided. The 
Investigator or a person designated by the Investigator must also explain to each 

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participant that participation is voluntary and that consent can be withdrawn at any time 
and without reason. Participants will receive a signed and dated copy of the signed ICF 
before any study-specific procedures are conducted. 
In the event that new safety information emerges that represents a significant change in 
the risk/benefit assessment, the ICF should be updated accordingly. All participants 
should be informed of the new information, provide their consent to continue in the 
study, and be provided with a signed and dated copy of the revised signed ICF. 
15.5
Study Files and Record Retention
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 (e.g., 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 (e.g., Health Insurance Portability 
and Accountability Act [HIPAA] documents), completed CRFs, source records 
(participant records, 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 (e.g., 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 back-up 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 in accordance with 
local regulations. If the Investigator withdraws from the study (e.g., relocation, 
retirement) all study-related records should be transferred, in a written agreement with 
Indivior, to a mutually agreed upon designee within Indivior-specified timeframe.

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16  AUDITING AND MONITORING
The purpose of an audit or regulatory inspection is to verify the accuracy and reliability 
of clinical study data submitted to a regulatory authority in support of research or 
marketing applications, and to assess compliance with statutory requirements regulations 
governing the conduct of clinical study. 
In accordance with applicable regulations, GCP, and Indivior procedures, the clinical 
monitor(s) will periodically contact the site, including conducting on-site monitoring 
visits at intervals agreed by the Investigator and documented in the Clinical Monitoring 
Plan. 
The clinical monitor(s) will contact the site prior to the start of the study to discuss the 
protocol and data collection procedures with site personnel. In accordance with 
applicable regulations and GCP guidelines, the Investigator shall make available for 
direct access all study-related records upon request by Indivior, Indivior’s agents, clinical 
monitor(s), auditors, and/or IRB/IEC. The monitors will visit the site during the study in 
addition to maintaining frequent telephone and written communication. The extent, 
nature, and frequency of on-site monitoring visits will be based on such considerations as 
the study objectives and/or endpoints, the purpose of the study, study design complexity 
and enrolment rate. 
The Investigator must allow the clinical monitor(s) direct access to all relevant 
documents and to allocate his/her time and the time of his/her staff to the clinical 
monitor(s) to discuss findings and any relevant issues. 
Upon completion of the study, study closeout activities must be conducted by Indivior or 
its designee in conjunction with the Investigator, as appropriate. 
Steps to be taken to ensure the accuracy and reliability of data include the selection of 
qualified Investigators and appropriate study sites, review of protocol procedures with the 
Investigators and associated personnel before the study, periodic monitoring visits by 
Indivior, and direct transmission of clinical laboratory data from a central laboratory into 
Indivior’s (or designee’s) database. Written instructions will be provided for study drug 
preparation and dosing, collection, preparation, and shipment of blood, plasma and urine 
samples. Guidelines for CRF completion will be provided and reviewed with study 
personnel before the start of the study. Indivior (or designee) will review CRFs for 
accuracy and completeness during on-site monitoring visits and after transmission to 
Indivior (or designee). Any discrepancies will be resolved with the Investigator or 
suitably qualified designee, as appropriate. 

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This study will be organised, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines. 
In accordance with the standards defined in Indivior SOPs and applicable regulatory 
requirements, clinical studies sponsored by Indivior are subject to Indivior Quality 
Assurance Investigator Site Audits that may be delegated to a contract research 
organisation or Indivior contract auditors. Investigator Site Audits will include review of, 
but are not limited to, drug supply, presence of required documents, the informed consent 
process, and comparison of CRFs with source documents. 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 contract research organisation’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.

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17 AMENDMENTS
Protocol modifications, except those intended to reduce immediate risk to study 
participants, may be made only by Indivior. A protocol change intended to eliminate an 
apparent immediate hazard to participants may be implemented immediately, provided 
the IRB/IEC is notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment. The 
written amendment must be submitted to the IRB/IEC and the Investigator must await 
approval before implementing the changes. Indivior or designated representative will 
submit substantial protocol amendments to the appropriate Regulatory Authorities for 
approval. 
If in the judgment of the IRB/IEC, the Investigator, and/or Indivior, the amendment to the 
protocol substantially changes the study design and/or increases the potential risk to the 
participant and/or has an impact on the participant’s involvement as a study participant, 
the currently approved written ICF will require similar modification. In such cases, 
informed consent will be renewed for participants enrolled in the study before continued 
participation, based on IRB/IEC determination.

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18 STUDY REPORT AND PUBLICATIONS
A clinical study report 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. 
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.

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19 STUDY DISCONTINUATION 
Both Indivior and the Investigator reserve the right to terminate the study at the 
Investigator’s site at any time. 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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20 CONFIDENTIALITY
All participant-identifying documentation generated in this study is confidential and may 
not be disclosed to any persons not directly concerned with the study without written 
permission from the participant. However, authorised regulatory officials and Indivior 
personnel (or their representatives) will be allowed full access to inspect and copy the 
records. All participant bodily fluids and/or other materials collected shall be used solely 
in accordance with this protocol and the ICF signed by the participant, unless otherwise 
agreed to in writing by Indivior. 
Each participant will be identified by an assigned participant identification number when 
reporting study information to any entity outside of the study site. Data containing 
participant identification will not be removed from the study site without first redacting 
participant identifiers.

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21 REFERENCES
Chou R, Ballantyne JC, Fanciullo GJ, Fine PG, Miaskowski C. Research gaps on use of 
opioids for chronic noncancer pain: findings from a review of the evidence for an 
American Pain Society and American Academy of Pain Medicine clinical practice 
guideline. J Pain. 2009 Feb 1;10(2):147-59.
European Monitoring Centre for Drugs and Drug Addiction. European Drug Report 2014 
(data and statistics): high-risk drug use — an overview of the methods and definitions 
used. Accessed at https://www.emcdda.europa.eu/data/2014/methods-hrdu  on 06 Apr 
2022).
Fals-Stewart W, O’Farrell TJ, Freitas TT, McFarlin SK, Rutigliano P. The timeline 
followback reports of psychoactive substance use by drug abusing patients: psychometric 
properties. J Consult Clin Psychol. 2000. 68(1):134-44.
Food and Drug Administration. Guidance for Industry. Drug-induced liver injury: 
premarketing clinical evaluation. July 2009.
Food and Drug Administration. Guidance for Industry. Opioid use disorder: developing 
depot buprenorphine products for treatment. February 2019.
Hillhouse M, Canamar CP, Doraimani G, Thomas C, Hasson A, Ling W. Participant 
characteristics and buprenorphine dose. Am J Drug Alcohol Abuse. 2011 
Sep 1;37(5):453-9.
Hoffman K, Peyton ML, Sumner M. Safety of a rapidly dissolving 
buprenorphine/naloxone sublingual tablet (BNX-RDT) for treatment of opioid 
dependence: a multicenter, open-label extension study. J Addict Med. 2017 
May/Jun;11(3):217-23.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen 
overdose and acute liver failure. Drug Metabol Disposit. 2009 Aug 1;37(8):1779-84.
Kampman K, Jarvis M. ASAM National Practice Guideline for the Use of Medications in 
the Treatment of Addiction involving Opioid Use. J Addict Med. 2015, 9:358-67.
Koch GG, Tangen CM, Jung JW, Amara IA (1998). “Issues for covariance analysis of 
dichotomous and ordered categorical data from randomized clinical trials and 
non-parametric strategies for addressing them.” Statistics in Medicine, 17, 1863–92.

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Laird J, Nielsen T. The effects of physician prescribing behaviors on prescription drug 
use and labor supply: evidence from movers in Denmark. Job Market Paper. 
http://scholar. harvard. edu/files/lairdja/files/Laird_JMP. pdf. 2016 Nov 21.
Mariani  JJ, Mahony A, Iqbal MN, Luo SX, Naqvi NH, Levin FR. Case Series: Rapid 
Induction Onto Long Acting Buprenorphine Injection for High Potency Synthetic Opioid 
Users. Am J Addict. 2020 Jul;29:345-8. 
National Cancer Institute. Cancer pain (PDQ®) – health professional version. Last 
updated 03 Sep 2020. Accessed at https://www.cancer.gov/about-cancer/treatment/side-
effects/pain/pain-hp-pdq#link/_63_toc  on 06 Apr 2022.
Romero-Gonzalez M, Shahanaghi A, DiGirolamo GJ, Gonzalez G. 
Buprenorphinenaloxone treatment responses differ between young adults with heroin 
and prescription opioid use disorders. Am J Addict. 2017 Dec;26(8):838-44.
Rook EJ, van Ree JM, van den Brink W, Hillebrand MJ, Huitema AD, Hendriks VM, 
Beijnen JH. Pharmacokinetics and pharmacodynamics of high doses of pharmaceutically 
prepared heroin, by intravenous or by inhalation route in opioid-dependent patients. Basic 
Clin Pharmacol Toxicol. 2006 Jan;98(1):86-96.
SUBLOCADE® (extended-release buprenorphine) injection, for subcutaneous use (CIII) 
USPI. Indivior; June 2021.

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Substance Abuse and Mental Health Services Administration (SAMHSA). Center for 
Substance Abuse Treatment. Treatment Improvement Protocol (TIP) 63, Medications for 
Opioid Use Disorder. HHS Publication No. PEP20-02-01-006. 2020.
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.
Tompkins DA, Bigelow GE, Harrison JA, Johnson RE, Fudala PJ, Strain EC. Concurrent 
validation of the Clinical Opiate Withdrawal Scale (COWS) and single-item indices 
against the Clinical Institute Narcotic Assessment (CINA) opioid withdrawal instrument. 
Drug Alcohol Depend. 2009;105(1-2):154-9.
van Elteren, PH. On the Combination of Independent Two Sample Tests of Wilcoxon. 
Bulletin of the Institute of International Statistics, 1960; 37:351–361.
Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive 
Drugs. 2003;35(2):253-9.
Zink RC, Koch GG . NParCov3: A SAS/IML macro for nonparametric randomization-
based analysis of covariance. J Stat Software. 2012;50(3):1-17.

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22.2
Schedule of Events – Rapid Induction Day 1 (Injection 1)
Visit Name (Window)
First Induction Day1 / Repeat Induction Day
Week 1 Day 1
Timepoint
Check in2
Pre-TM BUP
TM BUP
Post- TM BUP
Pre–RBP-6000
RBP-6000
Post RBP-6000
Planned Time 
-1 hr
0 hr
1 hr
2 hr 
4 hr
Urine Pregnancy Test3
X
UDS4
X
Self-Reports/TLFB5
X
COWS6 
X
X7
X
X
X
AE Assessment and Concomitant 
Medications8
Dosing Criteria 
X9
X10
Open-Label Randomisation11
X
Vital Signs13
X
X14
12-Lead ECG15
X
TM Buprenorphine 
Administration16
X
300-mg RBP-6000 Administration
X
Injection Site Evaluation19
X
X
Counselling20
AE=adverse event; COWS=Clinical Opiate Withdrawal Scale; ECG=electrocardiogram; 
TLFB=TimeLine Follow Back; TM=transmucosal; UDS=urine drug screen 

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22.3Schedule of Events – Standard of Care (SoC) Induction 
Visit Name (Window)
First Induction Day - TM Buprenorphine Induction 
Dose 
Adjustment 
Day(s)
W1 D1
Timepoint
Check 
in1
Pre-TM 
BUP
TM BUP 
Post TM BUP
Pre–
RBP-6000
RBP-
6000
Post RBP-6000
Planned Time 
1 hr
2 hr
3 hr
5 hr
0 hr
1 hr
2hr
4 hr
Urine Pregnancy Test2
X
X
UDS3
X
X
Self-Reports/TLFB 4
X
X
COWS5 
X
X6
X
X
X
X
X
X
X
AE Assessment and Concomitant 
Medications7
Dosing Criteria
X8
X9
Open-Label Randomisation10
X
Vital Signs12
X
X
12-Lead ECG13
X
X
TM Buprenorphine Administration14
X
X
TM Buprenorphine Dispensation14
X
X
300-mg RBP-6000 Administration
X
Injection Site Evaluation18
X
X

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22.5
Schedule of Events – Week 18 to 36 – All On-site Visits 
Visit Name
W18 
D120
W20 
D134
W22 
D148
W24
D162
W26 
D176
W28
D190
W30 
D204
W32 
D218
W34 
D232
W36 
D246
RBP-6000 Injection Number 
6
7
8
9
10
Window (days)
-2/+4
-7/+7
-2/+4
-7/+7
-2/+4
-7/+7
-2/+4
-7/+7
-2/+4
-2/+4
Urine Pregnancy Test1
X
X
X
X
X
UDS2
X
X3
X
X3
X
X3
X
X3
X
X
Self-reports/TLFB4 
X
X3
X
X3
X
X3
X
X3
X
X
Vital Signs6
X
X
X
X
X
X
000 
ents
Weight/BMI9
X
X
X
X
X
X
AE Assessment and Concomitant 
Medications10
RBP-6000 Administration11
X
X
X
X
X
Injection Site Evaluation12
X
X
X
X
X
X
Counselling 13
X

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22.7
Liver Safety
The following should occur if a participant meets any of the Liver Chemistry Stopping 
Criteria as outlined in Section 6.7.3 of the protocol: 

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Please refer to the FDA Guidance for Industry Drug-Induced Liver Injury: Premarketing 
Clinical Evaluation (FDA 2009). for standard of care for the evaluation of aetiology in 
participants who meet any of the above criteria.

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22.8Morphine Dose Analgesic Equivalence Table 
It should be noted that below conversions are only intended to convert an IV 
administered opioid to morphine equivalents based on analgesic dose ranges (Laird 
2016). For opioids administered by other routes, see footnotes to table below. 
Opioid
IV (mg)
Buprenorphine
41.7*
Codeine
1250
Heroin
500
Hydrocodone
NA*
Hydromorphone
187.5
Meperidine
9375
Morphine
1250
Oxycodone
NA*
Oxymorphone
125
Tapentadol
NA*
Tramadol
NA*
IV=intravenous
Notes: Heroin is generally 2.5-fold more potent than morphine, i.e., 1250 mg IV 
morphine is equivalent to 500 mg IV heroin. For smoking/nasal use, assume a 50% 
bioavailability compared to IV (Rook 2006). 
*For oral/transmucosal preparations with even poorer bioavailability, it is 
considered impractical to achieve exposures equivalent to 500 mg IV heroin. For 
example, transmucosal buprenorphine 139 mg x 12 (relative heroin potency) x 0.3 
(bioavailability) = 500 mg IV heroin equivalents. 
Source: National Cancer Institute 2020, Chou 2009

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22.9Open-Label Induction Sub-study
1. SUB-STUDY INTRODUCTION AND RATIONALE
See main protocol Section 1.2.2 for the Open-label Induction Sub-study rationale.
2. SUB-STUDY OBJECTIVES
The primary objective of this sub-study is to compare treatment retention of participants 
following rapid induction or SoC induction onto RBP-6000. 
The secondary objective of this sub-study is to evaluate the safety and tolerability of 
RBP-6000 in participants during the Open-label Induction Sub-study.
3. SUB-STUDY ENDPOINTS 
The primary endpoint of this sub-study is treatment retention at Injection 2  defined as the 
proportion of participants receiving Injection 2 at the Week 2 visit among those who 
received at least 1 dose of TM buprenorphine for induction and did not demonstrate 
idiosyncratic response to the first dose of TM buprenorphine. Participants who 
discontinue treatment due to not meeting Inclusion/Exclusion criteria  will be excluded.
The secondary endpoints of this sub-study are the following:

time to treatment discontinuation from the first dose of TM buprenorphine used for 
induction during the Open-label Treatment Period (OLTP) defined as the number of 
days from the first dose of TM buprenorphine until the last scheduled visit observed 
during the OLTP. Participants receiving the third RBP-6000 injection (i.e., the first 
randomised injection) will be censored administratively at the end of the OLTP; 
otherwise participants will be viewed as having discontinued treatment at their last 
scheduled visit observed during the OLTP. Participants discontinued due to 
idiosyncratic response to the first dose of TM buprenorphine or not met meeting 
Inclusion/Exclusion criteria  will not be included.

adverse events up to Injection 2, and between Injections 2 and 3 

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4. SUB-STUDY PLAN
Study plan activities that will provide data to be analysed as part of the Open-label 
Induction Sub-Study are described in main protocol Section 4.1.1 (Screening and 
Induction Qualification), 4.1.2 (Induction) and 4.1.3 (Second Dose of RBP-6000).
5. SUB-STUDY POPULATION
In the main study, it is planned for approximately 390 participants to be randomised 
immediately prior to their third injection. Assuming a minimal 20% discontinuation rate 
during the OLTP prior to the third injection of RBP-6000, it is estimated that at least 
489 participants will need to be randomised to the 2 induction arms (Rapid Induction vs 
SoC) in the sub-study to achieve the planned number of participants (n=390) in the main 
study. 
For this sub-study, 2 planned interim analyses may be performed when at least 120 and at 
least 240 participants (respectively), who received TM buprenorphine treatment, have 
either received Injection 3 or discontinued prior to Injection 3. 
6. SUB-STUDY CONDUCT
6.1.
Sub-study Screening
All participants are considered screened for both the main study and sub-study once 
written informed consent is obtained; a participant identification number is then assigned. 
There is no separate informed consent for this sub-study. 
6.2.
Sub-study Enrolment
A participant will be considered enrolled in the sub-study if he/she gives informed 
consent and is randomised in the sub-study.

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7. DESCRIPTION OF SUB-STUDY PROCEDURES
Assessments to be analysed for the Open-label Induction Sub-study will be collected as 
described in the main protocol.
8. SUB-STUDY STATISTICS
8.1.
General Procedures
8.1.1. Analysis Conduct
A SAP will be prepared after the protocol is approved and will be signed off before 
database lock occurs. The SAP will provide further details regarding analysis. Additional 
unplanned analyses may be required after all planned analyses have been completed. Any 
deviations from the analyses described below will be outlined in the SAP. Any unplanned 
analyses will be clearly identified in the clinical study report. 
The interim and final analyses (Section 8.10) will be performed following lock of the 
CRF data required for each analysis.
8.1.2. Analysis Conventions
Continuous variables will be summarised using descriptive statistics such as mean, SD, 
coefficient of variation, geometric mean, median, minimum and maximum. Categorical 
variables will be reported as frequency counts (including number missing) and the 
percentage of participants in corresponding categories. Individual participant data will be 
presented by participant in data listings. Data listings will include all data collected.
8.1.3. Groups for Comparison
Data will be summarised and comparisons will be made (where applicable) by RBP-6000 
induction arm: rapid induction and SoC induction.
8.2.
Statistical Hypothesis
For the primary endpoint (treatment retention at Injection 2), the null hypothesis H0 is 
retention rate of rapid induction – SoC induction 
≤ -10% (non-inferiority margin of 10%), the alternative hypothesis HA is retention rate of 
rapid induction – SoC induction > -10%. The criterion for success (i.e., demonstrating 
non-inferiority) at an interim analysis (IA) or final analysis is based on the posterior 
probability of retention rate difference (rapid – SoC) > -10%. The non-inferiority of rapid 
induction to the SoC induction will be declared if the posterior probability is higher than 

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96%. The 96% critical value is chosen so that the overall 1-sided Type I error is less than 
10%. 
8.3.
Sample Size and Power for Sub-study
The sample size for the sub-study is based on the required sample size for the main study 
and the assumed premature discontinuation rate in the sub-study, as the sub-study is an 
integral part of the main study. Approximately 489 participants will be randomised in a 
2:1 ratio to rapid induction or SoC induction arms. Under the assumption of 70% 
retention rate at Injection 2  for both arms and with 2 planned IAs at 120 and 
240 participants, a total of 489 participants will provide 77.2% power to conclude 
non-inferiority (NI) of rapid induction to SoC induction under 10% NI margin. Sub-study 
Table 1 provides cumulative power at the 2 planned IAs and the final analysis under 
different assumptions of retention rate at Injection 2, with scenarios of same retention for 
both arms or greater retention rate for rapid induction. The assumption about the possible 
retention rate at Injection 2 was based on the retention rates observed in the 2 previous 
Phase 3 studies. Among the OUD participants who initiated SoC induction, about 65.7% 
(or 72.1%) received their second RBP-6000 injection. For injection route users, the 
retention rate was about 64.4% (or 70.1%). 
Sub-study Table 1
Cumulative Power at 2 Planned Interim Analyses and Final 
Analysis Under Different Assumptions of Retention Rate at 
Injection 2
Assumptions of Retention Rate at Injection 2
Analysis
PSoC=PR=0.65
PSoC=PR=0.70
PSoC=PR=0.75
PSoC=PR=0.80
PSoC=PR=0.85
IA at n=120
0.277
0.294
0.324
0.369
0.449
IA at n=240
0.489
0.517
0.564
0.627
0.723
FA at n=489
0.742
0.772
0.817
0.869
0.932
PSoC=0.65
PR=0.70
PSoC=0.7
PR=0.75
PSoC=0.75
PR=0.80
PSoC=0.80
PR=0.85
PSoC=0.85
PR=0.90
IA at n=120
0.498
0.538
0.598
0.679
0.804
IA at n=240
0.780
0.816
0.867
0.922
0.974
FA at n=489
0.963
0.976
0.988
0.996
>0.999
PSoC=0.65
PR=0.75
PSoC=0.70
PR=0.80
PSoC=0.75
PR=0.85
PSoC=0.80
PR=0.90
PSoC=0.85
PR=0.95
IA at n=120
0.726
0.781
0.844
0.924
0.988
IA at n=240
0.945
0.968
0.986
0.998
>0.999
FA at n=489
0.998
0.999
>0.999
>0.999
>0.999
FA=Final Analysis; IA=Interim Analysis; PR=retention rate of rapid induction; PSoC=retention rate of SoC 

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Induction; SoC=standard of care
A total of 100,000 simulations are performed per scenario.
8.4.
Analysis Populations
8.4.1. Sub-study Enrolled Population
The Sub-study Enrolled Population (SEP) will be used for analyses of participant 
disposition. The SEP will comprise all participants who give informed consent and are 
randomised to sub-study treatment. The participants will be analysed corresponding to 
the induction arm to which they were randomised. 
8.4.2. Sub-study Full Analysis Set
The Sub-study Full Analysis Set (SFAS) will serve as the primary population for the 
analysis in this sub-study. The SFAS will comprise all participants who are randomised 
to sub-study treatment and receive the first dose of TM buprenorphine and do not 
demonstrate idiosyncratic response to the first dose of TM buprenorphine. The 
participants will be analysed corresponding to the induction arm they received. For 
analysis pertaining to treatment retention and time-to-treatment discontinuation, the 
participants who discontinue treatment due to not meeting Inclusion/Exclusion criteria  
will be excluded. The analysis population for the IA is defined in Section 8.10.
8.5.
Primary Endpoint Analysis: Treatment Retention at Injection 2 
(received at Week 2 visit)
Retention rate will be estimated by Bayesian beta-binomial model using non-informative 
uniform prior, i.e., Beta (1,1), within individual induction arms. The posterior distribution 
of retention rate difference between the 2 arms will be obtained and utilised to calculate 
the posterior probability of non-inferiority of the rapid induction to SoC induction using a 
10% NI margin or a favourable trend of the rapid induction over the SoC induction. The 
criterion for success (i.e., demonstrating NI) is based on the posterior probability of 
retention rate difference (rapid – SoC) greater than -10%. The NI of rapid induction will 
be declared if the posterior probability is at 96% or greater. If the NI is declared, the 
posterior possibility for superiority of rapid induction over SoC induction will be 
evaluated.
8.6.
Secondary Endpoint Analysis: Time to Treatment Discontinuation 
from the First Dose of TM Buprenorphine Induction 
The time from the first dose of TM buprenorphine to treatment discontinuation will be 
presented by induction arm using a Kaplan-Meier (KM) curve within the randomisation 
strata (UDS fentanyl negative vs. positive at the day of first dose of TM buprenorphine) 
and for overall. Participants receiving the third RBP-6000 injection (i.e., the first 

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randomised injection) will be censored administratively at the end of the OLTP. 
Retention rate (with 95% CI) at specific time point will be estimated using KM product 
limit method for each induction arm. Hazard ratio (with 95% CI) of RBP-6000 rapid 
induction to SoC induction will be estimated using a Cox proportional hazard model, 
with arm as a single covariate, stratified by the randomisation strata.
8.8.
Safety Analysis
Safety data will be summarised by induction arm and overall for the analysis period up to 
Injection 2 and overall only for the analysis period between Injections 2 and 3. Complete 
details of the safety analyses will be provided in the SAP.
8.8.1. Extent of Exposure
Exposure to TM buprenorphine and RBP-6000 will be summarised by induction arm and 
overall. 
8.8.2. Adverse Events
Adverse events will be coded using MedDRA and grouped by system organ class. For 
this sub-study, events that occurred after the first induction dose of TM buprenorphine up 
to Injection 3 will be listed and summarised. 
Events will be summarised with frequency and percentage, by system organ class and 
preferred term, by induction arm overall and within individual randomisation stratum and 
overall up to Injection 2 and overall only between Injections 2 and 3. Separate summaries 
will be provided for all TEAEs, drug-related TEAEs, TEAEs by severity, serious TEAEs, 
TEAEs leading to discontinuation of study treatment, TEAEs of special interest 
(including exacerbated withdrawal symptoms) and injection site reaction TEAEs. 
The incidence of deaths will also be reported and the primary causes of death 
summarised.
8.9.
Other Analyses
Additional details of these other analyses will be provided in the SAP.

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Demographic and disease characteristics at Screening (e.g., sex, race, age, weight, and 
BMI) will be summarised for the SFAS overall and by induction arm using descriptive 
statistics.
Results of UDS and TLFB on the first induction day will be summarised by substance for 
the SFAS overall and by induction arm, for the UDS and TLFB assessments separately 
and combined across both assessments using descriptive statistics.
The number and percentage of participants taking concomitant medications (any 
medication and medications to treat withdrawal symptoms) during the time period from 
the first dose of TM buprenorphine through Injection 2 will be summarised for the SFAS 
overall and by induction arm overall and within individual randomisation stratum using 
descriptive statistics.
The COWS scores at each timepoint and visit during the OLTP will be summarised 
overall, and by induction arm overall and within individual randomisation stratum using 
descriptive statistics; the difference in group mean will be estimated with a 95% CI for 
each timepoint and visit.
8.10.
Interim Analysis
As the sub-study is sponsor open-label and maintaining the treatment blind is not a factor 
in sub-study integrity, study personnel will perform the interim analysis(es). Two interim 
analyses will be performed when at least 120 and at least 240 participants (respectively) 
treated with TM buprenorphine, who have either received Injection 3 or discontinued 
prior to Injection 3, to allow early declaration of non-inferiority of rapid induction to SoC 
induction with respect to treatment retention at Injection 2. At each IA, the criterion of NI 
is the posterior probability of retention rate difference (rapid – SoC) > -10% being 96% 
or greater. 
If NI is declared at the IA, the results will be shared within Indivior. 
The final analysis for the sub-study will occur after all participants have enrolled and 
completed the sub-study. The sub-study will be considered positive for the primary 
endpoint, if the posterior probability of retention rate difference (rapid – SoC) > -10% is 
96% or greater. If the NI of rapid induction to SoC induction is concluded, the posterior 
possibility for superiority of rapid induction over SoC induction will be evaluated.

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A 96% critical value at each IA and the final analysis is chosen to provide overall 1-sided 
Type I error less than 10%. Sub-study Table 2 shows 1-sided Type I error at each IA, 
final analysis and overall, for 5 null hypothesis scenarios for 10% NI margin where the 
retention rate of rapid induction is truly 10% less than control. 
Sub-study Table 2
1-sided Type I Error at Each IA, Final Analysis and Overall, 
Under Different Null Scenarios for 10% Non-inferiority 
Margin
Assumptions of Retention Rate at Injection 2
Analysis
PSoC=0.65
PR=0.55
PSoC=0.70
PR=0.60
PSoC=0.75
PR=0.65
PSoC=0.80
PR=0.70
PSoC=0.85
PR=0.75
IA at n=120
0.0426
0.0439
0.0446
0.0462
0.0467
IA at n=240
0.0258
0.0267
0.0258
0.0263
0.0276
FA at n=489
0.0232
0.0234
0.0237
0.0235
0.0235
Overall
0.0916
0.0941
0.0941
0.0959
0.0978
FA=Final Analysis; IA=Interim Analysis; PR=retention rate of rapid induction; PSoC=retention rate of 
SoC induction; SoC=standard of care
A total of 100,000 simulations are performed per scenario.
For the interim analysis(es), the analysis population will be defined as the first 
120/240 participants (at minimum) who are randomised and receive TM buprenorphine, 
based on the date of the first dose of TM buprenorphine. Participants will be included in 
the treatment group (rapid induction or SoC induction) to which they actually received.
If NI is declared at the first IA, then the second IA might not be performed. The final 
analysis will be performed irrespective of the number of IAs.
8.11.
Handling of Missing Data
Observed data will be used for the analysis with no imputation of missing values.
For graphical and summary purposes, buprenorphine plasma concentration values below 
the limit of quantification will be set to zero. 
The handling of spurious data will be documented in the study report.