Clinical trial NCT04060654
Conditions: Opioid Use Disorder, Severe Opioid Use Disorder, Moderate
Sponsor: Indivior Inc.
Start date: 2019-10-21; Completion date: 2020-05-15
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A single center, open-label SUBLOCADE treatment extension study in which up to 25 participants diagnosed with moderate to severe opioid use disorder (OUD) could be enrolled.

Detailed description:
This study is being conducted to assess the longer-term safety of an abbreviated initiation protocol of SUBLOCADE in subjects who have completed the INDV-6000-403 study. It is also to provide treatment to these individuals while they seek longer-term treatment arrangements, as on average it can take an individual with opioid use disorder (OUD) 6 months between seeking treatment and achieving an appointment at a provider in the United States (US).

Subjects who have completed the end of treatment (EOT) procedures for the INDV-6000-403 study may be eligible for participation. It is planned that the EOT visit for INDV-6000-403, which will occur approximately 28 days after the subject's first dose of SUBLOCADE, and Day 1 for INDV-6000-404 will occur within 2 days of the EOT visit, and that EOT assessments will serve as the screening assessments for this study.

On Day 1, eligible subjects will receive a subcutaneous (SC) injection of 300 mg SUBLOCADE. Subjects will return to the clinic for subsequent injections approximately every 4 weeks for a total of up to 5 injections. Adverse events and concomitant medications will be captured throughout the study, female subjects of childbearing potential will receive urine pregnancy tests and all subjects will have urine drug screening (UDS) and evaluation of the previous injection site performed. Subjects will otherwise be treated in accordance with local standard of care, and SUBLOCADE doses will be based on the medical judgment of the Investigator.

Arms: arm 1: All subjects will receive SUBLOCADE 300mg on Day 1, followed by injections every 4 weeks at a dose determined by the Investigator (either 100 mg or 300 mg) for up to 5 total injections
Interventions: intervention 1: Sublocade
Intervention descriptions: intervention 1: SUBLOCADE to be administered approximately every 4 weeks per local standard of care

Protocol documents:
Prot_001.pdf: 
PROTOCOL 
 
STUDY NUMBER:   
INDV-6000-404 
 
PROTOCOL TITLE:   
An Open-label treatment extension study for eh Rapid Initiation of Extended-
Release Buprenorphine Subcutaneous Injection (SUBLOCADE™) 
 
NCT NUMBER:   
NCT04060654 
 
DATE:  
 
04Dec2019 
 
 


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16.1.1 CLINICAL RESEARCH PROTOCOL 
DRUG: 
SUBLOCADE™ (extended-release 
buprenorphine) 
STUDY NUMBER: 
INDV-6000-404 
PROTOCOL TITLE: 
An Open-label, treatment extension study for 
the Rapid Initiation of Extended-Release 
Buprenorphine Subcutaneous Injection 
(SUBLOCADE™) 
SHORT TITLE: 
SUBLOCADE Rapid Initiation Extension Study 
IND NUMBER: 
107,607 
PHASE: 
IV 
SPONSOR: 
 
Indivior Inc. 
10710 Midlothian Turnpike, Suite 125 
North Chesterfield, VA 23235 
USA 
ORIGINAL PROTOCOL 
DATE: 
07 August 2019 
 
PROTOCOL AMENDMENT 1 
DATE: 
04 December 2019 
 
 
 
Confidentiality Statement 
This document is a confidential communication of Indivior. The recipient agrees that no 
unpublished information contained herein will be published or disclosed without prior 
written approval of Indivior, except that this document may be disclosed to appropriate 
ethics committees or duly authorized representatives of the US Food and Drug 
Administration or other responsible Regulatory Authorities under the condition that they are 
requested to keep it confidential.  






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SUMMARY OF CHANGES 
 
 
Change 
Section  
Affected 
Summary of Change(s) 
1.  
Number of subjects 
increased from up to 15, 
to 25.  
Section 4.1 
Section 5.1 
Section 14.2 
 
Number of subjects increased to account for 
additional subjects enrolled onto INDV-6000-
403 study.  
2.  
Concomitant medications 
or indications for such, 
will not be coded or 
summarized. 
Section 13.1 
Section 14.4.3 
Concomitant medications are required to be 
listed only for this study.  
3.  
Detox and MOUD history 
will be collected and 
summarized. 
Section 4.1 
Section 4,2 
Section 8.1 
Section 14.4.3 
 
This will be collected retrospectively for 
subjects enrolled in the study at the time of 
this amendment.  
4.  
Added that the safety 
population will be the 
primary population for all 
analyses. 
Section 14.3 
The safety population was defined but 
utilization for analyses not stated. 
5.  
 Typographical error 
corrected. 
Section 4.2  
Injection 3 Visit, corrected to “Visit 3”  
6.  
Typographical error 
corrected. 
Section 9.8 
Subjects do not “check-in” to the clinic on 
day 1, therefore text updated to state subjects 
abstain from alcohol throughout the study. 
 
 
 


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STUDY PERSONNEL INFORMATION 
 
Medical Monitor: 
(24-hour coverage) 
 
 
   
Back-up Medical 
Monitor 
 
 
 
 
 
 
 
 
 
 


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STUDY SUMMARY 
Protocol 
Number: 
INDV-6000-404 
Title:  
An Open-label, treatment extension study for the Rapid Initiation of 
Extended-Release Buprenorphine Subcutaneous Injection 
(SUBLOCADE™) 
Rationale:  
This study (INDV-6000-404) is to provide ongoing treatment with 
SUBLOCADE for up to 5 additional injections and safety monitoring for 
subjects who initiated SUBLOCADE following a single dose of 
transmucosal (TM) buprenorphine in study INDV-6000-403. 
Target 
Population: 
Subjects with moderate or severe opioid use disorder (OUD) who are 
seeking medication for OUD (MOUD) and have completed INDV-6000-
403 study.  
Number of 
Subjects: 
Up to 25 adult subjects 
Objective:  
The objective of this study is to assess the longer-term safety of an 
abbreviated initiation protocol of SUBLOCADE in subjects who have 
completed INDV-6000-403.  It is also to provide treatment to these 
individuals while they seek longer-term care arrangements, as it (on 
average) takes an individual with OUD 6 months between seeking treatment 
and achieving an appointment at a provider within the US.  
Study Design: 
 
Only subjects who have completed the End of Treatment (EOT) procedures 
for Study INDV-6000-403, have signed the INDV-6000-404 informed 
consent form (ICF), and meet all the enrollment criteria may be considered 
for inclusion in this study.  
 
The INDV-6000-403 EOT visit is 28 days after the subject’s first dose of 
SUBLOCADE in INDV-6000-403, therefore the INDV-6000-403 EOT and 
the INDV-6000-404 screening and Day 1 visit for this study will occur 
within 2 days, thus the INDV-6000-403 EOT assessments will serve as the 
screening assessments for the Screening Visit (Day 1) of this study.  


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Any AEs and concomitant medications ongoing at the INDV-6000-403 
EOT will be re-recorded for this study. In addition, demographics, height, 
medical/psychiatric, substance and drug of abuse history will not be re-
collected and will be taken from the INDV-6000-403 screening 
assessments.  A detailed detox and MOUD treatment history will be 
collected at screening. For those subjects who have enrolled in the study 
prior to approval of protocol amendment 1, their detox and MOUD 
treatment history will be collected retrospectively at their next visit. 
 
On Day 1, eligible subjects will receive a SC injection of 300mg 
SUBLOCADE. Before departing the site, any new adverse events (AEs) or 
concomitant medications will be recorded. 
 
Subjects will return to the site for monthly injection visits every 4 weeks (-2 
/ +7 days) for a total of up to 5 injections. At Injection Visits 2 through 5, 
subjects will be evaluated in accordance with local standard of care and 
results for the following procedures will be recorded: urine pregnancy test 
(to be performed before SUBLOCADE administration for all female 
subjects who are of childbearing potential); urine drug screen (UDS) and 
evaluation of previous injection site for potential reaction and evidence of 
attempts to remove the depot. For injections 2 to 5, subjects may receive 
either a dose of 100 mg SUBLOCADE or 300 mg SUBLOCADE, based on 
the medical judgment of the Investigator, per the SUBLOCADE USPI. 
During each visit the subject will be assessed for AEs and use of 
concomitant medications.  
All subjects will receive counselling as determined by local standard of care 
throughout the study from Day 1 through EOT. 
All subjects who receive SUBLOCADE (including those who wish to 
discontinue early), will be encouraged to attend the EOT/ET visit 4 weeks 
after SUBLOCADE administration.  
At the EOT/ET Visit, results for the following procedures and assessments 
will be recorded:  urine pregnancy test for all female subjects who are of 
childbearing potential; evaluation of previous injection site for potential 
reaction and evidence of attempts to remove the depot; UDS; use of 
concomitant medications and assessment for AEs. At every Visit options for 
continued care should be discussed with the subject. 


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Any subject with ongoing AEs or concomitant medications at the EOT Visit 
will also be followed up by telephone 4 weeks later for a safety follow up to 
assess the ongoing AEs or concomitant medications only. 
 
Primary 
Endpoint:  
The proportion of subjects with treatment emergent adverse events (TEAEs) 
at any time during the treatment period.  
Other Safety 
Assessments: 
Additional safety endpoints will include assessment of: drug-related 
TEAEs, serious TEAEs, drug-related serious TEAEs, TEAEs leading to 
treatment discontinuation and concomitant medications. 
 
 
 


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TABLE OF CONTENTS 
1 
INTRODUCTION AND RATIONALE .................................................................14 
1.1 
Background ..........................................................................................................14 
1.2 
Study Rationale ....................................................................................................14 
1.2.1 
Dosing Regimen ..............................................................................................14 
1.3 
Risk-Benefit Assessment ......................................................................................15 
1.3.1 
Risk Assessment .............................................................................................15 
1.3.2 
Benefit Assessment .........................................................................................15 
1.3.3 
Overall Risk-Benefit Summary ....................................................................16 
2 
STUDY OBJECTIVE ...............................................................................................17 
3 
STUDY ENDPOINTS ..............................................................................................18 
3.1 
Primary .................................................................................................................18 
3.2 
Other Safety Assessments....................................................................................18 
4 
STUDY PLAN ...........................................................................................................19 
4.1 
Study Design .........................................................................................................19 
4.2 
Schedule of Assessments ......................................................................................20 
5 
POPULATION ..........................................................................................................23 
5.1 
Number of Subjects..............................................................................................23 
5.2 
Inclusion Criteria .................................................................................................23 
5.3 
Exclusion Criteria ................................................................................................23 
5.4 
Subject Screening .................................................................................................23 
5.5 
Deviation from Inclusion/Exclusion Criteria ....................................................23 
6 
STUDY CONDUCT ..................................................................................................24 
6.1 
Subject Screening .................................................................................................24 
6.2 
Enrolled .................................................................................................................24 
6.3 
Not Enrolled .........................................................................................................24 
6.4 
Treatment Period .................................................................................................24 
6.5 
Treatment Period Completion ............................................................................24 
6.6 
Study Completion.................................................................................................24 
6.7 
Early Termination ...............................................................................................25 
6.8 
Withdrawal and Stopping Criteria ....................................................................25 
6.8.1 
Subject Withdrawal from the Study ............................................................25 
6.8.2 
Subject Withdrawal of Consent ....................................................................25 
6.8.3 
Subjects Lost to Follow-up ............................................................................25 
7 
STUDY SUSPENSION OR TERMINATION .......................................................26 
8 
DESCRIPTION OF STUDY PROCEDURES .......................................................26 
8.1 
Demographics and Medical/Psychiatric History ...............................................26 
8.2 
Safety Assessments ...............................................................................................26 
8.2.1 
Clinical Laboratory Tests..............................................................................26 
8.2.1.1 
Urine Drug Screening (UDS) ..................................................................27 


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8.2.1.2 
Urine Pregnancy Test ..............................................................................27 
8.2.2 
Injection site Evaluation ................................................................................27 
8.3 
Protocol Deviations ..............................................................................................27 
9 
STUDY DRUG MANAGEMENT ...........................................................................28 
9.1 
Description ............................................................................................................28 
9.1.1 
Formulation ....................................................................................................28 
9.1.2 
Storage ............................................................................................................28 
9.2 
Packaging and Labelling .....................................................................................28 
9.3 
Shipment ...............................................................................................................29 
9.4 
Dose and Administration .....................................................................................29 
9.5 
Accountability ......................................................................................................29 
9.6 
Concomitant Therapies .......................................................................................30 
9.7 
Prohibited Concomitant Therapies ....................................................................30 
9.8 
Lifestyle Restrictions ...........................................................................................31 
9.9 
Permitted Concomitant Therapies .....................................................................31 
9.10 
Compliance ...........................................................................................................31 
9.11 
Reporting Product Complaints ...........................................................................31 
10  ADVERSE EVENTS ................................................................................................33 
10.1 
AEs of Special Interest.........................................................................................34 
10.2 
Assessing and Documenting Adverse Events ....................................................34 
10.3 
Time Period for Collecting Adverse Events ......................................................34 
10.4 
Assessment of Intensity........................................................................................34 
10.5 
Assessment of Causality ......................................................................................35 
10.6 
Clinical Laboratory Changes ..............................................................................36 
10.7 
SUBLOCADE Depot Removal ...........................................................................36 
11  SERIOUS ADVERSE EVENT ................................................................................37 
11.1 
Definition of Serious Adverse Event ..................................................................37 
11.2 
Documenting Serious Adverse Events ...............................................................38 
11.2.1 
Investigator Reporting of Serious Adverse Events .....................................38 
11.2.2 
Regulatory Reporting Requirements for Serious Adverse Events ............39 
12  PREGNANCY ...........................................................................................................39 
12.1 
Collecting and Reporting Pregnancy Information ...........................................39 
12.2 
Action to be Taken if Pregnancy Occurs in a Female Subject ........................40 
13  DATA MANAGEMENT ..........................................................................................40 
13.1 
Data Collection and Management ......................................................................40 
13.2 
Database Quality Assurance ...............................................................................40 
13.3 
Source Documentation.........................................................................................40 
14  STATISTICS .............................................................................................................41 
14.1 
General Procedures .............................................................................................41 
14.2 
Sample Size ...........................................................................................................41 
14.3 
Analysis Populations ............................................................................................41 


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14.4 
Analysis of Primary, Secondary and Exploratory Endpoints .........................41 
14.4.1 
Primary Endpoint ..........................................................................................41 
14.4.2 
Analysis of Other Safety Data .......................................................................42 
14.4.3 
Other Safety Variables ..................................................................................42 
14.5 
Demographic and Baseline Characteristics .......................................................42 
14.6 
Interim Analysis ...................................................................................................42 
15  ETHICS AND RESPONSIBILITIES .....................................................................43 
15.1 
Good Clinical Practice .........................................................................................43 
15.2 
Data and Safety Monitoring Committee ............................................................43 
15.3 
Institutional Review Board/Independent Ethics Committee ...........................43 
15.4 
Informed Consent ................................................................................................43 
15.5 
Study Files and Record Retention ......................................................................44 
16  AUDITING AND MONITORING ..........................................................................44 
17  AMENDMENTS .......................................................................................................46 
18  STUDY REPORT AND PUBLICATIONS ............................................................47 
19  STUDY DISCONTINUATION ...............................................................................48 
20  CONFIDENTIALITY ..............................................................................................49 
21  REFERENCES .........................................................................................................50 
22  APPENDIX 1 .............................................................................................................51 
LIST OF TABLES 
Table 1 
Schedule of Assessments – Overview of Study ......................................21 
 
 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
BMI 
body mass index 
CRF 
case report form 
EOT 
end of treatment 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MAOI 
monoamine oxidase inhibitor 
MOUD 
Medication for Opioid Use disorder 
NNRTI 
non-nucleoside reverse transcriptase inhibitor 
NMP 
N-methyl-2-pyrrolidone 
OUD 
opioid use disorder 
PLGH 
poly(DL-lactide-co-glycolide) with a carboxylic acid end group 
QA 
quality assurance 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous(ly) 


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SD 
standard deviation 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TM 
Transmucosal 
UDS 
urine drug screen 
ULN 
upper limit of normal 
USPI 
United States Prescribing Information 
WHO 
World Health Organization 
 


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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. Medications for OUD (MOUD) are 
recommended by treatment guidelines as the current standard of care for OUD 
(Kampman 2015), combined with counselling/behavioural therapy to provide a whole-
patient approach to the treatment of OUD.   
SUBLOCADE™ (extended-release buprenorphine) injection, for subcutaneous (SC) use 
(CIII) is an extended-release formulation of buprenorphine, a mu-opioid receptor partial 
agonist. SUBLOCADE is administered once monthly by SC injection and provides 
sustained plasma levels of buprenorphine over the dosing interval. SUBLOCADE uses 
buprenorphine and the ATRIGEL® Delivery System, which consists of a biodegradable 
polymer poly (DL-lactide-co-glycolide) with a carboxylic acid end group (PLGH), 
dissolved in a biocompatible solvent, N-methyl-2-pyrrolidone (NMP). SUBLOCADE is 
injected as a solution, and subsequent precipitation of the polymer creates a solid depot 
containing buprenorphine. After initial formation of the depot, buprenorphine is released 
via diffusion from, and the biodegradation of, the depot.  
See SUBLOCADE USPI for further information.  
1.2 
Study Rationale 
Currently, patients who are appropriate candidates for SUBLOCADE must initiate 
treatment with transmucosal (TM) buprenorphine for a minimum of 7 days before 
receiving their first injection 
(SUBLOCADE United States Prescribing Information [USPI]).  Study INDV-6000-403 
is being conducted to evaluate the safety and tolerability of starting SUBLOCADE 
treatment following a shorter period of TM buprenorphine treatment. This study (INDV-
6000-404) is to provide ongoing treatment with SUBLOCADE for up to 5 additional 
injections and safety monitoring for subjects who initiated SUBLOCADE following a 
single dose of transmucosal (TM) buprenorphine in study INDV-6000-403.  
1.2.1 
Dosing Regimen 
SUBLOCADE should be administered as per the instructions for use in the 
SUBLOCADE USPI.  
The recommended initial dose of SUBLOCADE is 300mg monthly for the first 2 
injections of treatment. Subjects have received 1 x 300mg SUBLOCADE injection in the 


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INDV-6000-403 study, therefore subjects must receive 300mg SUBLOCADE for the 
first injection of this study. Subjects may receive either 100 mg or 300 mg SUBLOCADE 
for the maintenance dose (all subsequent injections), based on the medical judgment of 
the Investigator as per the SUBLOCADE USPI.  
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 
compared with full agonists. Buprenorphine has been shown to be an efficacious and safe 
treatment for OUD when used as directed. For this extension study, SUBLOCADE will 
be administered as recommended in the SUBLOCADE USPI.  
1.3.1 
Risk Assessment  
The safety profile of buprenorphine is well-established, and the AE profile of 
buprenorphine is well characterised. Commonly reported treatment-emergent AEs 
include drug withdrawal syndrome, constipation, headache, nausea and vomiting. 
Buprenorphine has been approved for multiple indications and routes of administration 
(e.g., TM, buccal, intramuscular, intravenous, transdermal, rectal and subcutaneous) in 
multiple countries and by various manufacturers. Buprenorphine extended-release SC 
injection was approved as a monthly treatment for OUD in 2017 (SUBLOCADE USPI).   
The most common adverse drug reactions with SUBLOCADE were constipation, nausea, 
hepatic enzyme increased, headache, injection site pain, injection site pruritus, vomiting 
and fatigue. Injection site reactions were generally mild to moderate in severity, none 
were serious, and they decreased in frequency with subsequent injections. There were no 
unexpected safety findings. The safety profile of SUBLOCADE observed in the Phase III 
studies was generally consistent with the known safety profile of buprenorphine, with the 
expected exception of injection site tolerability and reaction.  
1.3.2 
Benefit Assessment  
Clear efficacy was demonstrated both in the pivotal and in additional supporting studies 
of the SUBLOCADE clinical development programme (SUBLOCADE USPI). While 
subjects will receive limited benefit from participation in the single-dose (of 
SUBLOCADE) study (INDV-6000-403), participation in the combined INDV-6000-403 
and INDV-6000-404 studies will allow more meaningful engagement with MOUD and 
the results could provide support for more rapid SUBLOCADE initiation, which is 
expected to improve treatment compliance, engagement and retention in treatment.  With 
increasing amounts of fentanyl contamination of the heroin drug supply, it is also 
important to treat patients with a medicine that can protect them from overdose as soon as 
they are willing to engage in treatment.  Recently reported data (Wiest 2019) supports 
that buprenorphine, administered at doses resulting in consistent plasma levels of 2ng/mL 


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and 5ng/mL (similar to the concentrations resulting from both labelled doses of 
SUBLOCADE), is able to dose dependently inhibit fentanyl-induced respiratory 
depression.  Being able to initiate treatment-seeking patients with SUBLOCADE on the 
1st day of treatment may therefore help to protect patients when they are most vulnerable.  
1.3.3 
Overall Risk-Benefit Summary  
Taken together, these findings indicate a favourable benefit/risk assessment for this 
extension of the single dose study (INDV-6000-403) to evaluate a more rapid treatment 
initiation protocol for SUBLOCADE in patients with OUD. 


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2 STUDY OBJECTIVE 
The objective of this study is to assess the longer-term safety of an abbreviated initiation 
protocol of SUBLOCADE in subjects who have completed INDV-6000-403.  It is also to 
provide treatment to these individuals while they seek longer-term care arrangements, as 
it (on average) takes an individual with OUD 6 months between seeking treatment and 
achieving an appointment at a provider within the US.  


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3 STUDY ENDPOINTS  
3.1 
Primary 
The proportion of subjects with treatment emergent adverse events (TEAEs) at any time 
during the treatment period (i.e., any time after administration of SUBLOCADE).  
3.2 
Other Safety Assessments 
Additional safety endpoints will include assessment of: drug-related TEAEs, serious 
TEAEs, drug-related serious TEAEs, TEAEs leading to treatment discontinuation and 
concomitant medications. 


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4 STUDY PLAN 
4.1 
Study Design 
 
This is a single center, open-label, SUBLOCADE treatment extension study in which up 
to 25 subjects diagnosed with moderate or severe OUD will be enrolled. A subject is 
defined as enrolled when the first dose of SUBLOCADE is administered for this study.  
Only subjects who have completed the End of Treatment (EOT) procedures for Study 
INDV-6000-403, have signed the INDV-6000-404 informed consent form (ICF), and 
meet all the enrollment criteria may be considered for inclusion in this study.  
The INDV-6000-403 EOT visit is 28 days after the subjects first dose of SUBLOCADE 
in INDV-6000-403, therefore the INDV-6000-403 EOT and the INDV-6000-404 
screening and Day 1 visit for this study will occur within 2 days.  
The ICF may be shared with the potential subject before the INDV-6000-403 EOT Visit 
to discuss this study as a possible treatment option. However, the ICF must not be signed 
until all assessments for the INDV-6000-403 EOT Visit are complete. 
 
The INDV-6000-403 EOT assessments will serve as the screening assessments for the 
Screening Visit (Day 1) of this study. Any AEs and concomitant medications ongoing at 
the INDV-6000-403 EOT will be re-recorded for this study. In addition, demographics, 
height, medical/psychiatric, substance and drug of abuse history will not be re-collected 
and will be taken from the INDV-6000-403 screening assessments. A detailed detox and 
MOUD treatment history will be collected at screening. For those subjects who have 
enrolled in the study prior to approval of protocol amendment 1, their detox and MOUD 
treatment history will be collected retrospectively at their next visit. 
 
On Day 1, eligible subjects will receive a SC injection of 300mg SUBLOCADE.  
Before departing the site, any new adverse events (AEs) or concomitant medications will 
be recorded. 
 
Subjects will return to the site for monthly injection visits every 4 weeks (-2 / +7 days) 
for a total of up to 5 injections. At Injection Visits 2 through 5, subjects will be evaluated 
in accordance with local standard of care and results for the following procedures will be 
recorded: urine pregnancy test (to be performed before SUBLOCADE administration for 
all female subjects who are of childbearing potential); urine drug screen (UDS) and 
evaluation of previous injection site for potential reaction and evidence of attempts to 
remove the depot. For injections 2 to 5, subjects may receive either a dose of 100 mg 
SUBLOCADE or 300 mg SUBLOCADE, based on the medical judgment of the 
Investigator, per the SUBLOCADE USPI. During each visit the subject will be assessed 
for AEs and use of concomitant medications.  


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All subjects will receive counselling as determined by local standard of care throughout 
the study from Day 1 through EOT. 
All subjects who receive SUBLOCADE (including those who wish to discontinue early), 
will be encouraged to attend the EOT/ET visit 4 weeks after SUBLOCADE 
administration.  
At the EOT/ET Visit, results for the following procedures and assessments will be 
recorded:  urine pregnancy test for all female subjects who are of childbearing potential; 
evaluation of previous injection site for potential reaction and evidence of attempts to 
remove the depot; UDS; use of concomitant medications and assessment for AEs. At 
every Visit options for continued care should be discussed with the subject. 
Any subject with ongoing AEs or concomitant medications at the EOT Visit will also be 
followed up by telephone 4 weeks later for a safety follow up to assess the ongoing AEs 
or concomitant medications only. 
4.2 
Schedule of Assessments 
An overview of the schedule of assessments for the study is provided in Table 1. 




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3. This data will not be re-collected; the data from the INDV-6000-403 EOT visit will be used.  
4. Any ongoing (at the INDV-6000-403 EOT) or new AEs or concomitant medications in this study will be recorded.  
5. Required for female subjects of childbearing potential only, to be performed before SUBLOCADE dosing at Visits 1 to 6.  
6. Qualitative test to be performed before SUBLOCADE dosing at Visits 1 to 6.  
7. Injection site will be evaluated for signs of attempted removal before SUBLOCADE dosing at Visits 1 to 6. Any injection site reactions or infections will be 
recorded as AEs. 
8. All subjects will receive counselling as determined by local standard of care throughout the study from Day 1 through EOT. 
9. All subjects who receive SUBLOCADE (including those who wish to discontinue early), will be encouraged to attend the EOT visit 4 weeks after 
SUBLOCADE administration.  
10.  Any subject with ongoing AEs or concomitant medications at the EOT/ET Visit will also be followed up by telephone 4 weeks later for a safety follow up to 
assess the ongoing AEs or concomitant medications only.  
11. A detailed detox and MOUD treatment history will be collected at screening. For those subjects who have enrolled in the study prior to approval of protocol 
amendment 1, their detox and MOUD treatment history will be collected retrospectively at their next visit. 
 


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5 POPULATION 
5.1 
Number of Subjects 
Up to 25 adult subjects with moderate or severe OUD who are seeking MOUD and have 
completed the EOT Visit for the INDV-6000-403 study are planned to be enrolled into 
the study.  
5.2 
Inclusion Criteria 
Subjects must meet all the following criteria to be eligible for the study:  
1. Signed the informed consent form (ICF) and have the ability to comply with the 
requirements and restrictions listed therein.  
2. Completed the EOT Visit for the INDV-6000-403 Study.  
3. Is an appropriate candidate in the opinion of the Investigator or medically qualified 
sub-Investigator. 
5.3 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Subject compliance issues during participation in the INDV-6000-403 study which, 
in the opinion of the Investigator, could potentially compromise subject safety. 
2. Subjects who are unable, in the opinion of the Investigator or Indivior, to comply 
fully with the study requirements including those who are currently incarcerated or 
pending incarceration/legal action. 
5.4 
Subject Screening 
Subjects who provide written informed consent will have their INDV-6000-403 
assessments (per Table 1) re-reviewed to confirm study eligibility. 
5.5 
Deviation from Inclusion/Exclusion Criteria 
Waivers from inclusion and exclusion criteria are not allowed because they have the 
potential to jeopardise subject 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. 


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6 STUDY CONDUCT 
6.1 
Subject Screening 
Study screening begins once written informed consent is obtained; the same subject 
identification number from INDV-6000-403 will be assigned. The subject identification 
number will be used to identify the subject during the screening process and throughout 
study participation, if applicable.  
The Investigator is responsible for maintaining a master list (i.e., a subject identification 
list) of all consented subjects and will document all subjects that do not meet study 
eligibility criteria (i.e., screen failures), including reason(s) for ineligibility (i.e., a subject 
screening and enrolment log). This document will be reviewed by Indivior or designated 
representative for accuracy and completeness. Ineligible subjects, as defined by the 
protocol-specific inclusion and exclusion criteria, should not receive study drug and 
should be documented as screen failures.   
6.2 
Enrolled 
A subject will be considered enrolled if he/she receives at least 1 dose of SUBLOCADE. 
6.3 
Not Enrolled 
A subject will be considered not enrolled if written informed consent is obtained but the 
subject does not receive SUBLOCADE. Reasons for not enrolling (e.g., withdrawal of 
consent, does/not meet specified inclusion or exclusion criteria) will be recorded in the 
case report form (CRF).  
6.4 
Treatment Period 
Treatment period begins when the SUBLOCADE injection is given on Day 1 and ends 
after all assessments have been made at the EOT Visit.  
6.5 
Treatment Period Completion  
A subject will be considered as completing the treatment period if they have received 
Injection 1 and Injection 5.   
6.6 
Study Completion  
A subject will be considered to have completed the study if they have completed the last 
injection visit (Injection 5) and the scheduled EOT visit.   


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6.7 
Early Termination  
A subject will be considered an Early Termination if he/she is dosed with SUBLOCADE 
and does not complete the study (did not complete the last injection visit [Injection 5]) 
and the scheduled EOT visit.  
Reasons for early termination (e.g., withdrawal of consent, lost to follow up, 
identification / move to alternative treatment site) will be recorded in the CRF. Subjects 
who Early Terminate from the study will be encouraged to attend the ET visit 4 weeks 
after SUBLOCADE administration, as well as a safety follow up via telephone if any 
AEs and concomitant medications are ongoing at the time of the ET visit.  
6.8 
Withdrawal and Stopping Criteria   
6.8.1 
Subject Withdrawal from the Study  
If the subject has discontinued study treatment (including depot removal) 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 CRF (e.g., subject is lost to follow-up, Indivior 
terminates the study or Investigator’s discretion).   
6.8.2 
Subject Withdrawal of Consent  
If a subject withdraws consent, the subject will not receive any additional doses of study 
drug. However, the subject may be offered additional tests as needed to monitor safety 
(e.g., EOT safety assessments or procedures).  
6.8.3 
Subjects Lost to Follow-up  
In cases of a missed visit, the Investigator or designee must attempt to contact the subject 
and re-schedule as soon as possible. The Investigator or designee must counsel the 
subject on the importance of maintaining the assigned visit schedule and ascertain 
whether or not the subject wishes to and/or should continue in the study.   
In the event a subject is lost to follow-up, the Investigator or designee must make a 
reasonable effort to contact the subject. Two documented attempts (e.g., telephone, email, 
etc.) to contact the subject followed by a certified mailed letter is considered reasonable.  
For the purpose of documenting date of discontinuation for a subject confirmed to be lost 
to follow-up, the date of discontinuation should be the date of last contact with the 
subject.   
In the case where a certified letter is sent but not confirmed as received by the subject, the 
date of discontinuation is the date the certified letter was sent.  


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In the case where a certified letter is sent and has been confirmed as received by the 
subject, the date of discontinuation is the date of the confirmed subject 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 subject's last study visit.  
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 (IRB) promptly and provide the reason(s) for the suspension or 
termination. If the study is prematurely discontinued, all study data and study drug 
remaining at the clinic must be returned to Indivior or its designated representative.  
8 DESCRIPTION OF STUDY PROCEDURES 
Study subjects will be evaluated in accordance with local standard of care, and only 
results for study specific assessments and procedures will be recorded in the CRF. Study 
assessments and procedures, including the timing of assessments, are summarised in 
Table 1. Further details on safety assessments are provided in Section 8.2.  
A signed written ICF must be obtained from the subject before any study assessments or 
procedures may be performed. All assessments and procedures may be performed more 
frequently, if clinically indicated.  
8.1 
Demographics and Medical/Psychiatric History 
A detailed medical and psychiatric history was collected during the INDV-6000-403 
study and will not be re-collected. A detailed detox and MOUD treatment history will be 
collected at screening. For those subjects who have enrolled in the study prior to approval 
of protocol amendment 1, their detox and MOUD treatment history will be collected 
retrospectively at their next visit. 
8.2 
Safety Assessments 
Definitions and procedures for reporting AEs and SAEs are provided in Sections 10 and 
11, respectively. 
8.2.1 
Clinical Laboratory Tests  
Clinical laboratory tests for Virology, Haematology, Serum Chemistry and Urinalysis 
were collected during the INDV-6000-403 study and will not be re-collected.  


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8.2.1.1 
Urine Drug Screening (UDS) 
A qualitative UDS will be conducted at each Visit, as per the schedule of events in 
Table 1. The UDS will include the following substances:  
 Opioids 
 Oxycodone  
 Morphine 
 Fentanyl 
 Methadone 
 Cocaine 
 Amphetamines 
 Cannabinoids 
 Barbiturates 
 Benzodiazepines 
 Methamphetamine 
 Phencyclidine 
Additional information related to the collection and handling of urine specimens is 
located in the laboratory manual.  
8.2.1.2 
Urine Pregnancy Test 
A urine pregnancy test will be performed at each visit using a licensed test (dipstick), for 
females of child bearing potential only.  
Additional information related to the collection and handling of urine specimens is 
located in the laboratory manual.  
8.2.2 
Injection site Evaluation  
The Injection site will be evaluated for signs of attempted removal before dosing with 
SUBLOCADE at each visit, as shown in Table 1. Any attempts at a SUBLOCADE depot 
removals by the subject should be reported as an AE, and any removals should be 
reported as an AE of Special Interest, see Section 10.7. Any injection site reactions or 
infections will be recorded as AEs. 
8.3 
Protocol Deviations 
A protocol deviation is any non-compliance with the clinical study protocol or ICH/GCP 
requirements. The non-compliance may be on the part of the subject, the Investigator or 
the study clinic staff. As a result of deviations, corrective actions are to be developed by 
the clinic and implemented promptly and in accordance with ICH E6. It is the 
responsibility of the Investigator and study clinic staff to use continuous vigilance to 
identify and report deviations to Indivior or specified designee and the IRB. All 
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sent to the IRB as required. The Investigator and study clinic staff are responsible for 
knowing and adhering to the IRB’s requirements. 
9 STUDY DRUG MANAGEMENT 
The study drug, SUBLOCADE, will be provided by the Sponsor in two strengths 100mg 
and 300mg buprenorphine.  
9.1 
Description 
9.1.1 
Formulation  
SUBLOCADE is a colourless to amber sterile solution for SC injection designed to 
deliver a buprenorphine dose at a controlled rate over a 1-month period. The active 
ingredient in SUBLOCADE 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.  
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 
SUBLOCADE must be stored in a refrigerator at 2° to 8°C (35.6° to 46.4°F) in 
accordance with the USPI, in a secure location with limited access. Once outside the 
refrigerator, SUBLOCADE 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 SUBLOCADE if left at room temperature for longer than 7 days. 
Temperature excursions outside of the defined ranges should be reported to the Sponsor, 
the product should be immediately quarantined and only used if/after Sponsor approval 
has been obtained (see Pharmacy Manual).  
The study drugs must be handled strictly in accordance with the protocol, USPI, 
Pharmacy Manual and applicable local laws and regulations. 
9.2 
Packaging and Labelling 
The SUBLOCADE clinical study labels will be developed in accordance with Good 
Manufacturing Practice (GMP) and local regulatory requirements. Detailed information 
regarding the commercial packaging of SUBLOCADE is outlined in the USPI.  
SUBLOCADE inner packaging (pouch) must remain with the outer product carton until 
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9.3 
Shipment 
SUBLOCADE will be shipped under monitored refrigerated temperatures between 2ºC to 
8ºC (35.6°F to 46.4°F).  
9.4 
Dose and Administration 
SUBLOCADE 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 licensed 
healthcare provider as delegated by the Investigator.  
SUBLOCADE should be administered as per the instructions for use in the 
SUBLOCADE USPI. The recommended initial dose of SUBLOCADE is 300mg monthly 
for the first 2 injections of treatment. Subjects have received 1 x 300mg SUBLOCADE 
injection in the INDV-6000-403 study, therefore subjects must receive 300mg 
SUBLOCADE for the first injection of this study.  
Subjects may receive either 100 mg or 300 mg SUBLOCADE for the maintenance dose 
(all subsequent injections), based on the medical judgment of the Investigator as per the 
SUBLOCADE USPI. Reasons for dose adjustments should be recorded in the source and 
CRF.  
Time of dose for SUBLOCADE 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 CRF.  
The Investigator will not supply SUBLOCADE to any person except study personnel for 
SC injection of subjects in this study.  SUBLOCADE will be dispensed under the 
supervision of the Investigator, a suitably qualified member of the study team, or by a 
pharmacist. The Investigator or designee agrees to neither administer SUBLOCADE 
from, nor store it at any location other than the study clinic agreed upon with the Sponsor. 
Clinic personnel must maintain accountability records per the Pharmacy Manual.  
9.5 
Accountability 
The Investigator is responsible for ensuring that all study drug received at the clinic is 
inventoried, accounted for and documented in accurate accountability records.  
Accountability records will be provided to Indivior. All unused study drug will be 
destroyed by the Investigator, as per local standard operating procedures (SOP). The 
study drug must be handled strictly in accordance with the protocol, handling guidelines 
and the USPI; it must be stored in a locked, limited-access area under appropriate 
environmental conditions.   
The dispensing of study drug to the subject must be documented on the drug dispensing 
form. All study drug dispensation will be performed by a pharmacist or designee, 
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Unused study drug must be available for verification by the monitor during on-site 
monitoring visits.   
9.6 
Concomitant Therapies 
Concomitant medications will be collected from screening (including ongoing 
concomitant medications recorded at the INDV-6000-403 EOT) until the INDV-6000-
404 EOT at the time points listed in Table 1. Any subject with ongoing concomitant 
medications at the INDV-6000-404 EOT will be followed up by telephone 4 weeks later 
for a safety follow up to assess the ongoing concomitant medications.  
Any concomitant medications (including herbal preparations) taken during the study will 
be recorded in the source documents and in the CRF. Any changes in concomitant 
therapy during the study will be documented, including cessation of therapy, initiation of 
therapy and dose changes. 
9.7 
Prohibited Concomitant Therapies 
Subjects should be instructed not to take any medications, including over-the-counter 
products, without first discussing with the Investigator.   
Supplemental TM buprenorphine (after SUBLOCADE injection) may only be permitted 
after discussions with the medical monitor.   
Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other 
CNS depressants, including alcohol, increases the risk of respiratory depression, 
profound sedation, coma and death.  
The SUBLOCADE USPI should be referenced regarding use of the below concomitant 
therapies.  
benzodiazepines and other CNS depressants 
cytochrome P450 3A4 inhibitors or inducers (see Appendix 1) 
antiretrovirals: non-nucleoside reverse transcriptase inhibitors (NNRTIs) 
antiretrovirals: protease inhibitors 
serotonergic drugs 
monoamine oxidase inhibitors (MAOIs) 
muscle relaxants 
diuretics 
anticholinergic drugs 
The Indivior medical monitor should be notified if a subject receives any of these 
treatments during the study. 


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9.8 
Lifestyle Restrictions 
Eligible subjects 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 (SUBLOCADE USPI). 
9.9 
Permitted Concomitant Therapies 
The Investigator may prescribe concomitant medications or treatments deemed necessary 
to the subject, except those medications defined in Section 9.7 of this protocol. 
If the subject experiences withdrawal symptoms at any time, he/she may be treated 
symptomatically (SAMHSA TIP 63 2018): 
Nausea: ondansetron or metoclopramide 
Diarrhoea: loperamide 
Anxiety, irritability, sweating: clonidine 
Insomnia: diphenhydramine, trazodone 
Pain: nonsteroidal anti-inflammatory drugs 
Supplemental buprenorphine may only be permitted after discussions with the medical 
monitor. Subjects will not be discontinued from treatment due to illicit opioid use 
(including buprenorphine). 
9.10 
Compliance 
All study drugs will be administered in the clinic and documented in the source and 
recorded in the CRF.  
SUBLOCADE compliance will be assessed by inspecting the injection site for evidence 
of attempted removal of the depot by the subject, documented in the source and recorded 
in the CRF. Likewise, surgical removal by a physician will be documented in the source 
and recorded in the CRF. 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 Table 1, documented in the source and recorded in 
the CRF. 
9.11 
Reporting Product Complaints  
The Investigator and study clinic staff are responsible for prompt recognition and 
reporting of product quality complaints to Indivior. A product complaint is any concern 
pertaining to the manufacturing or quality control of the study drug and includes, but is 
not limited to, 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.   


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All product complaints should be reported to Indivior in a timely manner and the 
following information provided:  
 study number 
 site contact/reported by  
 subject number (if already assigned to a subject)  
 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. 


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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 subject 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 or an overdose 
of either study drug or a concomitant medication.  
 Signs, symptoms or the clinical sequelae resulting from special interest conditions 
(e.g., medication error, SUBLOCADE depot removal, etc.).  
 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.  
 Evidence of a subject attempting removal of the SUBLOCADE depot  
Events that do not meet the definition of an AE include:  
 Medical or surgical procedures; the condition that leads to the procedure is an AE.  
 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.  


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10.1 
AEs of Special Interest 
In this study, an AE of special interest is any occurrence of a SUBLOCADE depot 
removal (see Section 10.7); Subjects with alanine aminotransferase (ALT) ≥3 × upper 
limit of normal (ULN) and bilirubin ≥2 × ULN (> 35% direct) are defined as SAEs of 
special interest.  
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. 
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 suspected causal relationship to the study drug 
will be reported as described in this protocol.  
Adverse events should be volunteered by the subject or solicited from the subject using a 
standard statement, obtained from examination of the subject at a clinic visit, or from 
observations of clinically significant laboratory values or special examination abnormal 
values.  
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 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. 
10.3 
Time Period for Collecting Adverse Events 
Adverse events will be collected from the time of signed informed consent (including 
ongoing AEs at the INDV-6000-403 EOT) until completion of the EOT visit. Any subject 
with ongoing AEs at the INDV-6000-404 EOT will be followed up by telephone 4 weeks 
later for a safety follow up to assess the ongoing AEs. 
Subjects with ongoing SAEs at the safety follow up 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. Subjects with ongoing AEs at safety follow up telephone contact 
that, in the opinion of the Investigator, are associated with the study drug, will be 
followed and reported as described in Section 10.2. 
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 


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significance (such as a severe headache). This is not the same as “serious”, which is 
based on subject/event outcome or action criteria usually associated with events that pose 
a threat to a subject’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:  
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 subject’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 USPI 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 


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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 Changes 
Clinical Laboratories are not collected for this study. However, if an Investigator 
performs these tests as part of the local standard of care the results may be considered a 
reportable AE 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.   
If a subject experiences any of the below Liver Chemistry criteria the Indivior medical 
monitor should be notified to discuss the subject’s course of action: 
1. The subject has ALT >3 × ULN and bilirubin >2 × ULN (˃35% direct bilirubin). 
2. The subject has ALT >3 × ULN and associated with symptoms (new or 
worsening) believed to be related to hepatitis (such as fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, or jaundice) or hypersensitivity (such as 
fever, rash or eosinophilia). 
3. The subject has ALT >5 × ULN but <8 × ULN persisting for >2 weeks. 
4. The subject has ALT >5 × ULN but <8 × ULN and cannot be monitored weekly 
for ≥2 weeks.  
5. The subject has ALT >8 × ULN. 
If the subject experiences Criterion 1, this is an SAE (important medical event) of special 
interest, that must be reported to Indivior as per Section 11.2.1.  
10.7 
SUBLOCADE Depot Removal 
If clinically indicated, the SUBLOCADE 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., whether the depot was removed by the subject or the Investigator and 
whether this was voluntary or involuntary [i.e., whether the subject 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 subject who received study drug 
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 subject 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 
Subjects with ALT ≥3 × ULN and bilirubin ≥2 × ULN (> 35% direct) are defined as 
SAEs of special interest (important medical event). 
An AE is considered “life-threatening” if the subject 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.  
The AEs requiring hospitalisation should be considered SAEs. Hospitalisation for 
elective surgery or routine clinical procedures that are not the result of AE (e.g., elective 
surgery for a pre-existing condition that has not worsened) should not be considered AEs 
or SAEs. If anything untoward is reported during the procedure, that occurrence must be 
reported as an AE (either “serious” or “non-serious”) according to the usual criteria.  
In general, hospitalisation signifies that the subject has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or other 


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outpatient setting. Complications that occur during hospitalisation are AEs. If a 
complication prolongs hospitalisation or fulfils any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalisation” occurred or was necessary, the AE 
should be considered serious.  
An AE is incapacitating or disabling if the experience results in a substantial and/or 
permanent disruption of the subject’s ability to carry out normal life functions. 
11.2 
Documenting Serious Adverse Events 
When an SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory and diagnostic reports) pertaining 
to the event. The Investigator will then record all relevant information regarding an SAE 
on the appropriate electronic or paper form(s).  
It is not acceptable for the Investigator to send photocopies of the subject’s medical 
records to Indivior in lieu of completion of the SAE Reporting Form. However, there 
may be cases where copies of medical records are requested by Indivior or designated 
representative. In this instance, all subject identifiers, with the exception of subject 
number, will be redacted on the copies of the medical records prior to submission to 
Indivior.  
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms and/or other clinical information. In such cases, the diagnosis will be 
documented as an AE or SAE and not the individual signs/symptoms. 
11.2.1 
Investigator Reporting of Serious Adverse Events  
Once the Investigator determines that an event meets the protocol definition of an SAE, 
the SAE will be reported to Indivior (or designated representative) by the Investigator (or 
designee) within 24 hours from first being aware of the event. Any follow-up 
information on a previously reported SAE will also be reported to Indivior within 
24 hours.  
Where additional information is needed or expected, the Investigator will not wait to 
receive all information before reporting the event to Indivior. The Investigator must 
provide an assessment of causality at the time of the initial report as described in 
Section 10.5 of the protocol.   


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In the event of an SAE, the Investigator or designee will notify Indivior Global Safety by 
completing the paper SAE Reporting Form and submitting the form to Indivior Global 
Safety via email or fax: 
Email: PatientSafetyNA@indivior.com   
Fax: (804) 423-8951 
11.2.2 
Regulatory Reporting Requirements for Serious Adverse Events  
Prompt receipt of notifications of SAEs to Indivior or designated representative from 
Investigators is essential in ensuring that legal obligations and ethical responsibilities 
regarding the safety of subjects 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 or designated 
representative will comply with country-specific regulatory requirements pertaining to 
safety reporting to Regulatory Authorities, IRBs 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 USPI. 
Indivior Global Safety will determine if an SAE meets the definition of a SUSAR and 
distribute SUSAR reports according to local regulatory requirements and Indivior policy. 
An Investigator who receives the 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 USPI and will notify the IRB, if required according to local requirements.   
12 PREGNANCY  
12.1 
Collecting and Reporting Pregnancy Information  
Information on all pregnancies will be collected from receipt of study drug until 12 
months following the last dose of SUBLOCADE (approximately 5 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 subject without associated unexpected or adverse sequelae is not a 
reportable AE but must be reported to Indivior Global Safety (or designated 
representative) using the Clinical Trial Pregnancy Tracking 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) 
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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 subject 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 subjects, he or she may learn of a pregnancy 
through spontaneous reporting.  
12.2 
Action to be Taken if Pregnancy Occurs in a Female Subject  
If a female subject suspects that she is pregnant (e.g., missed period, self-administered 
pregnancy test) between scheduled visits, the subject will be asked to return to the clinic 
at the next scheduled visit. Removal of the SUBLOCADE depot will not be required if 
pregnancy occurs. 
If a urine pregnancy test during a subject’s visit confirms that a subject is pregnant, the 
subject will receive no further injections, and the current visit will be considered the 
subject’s ET Visit. If the subject any ongoing AEs or concomitant medications at the ET 
Visit, she will also be followed up by telephone 4 weeks later for the safety follow up to 
assess the ongoing AEs or concomitant medications only. 
The Investigator should fully inform the female subject of the potential risk to the foetus.  
13 DATA MANAGEMENT 
13.1 
Data Collection and Management  
Data will be entered onto a CRF and will be managed in accordance with the data 
management plan to ensure that the integrity of the data is maintained. Adverse events 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).. 
Subject identifiers will not be collected or transmitted to Indivior according to Indivior 
standards and procedures. Data collection will be completed according to the study plans.  
13.2 
Database Quality Assurance  
The CRFs will be reviewed and checked for omissions, apparent errors and values 
requiring further clarification using manual procedures. Data queries requiring 
clarification will be generated and addressed by the investigational site. Only authorized 
personnel will make corrections to the CRFs, and all corrections will be documented in 
an audit trail. 
13.3 
Source Documentation 
The Investigator is responsible for the quality of the data recorded in the CRF. The data 
recorded should be a complete and accurate account of the subject’s record collected 
during the study.  


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Study data will not be recorded solely onto the CRF but will be initially documented in 
source documents.  Source documents may be electronic, hard copy, or a combination of 
both and are defined as the results of original observations and activities of a clinical 
investigation. Source documents will include, but are not limited to, progress notes, 
electronic data, screening logs and recorded data from automated instruments. All source 
documents pertaining to this study will be maintained by the Investigator and made 
available for direct inspection by the authorized study personnel. 
14 STATISTICS 
This section describes sample size determination, analysis populations and planned 
analyses for safety measures.  
14.1 
General Procedures 
All safety data will be listed. 
Continuous variables will be summarised using descriptive statistics such as mean, 
standard deviations (SD), median, minimum and maximum. Categorical variables will be 
reported as frequency counts (including number missing) and the percentage of subjects 
in corresponding categories. Individual subject data will be presented by subject in data 
listings. Data listings will include all data collected from the initial screening visit to the 
safety follow up for all subjects enrolled. A statistical analysis plan (SAP) will be 
prepared after the protocol is approved and 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. 
14.2 
Sample Size 
Up to 25 adult subjects with moderate to severe OUD are planned to be enrolled onto the 
study.  
14.3 
Analysis Populations 
The Safety population will consist of all subjects who received at least 1 dose of 
SUBLOCADE, and will be the primary population for all analyses 
14.4 
Analysis of Primary, Secondary and Exploratory Endpoints 
14.4.1 
Primary Endpoint 
All TEAEs collected during the treatment period will be presented by system organ class 
and preferred term, each in descending order of frequency, unless otherwise specified.  


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A TEAE is defined as an AE observed after starting administration of SUBLOCADE in 
this study. If subject experiences an event both prior to starting administration of 
SUBLOCADE and ongoing during the treatment, the event will be considered a TEAE 
(of the treatment) only if it has worsened in severity (i.e., it is reported with the date of 
worsening as the new start date/time) after starting administration of SUBLOCADE in 
this study. 
Adverse events will be coded using the most up-to-date version of the 
MedDRA dictionary and grouped by primary system organ class. The Investigator 
determines the intensity of AEs and the relationship of AEs to study therapy.  
14.4.2 
Analysis of Other Safety Data 
Drug-related TEAE, serious TEAE, drug-related serious TEAE and TEAE leading to 
treatment discontinuation will be summarised by system organ class and preferred term. 
Other safety data will be analysed using descriptive statistics for continuous endpoints 
(e.g., n, mean, median, SD, minimum and maximum) and frequency counts with 
percentages for discrete endpoints. Complete details of the safety analyses will be 
provided in the SAP. 
14.4.3 
Other Safety Variables   
The results of scheduled assessments of pregnancy tests and concomitant medications 
will be  listed. Further details will be provided in the SAP. 
Substance/drug use, detox and MOUD treatment history will be summarized and listed.  
14.5 
Demographic and Baseline Characteristics 
Demographic and disease characteristics at screening, (e.g., age, gender, race, ethnicity, 
weight, height, Body Mass index (BMI), tobacco use, alcohol use and illicit drug use, 
baseline disease history) will be summarised using descriptive statistics. Qualitative 
variables, (e.g., gender, race) will be summarised using frequencies; quantitative 
variables, (e.g., age, weight, height) will be summarised using (n, mean, SD, median, 
minimum and maximum). 
14.6 
Interim Analysis 
No formal interim analyses are planned for this study. 


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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 subject 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 
subjects will be reviewed by an independent and appropriately constituted IRB. If 
required by local regulations, the protocol should be re-approved by the IRB annually. 
The IRB 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 from each subject 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 prior to presenting them to a 
potential participant.  
Any changes to the ICF must be reviewed by Indivior before submission to the IRB.  
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 subject 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 subject 
that participation is voluntary, and that consent can be withdrawn at any time and without 
reason. Subjects will receive a signed and dated copy of the signed ICF before any study-
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In the event that new safety information emerges that represents a significant change in 
the risk/benefit assessment, the signed ICF should be updated accordingly. All subjects 
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, 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 (subject 
records, subject 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. 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 time frame. 
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 studies.   
In accordance with applicable regulations, GCP and Indivior procedures, the clinical 
monitor(s) will periodically contact the site, including conducting on-site visits at 
intervals agreed by the Investigator and documented in the Clinical Monitoring Plan and 
the Site Initiation Visit Report.  
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 


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direct access all study-related records upon request by Indivior, Indivior’s agents, clinical 
monitor(s), auditors and/or IRB. 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 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.  
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 (QA) 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 QA 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 subjects, 
may be made only by Indivior. A protocol change intended to eliminate an apparent 
immediate hazard to subjects may be implemented immediately, provided the IRB 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 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, the Investigator and/or Indivior, the amendment to the 
protocol substantially changes the study design and/or increases the potential risk to the 
subject and/or has an impact on the subject’s involvement as a study participant, the 
currently approved written ICF will require similar modification. In such cases, informed 
consent will be renewed for subjects enrolled in the study before continued participation, 
based on IRB 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 of the same. In 
terminating the study, Indivior and the Investigator will assure that adequate 
consideration is given to the protection of the subjects’ interests. 
 


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20 CONFIDENTIALITY 
All subject-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 subject. However, authorized regulatory officials and Indivior 
personnel (or their representatives) will be allowed full access to inspect and copy the 
records. All subject bodily fluids and/or other materials collected shall be used solely in 
accordance with this protocol and the ICF signed by the subject, unless otherwise agreed 
to in writing by Indivior.  
Each subject will be identified assigned subject number when reporting study information 
to any entity outside of the study centre. Data containing subject identification will not be 
removed from the clinic without first redacting subject identifiers. 
 


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21 REFERENCES 
Cytochrome P450 3A4 and 2C8 inhibitors and inducers, 
http://medicine.iupui.edu/clinpharm/ddis/clinical-table/ , Accessed 08 July 2019 
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. 
SUBLOCADE™ (extended-release buprenorphine) injection, for subcutaneous (SC) use 
(CIII) USPI. Indivior; March 2018. 
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. (SMA) 18-5063. 2018. 
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. 
Wiest K, Algera MH, Moss L, van Velzen M, Dobbins R. High Plasma Buprenorphine 
Concentrations Decrease Respiratory Effects of Intravenous Fentanyl. 50th Annual 
ASAM Conference. 2019.  
 





SAP_000.pdf: 
STATISTICAL ANALYSIS PLAN 
 
STUDY NUMBER:   
INDV-6000-404 
 
PROTOCOL TITLE:   
An Open-label treatment extension study for eh Rapid Initiation of Extended-
Release Buprenorphine Subcutaneous Injection (SUBLOCADE™) 
 
NCT NUMBER:   
NCT04060654 
 
DATE:  
 
02Jul2020 
 
 


 
 
 
SAP for INDV-6000-404 - SUBLOCADE Rapid Initiation Extension Study 
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Title Page  
 
Protocol Title: An Open-label, Treatment Extension Study for the Rapid Initiation Study 
for Extended-Release Buprenorphine Subcutaneous Injection (SUBLOCADE™) 
Protocol Number:  INDV-6000-404 
Drug: SUBLOCADE™ (extended-release buprenorphine)  
 
Short Title: SUBLOCADE Rapid Initiation Extension Study 
Sponsor Name:  
Indivior Inc. 
Legal Registered Address:  10710 Midlothian Turnpike, Suite 125 
North Chesterfield, VA 23235 
USA 
Regulatory Agency Identifier Number(s) 
Registry 
ID  
ClinicalTrials.gov NCT04060654   
Final v2.0: 02 Jul 2020 
 
Confidentiality Statement 
The information contained in this document is privileged and confidential.  Do not copy, 
circulate, or otherwise distribute without written authorization from  
Indivior Inc. 
 
 
 




 
 
 
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LIST OF TABLES 
Table 1 
SAP Version History Summary .................................................. 7 
Table 2 
Objectives and Endpoints ......................................................... 10 
Table 3 
Schedule of Assessments – Overview of Study ....................... 12 
Table 4 
TEAE Summary Categories ..................................................... 17 
Table 5 
List of Abbreviations ................................................................ 19 
 
 
 


 
 
 
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TABLE OF CONTENTS 
LIST OF TABLES ..................................................................................................... 3 
1 
INTRODUCTION ....................................................................................... 6 
1.1 
Version History .................................................................................. 7 
1.2 
Objectives and Endpoints ................................................................ 10 
1.3 
Study Design .................................................................................... 10 
2 
STATISTICAL HYPOTHESES ............................................................... 14 
2.1 
Multiplicity Adjustment ................................................................... 14 
3 
SAMPLE SIZE DETERMINATION ........................................................ 14 
4 
POPULATIONS FOR ANALYSIS .......................................................... 14 
5 
STATISTICAL ANALYSES .................................................................... 14 
5.1 
General Considerations .................................................................... 14 
5.1.1 
INDV-6000-403 Data ........................................................ 14 
5.1.2 
Statistical Analyses and Coding ........................................ 14 
5.1.3 
Treatment Label ................................................................. 14 
5.1.4 
Study Definitions ............................................................... 14 
5.1.4.1  Subject Screening .................................................... 14 
5.1.4.2  Enrolled ................................................................... 14 
5.1.4.3  Not Enrolled ............................................................ 15 
5.1.4.4  Treatment Period ..................................................... 15 
5.1.4.5  Study Completion .................................................... 15 
5.1.4.6  Early Termination .................................................... 15 
5.1.5 
General Conventions for Analysis ..................................... 15 
5.2 
Subject Dispositions......................................................................... 15 
5.3 
Primary Endpoint Analysis .............................................................. 16 
5.3.1 
Treatment Emergent Adverse Events – Definition of 
Endpoint ........................................................................................... 16 


 
 
 
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5.3.2 
Treatment Emergent Adverse Events – Main Analysis 
Approach .......................................................................................... 16 
5.4 
Analysis of Other Safety Endpoints ................................................. 16 
5.4.1 
Study Medication-related Adverse Events, Serious Adverse 
Events and Adverse Events Leading to Study Medication 
Discontinuation ................................................................................ 17 
5.4.2 
Prior and Concomitant Medications .................................. 17 
5.5 
Analysis of Other Safety Variables .................................................. 17 
5.5.1 
Adverse Events – Additional Analyses ............................. 17 
5.5.2 
Extent of Exposure ............................................................ 18 
5.5.3 
Adverse events of special interest (AESI) ......................... 18 
5.5.4 
Pregnancy Tests ................................................................. 18 
5.5.5 
Drug Use History ............................................................... 18 
5.5.6 
Medication for Opioid Use Disorder Treatment History .. 19 
5.5.7 
Urine Drug Screen Results ................................................ 19 
5.6 
Interim Analyses .............................................................................. 19 
6 
SUPPORTING DOCUMENTATION ...................................................... 19 
6.1 
Appendix 1 List of Abbreviations.................................................... 19 
6.2 
Appendix 2: Changes to Protocol-Planned Analyses ...................... 20 
6.3 
Appendix 3: Definition and Use of Visits and Visit Windows in 
Reporting ................................................................................................... 21 
6.4 
Appendix 4: Definition of Protocol Deviations ............................... 21 
6.5 
Appendix 5: Methods to Manage Missing Data .............................. 21 
6.5.1 
Missing Date Information for Adverse Events .................. 21 
6.6 
Appendix 6: Data Transferred from Study INDV-6000-403 ........... 22 
6.7 
Appendix 7: Demographic and Baseline Characteristics ................. 22 
7 
REFERENCES .......................................................................................... 23 
 
 
 


 
 
 
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1 INTRODUCTION 
This statistical analysis plan (SAP) provides the detailed methodology for summary, 
pharmacokinetic and statistical analyses of the data collected in Study INDV-6000-404.  
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified in Section 6.2. Any 
deviations from the analyses described below, as well as Post-hoc analyses, will be 
documented in the clinical study report (CSR). 
Specification of tables, listings and figures (TLFs) are provided in a separate document. 


 
 
 
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1.1 
Version History 
Table 1 
SAP Version History Summary 
SAP 
Version 
SAP 
Approval 
Date 
Associated 
Protocol  
Protocol 
Amendment 
Approval 
Date 
Change 
Rationale 
1.0 
08 Apr 2020 
Amendment 1 
04Dec2019 Not Applicable 
Original version 
2.0 
02 Jul 2020 
Amendment 1 
04Dec2019 In Section 4 added that 
all subjects screened 
received 
SUBLOCADE, so a 
screened population 
was not defined 
Clarification. 
 
 
 
 
Section 5.1.4.5, 
definition of treatment 
completion was 
removed. 
Not needed for analysis. 
 
 
 
 
In Section 5.1.5, 
removed the statement 
regarding concomitant 
medication summary 
tables being produced 
Concomitant medications are 
only being listed, not 
summarized, so this statement 
was not applicable. 


 
 
 
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only if there are >6 
medications. 
 
 
 
 
In Section 5.4.2, 
removed information 
about derived variables. 
The prior and concomitant 
medication data is only being 
listed and not summarized, so 
derived variables are not 
necessary. 
 
 
 
 
In Section 5.5.1, 
removed adverse 
events of special 
interest from the 
adverse event overall 
summary table. 
A flag for adverse events of 
special interest was not derived 
since there were no adverse 
events reported in the study. 
 
 
 
 
In Section 5.5.5, 
correct the description 
of the IV opioid use 
analysis. 
Data is from study 403 
screening, not each visit. 
 
 
 
 
In Section 6.2, removed 
‘the reporting of 
concomitant 
medications as a listing 
only and no summary 
table in the case of ≤ 6 
medications’ as a 
change from the 
The protocol states prior and 
concomitant medications will 
only be listed, so there was no 
change to the protocol planned 
analysis regardless of number of 
medications reported. 


 
 
 
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protocol planned 
analysis. 
 
 
 
 
Removed Section 6.5.2 
regarding partial 
prior/concomitant 
medication start/stop 
dates and assignment of 
prior and concomitant 
medication flags. 
The prior and concomitant 
medication data is only being 
listed and not summarized, so 
derived variables are not 
necessary. 
 
 
 
 
In Section 6.7, remove 
variables not being 
summarized 
COWS and OC-VAS were not 
transferred and analysis of UDS 
is described in Section 5.5.7. 




 
 
 
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Any AEs and concomitant medications ongoing at the INDV-6000-403 EOT will be re-
recorded for this study. In addition, demographics, height, medical/psychiatric, substance 
and drug of abuse history will not be re-collected and will be taken from the INDV-6000-
403 screening assessments. As per protocol amendment 1, a detailed detox and MOUD 
(medication for opioid use disorder) treatment history will be collected at screening. For 
those subjects who have enrolled in the study prior to approval of protocol amendment 1, 
their detox and MOUD treatment history will be collected retrospectively at their next 
visit. 
On Day 1, eligible subjects will receive a subcutaneous injection of 300mg 
SUBLOCADE. Before departing the site, any new adverse events (AEs) or concomitant 
medications will be recorded. 
Subjects will return to the site for monthly injection visits every 4 weeks (-2 / +7 days) 
for a total of up to 5 injections. At Injection Visits 2 through 5, subjects will be evaluated 
in accordance with local standard of care and results for the following procedures will be 
recorded: urine pregnancy test (to be performed before SUBLOCADE administration for 
all female subjects who are of childbearing potential); urine drug screen (UDS) and 
evaluation of previous injection site for potential reaction and evidence of attempts to 
remove the depot. For injections 2 to 5, subjects may receive either a dose of 100 mg 
SUBLOCADE or 300 mg SUBLOCADE, based on the medical judgment of the 
Investigator, per the SUBLOCADE United States Prescribing Information (USPI). 
During each visit the subject will be assessed for AEs and use of concomitant 
medications.  
All subjects will receive counselling as determined by local standard of care throughout 
the study from Day 1 through EOT. 
All subjects who receive SUBLOCADE (including those who wish to discontinue early), 
will be encouraged to attend the EOT/ET visit 4 weeks after SUBLOCADE 
administration.  
At the EOT/ET Visit, results for the following procedures and assessments will be 
recorded:  urine pregnancy test for all female subjects who are of childbearing potential; 
evaluation of previous injection site for potential reaction and evidence of attempts to 
remove the depot; UDS; use of concomitant medications and assessment for AEs. At 
every visit, options for continued care should be discussed with the subject. 
Any subject with ongoing AEs or concomitant medications at the EOT Visit will also be 
followed up by telephone 4 weeks later for a safety follow up to assess the ongoing AEs 
or concomitant medications only. 




 
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1. Written informed consent must be obtained after completion of all INDV-6000-403 EOT procedures and before any INDV-6000-404 study-specific assessments/procedures 
are initiated. 
2. This data will not be re-collected; the data from the INDV-6000-403 screening visit will be used. 
3. This data will not be re-collected; the data from the INDV-6000-403 EOT visit will be used.  
4. Any ongoing (at the INDV-6000-403 EOT) or new AEs or concomitant medications in this study will be recorded.  
5. Required for female subjects of childbearing potential only, to be performed before SUBLOCADE dosing at Visits 1 to 6.  
6. Qualitative test to be performed before SUBLOCADE dosing at Visits 1 to 6.  
7. Injection site will be evaluated for signs of attempted removal before SUBLOCADE dosing at Visits 1 to 6. Any injection site reactions or infections will be recorded as 
AEs. 
8. All subjects will receive counselling as determined by local standard of care throughout the study from Day 1 through EOT. 
9. All subjects who receive SUBLOCADE (including those who wish to discontinue early), will be encouraged to attend the EOT visit 4 weeks after SUBLOCADE 
administration.  
10.  Any subject with ongoing AEs or concomitant medications at the EOT/ET Visit will also be followed up by telephone 4 weeks later for a safety follow up to assess the 
ongoing AEs or concomitant medications only.  
11. A detailed detox and MOUD treatment history will be collected at screening. For those subjects who have enrolled in the study prior to approval of protocol amendment 1, 
their detox and MOUD treatment history will be collected retrospectively at their next visit. 
 


 
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2 
STATISTICAL HYPOTHESES 
For this single arm study, the analysis methods are descriptive. Therefore, statistical testing 
and hypotheses are not applicable. 
2.1 Multiplicity Adjustment 
There is no multiplicity adjustment. 
3 
SAMPLE SIZE DETERMINATION 
Up to 25 adult subjects with moderate to severe OUD are planned to be enrolled into the 
study. 
4 
POPULATIONS FOR ANALYSIS 
The safety population will consist of all subjects who received at least 1 dose of 
SUBLOCADE in this study and will be the primary population for all analyses. All subjects 
who were screened received SUBLOCADE. Therefore, a screened population was not defined 
as it would comprise the same set of subjects. 
5 
STATISTICAL ANALYSES 
5.1 
General Considerations 
5.1.1 INDV-6000-403 Data  
Per the Schedule of Assessments (Table 3), some data will not be re-collected in this study, as 
the INDV-6000-403 data will be used. Further details of the transfer of these data into the 
INDV-6000-404 database are described in the analysis sections below. 
5.1.2 Statistical Analyses and Coding 
Statistical analyses will be performed using version 9.4 (or higher) of SAS. 
The AEs and medical/psychiatric conditions will be coded using the process and MedDRA 
version per the study coding guidelines. 
The final analysis will occur after the database lock. 
5.1.3 Treatment Label 
The treatment label will be presented in the tables, listings and figures (TLFs) as 
SUBLOCADE.  
5.1.4 Study Definitions 
5.1.4.1 
Subject Screening 
Study screening begins once written informed consent is obtained; the same subject 
identification number from INDV-6000-403 will be assigned.  
5.1.4.2 
Enrolled 
A subject will be considered enrolled if he/she receives at least 1 dose of SUBLOCADE in 
this study. 


 
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5.1.4.3 
Not Enrolled 
A subject will be considered not enrolled if written informed consent is obtained but the 
subject does not receive SUBLOCADE in this study. Reasons for not enrolling (e.g., 
withdrawal of consent, does/not meet specified inclusion or exclusion criteria) will be 
recorded in the case report form (CRF).  
5.1.4.4 
Treatment Period 
Treatment period begins when the SUBLOCADE injection is given on Day 1 and ends after 
all assessments have been made at the EOT Visit.  
5.1.4.5 
Study Completion  
A subject will be considered to have completed the study if they have completed the last 
injection visit (Injection 5) and the scheduled EOT visit.   
5.1.4.6 
Early Termination  
A subject will be considered an Early Termination (discontinued) if he/she is dosed with 
SUBLOCADE and does not complete the study (did not complete the last injection visit 
[Injection 5]) and the scheduled EOT visit.  
5.1.5 General Conventions for Analysis 
Continuous variables will be summarised using the descriptive statistics mean, standard 
deviations (SD), median, minimum and maximum, unless other statistics are specified. 
Categorical variables will be reported as frequency counts (including number missing) and the 
percentage of subjects in corresponding categories. 
Individual subject data will be presented by subject in data listings. Data listings will include 
all data collected from the initial screening visit to the Safety follow-up visit (including 
unscheduled visits). 
The derivation of Study Day will be made relative to the date/time of the first administration 
of SUBLOCADE in this study. 
Observed data is used for analysis, unless handling of missing data is described otherwise 
within the analysis description or in Section 6.5. 
If there are ≤ 6 AEs reported, only a listing and no AE summary tables will be produced, 
except for the table of AE occurrences used for public disclosure.  The table of AE 
occurrences for public disclosure will only be produced if there are ≥ 1 AEs reported. 
 
5.2 
Subject Dispositions 
The number and percentage of subjects who were screened and were enrolled or not enrolled 
(See Sections 5.1.4.2 and 5.1.4.3), and the reasons for not enrolling (if applicable), will be 
summarized for the screened population.  The number and percentage of enrolled subjects 
who completed the study, discontinued and the reasons for discontinuing will be summarized.  


 
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The number and percentage of subjects failing entry criteria will be summarized overall and 
by individual criterion for the screened population. 
The number and percentage of subjects in each analysis set will be summarized. 
5.3 
Primary Endpoint Analysis 
The analysis will be performed using the safety population. See Section 6.5  for methods to 
handle missing data. 
5.3.1 Treatment Emergent Adverse Events – Definition of Endpoint 
A TEAE is defined as an AE observed after starting, that is having a start date/time on or after 
the date/time of the first administration of SUBLOCADE in this study.  Any AEs ongoing at 
the INDV-6000-403 EOT were to be recorded in this study; however, note that these are not 
TEAEs in this study per this definition. 
If subject experiences an event both prior to starting administration of SUBLOCADE and 
ongoing during the treatment, the event will be considered a TEAE (of the treatment) only if it 
has worsened in severity (i.e., it is reported with the date of worsening as the new start 
date/time) after starting administration of SUBLOCADE in this study. 
Adverse events will be coded using the MedDRA dictionary and grouped by primary system 
organ class. The Investigator determines the intensity of AEs and the relationship of AEs to 
study therapy. 
5.3.2 Treatment Emergent Adverse Events – Main Analysis Approach 
If > 6 AEs are reported, the summaries will be produced as described below.  Otherwise, no 
summaries and only the AE listing will be produced. 
The number and percentage of subjects reporting TEAEs at any time during the treatment 
period (Section 5.1.4.4) will be presented by MedDRA system organ class (SOC) and 
preferred term (PT), each in descending order of frequency (then alphabetically in case of 
ties).  
All TEAEs collected during the treatment period will be presented by system organ class and 
preferred term, each in descending order of frequency, unless otherwise specified.  
If more than one TEAE is coded to the same PT for the same subject, the subject will be 
counted only once for that PT using the most severe and most related occurrence for the 
summarizations by severity and by relationship to the study medication. 
5.4 
Analysis of Other Safety Endpoints 
Other safety endpoints include study-medication-related TEAEs, serious TEAEs, study 
medication-related serious TEAEs, TEAEs leading to treatment discontinuation and 
concomitant medications (see Section Error! Reference source not found.).  
The analyses will be performed using the safety population if > 6 AEs are reported. See 
Section 6.5 for methods to handle missing safety data (e.g., partial dates). 


 
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5.4.1 Study Medication-related Adverse Events, Serious Adverse Events and Adverse 
Events Leading to Study Medication Discontinuation  
The number and percentage of subjects reporting study medication-related TEAE, serious 
TEAE, study medication-related serious TEAE and TEAE leading to study medication 
discontinuation will be summarised by system organ class and preferred term, as described 
above in Section 5.3.2. 
5.4.2 Prior and Concomitant Medications 
Any medications ongoing at the INDV-6000-403 EOT were to be recorded in this study. The 
prior and concomitant medications will be listed. 
5.5 
Analysis of Other Safety Variables 
The analyses will be performed using the safety population. See Section 6.5 for methods to 
handle missing safety data (e.g., partial dates). 
5.5.1 Adverse Events – Additional Analyses 
If > 6 AEs are reported, the summaries described below will be produced.  If there are ≥1 but 
≤ 6 AEs reported, only the AE occurrences summary will be produced. 
The TEAE summary table will present the number and percentage of subjects reporting a 
TEAE in the categories listed in Table 4. 
Table 4 
TEAE Summary Categories 
Category 
Subjects with Any TEAEs 
With Study Medication-Related TEAEs 
With Serious TEAEs (SAE) 
With Study Medication-Related Serious TEAEs 
With Severe TEAEs 
With TEAE Leading to Death 
With TEAE Leading to Study Medication Discontinuation 
With TEAE Leading to Study Medication Interruption 
With TEAE Leading to Study Medication Dose Decrease 
With TEAE Leading to Study Medication Dose Increase 
With Serious TEAE Leading to Study Medication Discontinuation 
With Serious TEAE Leading to Study Medication Interruption 
With Serious TEAE Leading to Study Medication Dose Decrease 
With Serious TEAE Leading to Study Medication Dose Increase 
 
The additional categories of TEAE listed above in Table 4 will be summarized in the same 
manner as TEAEs (Section 5.3.2) if > 6 AEs are reported. TEAEs will also be summarized by 
maximum intensity, system organ class and preferred term. The number of occurrences of 
TEAEs and study medication-related TEAEs will be summarized by PT. In addition, the 
number and percentage of fatal and fatal study medication-related treatment-emergent SAEs 
will be summarized separately by PT. 


 
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If more than one TEAE is coded to the same SOC/PT for the same subject, the subject will be 
counted only once for that SOC/PT using the most severe and most related occurrence for the 
summarizations by severity and by relationship to the study medication. 
If > 6 AEs are reported, listings will be presented for subjects with AEs, SAEs, AEs 
leading to discontinuation, and subjects who died (if any).  Otherwise, the only listing 
of AEs presented will be all the AEs listing.  
AEs that are not treatment emergent (i.e., AEs that were ongoing at the time of completion of 
the feeder study INDV-6000-403 and recorded in this study database) will be listed. 
5.5.2 Extent of Exposure 
The number and percentage of subjects who received at least 1 dose of SUBLOCADE and 
who received 1, 2, 3, 4 or 5 doses of SUBLOCADE will be summarized. The number and 
percentage of subjects who received SUBLOCADE 300mg and 100mg will be summarized 
by injection. The data will be listed. 
5.5.3 Adverse events of special interest (AESI) 
Adverse events of special interest are: 
 SUBLOCADE depot removal 
 Occurrences of ALT >3 × ULN and bilirubin >2 × ULN (> 35% direct)  
The AESI will be included in the AE and SAE summaries and listings as reported.  
5.5.4 Pregnancy Tests 
The pregnancy test result data will be listed. 
5.5.5 Drug Use History 
The screening visit drug use history results will be transferred from the INDV-6000-403 
database to serve as the screening visit results for this study.  
The following information describes the transferred data: 
 Dates of drug use history were collected as month and year. 
 The overall lifetime drug use across all substances in years was derived by subject as (the 
latest Stop Date – the earliest Start Date +1)/12.  
 The lifetime use in years was derived for each drug class by subject, as the sum of the [ ( 
Stop Date – Start Date +1) / 12] for each drug in the class used by the subject. Where use 
of individual drugs within a class overlapped, this overlapped time was not be double-
counted in the derivation.  
 For these derivations, missing end dates (month and year are missing) were set to the 
month and year of first study medication dose of transmucosal buprenorphine for 


 
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induction from the INDV-6000-403 study. Partial dates (i.e., only year is collected) will 
be imputed as follows: 
o Partial start dates were set to the first month of the year.  
o Partial end dates were set to the last month of the year. 
The number and percentage of subjects reporting each drug class, the years of lifetime use 
overall and for each drug class, and the use in the last 30 days will be summarized using 
observed data. 
An additional analysis will summarize the number and percentage of subjects who use any 
opioid via the I.V route. 
The drug use history data will be listed. 
5.5.6 Medication for Opioid Use Disorder Treatment History 
The MOUD treatment history data will be listed. 
5.5.7 Urine Drug Screen Results 
For each visit, data from the urine drug screen (UDS) results will be assessed to derive the 
number and percentage of subjects with positive opioid use, using observed data.   
For this analysis, opioids will include the results for opioids, methadone, fentanyl, oxycodone, 
and morphine.  If the result for any of these are positive, the subject will be considered 
positive for opioids.   
The usage of individual substances collected via the UDS will be listed. 
5.6 
Interim Analyses  
No formal interim analyses are planned for this study. 
6 
SUPPORTING DOCUMENTATION 
6.1 
Appendix 1 List of Abbreviations 
Table 5 
List of Abbreviations 
Abbreviation 
Term 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alkaline aminotransferase 
BMI 
body mass index 
CRF/eCRF 
case report form/electronic case report form 
CSR 
clinical study report 
ECG 
electrocardiogram 
EOT 
end-of-treatment 
ET 
early termination  
ICF 
informed consent form 
INDV 
Indivior 


 
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Abbreviation 
Term 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOUD 
medication for opioid use disorder 
OUD 
opioid use disorder 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 
TLF 
tables, listings and figures 
UDS 
urine drug screen 
ULN 
upper limit of normal 
USPI 
United States Prescribing Information 
6.2 
Appendix 2: Changes to Protocol-Planned Analyses 
The definitions of completion of the treatment period versus completing treatment were 
clarified. 
The MOUD  treatment history data will be listed only and not summarized. 
The reporting of AEs was specified as a listing only and no summary tables in the case of ≤ 6 
AEs. 


 
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6.3 
Appendix 3: Definition and Use of Visits and Visit Windows in Reporting 
Nominal visits will be used for the analysis without regard to visit windows.   The nominal 
visits will be labelled in TLFs as Injection 1 – Injection 5 and ET/EOT. 
Unscheduled visits will be given an analysis visit number in sequential order according to 
chronological date/time following the most recent scheduled visit.   
6.4 
Appendix 4: Definition of Protocol Deviations  
A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol.  Important protocol deviations are a subset of protocol 
deviations that may significantly impact the completeness, accuracy and/or reliability of the 
study data or that may significantly impact a subject’s rights, safety, or wellbeing. 
The important deviations will not be considered in the statistical analyses or in the definitions 
of analysis populations. All deviations will be listed.  
6.5 
Appendix 5: Methods to Manage Missing Data 
Observed data is used for analysis, unless handling of missing data is described otherwise 
within the analysis description or in the sections below. 
6.5.1 Missing Date Information for Adverse Events 
If the AE start date is missing, and the AE stop date is on or after the first dose of study 
medication, then the AE start date will be imputed as the date of the first dose of study 
medication. 
If the AE start date is missing, and the AE stop date is not missing and before the first dose of 
study medication, then the AE start date will be imputed as the stop date. 
Partial AE Start Date  
Missing day and month 
 If the year is the same as the year of the date of the first dose of study medication, then 
the day and month of the date of the first dose of study medication will be assigned to 
the missing fields. 
 If the year is before the year of the date of the first dose of study medication, then 
December 31 will be assigned to the missing fields. 
 If the year is after the year of the date of the first dose of study medication, then 
January 1 will be assigned to the missing fields. 
Missing month only 
 The day will be treated as missing and both month and day will be replaced according 
to the above procedure. 


 
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Missing day only  
 If the month and year are the same as the month and year of the date of the first dose 
of study medication, then the day of the first dose of study medication will be assigned 
to the missing day. 
 If either the year is before the year of the date of the first dose of study medication or 
if both years are the same but the month is before the month of the date of the first 
dose of study medication, then the last day of the month will be assigned to the 
missing day. 
 If either the year is after the year of the date of the first dose of study medication or if 
both years are the same but the month is after the month of the date of the first dose of 
study medication, then the first day of the month will be assigned to the missing day. 
If the imputed AE start date is after the AE stop date, then the imputed AE start date will be 
set to the AE stop date. 
 
6.6 
Appendix 6: Data Transferred from Study INDV-6000-403 
Some data will be transferred from the INDV-6000-403 study database to serve as the 
screening visit results, as these data are not being re-collected in this extension study (see 
Table 3).   
 Demographic data (age, age category, sex, race ethnicity, child-bearing potential, and 
height) will be transferred from the screening visit of the INDV-6000-403 database.  
Weight, and BMI will be transferred from the EOT visit of the INDV-6000-403 
database.  Together, these data will serve as the demographic data at the screening 
visit for this study. 
 Medical/psychiatric history and substance use history (tobacco use, caffeine use, drug 
use history) will be transferred from the screening visit of the INDV-6000-403 
database to serve as the data for the screening visit of this study.  The 
medical/psychiatric history conditions will be coded using the process and MedDRA 
version per the study coding guidelines. 
 The EOT urine pregnancy test result (from the eCRF entry) will be transferred from 
the INDV-6000-403 database to serve as the screening visit result for this study.  
 The EOT UDS test results (from the eCRF entry) will be transferred from the INDV-
6000-403 database to serve as the screening visit results for this study.  
6.7 
Appendix 7: Demographic and Baseline Characteristics 
The demographic and disease characteristics at screening (age, age category, sex, race, 
ethnicity, weight, height, BMI, BMI category, tobacco use, caffeine use) will be summarised 
for the safety population using descriptive statistics.  
 


 
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The number and percentage of subjects reporting medical/psychiatric history events will be 
tabulated by SOC and PT, by decreasing frequency, using observed data. 
7 
REFERENCES 
No references.